Australian and New Zealand College ofAnaesthetists and Faculty of Pain Medicine

Acute PainManagement:
Scientific
Evidence
Fifth edition 2020

Edited by:
Stephan A Schug
Greta M Palmer
David A ScottMark Alcock
Richard Halliwell
Jeffrey F Mott

Acute Pain Management:
Scientific Evidence
Australian and New Zealand College of Anaesthetists
and Faculty of Pain Medicine

Endorsed by:Faculty of Pain Medicine, Royal College of Anaesthetists, United Kingdom
Hong Kong College of Anaesthesiologists
Royal College of Anaesthetists, United Kingdom
American Academy of Pain Medicine
Australian Pain Society
Australasian College for Emergency Medicine
Australasian College of Sport and Exercise Physicians
Australian College of Rural and Remote Medicine
College of Anaesthesiologists, Academy of Medicine, Malaysia
College of Intensive Care Medicine of Australia and New Zealand
European Pain Federation (EFIC)
European Society of Regional Anaesthesia and Pain Medicine (ESRA)
Faculty of Pain Medicine, College of Anaesthetists of Ireland
Indonesian Pain Society
Malaysian Association for the Study of Pain
New Zealand Pain Society
Pain SA, South Africa
Procedure Specific Postoperative Pain Management (PROSPECT)Royal Australasian College of SurgeonsRoyal Australian and New Zealand College of Psychiatrists
South African Society of Anaesthesiologists
Thai Association for the Study of Pain
Japanese Society for the Study of Postoperative Pain

5TH EDITION 2020

© Australian and New Zealand College of Anaesthetists 2020
ISBN Print: 978-0-9945075-7-0 Online: 978-0-9945075-8-7This work is copyright. Apart from any use as permitted under the Copyright Act 1968, no partmay be reproduced by any process without prior written permission from ANZCA. Requests andenquiries concerning reproduction and rights should be addressed to the Chief Executive Officer,
Australian and New Zealand College of Anaesthetists, 630 St Kilda Road, Melbourne, Victoria
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This document should be cited as:
Schug SA, Palmer GM, Scott DA, Alcock M, Halliwell R, Mott JF; APM:SE Working Group of theAustralian and New Zealand College of Anaesthetists and Faculty of Pain Medicine (2020), AcutePain Management: Scientific Evidence (5th edition), ANZCA & FPM, Melbourne.
Copyright information for Tables 9.1 and 9.2
The material presented in Table 9.1 and Table 9.2 of this document has been reproduced withpermission from Prescribing Medicines in Pregnancy, 2011 and 2020, Therapeutic Goods
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This work is copyright. You may download, display, print and reproduce the whole or part of thiswork in unaltered form for your own personal use or, if you are part of an organisation, forinternal use within your organisation, but only if you or your organisation do not use thereproduction for any commercial purpose and retain this copyright notice and all disclaimer
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Disclaimer
This document aims to combine a review of the best available evidence for acute pain
management with current clinical and expert practice, rather than to formulate specific clinicalpractice recommendations. It is designed to provide information based on the best evidence
available at the time of publication to assist in decision-making. The information provided is notintended to over-ride the clinical expertise of health care professionals and its use is subject tothe clinician’s judgement and the patient’s preference in each individual case. There is no
substitute for the skilled assessment of each individual patient’s health status, circumstancesand perspectives, which health care practitioners will then use to select the treatments that are
relevant and appropriate to that person.
This document can be downloaded from the ANZCA website: http://www.anzca.edu.au/resources/college-publications. Copies of the document can be ordered through the Australianand New Zealand College of Anaesthetists on +61 3 9510 6299.

FOREWORD

Foreword
The imperative to treat acute pain with innovative evidence-based, patient-centred strategies
has never been greater. The lofty goal of personalised, harm-free and adequate relief for every
person experiencing acute pain remains just that. The fact that it is not yet reality is more of atestimony to the enormity and complexity of the task rather than for want of trying as can beseen by the exponential increase in publications on this topic.
In 2007, Dr Frank Brennan, Prof Daniel Carr and Prof Michael Cousins, chair of the committeethat developed the first edition of Acute Pain Management: Scientific Evidence, highlighted themoral imperative to treat pain (Brennan 2007). Indeed, they stated that there is an obligation totreat pain on the basis of restoring patient autonomy and an ethical duty to relieve suffering.
This was followed by the “Declaration of Montreal”, the outcome of the first International Pain
Summit in 2010, which called for “access to pain management as a fundamental human right”(Cousins 2011).
The moral imperative to treat all forms of pain remains. Not only does unrelieved pain impair
an individual’s ability to exercise their fundamental autonomy, it can lead to a wide range ofharms even in the short term (Brennan 2007). The well-intentioned promotion that occurred at
the turn of this century of the greater use of opioids, in pursuit of the elusive goal of effective
pain management for all, has, with the benefit of hindsight, resulted in unexpected injury for
many. The number of unintentional drug-induced deaths in Australia continues to rise;prescription opioids and benzodiazepines being the main culprits (Penington Institute 2019).
Although many unwanted side-effects are the consequence of long-term use, many opioids arestarted in the acute pain setting, particularly postoperatively, setting patients on the path to longterm use (Bergomi 2018, Brummett 2017, Roughead 2019). Indeed, the use of opioids in acute pain
is not without other risks either including opioid-induced ventilatory impairment, cognitive
impairment, falls and gastrointestinal adverse effects (Macintyre 2011).
The pendulum seems to be swinging back to a more opioid-phobic position which is unlikely
to deliver high-quality care for many individuals either (Kharasch 2020. The pressing need is tobetter understand what does and does not work from what is already known so that better
choices can be made for individuals. The publication of the fifth edition of Acute PainManagement: Scientific Evidence is therefore very timely. Recognising the limitations of opioids
in the management of acute pain has driven a surge in interest of alternative pain management
techniques such as novel non-opioid drugs, new options for regional blockade and nonpharmacological techniques over the last decade (Albrecht 2020, Guay 2017).
For a small percentage of patients however acute pain is still not adequately managed
despite the burgeoning range of multimodal pain management techniques, leaving patients at
risk of transition to chronicity. Many of the risk factors lie in the psychological, social, culturaland spiritual realms (Sobol-Kwapinska 2016). The need for a broader sociopsychobiomedical
approach has been recognised as evidenced by the development of new approaches topreoperative preparation for surgery and extended postoperative care. Transitional pain
services and Acute Pain Service outpatient clinics are now being employed to specificallysupport patients to safely taper medications and identify those who may need early referralto chronic pain services (Huang 2016). Pleasingly, there is now an emerging evidence baseaddressing the effectiveness of such services from a range of perspectives (Gray 2017).
At a time when health system budgets are under huge scrutiny as the costs of new drugs andtechnologies escalate at unsustainable rates, pain services and even individual
pain management techniques are under more pressure than ever to demonstrate cost
5th Edition | Acute Pain Management: Scientific Evidenceiii

benefit especially from reducing complications and facilitating early discharge from hospital(Schofield 2019).
Acute Pain Management: Scientific Evidence: 5th Edition is larger than ever yet
comfortingly familiar. In this fifth edition, Professor Schug and the editorial team havecompiled the latest high-quality offering of this internationally renowned publication from theAustralian and New Zealand College of Anaesthetists and its Faculty of Pain Medicine. It brings
together the most recent evidence in acute pain management from the last five years, properly
evaluated and collated in the one resource. Its structure has evolved from the solid
foundations established in the previous editions, commencing with the first edition publishedin 1999 by the National Health and Medical Research Council (NHMRC). The foresight ofProfessor Michael Cousins and the first multidisciplinary committee to develop this first text
based on the NHMRC designation of levels of evidence was visionary. Professor Pamela
Macintyre and the editorial teams of the subsequent editions in 2005 and 2010 meticulously
built on this. In 2015 Professor Stefan Schug and the editorial team enhanced the fourth
edition by adding quality scoring using the Jadad Score to the assessment of the evidence. This
enabled conflicting evidence to be addressed and enhanced the production of the Key
Messages. The fifth edition retains this now standard structure.
Once again, the medical community is indebted to Professor Schug and the editorial team fortheir diligence and dedication over the last two years. The production of the fifth edition has
been an enormous task as the evidence base has more than doubled in some domains and growneven more in others with the addition of some new topic areas to assess. Most sections havemore than doubled or trebled in size and, indeed, a second volume has been required for acutepain management in children to contain the growing evidence base in this domain that has
tripled. The benefit of the five-yearly cycle of literature review over time is the consolidation of
Key Messages with the strengthening of many and only a few being reversed. Many new Key
Messages have also been added. Users of this text can feel confident that the information has
been expertly assessed and can be relied on to inform their clinical practice which was exactly
the original aim of the first edition.
In this edition of Acute Pain Management: Scientific Evidence, the chapters on predisposing
factors, psychological contributors, hypnosis and alternative strategies to medications containmuch new information, reflecting the increasing interest in a “whole-person” approach inaddition to more traditional techniques. However, the latter remain of interest as shown bysections on new routes of administration, novel opioids and new uses for old drugs. Cannabis
products are just the latest to be addressed. Contemporary cannabis research has been mostly
focused on the chronic pain setting where the evidence to date suggests significant limitationsin effectiveness and efficacy (Beaulieu 2016, Stockings 2018). However, newer research isaddressing a range of acute pain settings with particular interest in the potential for opioid
sparing and tapering (Khan 2019).
The use of ultrasound scanning to guide neuraxial and peripheral regional blockade,especially catheter techniques, has become the accepted norm and is being used to explore an
increasing number of regional anaesthesia techniques (Anim-Somuah 2018, Smith 2020).
Optimal pain management for every person experiencing acute pain remains elusive;
however, the evidence base continues to grow taking us step by step closer to the lofty goal of
personalised pain management. The imperative to manage acute pain remains with the caveats
that it must be safe and best be personalised. Acute Pain Management: Scientific Evidence: 5th
Edition provides the latest evidence to support decision-making with that goal in mind foreveryone experiencing acute pain.

iv

5th Edition | Acute Pain Management: Scientific EvidenceFOREWORD

Dr Rodney Mitchell
BMBS FANZCA FAICD
Consultant Anaesthetist,
The Queen Elizabeth Hospital
Head of Unit Modbury HospitalHigh Dependency Unit Clinical Lecturer,
The University of Adelaide,
Adelaide, South Australia
Immediate Past President, Australianand New Zealand College of Anaesthetists

A/Prof Meredith Craigie
MB BS, BMedSc, MM(PM), FANZCA,FFPMANZCA, GAICD
Staff Specialist, CALHN Pain Management Unit,
The Queen Elizabeth Hospital
Clinical Associate Professor
The University of Adelaide,
Adelaide, South Australia
Immediate Past Dean, Faculty of Pain Medicine

References
Albrecht E & Chin KJ (2020) Advances in regional anaesthesia and acute pain management: a narrative review.
Anaesthesia 75 Suppl 1: e101-e10.
Anim-Somuah M, Smyth RM, Cyna AM et al (2018) Epidural versus non-epidural or no analgesia for pain management
in labour. Cochrane Database Syst Rev 5(CD000331).
Beaulieu P, Boulanger A, Desroches J et al (2016) Medical cannabis: considerations for the anesthesiologist and pain
physician. Can J Anaesth 63(5): 608-24.
Bergomi P, Scudeller L, Pintaldi S et al (2018) Efficacy of Non-pharmacological Methods of Pain Management inChildren Undergoing Venipuncture in a Pediatric Outpatient Clinic: A Randomized Controlled Trial of Audiovisual
Distraction and External Cold and Vibration. J Pediatr Nurs 42: e66-e72.
Brennan F, Carr DB & Cousins M (2007) Pain management: a fundamental human right. Anesth Analg 105(1): 205-21.
Brummett CM, Waljee JF, Goesling J et al (2017) New Persistent Opioid Use After Minor and Major Surgical Proceduresin US Adults. JAMA Surg 152(6): e170504.
Cousins MJ & Lynch ME (2011) The Declaration Montreal: access to pain management is a fundamental human right.
Pain 152(12): 2673-4.
Gray CF, Smith C, Zasimovich Y et al (2017) Economic Considerations of Acute Pain Medicine Programs. Tech Orthop
32(4): 217-25.
Guay J, Parker MJ, Griffiths R et al (2017) Peripheral nerve blocks for hip fractures. Cochrane Database Syst Rev 5:CD001159.
Huang A, Azam A, Segal S et al (2016) Chronic postsurgical pain and persistent opioid use following surgery: the needfor a transitional pain service. Pain Manag 6(5): 435-43.
Khan SP, Pickens TA & Berlau DJ (2019) Perspectives on cannabis as a substitute for opioid analgesics. Pain Manag 9(2):191-203.
Kharasch ED, Avram MJ & Clark JD (2020) Rational Perioperative Opioid Management in the Era of the Opioid Crisis.
Anesthesiology 132(4): 603-05.
Macintyre PE, Loadsman JA & Scott DA (2011) Opioids, ventilation and acute pain management. Anaesth Intensive Care
39(4): 545-58.
Penington Institute (2019) Australia’s annual overdose report 2019. At http://www.penington.org.au/australiasannual-overdose-report-2019/. Accessed 27 Oct 2019.
Roughead EE, Lim R, Ramsay E et al (2019) Persistence with opioids post discharge from hospitalisation for surgery inAustralian adults: a retrospective cohort study. BMJ Open 9(4): e023990.
Schofield D, Shrestha RN, Zeppel MJB et al (2019) Economic costs of informal care for people with chronic diseases in
the community: Lost income, extra welfare payments, and reduced taxes in Australia in 2015-2030. Health Soc
Care Community 27(2): 493-501.
Smith LM, Barrington MJ & St Vincent's Hospital M (2020) Ultrasound-guided blocks for cardiovascular surgery: whichblock for which patient? Curr Opin Anaesthesiol 33(1): 64-70.
Sobol-Kwapinska M, Babel P, Plotek W et al (2016) Psychological correlates of acute postsurgical pain: A systematic
review and meta-analysis. Eur J Pain 20(10): 1573-86.
Stockings E, Campbell G, Hall WD et al (2018) Cannabis and cannabinoids for the treatment of people with chronic
noncancer pain conditions: a systematic review and meta-analysis of controlled and observational studies. Pain
159(10): 1932-54.

5th Edition | Acute Pain Management: Scientific EvidencevIntroduction
This is the fifth edition of the book Acute Pain Management: Scientific Evidence. The first edition
was written by a multidisciplinary committee headed by Professor Michael Cousins andpublished by the National Health and Medical Research Council (NHMRC) in 1999.
The second and third editions were written by multiple contributors and a working groupchaired by Professor Pam Macintyre. The editions were approved by the NHMRC and publishedby the Australian and New Zealand College of Anaesthetists (ANZCA) and its Faculty of Pain
Medicine (FPM) in 2005 and 2010. They were also endorsed by other major organisations
worldwide.
As guidelines and key sources of information should be revised as further evidence
accumulates (ideally every 5 years), a fourth edition was written by multiple contributors and an
editorial working group chaired by Professor Stephan Schug and published by ANZCA and its FPM
in 2015. In view of the NHMRC changing its criteria, this edition was not submitted for NHMRC
approval, but it was widely endorsed by many significant national and international organisations- the International Association for the Study of Pain (IASP), the Royal College of Anaesthetists
and its Faculty of Pain Medicine, the American Academy of Pain Medicine, the Australian Pain
Society, Australasian College of Sport and Exercise Physicians, the Australasian Faculty of
Rehabilitation Medicine, the College of Anaesthesiologists of the Academies of Medicine of
Malaysia and Singapore, the College of Intensive Care Medicine of Australia and New Zealand,
the European Society of Regional Anaesthesia and Pain Therapy (ESRA), the Faculty of Pain
Medicine of the College of Anaesthetists of Ireland, the Hong Kong College of Anaesthesiologists,
the Hong Kong Pain Society, the Malaysian Association for the Study of Pain, the New ZealandPain Society, the Pain Association of Singapore, PainSA (South Africa), PROSPECT (ProcedureSpecific Postoperative Pain Management), the Royal Australasian College of Physicians, the Royal
Australian and New Zealand College of Psychiatrists, the Royal Australasian College of Surgeons
and the South African Society of Anaesthesiologists.
With 5 years’ further growth in evidence, it was seen as timely to reassess the available
evidence, aiming for a release of the new document in 2020. ANZCA and the FPM therefore again
took responsibility for revising and updating this reference to its fifth edition. As for the fourth
edition, endorsement is currently being sought from a number of key organisations.
An editorial working group was convened to coordinate and oversee the development
process, to edit the reference and also contribute updates to some sections – members wereProf Stephan Schug, A/Prof Greta Palmer, Prof David Scott, Dr Mark Alcock, Dr Richard Halliwell,and Dr Jeff Mott. While all members of the working group contributed to the whole document,
A/Prof Greta Palmer and Dr Mark Alcock provided specific input and expertise to the paediatricsection. This section will remain as Chapter 10 in the PDF of the book, but In view of the largely
increased amount of information in the paediatric section, it will be published as a separate
volume II of the hardcopy of the book.
The working group was also assisted by an editorial advisory group comprising Dr MarkRockett, nominated by the Faculty of Pain Medicine, Royal College of Anaesthetists in the United
Kingdom, and Dr Clara Sze Ming Wong, nominated by the Hong Kong College ofAnaesthesiologists.
A large panel of contributors was enlisted to draft sections of the document and amultidisciplinary consultative committee was chosen to review the draft of the document andcontribute more broadly as required. To ensure general applicability and inclusiveness, there
was a very wide range of experts on the contributor and multidisciplinary committees, including
medical, nursing, allied health and complementary medicine professionals and consumers.

vi

5th Edition | Acute Pain Management: Scientific EvidenceINTRODUCTION

Acute Pain Management: Scientific Evidence: 5th Edition covers a wide range of clinical areas.
The aim of the document is, as with the first four editions, to combine a review of the best
available evidence for acute pain management with current clinical and expert practice, rather
than to formulate specific clinical practice guidelines. Accordingly, the document aims tosummarise the substantial amount of evidence currently available for the management of acutepain in a concise, accessible, and easily readable form to assist the practising health professional.
New and updated content has been incorporated with that of the previous version of the book.
A detailed description of the methodology used to generate this document can be found in
Appendix B. The following summarises the most important information on the methodology.
Review of the evidenceThis document is a revision of the previous edition of Acute Pain Management: Scientific
Evidence published in 2015. Therefore most of the new evidence included in this fifth edition has
been published from August 2014 onwards, which was the cut-off date for literature inclusion in
the fourth edition. Literature was considered when published between this date and the cut-off
date for this fifth edition (August 2019). However, in rare circumstances, references publishedafter this cut-off were considered but only if they were of high relevance and encountered in theeditorial process. In addition, high-quality evidence-based guidelines have been publishedindependently by a number of organisations in the areas of acute back and musculoskeletal pain
and the chapters relevant to the management of these conditions refer to these guidelines.
Levels of evidence
Levels of evidence continue to be documented according to the NHMRC designation ( NHMRC
1999 GL).
Levels of evidence
I

Evidence obtained from a systematic review of all relevant randomised controlled
trials (RCTs)

II

Evidence obtained from at least one properly designed randomised controlled trial

III-1

Evidence obtained from well-designed pseudo-randomised controlled trials(alternate allocation or some other method)

III-2

Evidence obtained from comparative studies with concurrent controls and allocation
not randomised (cohort studies), case-controlled studies or interrupted time series
with a control group

III-3

Evidence obtained from comparative studies with historical control, two or more
single-arm studies, or interrupted time series without a parallel control group

IV

Evidence obtained from case series, either post test or pretest and post-test

Clinical practice points
🗹

Recommended best practice based on clinical experience and expert opinion

5th Edition | Acute Pain Management: Scientific Evidencevii

Quality scoring
As for the fourth edition, evidence was subjected to quality scoring and other types of references
identified to enhance the value of the information provided.
Systematic reviews and meta-analyses• Reviews performed by the Cochrane Collaboration are identified as [Cochrane] in the texteg (Derry 2013 Level I [Cochrane]);• Reviews that overtly state that the review conformed with an evidence-based minimum
set of items for reporting referred to as Preferred Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) (Liberati 2009 GL) are identified as [PRISMA] eg (Moore 2014
Level I [PRISMA]);• Reviews that overtly state that the review conformed with standards previously publishedas Quality of Reporting of Meta-analyses (QUOROM) (Moher 1999 GL), a precursor of
PRISMA, are identified as [QUOROM] eg (Macedo 2006 Level I [QUOROM]);• Non-Cochrane meta-analyses (of RCTs) that did not provide evidence of using PRISMA or
QUOROM quality and reporting methods are only labelled Level I eg (Thorlund 2014 Level I);• Systematic reviews that included studies other than RCTs are assigned the level ofevidence of their lowest level component studies (as outlined in the NHMRC designationof evidence levels [NHMRC 1999 GL]) and identified by SR following the level of evidenceeg (von Plato 2018 Level IV SR [PRISMA], 9 RCTs & 10 studies, n=949);• Network meta-analyses are identified as [NMA] eg (Martinez 2017 Level I (NMA),
135 RCTs, n=13,287).

For all systematic reviews and meta-analyses, the number of RCTs for Level I and the numberof studies for all other levels is reported as well as the number of subjects included in these, if
reported or immediately obvious eg (Rabbie 2013 Level I [Cochrane], 9 RCTs, n=4,473); if this is not
the case, the term unspecified is used eg (Hughes 2011 Level IV SR, 5 studies, n unspecified).
Randomised-controlled trials
The Jadad scoring instrument was used to score the quality of all RCTs (Level II) ( Jadad 1996).
The Jadad Score (JS) ranges from 0 (lowest quality) to 5 (highest quality) and is based on
randomisation and blinding methods used and accurate accounting of study participants.
In addition to the Jadad score, the number of patients randomised (prior to dropouts)
is reported for all Level II references eg (Chan 2010 Level II, n=4,484, JS 5).
Other evidence
No quality evaluation was undertaken for lower ranked evidence (Level III and Level IV), when
this was the highest available level of evidence. However, the number of patients or events
included is provided if reported in the publication and the size of the study relates to the qualityof the evidence eg (Morton 2010 Level IV, n=5,065).
Identification of other types of references
Narrative reviews containing such evidence are identified by NR following the reference eg(Graham 2013 NR). Other study types have been included where relevant and identified by aresearch identifier following the reference. Thus, readers will find CR (for case report) eg (Madadi
2010 CR), GL for clinical practice guidelines eg (Kowalski 2011 GL), BS if presenting basic science oranimal data eg (LaCrois-Fralish 2011 BS), PK if presenting pharmacokinetic study eg (Holford 2012PK) and EH if presenting human experimental data eg ( Saxena 2013 EH). The latter two were also
assigned an evidence level in line with NHMRC hierarchy if applicable eg (Williams 2002 Level II PK,
n=96, JS 4).

viii

5th Edition | Acute Pain Management: Scientific EvidenceINTRODUCTION

Conflicting evidence
If evidence was consistent, the most recent, highest hierarchy and highest quality referenceswere used. If evidence was conflicting, the same approach was taken (identifying highest level,
highest quality evidence); however, examples were given of differences within the literature sothat readers could appreciate the ongoing debate. In some instances, particularly in acute pain
management in various patient populations, evidence was limited to case reports only, which ismade clear in the document as the best available evidence in this instance.
Key messages
Key messages for each topic are given ranked by the highest level of evidence available tosupport them, or with a tick box symbol indicating that they are based on clinical experience orexpert opinion. Levels of evidence were documented according to the NHMRC designation and,as for the previous four editions of this document, clinical practice points have been added.
Key messages are presented in order of level of evidence from the highest to the lowest. Key
messages referring to information extracted from Cochrane meta-analyses were marked “Level I[Cochrane Review]”, and these were listed first, followed by those marked “Level I [PRISMA]”,“Level I [QUOROM]” and “Level I”. Level II evidence was included in key messages if supported bya single sufficiently large, or at least two smaller, high quality Level II studies as determined by theeditors. Key messages based on lower levels of evidence than Level II are presented with those
based upon systematic reviews listed before those based on studies at each level of evidence.
There is no standard approach to updating wording or strength of evidence of existing
guideline recommendations (Vernooij 2014 GL). An indication of how the key messages in this fifth
edition relate to those in the preceding fourth edition is provided. An adapted version of thesystem used by Johnston et al (Johnston 2003) to reflect the implications of new evidence on
clinical recommendations was therefore used as previously. Where the new evidence led toreversal of a conclusion and key message, this was noted in the text.
Review and revision of key messages
New

New evidence leads to new key message(s).

Unchanged

The new evidence is consistent with the data used to formulate the original
key message. The key message in the original report remains unchanged.

Strengthened

The new evidence is consistent with the data used to formulate the original
key message. The key message in the original report remains unchanged or
expanded. The level of evidence and/or content of the key message in theoriginal report has been strengthened to reflect this additional evidence.

Weakened

The new evidence is inconsistent with the data used to inform the original
key message(s). However, the new evidence does not alter the key
message but weakens the level of evidence.

Qualified

The new evidence is consistent with the data used to formulate the original
key message. The key message in the original report remains unchanged
but applicability may be limited to specific patient groups/ circumstances.

Reversed

The new evidence is inconsistent with the data used to inform the original
key message(s). The strength of the new evidence alters the conclusions of
the original document.
5th Edition | Acute Pain Management: Scientific Evidence

ix

Note

Clinical and scientific judgement informed the choices made by the editorial working
group members; there was no mandatory threshold of new evidence (eg number ofstudies, types of studies, magnitude of statistical findings) that had to be met before
classification into categories occurred.
The first letter of each of the words (New, Unchanged etc) was used to denote thechanges (if any) from the last edition of this document.

Acknowledgements
The production of a document such as this requires a considerable amount of time over a long
period and the generous input of many. All contributions were honorary and the time
contributed freely by the members of the editorial working group and the many contributors
need to be acknowledged in particular. The institutional support in terms of time and resourcesfrom many hospital departments, including Departments of Anaesthesia throughout Australia
and New Zealand, is difficult to quantify but is gratefully acknowledged; these include
Queensland Children’s Hospital, Redcliffe Hospital, St Vincent’s Hospital Melbourne andWestmead Hospital.
A/Prof Greta Palmer would like to specifically thank both the Royal Children's and Royal
Melbourne Hospitals for protected non-clinical time to dedicate to the editing task and the
University of Melbourne for access to its expansive online journal subscriptions.
Special thanks are also extended to the staff at ANZCA and the FPM, in particular Ms Liane
Reynolds and Ms Frances Rowsell for their ongoing input to the process. The ANZCA library wasan extremely effective and valuable resource once more, in particular for provision of difficult toaccess references.
Stephan SchugOn behalf of the Editorial Working Group of the Australian New Zealand College of Anaesthetists
and its Faculty of Pain Medicine

References
Jadad AR, Moore RA, Carroll D et al (1996) Assessing the quality of reports of randomized clinical trials: is blinding
necessary? Control Clin Trials 17(1): 1–12.
Johnston ME, Brouwers MC & Browman GP (2003) Keeping cancer guidelines current: results of a comprehensive
prospective literature monitoring strategy for twenty clinical practice guidelines. Int J Technol Assess Health Care19(4): 646–55.
Liberati A, Altman DG, Tetzlaff J et al (2009) The PRISMA statement for reporting systematic reviews and meta-analysesof studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339: b2700.
Moher D, Cook DJ, Eastwood S et al (1999) Improving the quality of reports of meta-analyses of randomised controlled
trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet 354(9193): 1896–900.
NHMRC (1999) A guide to the development, evaluation and implementation of clinical practice guidelines.
https://www.nhmrc.gov.au/guidelines-publications/cp30 Accessed 29 August 2015
Vernooij RW, Sanabria AJ, Sola I et al (2014) Guidance for updating clinical practice guidelines: a systematic review ofmethodological handbooks. Implement Sci 9: 3x

5th Edition | Acute Pain Management: Scientific EvidenceContents
FOREWORD ............................................................................................................................ iii
INTRODUCTION ...................................................................................................................... vi
SUMMARY OF KEY MESSAGES ............................................................................................. xxiv
1.0 | PHYSIOLOGY AND PSYCHOLOGY OF ACUTE PAIN ............................................................ 2
1.1 | Applied physiology of acute pain ............................................................................ 2
1.1.1 | Definition of acute pain ................................................................................... 2
1.1.2 | Nociceptive pathways and pain perception .................................................... 2
1.1.3 | Physiological and pathological pain ................................................................ 9
1.2 | Psychological aspects of acute pain ...................................................................... 11
1.2.1 | Psychological factors ..................................................................................... 11
1.2.2 | Patient-controlled analgesia ......................................................................... 14
1.3 | Placebo and nocebo effects in acute pain ............................................................. 16
1.3.1 | Mechanisms .................................................................................................. 16
1.3.2 | Clinical findings .............................................................................................. 19
1.3.3 | Clinical Implications ....................................................................................... 19
1.4 | Progression of acute to chronic pain ..................................................................... 21
1.4.1 | Epidemiology of chronic postsurgical pain .................................................... 21
1.4.2 | Characteristics of chronic postsurgical pain .................................................. 23
1.4.3 | Opioids and CPSP........................................................................................... 23
1.4.4 | Predictive factors for chronic postsurgical pain ............................................ 24
1.4.5 | Mechanisms for the progression from acute to chronic pain ....................... 27
1.4.6 | Prevention of chronic postsurgical pain ........................................................ 28
1.5 | Pre-emptive and preventive analgesia .................................................................. 33
1.5.1 | Pre-emptive analgesia ................................................................................... 34
1.5.2 | Preventive analgesia...................................................................................... 35
1.6 | Adverse physiological and psychological effects of acute pain.............................. 38
1.6.1 | Acute pain and the injury response............................................................... 38
1.6.2 | Adverse physiological effects ........................................................................ 40
1.6.3 | Pain and analgesia: effects on injury-induced organ dysfunction ................. 40
1.6.4 | Adverse psychological effects ....................................................................... 41
1.7 | Genetics and acute pain ....................................................................................... 43
1.7.1 | Single gene pain disorders............................................................................. 43
1.7.2 | Genetic influences on sensitivity to pain....................................................... 44
1.7.3 | Drug metabolism ........................................................................................... 46
References .................................................................................................................... 49

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2.0 | ASSESSMENT AND MEASUREMENT OF PAIN AND PAIN TREATMENT ........................... 62
2.1 | Assessment........................................................................................................... 64
2.2 | Measurement ....................................................................................................... 66
2.2.1 | Unidimensional measures of pain ................................................................. 67
2.2.2 | Functional impact of acute pain .................................................................... 68
2.2.3 | Multidimensional measures of pain .............................................................. 69
2.2.4 | Patients with special needs ........................................................................... 70
2.3 | Outcome measures in acute pain management .................................................... 72
2.3.1 | Outcome measures ....................................................................................... 72
References .................................................................................................................... 75
3.0 | PROVISION OF SAFE AND EFFECTIVE ACUTE PAIN MANAGEMENT ............................... 78
3.1 | Education ............................................................................................................. 80
3.1.1 | Patients.......................................................................................................... 80
3.1.2 | Staff ............................................................................................................... 84
3.2 | Organisational requirements ................................................................................ 89
3.2.1 | General requirements ................................................................................... 89
3.2.2 | Acute pain services ........................................................................................ 90
3.3 | Economic considerations in acute pain management ........................................... 94
3.3.1 | Economic evaluation of PCA .......................................................................... 95
3.3.2 | Economic evaluation of Acute Pain Services ................................................. 96
3.3.3 | Economic benefit related to improved patient outcome and reduced
chronic postsurgical pain............................................................................... 97
References .................................................................................................................... 99
4.0 | ANALGESIC MEDICINES ............................................................................................... 106
4.1 | Paracetamol ....................................................................................................... 108
4.1.1 | Mechanism of action ................................................................................... 108
4.1.2 | Efficacy ........................................................................................................ 108
4.1.3 | Adverse effects ............................................................................................ 109
4.2 | Nonselective NSAIDs and coxibs ......................................................................... 112
4.2.1 | Systemic nonselective nonsteroidal anti-inflammatory drugs .................... 112
4.2.2 | Systemic cyclooxygenase-2 selective inhibitors (Coxibs) ............................ 117
4.2.3 | Nonsystemic administration of nonsteroidal anti-inflammatory drugs ...... 123
4.3 | Opioids ............................................................................................................... 126
4.3.1 | Systemic opioids .......................................................................................... 126
4.3.2 | Neuraxial opioids ......................................................................................... 152
4.3.3 | Peripheral opioids ....................................................................................... 159

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4.4 | Local anaesthetics and other membrane stabilisers ........................................... 163
4.4.1 | Systemic local anaesthetics and other membrane stabilisers ..................... 163
4.4.2 | Regional local anaesthetics ......................................................................... 166
4.4.3 | Local anaesthetic toxicity ............................................................................ 170
4.5 | Inhalational agents ............................................................................................. 174
4.5.1 | Nitrous oxide ............................................................................................... 174
4.5.2 | Methoxyflurane ........................................................................................... 177
4.6 | NMDA-receptor antagonists ............................................................................... 180
4.6.1 | Systemic NMDA-receptor antagonists ........................................................ 180
4.6.2 | Regional NMDA-receptor antagonists......................................................... 188
4.7 | Antidepressant medicines .................................................................................. 191
4.7.1 | Acute pain ................................................................................................... 191
4.7.2 | Chronic pain ................................................................................................ 191
4.7.3 | Specific pain conditions ............................................................................... 192
4.8 | Anticonvulsant medicines ................................................................................... 194
4.8.1 | Acute pain ................................................................................................... 194
4.8.2 | Chronic pain ................................................................................................ 197
4.9 | Alpha-2 agonists ................................................................................................. 200
4.9.1 | Systemic alpha-2 agonists ........................................................................... 200
4.9.2 | Regional alpha-2 agonists............................................................................ 201
4.10 | Salmon calcitonin and bisphosphonates ........................................................... 207
4.10.1 | Calcitonin ................................................................................................... 207
4.10.2 | Bisphosphonates ....................................................................................... 208
4.11 | Cannabis, cannabinoids and cannabimimetics .................................................. 209
4.11.1 | Pharmacology ............................................................................................ 209
4.11.2 | Efficacy ...................................................................................................... 210
4.11.3 | Adverse effects .......................................................................................... 211
4.11.4 | General considerations ............................................................................. 212
4.12 | Corticosteroids ................................................................................................. 214
4.12.1 | Systemic corticosteroids ........................................................................... 214
4.12.2 | Regional corticosteroids ............................................................................ 218
4.13 | Other regional analgesic medicines .................................................................. 223
4.13.1 | Midazolam ................................................................................................. 223
4.13.2 | Neostigmine .............................................................................................. 224
4.13.3 | Botulinum toxin A ...................................................................................... 225

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4.14 | Complementary and alternative medicine ........................................................ 227
4.14.1 | Vitamins ..................................................................................................... 227
4.14.2 | Herbal Medicines....................................................................................... 227
4.14.3 | Aromatherapy ........................................................................................... 230
4.14.4 | Melatonin .................................................................................................. 230
4.14.5 | Honey ........................................................................................................ 230
References .................................................................................................................. 232
5.0 | ADMINISTRATION OF ANALGESIC MEDICINES ............................................................. 286
5.1 | Oral and sublingual route ................................................................................... 288
5.1.1 | Paracetamol ................................................................................................ 292
5.1.2 | Nonselective NSAIDs and coxibs ................................................................. 293
5.1.3 | Conventional and atypical opioids .............................................................. 293
5.2 | Intravenous route ............................................................................................... 298
5.2.1 | Paracetamol ................................................................................................ 298
5.2.2 | Nonselective NSAIDs and coxibs ................................................................. 298
5.2.3 | Conventional and atypical opioids .............................................................. 299
5.3 | Intramuscular and subcutaneous routes............................................................. 302
5.3.1 | Nonselective NSAIDs and coxibs ................................................................. 302
5.3.2 | Conventional and atypical opioids .............................................................. 302
5.4 | Transdermal route .............................................................................................. 304
5.4.1 | Opioids ........................................................................................................ 304
5.4.2 | Other medicines .......................................................................................... 305
5.5 | Transmucosal routes .......................................................................................... 306
5.5.1 | Rectal route ................................................................................................. 306
5.5.2 | Intranasal route ........................................................................................... 308
5.5.3 | Sublingual and buccal routes....................................................................... 311
5.5.4 | Pulmonary ................................................................................................... 313
5.6 | Epidural analgesia............................................................................................... 316
5.6.1 | Efficacy ........................................................................................................ 316
5.6.2 | Medicines used for epidural analgesia ........................................................ 323
5.6.3 | Patient-controlled epidural analgesia ......................................................... 324
5.6.4 | Adverse effects ............................................................................................ 325
5.7 | Intrathecal analgesia .......................................................................................... 333
5.7.1 | Medicines used for intrathecal analgesia .................................................... 333

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5.8 | Other regional and local analgesic techniques .................................................... 342
5.8.1 | Needle and catheter localising techniques ................................................. 342
5.8.2 | Continuous and single-injection peripheral nerve blocks ........................... 343
5.8.3 | Upper limb blocks ........................................................................................ 343
5.8.4 | Lower limb blocks ........................................................................................ 344
5.8.5 | Truncal blocks .............................................................................................. 348
5.8.6 | Head and Neck Blocks ................................................................................. 353
5.8.7 | Periarticular and intra-articular analgesia ................................................... 353
5.8.8 | Wound catheter infusion, instillation and wound infiltration ..................... 354
5.8.9 | Topical application of local anaesthetics ..................................................... 355
5.8.10 | Neuromodulation ...................................................................................... 356
5.8.11 | Safety ......................................................................................................... 356
5.9 | Regional analgesia and concurrent anticoagulant medications .......................... 361
5.9.1 | Neuraxial block and anticoagulant medication ........................................... 361
5.9.2 | Plexus and other peripheral regional block and anticoagulant medication 364
References .................................................................................................................. 371
6.0 | PATIENT-CONTROLLED ANALGESIA ............................................................................. 402
6.1 | Efficacy of intravenous PCA ................................................................................ 404
6.1.1 | Analgesia, patient preference and outcomes ............................................. 404
6.2 | Cost of PCA ......................................................................................................... 405
6.3 | Medicines used for parenteral PCA ..................................................................... 405
6.3.1 | Opioids ........................................................................................................ 405
6.3.2 | Adverse effects of PCA opioids .................................................................... 408
6.3.3 | Adjuvant medicines ..................................................................................... 409
6.4 | Program parameters for IV PCA .......................................................................... 412
6.4.1 | Bolus dose ................................................................................................... 412
6.4.2 | Lockout interval ........................................................................................... 412
6.4.3 | Concurrent background (continuous) infusions .......................................... 413
6.4.4 | Dose limits ................................................................................................... 413
6.4.5 | Loading dose ............................................................................................... 413
6.5 | Efficacy of PCA using other systemic routes of administration............................ 414
6.5.1 | Subcutaneous PCA....................................................................................... 414
6.5.2 | Oral PCA....................................................................................................... 414
6.5.3 | Sublingual PCA ............................................................................................. 414
6.5.4 | Intranasal PCA ............................................................................................. 414
6.5.5 | Transdermal PCA ......................................................................................... 415
6.6 | Safety and complications related to PCA ............................................................ 415

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6.7 | Equipment .......................................................................................................... 417
6.7.1 | Programmable PCA pumps .......................................................................... 417
6.7.2 | Disposable PCA devices ............................................................................... 417
6.7.3 | Equipment-related complications ............................................................... 418
6.8 | Patient and staff factors ..................................................................................... 419
6.8.1 | Patient factors ............................................................................................. 419
6.8.2 | Nursing and medical staff ............................................................................ 420
6.9 | PCA in specific patient groups............................................................................. 420
References .................................................................................................................. 423
7.0 | NONPHARMACOLOGICAL TECHNIQUES ...................................................................... 430
7.1 | Psychological interventions ................................................................................ 432
7.1.1 | Provision of information.............................................................................. 432
7.1.2 | Relaxation techniques ................................................................................. 433
7.1.3 | Mindfulness-based interventions (MBI) ...................................................... 434
7.1.4 | Hypnosis ...................................................................................................... 435
7.1.5 | Attentional techniques ................................................................................ 436
7.1.6 | Cognitive-behavioural interventions ........................................................... 437
7.2 | Transcutaneous electrical nerve stimulation ...................................................... 441
7.2.1 | Orthopaedic surgery .................................................................................... 441
7.2.2 | General and thoracic surgery ...................................................................... 441
7.2.3 | Procedural pain and prehospital analgesia ................................................. 442
7.2.4 | Gynaecological surgery and obstetrics ........................................................ 442
7.2.5 | Migraine ...................................................................................................... 443
7.2.6 | Musculoskeletal pain ................................................................................... 443
7.2.7 | Neuropathic and phantom limb pain .......................................................... 443
7.3 | Acupuncture and acupressure ............................................................................ 444
7.3.1 | Postoperative pain ...................................................................................... 444
7.3.2 | Other acute pain states ............................................................................... 447
7.4 | Photobiomodulation .......................................................................................... 452
7.4.1 | Mucositis and stomatitis ............................................................................. 452
7.4.2 | Maxillofacial, ENT and dental surgery ......................................................... 452
7.5 | Physical therapies ............................................................................................... 455
7.5.1 | Active exercise-based therapies .................................................................. 455
7.5.2 | Manual and massage therapies ................................................................... 459
7.5.3 | Warming and cooling interventions ............................................................ 460
References .................................................................................................................. 464

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8.0 | SPECIFIC CLINICAL SITUATIONS ................................................................................... 474
8.1 | Postoperative pain ............................................................................................. 476
8.1.1 | Multimodal postoperative pain management ............................................ 476
8.1.2 | Procedure-specific postoperative pain management ................................. 479
8.1.3 | Acute rehabilitation after surgery, “fast-track” surgery andenhanced recovery after surgery (ERAS) ..................................................... 481
8.1.4 | Risks of acute postoperative neuropathic pain ........................................... 483
8.1.5 | Acute postamputation pain syndromes ...................................................... 485
8.1.6 | Other postoperative pain syndromes ......................................................... 489
8.1.7 | Ambulatory or short-stay surgery ............................................................... 494
8.1.8 | Cranial neurosurgery ................................................................................... 506
8.1.9 | Spinal surgery .............................................................................................. 509
8.2 | Acute pain following spinal cord injury ............................................................... 513
8.2.1 | Treatment of acute neuropathic pain after spinal cord injury .................... 513
8.2.2 | Treatment of chronic neuropathic pain after spinal cord injury ................. 514
8.2.3 | Treatment of nociceptive and visceral pain after spinal cord injury ........... 516
8.3 | Chest trauma (Rib fractures) ............................................................................... 517
8.3.1 | Paracetamol ................................................................................................ 517
8.3.2 | NSAIDS ......................................................................................................... 517
8.3.3 | Adjuvant medications .................................................................................. 517
8.3.4 | Epidural analgesia ....................................................................................... 517
8.3.5 | Peripheral regional analgesia ...................................................................... 518
8.3.6 | Surgical fixation ........................................................................................... 518
8.3.7 | Non-pharmacological therapy ..................................................................... 518
8.4 | Acute pain after hip (neck of femur) fractures .................................................... 520
8.4.1 | Nerve Blocks ................................................................................................ 520
8.4.2 | Systemic analgesia....................................................................................... 521
8.5 | Acute burns injury pain ...................................................................................... 524
8.5.1 | Management of background nociceptive pain ............................................ 524
8.5.2 | Management of acute neuropathic pain and hyperalgesia ........................ 525
8.5.3 | Management of procedural pain ................................................................ 525
8.5.4 | Regional analgesia for donor site pain management .................................. 527
8.5.5 | Nonpharmacological pain management ..................................................... 527
8.6 | Acute medical pain ............................................................................................. 529
8.6.1 | Acute abdominal pain ................................................................................. 529
8.6.2 | Herpes zoster-associated pain .................................................................... 534
8.6.3 | Acute cardiac pain ....................................................................................... 538
8.6.4 | Acute pain associated with haematological disorders ................................ 540
8.6.5 | Acute headache ........................................................................................... 545

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8.6.6 | Acute pain associated with neurological disorders ..................................... 560
8.6.7 | Acute orofacial pain .................................................................................... 565
8.6.8 | Acute pain in patients with HIV infection .................................................... 575
8.7 | Acute back pain .................................................................................................. 578
8.8 | Acute musculoskeletal pain ................................................................................ 579
8.9 | Acute cancer pain ............................................................................................... 580
8.9.1 | Assessment of acute cancer pain ................................................................ 580
8.9.2 | Principles of management of acute cancer pain ......................................... 580
8.9.3 | Medicines for acute cancer pain ................................................................. 581
8.9.4 | Breakthrough pain ....................................................................................... 587
8.9.5 | Acute neuropathic cancer pain ................................................................... 587
8.9.6 | Procedural pain in cancer patients .............................................................. 590
8.9.7 | Acute pain due to bone cancer ................................................................... 591
8.9.8 | Other acute cancer pain syndromes ........................................................... 596
8.9.9 | Interventional therapies for acute cancer pain ........................................... 598
8.10 | Acute pain management in intensive care ........................................................ 603
8.10.1 | Aetiology of pain in the intensive care unit (ICU)...................................... 603
8.10.2 | Barriers to pain management in the ICU ................................................... 604
8.10.3| Pain assessment in the ICU ........................................................................ 605
8.10.4 | Analgesic management strategies in the ICU ............................................ 605
8.10.5 | Nonpharmacological analgesic management ........................................... 606
8.10.6 | Pharmacological analgesic management .................................................. 606
8.11 | Acute pain management in emergency departments ....................................... 611
8.11.1 | Systemic analgesics ................................................................................... 611
8.11.2 | Analgesia in specific conditions ................................................................. 615
8.11.3 | Nonpharmacological management of pain ............................................... 618
8.12 | Prehospital analgesia ........................................................................................ 621
8.12.1 | Incidence and undertreatment of acute pain in prehospital settings ....... 621
8.12.2 | Opioid use in the prehospital setting ........................................................ 623
8.12.3 | Principles of management of acute pain in the prehospital setting ......... 623
8.12.1 | Assessment of pain in the prehospital environment ................................ 624
8.12.4 | Systemic analgesics ................................................................................... 625
8.12.5 | Anxiolytics ................................................................................................. 628
8.12.6 | Regional analgesia ..................................................................................... 628
8.12.7 | Nonpharmacological management of pain ............................................... 628
8.12.8 | Analgesia in specific conditions ................................................................. 629

5th Edition | Acute Pain Management: Scientific Evidencexix

8.13 | Discharge opioid medication for acute pain management ................................ 631
8.13.2 | Adverse effects of opioids ......................................................................... 631
8.13.3 | Selection of opioid for discharge medication ............................................ 638
8.13.4 | Identification of patients at risk of opioid misuse ..................................... 638
8.13.5 | Practical opioid prescribing on discharge .................................................. 638
References .................................................................................................................. 641
9.0 | OTHER SPECIFIC PATIENT GROUPS .............................................................................. 708
9.1 | The pregnant patient .......................................................................................... 710
9.1.1 | Management of acute pain during pregnancy ............................................ 710
9.1.2 | Pain syndromes in pregnancy...................................................................... 721
9.1.3 | Management of acute pain during labour and after birth .......................... 723
9.1.4 | Pain management during lactation ............................................................. 742
9.1.5 | Pain in the puerperium................................................................................ 750
9.2 | The older patient ................................................................................................ 753
9.2.1 | Physiology and perception of pain .............................................................. 753
9.2.2 | Assessment of pain...................................................................................... 755
9.2.3 | Pharmacokinetic and pharmacodynamic changes ...................................... 758
9.2.4 | Drugs used in the management of acute pain in older people ................... 760
9.2.5 | Patient-controlled analgesia ....................................................................... 764
9.2.6 | Epidural analgesia ....................................................................................... 765
9.2.7 | Intrathecal opioid analgesia ........................................................................ 765
9.2.8 | Other regional analgesia ............................................................................. 766
9.3 | Culturally responsive care for Culturally and Linguistically Diverse patients ....... 768
9.3.1 | Aboriginal and Torres Strait Islander Peoples ............................................. 772
9.3.2 | Māori peoples ............................................................................................. 776
9.4 | The patient with sleep-disordered breathing including obstructive
sleep apnoea ..................................................................................................... 779
9.4.1 | Opioids and obstructive sleep apnoea ........................................................ 781
9.4.2 | Obesity as a risk factor ................................................................................ 783
9.4.3 | Approaches to treatment ............................................................................ 783
9.5 | The obese Patient ............................................................................................... 787
9.5.1 | Definitions of obesity .................................................................................. 787
9.5.2 | Prevalence ................................................................................................... 787
9.5.3 | Morbidity associated with obesity .............................................................. 787
9.5.4 | Pharmacokinetic impact of obesity ............................................................. 788
9.5.5 | Drugs used in the management of acute pain in the obese patient ........... 789
9.5.6 | Local and regional anaesthetic techniques used in the managementof acute pain in the obese patient .............................................................. 792

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9.5.7 | Non-pharmacological techniques used in the managementof acute pain in the obese patient .............................................................. 793
9.5.8 | Multimodal concepts................................................................................... 794
9.6 | The patient with concurrent renal or hepatic disease ......................................... 795
9.6.1 | Patients with renal disease.......................................................................... 795
9.6.2 | Patients with hepatic disease ...................................................................... 801
9.7 | The opioid-tolerant patient ................................................................................ 806
9.7.1 | Definitions ................................................................................................... 806
9.7.2 | Clinical implications of opioid tolerance and opioid-induced
hyperalgesia ................................................................................................ 808
9.7.3 | Patient groups ............................................................................................. 809
9.7.4 | Chronic opioid use and perioperative outcomes ........................................ 812
9.7.5 | Chronic opioid use and sleep-disordered breathing ................................... 813
9.7.6 | Assessment and management of acute pain .............................................. 814
9.8 | The patient with a substance use disorder ......................................................... 824
9.8.1 | CNS-depressant drugs ................................................................................. 825
9.8.2 | CNS-stimulant drugs .................................................................................... 829
9.8.3 | Drugs used in the treatment of addiction disorders ................................... 830
9.8.4 | The therapeutic relationship and behavioural management ...................... 834
9.8.5 | Assessment including screening for risk of opioid use disorderand mitigation strategies............................................................................. 835
9.8.6 | Transition to community care ..................................................................... 836
9.8.7 | Patients in recovery from substance use disorders .................................... 836
9.8.8 | Acute pain in pregnant patients with an opioid use disorder ..................... 837
References .................................................................................................................. 840
10.0 | PAEDIATRIC VOLUME II ............................................................................................. 882
10.1 | Developmental neurobiology of pain ............................................................... 885
10.2 | Consequences of early pain and injury ............................................................. 888
10.2.1 | Early neurodevelopmental consequences ................................................ 888
10.2.2 | Longer term consequences of early pain and injury ................................. 889
10.2.3 | Modification by pain management intervention ...................................... 890
10.3 | Paediatric pain assessment ............................................................................... 891
10.3.1 | Pain assessment in neonates .................................................................... 891
10.3.2 | Pain assessment in infants and children ................................................... 895
10.3.3 | Self-report in children and adolescents .................................................... 896
10.3.4 | Children with cognitive impairment or intellectual disability ................... 899

5th Edition | Acute Pain Management: Scientific Evidencexxi10.4 | Analgesic agents ............................................................................................... 907
10.4.1 | Paracetamol (acetaminophen) .................................................................. 907
10.4.2 | Nonselective NSAIDs ................................................................................. 918
10.4.3 | Coxibs ........................................................................................................ 926
10.4.4 | Conventional and atypical opioids ............................................................ 928
10.4.5 | Discharge opioid prescribing for children ................................................. 947
10.4.6 | Opioid tolerance in children and adolescents ........................................... 956
10.4.7 | Systemic NMDA-receptor antagonists ...................................................... 959
10.4.8 | Alpha-2 agonists ........................................................................................ 965
10.4.9 | Alpha-2-delta ligands (gabapentinoids) .................................................... 971
10.4.10 | Corticosteroids ........................................................................................ 973
10.4.11 | Systemic lidocaine infusions .................................................................... 976
10.5 | Opioid infusions and Patient Controlled Analgesia (PCA) in children ............... 977
10.5.1 | Opioid infusions......................................................................................... 977
10.5.2 | Patient-controlled analgesia (PCA) ............................................................ 979
10.5.3 | Nurse-controlled analgesia ....................................................................... 982
10.5.4 | PCA by proxy ............................................................................................. 983
10.5.5 | Overall safety of parenteral opioid use in children ................................... 984
10.6 | Paediatric Regional Analgesia ........................................................................... 986
10.6.1 | Peripheral nerve blocks and catheters ...................................................... 986
10.6.2 | Specific peripheral nerve blocks and catheters ......................................... 990
10.6.3 | Neuraxial blocks ...................................................................................... 1000
10.6.4 | Intrathecal opioids .................................................................................. 1017
10.6.5 | Topical therapies ..................................................................................... 1018
10.6.6 | Use of Paediatric Regional Analgesia (PRA) in SpecificPaediatric Surgical Procedures .................................................................. 1019
10.7 | Management of procedural pain in children ................................................... 1031
10.7.1 | Procedural pain in the neonate ............................................................... 1031
10.7.2 | Procedural pain in infants and older children ......................................... 1036
10.7.3 | Vaccine injection pain in infants and children ......................................... 1048
10.7.4 | Procedural pain management in the emergency department ................ 1055
10.7.5 | Nonpharmacological strategies in children and adolescents .................. 1059
10.8 | Acute pain in children with cancer .................................................................. 1064
10.8.1 | Cancer-related pain ................................................................................. 1064
10.8.2 | Procedure-related pain ........................................................................... 1066
10.8.3 | Treatment-related pain ........................................................................... 1067

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10.9 | Other acute pain conditions in children .......................................................... 1071
10.9.1 | Management of pain due to trauma and burns in children .................... 1071
10.9.2 | Management of acute burn injury in children ........................................ 1076
10.9.3 | Paediatric migraine ................................................................................. 1081
10.9.5 | Acute pain associated with haematological disorders in children .......... 1086
10.10 | The overweight or obese child or adolescent ................................................ 1092
10.10.1 | Definitions of obesity ............................................................................ 1092
10.10.2 | Prevalence of childhood obesity ........................................................... 1092
10.10.3 | Morbidity associated with paediatric obesity ....................................... 1092
10.10.4 | Medication dosing in paediatric obesity ............................................... 1093
10.10.5 | Weight/mass adjusted dosing for individual drugs ............................... 1094
10.11 | Complementary and alternative medicines and therapies in children ......... 1096
10.11.1 | Natural products ................................................................................... 1096
10.11.2 | Acupuncture .......................................................................................... 1097
10.11.3 | Mind-body practices.............................................................................. 1098
10.11.4 | Infantile colic ......................................................................................... 1099
References ................................................................................................................ 1102
APPENDIX A: THE EDITORIAL WORKING PARTY AND CONTRIBUTORS ............................... 1176
APPENDIX B: PROCESS REPORT ......................................................................................... 1192
ACRONYMS AND ABBREVIATIONS ..................................................................................... 1206
INDEX ..................................................................................................................................... i1

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List of tables
Review and revision of key messages ............................................................................................ix
Table 1.1 | Examples of receptors and ligands that function in transduction
or primary and secondary hyperalgesia of nociceptive primary afferentor spinal cord neurons ................................................................................................ 4
Table 1.2 | Incidence of chronic pain after surgery ................................................................... 22
Table 1.3 | Risk factors for chronic postsurgical pain ................................................................ 27
Table 1.4 | Definitions of pre-emptive and preventive analgesia .............................................. 33
Table 1.5 | Metabolic immunological and endocrine responses to injury ................................. 40
Table 2.1 | Fundamentals of a pain history ................................................................................ 65
Table 3.1 | Possible benefits of an acute pain service ............................................................... 92
Table 3.2 | Definitions of health economic assessment measures ............................................ 95
Table 5.1 | Table of analgesic efficacy (in all types of surgery) ................................................ 289
Table 5.2 | Recommendations for timing of antithrombotic or antifibrinolytic
administration in relation to neuraxial blockade .................................................... 366
Table 5.3 | Dosing of prophylactic LMWH in renal impairment ............................................... 370
Table 8.1 | Taxonomy of acute pain associated with spinal cord injury pain .......................... 513
Table 8.2 | Aetiology of acute pain in the ICU ......................................................................... 603
Table 8.3 | Barriers to effective pain management in the ICU ................................................ 604
Table 8.4 | Factors that influence the provision of prehospital analgesia and the
direction of this influence ..................................................................................... 624
Table 9.1 | TGA medicine categorisation according to fetal risk ............................................. 715
Table 9.2 | Categorisation of medicines used in pain management ........................................ 716
Table 9.3 | The breastfeeding patient and medications used in pain management ............... 748
Table 9.4 | Physiological changes in older people, resulting changes of pharmacokinetic
variables and consequences for pharmacological treatment ................................ 758
Table 9.5 | Barriers to effective Pain Management ................................................................. 775
Table 9.6 | Analgesic medicines in patients with renal impairment ........................................ 796
Table 9.7 | Analgesic medicines in patients with hepatic impairment .................................... 801
Table 9.8 | Definitions of relevant terms ................................................................................. 806
Table 9.9 | Pain-related assessment in opioid-tolerant patient .............................................. 816
Table 10.1 | Acute pain intensity measurement tools — neonates ........................................ 903
Table 10.2 | Composite scales for infants and children ........................................................... 904
Table 10.3 | Self-report tools for children ............................................................................... 905
Table 10.4 | Sample of observational pain assessment scales for intellectuallydisabled children .................................................................................................. 906
Table 10.5 | Suggested paracetamol dosing for infants and children ...................................... 910

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CONTENTS

Table 10.6 | Common nsNSAIDs and dosing recommendations in children ............................ 925
Table 10.7 | Coxib dosing recommendations in children ......................................................... 928
Table 10.8 | Opioid prescription data (USA) for children and adolescents including
subtypes of opioids and adverse events .............................................................. 935
Table 10.9 | Block height following caudal injection in children using different formulae ......1003
Table 10.10 | Incidence of adverse effects in large-scale audits of paediatricregional analgesia ............................................................................................ 1012
Table 10.11 | Dosing suggestions for common analgesics relevant to body weight ............. 1094

List of figures
Figure 1.1 | The main ascending and descending spinal nociceptive pathways .......................... 8
Figure 1.2 | The injury response.................................................................................................. 38
Figure 10.1 | Faces Pain Scale — Revised ................................................................................. 902

5th Edition | Acute Pain Management: Scientific EvidencexxvSummary of key messages
A description of the levels of evidence and associated symbols can be found in the Introduction(see pages vi to x).

1.0 | Physiology and psychology of acute pain
Applied physiology of acute pain
1. High pain-related fear avoidance beliefs in patients with back pain of less than 6 months
duration are associated with poor outcomes, which may be improved by treatment
approaches aimed at fear avoidance (U) (Level I [PRISMA]).
2. There is a significant association between high levels of catastrophising in acute andsubacute back pain and pain and disability at later points of time (U) (Level III-2 SR).
3. Psychological factors associated with poor postoperative pain control are in particularanxiety (state and trait) and catastrophising, but also expectation of pain, depression,negative affect and neuroticism/psychological vulnerability (S) (Level IV SR [PRISMA]).
4. There is significant association between anxiety, pain catastrophising (U) (Level III-2 SR),depression, psychological vulnerability and stress (U) (Level IV SR) and the subsequentdevelopment of chronic postsurgical pain.
5. Preoperative anxiety and depression are associated with an increased number of PCA
demands and dissatisfaction with PCA (U) (Level IV).
 Pain is an individual, multifactorial experience influenced by culture, previous pain events,
beliefs, mood and ability to cope (U).
Placebo and nocebo effects in acute pain
1. Responses to placebo across all clinical conditions are small but consistently positive. They
are more prominent, although highly variable in magnitude, in studies of pain (U) (Level I[Cochrane Review]).
2. Nocebo effects in studies of pain are of moderate to large size and of high variability (U)(Level I [PRISMA]).
3. Trials aimed at studying placebo effects demonstrate larger placebo effects than those
assessing responses in placebo-control groups (U) (Level I [QUOROM]).
4. Analgesic placebo effects are based upon multiple neurobiological mechanisms, including
involvement of endogenous opioid, cholecystokinin (U) (Level II), endogenous
cannabinoid systems (U)(Level III-1) and genotype (N) (Level III-2).
5. Analgesic placebo effects are based upon multiple psychological determinants including
expectancy, classical conditioning and social and observational learning (S) (Level II).
6. Placebo and nocebo effects have significant influence on the efficacy of analgesics (U)(Level II).
 Placebo effects are the consequence of the psychosocial context (or treatment ritual) on
the patient’s mind, brain and body (U).

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SUMMARY OF KEY MESSAGES Placebo effects occur in routine clinical care even when no traditional placebo is given.
The outcome of a treatment is attributable to both the treatment itself and the contextual(or placebo) component (U).
 Nocebo effects occur in routine clinical care and are seen as an increased pain response toa painful stimulus or the development of adverse effects not caused by, or separate from,the intervention (U).
 Ethical harnessing of placebo and minimisation of nocebo effects will improve response toclinical management interventions (U)Progression of acute to chronic pain
1. Perioperative IV ketamine reduces the incidence of chronic postsurgical pain in selected
procedures (S) (Level I [Cochrane Review]).
2. Following thoracotomy, epidural analgesia reduces the incidence of chronic postsurgical
pain (S) (Level I [Cochrane Review]).
3. Following breast cancer surgery, paravertebral block (S), local infiltration (N) (Level I[Cochrane Review]) and IV lidocaine reduce the incidence of chronic postsurgical pain (N)(Level I [PRISMA]).
4. For iliac crest bone graft harvest, continuous local anaesthetic infiltration reduces theincidence of chronic postsurgical pain (N) (Level I [Cochrane Review])
5. Pregabalin reduces the incidence of chronic postsurgical neuropathic pain, but does notaffect non-neuropathic chronic postsurgical pain (N) (Level I [PRISMA]).
6. Sparing of the intercostobrachial nerve during mastectomy does not decrease chest wall
hypersensitivity (U) (Level I [PRISMA]).
7. Cryoanalgesia of the intercostal nerves at the time of thoracotomy results in no
improvement in acute pain but an increase in chronic pain (U) (Level I).
8. There is significant association between anxiety, pain catastrophising (U) (Level III-2 SR),depression, psychological vulnerability and stress (U) (Level IV SR) and the subsequentdevelopment of chronic postsurgical pain.
9. Other risk factors that predispose to the development of chronic postsurgical pain include
the severity of presurgical chronic pain and postsurgical acute pain and intraoperative
nerve injury (U) (Level IV SR).
10. Spinal anaesthesia in comparison to general anaesthesia reduces the risk of chronic
postsurgical pain after hysterectomy and Caesarean section (U) (Level III-2).
11. Chronic postsurgical pain is common and may lead to significant disability (S) (Level IV).
12. Chronic postsurgical pain often has a neuropathic component (S) (Level IV).
 Gabapentin has no demonstrated effect in preventing chronic postsurgical pain;
considerable uncertainty exists regarding efficacy with contradictory meta-analyses of afew, usually small, studies with a large degree of heterogeneity (Q).
 Implementation of transitional pain services may help manage the complex issues of
prolonged postoperative opioid use and chronic postsurgical pain (N).

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Pre-emptive and preventive analgesia
Pre-emptive analgesia
1. The timing of opioid administration (preincision rather than postincision) may reduce
further opioid consumption over 24 h, but has no effect on pain scores (N) (Level I[Cochrane Review])
2. Pre-emptive use of paracetamol across a range of procedures reduces pain scores up to 2 h,opioid consumption for up to 24 h and postoperative nausea and vomiting (N) (Level I [PRISMA]).
3. Pre-emptive epidural analgesia has a significant effect on postoperative pain relief (S) (Level I).
Preventive analgesia
4. Epidural, regional and systemic local anaesthetic administration shows preventive
analgesic effects in reducing chronic postsurgical pain (S) (Level I [Cochrane Review])
5. NMDA-receptor antagonists (ketamine) reduce the incidence of chronic postsurgical pain
in selected procedures (S) (Level I [Cochrane Review]).
 In clinical trials assessing acute postoperative pain for many systemic medicines, the rangeof doses administered, the variable durations of follow-up and variable half-lives following
infusion or repeated dosing means that “early” preventive effects, although possible, aredifficult to discern from persistence of direct pharmacological effects (U).
Adverse physiological effects of acute pain
1. Recognition of the importance of postoperative rehabilitation including pharmacological,
physical, psychological and nutritional components has led to enhanced recovery (U)(Level I [PRISMA]).
 Acute pain and injury of various types are inevitably interrelated and, if severe andprolonged, the injury response becomes counterproductive and can have adverse effects
on outcome (U).
Adverse psychological effects of acute pain
1. Postoperative delirium is exacerbated by unrelieved acute pain and by overuse of
sedating analgesics, in particular opioids (N) (Level IV).
 Failure to relieve acute pain can lead to psychological distress (N).
Genetics and acute pain
1. CYP2D6 polymorphisms affect plasma concentrations of active metabolites of codeine,
oxycodone and tramadol with variable effects on analgesic efficacy (U) (Level II).
2. The mu opioid receptor OPRM1 polymorphism is unlikely to be clinically relevant as asingle gene mutation in Caucasian populations and is more likely to be of clinicalrelevance in Asian populations (U) (Level III-2 SR).
3. CYP2D6 ultrarapid metabolisers are at increased risk of codeine and tramadol toxicity (U)(Level IV).
 Genetic polymorphisms contribute to the wide interindividual variability in plasma
concentrations of a given dose of methadone (U).

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2.0 | Assessment and measurement of pain and pain treatment
Assessment
1. There is good correlation between the visual analogue and verbal numerical rating scales(S) (Level I).
2. Regular assessment of pain leads to improved acute pain management (U) (Level III-3).
3. Appropriate assessments (including screening tools) are required to determine thepresence of neuropathic pain (N) (Level III-2).
 Functional outcomes rather than pain scores alone should be used to guide acute pain
management, including non-pharmacological approaches (N).
 Self-reporting of pain should be used whenever appropriate as pain is by definition a
subjective experience (U).
 The pain measurement tool chosen should be appropriate to the individual patient andthe clinical context (eg intensive care, ward, community). Developmental, cognitive,
emotional, language and cultural factors should be considered (U).
 Scoring should incorporate different components of pain including the functional capacityof the patient. In the postoperative patient, this should include static (rest) and dynamic(eg pain on sitting, coughing) pain (U).
 Uncontrolled or unexpected pain requires a reassessment of the diagnosis andconsideration of alternative causes for the pain (eg new surgical/ medical diagnosis,
neuropathic pain) (U).
Outcome measures in acute pain management
1. Assessment of pain relief (with total pain relief [TOTPAR]) may be more sensitive totreatment effects than assessment of intensity (with summed pain intensity difference[SPID]) (N) (Level I [PRISMA]).
 Multiple outcome measures are required to adequately capture the complexity of thepain experience and how it may be modified by pain management interventions (U).

3.0 | Provision of safe and effective acute pain management
Education
1. There is no good evidence in favour of general education for acute neck pain having
significant effects on any relevant outcomes (U) (Level I [Cochrane Review]).
2. Short educational interventions in acute whiplash injury reduce pain and disability andenhance recovery and mobility (U) (Level I [PRISMA])
3. There is limited evidence that preoperative education may lead to small improvements inpostoperative outcomes such as pain, preoperative and postoperative anxiety, but not in
analgesic requirements (Q) (Level I [PRISMA]).

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4. General “biomedical” education in patients with acute back pain does not reduce pain or
improve other outcomes (S) (Level I); however, education using a “biopsychosocial/
neuroscience” approach reduces a composite of anxiety, fear, worry, distress andhealthcare utilisation (N) (Level I [PRISMA]).
5. Targeted reassurance in acute back pain by physicians in primary care can result in
improved changes in psychological factors such as fear, worry, anxiety, catastrophisationand healthcare utilisation (U) (Level I [PRISMA].
6. Preoperative education improves patient or carer knowledge of pain and encourages amore positive attitude towards pain relief (U) (Level II).
7. Specific pain neuroscience education in specific surgical settings may result in lesshealthcare utilisation (U) (Level II).
8. Written information given to patients is better than verbal information given at the timeof the interview (S) (Level II).
9. Educational interventions in cancer pain patients improve knowledge, attitudes and pain
control (U) (Level III-1 SR).
10. While evidence for the benefit of patient education in terms of better pain relief isinconsistent, structured preoperative education may be better than routine information(U) (Level III-2).
11. Staff education and the use of guidelines improve pain assessment, pain relief andprescribing practices (S) (Level III-3).
12. Pain psychoeducation undertaken before surgery (pre-emptive) or throughout theperioperative period (preventive) is an underutilised component of multimodal analgesia
which may reduce pain intensity, analgesic use, length of stay, return to the emergency
department, patient anxiety and possibly chronic postsurgical pain (N) (Level IV SR).
13. Pain score documentation improves with various forms of nursing education, but the impact of
this behaviour change has not been adequately assessed (N) (Level IV SR).
14. Pain medicine education in medical school curricula is restricted in scope and content (N)(Level IV SR).
 Successful management of acute pain requires close liaison between all personnel
involved in the care of the patient (U).
 More effective acute pain management will result from appropriate education andorganisational structures for the delivery of pain relief rather than the analgesic
techniques themselves (U).
Organisational requirements
1. Implementation of an acute pain service may improve pain relief and reduce the incidenceof adverse effects (U) (Level III-3).
2. Even “simple” techniques of pain relief can be more effective if attention is given to
education, documentation, patient assessment and provision of appropriate guidelines andpolicies (U) (Level III-3).

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3. Implementation of root-cause analysis to follow up critical incidents improved the safety ofpatients under care of an acute pain service (U) (Level III-3).
 Successful management of acute pain requires close liaison between all personnel
involved in the care of the patient (U).
 More effective acute pain management will result from appropriate education andorganisational structures for the delivery of pain relief rather than the analgesic
techniques themselves (U).
 Appropriate institutional support and engagement is important for the effective
implementation of an acute pain service (U).
 Procedure-specific analgesic protocols can help optimise analgesia for the individual
patient while reducing adverse effects (U).
 The adoption of individualised care pathways (eg SCAMPS) can improve patient outcomes
and reduce clinical variation (N).
 The benefit of an acute pain service can be enhanced when acute pain management is
integrated into the pre, intra and postoperative periods (N).
 The recruitment of patients ‘at-risk’ for persistent pain and/or excessive opioid use into a
post-discharge treatment service for early review can improve outcomes (N).
 Appropriately designed, implemented and integrated Electronic Medical Records (EMR)
can improve the standards of clinical care (N).
Economic considerations in acute pain management
1. Long term economic consequences from the progression of acute to chronic postsurgicaland post-traumatic pain can be significant (S) (Level IV).
2. Strategies to optimise acute and subacute pain management (including involvement oftransitional pain services) may reduce the economic burden of chronic pain andinappropriate prescription opioid use (N) (Level IV).
3. The early pattern of prescription opioid use after surgery may increase the risk of chronic
use with significant direct and indirect economic costs (N) (Level IV).
4. Patients’ willingness to pay for good pain relief is high (S) (Level IV).
5. Costs from PCA errors can be considerable; the most common high cost errors arise fromstaff communication error and operator error (S) (Level IV).
 There are different measures of economic assessment and analysis used in healthcare; noone method is the most appropriate (U).
 Prescription drug monitoring may reduce the economic burden through its impact oninappropriate opioid prescribing (N).

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4.0 | Analgesic medicines
Paracetamol
1. Paracetamol is an effective analgesic for acute pain; the incidence of adverse effects iscomparable to placebo (U) (Level I [Cochrane Review]).
2. Paracetamol given in addition to PCA opioids reduces opioid consumption but does not
result in a decrease in opioid-related adverse effects (U) (Level I).
3. Hepatotoxicity with therapeutic doses of paracetamol is extremely rare (U) (Level IV) andnot associated with alcohol consumption (U) (Level I [PRISMA]).
 Emerging evidence suggests that maternal paracetamol use may influence premature
closure of the fetal ductus arteriosus (N).
Nonselective NSAIDs and coxibs
Efficacy of systemic NSAIDs
1. Nonselective NSAIDs are effective in the treatment of acute postoperative pain, renal colic,migraine, primary dysmenorrhoea (S) (Level I [Cochrane Review]), acute muscle injury (N) (Level
I [PRISMA]), chronic low-back pain (U) (Level I [PRISMA]) and acute ankle sprain (U) (Level I).
2. Coxibs are as effective as nonselective NSAIDs in the treatment of acute pain (including
postoperative pain) (S) (Level I [Cochrane Review]), chronic low-back pain (U) (Level I[PRISMA]) and osteoarthritis of the knee (N) (Level I [PRISMA]).
3. Nonselective NSAIDs given in addition to paracetamol improve analgesia compared witheither medicine given alone (S) (Level I), in particular ibuprofen combined with paracetamol(U) (Level I [Cochrane Review]).
4. The risk-benefit ratio for coxibs as a discharge medication after orthopaedic surgery issuperior to that for nonselective NSAIDs (U) (Level I [PRISMA]).
5. Nonselective NSAIDs given in addition to PCA opioids reduce opioid consumption and theincidence of nausea and vomiting (U) (Level I).
6. Coxibs given in addition to PCA opioids reduce opioid consumption but do not result in adecrease in opioid-related adverse effects (U) (Level I), except after total knee arthroplasty,
where they reduce pain scores and adverse effects and improve outcomes (U) (Level I).
7. Celecoxib given as a single pre-operative dose is effective at reducing opioid usage, painscores at 24 hours and postoperative nausea and vomiting (N) (Level I).
Adverse effects of systemic NSAIDs
8. In patients with normal preoperative renal function nonselective NSAIDs slightly increase
serum creatinine, but effects on acute kidney injury and need for renal replacement
therapy are uncertain due to lack of evidence (W) (Level I [Cochrane Review]).
9. Nonselective NSAIDs may increase the risk of any bleeding-related outcome after
tonsillectomy in adults (U) (Level I); however, not in paediatric patients (U) (Level I[Cochrane Review]) except in a large non-inferiority RCT where need for surgicalintervention was increased with ibuprofen versus paracetamol (Q) (Level II). There is anincrease in bleeding complications with aspirin in adults and children (U) (Level I) and withketorolac in adults only (U) (Level III-2 [PRISMA]).

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10. Nonselective NSAIDS, but not coxibs, may cause bronchospasm in individuals known tohave NSAID-exacerbated respiratory disease (U) (Level I [PRISMA]).
11. Coxibs and nonselective NSAIDs exert individual (non-class) adverse effects on the
cardiovascular system with rofecoxib appearing to be worse than other coxibs andnonselective NSAIDs (N) (Level I). Celecoxib is no worse than naproxen or ibuprofen (N)(Level II) and better than ibuprofen when combined with aspirin (N) (Level II).
12. Short-term use of parecoxib (S) (Level I) and other NSAIDs (U) (Level III-2) compared withplacebo does not increase the risk of cardiovascular adverse effects after noncardiac
surgery.
13. Use of parecoxib followed by valdecoxib after coronary artery bypass graft surgery
increases the incidence of cardiovascular and cerebrovascular effects and is therefore
contraindicated (U) (Level I).
14. Perioperative nonselective NSAIDs may increase the risk of minor and major bleeding after
surgery compared with placebo (W) (Level I).
15. Coxibs do not impair platelet function and are not associated with increased perioperative
blood loss (S) (Level I).
16. In patients with normal renal function, parecoxib perioperatively does not increase renal
failure (N) (Level I).
17. NSAIDs hasten bowel recovery after colorectal surgery (N) (Level I).
18. With regard to renal function, celecoxib and naproxen are safer than ibuprofen with longterm use (N) (Level II).
19. Short-term use (5–7 days) of coxibs results in gastric ulceration rates similar to placebo andlower than nonselective NSAIDs (U) (Level II).
20. The cardiovascular protective effects of low-dose aspirin are reduced by concomitantadministration of some NSAIDs, in particular ibuprofen (S) (Level II).
21. Nonselective NSAIDs, but not coxibs increase the risk of anastomotic leak after colorectal
surgery (N) (Level III-2).
22. Short term use of ketorolac or ibuprofen do not increase bone healing complications inchildren undergoing posterior spinal fusion, osteotomy, or fractures managed surgically(S) (Level III-3) or conservatively (N) (Level III-3).
23. Chronic administration of nsNSAIDs or coxibs is associated with an increased risk of renal
impairment (N) (Level III-3 SR).
 The risk of adverse renal effects of nonselective NSAIDs and coxibs may be increased in thepresence of factors such as pre-existing renal impairment, hypovolaemia, hypotension anduse of other nephrotoxic agents including angiotensin-converting enzyme inhibitors (W).
Nonsystemic administration of NSAIDs
1. Topical NSAIDs are effective in treating acute strains, sprains or sports injuries withsystemic adverse effects comparable to placebo; gel formulations show superior efficacy
over creams (S) (Level I [Cochrane Review]).

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2. Topical NSAIDs are of limited analgesic efficacy for traumatic corneal abrasions, but reduce
rescue analgesia requirements (W) (Level I [Cochrane Review]).
3. Topical NSAIDs reduce anterior chamber inflammation and thereby pain after cataract
surgery (N) (Level I [PRISMA]).
4. The efficacy of NSAIDs for peri- or intra-articular injection as a component of local
infiltration analgesia compared with systemic administration remains unclear (U) (Level I[PRISMA]).
5. Intra-articular nonselective NSAIDs may provide more effective analgesia following
arthroscopy than intravenous administration (U) (Level I).
6. Mucosal administration of flurbiprofen provides long-lasting pain relief for sore throat (N)(Level II).
Opioids
Systemic opioids
1. Dextropropoxyphene has low analgesic efficacy (U) (Level I [Cochrane Review]).
2. Tramadol is an effective treatment for neuropathic pain (S) (Level I [Cochrane Review]).
3. Droperidol, metoclopramide, ondansetron, tropisetron, dolasetron, dexamethasone,
cyclizine, granisetron (U) (Level I [Cochrane Review]), supplemental crystalloid infusions(N) (Level I [Cochrane Review]), palonosetron and mirtazapine (N) (Level I [PRISMA]) are
effective in the prevention of postoperative nausea and vomiting.
4. PC6 acupoint stimulation by multiple techniques reduces postoperative nausea andvomiting (S) (Level I [Cochrane Review]).
5. Neurokinin-1 receptor antagonists aprepitant (S) (Level I [PRISMA]) and fosaprepitant (U)(Level II) are effective in the prevention of postoperative nausea and vomiting.
6. Intraoperative administration of the long acting opioid methadone reduces consumptionof shorter acting opioids in the 24 hours after surgery (N) (Level I [PRISMA]). Safety datasuggest an increased risk of opioid induced ventilatory impairment due to the long andunpredictable half-life of methadone (N) (Level IV).
7. Opioids in high doses, in particular remifentanil, can induce hyperalgesia and/or acute
tolerance (S) (Level I [PRISMA]).
8. Propofol (U) (Level I [PRISMA]), NMDA-receptor antagonists (U) (Level I [QUOROM]),
pregabalin (U) (Level II), nitrous oxide (N) (Level II) and gradual tapering of remifentanil
dose (N) (Level II) attenuate acute tolerance and/or hyperalgesia induced by remifentanil.
9. NSAIDs, gabapentin, pregabalin, systemic lidocaine and ketamine are opioid-sparing
medications and reduce opioid-related adverse effects (S) (Level I [PRISMA]).
10. Paracetamol given preoperatively and intraoperatively reduces postoperative nausea andvomiting; this effect is associated with improved analgesia, not reduced opioid
requirements (S) (Level I [PRISMA]).
11. Opioid antagonists (methylnaltrexone, naloxone, naloxegol, alvimopan, axelopran, or
naldemedine) are effective (more so than laxatives) and safe to treat opioid-induced
constipation (S) (Level I [PRISMA]).

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12. Alvimopan is an effective treatment for postoperative ileus (U) (Level I [QUOROM]).
13. Haloperidol, perphenazine and transdermal scopolamine are effective in the preventionof postoperative nausea and vomiting (U) (Level I).
14. The incidence of clinically meaningful adverse effects (nausea, vomiting) of opioids isdose-related (U) (Level I).
15. Paired combinations of 5HT3 antagonists, droperidol or dexamethasone provide superior
prophylaxis of postoperative nausea and vomiting than either compound alone (U) (Level I).
16. Naloxone, naltrexone, droperidol (U), nalbuphine (S) (Level I) and ondansetron (N) (Level I[PRISMA]) are effective treatments for opioid-induced pruritus.
17. Opioids administered by PCA, in particular morphine, show higher analgesic efficacy infemales than in males (U) (Level I).
18. Tapentadol has similar efficacy to conventional opioids with a reduced rate ofgastrointestinal adverse effects (nausea, vomiting, constipation) (S) (Level I).
19. Tramadol has a lower risk of respiratory depression and impairs gastrointestinal motor
function less than other opioids at equianalgesic doses (U) (Level II).
20. Pethidine is not superior to morphine or hydromorphone in treatment of pain of renal
colic (U) (Level II).
21. Morphine-6-glucuronide is an effective analgesic (U) (Level II).
22. In the management of acute pain, one opioid is not superior to others but some opioids
are better in some patients (U) (Level II).
23. High doses of methadone can lead to prolonged QT interval (U) (Level II).
24. Opioid antagonists are effective treatments for opioid-induced urinary retention (U)(Level III-1).
25. Pethidine use is associated with an increased risk of delirium in the postoperative period
compared to other opioids (S) (Level III-2 SR).
26. In clinically relevant doses, there is a ceiling effect for respiratory depression withbuprenorphine but not for analgesia (U) (Level III-2).
27. Tapentadol has lower rates of abuse and doctor shopping than oxycodone (S) (Level III-2).
28. Opioid-related adverse effects in the postoperative period are associated with increased
inpatient mortality, length of hospital stay, costs and rates of readmission (S) (Level III-2).
29. Assessment of sedation is a more reliable way of detecting early opioid-induced
ventilatory impairment than a decreased respiratory rate (S) (Level III-3).
30. The evidence for significant QT prolongation and risk of cardiac arrhythmias following
low-dose droperidol, haloperidol and dolasetron is weak (U) (Level III-3).
31. Opioid-induced ventilatory impairment occurs in particular in the first 24 h after surgery
and important risk factors are cardiac and pulmonary disease, obstructive sleep apnoea
and use of higher opioid doses (N) (Level IV SR [PRISMA]).

5th Edition | Acute Pain Management: Scientific Evidencexxxiii32. Continuous pulse oximetry in patients receiving opioids postoperatively increases
detection rate of desaturation, but continuous capnography is superior in identifying
episodes of opioid-induced ventilatory impairment (N) (Level IV SR [PRISMA]).
33. In adults, patient age rather than weight is a better predictor of opioid requirements,
although there is a large interpatient variation (U) (Level IV).
34. Impaired renal function and the oral route of administration result in higher levels of themorphine metabolite morphine-6-glucuronide with increased risk of sedation andrespiratory depression (U) (Level IV).
34. CYP2D6 ultrarapid metabolisers are at increased risk of codeine toxicity (N) (Level IV).
 Opioid-induced ventilatory impairment is a more appropriate term to describe the effects
of opioids on ventilation as it encompasses the central respiratory depression caused by
opioids and also the depressed consciousness and the subsequent upper airway
obstruction resulting from excessive opioid use (U).
 The use of pethidine and dextropropoxyphene should be discouraged in favour of otheropioids (S).
 Drug interactions relevant for opioids include pharmacodynamic considerations (egcoadministration of sedative agents) and pharmacokinetic effects (eg CYP 450 enzyme
inducers or inhibitors [antidepressants for CYP2D6 and antifungals, antibiotics for CYP3A4
and complementary medicines for both]) (N).
Neuraxial opioids
Intrathecal opioids
1. Intrathecal morphine and intrathecal fentanyl prolong spinal local anaesthetic block, withfentanyl being associated with fewer adverse effects (U) (Level I [PRISMA]).
2. Intrathecal morphine produces better postoperative analgesia than intrathecal fentanyl or
sufentanil after Caesarean section (U) (Level I).
3. Intrathecal morphine doses of 300 mcg or more increase the risk of respiratory depression(U) (Level I).
Epidural opioids
4. Epidural morphine provides similar analgesia to epidural fentanyl when combined with local
anaesthetic, although the incidence of nausea is greater with morphine (U) (Level I[PRISMA]).
5. Extended-release epidural morphine provides analgesia for up to 48 hours (U) (Level II),
however it is associated with more respiratory depression than intravenous PCA following
abdominal surgery (U) (Level I).
6. Epidural pethidine produces better pain relief and less sedation than intravenous pethidine
after Caesarean section (U) (Level II).
 No neurotoxicity has been shown at normal clinical intrathecal doses of morphine,fentanyl and sufentanil (U).
 Neuraxial administration of bolus doses of hydrophilic opioids carries an increased risk ofdelayed sedation and respiratory depression compared with lipophilic opioids (U).

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Peripheral opioids
1. Intra-articular morphine (1 mg) following knee arthroscopy does not improve analgesia
compared with placebo (S) (Level I [Cochrane Review]).
2. Intra-articular morphine/bupivacaine following knee arthroscopy compared to bupivacaine
alone improves analgesia without increasing adverse effects (N) (Level I [PRISMA]).
3. Perineural buprenorphine/local anaesthetic for peripheral nerve blocks compared to local
anaesthetic and to systemic buprenorphine/local anaesthetic prolongs duration ofanalgesia (N) (Level I [PRISMA]).
4. Perineural tramadol/local anaesthetic for brachial plexus block compared to local
anaesthetic alone prolongs duration of analgesia (N) (Level I [PRISMA]).
5. Peripherally applied opioids (excluding intra-articular, perineural and mucosal
administration) show no clinically relevant analgesic effect (N) (Level I [PRISMA]).
6. Intra-articular tramadol/bupivacaine following knee arthroscopy compared to bupivacaine
alone improves analgesia without increasing adverse effects (N) (Level I).
7.

Morphine mouthwash may have analgesic effects in chemotherapy-induced mucositis (N)(Level II).

8.

Evidence for intra-articular analgesic administration is inconclusive for temporomandibular
joint arthrocentesis (N) (Level IV SR [PRISMA]).

Local anaesthetics and other membrane stabilisers
Systemic local anaesthetics and membrane stabilisers
1. Perioperative intravenous lidocaine reduces pain and opioid requirements to a limited
extent following a range of surgery types, as well as nausea, but not vomiting, incidence
and duration of ileus and length of hospital stay (W) (Level I [Cochrane Review]).
2. In breast surgery, perioperative lidocaine infusion does not improve pain scores for up to
72 hours, but is associated with lower acute opioid requirements and less chronic
postsurgical pain at 3 to 6 months (N) (Level I [PRISMA])
3. Perioperative intravenous lidocaine has a preventive analgesic effect (extending beyond
5.5 half-lives of lidocaine, ie > 8 hrs after cessation of administration) after a wide range of
operations (U) (Level I).
4. Both intravenous lidocaine and mexiletine are effective in the treatment of chronic
neuropathic pain (U) (Level I [Cochrane Review]); however, guidelines advise against theuse of mexiletine for this indication (N) (GL Level I [PRISMA]).
5. Perioperative IV lidocaine reduces chronic postsurgical pain at 3 months compared toplacebo (N) (Level I [PRISMA]).
 The optimal and safe dose and duration of perioperative intravenous lidocaine infusions
has yet to be clearly established (N).
 Based on the experience in chronic neuropathic pain states, it would seem reasonable touse membrane stabilisers including systemic lidocaine in the management of acuteneuropathic pain (U).

5th Edition | Acute Pain Management: Scientific Evidencexxxv The role and safety of IV lidocaine for analgesia in the emergency department still requires
clarification (N).
Regional local anaesthetics
1. Lidocaine intrathecal is more likely to cause transient neurologic symptoms thanbupivacaine, prilocaine and procaine (S) (Level I [Cochrane Review NMA]).
2. Local anaesthetics have chondrotoxic effects on articular cartilage, with ropivacaine theleast toxic (N) (Level I [PRISMA]).
3. Wound infiltration with liposomal preparations of bupivacaine is no more effective thanropivacaine or plain bupivacaine for analgesic outcomes up to 48 hours (N) (Level I[PRISMA]).
4. The quality of epidural analgesia with local anaesthetics is improved with the addition of
opioids (U) (Level I).
5. Ultrasound guidance reduces the risk of vascular puncture during the performance ofregional blocks (S) (Level I).
6. Local anaesthetic systemic toxicity is reduced by the use of ultrasound guidance for regional
anaesthesia (S) (Level I).
7. Continuous perineural infusions of lidocaine result in less effective analgesia and more
motor block than long‐acting local anaesthetic agents (U) (Level II).
8. There are no consistent differences between ropivacaine, levobupivacaine and bupivacaine
in terms of quality of analgesia or motor block, when given in low doses for regional
analgesia (epidural and peripheral nerve block) (U) (Level II).
9. Cardiovascular and central nervous system toxicity of the stereospecific isomers ropivacaine
and levobupivacaine is less severe than with racemic bupivacaine (U) (Level II).
10. Local anaesthetic systemic toxicity is increased in paravertebral and upper limb blocks, withthe use of lidocaine and higher doses of local anaesthetics (U) (Level IV).
11. Lipid emulsion is effective in resuscitation of circulatory collapse due to local anaesthetic
toxicity (S) (Level IV SR); however, uncertainties relating to dosage, efficacy and adverse
effects still remain; therefore, it is appropriate to administer lipid emulsion only once
ventilatory support has begun and convulsions are controlled (S) (Level IV).
 Case reports following accidental overdose with ropivacaine, levobupivacaine andbupivacaine suggest that resuscitation is less likely to be successful with bupivacaine (U).
Inhalational agents
1. Nitrous oxide has some analgesic efficacy in labour pain (U), increases maternal adverse
effects (nausea, vomiting, dizziness) (U), with no adverse effects on the newborn (U) (Level I[Cochrane Review]) and increases maternal satisfaction compared to pethidine and epidural
analgesia (U) (Level IV SR).
2. Nitrous oxide has equivalent effectiveness and more rapid recovery compared withintravenous sedation in patients having lower gastrointestinal endoscopy (U) (Level I).

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3. Methoxyflurane, in low doses, is an effective analgesic with rapid onset in the prehospitalsetting, and a range of procedures in the hospital setting (U) (Level II) with good safety data(S) (Level IV); it may have comparable efficacy to nitrous oxide (N) (Level I [NMA]), but isinferior to IV morphine and IN fentanyl (N) (Level III-2 SR).
4. Nitrous oxide is an effective analgesic agent in a variety of other acute pain situations(U) (Level II).
5. Intraoperative use of nitrous oxide reduces the incidence of chronic postsurgical pain in
Asian populations (N) (Level II).
6. Subacute combined degeneration of the spinal cord, myelopathy and generalised
demyelinating polyneuropathy are rare but potentially serious complications of nitrous
oxide use including in those abusing nitrous oxide (S) (Level IV SR).
7. Vitamin B12 deficiency (identified by vitamin B12 level 74 pmol/L and MCV >100 fL) and age
40 years are relevant risk factors in nitrous oxide neurotoxicity; total nitrous oxide
exposure may not be a risk factor (N) (Level IV SR).
8. Early supplementation with Vitamin B12 in subacute combined degeneration of the spinal
cord exacerbated by nitrous oxide use improves neurological recovery (N) (Level IV SR).
 In patients receiving nitrous oxide repeatedly, supplementation with vitamin B 12,
methionine and folic or folinic acid is a consideration, in particular in those with risk
factors (Q).
 If nitrous oxide is used with other sedative or analgesic agents, appropriate clinicalmonitoring should be used (U).
NMDA-receptor antagonists
Systemic NMDA-receptor antagonists
1. Perioperative IV ketamine reduces opioid consumption, pain intensity and postoperative
nausea and vomiting compared to placebo (S) (Level I [Cochrane Review]); similar
outcomes are achieved when ketamine is added to an opioid in a PCA pump (S) (Level I[PRISMA]).
2. Perioperative IV ketamine reduces the incidence of chronic postsurgical pain in selected
procedures (S) (Level I [Cochrane Review]).
3. NMDA-receptor antagonists reduce the development of acute tolerance/opioid-induced
hyperalgesia associated with remifentanil use (S) (Level I [PRISMA]).
4. IV ketamine reduces ischaemic pain intensity in critical limb ischaemia (N) (Level I [PRISMA]).
5. IV magnesium as an adjunct to morphine analgesia has an opioid-sparing effect andimproves pain scores (S) (Level I [PRISMA]).
6. IV magnesium is effective in treatment of acute migraine attacks (N) (Level I [PRISMA]).
7. IV ketamine is effective in the treatment of neuropathic pain following spinal cord injury(U) (Level I).
8. Morphine/ketamine compared with higher doses of morphine alone improves analgesia
and reduces sedation and postoperative nausea and vomiting in postoperative patients(U) (Level I).
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xxxvii9. IV ketamine does not increase intracranial pressure or reduce cranial perfusion pressurecompared to opioids (U) (Level I).
10. Perioperative dextromethorphan reduces opioid consumption and pain intensity
compared to placebo (N) (Level I)
11. Ketamine is a safe and effective analgesic in the prehospital setting (U) (Level II).
12. Ketamine reduces postoperative pain and opioid requirements in opioid-tolerant patients(S) (Level II).
13. IV magnesium extends the duration of sensory block with spinal anaesthesia and reduces
subsequent postoperative pain (N) (Level II).
 Increasing rates of ketamine abuse are reported, in particular from South-East Asia andChina (S).
 Ketamine toxicity leads to cognitive impairment and abuse to chronic organ toxicity(bladder, liver) (U).
Regional NMDA-receptor antagonists
1. Neuraxial magnesium reduces pain intensity and analgesic requirements after Caesarean
section (N) (Level I [PRISMA].
2. Oral topical magnesium or ketamine (as gargle or lozenge) reduce the incidence of
postoperative sore throat (N) (Level I [PRISMA].
3. Intra-articular magnesium improves analgesia after arthroscopic surgery compared toplacebo (N) (Level I [PRISMA].
4. Magnesium added to local anaesthetics in peripheral nerve blocks prolongs sensory blockand analgesic effects (N) (Level I [PRISMA].
5. Epidural ketamine (without preservative) added to opioid-based epidural analgesia
regimens improves pain relief without reducing adverse effects (U) (Level I).
6. Caudal ketamine in children, in combination with local anaesthetic or as the sole
medication, improved and prolonged analgesia with few adverse effects (U) (Level I).
 Variable results for regional and topical administration of ketamine and magnesium may
reflect systemic effects (N).
Antidepressant medicines
1. In chronic neuropathic pain and fibromyalgia, tricyclic antidepressants and serotonin–
noradrenaline-reuptake inhibitor are effective analgesics (W) and more effective thanselective serotonin-reuptake inhibitors (U) (Level I [Cochrane Review]).
2. Tricyclic antidepressants are effective in the treatment of chronic headaches (U)(Level I [PRISMA]).
3. Duloxetine is as effective as other first-line treatments for pain and disability ofosteoarthritis (U) (Level I).
4. Some antidepressants, in particular duloxetine, may be effective in the treatment ofchronic low-back pain (U) (Level I).

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5. Perioperative serotonin-noradrenaline reuptake inhibitors reduce acute pain and opioid
requirements in a limited number of studies (U) (Level II).
 Based on the experience in chronic neuropathic pain states, it would seem reasonable touse tricyclic antidepressants and serotonin–noradrenaline-reuptake inhibitors in the
management of acute neuropathic pain (U).
 To minimise adverse effects, it is advisable to initiate treatment with tricyclic
antidepressants at low doses (U).
Anticonvulsant medicines
1. Alpha-2-delta ligands (gabapentinoids) are the only anticonvulsants with proven efficacy
in the treatment of chronic neuropathic pain (S) (Level I [Cochrane Review]).
2. Pregabalin is the only anticonvulsant with proven but limited efficacy in chronic pain due
to fibromyalgia (S) (Level I [Cochrane Review]).
3. Perioperative alpha-2-delta ligands (gabapentinoids) reduce postoperative pain andopioid requirements, in particular after more painful surgery (Q) and reduce the incidenceof postoperative nausea and vomiting (S) as well as pruritus (S), but increase the risk ofsedation (S) and visual disturbances (N) (Level I [PRISMA]).
4. Overdose toxicity of alpha-2-delta ligands is increased when taken in combination withother agents that cause sedation, particularly opioids (N) (Level III-2).
5. Alpha-2-delta ligands have the potential for misuse and abuse, in particular in patientswith opioid use disorder or psychiatric comorbidity (N) (Level IV SR).
 Based on the experience in chronic neuropathic pain states, it would seem reasonable touse alpha-2-delta ligands in the management of acute neuropathic pain (U).
Alpha-2 agonists
Systemic alpha-2 agonists
1. Alpha-2 agonists such as clonidine are more effective than placebo in the management of
opioid-withdrawal symptoms (U) (Level I [Cochrane Review]).
2. The perioperative use of clonidine systemically (excluding transdermal administration)
does not reduce pain intensity (at 24 or 48 hours) (Q) (Level I) but reduces opioid
consumption and postoperative nausea and vomiting versus placebo (Q) (Level I[PRISMA]).
3. The perioperative use of the systemic dexmedetomidine reduces postoperative pain
intensity, opioid consumption and requirements for rescue analgesia (S) without effect on
postoperative nausea and vomiting (N) (Level I [PRISMA]).
4. The IV administration of dexmedetomidine combined with intrathecal local anaesthetic
prolongs time to first analgesic request (N) (Level I [PRISMA]).
Regional alpha-2 agonists
1. Neuraxial clonidine improves duration and quality of analgesia and is opioid sparing whenused as an adjuvant to neuraxial local anaesthetics (in particular after Caesarean section)(S) (Level I [PRISMA]) or to morphine (U) (Level I [PRISMA]), but increases the risk ofhypotension and sedation (N) (Level I [PRISMA]).
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2. Neuraxial dexmedetomidine improves duration and quality of analgesia when used as an
adjuvant to neuraxial local anaesthetics (S) (Level I [PRISMA]).
3. Intrathecal adrenaline (epinephrine) when combined with local anaesthetic, but not withintrathecal opioids, prolongs analgesia duration (U) (Level I [PRISMA]).
4. Dexmedetomidine when added to local anaesthetics for peripheral nerve blocks improves
duration and quality of analgesia, but is associated with increased hypotension andbradycardia (S) (Level I [PRISMA]).
5. Intra-articular clonidine reduces pain scores for 4 hours, need for rescue analgesia andincidence of nausea, but increases hypotension (N) (Level I [PRISMA])
6. Clonidine improves duration of analgesia and anaesthesia when used as an adjuvant tolocal anaesthetics for peripheral nerve and plexus blocks but is associated with increased
hypotension and bradycardia (U) (Level I).
7. Dexmedetomidine added to intravenous regional anaesthesia improves and prolongs
analgesia (U) (Level II).
8. Epidural adrenaline (epinephrine) in combination with a local anaesthetic improves thequality of postoperative thoracic epidural analgesia (U) (Level II).
 The benefits of perineural adjuvant administration of alpha-2-agonists over systemic
administration remains unclear (N).
Salmon calcitonin and bisphosphonates
1. Bisphosphonates reduce bone pain associated with metastatic breast cancer (U), multiple
myeloma (S) and Paget’s disease (N) (Level I [Cochrane Review]), but have no beneficial
effect for knee arthritis (N) (Level I).
2. Salmon calcitonin reduces pain and improves mobilisation in the acute phase after
osteoporosis-related vertebral compression fractures (U) (Level I [PRISMA]).
3. Bisphosphonates reduce pain in patients with CRPS Type 1 in the early phase of thedisease (N) (Level I).
4. Salmon calcitonin reduces acute, but not chronic, phantom limb pain (U) (Level II).
5. Pamidronate reduces pain associated with acute osteoporotic vertebral compression
fractures (U) (Level II).
Cannabis, cannabinoids and cannabimimetics
1. Adverse effects including dizziness, cognitive changes and psychiatric symptoms(eg psychosis) may limit the usefulness of cannabinoids in pain treatment (S) (Level I[Cochrane Review]).
2. Current evidence does not support the use of cannabinoids in acute pain management (S)(Level I [PRISMA]).
3. Smoking cannabis has short-term efficacy in neuropathic pain in patients with HIV/AIDS,
although potential study bias means that this is not recommended as routine treatment(Q) (Level I [PRISMA]).

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4. Cannabinoids appear to be mildly effective when used in the treatment of pain andspasticity associated with multiple sclerosis and HIV (W) (Level III-2 SR [PRISMA]).
5. Smoked cannabis increases the risk of acute coronary syndrome and chronic
cardiovascular disease (N) (Level IV SR).
Corticosteroids
Systemic corticosteroids
1. Mild increase in blood glucose concentration follows perioperative administration of
dexamethasone (S) (Level I [Cochrane Review]) and all corticosteroids (S) (Level I[PRISMA), particularly in patients with diabetes mellitus.
2. Perioperative administration of dexamethasone (N) (Level I [Cochrane Review]) and all
corticosteroids (N) (Level I [PRISMA]) does not increase the risk of infection.
3. Perioperative administration of dexamethasone reduces postoperative pain and opioid
requirements to a limited extent but also reduces nausea and vomiting, fatigue, andimproves the quality of recovery compared with placebo (U) (Level I [PRISMA]).
4. Preoperative dexamethasone appears to be more effective than intraoperative or
postoperative administration (U) (Level I [PRISMA]).
5. Perioperative corticosteroids do not increase the risk of impaired wound healing,
anastomotic leakage or postoperative haemorrhage (N) (Level I [PRISMA]).
6. A single dose of corticosteroids provides more effective and faster relief of pain from sorethroat than placebo (N) (Level I) and decreases incidence and severity of sore throat after
extubation when administered at induction (N) (Level I [PRISMA]).
7. Systemic dexamethasone reduces pain intensity and opioid requirements after spinal
anaesthesia (N) (Level I [PRISMA].
 As all adverse event data on corticosteroid use in surgical populations are based to date on
efficacy trials (with methodological differences), their long-term safety awaits further
evaluation (N).
Regional corticosteroids
1. For brachial plexus blocks, addition of dexamethasone to local anaesthetic prolongs theduration of sensory and motor block and improves postoperative analgesia with only very
limited benefits over systemic administration (S) (Level I [Cochrane Review]).
2. For transverse abdominis plane blocks, addition of dexamethasone to local anaesthetics
prolongs the duration of sensory block, improves postoperative analgesia and PONV withno comparison to systemic administration (N) (Level I [PRISMA]).
3. After spinal surgery, epidural steroid application intraoperatively by the surgeon provides
analgesic benefit up to 24 hours and reduces length of stay (N) (Level I [PRISMA]).
4. For acute radicular pain, lumbar epidural corticosteroid administration is effective forshort-term relief (S) (Level I [PRISMA]).
5. Subacromial injections of corticosteroids are superior to oral NSAIDs in treating rotator
cuff tendonitis (U) (Level I [QUOROM]).

5th Edition | Acute Pain Management: Scientific Evidencexli6. For peripheral nerve blocks, addition of dexamethasone to local anaesthetics prolongs theduration of sensory block and improves postoperative analgesia with only limited benefits
over systemic administration (N) (Level II).
7. For epidural analgesia, addition of dexamethasone improves postoperative analgesia andreduces opioid requirements (N) (Level II).
8. Addition of dexamethasone to intravenous regional anaesthesia with lidoocaine improves
analgesia for up to 24 hours (U) (Level II).
9. Addition of corticosteroid to periarticular injection of local anaesthetic does not improvepain relief or range of movement following total knee arthroplasty (U) (Level II).
10. Following knee joint arthroscopy, intra-articular steroids in combination with either local
anaesthetic or opioids reduce pain, analgesic consumption and duration of immobilisation(U) (Level II).
11. There is a risk of septic arthritis with intra-articular steroids (U) (Level IV).
12. Repeat epiudural steroid injections are associated with reduced bone mineral density andincreased risk of vertebral fractures (N) (Level IV SR).
 Concerns have been raised regarding the safety of epidural steroids (U).
 There is little data in humans regarding the neurotoxicity of perineural corticosteroids (N).
Other regional analgesic medicines
1. Intrathecal midazolam combined with a local anaesthetic improves and prolongs analgesia
and reduces postoperative nausea and vomiting (U) (Level I).
2. Intrathecal neostigmine improves perioperative and peripartum analgesia in combination
with other intrathecal medications (S) (Level I) but is associated with dose-dependentsignificant adverse effects, in particular nausea and vomiting (Q) (Level I).
3. Epidural neostigmine combined with local anaesthetics improves postoperative andperipartum analgesia without increasing the incidence of adverse effects (U) (Level I).
4. Epidural neostigmine combined with an opioid reduces the dose of epidural opioid that isrequired for analgesia (U) (Level I).
Complementary and alternative medicine
1. White willow bark (Salix alba) and devil's claw (Harpagophytum procumbens) are effectivein treating acute episodes of low back pain (U) (Level I [Cochrane Review])
2. A variety of complementary medicines may show efficacy in prevention and treatment ofprimary dysmenorrhoea based on very limited evidence (W) (Level I [Cochrane Review]),
including aromatherapy (N) (Level III-1 SR).
3. Curcuminoids and extracts of Zingiberaceae may reduce pain intensity in acute andchronic pain states compared to placebo (N) (Level I [PRISMA]).
4. Oral administration of honey versus control reduces postoperative pain and analgesic use
after tonsillectomy (N) (Level I [PRISMA]).

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5. Vitamin C reduces postoperative opioid requirements (N) (Level I [PRISMA] andpostoperative pain compared to placebo (N) (Level IV SR [PRISMA]).
6. Aromatherapy (N) (Level I), homeopathic preparations of arnica (Arnica montana) (U)(Level I [PRISMA]) and St John’s wort (Hypericum perforatum) are not effective in treating
acute postoperative pain (U) (Level I [QUOROM]).
7. St John’s wort (Hypericum perforatum) induces metabolism of oxycodone reducing its
plasma concentrations and efficacy (U) (Level II).
 There is some evidence that some complementary and alternative medicines may beeffective in some acute pain states. Adverse effects and interactions with medications
have been described with complementary and alternative medicines and must be
considered before their use (U).
 The evidence on complementary and alternative medicines is characterised by small
sample sizes and study designs prone to bias and caution is urged in interpreting results.
Additionally, the safety and potential drug interactions of many complementary andalternative medicines have not been adequately assessed (N).

5.0 | Administration of analgesic medicines
Oral and sublingual route
1. Oral combinations of paracetamol/ibuprofen provide superior analgesia toparacetamol/codeine; both combinations are more effective than the individual
medicines and have a dose-response effect (S) (Level I [Cochrane Review]).
2. Oral combinations of paracetamol/tramadol are more effective than the individual
medications and have a dose-response effect (U) (Level I).
3. NSAIDs given parenterally or rectally are not more effective and do not result in fewer
adverse effects than the same medicines given orally (U) (Level I).
4. The formulation of oral NSAIDs (eg fast acting [dispersible, solution or gel], sodium versus
potassium salt) can greatly affect their efficacy (N) (Level I).
5. Early postoperative oral administration of paracetamol results in highly variable plasma
concentrations that may remain subtherapeutic in some patients (U) (Level II). However, nodifference in clinical efficacy to intravenous administration is seen in hip and knee arthroplasty(N) (Level I), Caesarean section (N) (Level II) or laparoscopic cholecystectomy (N) (Level II).
 Other than in the treatment of severe acute pain, and providing there are nocontraindications to its use, the oral route is the route of choice for the administration ofmost analgesic medicines (U).
 Slow-release opioid preparations (particularly conventional opioids including transdermal
fentanyl and methadone) are not recommended in general for the management of acutepain in opioid-naïve patients due to difficulties in short-term dose adjustments needed fortitration, an increased risk of opioid-induced ventilatory impairment and risk of initiating
long-term use (S). In some patients with prolonged postoperative and post-traumaticacute pain states, the use of slow-release opioid preparations may be appropriate on ashort-term basis with preference for use of atypical opioids (N).
 Slow-release oral opioid preparations should only be given at set time intervals (U).
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xliiiIntravenous route
1. Intravenous paracetamol is more effective in reducing pain, opioid consumption and
PONV when given prior to versus after surgical incision (U) (Level I [PRISMA]).
2. The onset of analgesia is faster when NSAIDs are given intravenously for the treatment ofrenal colic (U) (Level I).
3. Continuous intravenous infusion of opioids in the general-ward setting is associated withan increased risk of respiratory depression compared with other methods of parenteral
opioid administration (U) (Level IV).
 Titration of opioids for severe acute pain is best achieved using intermittent intravenous
bolus doses as it allows more rapid titration of effect and avoids the uncertainty of
medicine absorption by other routes (U).
Intramuscular and subcutaneous route
1. Intermittent subcutaneous morphine injections are as effective as intramuscular
injections and have better patient acceptance (U) (Level II).
Transdermal route
1. Transdermal buprenorphine reduces postoperative pain with a low rate of adverse effects(N) (Level II).
2. Transdermal fentanyl (except for iontophoretic patient-controlled transdermal devices)
should not be used in the management of acute pain because of safety concerns anddifficulties in short-term dose adjustments needed for titration (S) (Level IV).
 Transdermal fentanyl preparations should not be used in opioid-naïve patients or in acutepain settings because of safety concerns and, in most countries, the lack of regulatory
approval for use in other than chronic pain in opioid-tolerant patients (S).
Transmucosal route
1. Intranasal, sublingual and buccal fentanyl preparations are effective treatments forbreakthrough pain in cancer patients (U) (Level I [Cochrane Review]) with similar efficacy
to IV administration (U) (Level I [PRISMA]) and superiority to oral morphine (U) (Level I).
2. Intranasal fentanyl is an effective treatment for paediatric acute pain management, withan acceptable adverse effect profile and ease of delivery (N) (Level I).
3. Intranasal fentanyl provides faster and better analgesia for breakthrough pain in cancer
patients than oral transmucosal fentanyl and fentanyl buccal tablets (U) (Level I).
4. Sublingual sufentanil delivered by a PCA device provided analgesia comparable to IV PCA
opioids in a number of acute pain settings (N) (Level II).
 Neither transmucosal immediate-release nor transdermal fentanyl preparations should be
used in the management of acute pain in opioid-naïve patients because of safety concerns
and, in most countries, the lack of regulatory approval for use in other than opioidtolerant patients (U).

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Epidural analgesia
1. For all types of surgery, epidural analgesia provides better postoperative pain relief
compared with parenteral (including PCA) opioid administration (S) (Level I [Cochrane
Review]); except epidural analgesia using a hydrophilic opioid only (U) (Level I).
2. Thoracic epidural analgesia for open abdominal aortic surgery reduces pain intensity, timeto tracheal extubation, time spent in the intensive care unit, rate of acute respiratory
failure, myocardial infarction and gastrointestinal bleeding when compared withintravenous opioids (S) (Level I [Cochrane Review]).
3. High thoracic epidural analgesia used for coronary artery bypass graft surgery reduces
postoperative pain, risk of dysrhythmias, pulmonary complications and time to extubation
when compared with intravenous opioid analgesia (Q) (Level I [Cochrane Review]).
4. Thoracic epidural analgesia for thoracotomy reduces the risk of chronic postsurgical pain (S)(Level I [Cochrane Review]).
5. Thoracic epidural analgesia improves bowel recovery after abdominal surgery (includingcolorectal surgery) (S) (Level I [Cochrane Review]).
6. Epidural analgesia is not associated with increased risk of anastomotic leakage after bowel
surgery (S) (Level I [Cochrane Review]).
7. Epidural analgesia provided with local anaesthetics for at least 24 hours compared tosystemic opioid analgesia reduces perioperative mortality and multiple morbidities(including ileus, pneumonia, respiratory depression and arrhythmias) but increases
hypotension (U) (Level I [PRISMA]).
8. After laparoscopic colectomy, thoracic epidural analgesia compared to intravenous PCA
reduces initial pain scores and time to first bowel opening, but length of hospital stay, total
rate of complications (S) (Level I [PRISMA]), urinary tract infection rates and hospital costs
are increased (U) (Level III-2).
9. Combinations of low concentrations of local anaesthetic agents and opioids for epidural
analgesia provide consistently superior pain relief compared with either of the medications
alone; epidural opioids alone have no advantage over parenteral opioids (U) (Level I).
10. Epidural local anaesthetic administration improves oxygenation and reduces pulmonary
infections and other pulmonary complications compared with parenteral opioids (U)(Level I).
11. Chlorhexidine‐impregnated dressings of epidural catheters in comparison to placebo‐ or
povidone‐iodine‐impregnated dressings reduce the incidence of catheter colonisation (U)(Level I).
12. In patients with multiple rib fractures, thoracic epidural analgesia improves pain relief
versus parenteral opioids (N) (Level III-2 SR), but does not reduce incidence of pneumonia
and mortality (U) (Level I) and may not reduce need for ventilation (Q)(Level III-2 SR).
13. The combination of thoracic epidural analgesia with local anaesthetics and nutritional
support leads to preservation of total body protein after upper abdominal surgery (U)(Level II).

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14. The incidence of permanent neurological damage in association with epidural analgesia is
extremely low, especially in the obstetric population, but increases with various
comorbidities and risk factors; the incidence is higher where there have been delays indiagnosing an epidural haematoma or abscess (S) (Level IV SR).
15. Immediate decompression of an epidural haematoma (within 8 hours of the onset ofneurological signs) increases the likelihood of partial or good neurological recovery (S)(Level IV SR).
16. Epidural abscesses present mainly with neurological deficits and back pain; they are
best diagnosed with early MRI and best treated with empiric antibiotics (until abscessculture) and immediate surgical decompression when neurological deficits are present (S)(Level IV SR).
 The provision of epidural analgesia by continuous infusion, programmed intermittent
bolus or patient-controlled administration of local anaesthetic-opioid mixtures is safe on
general hospital wards, as long as supervised by an anaesthesia-based pain service with
24-hour medical staff cover and monitored by well-trained nursing staff (U).
 Prior to insertion of an epidural catheter, thorough handwashing with surgical scrub
solution, the use of barrier precautions including the wearing of a cap, mask, sterile gown
and gloves and use of chlorhexidine in alcohol for skin preparation are recommended; but
meticulous care must be taken to avoid the chlorhexidine solution from reaching epiduralspace or cerebrospinal fluid (U).
Intrathecal analgesia
1. Intrathecal morphine improves analgesia and is opioid-sparing for up to 24 hours after
major surgery including abdominal (S), orthopaedic (N), spinal (N) (Level I [PRISMA]) andcardiothoracic surgery (N) (Level II).
2. Adding intrathecal morphine to intrathecal bupivacaine/fentanyl or intrathecal
bupivacaine/sufentanil prolongs pain relief after labour (N) (Level I [PRISMA]).
3. The addition of intrathecal fentanyl (N) (Level I [PRISMA]) and morphine to spinal
anaesthesia prolongs time to first analgesic request after Caesarean section (N) (Level I).
4. Intrathecal morphine in comparison to peripheral regional analgesia techniques offers
similar analgesic benefits, but increases adverse effects (nausea, vomiting, pruritus) after
lower limb arthroplasty (N) (Level I).
5. The incidence of opioid-induced ventilatory impairment, pruritus and postoperative
nausea and vomiting is higher with intrathecal morphine compared with intravenous PCA
opioids (S) (Level I).
6. Pruritus with intrathecal opioids is dose-dependent (N) (Level I) and can be effectively
prevented and treated with 5HT3 antagonists in non-obstetric patients, but only treated
but not prevented in obstetric patients (Q) (Level I)
7. The addition of intrathecal magnesium to opioids and/or local anaesthetics results inslightly longer analgesia in non-obstetric patients (U) (Level I).
8. The addition of intrathecal clonidine to intrathecal morphine results in slightly longer
analgesia and reduced opioid requirements (U) (Level I).

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9.

Pruritus with intrathecal opioids cannot be treated with methylnaltrexone (N) (Level II).

 The absence of consistent dose-responsiveness to the efficacy of intrathecal opioids andthe increase in adverse effects with higher doses suggests that the lowest effective dose(typically 50-200 mcg morphine) should be used (Q).
 Patients receiving intrathecal opioids should be monitored for opioid-induced ventilatory
impairment for the anticipated duration of opioid effects, eg 18 to 24 hours after
intrathecal morphine (S).
 Clinical experience with morphine, fentanyl and sufentanil has shown no neurotoxicity or
behavioural changes at normal clinical intrathecal doses (U), however caution isrecommended in patients who are at risk of spinal cord ischaemia (U).
Other regional and local analgesic techniques
1. Topical EMLA cream (eutectic mixture of lignocaine [lidocaine] and prilocaine) is
effective in reducing the pain associated with venous ulcer debridement (U) (Level I[Cochrane Review]).
2. Transversus abdominis plane blocks provide pain relief superior to local anaesthetic
infiltration for a range of abdominal surgeries (N) (Level I [PRISMA]).
3. Intraperitoneal local anaesthetic instillation after laparoscopic gastric surgery (N) (Level I[PRISMA]) and laparoscopic cholecystectomy (U) (Level I) improves postoperative pain
outcomes.
4. Adductor canal block results in similar postoperative pain outcomes following total knee
arthroplasty versus femoral nerve block with less quadriceps weakness, earlier mobilisation
and better functional recovery (S) (Level I [PRISMA]).
5. Following thoracotomy, thoracic paravertebral block provides comparable analgesia tothoracic epidural analgesia (U) (Level I).
6. Continuous peripheral nerve block, compared with single-injection peripheral nerve block,results in improved pain control, decreased need for opioid analgesics, reduced nausea andimproved patient satisfaction in some settings, in particular in the first 24 hours
postoperatively (W) (Level I).
7. Femoral nerve block, either single-injection or continuous, provides better analgesia anddecreased nausea compared with parenteral opioid-based techniques after total knee
arthroplasty (U) (Level I).
8. Compared with opioid analgesia, continuous peripheral nerve block (regardless of catheter
location) provides better postoperative analgesia and leads to reductions in opioid use as
well as nausea, vomiting, pruritus and sedation (U) (Level I).
9. Blocks performed using ultrasound guidance are more likely to be successful, faster toperform, with faster onset and longer duration compared with localisation using aperipheral nerve stimulator (U) (Level I).
10. Morphine injected into the intra-articular space following knee arthroscopy does not
improve analgesia compared with placebo (U) (Level I).

5th Edition | Acute Pain Management: Scientific Evidence

xlvii11. Following total knee arthroplasty, local infiltration analgesia reduces postoperative pain for
up to 32 hours when compared to systemic analgesics alone; however, there is limited
benefit in comparison to femoral nerve block (U) (Level I).
12. Following total hip arthroplasty, there is no additional analgesic benefit for local infiltration
analgesia over conventional multimodal analgesia (S) (Level I) and peripheral nerve blocks
have limited or no effect on postoperative pain (Q) (Level II).
13. Following either knee or hip arthroplasty, there is insufficient evidence to support
postoperative administration of local infiltration analgesia via catheter (U) (Level I).
14. Local anaesthetic infusions or intermittent injections through wound catheters provide
analgesic benefits following gynaecological and obstetric surgery, but not other abdominal
or nonorthopaedic surgery (Q) (Level I).
15. Intraurethral instillation of lignocaine gel provides analgesia during flexible cystoscopy (U)(Level I).
16. The benefit of routine sciatic nerve block in addition to femoral nerve block for analgesia
following total knee joint arthroplasty remains unclear (U) (Level I).
17. Continuous interscalene analgesia provides better analgesia, reduced opioid-related
adverse effects and improved patient satisfaction compared with intravenous PCA or singleinjection interscalene block after open shoulder surgery (U) (Level II).
18. Erector spinae plane blocks provide postoperative analgesia superior to systemic analgesia
after cardiac surgery (N) (Level II) and to transverse abdominis blocks after laparoscopiccholecystectomy (N) (Level II).
19. Quadratus lumborum block reduces pain scores and opioid requirements following
Caesarean section compared to placebo or control (N) (Level II).
20. Intra-articular bupivacaine infusions have been associated with chondrolysis and their use
has been cautioned against (U) (Level IV).
21. Postoperative neurologic symptoms or dysfunction is often related to patient and surgicalfactors and the incidence of neuropathy directly related to peripheral regional anaesthesia
is rare (S) (Level III-3).
22. Ultrasound guidance of regional blocks is associated with a reduced risk of local anaesthetic
systemic toxicity in adults (N) (Level IV).
 Continuous peripheral nerve blocks carry a risk of infection; skin preparation with alcoholbased chlorhexidine and full barrier precautions (including face masks) are recommended
for insertion of peripheral nerve catheters (U).
 Ultrasound-guided techniques should be practiced with a high degree of skill and care,including aseptic techniques, as they do not eliminate the risks of injury to tissues andstructures, local anaesthetic systemic toxicity or site contamination (U).
 Caution should be used when considering and performing some peripheral nerve or plexus
blocks in patients with impaired coagulation, in particular where the PNB is performed at a
deep location that prevents external compression, should bleeding occur (N).

xlviii5th Edition | Acute Pain Management: Scientific Evidence

SUMMARY OF KEY MESSAGESRegional analgesia and concurrent anticoagulant medications
1. Anticoagulation and coagulopathy are the two most important risk factors for thedevelopment of epidural haematoma after neuraxial block (U) (Level IV).
 Consensus statements of experts guide the timing and choice of regional anaesthesia andanalgesia in the context of anticoagulation but do not represent a standard of care andwill not substitute the risk/benefit assessment of the individual patient by the individualanaesthetist (S).
 Caution should be used when considering and performing some peripheral nerve or plexus
blocks in patients with impaired coagulation, in particular where the peripheral nerve
block is performed at a deep location that prevents external compression, should
bleeding occur (S).

6.0 | Patient-controlled analgesia
1. Intravenous opioid PCA provides better analgesia than conventional parenteral opioid
regimens (S) (Level I [Cochrane Review]).
2. Opioid administration by IV PCA leads to higher opioid consumption, a higher incidence ofpruritus, but no difference in other opioid-related adverse effects, or hospital staycompared with traditional methods of intermittent parenteral opioid administration (S)(Level I [Cochrane Review]).
3. Patient satisfaction with intravenous PCA is higher when compared with conventional
regimens (S) (Level I [Cochrane Review]).
4. The adjuvant use of ketamine with PCA opioid (in varying ratios) improves pain relief andreduces opioid consumption along with nausea and vomiting, with no increase inneurocognitive effects including hallucinations (N) (Level I [PRISMA]).
5. Iontophoretic transdermal fentanyl PCA is not as effective as intravenous morphine PCA,
with more patients withdrawing from studies because of inadequate pain relief (U) (Level I[QUOROM]).
6. In settings where there are high nurse to patient ratios, there may be no difference in theeffectiveness of PCA and conventional parenteral opioid regimens (U) (Level I).
7. Tramadol via intravenous PCA provides effective analgesia comparable to morphine byintravenous PCA (U) (Level I).
8. The addition of a background infusion to intravenous PCA morphine in adults increases theincidence of respiratory depression (U) (Level I) and does not improve pain relief or sleep,or reduce the number of PCA demands (U) (Level II).
9. Different opioids by intravenous PCA show different rates of adverse effects; fentanyl PCA
has the least rates of sedation, nausea and vomiting while pruritus is most frequent withmorphine PCA (N) (Level I [NMA]). Furthermore, on an individual patient basis, one opioid
may be better tolerated than another (U) (Level II).
10. There is no analgesic benefit in adding naloxone to the PCA morphine solution; however,
the incidence of nausea and pruritus may be decreased (U) (Level II).
11. Subcutaneous PCA opioids can be as effective as intravenous PCA (U) (Level II).
5th Edition | Acute Pain Management: Scientific Evidencexlix12. Intranasal PCA opioids can be as effective as intravenous PCA (U) (Level II).
13. In the emergency department, PCA morphine compared with IV morphine administered bynursing staff, provides more effective analgesia with more rapid onset and with higher
patient satisfaction (U) (Level II).
14. The safety of PCA use can be significantly improved by hospital-wide safety initiatives(equipment, guidelines, education, monitoring) (U) (Level III-3).
15. The adoption of “smart pump” technologies in PCA design can improve documentation ofpatient care (N) (Level III-3), reduce programming errors and improve safety (N) (Level IV SR).
16. Operator-error, in particular programming error, remains a common safety problem with
PCA useoften leading to patient harm (S) (Level IV).
 There is insufficient data to compare the risk of rare but serious adverse events with PCA
opioid use to conventionally administered opioid analgesia (N).
 Adequate analgesia needs to be attained prior to commencement of PCA. Initial orders forbolus doses should consider individual patient factors such as a history of prior opioid use andpatient age. Individual PCA prescriptions may need to be adjusted (U).
 The routine addition of antiemetics to PCA opioids is not encouraged, as it is of no benefit
compared with selective administration (U).
 PCA infusion systems must incorporate anti-siphon valves and, in non-dedicated lines,
antireflux valves (U).
 Drug concentrations, prescription and observation forms should be standardised to
improve patient safety (U).
 The pharmacokinetics of morphine (long equilibration half-time and active metabolites)
may make it less suitable for PCA use than other opioids (U).
 Pethidine, when used in PCA, may cause central nervous system toxicity due to theaccumulation of norpethidine (U).
 Improved methods of patient monitoring (eg continuous pulse oximetry, continuous
capnography) may offer opportunities to improve safety in at-risk patient groups (N).

7.0 | Nonpharmacological techniques
Psychological interventions
1. Preoperative psychological interventions may be effective at reducing pain, length of stayand negative affect after various procedures (N) (Level I [Cochrane Review]) but may not beeffective after cardiac surgery (N) (Level I [Cochrane Review]).
2. Distraction (including with video, toys, music or stories) and hypnosis reduces needle
related pain (S) and distress (N) in children and adolescents (Level I [Cochrane Review])
3. Hypnosis may reduce procedural pain and anxiety (N) (Level I [Cochrane Review]),
postoperative pain (R) (Level I), postoperative anxiety (N) and analgesia consumption inlabour (R) (Level I [Cochrane Review]).

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4. Listening to music produces a small reduction in postoperative or procedural pain, analgesic
requirements and emotional distress (S) (Level I); patient selected music may be more
effective than clinician selected music (N) (Level II).
5. Patient education regarding the procedure or recovery may reduce postoperative pain (Q),preoperative anxiety (N) and postoperative anxiety (N) but does not affect analgesia use (U)(Level I [PRISMA]).
6. Training in coping methods or behavioural instruction prior to surgery reduces pain,
negative affect and analgesic use (U) (Level I).
7. Relaxation techniques may reduce postoperative pain but do not reduce analgesic
consumption (S) (Level I).
8. Immersive virtual reality distraction is effective in reducing pain (S) and anxiety (N) in someclinical situations (Level III-2 SR [PRISMA]).
9. In work injury-related acute pain, psychologically informed and workplace-oriented
interventions may reduce time lost from work (N) (Level III-2 SR).
 Pain catastrophisation and anxiety negatively impact the postoperative experience andare risk factors for the development of chronic postsurgical pain and prolonged opioid use.
Interventions aimed at reducing catastrophisation may be useful in improving patient
outcomes, but retaining patient engagement with perioperative psychoeducation may
also prove challenging (N).
 Preoperative psychoeducation may be cost effective from the perspective of reducing
length of stay (N).
 The evidence that sensory and combined sensory-procedural information is effective in
reducing procedure-related pain is equivocal and not sufficient to make recommendations (U).
 There is insufficient evidence to make a recommendation about the role of brief
mindfulness-based interventions in acute pain (N).
Transcutaneous electrical nerve stimulation
1. Transcutaneous electrical nerve stimulation compared to sham reduces acute pain(procedural and nonprocedural) (U) (Level I [Cochrane Review]), including pain after
thoracic surgery (U) (Level I [PRISMA), after total knee replacement (N) and in theprehospital setting (N) (Level I [PRISMA]).
2. High-frequency transcutaneous electrical nerve stimulation is effective in primarydysmenorrhoea (U) (Level I [Cochrane Review]).
3. Transcutaneous electrical nerve stimulation has no effect on pain, interventions or
outcomes in labour with the exception of a reduction of reports of severe pain whenapplied to acupuncture points (U) (Level I [Cochrane Review]).
4. Transcutaneous electrical nerve stimulation used preventatively in migraine reduces
attack frequency and medication use (N) (Level I [PRISMA])

5th Edition | Acute Pain Management: Scientific EvidenceliAcupuncture and acupressure
1. Acupuncture and acupressure for labour pain may reduce pain, use of pharmacological
pain relief and increase satisfaction with pain management versus standard care orplacebo (Q) (Level I [Cochrane Review]); Caesarean section rates are unchanged (R)(Level I [Cochrane Review]).
2.

For oocyte retrieval, electroacupuncture plus sedation reduced procedural andpostoperative pain compared with sedation plus placebo or sedation alone (U), but may
be inferior to paracervical block plus sedation (Q) (Level I [Cochrane Review]).

3.

Acupuncture or acupressure may be effective in the treatment of primary dysmenorrhoea(S) (Level I [Cochrane Review]).

4.

Acupuncture may reduce the frequency of tension-type headaches and migraine (U)(Level I [Cochrane Review]); in migraine, it may be better tolerated than pharmacologicalprophylaxis (N) (Level I [Cochrane Review]).

5.

Acupuncture may be effective in a variety of acute pain conditions in the emergency
department setting (S) (Level I [PRISMA]) including back pain (N) (Level I [PRISMA])

6.

Acupuncture by a variety of techniques may reduce postoperative pain and opioid
consumption for a variety of surgical types (S) (Level I); specifically, the benefit may occur
after lumbar spinal surgery (U) (Level I [PRISMA]), total knee arthroplasty (U) (Level I[PRISMA]), total hip arthroplasty (N) (Level I) and craniotomy (N) (Level I [PRISMA]).

7.

There is no difference between distant acupuncture and acupuncture at the incisional site
for open abdominal surgery (S) (Level I [PRISMA]).

8.

Acupuncture may reduce post-stroke pain (N) (Level I [PRISMA]).

Photobiomodulation
1. Photobiomodulation may be effective for both prophylaxis and treatment of mucositis inoncology patients (S) (Level I [PRISMA]).
2. Photobiomodulation may reduce pain after 3rd molar extraction (N) (Level I [PRISMA]).
3. Needle related pain after arteriovenous fistula access may be reduced byphotobiomodulation (N) (Level I)
4. After episiotomy, photobiomodulation may not reduce pain (N) (Level II).
 Photobiomodulation may have a role in acute postsurgical pain management, however
evidence is currently insufficient to make any furrher recommendations (N).
Physical therapies
Exercise therapy
1. Following total knee arthroplasty, an exercise intervention in addition to standard postoperative interventions for 8 weeks after discharge may reduce pain and improve function(N) (Level I).
2. In primary dysmenorrhoea, exercise may reduce acute pain intensity and pain duration(N) (Level I).

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3. Use of a birth ball may improve labour pain (N) (Level I).
 Clear recommendations on the components of exercise interventions (including time
point of application, frequency, mode, dose and duration) for acute postoperative pain
management cannot be made; different surgical procedures may require different
exercise-based interventions (N).
 Immediate post-operative weight bearing post anterior cruciate ligament reconstruction
may reduce pain and does not appear to result in increased joint laxity (N).
Prehabilitation
1. Prior to total hip arthroplasty, prehabilitation may reduce postoperative hip pain at 3
months (N) (Level I [PRISMA]).
 A recommendation for the specific type of prehabilitation and dosing parameters cannot
be made at this time (N).
Rehabilitation
1. Early comprehensive active physiotherapy in the first 4 weeks post spinal surgery may
reduce pain and does not appear to increase adverse events (N) (Level I [PRISMA]).
2. Movement representation interventions (mirror therapy/motor imagery) may reduce
acute pain after trauma and surgery (N) (Level I [PRISMA]).
 Accelerated rehabilitation, started within 24 hours post total knee arthroplasty, may
reduce pain at the time of discharge (N).
Manual and massage therapies
1. Single and multiple doses of massage in the early postoperative period may reduce pain
after surgical procedures, including cardiac surgery (N) (Level I [PRISMA])
2. Massage may decrease pain in the first stage of labour pain compared to standard care(N) (Level I [Cochrane Review])
 The role of manipulative therapy in primary dysmenorrhea is currently unclear (N).
Warming and cooling interventions
1. Heat packs may reduce labour pain during the first and second stages (N) (Level I [Cochrane
Review]).
2. Vapocoolants may reduce the pain of intravenous cannulation in adults but its application isassociated with discomfort (N) (Level I [Cochrane Review]).
3. Cryotherapy may reduce pain after total knee arthroplasty but is not superior tocompression (N) (Level I [PRISMA]).
4. Compression cryotherapy may reduce acute pain and analgesia requirements post
anterior cruciate ligament reconstruction and pain on day one to three post knee surgery(N) (Level I [PRISMA]).
5. Intraoperative cryotherapy may reduce post-tonsillectomy pain (N) (Level I [PRISMA]).
6. Hilotherapy (the application of cold compression at a regulated temperature through aface mask) may reduce pain and swelling after facial skeletal surgery vs cold compression(N) (Level I [PRISMA]).
5th Edition | Acute Pain Management: Scientific Evidenceliii8.0 | Specific clinical situations
Postoperative pain
Multimodal postoperative pain management
1. Multimodal analgesia compared to mainly opioid-based analgesia improves pain control andreduces opioid consumption (“opioid-sparing”) and adverse effects (S) (Level I [NMA]).
 The concept of multimodal (or “balanced”) analgesia suggests the use of combinations ofanalgesics with different mode or site of action (S).
Procedure-specific postoperative pain management
1. An analgesic may have different efficacy in different surgical settings (U) (Level I).
2. Different surgical procedures cause different pain states (eg musculoskeletal vs visceral) ofdifferent severity in different locations, thereby requiring a procedure-specific approach (S)(Level III-2).
 Pooling of data from different postoperative pain states may ignore the specific effects ofa specific analgesic in a specific postoperative pain state (U).
Acute rehabilitation after surgery, “fast-track” surgery and enhanced recovery after surgery(ERAS)
1. Adherence to multimodal enhanced recovery protocols after surgery protocols reduces
hospital length of stay, complication rates (S) (Level I), postoperative pain severity andopioid requirements (N) (Level III-2 SR).
 Provision of appropriate analgesia is only one of several elements of enhanced recovery
after surgery protocols (S).
 Analgesic techniques, which permit early mobilisation and early enteral feeding, inparticular those that are opioid-sparing, may contribute to early recovery after surgery
protocols (S).
Risks of acute postoperative neuropathic pain
1. Positive screening for acute postoperative neuropathic pain is a risk factor for positive
screening of chronic postsurgical neuropathic pain (N) (Level III-2).
2. Acute neuropathic pain occurs after trauma and surgery (S) (Level IV).
 Treatment of acute neuropathic pain should follow guidelines for chronic neuropathic
pain; ketamine, opioids (including tramadol and tapentadol in particular) and alpha-2delta ligands may offer faster onset of effect than other treatment options (U).
Acute postamputation pain syndromes
1. Morphine, gabapentin, ketamine and dextromethorphan reduce phantom limb pain
compared to placebo (U) (Level I [Cochrane Review]).
2. Calcitonin reduces phantom limb pain in the acute (<7 days post amputation) but not thechronic setting (U) (Level I [Cochrane Review]).
3. Continuous regional block via nerve sheath catheters provides postoperative analgesia after
amputation but has no preventive effect on phantom limb pain (U) (Level I).

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4. Treatments aiming at cortical reorganisation such as mirror therapy (W) (Level IV SR),sensory discrimination training and motor imagery may reduce chronic phantom limb pain(W) (Level III-2 SR).
5. Perioperative epidural analgesia reduces the incidence of severe phantom limb pain (U)(Level III-2 SR).
6. Anxiety may be a predictor of phantom limb pain (N) (Level IV).
 Perioperative ketamine may prevent severe phantom limb pain (U).
Other postoperative pain syndromes
1. Following thoracotomy, epidural analgesia reduces the incidence of chronic postsurgical
pain (S) (Level I [Cochrane Review]).
2. Following breast cancer surgery, paravertebral block (S) (Level I [Cochrane Review]) andlidocaine IV infusions reduce the incidence of chronic postsurgical pain (N) (Level I
PRISMA]).
3. Cryoanalgesia of the intercostal nerves at the time of thoracotomy results in no
improvement in acute pain, but an increase in chronic pain (U) (Level I).
4. Video-assisted thoracoscopic surgery versus open thoracic surgery resulted in a reduced
rate of chronic post-thoracotomy pain (N) (Level III-3).
5. Post‐thoracotomy, post-mastectomy, post-herniotomy and post-hysterectomy pain
syndromes occur frequently (S) (Level IV) and psychological factors (eg anxiety,catastrophising), chronic preoperative pain and severe acute postoperative pain are
consistently reported risk factors for these pain syndromes (N) (Level IV).
Ambulatory or short-stay surgery
1. Wound infiltration and intraperitoneal instillation with local anaesthetics for short-staylaparoscopic cholecystectomy has good analgesic efficacy, in particular when combined andadministered prior to trocar insertion and at commencement of pneumoperitoneum
respectively (S) (Level I [Cochrane Review]).
2. Intraperitoneal instillation with local anaesthetic provides good analgesia for up to 6 hours
after short-stay gynaecological laparoscopy (U) (Level I) and reduces shoulder tip pain for
24 h (N) (Level I [Cochrane Review]).
3. Ketamine added to caudal local anaesthetic for paediatric day-stay surgery prolongs
analgesia, but not motor block (U) (Level I [PRISMA]); however, concerns regarding
neurotoxicity remain.
4. Continuous peripheral nerve blocks after short-stay surgery provide extended analgesia for atleast 24 h, leading to reduced opioid requirements (S) (Level I [PRISMA]), earlier achievementof discharge criteria, less sleep disturbance and improved early rehabilitation (S) (Level II).
5. Paravertebral block improves pain-related outcomes after short-stay hernia repair (S) (Level I[PRISMA]) and major breast surgery (U) (Level II).
6. After ambulatory anterior cruciate ligament repair, analgesia is superior with local
infiltration anaesthesia versus femoral nerve blocks and adductor canal blocks; multimodal
systemic analgesia, early mobilisation and cooling/compression are also supported (N)(Level I [PRISMA]).
5th Edition | Acute Pain Management: Scientific Evidencelv7. After ambulatory shoulder arthroscopy, interscalene nerve block is superior to otherperipheral nerve blocks; adjuvants to increase block duration and systemic multimodal
analgesia are also supported (N) (Level I [PRISMA]).
8. Gynaecological paracervical block provides superior analgesia to intracervical andtranscervical block and topical local anaesthetic administration (the latter both without
analgesic effect) for ambulatory hysteroscopy (N) (Level I).
9. Dexamethasone added to local anaesthetics in peripheral nerve blocks and for caudal
analgesia or given systemically prolongs duration of analgesia after short-stay surgery(S) (Level I).
10. Single injection peripheral nerve blocks with long-acting local anaesthetics provide longlasting postoperative analgesia after short-stay surgery (S) (Level II).
11. Infiltration of the wound with local anaesthetic provides effective and long-lasting analgesia
after many short-stay procedures (U) (Level II).
12. In the short-stay surgery setting, anti-inflammatories (nonselective NSAIDs, coxibs anddexamethasone) and paracetamol contribute to reduced pain and improved recovery (U)(Level II).
13. Buprenorphine or dexmedetomidine added to local anaesthetics for peripheral nerve blocks
prolong duration of analgesia after short-stay surgery (U) (Level II).
14. Anterior cruciate ligament repair performed as a short-stay procedure in comparison to an
inpatient setting achieves comparable quality of pain relief and better outcomes (N) (Level
III-3 SR).
15. Pain relief after short-stay surgery remains poor (U) (Level IV) and is a common cause of
unplanned re-presentation (U) (Level III-3).
16. Continuous peripheral nerve blocks have been shown to be safe at home after short stay
surgery, if adequate resources and patient education are provided (U) (Level IV).
17. Predictive factors of severe pain after short-stay surgery are preoperative pain, highexpectation of postoperative pain, younger age and certain types of surgery (in particularorthopaedic surgery) (N) (Level IV).
 Preoperative patient-centered education (verbal and written) and telephone follow-ups
may improve anxiety, pain and functional outcomes and patient satisfaction after
ambulatory surgery (N).
Cranial neurosurgery
1. Local anaesthetic infiltration of the scalp provides early analgesia after craniotomy andreduces opioid requirements (S) (Level I [PRISMA]).
2. Intraoperative dexmedetomidine provides early analgesia after craniotomy and reduces
opioid requirements compared to placebo or remifentanil (S) (Level I [PRISMA]).
3. Morphine is more effective than codeine and tramadol for pain relief after craniotomy(U) (Level II).
4. Craniotomy leads to significant pain in the early postoperative period (U) (Level IV), which is
however not as severe as pain from other surgical interventions (U) (Level III-2).
5. Craniotomy can lead to significant chronic headache (U) (Level IV).

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SUMMARY OF KEY MESSAGES Acute pain following craniotomy is underestimated and often poorly treated (U).
Spinal surgery
1. Epidural analgesia compared to systemic analgesia after spinal surgery in children
improves pain up to 72 hours postoperatively (N) (Level I[Cochrane Review]).
2. Perioperative use of gabapentin or pregabalin improves analgesia and reduces opioid
requirements after spinal surgery (S) (Level I [PRISMA]).
3. NSAIDs provide analgesic benefits as well as opioid-sparing effects after spinal surgery (S)(Level I [PRISMA]).
4. Intravenous dexmedetomidine improves early postoperative analgesia and reduces
analgesic requirement up to 48 hours after spinal surgery (N) (Level I [PRISMA]).
5. Intravenous corticosteroids improve analgesia and reduce nausea and length of stay after
spinal surgery (N) (Level I [PRISMA]).
6. Epidural steroid application intraoperatively by the surgeon provides analgesic benefit up
to 24 hours and reduces length of stay after spinal surgery(N) (Level I [PRISMA]).
7. Perioperative pregabalin improves functional outcome after laminectomy at 3 months (U)(Level II).
8. Local infiltration anaesthesia improves analgesia and reduces opioid requirements after
spinal surgery; this benefit is enhanced with preincision infiltration compared toinfiltration at wound closure (U) (Level II).
9. Perioperative systemic lidocaine infusion improves analgesia and reduces opioid
requirements after spinal surgery (W) (Level II).
10. NSAID use for less than 14 days does not increase the risk of nonunion after spinal fusion,
except with high-dose ketorolac (U) (Level III-3).
 Acute pain management following spinal surgery is often complicated by preoperative
chronic pain and long term medication use (U).
Acute pain following spinal cord injury
1. Alpha-2-delta ligands (gabapentin/pregabalin) are effective in the treatment ofneuropathic pain following spinal cord injury (S) (Level I).
2. Antidepressants (amitriptyline, duloxetine and venlafaxine) are effective in the treatmentof neuropathic pain following spinal cord injury but only in those with co-morbid
depression (N) (Level I).
3. Intravenous opioids, ketamine ((U) (Level I), lidocaine and tramadol are effective in thetreatment of neuropathic pain following spinal cord injury (U) (Level II).
 Treatment of acute spinal cord injury pain is largely based on evidence from studies ofother neuropathic and nociceptive pain syndromes (U).
 There is currently insufficient evidence to support non-pharmacological treatments (TENS,
acupuncture, self-hypnosis or cognitive behavioural therapy) for spinal cord injury pain (N).

5th Edition | Acute Pain Management: Scientific EvidencelviiChest trauma (Rib fractures)
1. Surgical fixation in patients with 3 or more fractured ribs improves outcome with regard
to incidence of pneumonia and need for tracheostomy (N) (Level I [Cochrane Review]),
duration of ventilation, ICU and hospital stay (N) (Level I) and mortality (N) (Level III-2 SR).
2. Continuous thoracic epidural analgesia and continuous intercostal and paravertebral
blocks provide similar analgesia and are superior to intravenous opioids for rib fracture
related pain (N) (Level I [PRISMA]).
3. Systemic NSAIDs and ketamine are efficacious analgesic adjuvants for rib fracture related
pain (N) (Level III-3)
 Emerging regional techniques such as serratus anterior and erector spinae plane blocks(single shot and continuous infusion) are supported by case series and could beconsidered for rib fracture analgesic management (N).
 Chest trauma with rib fractures carries a high risk of potentially life-threatening
complications; excellent analgesia and aggressive physical rehabilitation, ideally provided
in a protocolised clinical pathway, can improve outcome (N)Acute pain after hip (neck of femur) fractures
1. Lower limb nerve blocks with local anaesthetics reduce pain, analgesia requirements andlengthen time to rescue analgesia in hip fracture patients compared to systemic analgesia;
there is no advantage of a specific nerve block, insertion technique or continuous versus
single injection administration (S) (Level I [Cochrane Review]).
2. Lower limb nerve blocks decrease the risk of pneumonia in hip fracture patients, but do
not decrease the risk of delirium, myocardial infarction/ischaemia or mortality (N) (Level I[Cochrane Review]).
3. Morphine should be avoided due to increased risk of delirium in hip fracture patients,
who have a high prevalence of renal impairment (N) (Level III-3 SR).
4. Arthroplasty techniques in hip fracture patients are associated with less pain and opioid
requirements than non-arthroplasty techniques (N) (Level III-2).
 Integrated orthogeriatric care, utilisation of care bundles and adherence to clinical carestandards improve outcomes in hip fracture patients (N).
Acute burns injury pain
1. The use of biosynthetic dressings is associated with a decrease in time to healing and areduction in pain during burns dressings changes (U) (Level I [Cochrane Review]).
2. Virtual reality distraction, augmented reality techniques and multimodal distraction
methods reduce pain and unpleasantness during burns dressings (S) (Level I [PRISMA]).
3. Music interventions are helpful in reducing pain, anxiety and heart rate in burns patients(N) (Level I [PRISMA])
4. Opioids, particularly via PCA, are effective in burns pain, including procedural pain (U)(Level II).

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5. Pregabalin reduces pain following acute burns injury (U) (Level II).
6. Sedation and anxiolysis with lorazepam improves procedural pain relief in acute burns
injury (U) (Level II).
7. Regional analgesia reduces donor site pain in selected burns patients (U) (Level II).
8. Gabapentin reduces pain and opioid consumption following acute burns injury (U) (Level
III-3).
9. PCA with ketamine and midazolam mixture provides effective analgesia and sedation forburns dressings (U) (Level IV).
 Acute pain following burns injury can be nociceptive and/or neuropathic in nature andmay be constant (background pain), intermittent or procedure-related (U).
 Acute pain following burns injury requires aggressive multimodal and multidisciplinary
treatment and may benefit from protocolised management approaches (S). This isparticularly important as severely burn injured patients require repeated procedures andfrequently have persistent issues of chronic pain, pruritus, post-traumatic stress and otherpsychological consequences.
 Pruritus is a common symptom following burns injury and alpha-2-delta ligands are usefulin its management (N).
Acute medical pain
Acute abdominal pain
1. Provision of analgesia does not interfere with the diagnostic process in acute abdominal
pain and does not increase the risk of errors in clinical management (U) (Level I [Cochrane
Review]).
2. NSAIDs, opioids and intravenous metamizole (dipyrone) provide effective analgesia forrenal colic (S) (Level I [Cochrane Review]).
3. NSAIDs given for renal colic reduce pain (N) (Level I [PRISMA]) and rescue analgesia
requirements with less vomiting compared with opioids, particularly pethidine(meperidine) (S) (Level I [Cochrane Review]).
4. Alpha blockers as expulsive therapy for ureteral stones reduce the number of pain
episodes and analgesic requirements (S) (Level I [Cochrane Review]).
5. Antispasmodics and tricyclic antidepressants, but not bulking agents, are effective for thetreatment of acute pain in irritable bowel syndrome (S) (Level I [Cochrane Review]) as
well as psychological interventions (N) (Level I).
6. NSAIDs are effective in primary dysmenorrhoea and superior to paracetamol (S)(Level I [Cochrane Review]).
7. The smooth muscle relaxant buscopan does not add further analgesic benefit whencombined with metamizole (dipyrone) (U) (Level I [Cochrane Review]), opioids or NSAIDS
to treat pain of renal colic (U) (Level II).
8. High-frequency TENS, possibly some dietary supplements and acupuncture/acupressure
are effective in the treatment of primary dysmenorrhoea (S) (Level I [Cochrane Review]).

5th Edition | Acute Pain Management: Scientific Evidencelix9. NSAIDS are superior to placebo and spasmolytics and as effective as opioids in thetreatment of biliary colic (S) (Level I [Cochrane Review])
10. The perioperative use of NSAIDs for endoscopic retrograde cholangiopancreatography(ERCP) reduces the risk of post ERCP pancreatitis (S) (Level I [PRISMA]).
11. 5HT3 antagonists reduce some of the symptoms of irritable bowel syndrome (S)(Level I [QUOROM).
12. The onset of analgesia is faster when NSAIDs are given intravenously for the treatment ofrenal colic (U) (Level I).
13. Intravenous paracetamol is as effective as intravenous morphine and superior to
intramuscular piroxicam for analgesia in renal colic (U) (Level II).
14. There is no difference between pethidine and morphine for analgesia in renal colic (U)(Level II).
15. Low-dose ketamine is an effective analgesic for renal colic pain (N) (Level II).
16. IV lidocaine is an effective analgesic for renal colic pain (N) (Level IV SR).
Herpes zoster-associated pain
1. Antiviral agents started within 72 hours of onset of the herpes zoster rash accelerate theresolution of acute pain (U) (Level I) but do not reduce the incidence, severity andduration of postherpetic neuralgia (U) (Level I [Cochrane Review]).
2. Immunisation of persons aged 60 years or older reduces the incidence of herpes zoster
and thereby postherpetic neuralgia with Zostavax® (U) (Level I [Cochrane Review]) and
Shingrix® (N) (Level II).
3. Continuous or repeated paravertebral blocks in the acute phase of herpes zoster reducethe incidence of postherpetic neuralgia at 3, 6 and 12 months (N) (Level I).
4. Amitriptyline (used in low doses for 90 days from onset of the herpes zoster rash) reduces
the incidence of postherpetic neuralgia (U) (Level II).
5. Topical aspirin, topical lignocaine patch or controlled-release oxycodone provide analgesia
in acute pain due to herpes zoster (U) (Level II).
6. Nerve blocks in the acute phase of herpes zoster reduce the duration of herpes zosterassociated pain (N) (Level III-I SR).
6. Continuous epidural analgesia in the acute phase of herpes zoster reduces the incidenceof postherpetic neuralgia at 3 months (N) (Level III-I SR).
 Provision of early and appropriate analgesia is an important component of the
management of herpes zoster and may have benefits in reducing the incidence ofpostherpetic neuralgia (U).
Acute cardiac pain
1. The routine use of oxygen in normoxic patients with acute myocardial infarction does not
reduce pain or mortality (S) (Level I [Cochrane].
2. Morphine is an effective and appropriate analgesic for acute cardiac pain, but may interferewith pharmacokinetics and pharmacodynamics of some platelet inhibitors (Q) (Level II).

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3. Nitroglycerine is an effective and appropriate agent in the treatment of acute ischaemic
chest pain (S) (Level IV).
 The mainstay of analgesia in acute coronary syndrome is the restoration of adequate
myocardial oxygenation, nitroglycerine, beta blockers and strategies to improve coronary
vascular perfusion (U).
Acute pain associated with haematological disorders
1. Parenteral corticosteroids reduce the duration of severe pain, analgesia requirements andhospital length of stay, without major adverse effects, during vaso-occlusive crises insickle cell disease (U) (Level I [Cochrane Review]).
2. There is no evidence that fluid replacement therapy (S) or intravenous or oral magnesium
reduces pain associated with vaso-occlusive crises in sickle cell disease (N) (Level I[Cochrane Review]).
3. Hydroxyurea decreases the frequency of vaso-occlusive crises, life-threatening
complications and transfusion requirements in sickle cell disease (S) (Level I [Cochrane
Review]).
4. Zinc reduces the incidence of painful vaso-occlusive crises in sickle cell disease (U) (Level I[Cochrane Review]).
5. Intravenous opioid loading optimises analgesia in the early stages of a vaso-occlusive crisis
in sickle cell disease; effective analgesia may be continued with intravenous opioid
therapy, optimally as PCA, or as oral opioids (S) (Level II).
6. Single-dose ketorolac does not reduce opioid requirements in vaso-occlusive crisis in sickle
cell disease (N) (Level II), but may increase the risk of acute kidney injury (N) (Level III-3).
7. Oxygen supplementation does not decrease pain during a vaso-occlusive crisis in sickle
cell disease (U) (Level II), but hyperbaric oxygen may be effective (U) (Level III-3).
8. Intravenous ketamine and intravenous lidocaine reduced pain intensity and opioid
requirements in vaso-occlusive crisis in sickle cell disease (N) (Level IV).
Acute headache
Tension‐type headache
1. Acupuncture may be effective in the treatment of tension‐type headache (S) (Level I[Cochrane Review]).
2. Simple analgesics such as paracetamol or NSAIDs, either alone or combined, are effectivein the treatment of episodic tension‐type headache (S) (Level I [PRISMA]).
3. Metoclopramide, metamizole and chlorpromazine as parenteral treatments of tensiontype headache have high efficacy (U) (Level I [PRISMA]).
4. The combination of caffeine/aspirin/paracetamol is superior to paracetamol in thetreatment of episodic tension‐type headache (U) (Level I).
Migraine
5. Paracetamol is effective in the treatment of migraine, however less than other analgesics;
the efficacy is increased when combined with metoclopramide (U) (Level I [Cochrane
Review]).
5th Edition | Acute Pain Management: Scientific Evidencelxi

6. Aspirin, ibuprofen, diclofenac and dipyrone are effective in the treatment of migraine;soluble preparations of ibuprofen provide a faster onset (U) (Level I [Cochrane Review]).
7. For sumatriptan, subcutaneous administration achieves the fastest onset of effect andhighest efficacy (U) (Level I [Cochrane Review]).
8. The combination naproxen/sumatriptan has increased efficacy and better tolerability thansumatriptan on its own (N) (Level I [Cochrane Review]).
9. The addition of caffeine to simple analgesics improves their analgesic efficacy andtolerability in acute migraine (N) (Level I [Cochrane Review]).
10. Hyperbaric oxygen therapy is effective in controlling pain in migraine, but no othersymptoms and outcomes (U) (Level I [Cochrane Review]).
11. A significant placebo effect occurs in migraine treatment (N) (Level I [QUOROM]),
leading to an underestimation of treatment effects of analgesic medications (N) (Level II).
12. Parenteral antiemetics, metoclopramide (S) (Level I [PRISMA]) and droperidol (U) (Level I)
are effective in the treatment of migraine.
13. Phenothiazines and butyrophenones (at the expense of more adverse effects) are
effective in the treatment of migraine, in particular in the emergency department (S)(Level I).
14. All triptans are more effective than placebo in the treatment of severe migraine (S) (Level I),
however 30 to 40% of patients may not respond (N) (Level I).
15. Triptans and mefenamic acid are effective in treatment of menstruation-related migraine(U) (Level I).
16. Some opioids are more effective than placebo in the treatment of acute migraine (U)(Level I), but their use in this setting is associated with significant adverse effects andpoor outcomes (S) (Level III-2).
17. Pethidine is less effective than most other migraine treatments and should not be used(U) (Level I).
18. Intravenous magnesium may have some analgesic effect compared to placebo in migraine(Q) (Level I [PRISMA]).
19. A “stratified care strategy” is effective in treating migraine (U) (Level II).
20. Ergotamine derivatives, but not triptans, increase the rate of severe myocardial ischaemic
events (U) (Level III-2 SR).
21. Migraine in pregnancy is a risk factor for gestational hypertension, preeclampsia andcardiovascular complications (U) (Level III-2).
Cluster headache
22. Parenteral triptans (sumatriptan or zolmitriptan) or high-flow oxygen therapy are
effective treatments for cluster headache attacks (S) (Level I [Cochrane Review]).
23. Sphenopalatine ganglion local anaesthetic block has moderate evidence support for thetreatment of acute cluster headaches (N) (Level IV SR).

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Postdural puncture headache
24. There is no evidence that bed rest or fluid supplementation are beneficial in thetreatment and prevention of postdural puncture headache (S) (Level I [Cochrane
Review]).
25. Epidural blood patch administration is more effective than conservative treatment or asham procedure in the treatment of postdural puncture headache (S) (Level I [Cochrane
Review]).
26. Risk of postdural puncture headache is reduced with preventive use of morphine,
cosyntropin or aminophylline, especially in patients at high risk; preventive
dexamethasone use increases risk of postdural puncture headache (N) (Level I [Cochrane
Review]).
27. Caffeine, gabapentin, hydrocortisone or theophylline are effective treatments for
postdural puncture headache (S) (Level I [Cochrane Review]).
28. The incidence of postdural puncture headache is reduced by using smaller‐gauge
spinal or non‐cutting bevel needles or by orientating the cutting bevel parallel to thespinal sagittal plane (U) (Level I).
Medication overuse headache
29. Frequent use (>8–10 days/month) of paracetamol, NSAIDs and opioids for recurrent
acute headache (more so than triptans and ergot derivatives) may lead to medication
overuse headache; weaning and use of preventive medication are recommended
management approaches (S) (Level IV SR).
 Opioids should be used with extreme caution in the treatment of headache;pethidine should not be used at all (S).
Acute pain associated with neurological disorders
1. Various anticonvulsants (U) (Level I [PRISMA]) and duloxetine (N) (Level II) have beneficial
effects in the treatment of neuropathic pain associated with multiple sclerosis
2. Cannabinoids have a clinically small effect on spasticity caused by multiple sclerosis (U)(Level I); the effect on neuropathic pain associated with multiple sclerosis is unclear andmay depend on the preparation used (W) (Level I [PRISMA]).
3. With cannabinoid use in multiple sclerosis, there is a high rate of minor adverse effects andserious adverse psychopathological effects occur in nearly 1% of patients (U) (Level I).
4. Acupuncture (N) (Level I), non-invasive brain stimulation (N) (Level III-3 SR) and motor
cortex stimulation (N) (Level IV SR) may reduce post-stroke pain.
5. Local anaesthetics (mainly lidocaine) by local and systemic administration, anticonvulsants(phenytoin or IV fosphenytoin) and sumatriptan reduce pain in acute exacerbations oftrigeminal neuralgia (N) (Level IV SR).
6. Motor cortex stimulation may reduce acute pain in trigeminal neuralgia (N) (Level IV SR)
7. Deep brain stimulation may improve pain relief in Parkinson’s disease (N) (Level IV).
 Treatment of acute pain associated with neurological disorders is based largely on evidence
from trials for the treatment of a variety of chronic neuropathic pain states (S).

5th Edition | Acute Pain Management: Scientific EvidencelxiiiAcute orofacial pain
Acute dental pain
1. NSAIDs and emergency pulpectomy reduce pain in patients with acute apical periodontitis(U) (Level I) with insufficient evidence to support analgesic benefit from adding antibiotics(S) (Level I [Cochrane Review]).
Dental extraction
2. Paracetamol, nonselective NSAIDs and coxibs provide safe and effective analgesia withminimal adverse effects after dental extraction (S) (Level I [Cochrane Review]).
3. Combinations of paracetamol with ibuprofen (U) (Level I [Cochrane Review]) and othernonselective NSAIDs (U) (Level I) provide superior analgesia to either drug alone after
dental extraction.
4. Tramadol provides equal analgesia to paracetamol/weak opioid and aspirin/weak opioid
combinations (U) (Level I [Cochrane Review]) and tramadol/paracetamol combinations
provide superior analgesia to tramadol alone after dental extraction (U) (Level I).
5. Nonselective NSAIDs and coxibs provide similar analgesia, which is superior toparacetamol, codeine, combinations of paracetamol/codeine (U) (Level I), tramadol (S)(Level I) and pethidine (U) (Level II) after dental extraction.
6. Perioperative corticosteroid administration reduces swelling, but not pain (U) (Level I),
and reduces postoperative nausea (U) (Level II) after third molar extraction.
Tonsillectomy
7. Nonselective NSAIDs (U) (Level I), in particular aspirin and ketorolac (U) (Level II), increase
the risk of reoperation for bleeding after tonsillectomy in adults, but not in children (U)(Level I [Cochrane Review]).
8. Intraoperative dexamethasone administration reduces postoperative pain, nausea andvomiting and time to resumption of oral intake after tonsillectomy (S) (Level I [Cochrane
Review]), with no increase in adverse effects (U) (Level I [Cochrane Review]).
9. Paracetamol, NSAIDs (S) (Level I [PRISMA]), dexamethasone, preoperative alpha-2-delta
ligands (S) and dextromethorphan are effective analgesics after tonsillectomy (N) (Level I[PRISMA]).
10. Intraoperative cryothgerapy may reduce post-tonsillectomy pain (N) (Level I [PRISMA]).
11. Oral administration of honey versus control reduces postoperative pain and analgesic use
after tonsillectomy (N) (Level I [PRISMA]).
12. Peritonsillar infiltration or topical application of local anaesthetics are equally effective in
producing a modest reduction in acute post-tonsillectomy pain (U) (Level I).
13. Dexamethasone, magnesium (and with limited support pethidine and tramadol)
combined with local anaesthetics for peritonsillar infiltration improve analgesia and otheroutcomes after tonsillectomy (N) (Level I).
14. Perioperative antibiotics show no benefit in post-tonsillectomy pain, but increase adverse
effects (S) (Level I).
15. Acupuncture may reduce post-tonsillectomy pain compared to control group or shamacupuncture (N) (Level I)

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16. Peritonsillar infiltration with tramadol or ketamine may reduce post-tonsillectomy pain
and analgesia requirements but was no more effective than equivalent doses
administered parenterally (U) (Level II).
Pharyngitis
17. Corticosteroids (S) (Level I [Cochrane Review]) and antibiotics (U) (Level I [Cochrane
Review]) improve analgesia and reduce duration of pain in pharyngitis.
18. Amylmetacresol/2,4-dichlorobenzylalcohol (AMC/DCBA) lozenges (N) (Level I [PRISMA]),ketamine gargle (N) (Level I [PRISMA]), benzydamine spray (U) (Level I) and other topicalanalgesics (U) (Level II) provide analgesia superior to placebo in acute sore throat withminimal adverse effects.
19. Corticosteroids reduce acute pain associated with peritonsillar abscess (following drainage
and antibiotics) (S) (Level I [PRISMA]).
20. Paracetamol, NSAIDs (nonselective NSAIDs or coxibs) and opioids, administered as
monotherapy or in combination, are effective analgesics in acute pharyngitis (U) (Level I).
Sinusitis and otitis media
21. Oral corticosteroids have no analgesic effect in sinusitis (U) (Level I [Cochrane Review]),
but intranasal corticosteroids reduce facial pain and improve recovery (S) (Level I[Cochrane Review]).
22. Antibiotic treatment of acute otitis media vs placebo or control has no effect on acutepain, only limited effect on later pain, but increases the risk of adverse effects (N) (Level I[Cochrane Review]).
23. In acute otitis media, topical local anaesthetic drops are effective in children compared toplacebo and equivalent to naturopathic drops (S) (Level I [Cochrane Review]).
 Codeine should not be used in children, especially after adenoidectomy or tonsillectomy,
due to an increased risk of opioid-induced ventilatory impairment and death (U).
 Recurrent or persistent orofacial pain requires biopsychosocial assessment andappropriate multidisciplinary approaches (U).
 Neuropathic orofacial pain, which is often post-traumatic (iatrogenic), may be
exacerbated by repeated dental procedures, incorrect drug therapy or psychosocial
factors (U).
Acute pain in patients with HIV infection
1. High-concentration capsaicin patches have some efficacy in treating neuropathic pain inpatients with HIV/AIDS (S) (Level I [Cochrane Review]).
2. Smoking cannabis has short-term efficacy in treating neuropathic pain in patients with
HIV/AIDS, although potential study bias means that this is not recommended as routine
treatment (Q) (Level I [PRISMA]).
3. HIV/AIDS patients with a history of problematic drug use report higher opioid analgesic
use but also more intense pain (U) (Level III-2).
4. Pain, and notably neuropathic pain, is common in patients with HIV (U) (Level IV).

5th Edition | Acute Pain Management: Scientific Evidencelxv HIV/AIDS has become a chronic, manageable condition; in view of limited specificevidence, the treatment of pain in patients with HIV/AIDS should be based on similar
principles to those for the management of acute, cancer and chronic pain in the general
population (S).
 Interactions between antiretroviral medications, antibiotics and analgesics should beconsidered in this population and reference to a current guide of likely drug interactions isstrongly recommended (S).
Acute cancer pain
1. Intranasal, sublingual and buccal fentanyl preparations are effective treatments forbreakthrough pain in cancer patients (U) (Level I [Cochrane Review]) with similar efficacy
to intravenous administration (U) (Level I [PRISMA]) and superior to oral morphine (U)(Level I).
2. Radiotherapy is an effective treatment of acute cancer pain due to bone metastases (U)(Level I [Cochrane Review]), while bone-targeting agents (bisphosphonates, denosumab)
are beneficial in delaying the onset of bone pain rather than providing analgesia (W)(Level I [PRISMA]).
3. Neurolytic coeliac plexus block in pancreatic cancer lowers pain intensity and opioid
analgesic requirements for at least 8 weeks (U) (Level I [Cochrane Review]).
4. Opioids, via PCA or a continuous infusion, provide effective analgesia in mucositis; PCA isassociated with reduced opioid requirements and pain duration (U) (Level I [Cochrane
Review]).
5. Oral cryotherapy (sucking on ice chips or holding ice water in the mouth before, during,
and/or after rapid infusions of systemic therapies that result in mucositis) effectively
prevents mucositis (N) (Level I [Cochrane Review]).
6. Music interventions may be effective in reducing pain intensity in patients with cancer (N)(Level I [Cochrane Review]).
7. Topical treatment with doxepin (S), amitriptyline (N), diclofenac (N), benzydamine (N)(Level I [PRISMA]), povidone-iodine (U) (Level I) and morphine (S) (Level II) compared toplacebo improve pain relief due to mucositis.
8. Low-level laser therapy reduces and when used prophylactically prevents pain andseverity of mucositis (S) (Level I [PRISMA]).
9. Patient education about cancer pain is a key factor in optimising pain management (U)(Level I).
10. Opioid doses for individual patients with cancer pain should be titrated to achieve
maximum analgesic benefit with minimal adverse effects (U) (Level II).
11. Analgesic medications prescribed for cancer pain should be adjusted to alterations of pain
intensity (U) (Level III-2).
12. Neuropathic pain or mixed nociceptive-neuropathic pain has an estimated frequency of
30-40% in patients with cancer (S) (Level IV SR).

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SUMMARY OF KEY MESSAGES Acute pain in patients with cancer often signals disease progression; sudden severe pain inpatients with cancer should be recognised as a medical emergency and immediately
assessed and treated (U).
 Prompt assessment and fast coordinated management of spinal metastases with suspectedspinal cord compression is required to mitigate against neurological deficit (U).
 Cancer patients receiving controlled-release opioids need access to immediate-release
opioids for titration of breakthrough pain; selection of breakthrough medication should
consider the time course and aetiology of the pain flare (U).
 If nausea and vomiting accompany acute cancer pain, parenteral opioids are needed (U).
 Transdermal opioids are inappropriate to control acute unstable pain (U).
 High interindividual variability in opioid conversion rates dictates that all opioid rotations
should be individualised and monitored, particularly where higher opioid doses are inuse (U).
Acute pain management in intensive care
1. Plasma exchange in acute Guillain-Barre syndrome improves outcome including analgesia(U) (Level I [Cochrane Review]).
2. Carbamazepine and gabapentin may reduce the pain associated with Guillain-Barre
syndrome, based on limited and low-quality evidence (U) (Level I [Cochrane Review]).
3. Non-opioids including NSAIDs and paracetamol improve analgesia in selected intensive careunit patients (S) (Level I [PRISMA]).
4. Remifentanil provides no advantages over other opioids in ventilated intensive care unit
patients (U) (Level I).
5. Ketamine decreases cumulative opioid doses in mechanically ventilated patients, withpositive effects on haemodynamics and reduced requirements for sedation, but with anincreased risk of psychomimetic adverse effects (N) (Level II).
6. The formal assessment and management of pain and agitation in ventilated intensive careunit patients decreases the incidence of pain, the duration of ventilation, the length of ICU
stay and mortality (U) (Level III-1).
7. Prolonged opioid infusions for >6 days and higher cumulative opioid dose increase the riskof acute withdrawal if the opioid infusion is abruptly ceased (N) (Level III-2).
8. Procedures such as endotracheal tube suctioning are consistently reported as
uncomfortable and painful (U) (Level III-2).
 The aetiology of acute pain in critically ill patients is complex and encompasses all domainsof the sociopsychobiomedical model of pain (N).
 Observation of behavioural and physiological responses permits assessment of pain in
unconscious patients (U).
 Routine monitoring for pain in sedated intensive care patients should be performed, using
the Behavioural Pain Scale or the Critical-Care Pain Observation Tool (U).
 Analgesia management should be targeted to the potential aetiologies of acute pain (N).
5th Edition | Acute Pain Management: Scientific Evidencelxvii Opioids are the recommended first-line analgesic agents in ventilated intensive carepatients (U).
 The risk of NSAIDs in critically ill patients may be overestimated; NSAIDs may provide
effective analgesia as a part of multimodal analgesia (N).
 Regional analgesia techniques should be considered in patients undergoing large intraabdominal surgical procedures and trauma (N).
 Intensive care unit patients should be provided with appropriate analgesia prior to andduring potentially painful procedures, in particular as recall of discomfort, pain andprocedures can be a source of post-traumatic stress (S).
Acute pain management in emergency departments
1. Paracetamol, in particular if administered IV, and NSAIDs are effective primary analgesics
for use in the emergency department (N) (Level I [PRISMA]).
2. Sublingual buprenorphine (N) (Level I [PRISMA]) or intranasal fentanyl (N) (Level I) are
effective alternatives to parenteral opioids in the emergency department.
3. Low dose ketamine is a safe and effective analgesic alone or when combined with opioids
in the emergency department, but increases neuro-psychological adverse events (N)(Level I [PRISMA]).
4. Appropriate doses of intravenous opioids are effective in treating acute severe pain in theemergency department and ideally should be titrated according to nurse-initiated andpatient-driven protocols; there is no preference for a specific opioid (U) (Level I).
Abdominal pain
5. Provision of analgesia does not interfere with the diagnostic process in acute abdominal
pain and does not increase the risk of errors in clinical management (U) (Level I [Cochrane
Review]).
Migraine
6. NSAIDs, triptans (S) (Level I [Cochrane]), phenothiazines (prochlorperazine,
chlorpromazine), butyrophenones and metoclopramide are effective to treat migraine in
the emergency department (U) (Level I).
Fractured neck of femur
7. Lower limb nerve blocks with local anaesthetics reduce pain, analgesia requirements andlengthen time to rescue analgesia in hip fracture patients compared to systemic analgesia;
there is no advantage of a specific nerve block, insertion technique or continuous versus
single injection administration (S) (Level I [Cochrane Review]).
Shoulder dislocation
8. Intra-articular local anaesthetics provide comparable analgesia for reduction of glenohumeral dislocation to procedural sedation and analgesia methods with fewer adverse
events (N) (Level I [Cochrane Review]).
Wounds
9. Buffering of lignocaine with bicarbonate reduces the pain of infiltration, particularly whenusing lignocaine with adrenaline (U) (Level I [Cochrane Review]).

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10. Topical local anaesthetic agents (including those in liposomal formulations) (S) (Level I[Cochrane Review]) or topical local anaesthetic-adrenaline agents (U) (Level II) provide
effective analgesia for wound care in the emergency department.
Musculoskeletal Pain
11. Centrally acting muscle relaxants do not improve analgesia in the acute treatment oflower back pain (N) (Level II).
Non-pharmacological management of pain
12. Acupuncture may provide effective analgesia as a single agent or adjunct in theemergency department (N) (Level I [PRISMA]).
 To ensure optimal management of acute pain, emergency departments should adopt
systems to ensure adequate assessment of pain, provision of timely, adequate andappropriate analgesia, frequent monitoring and reassessment of pain (U).
Prehospital analgesia
1. Transcutaneous electrical nerve stimulation TENS provides pain relief in the prehospitalsetting (N) (Level I [PRISMA]).
2. Intravenous morphine, fentanyl and tramadol are equally effective in the prehospitalsetting (S) (Level II).
3. Nitrous oxide is an effective analgesic agent in prehospital situations (U) (Level II).
4. Methoxyflurane, in low concentrations, is an effective analgesic with rapid onset in theprehospital and hospital setting with good safety data (U) (Level II).
5. Ketamine is a safe and effective analgesic in the prehospital setting (U) (Level II).
6. Moderate to severe pain is common in both adult and paediatric patients in the prehospitalsetting (S) (Level IV) and is often poorly managed (N) (Level III-2).
7. Fascia iliaca compartment block is an effective analgesic technique for patients withisolated femoral shaft fractures in the prehospital setting (N) (Level IV SR).
8. The prehospital setting presents challenges beyond those encountered in hospital to theassessment, documentation, treatment and reassessment of pain in both adult andpaediatric patients (N) (Level IV).
 Nonpharmacological measures are effective in providing pain relief and should always be
considered and used if practical (U).
Discharge opioid medication for acute pain management
1. Short-term opioid therapy may lead to long term opioid use and misuse (S) (Level III-2); risk
factors for prolonged postoperative use include preoperative opioid use, type of surgery,slow-release opioids, psychological and social factors and pre-existing alcohol or substanceuse disorder (N) (Level III-2).
2. Recent introduction of opioid therapy may increase the risk of falls (S) (Level III-2).
3. Recent introduction of opioid therapy or recent dose escalation may impair driving (S)(Level III-2), thereby leading to increased driving accidents (N) (Level III-3 SR); this risk isfurther increased by combined use of opioids and alcohol (N) (Level III-2).
5th Edition | Acute Pain Management: Scientific Evidencelxix

4. Many patients who retain unused opioid tablets are willing to share them with others (S)(Level III-2); this contributes to increased risks of abuse and adverse effects in the recipients(N) (Level IV).
5. The most common source of prescription opioids for nonmedical use is a friend or relative(N) (Level III-3).
 Unused opioids prescribed for postoperative pain are potentially a large reservoir for
opioid abuse, misuse and diversion (S).
 A “universal precautions” approach for opioid prescribing should be used in the setting ofprescribing discharge medications (S).
 Prescribing discharge medications should be done in consideration of opioid requirementson the day before discharge, avoiding slow-release opioids and for a limited duration (N).
 Patient education about risks of opioids and safe disposal of unused medication by return
to a pharmacy and follow-up by GP or pain medicine services in case of ongoing issues
improve safety of discharge medications (N).

9.0 | Other specific patient groups
The pregnant patient
Use of analgesic medications in pregnancy
1. Short-term use of NSAIDs in late pregnancy is associated with an increase in the risk ofpremature closure of the ductus arteriosus (U) (Level I [Cochrane Review]).
2. The chronic use of opioids during pregnancy may be associated with some teratogenic
effects, childhood neurocognitive delay and/or negative neurobehavioural outcomes;
however, it is difficult to separate the influence of multiple confounders in this patientgroup (Q) (Level III-2 SR).
3. Retrospective epidemiological studies linking paracetamol use in pregnancy to later
development of childhood asthma are inherently confounded (U); when adjusted forrespiratory tract infections in the child the association is lost (Q) (Level III-2 SR).
4. The use of common nsNSAIDS during pregnancy is not associated with increased risk ofmajor congenital malformations, structural heart defects or difference in infant survival(N) (Level III-2).
5. Exposure to an nsNSAID or coxib is not an independent risk factor for spontaneousabortion (Q) (Level III-2)
6. The safety of alpha-2-delta ligand use in pregnancy remains unclear; limited data has notraised safety concerns (N) (Level III-2).
 For pain management in pregnancy, nonpharmacological treatment options should beconsidered where possible before analgesic medications are used (U).
 Use of medications for pain in pregnancy should be guided by publishedrecommendations; ongoing analgesic use requires close liaison between the patient, thehealth professional managing the pregnancy and the health professional managing thepain (U).

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SUMMARY OF KEY MESSAGES Most of the data reported in this setting are from episodes of prolonged use (eg forchronic conditions) and there is a lack of data on the risk of short-term exposure such as in
the treatment of acute pain (N).
 Studies of analgesic use during pregnancy may be confounded by the indication, recall bias
and often the lack of an active comparator; this is exemplified by reported associations
between NSAID use in pregnancy and low birth weight and asthma confounded by thematernal indications for their use (ie inflammatory diseases) (N).
 Nonselective NSAIDs and Coxibs should be used with caution in the last trimester ofpregnancy and should be avoided after the 32nd week (U).
 Emerging evidence suggests that maternal paracetamol use may influence premature
closure of the fetal ductus arteriosus (N).
 Neonates exposed to regular opioid in utero, particularly in the last three months ofpregnancy, are at risk of neonatal abstinence syndrome and should be monitored for itafter delivery (N).
Pain syndromes in pregnancy
1. Exercise reduces low back and pelvic girdle pain during pregnancy (S) (Level I [Cochrane
Review]).
2. Manual therapy interventions reduce intensity of pregnancy-related back and pelvic pain
versus usual care and relaxation, but not to sham interventions (N) (Level I [PRISMA]) The use of a pelvic support belt may reduce pelvic girdle pain during pregnancy (N).
Management of acute pain during labour and after birth
Neuraxial and regional analgesia for pain in labour
1. Epidural and combined spinal‐epidural analgesia provides superior pain relief for labourand delivery compared with all other analgesic techniques (S) along with improved
maternal satisfaction (R) (Level I [Cochrane Review]).
2. Epidural analgesia compared to systemic opioid reduces maternal nausea and/or
vomiting (N) and need for maternal oxygen supplementation (N), but increases theduration of the first and second stage of labour slightly (Q) (Level I [Cochrane Review]).
3. Epidural analgesia compared to systemic opioid does not increase the rate of Caesarean
section (S), long‐term backache (S), headache (N), pruritus (N) or postnatal depression (N)(Level I [Cochrane Review]).
4. Epidural analgesia compared to systemic opioids reduces the risk of fetal acidosis (S) andthe need for neonatal naloxone administration with no increase in special care/neonatal
intensive care unit admissions (N) (Level I [Cochrane Review]).
5. Epidural analgesia may increase the rate of assisted vaginal delivery (U), but not with
contemporary techniques of epidural analgesia (use of low-concentrations of local
anaesthetics) (Q) (Level I [Cochrane Review]).
6. Lower concentrations of local anaesthetics for epidural analgesia in labour result in ashorter duration of second stage of labour, fewer assisted vaginal deliveries, greater
ambulation and less urinary retention than higher concentrations (S) (Level I [Cochrane
Review]).
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7. Early versus late initiation of epidural analgesia leads to no clinically significant
differences in outcome (S) (Level I [Cochrane Review]).
8. In comparison with epidural analgesia, combined spinal‐epidural analgesia reduces timeto effective analgesia (U), does not increase maternal satisfaction (U), increases theincidence of mild pruritus (compared to low-dose epidurals) (U) (Level I [Cochrane
Review]) and reduces the risk of unilateral block (N) (Level I [PRISMA]).
9. Local anaesthetic nerve blocks (in particular paracervical blocks) provide better analgesia
than placebo, nonopioids and opioids for labour pain, but at an increased rate of adverse
effects (U) (Level I [Cochrane Review]).
10. Non-reassuring fetal heart rate tracings can be more common with combined spinal‐
epidural analgesia than epidural analgesia in labour (N) (Level I [PRISMA]).
11. Ultrasound guidance improves the success of epidural catheter insertion and intrathecal
needle placement and reduces traumatic insertions (N) (Level I [PRISMA]).
12. Patient-controlled epidural analgesia provides effective analgesia for labour (U) but
optimal settings (U) (Level I) and the need for a background infusion remain unclear (U)(Level I [PRISMA]).
13. Programmed intermittent epidural bolus versus continuous epidural infusion reduces theincidence of breakthrough pain without increasing adverse outcome (S) (Level I [PRISMA]).
14. Dural puncture epidural analgesia does not appear to offer benefit over standard epidural
analgesia (N) (Level I [PRISMA]).
15. There is no difference between the use of bupivacaine and ropivacaine for epidural
analgesia in labour for any outcome (U), except ropivacaine may reduce the incidence of
motor block (Q) (Level I).
16. Single-injection intrathecal opioids provide comparable early labour analgesia to epidural
local anaesthetics, with increased pruritus but no difference in nausea (U) (Level I).
Adding single injection intrathecal morphine (≤250 mcg) to local anaesthetic combinedwith shorter acting opioids increases time to first analgesic request, but is associated withincreased adverse effects (N) (Level I).
Systemic analgesia for pain in labour
17. Analgesic concentrations of inhaled volatile anaesthetics provide superior analgesia inlabour but more drowsiness, compared to inhaled nitrous oxide (U) (Level I [Cochrane
Review]).
18. Inhaled nitrous oxide has some analgesic efficacy in labour pain (U), increases maternal
adverse effects (nausea, vomiting, dizziness) (U) but has no adverse effects on the
newborn (U) (Level I [Cochrane Review]); pain relief is comparable to pethidine but
inferior to epidural analgesia (U) (Level IV SR).
19. Use of nonopioid analgesics alone for labour analgesia is not supported by current
evidence (U) (Level I [Cochrane Review]).
20. Parenteral opioids other than remifentanil intravenous PCA provide moderate analgesic
effects in labour pain (S), are inferior to epidural analgesia (S) and cause increased
adverse maternal effects (sedation, nausea, vomiting) (S) and adverse effects on the
newborn remain unclear (Q) (Level I [Cochrane Review]).

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21. Remifentanil intravenous PCA is inferior to epidural analgesia (U), but provides better
analgesia in labour compared to other parenteral opioids (S) (Level I [Cochrane]).
Complementary and other methods of pain relief in labour
22. Continuous or one‐to‐one support by a midwife or trained layperson during labour
reduces analgesic use, rate of assisted and operative birth and dissatisfaction (S)(Level I [Cochrane Review]).
23. Immersion in water during labour may reduce the requirements for regional and neuraxial
analgesia, with no difference in other maternal outcomes and insufficient evidence forneonatal outcomes compared to no immersion (W) (Level I [Cochrane Review]).
24. Relaxation by use of yoga, music or audio has limited benefit for pain relief or satisfaction
in labour (Q) (Level I [Cochrane Review]).
25. Acupuncture and acupressure for labour pain may reduce pain, use of pharmacological
pain relief and increase satisfaction with pain management vs standard care or placebo(Q) (Level I [Cochrane Review]); Caesarean section rates are unchanged (R) (Level I[Cochrane Review]).
26. Acupressure (vs sham) reduces labour pain, but has no effect on the use ofpharmacological analgesia (Q) (Level I [Cochrane Review]).
27. Massage may decrease pain in the first stage of labour pain compared to standard care(S) (Level I [Cochrane Review]).
28. Transcutaneous electrical nerve stimulation has no effect on pain, interventions or
outcomes in labour (U) (Level I [Cochrane Review]).
29. Biofeedback, sterile water injections intra- or subcutaneously and aromatherapy have noeffect on labour pain or other outcomes (U) (Level I [Cochrane Review]).
30. Use of a birth ball may improve labour pain (N) (Level I).
31. Heat packs may reduce labour pain during the first and second stages (N) (Level I[Cochrane Review]).
32. Hypnosis (mostly antenatal interventions) may reduce analgesic requirements for labour
pain (R) (Level I [Cochrane Review]).
Pain relief after Caesarean section
33. Local anaesthetic wound infiltration, in particular abdominal nerve blocks, reduces opioid
consumption following Caesarean section (U) (Level I [Cochrane Review]).
34. Local anaesthetic transversus abdominis plane blocks reduce postoperative opioid
requirements and pain scores after Caesarean section but only when intrathecal
morphine is not used (S) (Level I [PRISMA]).
35. In relation to controls only and with no direct comparison between the two approaches,
local anaesthetic transversus abdominis plane blocks performed by a posterior approachprovide a longer duration of benefit versus the lateral approach after lower abdominal
incision surgery including Caesarean section (U) (Level I [PRISMA]).
36. Intravenous paracetamol given before incision reduces opioid analgesic requirements
after Caesarean section (N) (Level I [PRISMA])

5th Edition | Acute Pain Management: Scientific Evidence

lxxiii37. Epidural (U) (Level I [QUOROM]) and intrathecal morphine (U) (Level I) and patientcontrolled epidural analgesia (U) (Level II) provide effective analgesia after Caesarean
section, but neuraxial morphine increases the rate of pruritus and nausea compared withsystemic administration (U) (Level I [QUOROM]).
38. Intrathecal morphine (range of 100 mcg to 250 mcg) increases time to first analgesic
request after Caesarean section, but pain scores and opioid consumption are unchanged,
and postoperative nausea, vomiting and pruritus increased (N) (Level I).
 Remifentanil IV PCA for relief of labour pain carries a risk of maternal respiratory
depression; use is recommended only if there is one-on-one continuous presence of a
midwife, continuous oxygen saturation monitoring and continuous cardiotocographmonitoring (as an indirect method of detecting global hypoxaemia) (U).
 Transversus abdominis plane blocks after Caesarean section may result in high plasma
concentrations of local anaesthetic and potential toxicity; minimum effective doses should
be used (U).
Pain management during lactation
1. Local anaesthetics, paracetamol and several NSAIDs, in particular ibuprofen, are considered
to be safe in the lactating patient (U) (Level IV).
2. Morphine, fentanyl, methadone, and short-term oxycodone immediately after delivery are
considered to be safe in the lactating patient and are preferred over pethidine (U) (Level
IV).
3. Repeated dosing of codeine or oxycodone in lactating patients should be avoided if possible
and the infant monitored for central nervous system depression (S) (Level IV).
 Prescribing medications during lactation requires consideration of possible transfer into
breast milk, uptake by the infant and potential adverse effects for the infant; it should
follow available prescribing guidelines (U).
 Breastfed neonates and infants may become sedated from the transfer of maternal
medications; in this case, observation and monitoring of the infant and seeking medical
advice is warranted. Maternal sedation may be an early warning sign (N).
Pain in the puerperium
1. Routine episiotomy does not reduce perineal pain (U) (Level I [Cochrane Review]).
2. Continuous suturing of all layers compared with interrupted suturing for repair ofepisiotomy or second-degree tears reduces perineal pain and analgesic use in the
postpartum period (U) (Level I [Cochrane Review]).
3. Paracetamol and NSAIDs are effective in treating perineal pain after childbirth comparedwith placebo (S) (Level I [Cochrane Review]).
4. NSAIDs, but not paracetamol, are effective in treating pain from uterine cramping aftervaginal birth (U) (Level I [Cochrane Review]).
5. There is limited evidence to support the effectiveness of local cooling treatments intreatment of perineal pain after childbirth (U) (Level I [Cochrane Review]).

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6. Topical local anaesthetic preparations are not effective for perineal pain after childbirth (U)(Level I [Cochrane Review]).
7. There is insufficient evidence to recommend any specific treatments for nipple pain andbreast engorgement (U) (Level I [Cochrane Review]).
 Pain after childbirth requires appropriate treatment as it coincides with new emotional,
physical and learning demands and may trigger postnatal depression (U).
 Management of breast and nipple pain should target the cause (U).
The older patient
1. Topical nsNSAIDs for localised pain provide effective analgesia (U) (Level I [Cochrane
Review] with lower plasma concentrations and fewer gastrointestinal adverse effects thanoral nsNSAIDs (U) (Level I); this may improve safety in the elderly.
2. PCA and epidural analgesia are more effective in older people than conventional opioid
regimens (U) (Level II).
3. Experimental pain thresholds to thermal stimuli are modestly increased in older people (U)(Level III-2 SR).
4. Reported frequency and intensity of acute pain in clinical situations may be reduced in theolder person (U) (Level III-2).
5. Common unidimensional self-report measures of pain can be used in the older patient in
the acute pain setting, but need to be appropriate for the individual patient; the verbal
descriptor and numerical rating scales are preferred in patients who can self-report (U)(Level III-2), while in the older patient with cognitive impairment, specific pain assessment
tools are more appropriate (N) (Level IV SR).
6. Undertreatment of acute pain is more likely to occur in cognitively impaired patients (U)(Level III-2).
7. The use of nsNSAIDs and coxibs in older people requires caution, although use of opioids
may result in more complications (U) (Level III-2); paracetamol is the preferred nonopioid
analgesic (U) (Level III-2).
8. The under-representation of older patients in clinical drug trials limits information about
efficacy, safety and pharmacokinetics of many types of medications including analgesic
medications (N) (Level IV SR}
9. The older patient is at increased risk from adverse effects of medications including many
analgesics (N) (Level IV).
10. Delirium is common in elderly hospitalised patients, including after surgery; risk factors
include inadequate pain management and excessive use of opioids and other sedating
analgesics (N) (Level IV).
11. There is an age-related decrease in opioid requirements; significant interpatient variability
persists (U) (Level IV).
12. The age-related decrease in opioid requirements is related more to the changes inpharmacodynamics that accompany ageing than to the changes in pharmacokinetics (U)(Level IV).
5th Edition | Acute Pain Management: Scientific Evidencelxxv The assessment of pain and evaluation of pain relief therapies in the older patient may
present problems, arising from differences in reporting, cognitive impairment anddifficulties in measurement (U).
 Measures of present pain may be more reliable than past pain, especially in patients withsome cognitive impairment (U).
 The physiological changes associated with ageing are progressive; while the rate of change
can vary markedly between individuals and is related to frailty, these changes may
decrease the dose (maintenance and/or bolus) of drug required for pain relief and maylead to increased accumulation of active metabolites (U).
 The high prevalence of frailty in the older patient is an independent risk factor forincreased adverse drug effects to analgesic medications (N).
 The use of regional analgesics techniques, as an alternative to systemic analgesics, canconfer benefits of improved pain relief, and minimise adverse effects (cognitive, pulmonary) (N).
 Cognitive impairment in the older patient may limit the appropriate use of PCA (N).
Culturally responsive care for Culturally and Linguistically Diverse patients
1. Disparities in assessment, analgesic requirements and effective treatment of pain exist
across ethnic groups (S) (Level III-2 SR).
2. Ethnic and cultural background of both healthcare professional and patient can influence
the ability to assess and treat acute pain (N) (Level III-2 SR).
 Cultural competence of health professionals supported by specific training improves
health outcomes for culturally and linguistically diverse patients (U).
 Pain assessment and management should be done on an individual patient basis.
Differences between ethnic and cultural groups should not be used to stereotype patients
but should only be used to inform of possible cultural preferences (U).
 Multilingual printed information and pain measurement scales are useful in managing
patients from different cultural or ethnic backgrounds (U).
 If language proficiency poses a communication barrier, then an accredited health careinterpreter should be included when conducting a pain assessment, to ensure correct
assessment; the use of friends, family or staff member should be avoided (N).
 The use of health-care specific language translation apps may be only considered as analternative option in non-clinical situations in the sub-acute setting (eg daily routine
communication) when formal healthcare interpreter services are not available (N).
Aboriginal and Torres Strait Islander Peoples
1. Verbal descriptor scales may be a better choice of pain measurement tool than verbal
numerical rating scales in some Aboriginal and Torres Strait Islander Peoples (U)(Level III-3).
2. Medical comorbidities such as renal impairment are more common in Aboriginal and Torres
Strait Islander Peoples and may influence the choice of analgesic agent (U) (Level IV).
 Heterogeneity between differing populations of Aboriginal Peoples may require tailoringof the service delivered to the population and individual being serviced (U).

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SUMMARY OF KEY MESSAGES Pain expression in Aboriginal and Torres Strait Islander Peoples may not reflect that whichis expected by the health professional’s cultural background. This places the onus on thehealth professional to understand nuances of pain expression and beliefs within such
populations (U).
 Aboriginal and Torres Strait Islander Peoples are at increased risk of underrecognition andundertreatment of pain (N).
Māori peoples
1. Experimental ischaemic pain is tolerated for longer in Māori people than in European New
Zealanders (U) (Level III-2).
2. Māori people report higher levels of pain and/or disability with dental pain, gout
and after trauma and joint replacement surgery than European New Zealanders (U)(Level III-2).
 High healthcare inequalities exist regarding access and quality of care (across age ranges,
genders and for various medical conditions) between the Māori and Pacific Islander
peoples compared with New Zealanders of European origin (S).
 Māori culture embraces the multidimensional aspects of pain experiences (S).
The patient with sleep-disordered breathing including obstructive sleep apnoea
1. Continuous pulse oximetry compared to intermittent nursing spot-checks detects more
episodes of hypoxaemia in postoperative patients with obstructive sleep apnoea prescribed
opioids (N) (Level I).
2. The STOP-Bang questionnaire has high sensitivity for the identification of patients at risk ofmoderate to severe obstructive sleep apnoea (S) (Level III-2 SR).
3. Patients with sleep-disordered breathing, including obstructive sleep apnoea, having
surgery are at increased risk of adverse cardiac and respiratory effects (S) (Level III-2 SR), in
particular cardiac arrest/shock, atrial fibrillation, aspiration pneumonia, acute respiratory
distress syndrome and need for intubation, mechanical and noninvasive ventilation (N)(Level III-2) and increased hospital length of stay (N) (Level III-2 SR).
4. Patients with obstructive sleep apnoea have an increased risk of exacerbation of
obstructive episodes and hypoxaemia during the postoperative period (U) (Level III-2), in
particular in the first 72 hours with peaks on the first and third postoperative night (N)(Level III-2).
5. Morbidly obese patients may be at increased risk of postoperative hypoxaemia,
independent of a diagnosis of obstructive sleep apnoea (U) (Level III-2).
6. Continuous positive airway pressure does not increase the risk of anastomotic leak after
upper gastrointestinal surgery (S) (Level III-2).
7. Increasing severity of obstructive sleep apnoea is associated with increased risk of
postoperative respiratory complications including opioid-induced ventilatory impairment(Q) (Level III-3).
8. The prevalence of obstructive sleep apnoea in the surgical patient population is high andthe majority (80%) of these patients are undiagnosed (S) (Level IV SR).

5th Edition | Acute Pain Management: Scientific Evidence

lxxvii9. Higher preoperative apnoea-hypopnoea index and identification of nocturnal hypoxemia
are risk factors associated with postoperative complications in patients with sleepdisordered breathing (N) (Level IV SR).
10. Patients with obstructive sleep apnoea have increased sensitivity to pain that improves withuse of continuous positive air way pressure (N) (Level IV SR).
11. Opioids in patients with obstructive sleep apnoea attenuate arousal to hypoxia and prolong
airway obstruction, and thereby lead to more severe hypoxaemia (S) (Level IV SR).
 Preoperative screening for obstructive sleep apnoea combined with treatment (ideallyinstituted preoperatively) and increased postoperative observation may decrease
postoperative morbidity and mortality (S).
 Management strategies that may increase the efficacy and safety of pain relief in patientswith obstructive sleep apnoea include multimodal nonsedating opioid-sparing analgesia
such as regional techniques, continuous positive airway pressure, monitoring andsupervision (in a high‐dependency area if necessary) and supplemental oxygen (U).
 Perioperative commencement of continuous positive airway pressure may be beneficial inpatients with obstructive sleep apnoea but requires high levels of supervision; significant
problems are poor patient acceptance and postoperative adherence (U).
 In patients with obstructive sleep apnoea, monitoring should be extended beyond 24
hours to capture the high-risk period for late postoperative hypoxaemia (N).
The obese patient
1. Perioperative dexmedetomidine infusion reduces pain intensity, opioid requirements and
PONV after bariatric surgery (N) (Level I [PRISMA]).
2. Intraoperative peritoneal local anaesthetic administration reduces pain intensity and opioid
requirements after bariatric surgery (N) (Level I [PRISMA]).
3. Paracetamol (multi-dosing) r educes opioid requirements, hospital length of stay andrepresentations for pain after bariatric surgery (N) (Level II).
4. Intraoperative systemic lidocaine infusions reduce pain intensity, opioid requirements andimprove the quality of recovery after bariatric surgery (N) (Level II).
5. Epidural administration of local anaesthetics in obese patients has been associated withincreased risk of cephalad spread (N) (Level III-2).
6. Obesity increases the failure rate of neuraxial and peripheral nerve blocks (N) (Level IV);
ultrasound guidance improves the success rate (N) (Level IV).
 Obesity has significant detrimental effects on respiratory function and is linked to anincreased rate of obstructive sleep apnoea (N).
 Obesity influences pharmacokinetic and pharmacodynamic parameters of analgesic
medications leading to uncertainty about dosing and caution should be used with weightbased dosing (N).
 Multimodal analgesic techniques including use of regional techniques result in opioidsparing effects and thereby improve safety of acute pain management after bariatricsurgery (N).

lxxviii 5th Edition | Acute Pain Management: Scientific Evidence

SUMMARY OF KEY MESSAGESThe patient with concurrent renal or hepatic disease Consideration should be given to the choice and dose regimen of analgesic agents inpatients with hepatic and particularly renal impairment (S).
The opioid-tolerant patient
1. Alpha-2 agonists (clonidine and lofexidine) reduce opioid-withdrawal symptoms (U) (Level I[Cochrane Review]).
2. Remifentanil use leads to opioid-induced hyperalgesia (U), which is attenuated by propofol(U) (Level I [PRISMA]), NMDA-receptor antagonists (U) (Level I [QUOROM]), pregabalin (U)(Level II), nitrous oxide (N) (Level II) and gradual tapering of remifentanil dose (N) (Level II).
3. Gabapentin and pregabalin attenuate opioid-induced hyperalgesia/tolerance and reduce
opioid-withdrawal symptoms (U) (Level II).
4. In opioid-tolerant patients, ketamine improves pain relief after surgery and reduces opioid
requirements (S) (Level II).
5. Long-term opioid use is a dose-dependent risk factor for sleep-disordered breathing, which
requires appropriate perioperative assessment, monitoring and management (S) (Level III-2
SR).
6. Long-term opioid use is associated with dose-dependent increased risks of injuries (N)(Level III-2) including fractures (N) (Level III-2 SR) and overdose (N) (Level III-2).
7. Preoperative opioid use is associated with worse outcomes after a variety of operations (N)(Level III-2).
8. Preoperative opioid tapering may ameliorate the risk of postoperative complications andmorbidity (N) (Level III-2)
9. Preoperative opioid use is a risk factor for prolonged postoperative opioid use (N)(Level III-2).
10. Opioid-tolerant patients report higher pain scores, have slower pain resolution leading tolonger hospital stay and increased readmissions but have a lower incidence of opioidinduced nausea and vomiting (U) (Level III-2).
11. Opioid-tolerant patients may have significantly higher opioid requirements and interpatientvariation in the doses needed than opioid-naïve patients (U) (Level III-2).
 Usual preadmission opioid regimens should be maintained where possible or appropriate
substitutions made (S).
 Liaison with all health care professionals involved in the treatment of the opioid-tolerant
patient is important (S).
 Opioid-tolerant patients are at risk of opioid withdrawal if nonopioid analgesic regimens,
tramadol or tapentadol alone are used (U).
 PCA settings may need to include a background infusion or other background opioid toreplace the usual opioid dose and a higher bolus dose (U).
 Neuraxial opioids can be used effectively in opioid-tolerant patients, although higher
doses may be required and these doses may be inadequate to prevent withdrawal (U).
5th Edition | Acute Pain Management: Scientific Evidencelxxix Adjuvants are used for their antitolerance, antihyperalgesic, and antiallodynic effects andthere is some evidence upon which to base the choice of agent (S).
 In patients with escalating opioid requirements, management considerations are thedevelopment of tolerance or opioid-induced hyperalgesia (S).
 Following short-term opioid dose escalation for acute pain, a “reverse analgesic ladder”
approach, using stepwise reduction to the patient’s usual opioid regimen isrecommended (S).
 For assessment of withdrawal reactions, the use of a validated withdrawal tool in opioidtolerant patients is recommended; management strategies vary and include weaning,rotation and adjuvant use (N).
The patient with a substance use disorder
1. Benzodiazepines are effective for alcohol-withdrawal symptoms, in particular reducing
seizures (U) (Level I [Cochrane Review]).
2. Opioid substitution therapy with methadone or buprenorphine is better than clonidine
and lofexidine in ameliorating withdrawal symptoms (N) (Level I [Cochrane Review]).
3. Methadone and buprenorphine maintenance regimens should be continued throughout
acute pain episodes wherever possible (S) (Level III-2 SR [PRISMA]).
4. Poorly managed acute pain episodes may decrease retention in opioid-maintenanceprograms (U) (Level III-2).
5. To achieve better analgesic efficacy, daily methadone maintenance doses should be
divided and given 8 to 12 hourly (S) (Level IV SR [PRISMA]).
 Pain management in patients with substance use disorder often presents significant
challenges for both clinicians and patients. Patients fear being stigmatised or
discriminated against, are concerned about inadequate pain relief with their pastexperiences leading to physician distrust; they fear experiencing withdrawal (before theirusual drugs are prescribed) and relapse precipitated by acute opioid exposure. The
challenges for the clinician Include mistrust, concerns about drug seeking, fear ofovertreatment with adverse events, concerns about diversion, and risk of discharge
against medical advice (N).
 A “universal precautions” approach is increasingly recommended for patients with
substance use disorder in acute pain settings; it may include use of multimodal analgesia,
abuse-deterrent formulations, urine drug screening, use of prescription drug monitoring
programs and risk management strategies (N).
 An acute admission offers opportunity to engage with patients with substance use
disorder as well as to treat the acute issues (N).
 There is no cross-tolerance between alcohol or benzodiazepines or central nervous system
stimulants and opioids (U).
 Oral naltrexone should be stopped at least 24 hours, ideally 72 hours, prior to elective
surgery (U); naltrexone implants may need surgical removal in cases of severe acute pain
where opioid responsiveness is required (U).

lxxx

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SUMMARY OF KEY MESSAGES Patients who have ceased naltrexone therapy should be regarded as opioid naïve; in theimmediate post-treatment phase they may be more opioid sensitive (U).
 To achieve better analgesic efficacy, daily buprenorphine maintenance doses could be
divided and given 8 to 12 hourly (U).
 Nicotine has a small to medium analgesic effect in volunteers and smoking abstinence
increased self-reported pain (N).

10.0 | PaediatricDevelopmental neurobiology of pain
1. Following birth, even the most preterm neonate responds to nociceptive stimuli (U)(Level IV).
2. In early development, more generalised reflex nociceptive responses occur in response tolower intensity stimuli (U) (Level IV).
Consequences of early pain and injury
1. Pain and injury in early life cause structural changes in cortical and subcortical pathways andare associated with alteration in somatosensory thresholds in later life (U) (Level III-2).
2. Analgesia may modulate the long term effects of pain and injury in early life but more
information is required to determine the optimal dosing and type of agents to avoid
negative impact of the pharmacological intervention itself (U) (Level III-2).
3. Improving quality of infant pain management delivery in neonatal intensive care (including
pharmacological and nonpharmacological interventions) may result in improved
neurodevelopmental outcomes (U) (Level III-2).
4. Understanding of the epigenetic factors that contribute to the behavioural pain trajectory is
evolving; this may lead to enhanced developmentally targeted care to reduce stress
exposure and long term impacts for infants (N) (Level IV SR [PRISMA]).
Paediatric pain assessment
1. Pain measurement tools are available for children of all ages (S) (Level IV SR).
2. Paediatric pain measurement tools must be matched to the age and development of thechild (U) (Level IV SR).
3. Adoption of written guidelines or pain management algorithms improves both assessmentand management of pain in neonates and children (N) (Level IV SR).
 Pain assessment and measurement are important components of paediatric pain
management (U).
 Pain scores generated from different pain scales may not be congruent and this should beconsidered when used clinically and in research (N).
 Pain scores and pain score subdivisions (cut-offs) should not be used as a sole guide toadministration of analgesia (N).

5th Edition | Acute Pain Management: Scientific Evidencelxxxi Children with neurodevelopmental disorders (with and without cognitive impairment andvarying levels of physical disability) may be more susceptible to pain and communicate it
in different ways (N).
 Pain measurement tools must be appropriate for the clinical context, be explained andused consistently (U) and be validated when translated into other languages (Q).
 Facial recognition software applications may reduce clinician bias and become useful
bedside tools in neonates and children with and without cognitive impairment (N).
Analgesic agents
Paracetamol (acetaminophen)
1. Post tonsillectomy in children, paracetamol (alone or combined with opioids) administered as
required compared to fixed schedule achieved similar pain scores over 3 days; with lower
dosing administered in the as required groups (N) (Level I [Cochrane Review]).
2. For pain of acute otitis media in children, paracetamol is similar to ibuprofen and both aresuperior to placebo in achieving pain freedom at 48 hours, but not other time points (N)(Level I [Cochrane Review]).
3. Paracetamol is effective for moderately severe pain and decreases opioid requirements
after major and minor surgery in children (U) (Level I [PRISMA]).
4. Paracetamol has a similar safety and tolerability profile compared with ibuprofen and placebo
if prescribed and administered at recommended doses in children (U) (Level IV SR).
5. Retrospective epidemiological studies linking paracetamol use in pregnancy or infancy tolater development of childhood asthma are inherently confounded (U); when adjusted forrespiratory tract infections in the child the association is lost (Q) (Level III-2 SR [PRISMA]).
6. Retrospective epidemiological studies report modest association of paracetamol use inpregnancy with childhood neurodevelopmental disorders such as attention deficit andhyperkinetic disorders; this is strengthened when adjusted for longer term use (>28 days)
and disappears for short term use (<8 days) (Q) (Level III-2 SR [PRISMA]).
7. Paracetamol has unclear vasoactive effects; in critically ill children, hypotension isreported with both IV formulations (N) (Level IV SR).
 Safe dosing of paracetamol requires consideration of the age and body weight of the childand the duration of therapy (U).
 Paracetamol related hepatotoxicity generally occurs in children who have received doses
greater than 120 mg/kg, as single or repeated daily dosing; with contributions fromrounding up or 10-fold dosing error and formulation substitution or confusion byprescribers and parents (N).
 Paracetamol is recommended routinely following tonsillectomy andpharmacokinetic/pharmacodynamic simulation is exploring the optimal combinations ofmultimodal analgesia in this surgical model (N).
 There is insufficient pharmacokinetic/pharmacodynamic and safety data of use ofparacetamol in preterm and term neonates; use for patent ductus arteriosus closure inpreterm neonates provides limited data in this age group of an improved safety profile
compared with nsNSAIDs (N).

lxxxii 5th Edition | Acute Pain Management: Scientific Evidence

SUMMARY OF KEY MESSAGES Emerging evidence suggests that maternal paracetamol use may influence premature
closure of the fetal ductus arteriosus (N); use in pregnancy should be limited to theminimum dose and duration that is clinically necessary.
 Intravenous paracetamol in haemodynamically unstable patients has been associated withhypotension (N).
Nonselective NSAIDs
1. Nonselective NSAIDs do not increase the risk of either surgical or nonsurgical intervention
for bleeding after paediatric tonsillectomy (U) (Level I [Cochrane Review]); however thiswas not supported by a large non-inferiority RCT where surgical intervention wasincreased with ibuprofen versus paracetamol (Q) (Level II).
2. Nonselective NSAID (ibuprofen) use for acute otitis media reduces pain (at 48 hours) vsplacebo, with similar efficacy to paracetamol (N) (Level I [Cochrane Review]).
3. Nonselective NSAIDs are effective for moderately severe pain and decrease opioid
requirements after major paediatric surgery (U) (Level I [PRISMA]) and postoperative
nausea and vomiting (U) (Level I [QUOROM]).
4. Serious adverse effects after nonselective NSAIDs are rare in children over 6 months ofage (U) (Level II).
5. Ibuprofen may increase severity of haemorrhage post tonsillectomy in patients returning
to theatre (N) (Level III-3).
6. Short term use of ketorolac or ibuprofen do not increase bone healing complications inchildren undergoing posterior spinal fusion, osteotomy, or fractures managed surgically(S) (Level III-3) or conservatively (N) (Level III-3).
 Aspirin for acute pain indications should be avoided in children (U).
 Combined population pharmacokinetic-pharmacodynamic modelling is required to informtargeted dosing recommendations of analgesics in children (U).
Coxibs
1. Parecoxib use in children reduces early postoperative pain scores, PONV (compared totramadol and fentanyl) and postoperative opioid consumption (N) (Level I [PRISMA]).
2. Parecoxib may have a ceiling analgesic effect in children in doses less than 1 mg/kg (N)(Level II).
 The safety profile of coxibs in the setting of allergy or contraindication to nonselective
NSAID in adults and children is encouraging; but safety data specific to short term use in
the perioperative period is limited (Q).
 Celecoxib for 3 days reduces pain and additional analgesic requirement post-tonsillectomy
in children (N).
 Some paediatric centres retain the 1 mg/kg (40 mg) maximum daily dosing schedule for
Parecoxib for off license use (N).

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Conventional and atypical opioids
Opioids
1. Young and obese children with history of obstructive sleep apnoea/sleep-disorderedbreathing are at higher risk of developing serious opioid-induced ventilatory impairment
and death (U) (Level IV).
2. Opioid-induced ventilatory impairment and death occur rarely with therapeutic dosing inchildren taking opioids at home (N) (Level IV).
3. Safe dosing of opioids requires consideration of the child’s age, body weight, comorbidities
and ethnicity (U) (Level IV).
Fentanyl
4. Intranasal fentanyl is an effective treatment for paediatric acute pain management, with anacceptable adverse effect profile and ease of delivery (N) (Level I).
Codeine5. The efficacy of oral codeine in children is unpredictable due to genetic differences in theability to generate the active metabolite morphine (U) (Level II), as are adverse effects andserious toxicity (U) (Level IV).
6. Codeine should not be used in children, especially after adenoidectomy or tonsillectomy, due
to an increased risk of opioid-induced ventilatory impairment and death (S) (Level IV).
Tramadol
7. Tramadol provides superior analgesia to placebo and has similar efficacy to conventional
opioids in children of all ages administered by various routes for multiple surgery types (S)(Level I [Cochrane]).
8. It is unclear if tramadol causes less ventilatory impairment than other opioids in children
due to insufficient trial size (N) (Level I [Cochrane]).
Buprenorphine
9. Buprenorphine administered IV or caudally has similar efficacy to morphine or caudal local
anaesthetic in children for different surgery types (N) (Level II).
Nalbuphine
10. Nalbuphine intravenously is effective for postoperative pain relief in children in several low
quality heterogeneous trials (N) (Level I [Cochrane]).
 Careful titration of opioids is advised according to the individual child’s response(analgesia and adverse effects) (U).
 Despite the regulatory response with boxed warning and upscheduling of codeine,prescription continues in at risk patients (with obstructive sleep apnoea/sleep-disorderedbreathing or post adenotonsillectomy) or has been replaced by prescription of potent
conventional opioids such as oxycodone and hydrocodone which present similar or
greater hazard (N).
 The practice of applying an occlusive dressing to the skin surface of a transdermal fentanyl
delivery system does not limit dose delivery (U).
 Tramadol shares some adverse effects with the conventional opioid class in children, withsimilar or reduced rates of nausea and vomiting, sedation and fatigue but less constipation

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SUMMARY OF KEY MESSAGES

and pruritus (U). Sedation (not necessarily associated with miosis), seizures, ventilatory
impairment and deaths have occurred (N).
 Naloxone has been used to treat tramadol overdose in children with effect (N).
 CYP2D6 phenotype has been the reason for codeine’s black box warning, but the clinicalsignificance in terms of tramadol/M1’s analgesic efficacy and adverse-effect profile
including safety is still unknown (S). Inadvertent overdose and formulation issues are likely
of greater risk than CYP phenotypes resulting in variable drug metabolism; evidence forharm from this second mechanism is lacking (N).
 Tramadol 100mg/mL concentrated drops formulation use is potentially harmful in children
with possible dosing confusion (drops with millilitres) and resultant overdose (U).
 In paediatric overdose, buprenorphine causes the spectrum of neurocognitive adverse
events as seen with conventional opioids which may be reversible with naloxone (N).
 More studies are required to determine tapentadol’s comparative efficacy in paediatricacute pain and if its adverse effect profile in children is improved versus placebo,
conventional opioids or tramadol (N).
 In paediatric overdose, tapentadol causes the spectrum of neurocognitive adverse events
seen with conventional opioids, which may be reversible with naloxone (N).
Discharge opioid prescribing for children
1. Postoperative opioid therapy in children and adolescents may lead to long term opioid use
and misuse in later life (N) (Level III-2); risk factors include type of surgery, psychologicaland social factors and other substance use (N) (Level III-2).
2. Long term opioid use following therapeutic medical prescription is uncommon in children
and adolescents (N) (Level IV). However, prior diagnosis of chronic pain, substance use ormental health conditions are risk factors (N) (Level IV).
3. Misuse of prescription opioids is common amongst adolescents and young adults either
as medical use (self-treatment) or nonmedical use (sensation seeking/recreational) (N)(Level IV).
4. Leftover prescribed opioids are a common source of nonmedical opioid use in adolescents,
with most adolescents gaining access through family or friends (N) (Level IV).
5. Unsafe storage of prescription opioids in the home and non-disposal of leftover opioids iscommon (N) (Level IV).
6. Prescription opioids are a large source of opioid-related poisonings: usually accidental inyoung children and related to recreational use or with intentional overdose in adolescents(N) (Level IV).
7. Adverse drug events in children and adolescents sent home with prescription opioids arecommon (N) (Level IV).
 As for adults, a sensible approach should be used in the setting of prescribing discharge
opioid medications for children and to adults with children at home (N).
 As for adults, prescribing discharge medications for children should be done withconsideration of the child’s anticipated opioid requirements. The tablet number andvolume of opioid solution prescribed should be judicious and individualised (N).
5th Edition | Acute Pain Management: Scientific Evidencelxxxv Understanding and education is required to determine procedure specific pain trajectories
in children (N).
 Carer/parental, patient and clinical staff education is necessary about risks of opioids andhow to safely dispose of unused medication by return to a pharmacy (N).
 Carer/parental and patient education in case of ongoing pain and analgesic issues isappropriate with follow-up by general practitioners or pain medicine services as indicated (N).
 Education and guidelines are desirable for adult and paediatric discharge and community
opioid prescribers with focus on information provision for staff delivering the advice(ideally written and verbal combined) to carers and families (N).
Opioid tolerance in children and adolescents
1. Iatrogenic withdrawal syndrome following prolonged inpatient intravenous opioid therapy
in critically ill children is common (N) (Level IV SR [PRISMA]).
 There are groups of paediatric patients who are opioid-tolerant, as in adults. They require
special consideration for inpatient pain management and perioperative care. In children
with opioid tolerance, inadequate pain relief and withdrawal (if opioids are acutelyceased) are specific risks. Acute pain service input can assist with preadmission planningand use of various adjuvants beyond standard multimodal interventions (N).
 For assessment of withdrawal reactions, the use of a validated withdrawal tool in
paediatric opioid-tolerant patients is recommended; management strategies vary andinclude opioid weaning, rotation and adjuvant use (N).
Systemic NMDA-receptor antagonists
Ketamine
1. Perioperative low-dose intravenous ketamine bolus is similarly effective to opioids andsuperior to placebo in reducing early pain scores and analgesic requirements in children (U)(Level I [PRISMA]).
2. Perioperative low-dose intravenous ketamine bolus does not increase the postoperative
incidence of nausea and vomiting, sedation, agitation, dreams or hallucinations in children(S) (Level I [PRISMA]).
3. Peritonsillar infiltration and topical application of ketamine for paediatric tonsillectomy
reduces early pain scores and analgesic requirements versus placebo (S) (Level I [PRISMA]).
4. When added to multimodal analgesia, perioperative ketamine (bolus with or without
intra/postoperative infusion) in children is not opioid-sparing vs placebo (S), although low
postoperative pain scores and small sample sizes mean the meta-analysis is underpowered(Q) (Level I [PRISMA]).
5. There is low level evidence that combination ketamine and opioid PCA improved painscores and PCA use post Nuss surgery (N) (Level II).
 High-dose long term ketamine is neurotoxic in animal models. The neurodevelopmental
impact in children of subanaesthetic/analgesic doses of ketamine administered by bolusor postoperative infusion is unclear (U).
 The benefit of perioperative ketamine in preventing remifentanil induced hyperalgesia
has not been adequately assessed in paediatric surgery (U).

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SUMMARY OF KEY MESSAGES

Magnesium
6. Magnesium (intravenous or peritonsillar infiltration) in children for tonsillectomy reduces
postoperative rescue medication use, and increases time to first analgesia versus control;
magnesium also reduces risk of postoperative emergence agitation and laryngospasm (N)(Level I [PRISMA]).
7. Magnesium (locally infiltrated) in children reduces late (24 hour) but not early (<1 hour)
pain scores post tonsillectomy versus control (N) (Level I [PRISMA]).
Alpha-2 agonists
1. Preoperative oral clonidine reduces postoperative pain scores and analgesic requirement inchildren compared to placebo or midazolam but not fentanyl (U) (Level I [Cochrane
Review]).
2. Preoperative oral clonidine reduces postoperative nausea and vomiting in children
compared to placebo or midazolam (U) (Level I [Cochrane Review]).
3. Preoperative intranasal dexmedetomidine reduces postoperative pain scores, rescue
analgesic requirements and emergence agitation with minimal adverse effects vs placebo(N) (Level I [PRISMA]) and mixed comparators (N) (Level I).
4. Intraoperative dexmedetomidine reduces postoperative pain scores (U) (Level I [PRISMA])
and need for postoperative rescue analgesia (Q) (Level I) including opioid (U) (Level I[PRISMA]) in children compared to placebo, with minimal impact on time to discharge (N)(Level I [PRISMA]) via intravenous (S) (Level I [PRISMA]) and intranasal routes (S) (Level I).
 Alpha-2 agonists offer benefits in addition to analgesia in children in the perioperative,
intensive care and procedural settings. These benefits include anxiolysis, sedation (MAC
sparing), behavioural modification, prevention or treatment of opioid withdrawal(facilitating opioid weaning) (U) and reduction of emergence agitation (S).
Alpha-2-delta ligands (gabapentinoids)
1. Multi-day perioperative (but not single preoperative) gabapentin dosing reduces
postoperative morphine consumption vs placebo following multilevel posterior spinal
fusion for adolescents with idiopathic scoliosis (N) (Level II).
2. Multiday perioperative gabapentin reduces phantom limb pain incidence vs placebo in
paediatric oncology amputation surgery (N) (Level II).
3. Preoperative gabapentin and likely pregabalin improve analgesia after tonsillectomy inchildren and reduce PONV without increasing adverse effects (N) (Level I [PRISMA]).
 Alpha-2 delta ligands use in children for acute (and chronic) pain conditions is expanding
based mostly on expert opinion and case series. The pain indications are similar to those
for adults with similar benefit and adverse event profiles (N).
 Gabapentin and pregabalin are used to manage pruritus and neuropathic pain following
burn injury in children (N).
 The use of alpha-2 delta ligands for the prevention of chronic postsurgical pain in children
has not been studied (N).

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Corticosteroids
1. Single dose intravenous dexamethasone reduces pain post tonsillectomy, postoperative
vomiting and time to soft diet commencement in children (U) (Level I [Cochrane Review]).
2. Intavenous dexamethasone does not increase the overall risk of bleeding post tonsillectomy
but increases the risk of reoperation for bleeding in children (S) (Level I).
3. Oral dexamethasone (given in addition to antibiotics) shortens the time to onset of pain
relief in pharyngitis in children (U) (Level I).
4. Oral prednisolone multiday course post tonsillectomy does not reduce pain outcomes at
day 3 or day 7 or postoperative nausea and vomiting (N) (Level I).
Systemic lidocaine infusions
1. Perioperative intravenous lidocaine infusion in abdominal surgery in children improved
various pain and non-pain related postoperative outcomes (N) (Level II).
 Dosing of perioperative lidocaine infusions have been extrapolated from use in adults andpharmacokinetic study is warranted to determine safe dosing practices in children (N).
Opioid infusions and Patient Controlled Analgesia (PCA) in children
1. Addition of a low-dose background infusion to patient controlled analgesia (PCA) bolus resultsin similar pain scores and total opioid consumption and improves sleep duration in children;
numbers are inadequate to assess safety of adding a background (N) (Level I).
2. In ventilated preterm neonates, routine use of morphine infusions does not affectmortality, duration of ventilation or neurological outcomes (U) (Level I [Cochrane Review]),
including when followed up as older children (S) (Level II).
3. Postoperative intravenous opioid requirements vary with age in neonates, infants andchildren (U) (Level II).
4. Intermittent intramuscular injections are distressing for children and are less effective forpain control than intravenous infusions (U) (Level III-1).
5. Patient-controlled analgesia (PCA) can provide safe and effective analgesia for children as
young as 5 years old (S) (Level III-3).
6. Intravenous opioids via continuous infusion, nurse-controlled analgesia and parental proxyuse of patient controlled analgesia (PCA) devices can be used effectively (U)(Level III-2) and safely (N) (Level IV) in children of all ages.
7. Nurse-controlled analgesia (U) (Level III-2) and parental proxy use of patient controlled
analgesia (PCA) devices in children (U) (Level III-3) may require more rescue interventions(such as naloxone, airway management or intensive care) than PCA, but this may reflect the
younger patient population where this technique is offered.
8. Morphine by patient controlled analgesia (PCA) is at least as safe as intermittent nurse
administered intravenous morphine (N) (Level IV).
 Initial doses of opioid should be based on the age, weight and clinical status of the childand then titrated against the individual’s response (U).

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SUMMARY OF KEY MESSAGES Effective patient controlled analgesia (PCA) prescription in children incorporates a bolusthat is adequate for control of movement-related pain (U).
Paediatric Regional Analgesia
1. Topical local anaesthetic does not adequately control pain associated with circumcision inawake neonates (U) (Level I [Cochrane Review]).
2. Caudal local anaesthetic, dorsal penile nerve block (U) (Level I [Cochrane Review]) and ring
block (N) (Level II) provide effective perioperative analgesia for circumcision in infants toadolescents.
3. Caudal local anaesthetic in addition to general anaesthesia for circumcision does not reduce
postoperative nausea and vomiting or the need for early rescue or other analgesia inchildren (infants to adolescents) when compared to parenteral analgesia (U) (Level I[Cochrane Review]).
4. In acute otitis media, topical local anaesthetic drops are effective in children compared toplacebo and equivalent to naturopathic drops (S) (Level I [Cochrane Review]).
5. For paediatric cleft lip repair, infraorbital nerve block with lidocaine or bupivacaine may
reduce postoperative pain versus placebo; duration is increased when opioids are added(with no systemic comparator) (N) (Level I [Cochrane Review]).
6. Epidural analgesia compared to systemic analgesia after spinal surgery in children
improves pain up to 72 hours postoperatively (N) (Level I[Cochrane Review]).
7. Local anaesthetics (by infiltration or nerve block) reduce pain scores post dental procedures(N) (Level I [PRISMA]).
8. Ketamine added to caudal local anaesthetic for paediatric day-stay surgery prolongs
analgesia but not motor block (U) (Level I [PRISMA]); however concerns regarding
neurotoxicity remain.
9. Dexamethasone (caudal, perineural or IV) prolongs the duration of analgesia of local
anaesthetic caudal (N) (Level I [PRISMA]) and peripheral nerve blocks (N) (Level II).
10. Magnesium added to caudal local anaesthetic blocks improves analgesia in children (N)(Level I [PRISMA]).
11. Clonidine (U) and dexmedetomidine (N) improve analgesia in children when added to local
anaesthetic caudal blocks, epidural infusions (Level I [PRISMA]) and peripheral nerve blocks(N) (Level II).
12. Peritonsillar dexamethasone or peritonsillar ketamine may reduce pain scores following
paediatric tonsillectomy compared to placebo (in trials with no systemic comparator arms)(N) (Level I).
13. Ultrasound guidance for epidural catheter insertion is a reliable predictor of depth to loss ofresistance (or of epidural space), offers visibility of the needle and catheter and may reducebone contacts (N) (Level IV SR).
14. In children having cardiac surgery, caudal injections with various medication combinations
vs control reduces postoperative analgesia requirements and pain scores (N) (Level IV SR[PRISMA]).

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lxxxix15. In children having scoliosis surgery, the addition of epidural local anaesthetic infusion to
intravenous PCA morphine improves pain scores and patient satisfaction (U) (Level I) anddecreases postoperative nausea (U) (Level II).
16. Peripheral nerve blocks (S) (Level I [PRISMA]), wound infiltration and caudal local anaesthetic
provide effective analgesia after day-stay paediatric inguinal surgery (S) (Level II).
17. Epidural infusions of local anaesthetic in children provide similar levels of analgesia comparedto systemic opioid infusion (U) (Level II) and intravenous PCA (U) (Level III-3 SR).
18. Epidural opioids alone are less effective than epidural local anaesthetic or combinations oflocal anaesthetic and opioid in children (U) (Level II).
19. Intrathecal opioids provide prolonged analgesia after surgery in children and reduce blood
loss during paediatric spinal fusion (U) (Level II). High doses of intrathecal morphine inchildren have been associated with respiratory failure and intensive care admission (N)(Level III-2).
20. Paediatric regional analgesia (peripheral nerve and neuraxial blocks as single injections andcontinuous catheters) are effective (Level II) and safe analgesic techniques in children (S)(Level IV); continous peripheral nerve catheters have been used in hospital and following
discharge, with low secondary failure rates (N) (Level IV).
21. Ultrasound guidance to assist peripheral block and catheter placement has increased block
success (Level II) but not impacted the incidence of local anaesthetic systemic toxicity orneurological complications in children; the latter having decreased independently over time(N) (Level IV).
22. Continuous wound catheter infusions of local anaesthetic are effective (N) (Level II) andsafe analgesic techniques (N) (Level IV).
23. Caudal local anaesthetic blocks provide effective analgesia for lower abdominal, perineal
and lower limb surgery (Level II) and have a low incidence of serious complications (S)(Level IV).
24. Continuous ultrasound-guided caudal injection versus landmark technique increases
success of first puncture and lowers risk of vascular puncture and inadvertent subcutaneous
injection (N) (Level II); while permitting real-time visualisation of injectate spread (N)(Level IV).
25. Sub Tenon block for paediatric ocular surgery achieved longer time to first analgesic
administration versus placebo or intravenous opioid (N) (Level II).
26. Complications of epidural infusions are rare; the rates are slightly higher in neonates andinfants versus older children (S) (Level III-2).
27. Continuous epidural infusions provide effective postoperative analgesia in children of allages (U) (Level III-2).
28. Continuous epidural infusions are safe in children of all ages (S) (Level III-2) if appropriate
doses and equipment are used by experienced practitioners, with adequate monitoringand management of complications (U) (Level IV).
29. Thoracic epidural, paravertebral catheters, wound catheters and intercostal nerve blocks
all provide effective analgesia for pectus excavatum repair surgery, with longer hospital
stays in thoracic epidural recipients (N) (Level III-3).

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30. Placement of paediatric regional analgesia (peripheral nerve and neuraxial blocks as single
injections and catheters) in children under general anaesthesia is not associated with anincreased rate of complications (S) (Level IV).
 An association between urethral fistula formation complicating hypospadias repair andcaudal block has not been consistently reported; variation in anatomical presentation andsurgical technique are more biologically plausible risk factors (N).
 Lipid emulsion (20%) has been used in successful resuscitation of paediatric patients(neonates to 18 years) with local anaesthetic systemic toxicity; dosing recommendations
are the same as for adults and higher doses have led to adverse effects (N).
 Dosing practices for peripheral nerve blocks vary and concerningly doses sometimes
approach or exceed the accepted safe dose limit; this occurs more commonly in younger
children (N).
Management of procedural pain in children
Neonates
1. In term neonates, venipuncture is less painful than heel lance (N) (Level I [Cochrane Review]).
2. Sucrose (S) (Level I [Cochrane Review]) and non-sucrose sweet solutions (mostly glucose)(N) (Level I [PRISMA]) reduce pain scores and behavioural response for skin-breaking
procedures in neonates.
3. Providing physical comfort measures, including kangaroo care (maternal or alternative skin toskin provider), non-nutritive sucking (alone or combined with sweet-tasting solutions),
facilitated tucking (swaddling) or rocking and holding (N) reduces pain experienced by term andpreterm neonates having skin-breaking procedures (S) (Level I [Cochrane Review]).
4. Pain from ocular examination for retinopathy of prematurity is reduced by sucrose and nonnutritive sucking (N) (Level I [Cochrane Review]) and topical local anaesthetic (N) (Level III-1
SR [Cochrane Review]).
5. Kangaroo care (or skin to skin contact) in neonates reduces the distress of vaccine injection(N) (Level III-1 SR).
6. Sucrose reduces distress after gastric tube placement in neonates (N) (Level III-1 SR).
Infants and children
7. Breastfeeding (<2 years of age) reduces pain intensity and crying duration for skinbreaking procedures including vaccine injection compared to positioning, holding bymother, maternal skin to skin contact (<1 months), topical anaesthetics, music therapy,
pacifier use (<4 months), placebo, no intervention and/or oral sucrose (S) (Level I[Cochrane Review]).
8. Non-nutritive sucking reduces pain after needle-related procedures in infants and young
children (<3 years) (N) (Level I [Cochrane Review]).
9. Oral sucrose and glucose reduce cry incidence and duration (U) (Level III-1 SR [Cochrane
Review]) and distress (N) (Level III-1 SR) of vaccine injection in infants.
10. Distraction in infants and young children (<3 years) reduces vaccine injection pain (N)(Level III-1 SR).

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xci11. Procedural modifications reduced distress of vaccine injection including injection without
aspiration (18 months), simultaneous injection of multiple vaccines (12 months) andinjection of most painful vaccine last (6 months) (N) (Level III-1 SR).
12. Topical local anaesthetic reduces distress of vaccine injection in infants (N) (Level III-1 SR).
13. Parental presence reduces prevaccine injection distress in infants and children (N)(Level III-1 SR).
14. Parental education before or on vaccination day increases use of evidence-based pain
management strategies and reduces distress in infants and children (N) (Level III-1 SR).
15. Physical interventions including holding by parent (during or after) and non-nutritive sucking
in infants (0─4 months) reduces the distress of vaccine injection (N) (Level III-1 SR).
16. The efficacy of supplemental/expressed breast milk for procedural pain management isunclear (N) (Level III-1 SR).
17. Needle-free pressure injected lidocaine is quick in onset and reduces pain from subsequent
needle-related procedures in infants and children (N) (Level II).
Children and adolescents
18. EMLA® is an effective topical local anaesthetic for children but amethocaine is superior for
reducing needle-insertion pain (U) (Level I [Cochrane Review]).
19. Topical local anaesthetic application (U) (Level I [Cochrane Review]), inhalation of nitrous
oxide 50─70% or the combination of both (U) (Level I [PRISMA]) provides effective and safe
analgesia for minor procedures in children.
20. Distraction (including with video, toys, music or stories) and hypnosis reduces needle
related pain (S) and distress (N) in children and adolescents (Level I [Cochrane Review]).
21. Buzzy (which combines vibration and cold) (N) (Level I [PRISMA]) and vibration by othermethods (S) (Level III-1 SR) reduces needle-related procedure pain, including vaccine
injection in children.
22. Active and passive music therapy reduces pain and anxiety associated with various needlerelated procedures in children (U) (Level I).
23. Immersive virtual reality reduces pain of medical procedures including wound dressing careand venipuncture (N) (Level III-1 SR [PRISMA]).
24. Immersive virtual reality for medical procedures in children reduces self-reported pain andanxiety (N) (Level III-1 SR).
25. Ketamine is effective for paediatric procedural pain management (Q) (Level IV).
26. Hospital wide initiatives to implement evidence-based standards of care for needle related
procedures can improve service delivery and patient satisfaction (N) (Level IV).
 Using combinations of evidence-supported single pain management strategies for painfulprocedures is strongly recommended (N). Non-pharmacological intervention should
always be incorporated (N).
 It is of concern that minor procedures are still undertaken in children, particularly
neonates and infants, in the elective and emergency hospital setting with minimal or no
pain management intervention (N).

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SUMMARY OF KEY MESSAGES Inadequate monitoring, lack of adequate resuscitation skills and equipment, and the useof multiple medicine combinations has been associated with major adverse outcomes
during paediatric procedural analgesia and sedation (U).
 Pain caused by injection is a barrier to vaccine uptake; thus managing vaccine injection
pain has immediate and long term implications for the wellbeing and health of individuals
and society (N).
 Based on data from other specific phobias, exposure-based therapy (in vivo or imagined) is
recommended for children and adolescents (7─17 years) with needle phobia receiving
vaccine injections (N).
 Hypnosis requires teaching by a trained professional, but distraction can be readily provided
by staff or parents and should be routinely offered in the paediatric setting (U).
 For children and adolescents, sitting upright may reduce procedural pain and distress (N).
Acute pain in children with cancer
1. PCA and continuous opioid infusions are equally effective in the treatment of pain in
mucositis in children, but opioid consumption and duration of pain is less with PCA (U)(Level I [Cochrane Review]).
2. Topical local anaesthetic application for children having central venous port access iseffective and analgesia is not further improved by oral analgesics (morphine orparacetamol) (U) (Level II).
3. Self-reported pain scores by children with cancer were higher in intensity compared withnurse-reported pain scores, with variable agreement with parent/carer-reported painscores (N) (Level III-2 SR).
4. There is limited evidence that low-level laser therapy reduces the severity of mucositis inchildren (U) (Level III-2 SR [PRISMA]).
5. QT interval prolongation with methadone in children with cancer has been reported
without complication; the clinical significance is not clear (N) (Level IV).
6. Poorly managed pain in children during the terminal stages of cancer is associated withhigher levels of long term parental grief (N) (Level IV).
7. Outpatient intravenous PCA opioid has been used to help children in the terminal stages ofcancer stay at home (N) (Level IV).
8. Transdermal fentanyl patch use may be appropriate in opioid tolerant children with cancer(N) (Level IV).
 In paediatric cancer pain management, the same therapeutic approaches as in adults areused, although evidence is limited (U).
 The World Health Organization has removed codeine from the management approach topaediatric cancer pain reducing the number of tiers from three to two: with tier one
including nonopioid analgesics and adjuvants and tier two including strong opioids; in 2019
the WHO withdrew the reference document, but it remains endorsed by organisations
throughout Australia, New Zealand and internationally until it is replaced (Q).

5th Edition | Acute Pain Management: Scientific Evidencexciii Caution must be taken during uptitration of transdermal systems due to thepharmacokinetic profile of transdermal delivery that has slow penetration and delayed
uptake from the stratum corneum (N).
Other acute pain conditions in children
Management of pain due to trauma and burns in children
1. For paediatric trauma patients in the prehospital setting, frequency of administration ofanalgesics is low (N) (Level IV SR) and documentation of pain assessment is variable (N) (Level IV).
2. Intranasal fentanyl is equivalent to intravenous or intramuscular morphine in reducing pain
associated with paediatric fracture presenting to the emergency department (U) (Level II).
3. Intranasal ketamine (1─2 mg/kg) achieves similar pain reduction to intranasal fentanyl(1.5─2 mcg/kg) for isolated limb fracture pain, but with an increased frequency of minorside effects (eg dizziness, bad taste) (N) (Level II).
4. The introduction of an intranasal fentanyl protocol for limb injury can reduce the time to firstanalgesia in the emergency department, compared to intravenous morphine (N) (Level III-3).
5. Single shot fascia iliaca compartment block is effective in managing femoral fracture pain(N) (Level III-3).
6. Methoxyflurane, intranasal or intravenous fentanyl and intravenous morphine are effective
and commonly used prehospital to manage pain from trauma (N) (Level IV); intravenous or
intranasal ketamine is also an effective analgesic in the prehospital setting (U) (Level IV).
7. Younger children (<3 years) with an isolated limb injury receive less analgesia in theemergency department than older children (N) (Level IV).
8. In children and adolescents admitted to hospital with burns, higher morphine doses duringadmission predict reduced post-traumatic stress symptoms (N) (Level IV).
9. Pruritus following burn injury in children is common; predictors for pruritus include greater
total body surface area of burn and greater number of days since burn injury (N) (Level IV).
 Administration of analgesia by emergency medical services and emergency departments
for trauma patients (including those with burns) is strongly recommended as part of theinitial resuscitation along with first aid measures such as cooling and dressings for burns
and splint application for trauma (N).
 Gabapentin and pregabalin are used to manage pruritus and neuropathic pain following
burn injury in children (N).
Paediatric migraine
1. In children (<12 years), effective acute migraine treatments include ibuprofen and triptans(Q) (Level I [Cochrane]), however there is a significant placebo response rate in this setting.
2. In adolescents (12–17 years), triptans are effective acute migraine treatments, however
there is a significant placebo response rate in this setting. One triptan cannot berecommended over another (Q) (Level I [Cochrane]).

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SUMMARY OF KEY MESSAGES

3. Nonpharmacological preventive therapies including relaxation training and cognitive
behavioural therapy reduce the frequency and intensity of headache in adolescents for
1 year (S) (Level I [Cochrane]). Biofeedback also reduces migraine attack duration (S) (Level I).
 Guidelines for the treatment of migraine in children and adolescents recommend
environment modification, paracetamol, ibuprofen, naproxen (or other nonselective
NSAIDs), dopamine antagonists (if nausea prominent), fluid therapy and triptans (U).
 Evidence is limited for standard of care second line therapies (single and multiple IV therapies
including fluids and antiemetics) and third line therapies (such as IV dihydroergotamine,magnesium, sodium valproate, lidocaine or propofol) for acute childhood migraine (N).
 The use of psychological interventions and stress management strategies have not beenassessed in acute migraine episodes; it must be recognised that many of these skills need
to be developed over time (N).
Acute abdominal pain in children
1. Probiotics improve pain in children with recurrent abdominal pain versus placebo (N)(Level I [Cochrane Review]) with no good evidence for positive effect of various
pharmacological treatments (N) (Level I [Cochrane Review]).
2. Cognitive behavioural therapy (CBT) and hypnotherapy reduce pain short term (over1 to 3 months) in children and adolescents with recurrent abdominal pain (N) (Level I[Cochrane Review]).
Acute pain associated with haematological disorders in children
Sickle cell disease
1. Hydroxyurea decreases the frequency of acute vaso-occlusive crises, life-threatening
complications and hospitalisations in children with sickle cell disease (S) (Level I [Cochrane
Review]).
2. Intravneous or oral magnesium does not reduce pain of vaso-occlusive crises associatedwith sickle cell crises or length of hospital stay (N) (Level I [Cochrane Review]).
3. Attention must be paid to acute kidney injury risk in sicker inpatients with sickle cell diseasereceiving multiple doses of nsNSAID (N) (Level III-3).
4. Parenteral corticosteroids reduced the duration of severe pain in children with vaso-occlusivecrises in sickle cell disease at the expense of more rebound attacks post cessation (Q) (Level II).
 It is standard of care for oral and IV paracetamol, nsNSAIDs and opioids to form part of anindividual at home or hospital care plan for children with vaso-occlusive crises. Upon
admission this is escalated to parenteral nsNSAID and opioid therapy (N).
 There is no evidence that fluid replacement therapy reduces pain in children with VOC,
although it is common practice (N).
 The impact on painful vaso-occlusive crises of oxygen supplementation in patients withand without obstructive sleep apnoea and CPAP in patients with obstructive sleep apnoea
requires assessment (N).
 Most children with sickle cell disease are not on opioids for chronic or frequent recurrent
pain (while adolescents are, at similar rates to affected adults). In patients with sickle celldisease, postoperative opioid requirements may be higher (N).
5th Edition | Acute Pain Management: Scientific Evidencexcv Adjunctive low-dose ketamine and IV lidocaine infusions reduce pain intensity and opioid
requirements in refractory pain of acute vaso-occlusive crisis in children with sickle celldisease (N).
Haemophilia
 In children with haemophilia, on demand and preventative use of recombinant factor
concentrates has improved pain-related quality of life measures. Otherwise the principles
of pain management in acute bleeds in affected children and adults involve rest, ice,compression and elevation and stepwise escalation of analgesia. Parents of young
affected children need education regarding analgesic medication (N).
The overweight or obese child or adolescent When dosing medication in the overweight or obese child or adolescent, age of the patient,each individual drug and the dose type (initial or maintenance) must be considered (N).
 Given the barriers to accurate dosing in overweight and obese children, judicious dosing
and titration to effect wherever possible is recommended. This requires consideration ofboth pharmacokinetic and pharmacodynamic factors (N).
 Young and obese children with history of obstructive sleep apnoea syndrome/sleepdisordered breathing are at higher risk of developing serious opioid-induced ventilatory
impairment and death (U) (Level IV).
Complementary and alternative medicines and therapies in children
1. Hypnosis for needle-related procedural pain (including for cancer-related procedures)
reduces pain intensity (S) and distress (N) versus control (Level I [Cochrane Review]).
2. Preventive use of probiotics does not reduce infantile colic incidence, but does reduce
crying duration versus placebo (N) (Level I [Cochrane Review]).
3. The probiotic Lactobacillus reuteri reduces cry/fuss time in breastfed infants with colic;there is insufficient evidence in formula fed infants (N) (Level I [PRISMA]).
4. Oral administration of honey versus control in children reduces pain and analgesic use after
tonsillectomy (N) (Level I [PRISMA]).
5. Perioperative acupuncture (including electroacupuncture) versus control in children having
tonsillectomy reduces postoperative pain intensity (in the first 48 h) and analgesic
consumption (N) (Level I [PRISMA]).
6. Acupuncture (invasive or non-invasive) versus control for preterm and term neonates
receiving heel lance does not reduce pain intensity (N) (Level I [PRISMA]).
 Complementary and alternative medicines and therapies encompass a wide variety ofinterventions with common use in the community; complementary medicines andtherapies are increasingly used as part of integrative approaches to hospital-based
healthcare in the paediatric population (N).
 The evidence on complementary and alternative medicines and therapies is characterisedby small sample sizes and study designs prone to bias and caution is urged in interpreting
results. Additionally, the safety and potential drug interactions of many complementary
and alternative medicines and therapies have not been adequately assessed (N).

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1Physiology and psychology of acute pain
Section Editor:
Prof David A Scott1.1 | Applied physiology of acute pain
Contributors: Prof Janet R Keast, Dr Peregrine B Osborne

1.2 | Psychological aspects of acute pain
Contributor: Prof Michael Nicholas

1.3 | Placebo and nocebo effects in acute pain
Contributor: A/Prof Damien Finniss

1.4 | Progression of acute to chronic pain
Contributor: Dr Mark Rockett

1.5 | Pre-emptive and preventive analgesia
Contributor: Prof David A Scott

1.6.1 | Acute pain and the injury response
1.6.2 | Adverse physiological effects
1.6.3 | Pain and analgesia: effects on injury-induced organ dysfunction
Contributor: Prof Mark Hutchinson

1.6.4 | Adverse psychological effects
Contributor: Prof Michael Nicholas

1.7 | Genetics and acute pain
Contributor: Prof Andrew Somogyi

11.1 | Applied physiology of acute pain
1.1.1 | Definition of acute pain
Pain is most commonly described as “an unpleasant sensory and emotional experience
associated with actual or potential tissue damage, or described in terms of such damage”,(Merskey 1994 GL). It should be noted that “pain is subjective and indicates that each individual
learns the application of the word through experiences related to injury in early life, andcharacterizes the experience as unpleasant, and therefore emotional as well as sensory in nature”(IASP 2019a GL). Chronic pain has gradually emerged as a distinct phenomenon in comparison
with acute pain with the IASP currently defining it as “pain that lasts or recurs for longer than
3 months” (Treede 2019 GL). Although acute pain cannot be precisely distinguished from chronic
pain using time-based definitions, for pragmatic purposes recommended definitions continue tobe time-based (Kent 2019 GL):
“Acute pain is considered to last up to seven days, with the following qualifications:
1. Its duration reflects the mechanism and severity of the underlying inciting event.
2. Prolongations from seven to 30 days are common.
3. Prolongations beyond the duration of acute pain but not extending past 90 days post
onset/-injury are common. This refers to the ill-defined but important period of“subacute” pain that warrants further specification and consideration in future
taxonomic, research, and regulatory efforts.
4. Our understanding of pain mechanisms is currently insufficient to link these durations
to specific physiologic mechanisms.”
This section focuses on the physiology and pathophysiology of pain resulting from
nociceptive activity in the sensory nervous system, but also introduces the neurobiology of pain
as a beneficial adaptive brain state that responds to and can be altered by psychological factors.
A more complete description of the classes of psychological factors that affect the experience of
pain is outlined in Section 1.2; for paediatric information se Section 10.1.

1.1.2 | Nociceptive pathways and pain perception
The ability of the somatosensory system to detect noxious and potentially tissue-damaging
stimuli (ie nociception) is an important protective feature that involves multiple interacting
peripheral and central mechanisms (Sommer 2018 NR). In addition to the sensory effects, theperception and experience of pain is multifactorial and will be influenced by genetic,
psychological and environmental factors in every individual ( Tracey 2019 NR EH; Porreca 2017 NR;
Vardeh 2016 NR).
1.1.2.1 | Peripheral nociceptors
The detection of noxious stimuli by peripheral sensory nerve endings (nociceptors) first requires
the transduction of noxious stimuli into electrical activity and the conduction of thesenociceptive signals in peripheral sensory nerves to the central nervous system (CNS) ( Sommer
2018 NR; Dubin 2010 NR; Woolf 2007 NR). Nociceptive primary afferents are widely distributed
throughout the body (skin, muscle, joints, viscera, meninges) and comprise both mediumdiameter lightly myelinated A-delta fibres and small-diameter, slow-conducting unmyelinated C
fibres. Distinct classes of nociceptors are activated by noxious stimuli, which include intensepressure, extreme temperatures (>40 to 45°C or <15°C) and damaging chemicals. The most2

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prevalent subclass of nociceptor is the C-fibre polymodal type, which responds to mechanical,
thermal and chemical stimuli, whereas other subclasses are specialised mechanical, heat or cold
nociceptors (Woolf 2007 NR).
The physiological properties of nociceptors are determined by the differential expression ofa repertoire of transduction molecules (Dubin 2010 NR). The particular expression of thesetransducers determines which modalities are detected by each set of nociceptors. For example,
the transient receptor potential (TRP) channel type vanilloid 1 (TRPV1) transduces noxious
temperatures from 39–51°C and generates electrical receptor potentials in a class of polymodal
C fibres. All nociceptor axons have free terminal endings without anatomically specialised
transducers such as the Meissner’s corpuscles and Merkel cells used by skin mechanoreceptors.
However, it is now known that molecular transducers used by mechanosensitive neurons, suchas Piezo1 and Piezo2, are also widely expressed by non-neuronal cells in skin and other organs
that can bidirectionally interact with somatosensory terminals including nociceptors ( Oetjen 2018
NR; Moehring 2018 NR). Nociceptors in visceral tissue show differences to those in somatic tissue
but are much less well studied. In the viscera, high threshold specific nociceptors are unusualand most mechanosensitive afferents code stimulation in a linear manner, which can reach thenoxious range. There is a large proportion of silent nociceptors in viscera, which are u nresponsive
under basal conditions and respond to heat and chemical stimuli in the presence of inflammation(Grundy 2019 NR; Gebhart 2016 NR).
Nociceptors may also be classified by their relationship to trophic factors ( Denk 2017 NR).
Some C-fibre nociceptors are dependent on nerve growth factor (NGF) and express tyrosine
kinase receptor (TrkA), which is a neurotrophin receptor. Most of these nociceptors also express
substance P and calcitonin gene-related peptide (CGRP) and are classed as peptidergic. Anotherclass of C fibres are not peptidergic but have glial cell line-derived neurotrophic factor (GDNF)
family receptors (GFR1, GFR2; and their co-receptor Ret) and are thereby targets for GDNF or
neurturin, respectively. Next generation sequencing and transcriptional profiling (by bulk
sequencing or single-cell RNA-Seq) has been used for unbiased classification of primary sensory
neurons, including nociceptors (Iadorola 2018 NR; Emery 2018 NR). A large proportion ofdifferentially expressed genes that define classes encode membrane ion channels and receptors
that function in nociceptor transduction and transmission ( Waxman 2014 NR; Gold 2010 NR).
However, the function of other transcripts identified by this unbiased approach have yet to be
determined. This is advancing our understanding and resolving the conflicting alignment
between classes previously defined by molecular, neurochemical, developmental andphysiological criteria (Gatto 2019 NR; Emery 2018 NR).
Nociceptor plasticity
Sensitisation is a characteristic of nociceptors (Woolf 2007 NR). The phenotypes of the nociceptors
change in response to nerve injury and inflammation and are not static. This dynamic neuralplasticity lowers the transduction threshold of nociceptors and contributes to primary
hyperalgesia, which is defined as abnormal intensity of pain relative to the stimulus ( Gold 2010
NR; Sandkuhler 2009 NR).
Sensitisation is most often produced by chemical signals of tissue damage: such as during
infection, inflammation or ischaemia; disruption of cells; degranulation of mast cells; secretions
from inflammatory cells; or following induction of enzymes such as cyclooxygenase-2 (COX-2)(Baral 2019 NR; Sommer 2018 NR; Oetjen 2018 NR). A majority of chemical mediators act locally at
nociceptor terminals by directly targeting ion channels or indirectly by activating intracellularsignalling via calcium-permeable channels (Bourinet 2014 NR) or membrane receptors (see Table
1.1). NGF, immune mediators and other chemicals including proteinases, cytokines such as

5th Edition | Acute Pain Management: Scientific Evidence3tumour necrosis factor (TNF) alpha, interleukins, and chemokines such as chemokine (C-C motif)
ligand 3 (CC L3) all have an impact on sensitisation of nociceptors (see Table 1.1).
TRPV1 is an example of a nociceptor transducer that contributes to sensitisation in nociceptor
terminals. This is achieved when the thermal and chemical sensitivity of TRPV1 is lowered
following direct or indirect modulation by local inflammatory mediators or by noxious
environmental chemicals such as capsaicin (which causes the perception of heat and pain elicitedby chillies) (Henrich 2015 Level III-1 EH). Neuropeptides (substance P and CGRP) released from theactivated peripheral terminals via peripheral antidromic axonal responses cause neurogenic
inflammation by promoting vasodilation and plasma extravasation. This promotes recruitment
of serum factors and inflammatory cells at the site of injury (Sousa-Valente 2018 NR). Nonsteroidal
anti-inflammatory drugs (NSAIDs) modulate peripheral pain by reducing prosta glandin E2 (PGE2)
synthesis from locally induced COX-2. Inflammation also induces changes in protein synthesis in
the cell body of neurons in the dorsal root ganglia (DRG) and trigeminal ganglia, and alters theexpression and transport of receptors, such as TRPV1 and opioid receptors, to the peripheral
nerve terminal (Woolf 2007 NR). The latter underlies the peripheral action of opioid agonists ininflamed tissue and could allow nociceptor modulation by immune cells ( Stein 2009 NR).
Table 1.1 | Examples of receptors and ligands that function in transduction or primary andsecondary hyperalgesia of nociceptive primary afferent or spinal cord neurons
SubtypeLigand/Stimulus

TRPV1heat (≥43°C, unsensitised),capsaicin, H+ (protons)

TRPV2

heat (≥52°C)

TRPV3, TRPV4

warm (32 to 39°C)

TRPA1

environmental irritants (mustardoil, nicotine, formaldehyde,
acrolein)

TRPM8cool (≤26°C)

acid sensing

ASIC1-4, TRAAK/TREK

H+ (protons)

glutamate

NMDA, AMPA Kainate,
GLurR1-5, NR1-2

glutamatenicotinicnACh (multiple subtypes)

acetylcholine

purineP2X1-6ATP

serotonin

5-HT3

5-HT

bradykinin

BI, B2bradykinin

cannabinoid

CB1, CB2(TRPs, non-canonical)

anandamide, cannabidiol

Ionotropic receptor
TRP

Metabotropic receptor

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SubtypeLigand/Stimulus

chemokineCXCR2,CXCR5, CX3CR1CXCL1, CXCl13, CCL2 (MCP1), et al.

histamine

H1histamineInterleukin

IL1R, IL-31A/OSMR, et al.

IL-1 alpha, IL-6, IL-31, et al.

LPS

Toll-like receptor 4

lipopolysaccharides

Mas-related GPCRs

MRGPRD, MRGPRA3,MRGPRX1β-alanine, BAM8-22, other orphan
ligands

metabotropic glutamate

mGLuR1,2/3,5

glutamateprostanoids

EP1-4
IP

PGE2 (prostaglandins)
PGI2 (prostacyclin)

proteinase

PAR1-4(TRPs non-canonical)

proteaseserotonin

5-HT1A, 5-HT2A, 5-HT4

5-HT (serotonin)tachykinin

neurokinin-1 (NK1)substance P, neurokinin A

tyrosine kinase receptor

TrkA,
p75 neurotrophin

NGF (nerve growth factor)

TNR receptor

TNFR1, TNFr2

TNF (tumour necrosis factor)

-haemolysin,
- haemolysin AB

Secreted by gram-positive bacteria(eg S. aureus)

Pore forming toxins
haemolysin

Sources: Baral 2019; Sommer 2018; Harding 2018; Oetjen 2018; Gold 2010.

Similarly, NGF increases with inflammation, binds to TrkA, which causes phosphorylationof the TRPV1 and facilitates the sodium channels, which both increase nociceptor activity. In
addition, NGF-TrkA complex is transported to the DRG, where it impacts on phenotypicchanges resulting in changes to receptors and channels ( Denk 2017 NR). NGF regulates relative
amounts of neuropeptides and the threshold of nociceptors. The number of receptors for NGF(TrkA) is also determined by the functions of the corresponding DRG cells. Visceral primaryafferents have a higher proportion of cells containing TrkA compared to somatic primaryafferent neurons.
Sodium, potassium, calcium and chloride ion channels also function in nociceptor
transduction and transmission. Sodium channels are a prerequisite for conduction of neuronalaction potentials to the CNS (Bennett 2019 NR). A rapidly inactivating fast sodium current that isblocked by tetrodotoxin is present in all sensory neurons. This is the principal site of action for
local anaesthetics but, as the channel is present in all nerve fibres, conduction in sympathetic
and motor neurons may also be blocked. Subtypes of slowly activating and inactivating
tetrodotoxin-resistant sodium currents are selectively present on nociceptive fibres. Following
injury, changes in sodium-channel kinetics and specific alterations in the expression of sodium
channels (upregulation or downregulation) contribute to hyperexcitability that occurs in
different pain states and may explain part of the mechanism of benefit of systemic local
anaesthetics in acute and chronic pain (see Section 4.4.1) . The importance of sodium channels
5th Edition | Acute Pain Management: Scientific Evidence5

in pain sensitivity is reflected by the impact of human mutations in the SCN9A gene encoding theNav1.7 channel (Dib-Hajj 2019 NR) (see Section 1.7.1). Loss of function results in insensitivity topain, whereas gain of function mutations can produce erythromelalgia and other severe pain.
These effects are not restricted to sodium channels; functional and expression changes in otherclasses of calcium, potassium and chloride channels also contribute to nociceptive transmission
and processing by nociceptors (Bennett 2019 NR).
Medicines that are specific blockers of sodium channel subtypes or cause state-dependent
reductions in sodium channel activity are becoming available for evaluation in human clinical
trials (Dib-Hajj 2019 NR). New ion channel targets are also emerging that, as well as regulators ofafferent fibre excitability, include a separate class of ion channels that regulate the transfer ofthe nociceptive signal (synaptic transmission) from primary afferent fibres to the second-orderneurons in the spinal cord (Yekkirala 2017 NR).
1.1.2.2 | Nociceptive transmission in the spinal cord
The cell bodies of nociceptive afferents that innervate the trunk, limbs and viscera are found in
the DRG, while those innervating the head, oral cavity and neck are in the trigeminal gan glia andproject to the brainstem trigeminal nucleus (Dubin 2010 NR). The central terminals of C and
A-delta fibres convey information to nociceptive-specific areas within laminae I and II of thesuperficial dorsal horn and to wide dynamic range neurons in lamina V, which encode both
innocuous and noxious information (Koch 2018 NR; Todd 2010 NR). By contrast, large myelinatedA-beta fibres transmit light touch or innocuous mechanical stimuli to the deeper laminae III andIV (Moehring 2018 NR).
Primary afferent terminals activate dorsal horn neurons by releasing two major classes ofneurotransmitter; glutamate as the primary transmitter and neuropeptides such as substanceP, CGRP, galanin and somatostatin as cotransmitters (Sandkuhler 2009 NR). Depolarisation of the
primary afferent terminal results in glutamate release, which activates postsynaptic ionotropic
α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors and rapidly signals
information relating to the location and intensity of noxious stimuli. In this “normal mode”, ahigh-intensity stimulus elicits brief localised pain and the stimulus-response relationshipbetween afferent input and dorsal horn neuron output is predictable and reproducible (Prescott2014 NR; Sandkuhler 2009 NR).
Summation of repeated C-fibre inputs results in a progressively more depolarised
postsynaptic membrane and removal of the magnesium block from the N-methyl-D-aspartate(NMDA) receptor. This is mediated by glutamate acting on ionotropic (non-NMDA) andmetabotropic (mGluR) glutamate receptors, and by substance P acting on neurokinin-1 (NK1)
receptors. A progressive increase in action potential output from the dorsal horn cell is seen
with each stimulus and this rapid increase in responsiveness during the course of a train of
inputs has been termed “wind-up”. Long-term potentiation (LTP) is induced by higher
frequency stimuli but the enhanced response outlasts the conditioning stimulus. Thismechanism has been implicated in learning and memory in the hippocampus and pain
sensitisation in the spinal cord ( Sandkuhler 2009 NR). Behavioural correlates of theseelectrophysiological phenomena have been seen in human volunteers as repeated stimuli
elicit progressive increases in reported pain ( Treede 2016 NR).
Intense and ongoing stimuli further increase the excitability of dorsal horn neurons, leading
to central sensitisation (Woolf 2014 NR; Baron 2013 NR; Woolf 2011 NR). Increases in intracellular
calcium due to influx through the NMDA receptor and release from intracellular stores activate
a number of intracellular kinase cascades. Subsequent alterations in ion channel and/or receptor
activity and trafficking of additional receptors to the membrane increase the efficacy of synaptic

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transmission. As a result of the increased excitability of central nociceptive neurons, theirthreshold for activation is reduced. In this situation, pain can occur in response to low-intensity
previously nonpainful stimuli (ie allodynia) and sensitivity spreads beyond the area of tissue
injury (ie secondary hyperalgesia) (Sandkuhler 2009 NR). Wind-up, LTP and secondary hyperalgesia
may all contribute to central sensitisation and may share some of the same cellular mechanisms
but are independent phenomena.
The intracellular changes associated with sensitisation may also activate a number oftranscription factors both in DRG and dorsal horn neurons, with resultant changes in gene andprotein expression (Ji 2018 NR; Simonetti 2013 NR). Unique patterns of either upregulation or
downregulation of neuropeptides, G-protein coupled receptors, growth factors and their
receptors, and many other signalling molecules occur in the spinal cord and DRG in inflammatory,
neuropathic and cancer pain. Further elucidation of changes specific to different pain states may
allow more accurate targeting of therapy in the future.
In addition to activity in neurons, central neuroinflammation involving surrounding glial andimmune cells (including microglia) can also modulate synaptic transmission (Baral 2019 NR; Ji 2018
NR). Strong evidence has accumulated to suggest glial and neuroimmune mechanisms contributeto sex differences in pain (Mapplebeck 2017 NR).
1.1.2.3 | Central projections of nociceptive pathways
Different qualities of the overall pain experience are subserved by five major ascending spinal
cord projection pathways; the spinothalamic, spinoreticular, spinomesencephalic,
cervicothalamic and spinohypothalamic pathways. The spinothalamic pathway ascends fromprimary afferent terminals in laminae I and II, via connections in lamina V of the dorsal horn, tothe thalamus and then to the somatosensory cortex (Craig 2003 NR). This pathway provides
information on the sensory-discriminative aspects of pain (ie the site and type of painfulstimulus). The spinoreticular and spinomesencephalic (spinoparabrachial) tracts project to the
medulla and midbrain and are important for integrating nociceptive information with arousal,
homeostatic and autonomic responses as well as projecting to central areas mediating theemotional or affective component of pain (Kobayashi 2012 NR; Craig 2009 NR; Price 2000 NR). Manyof the second-order projection neurons in these pathways are superficial dorsal horn lamina I
neurons that express the NK1 receptor and are stimulated by peptidergic C-fibre afferents (Todd2010 NR). Other connections include those to cortical areas involved in the affective andmotivational components of pain (eg anterior cingulate cortex, insular and prefrontal cortex),
projections back to the periaqueductal grey (PAG) region of the midbrain androstroventromedial medulla (RVM), which are crucial for fight or flight responses and stressinduced analgesia, and projections to the reticular formation that are important for the
regulation of descending pathways to the spinal cord. Descending projections from themedullary dorsal reticular nucleus (DRt) are important in facilitating the diffuse noxious
inhibitory control (DNIC) (see Figure 1.1) (Treede 2016 NR; Ossipov 2010 NR; Tracey 2007 NR).

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Figure 1.1 | The main ascending and descending spinal nociceptive pathways

In the ascending afferent pathways, the sensory components of pain are via the spinothalamic pathway to theventrobasal medial and lateral areas ①, which then project to the somatosensory cortex allowing for the location andintensity of pain to be perceived ②. The spinal cord also has spinoreticular projections and the dorsal column pathway
to the cuneate nucleus and nucleus gracilis ③. Other limbic projections relay in the parabrachial nucleus ④ before
contacting the hypothalamus and amygdala, where central autonomic function, fear and anxiety are altered ⑤.
Descending efferent pathways from the amygdala and hypothalamus ⑥ drive the periaqueductal grey, the locus
coeruleus, A5 and A7 nuclei and the rostroventral medial medulla. These brainstem areas then project to the spinal
cord through descending noradrenaline (inhibition via α2 adrenoceptors) and, in neuropathy, there is a loss of thiscontrol and increased serotonin descending excitation via 5-HT3 receptors ⑦. The changes induced by peripheral
neuropathy on peripheral and central functions are shown.
Reproduced with permission from Colloca 2017.

1.1.2.4 | Descending modulatory pathways
The brain has a remarkable capacity to modulate pain according to the competing demands ofphysiological, psychological and social factors. The neural contributors to this modulation arecomplex and only partly elucidated. Best understood is a descending pain-modulatory circuit thatprojects to the spinal cord and changes the experience of pain by directly or indirectly
modulating (inhibiting or facilitating) nociceptive traffic ( Ossipov 2010 NR). Descending pathways
contribute to the modulation of nociceptive transmission in the spinal cord via presynaptic
actions on primary afferent fibres, postsynaptic actions on projection neurons or via effects on
interneurons within the dorsal horn. Sources include direct corticofugal and indirect (via8

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modulatory structures such as the PAG) pathways from the cortex and from the hypothalamus,
which is important for coordinating autonomic and sensory information. The RVM receives
afferent input from brainstem regions (PAG, parabrachial nucleus and nucleus tractus solitarius)
as well as direct ascending afferent input from the superficial dorsal horn and is an importantsite for integration of descending input to the spinal cord (Ossipov 2010 NR). The relative balance
between descending inhibition and facilitation varies with the type and intensity of the stimulus
and also with time following injury (Chen 2019 NR). Serotonergic and noradrenergic pathways inthe dorsolateral funiculus (DLF) contribute to descending inhibitory effects and serotonergic
pathways have been implicated in facilitatory effects (Bannister 2017 NR).
Inhibitory modulation occurs within the dorsal horn and can be mediated by non-nociceptive
peripheral inputs, local inhibitory gamma-amino butyric acid (GABA) and glycine interneurons,
descending bulbospinal projections and higher-order brain function (eg distraction, cognitive
input). These inhibitory mechanisms are activated endogenously through neurotransmitterssuch as endorphins, enkephalins, noradrenaline (norepinephrine) to reduce the excitatory
responses to persistent C-fibre activity. Serotonin (5-HT) has been implicated as bothpronociceptive and inhibitory (Bannister 2017 NR).
Similar mechanisms are the basis of many exogenous analgesic agents ( Bannister 2017 NR;
Ossipov 2010 NR; Sandkuhler 2009 NR). Thus, analgesia may be achieved by either enhancing
inhibition (eg opioids, clonidine, antidepressants) or by reducing excitatory transmission(eg local anaesthetics, ketamine) (Yekkirala 2017 NR).
A feature of sensory processing is that not all of the signals received from receptors areperceived. The limited processing capacity of the brain is optimised by prioritising behaviourally
relevant signals, while suppressing less important signals. Advances in human functional brain
imaging have provided new evidence of how pain perception is shaped by other sensory
modalities and attentional or emotional processing by the cerebral cortex and basal forebrain(Wager 2015 NR; Carlino 2014 NR). The engagement of attention, expectation and reappraisal
mechanisms provides for complex cognitive modulation of pain (Bushnell 2013 NR; Wiech 2013 NR).
This is the basis of placebo-induced analgesia (see Section 1.3) and for using psychologicalinterventions to target endogenous pain modulation ( Flor 2014 NR; Carlino 2014 NR).

1.1.3 | Physiological and pathological pain
As discussed in the introduction, pragmatic working clinical definitions of acute and chronic pain
continue to be time-based and do not explicitly identify underlying pathophysiology. However,the development of mechanism-based functional classification schemes and identification ofclinically useful pain biomarkers continue to be intensively researched (Tracey 2019 NR; Vardeh
2016 NR).
The basic framework most commonly used addresses heterogeneity of pain by identifying“nociceptive” and “inflammatory” classes of physiological or adaptive pain, together with“neuropathic” and “CNS dysfunctional (nociplastic)” classes of pathological or maladaptive pain
(Tracey 2019 NR; Kosek 2016 NR; Vardeh 2016 NR; Woolf 2010 NR). Nociceptive and inflammatory
pain are considered to be physiological functions of the nociceptive division of thesomatosensory nervous system, which monitors the physical state of the body ( Sommer 2018 NR).
It has been understood from the earliest investigations by Sherrington and later landmark
studies by Wall and Melzack that this system does not simply locate and measure the intensityof painful sensory stimulation; it also encodes innate aversive reinforcing signals that drive
motivational, emotional and cognitive processing in the brain (as described below) ( Seymour 2019
NR). In humans and other animals, these systems support escape and defensive b ehaviours thatminimise potential lethal tissue damage, as well as coping behaviours that manage recovery from5th Edition | Acute Pain Management: Scientific Evidence

9such damage and avoidance behaviours that use learning signals to minimise the risk of suchdamage in the future (Seymour 2019 NR). This broad functionality can be shown to engage mostof the major functional brain subdivisions (Tracey 2019 NR). Their basic physiological importanceis shown by the unavoidable tissue damage suffered in humans with rare genetic mutations that
render them insensitive to pain (Dib-Hajj 2019 NR).
Neuropathic pain is defined as “pain caused by a lesion or disease in the somatosensory
nervous system” (Scholz 2019 GL; Jensen 2011 GL). The estimated prevalence of neuropathic pain
is much higher than commonly thought and in the range of 7–10% of the population ( van Hecke
2014 NR). Although commonly regarded as a cause of chronic symptoms, neuropathic pain canalso present acutely following trauma and surgery. The incidence has been conservatively
estimated as 3% of acute pain service (APS) patients ( Hayes 2002 Level IV). Similarly, acutemedical conditions may present with neuropathic pain ( Gray 2008 NR) (as discussed further in
Section 8.1.4). Nerve injury and associated alterations in afferent input or hyperexcitability
associated with central pain (eg caused by stroke, spinal cord injury [SCI], multiple sclerosis)
can induce structural and functional changes at multiple points in nociceptive pathways withcomplex long-term psychobiological consequences ( Alles 2018 NR; Colloca 2017 NR; Treede 2016
NR; von Hehn 2012 NR).
CNS dysfunctional pain syndromes such as migraine, fibromyalgia and chronic pelvic pain
show chronicity that often cannot be reliably linked to clinical pathophysiology in thesomatosensory system (Woolf 2010 NR). Historically, many terms have been used to refer toclinical CNS dysfunctional pain, including “functional pain syndromes”, “maldynia”, or“neuroplastic” (Mayer 2009 NR). The IASP, however, has recently endorsed “nociplastic pain”,
defined as “Pain that arises from altered nociception despite no clear evidence of actual or
threatened tissue damage causing the activation of peripheral nociceptors or evidence fordisease or lesion of the somatosensory system causing the pain” (IASP 2019a GL; Kosek 2016 NR).
This new term is matched in ICD-11 by the classification ‘chronic primary pain’ (Nicholas 2019 GL).
When viewed from this perspective, acute pain will most commonly be linked to
nociceptive and inflammatory pain but also to less common neuropathic pain. It is clear,
however, that the clinical definition will also capture early stages of chronicity that could
leadto neuropathic and nociplastic pain in some patients. It is important to recognise that it iscurrently not possible to identify in advance specific patients who will undergo this transition(Kent 2019 NR). The probability of chronic pain developing is subject to the influences of genetic
and physiological factors and how these interact with the accumulated psychological andsocial experiences of pain ( Borsook 2018 NR; Flor 2014 NR; Denk 2014 NR). How these combine
will determine how individuals experience pain and is also highly likely to determine theirunderlying resilience in coping with this experience ( Bushnell 2013 NR; Elman 2013 NR) (seeSections 1.2, 1.4 and 1.5).

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1.2 | Psychological aspects of acute pain
A new definition of pain has been proposed by the IASP: “An aversive sensory and emotional
experience typically caused by, or resembling that caused by, actual or potential tissue injury.”(IASP 2019b). The revised definition is broadened to include non-verbal presentations (eg inpeople with communication deficits and animals). A key part of the definition is the recognition
that pain is an experience that has emotional and sensory components (ie it is not just a
sensation).
This section emphasises several important points:• Pain is always a personal experience that is influenced to varying degrees by biological,
psychological and social factors;• Pain and nociception are different phenomena ─ the experience of pain cannot be
deduced from activity in sensory pathways;• Through their life experiences, individuals learn the concept of pain;• A person’s report of an experience as pain should be respected;• Although pain usually serves an adaptive role, it may have adverse effects on function andsocial and psychological well-being.
There is a consensus view that pain is an individual, multifactorial experience influenced,
among other things, by culture, previous pain experience, beliefs, expectations, mood and ability
to cope. Pain may be an indicator of tissue injury but may also be experienced in the absence of,or out of proportion to an identifiable tissue injury, especially when it becomes chronic.
The degree of pain and disability experienced in relation to similar tissue injury varies between
people; likewise, there is individual variation in response to methods to alleviate pain ( Flor
2012 NR).
Factors that might contribute to the individual’s pain experience include somatic (physical)
and psychological factors as well as contextual factors, such as situational and culturalcharacteristics. Pain expression, which may include facial expressions, body posture, language,
vocalisations and avoidance behaviour, partially represents the complexity of the psychologicalexperience but is not equivalent to it (Kunz 2004 Level III-2 EH, n=40; Vervoort 2009 Level IV EH, n=62).
Engel’s enunciation (Engel 1997 NR) of a biopsychosocial model of illness has provided aframework for considering pain phenomena.
Biopsychosocial models of pain (Turk 1995 NR) are based on the proposition thatpsychobehavioral processes are mediated via neurobiological processes and that they interact.
Biological factors are reflected in physiological and neurophysiological changes in the body andpsychological factors are reflected in the appraisal and perception of internal physiologicalphenomena. These appraisals and behavioural responses are, in turn, influenced by social orenvironmental factors, such as reinforcement contingencies (Flor 2002 Level III-2, n=60). At the sametime, the model also proposes that psychological and social factors can affect biological processes(eg hormonal/stress responses, endogenous pain regulation) and brain structures associated withthe exacerbation and maintenance of pain symptoms (Turk 2018 NR).

1.2.1 | Psychological factors
Psychological factors that influence the experience of pain include the processes of attention,other cognitive processes (eg learning, thinking styles, beliefs, mood), behavioural responses andinteractions with the person’s environment.

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11Importantly, psychological factors that contribute to the experience and impact of pain
(acute or chronic) can be amenable to change and thus influence outcomes for the individual(Nicholas 2011 NR).
1.2.1.1 | Attention
In relation to pain, attention is viewed as an active process and the primary mechanism by which
nociception accesses awareness and disrupts current activity (Legrain 2012 NR; Eccleston 1999 NR).
The degree to which pain may interrupt attention depends on factors such as the intensity ofpain, its novelty, unpredictability, degree of awareness of bodily information, threat value,catastrophic thinking, presence of emotional arousal, environmental demands (such as taskdifficulty) and emotional significance.
Concepts like somatosensory amplification and hypervigilance have been used to describe
the selective attention of patients towards pain to the detriment of more functional activities.
These processes have been characterised as attentional bias (ie the preferential allocation of
attention to information that is related to pain) and this has been extensively studied in relationto acute, chronic and experimentally induced pain. The most recent meta-analysis of thisliterature indicated that attentional bias appears to relate more towards the sensory aspects ofthe pain experience, rather than the emotional content (Todd 2018 Level IV SR, 52 studies, n=4,466).
It is important to note that these studies may not be completely representative of clinical acutepain (eg postsurgical pain). The role of attentional mechanisms in pain experience and impact is
not uniform and terms like “hypervigilance” should not be used loosely as other processes,
particularly emotional ones (eg sense of threat), are likely to be involved as well as attention.
1.2.1.2 | Learning processes
The role of learning processes has primarily been studied in laboratory settings withexperimentally induced pain. A number of studies using healthy subjects have demonstrated thatreports of pain (eg pain severity ratings) can be conditioned by their consequences and this effectcan be reflected in measures of associated skin conductance responses, facial activity andcortical responses (Jolliffe 2004, Level III-2 EH, n=46; Flor 2002 Level III-2, n=60). Taken together, thesestudies provide support for the thesis that the experience of pain is not solely due to noxious
input but that environmental reinforcement contingencies can also influence this experience(see also Section 1.3).
Learning processes have also been implicated in the development and maintenance ofchronic pain (Flor 2012 NR).
1.2.1.3 | Beliefs and thought processes
Empirical evidence supports a role for “fear of pain” contributing to the development of
avoidance responses following pain and injury, which ultimately lead to disability in many people
with persisting pain (Leeuw 2007 NR). From this perspective, appraisals of internal and external
stimuli as threats (eg catastrophising), negative affectivity and anxiety sensitivity can contributeto the development of pain-related fear and, in turn, lead to escape and avoidance behaviours,
as well as hypervigilance to internal and external illness information, muscular reactivity, andphysical disuse and behavioural changes.
Studies with a range of patient samples have confirmed that thinking styles that are overly
pessimistic, ruminative and helpless (eg catastrophic thinking) are frequently associated withmore severe acute pain and associated distress, as well as persisting pain.

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In patients who underwent anterior cruciate ligament repair, those with high Pain
Catastrophising Scale (PCS) scores assessed prior to surgery reported more pain immediately
after surgery and when walking at 24 h compared with those with low scores; however there
was no difference in analgesic consumption (Pavlin 2005 Level IV, n=48). After breast surgery,catastrophising was associated with increased pain intensity and analgesic use ( Jacobsen 1996
Level IV, n=59) and after abdominal surgery (Granot 2005 Level IV, n=38) and Caesarean section withhigher pain scores (Strulov 2007 Level IV, n=47). Preoperative PCS scores also predicted pain after
total knee arthroplasty (TKA) in the postoperative period (Roth 2007 Level IV). After a wide rangeof surgical procedures , the most important predictors of pain severity up to 5 d following surgery
were surgical fear and pain catastrophising (beside preoperative pain and expected pain)(Sommer 2010 Level IV, n=1,490). In a clinical sample of aged patients, attentional avoidance ofemotionally aversive stimuli prior to surgery predicted acute postoperative pain, measured by
the consumption of opioids via patient-controlled analgesia (PCA) (Lautenbacher 2011 Level IV,n=58). This measure was a better predictor of postoperative pain than depression, anxiety andpain catastrophising. Subsequently, a systematic review of studies of psychological factors
associated with acute postsurgical pain confirmed the most significant correlates are: pain
catastrophising, expectation of pain, anxiety (state and trait), depression, optimism, negative
affect and neuroticism/psychological vulnerability (Sobol-Kwapinska 2016 Level IV SR [PRISMA], 53
studies, n=10,749). This meta-analysis suggests that pain catastrophising is the most strongly
associated with acute postsurgical pain (r=0.41; 95%CI 0.28 to 0.52) (see also Section 1.4).
A significant association between anxiety or pain catastrophising and the subsequentdevelopment of chronic postsurgical pain (CPSP) was reported in a systematic review in 16 of 29
studies (Theunissen 2012 Level III-2 SR, 29 studies, n=6,628). Following TKA, a systematic review
found catastrophising is the strongest predictor of chronic pain (Lewis 2015 Level IV SR, 32 studies,
n=29,993). Another systematic review found patients with acute and subacute back pain withhigh levels of catastrophising complained of more pain and disability at 6 mth and more disability
at 1 y than those with low levels (Wertli 2014a Level III-2 SR, 16 studies, n unspecified).
High fear avoidance beliefs in patients with back pain of <6 mth duration are associated withpoor outcomes, which may be improved by treatment approaches aimed at fear avoidance(Wertli 2014b Level I [PRISMA], 17 RCTs, n=1,153). Early postoperative fear of movement also
predicted pain, disability and physical health 6 mth after spinal surgery for degenerative
conditions (Archer 2014 Level III-2, n=141).
1.2.1.4 | Depression and anxiety
Anxiety and depression have repeatedly been found to contribute to the experience and impact
of both acute and chronic pain.
Significant preoperative predictors of poor postoperative pain control included younger age(OR 1.18; 95%CI 1.05 to 1.3) (14 studies), female sex (OR 1.29; 95%CI 1.17 to 1.43) (20 studies),
smoking (OR 1.33; 95%CI 1.09 to 1.61) (9 studies), history of depressive symptoms (OR 1.71;
95%CI 1.32 to 2.22) (8 studies), history of anxiety symptoms (OR 1.22; 95%CI 1.09 to 1.36) (10studies), sleep difficulties (OR 2.32; 95%CI 1.46 to 3.69) (2 studies), higher body mass index (OR1.02; 95%CI 1.01 to 1.03) (2 studies), presence of preoperative pain (OR 1.21; 95%CI 1.10 to 1.32)(13 studies) and use of preoperative analgesia (OR 1.54; 95%CI 1.18 to 2.03) (6 studies) (Yang 2019
Level IV SR [PRISMA], 33 studies, n=53,362). Interestingly, pain catastrophising, American Society ofAnesthesiologists (ASA) status, chronic pain, marital status, socioeconomic status, education,
surgical history, preoperative pressure pain tolerance and orthopaedic surgery (vs abdominal
surgery) were not associated with increased odds of poor pain control.

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13Anxiety is one of the most significant predictive factors (in addition to pre-existing pain, age
and type of surgery) for the severity of postoperative pain (Ip 2009 Level IV SR, 48 studies, n=23,037).
Psychological distress (besides type of surgery and age) is the most significant predictor of
postoperative analgesic consumption, not sex as is commonly believed.
Among other factors, preoperative anxiety predicted pain intensity 48 h after hysterectomy
for benign conditions (Pinto 2012 Level IV, n=203). Subsequent multivariable analysis revealed thatpain catastrophising acted as a full mediator between presurgical anxiety and postsurgical pain
intensity. In the late phase after leg injury, anxiety has the only significant relationship to pain
(Castillo 2013 Level IV, n=545). Anxiety predicted pain over all time periods: 3 to 6 mth(standardised regression weights [SRW] 0.11), 6 to 12 mth (SRW 0.14) and 12 to 24 mth(SRW 0.18).
In opioid-tolerant patients, the anxiety and autonomic arousal associated with withdrawal(Tetrault 2008 NR) may also have an impact on acute pain experience and report (see Section 9.7
for further details).
There is a consistent association between chronic postsurgical pain and depression as well as
psychological vulnerability and stress (Hinrichs-Rocker 2009 Level IV, 50 studies, n≈25,000). Similarly,
there is a strong relationship between persistent knee pain and depression (with higher levels ofknee pain being positively related to higher levels of depression) but not with anxiety and poor
mental health in general (Phyomaung 2014 Level IV SR, 16 studies, n=15,113).
1.2.1.5 | Implications
The presence of modifiable psychological factors, especially anxiety, catastrophising anddepression, should be considered in acute pain settings and, if identified, should be targeted bytreatment. The results of research evaluating psychological interventions for these factors
are considered elsewhere (see Section 7.1). These psychological contributors to higher pain
levels and interference in daily activities are not universal and there is considerable variability
between individuals.

1.2.2 | Patient-controlled analgesia
In general, anxiety seems to be the most important psychological variable that affects PCA bolus
use. Preoperative anxiety correlates with increased postoperative pain intensity, the number of
PCA demands made by the patient (often “unsuccessful” presses during the lockout interval),degree of dissatisfaction with PCA and lower self-reports of quality of analgesia (Thomas 1995
Level III-1, n=110; De Cosmo 2008 Level IV, n=80; Hsu 2005 Level IV, n=40; Ozalp 2003 Level IV, n=99;
Brandner 2002 Level IV, n=71; Perry 1994 Level IV, n=99; Jamison 1993 Level IV, n=68). Another study

designed to look at predictors of PCA demands made during the lockout interval also found thatanxiety and negative affect positively predicted unsuccessful PCA demands and postoperative
pain, as did preoperative intrusive thoughts and avoidant behaviours about the impending
surgery (Katz 2008a Level IV, n=117).
Evidence regarding PCA opioid consumption and psychological variables is however
contradictory, with some studies showing no change (Jamison 1993 Level IV, n=68; Gil 1992 Level IV,
n=50; Gil 1990 Level IV, n=80) and others showing an increase in analgesia demands ( Katz 2008aLevel IV, n=117; De Cosmo 2008 Level IV, n=80; Ozalp 2003 Level IV, n=99).

In a study looking at the effect of a number of psychological factors on both pain and IV
morphine use (by PCA) in the immediate postoperative period, and on pain 4 wk after surgery,preoperative self-distraction and coping positively predicted postoperative pain levels andmorphine consumption; emotional support and religious-based coping positively predicted PCAmorphine consumption; and preoperative distress, behavioural disengagement, emotional

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support, and religious-based coping also positively predicted pain levels 4 wk after surgery (Cohen
2005 Level IV, n=122).
There was no relationship between locus of control and postoperative pain intensity,
satisfaction with PCA or PCA dose-demand ratio (Brandner 2002 Level IV, n=71). Preoperative
depression was associated with increased pain intensity, opioid requirements, PCA demands anddegree of dissatisfaction (Hsu 2005 Level IV, n=40; Ozalp 2003 Level IV, n=99) (for further details on
PCA see also Section 6.0).

KEY MESSAGES
1. High pain-related fear avoidance beliefs in patients with back pain of less than 6 months
duration are associated with poor outcomes, which may be improved by treatment
approaches aimed at fear avoidance (U) (Level I [PRISMA]).
2. There is a significant association between high levels of catastrophising in acute andsubacute back pain and pain and disability at later points of time (U) (Level III-2 SR).
3. Psychological factors associated with poor postoperative pain control are in particularanxiety (state and trait) and catastrophising, but also expectation of pain, depression,negative affect and neuroticism/psychological vulnerability (S) (Level IV SR [PRISMA]).
4. There is significant association between anxiety, pain catastrophising (U) (Level III-2 SR),depression, psychological vulnerability and stress (U) (Level IV SR) and the subsequentdevelopment of chronic postsurgical pain.
5. Preoperative anxiety and depression are associated with an increased number of PCA
demands and dissatisfaction with PCA (U) (Level IV).
The following tick box represents conclusions based on clinical experience and expert
opinion: Pain is an individual, multifactorial experience influenced by culture, previous pain
events, beliefs, mood and ability to cope (U).

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151.3 | Placebo and nocebo effects in acute pain
The study of placebo is directly relevant to the field of pain management, as it provides further
understanding of the mind–brain interaction in the modulation of pain and is a core element ofroutine clinical management (Finniss 2010 NR).
The term “placebo”, originally defined as an inert substance having therapeutic response, hasbeen used in the medical literature for over 200 y. Only in the last 50 y, however, has interest
grown in responses to placebo administration. The first major systematic review of the topic
showed a placebo effect for many interventions but particularly for those interventions aimed
at analgesia (Beecher 1955 Level I, 15 RCTs, n=1,082). The early studies included in this systematic
review of response to placebo were mainly studies of placebo vs active medicine or intervention
alone without a control no-treatment group (nonplacebo group).
Placebo effects are psychobiological effects that are attributable to the psychosocial context(or treatment ritual) surrounding the patient. Importantly, these genuine effects must be
distinguished from other causes of improvement following administration of a placebo (placebo
responses), such as spontaneous remission, regression to the mean and the natural history ofacute pain (Price 2008 NR). Defining placebo and placebo effects has been difficult, primarily due
to the traditional definition, which uses the word “inert”, therefore theoretically rendering it as
being unable to have any power to elicit an effect (Moerman 2002 NR). Recent
reconceptualisations of placebo effects have emphasised several key points which are highly
relevant to modern pain management practice ( Finniss 2010 NR; Miller 2008 NR).
• Placebo responses refer to all health changes following administration of an inert agent(including natural history and regression to the mean) (Evers 2018 NR).
• Placebo effects are changes attributable to specific psychobiological mechanisms,
whether a traditional placebo is given or as part of a routine clinical interaction (Evers 2018
NR).
• The key aspect of placebo administration is the act of simulating a treatment context or
ritual, regardless of the content of the placebo.
• Routine clinical care occurs in a rich therapeutic context and, on this basis, placebo effects
exist in everyday practice even though no traditional placebo is given. The overalloutcome of a treatment is related to both the treatment itself and the context in which it
is given (the component attributable to placebo effects).
The term “nocebo” has been used to express the opposite (negative) response following
placebo administration, particularly in relation to development of adverse effects frominterventions or, in the case of painful stimuli, with an increased pain response expressed.
Nocebo studies in pain show moderate to large nocebo effects of high variability ( Petersen 2014
Level I [PRISMA], 10 RCTs, n=619). The results are similar to those seen for placebo effects;
combinations of verbal suggestions and conditioning (see below) are more effective than verbal
suggestions alone. The authors suggest that these results demonstrate “the importance ofminimising nocebo effects in clinical practice”.

1.3.1 | Mechanisms
The study of placebo mechanisms has traditionally been divided into psychological andneurobiological categories, although it is the interplay between the two that is the key to the
topic area.

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1.3.1.1 | Psychological mechanisms
There are many psychological mechanisms of placebo effects proposed, including expectation,
conditioning, learning, reward and anxiety reduction ( Price 2008 NR).
Expectancy
Expectancy has been one of the most studied psychological mechanisms and relates to patient
expectations of a future response. Expectancy can result in increased pain response tonociceptive stimuli as well as a placebo response to an analgesic intervention ( Atlas 2012 NR). It
has been associated with placebo effects in studies, where verbal cue ranges from a simple
instruction “this is a powerful painkiller” (Price 1999 Level II, n=40, JS 4) to the use of conditioning
protocols to maximise expectancy (Voudouris 1989 Level II, n=20, JS 4; Voudouris 1990 Level III-1).
Furthermore, a “graded” effect can be seen in studies with variable levels of expectancy (such as
the classic “double-blind” instruction, which carries a 50% uncertainty) to more certain
information about treatment expectations “the drug I will give you is a powerful painkiller” (Vase2003 Level II, n=13, JS 4; Verne 2003 Level II, n=10, JS 4; Pollo 2001 Level II, n=38, JS 3). More recently, inthe setting of chronic low back pain, expectancies were associated with duration and stability ofplacebo effects following diagnostic injections (Finniss 2019 Level II, n=107, JS 5). This underscores
the dynamic nature of the construct and emphasises the role of repeated expectancy assessmentand modulation over the duration of a healthcare encounter.
Treatment expectations are also involved in studies of the open-hidden paradigm (Finniss
2010 NR). Giving a treatment “hidden”, without the patient’s knowledge (eg by a computerised
pump behind a curtain) and comparing the effects when the same treatment is given “open” (inthe usual therapeutic context with a health professional present) has shown that open
administration of a range of analgesics is, by far, more effective than hidden administration. Thisapproach permits measurement of the placebo effect as “the difference in effect between the
open and hidden administration”. An example of such a trial compared the efficacy of aremifentanil infusion (0.8 ng/mL effect site concentration) on experimental pain in volunteers
under three conditions (Bingel 2011 Level III-3 EH):
• without expectation of analgesia (hidden administration);• with expectancy of a positive analgesic effect (open administration by a clinician); and• with negative expectancy of analgesia (claimed discontinuation of analgesic infusion
while infusion continued).
The pain relief achieved by hidden administration of remifentanil was more than doubled by
the open administration and completely negated by the claimed discontinuation of the infusion.
Functional MRI (fMRI) showed that, during positive expectancy, activity in the endogenous pain
modulatory system was increased, while negative expectancy increased activity in the
hippocampus.
These findings and the results of other groups suggest that RCTs comparing an analgesic witha placebo may underestimate the efficacy of the analgesic (Lund 2014 Level II EH, n=48 [cross over],JS 5). The hypothesis that placebo effect and drug effect are additive, upon which calculation ofefficacy is based, is most likely flawed. This is particularly true when the placebo effect is large.
Expectations influence placebo and nocebo response to acute pain independently frompersonality factors (Corsi 2017 Level III-1 EH)
In conclusion, expectancy is a powerful determinant of placebo response, with only minorchanges in the way information is delivered to the patient having the ability to significantly alter
expectancy and the magnitude of the placebo effects.

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17Classical conditioning
Classical conditioning is a learning phenomenon whereby repeated associations between aneutral stimulus and an active treatment (unconditioned stimulus) can result in the ability of
the neutral stimulus itself being able to elicit an effect similar to that of the unconditioned
stimulus (Finniss 2010 NR). Typically, an opioid analgesic is given on repeated occasions andthen replaced with a placebo-treatment simulation. These phenomena have been
demonstrated in animals ( Pacheco-Lopez 2006 BS) and in humans (Voudouris 1989 Level II EH, n=20,
JS 4; Voudouris 1990 Level III-1 EH). In a similar way, treatment history can influence the efficacy
of a subsequent treatment (Kessner 2014 Level III-2 EH). In an experimental setting, induced
negative experience with a first treatment resulted in reduced response to a second analgesic
treatment; the size of the effect was modulated by psychological trait variables such as
anxiety, depression and locus of control. There is evidence that social or observational learning
may also be a determinant of placebo effects ( Colloca 2006 Level III-1 EH). For example, placebo
effects were larger in subjects who had higher empathy after witnessing another volunteer inpain (Colloca 2009 Level II EH, n=48, JS 2).
1.3.1.2 | Neurobiological mechanisms
Studies into placebo analgesia have provided a substantial component of the knowledge aboutplacebo mechanisms, although it is now known that there are multiple placebo effects that
operate across many different medical conditions (Benedetti 2008 NR).
At a biochemical level, pioneering studies have shown that placebo effects in acute pain are
either completely or in part mediated by endogenous opioids, by virtue of their reversibility withnaloxone (Benedetti 1995 Level II EH, n=47, JS 3; Levine 1978 Level II EH, n=93, JS 3). The role ofcholecystokinin (CCK) was demonstrated through the potentiation of placebo effects using a CCK
antagonist (proglumide) (Benedetti 1995 Level II EH, n=93, JS 3). Interestingly, CCK has also beenshown to be responsible for nocebo effects and this suggests that anxiety and panic mechanisms(also associated with CCK release) may be activated (Benedetti 2007 NR).
Using both conditioning and expectancy manipulations with the administration of an opioid
analgesic, the resulting placebo effect was mediated by endogenous opioids ( Amanzio 1999 Level
II EH, n=229, JS 3). In contrast, in patients who received a nonopioid analgesic during conditioning,
the placebo effect was not reversed by naloxone. These findings are a powerful demonstrationthat there is not one placebo effect but many. One mechanism for this nonopioid-mediatedplacebo analgesia was found to be the endogenous cannabinoid system (cannabinoid type 1[CB1] receptor) (Benedetti 2011 Level III-1 EH).
The neuroanatomy of placebo analgesic effects has been partially unravelled. A positive
emission tomography (PET) study demonstrated similar brain changes to placebo as seen with
opioid administration (Petrovic 2002 Level III-2 EH). Further PET and fMRI studies have supported the
involvement of key regions of the brain associated with opioid analgesia (Zubieta 2005 Level III-3 EH),
including subcortical (Bingel 2006 Level III-2 EH) and spinal cord mechanisms (Eippert 2009 Level III-1
EH). Taken together, these studies show growing neurobiological evidence of placebo-induced
brain and spinal cord modulation of pain, although much more research is needed in this area.
A meta-analysis of 25 neuroimaging studies identified that placebo analgesia and expectancybased pain modulation resulted in reductions of activity in brain regions involved in pain
processing (eg the dorsal anterior cingulate, thalamus and insula) (Atlas 2014 Level IV EH SR). Other
regions with reduced activity were the amygdala and the striatum; as these are related to affectand valuation, placebo effects involve these components too. In addition, regions such as theprefrontal cortex, the midbrain surrounding the PAG and rostral anterior cingulate showed
increased activity with expectations for pain reduction.

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There is a link between polymorphisms in the dopamine, opioid and endocannabinoid genes
and response to placebo, demonstrating potential genetic determinants of placebo effects(Colloca 2019 Level III-2 EH, n=160).

1.3.2 | Clinical findings
Many meta-analyses include studies that also have a control nonplacebo/nocebo group. One ofthese reveals a relatively small placebo effect size for all clinical conditions (60 assessed)(Hrobjartsson 2010 Level I [Cochrane], 234 RCTs, n unspecified), but did not consider nocebo. The
majority of studies measured continuous outcomes (158 RCTs, n=10,525) but the results are also
consistent in those assessing binary outcomes (44 RCTs, n=6,041). In the studies with continuous
outcomes, there is an effect of placebo treatment (SMD -0.23; 95%CI -0.28 to -0.17) (158 RCTs,
n=10,525), which is larger for patient-reported (SMD -0.26; 95%CI -0.32 to -0.19) (109 RCTs,
n=8,000) than for observer-reported outcomes (SMD -0.13; 95%CI -0.24 to -0.02) (49 RCTs,
n=2,513). Overall, larger placebo effects are seen with physical placebo interventions(eg acupuncture), patient-involved outcomes, smaller trials and trials that did not informpatients about the possible placebo intervention.
Importantly, trials aimed at studying placebo effects (rather than assessing responses inplacebo-control groups) demonstrate larger placebo effects, particularly in the case of analgesia(Vase 2002 Level I, 37 RCTs, n=2,298). Effect sizes can be five times higher in these studies than in
analysis of placebo effects on control groups, demonstrating an important difference when
understanding placebo effects in clinical trials (where instructions are uncertain and the context
does not replicate routine clinical care) (Vase 2009 Level I [QUOROM], 24 RCTs, n=602). Consistently
positive but highly variable placebo responses are obvious in studies involving analgesia
specifically (pooled SMD -0.28; 95%CI -0.36 to -0.19) (60 RCTs [continuous outcome, pain], n=4,154) witha wide range of response in the individual trials from around SMD -1.0 to 0.5. This variability isalso seen in targeted studies on placebo (Vase 2009 Level I [QUOROM], 24 RCTs, n=602).

1.3.3 | Clinical Implications
The clinical implications of placebo effects are widespread and there is much more researchneeded to understand how placebo effects operate and how they can be manipulated in clinicalpractice. However, the notion that placebo effects (and therefore mechanisms) may be acomponent of routine pain management practice is highly important (Klinger 2014 NR; Finniss 2009NR). If one can study how psychosocial factors alter the patient’s nociception and the experienceof pain (by running experiments in which placebos are given), this has direct implications forclinical care where, even though no placebo is given, placebo effects are present.
In recent times, the ethical debate has shifted somewhat as the concept of placebo is better
understood. It is widely accepted that placebos should not be administered in a deceptive manner(Finniss 2010 NR; Brody 1982 NR). However, there are not the same ethical problems associated withharnessing the placebo effects that coexist with routine “active” treatments, as the outcome of atreatment is attributable to both the treatment itself and the specific context in which it was given(the placebo component). An applied example is that of the PSYHEART trial, where a specific pretreatment intervention addressing patients expectations pre-cardiac surgery resulted in significant
reductions in biological markers (endocrine and immune markers of stress), reduced disability andimproved quality of life at 6 mth post-surgery (Rief 2017 Level II, n=124, JS 5).
It is suggested that, in a therapeutic interaction, the placebo effect can be clinically utilised
by enhancing expectations and using learning components ( Klinger 2014 NR). Practical examplesof this are listed below.
5th Edition | Acute Pain Management: Scientific Evidence19

To enhance expectations:
•
•
•
•
•
•
•

Assess and manage expectations over the entire time course of a treatment;
Emphasise positive effects of medicines;
Avoid stressing adverse effects;
Explain effects and mechanisms of action of medicines;
Interact personally with the patient;
Do not rely only on written handouts; andAvoid unrealistic expectations.

To enhance learning components:• Administer analgesics in an open manner;• Connect the administration to positive internal states and external conditions;• Combine analgesics with other pain-relieving approaches, preferably with timecontingent administration of analgesics; and• Reinforce positive and minimise negative experiences.

KEY MESSAGES
1. Responses to placebo across all clinical conditions are small but consistently positive.
They are more prominent, although highly variable in magnitude, in studies of pain (U)(Level I [Cochrane Review]).
2. Nocebo effects in studies of pain are of moderate to large size and of high variability (U)(Level I [PRISMA]).
3. Trials aimed at studying placebo effects demonstrate larger placebo effects than those
assessing responses in placebo-control groups (U) (Level I [QUOROM]).
4. Analgesic placebo effects are based upon multiple neurobiological mechanisms,
including involvement of endogenous opioid, cholecystokinin (U) (Level II), endogenous
cannabinoid systems (U)(Level III-1) and genotype (N) (Level III-2).
5. Analgesic placebo effects are based upon multiple psychological determinants including
expectancy, classical conditioning and social and observational learning (S) (Level II).
6. Placebo and nocebo effects have significant influence on the efficacy of analgesics (U)(Level II).
The following tick boxes represent conclusions based on clinical experience and expert opinion:
 Placebo effects are the consequence of the psychosocial context (or treatment ritual) on
the patient’s mind, brain and body (U).
 Placebo effects occur in routine clinical care even when no traditional placebo is given.
The outcome of a treatment is attributable to both the treatment itself and thecontextual (or placebo) component (U).
 Nocebo effects occur in routine clinical care and are seen as an increased pain response
to a painful stimulus or the development of adverse effects not caused by, or separate
from, the intervention (U).
 Ethical harnessing of placebo and minimisation of nocebo effects will improve response
to clinical management interventions (U)20

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1.4 | Progression of acute to chronic pain
Chronic pain is common in the community and is moderate to severe in intensity in approximately
20% of the population (Kennedy 2014 Level IV, n39,400,000 [chronic pain sufferers]). This inevitably leads
to significant personal and economic cost (Breivik 2006 Level IV, n=46,394; Deloitte Access Economics 2019
NR). Episodes of acute pain may result in chronic pain with subsequent impact on quality of life,
employment and mental health (Steyaert 2012 NR; Lavand'homme 2011 NR; McGreevy 2011 NR). The
prediction and prevention of transition to chronic pain may therefore convey health and economic
benefits (see also Section 3.3).
The 11th revision of the International Classification of Diseases (ICD-11) defines chronic
postsurgical pain (CPSP) as pain developing or increasing in intensity after a surgical procedure,in the area of the surgery, persisting beyond the healing process (ie at least 3 mth) and not better
explained by another cause such as infection, malignancy, or a pre-existing pain condition (Schug2019 GL).
CPSP is common and although often mild, may be of sufficient severity to interfere with function andquality of life in 1 to 10% of cases (De Kock 2009 Level IV). The currently accepted prevalence of CPSP isshown below, however some studies suggest the prevalence may be lower than previously thought (seeTable 1.2) (Chan 2016 Level II, n=2,924, JS 5; Fletcher 2015 Level IV, n=3,120).
CPSP often has identifiable neuropathic characteristics, although this is procedure specific,
and is often poorly responsive to opioids (Chan 2011 Level II, n=423, JS 5; Wylde 2011 Level IV,
n=1,334; Haroutiunian 2013 NR; Macrae 2008 NR; Kehlet 2006 NR). The lack of efficacy of opioids fortreating CPSP is one factor contributing to the current prescription opioid crisis (Neuman 2019 NR;
Hollmann 2019 NR) (see also Sections 1.4.3, 8.13 and 9.7).
Other well-characterised acute pain events may also lead to chronic pain, such as post-traumatic
pain (see below and Section 8.1), acute back pain (see Section 8.7) and herpes zoster (see Section
8.6.2). Although CPSP tends to be associated with major surgery, involving significant acute pain,
nerve injury and inflammation, it may also occur following minor operations. The surgical drive
towards minimally invasive surgery has reduced acute postsurgical pain but has had a limited effecton the incidence of CPSP (Roth 2018 Level IV, n=1,996; Lavand'homme 2017 NR).
This section will focus primarily on CPSP, although the underlying mechanisms and risk
factors are also relevant to the nonsurgical conditions mentioned above.

1.4.1 | Epidemiology of chronic postsurgical pain
There is a high prevalence of CPSP and chronic pain following trauma; 22.5% of 5,130 patients
attending chronic pain clinics in North Britain cited surgery as a cause for their pain and 18.7% feltthat trauma was the primary cause (Crombie 1998 Level IV, n=5,130). As chronic pain is very common
in the population and only a small percentage of people with chronic pain attend pain clinics, dataobtained from clinics may not accurately reflect the scale of the problem in the community. A
randomised population survey from Portugal found that only 6% of those identified with chronic
pain felt that it was due to surgery (Azevedo 2012 Level IV, n=2,213). In contrast, a Norwegian
population-based study found 40.4% prevalence of pain in the anatomical region of surgery 3 mth
to 3 y later (Johansen 2012 Level IV, n=2,043). In 18.3% (n=373), the pain was moderate to severe. The
prevalence of moderate to severe pain was reduced to 10.5% by excluding all respondents with thesame pain before surgery and to 6.2% by excluding all respondents with any pain before surgery.
Factors associated with CPSP were sensory abnormalities in the area of surgery (hyperaesthesia[OR 6.27; 95%CI 4.43 to 8.86] or hypoaesthesia [OR 2.68; 95%CI 1.05 to 3.50]) and psychologicaldistress (OR 1.69; 95%CI 1.22 to 2.36).
5th Edition | Acute Pain Management: Scientific Evidence21Chronic pain following trauma is common and approximately 70% of patients without priorpain reported significant pain 6 mth following injury in one UK study ( Rockett 2019 Level II, n=64,
JS 5). Preceding studies found similar high rates of 46% to 85% of polytrauma survivors withsubsequent chronic pain (Gross 2011 Level IV, n=229) and 72% of some pain in the last 24 h at 1 y
after serious trauma (Holmes 2010 Level III-2, n=290).
Less is known about CPSP in the paediatric population, but it has been estimated that 20% ofchildren experience CPSP 1 y after spinal and mixed major surgery (Rabbitts 2017 Level IV SR, n=628;(Williams 2017 NR).
The incidence of CPSP varies with the type of operation and it is particularly common where
nerve trauma is inevitable (eg amputation) or where the surgical field is richly innervated(eg chest wall) (see Table 1.2) (Wylde 2011 Level IV, n=1,294; Macrae 2008 NR; Kehlet 2006 NR). In aprospective cross-sectional study at a university-affiliated hospital and level 1 trauma centre,
14.8% of patients described CPSP, in particular those after trauma and major orthopaedic
surgery (Simanski 2014 Level IV, n=3,020). A similar study, focussing on neuropathic CPSP only
following two procedure types, identified an incidence of 3.2% for laparoscopic herniorrhaphy
vs 37.1% for breast cancer surgery at 6 mth after surgery ( Duale 2014 Level IV, n=3,112). Overall,these data support the high incidence of CPSP and the frequent linkage of CPSP to nerve injury.
Table 1.2 | Incidence of chronic pain after surgery
Type of surgery

Any CPSP (%)

Severe CPSP (%)

Neuropathic pain
(proportion)*

Abdominal surgery (visceral)

17-21%

Not reported

Not reported

Amputation

30-85%

5-10%

80%

Caesarean section

6-55%

5-10%

50%

Cholecystectomy

3-50%

Not reported

Not reported

Craniotomy

7-30%

25%

Not reported

Dental surgery

5-13%

Not reported

Not reported

Hip arthroplasty

27%

6%

1-2%

Inguinal herniotomy

5-63%

2-4%

80%

Knee arthroplasty

13-44%

15%

6%

Melanoma resection

9%

Not reported

Not reported

Mastectomy

11-57%

5-10%

65%

Sternotomy (CABG)

30-50%

4-28%

Not reported

Thoracotomy

5-65%

10%

45%

Vasectomy

0-37%

Not reported

Not reported

CABG-Coronary artery bypass graft surgery; * assessed by screening questionnaires in most studies.
Adapted from Glare 2019; Schug 2017.

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1.4.2 | Characteristics of chronic postsurgical pain
Efforts are now being made to standardise outcome measures to characterise CPSP in future
RCTs and epidemiological studies (Wylde 2014 Level IV, n=1,294; VanDenKerkhof 2013 GL). CPSP may
persist as a continuum from acute postsurgical pain or it may occur following a pain-free interval.
CPSP may occur in the skin or deep tissues of the region of surgery, it may be referred tocharacteristic areas due to viscerosomatic convergence or be related to the course of a nerve
injured by surgery.
A significant proportion of patients with CPSP demonstrate sensory abnormalities, suggestingthat CPSP often has a neuropathic component (Johansen 2016 Level IV, n=81; Aasvang 2008 Level IV,n=46). The incidence of acute neuropathic pain has been reported as 1 to 3%, based on patientsreferred to an APS, primarily after surgery or trauma (Hayes 2002 Level IV). The majority of thesepatients had persistent pain at 12 mth, suggesting that acute neuropathic pain is a risk factor forchronic pain. These qualitative results were confirmed in a subsequent study (Beloeil 2017 Level III-2,
n=593). Using a screening tool (DN-4), acute neuropathic pain was identified in 5.6% (95%CI 3.6 to8.3) on the day of surgery and in 12.9% (95%CI 9.7 to 16.7) on POD 1. Postsurgical neuropathic pain
was identified in phone follow-up 2 mth postsurgery in 33.3% of patients; acute neuropathic pain
was a risk factor for its development (OR 4.2; 95%CI 2.2 to 8.1). Similarly, immediately after
thoracotomy or video-assisted thoracic surgery (VATS), 8% of patients scored positively on anotherscreening tool for neuropathic pain (LANSS) and 22% 3 mth later; again acute neuropathic pain was
identified as a risk factor for chronic neuropathic pain (RR 3.5; 95%CI 1.7 to 7.2) (Searle 2009b Level
III-2, n=100). Following VATS, sensory changes suggestive of nerve injury were demonstrated in mostpatients but there was no difference in sensory abnormalities or measures of central sensitisation
between patients with and without CPSP (Wildgaard 2012 Level IV). Similarly, changes in sensory
thresholds (warmth detection and heat pain) were demonstrated in most pain-free patients
following open inguinal herniorrhaphy (Aasvang 2010b Level IV). This suggests that, although nerve
injury is frequently associated with CPSP, such injury does not inevitably lead to chronic pain. Itshould be recognised however that numbness might still be distressing to some patients.
Additionally, neuroplastic processes termed central sensitisation may occur without nerve injury
and may result in altered nociceptor function with a gain (sensitisation) or a loss (desensitisation)of function of nociceptors, resulting in sensory changes superficially resembling neuropathic pain.
Assessment of these sensory changes using techniques such as quantitative sensory testing may inthe future lead to more individualised treatment and drug development for the prevention andtreatment of CPSP (Arendt-Nielsen 2018 NR).
The intensity and character of CPSP is variable. Descriptors may relate to neuropathic pain
(shooting, burning, tingling) (VanDenKerkhof 2013 Level IV) but somatic / nociceptive paincharacteristics (aching, tender, stabbing, squeezing) are also commonly reported (Chan 2011 Level
III-1), especially associated with joint arthroplasty (Wylde 2011 Level IV, n=1,294). Typically around
10% of patients describe the CPSP as severe, although this proportion may be higher in somesurgical groups (Glare 2019 NR). The sequelae of CPSP vary from mild discomfort to a significant
impact on quality of life. The negative impact of CPSP is similar to that of other chronic pain
conditions and, along with psychological distress, may include the use of multiple analgesics,
regular medical attendances, inability to undertake certain activities and difficulty returning towork (Chan 2011 Level III-1, n=640; Steyaert 2012 NR).

1.4.3 | Opioids and CPSPIn recent years, the use of strong opioids to manage acute and chronic non-cancer pain has been
increasing. This has been one factor in the generation of a global opioid crisis, with opioid use
5th Edition | Acute Pain Management: Scientific Evidence

23and deaths from overdose of prescription drugs increasing dramatically in many countries ( Jones2018 NR). Surgery is a risk factor for both persistent pain and ongoing inappropriate opioid use(Hah 2017 NR). Prolonged opioid use after hospital discharge seems to be relatively common,
occurring in 10.5% of patients for greater than 90 d after surgery in an Australian study ( Stark
2017 Level IV, n=970), and in 3% of opioid naïve patients at 90 d in a large cohort study from
Canada (Clarke 2014 Level IV, n=39,140). In contrast, opioid use by outpatient pain clinics has been
decreasing in chronic non-cancer pain due to lack of evidence for their efficacy (Dowell 2016 GL;
Chou 2009 GL). For more details see also Section 8.13.
Not only is CPSP a risk factor for ongoing opioid use, but opioid use may trigger or worsen
symptoms of CPSP (see also Section 1.4.4 below). The use of high dose opioids in the acutesetting has been shown to activate neuroplastic processes which may result in CPSP (see also
Sections 1.1, 4.3.1 and 9.7). Opioid induced hyperalgesia (OIH) is a state of increased sensitivity
to noxious stimuli occurring after exposure to high dose opioids (usually remifentanil). Patients
exposed to high dose opioids in the perioperative period have higher postoperative pain scoresand increased opioid use. OIH may result in spiralling opioid use ( Fletcher 2014 Level I, 24 RCTs,
n=1,494). Endogenous opioid analgesic systems are protective against the development of CPSP
(Eippert 2009 Level III-1 EH; Yarnitsky 2008 Level IV, n=62). Prolonged opioid use leads tointernalisation of mu opioid receptors at a cellular level. This may impair the functioning of theendogenous opioid analgesic system and increase sensitivity to pain leading to OIH andpotentially CPSP (Glare 2019 NR).

1.4.4 | Predictive factors for chronic postsurgical pain
Risk evaluation for CPSP enables clinicians to address identified risk factors before surgery.
This guides planning and discussion regarding expectations, the scope of planned surgery andpossibility of changed approaches to the anaesthesia, pain management and even the procedure
itself. Risk factors for CPSP have been identified in the preoperative, intraoperative andpostoperative periods, and cover 6 broad domains: genetic, demographic, psychosocial, pain,
clinical, and surgical factors (Schug 2017 NR).
Demographic factors such as younger age for adults and female gender influence the frequencyof CPSP, as do psychological factors such as anxiety, depression, catastrophising, fear of surgery
and hypervigilance (Theunissen 2012 Level IV SR, 29 studies, n=6,628; Hinrichs-Rocker 2009 Level IV SR, 50
studies, n≈25,000; Weinrib 2017 NR). Very young age may be a protective factor as hernia repair inchildren <3 mth of age did not lead to chronic pain in adulthood (Aasvang 2007 Level IV, n=651). In
children aged 8–18 y, “parent pain catastrophising” was the main risk factor for the developmentof CPSP (Page 2013 Level IV, n-83). The significance of each risk factor varies with the operation but
pre-existing psychological factors (high state anxiety and pain magnification as a component ofcatastrophising) increased the risk across two types of surgery (TKA and breast cancer surgery)(Masselin-Dubois 2013 Level III-2, n=189; Weinrib 2017 NR).
The intensity of acute postsurgical pain is a consistent predictor of CPSP ( Chan 2011 Level II,
n=640, JS 5; Althaus 2012 Level IV, n=150). This has been shown following a wide range ofprocedures including breast surgery (Bruce 2014 Level IV, n=362), thoracic surgery (Yarnitsky 2008
Level IV, n=62; Katz 1996 Level IV, n=30), gynaecological surgery ( VanDenKerkhof 2012a Level IV,
n=433), Caesarean section ( Nikolajsen 2004 Level IV, n=220), lower limb amputation ( Hanley 2007
Level IV, n=57), total hip arthroplasty (THA) (Nikolajsen 2006 Level IV, n=1,231) and inguinal
herniotomy (Aasvang 2010a Level IV, n=464). After thoracic surgery, higher acute pain intensity
postoperatively predicted the incidence of CPSP (OR 1.80; 95%CI 1.28 to 2.77), nearly doubling
the chance of developing chronic pain for each point increase on a 10-point numerical rating
scale (NRS) (Yarnitsky 2008 Level IV, n=62). Large scale observational studies have confirmed the24

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importance of acute pain in the development of CPSP with a 10% increase in the percentageof time in severe acute pain associated with a 30% increase in the incidence of CPSP at 12 mth(Fletcher 2015 Level IV, n=3,120). Sensitisation and “wind-up” of nociceptive pathways within the
CNS is thought to play a significant role in the establishment and maintenance of chronic pain
following an intense nociceptive stimulus. Nociceptive processes occurring in the periphery,
including nerve injury, are also implicated in the transition from acute to chronic pain
(Baron 2013 NR).
Preoperative chronic pain is a universal risk factor (Johansen 2014 Level IV, n=12,981;
VanDenKerkhof 2012a Level IV, n=433; Wylde 2011 Level IV, n=1,294; Aasvang 2010a Level IV, n=464).
This is likely due to the increase in sensitivity of the nociceptive system found in patients withchronic pain. This may partly explain the relatively high rates of CPSP following THA and TKA (25and 44% respectively) (Wylde 2011 Level IV, n=1,294). Preoperative pain was the predictor thatmost commonly demonstrated a significant relationship with persistent pain following TKA
across uni- and multivariate analyses. In a meta-analysis of univariate models, the largest effectsizes were found for preoperative pain at other sites, catastrophising and depression (Lewis 2015
Level I, 28 RCTs, n=29,993). For data from multivariate models catastrophising, preoperative pain,
mental health and comorbidities had significant effects. Preoperative pain was also a risk factor
for CPSP at 3 mth in trauma patients requiring orthopaedic surgery (OR: 1.17; 95% CI: 1.03, 1.32)(Edgley 2019 Level III-2, n=229).
Given the potential for opioids to interfere with endogenous analgesic systems, it is perhaps
not surprising to find that preoperative opioid use increased the risk of CPSP after gynaecologicalsurgery (RR 2.0; 95%CI 1.2 to 3.3) (VanDenKerkhof 2012a Level IV, n=433). In a prospective study of
day case orthopaedic surgery, 8% developed CPSP if they were taking pre-operative analgesics
with adequate analgesia (Hoofwijk 2015 Level IV, n=908). However, patients taking analgesics
without relief had a much higher incidence of CPSP of 32%.
Presurgical sensitivity to painful stimuli, identified using some form of quantitative
sensory testing (QST), variably accounts for 5–54% of the variance in acute postoperative pain
and can predict risk for CPSP ( Werner 2010 Level I [QUOROM], 15 RCTs, n=962). The relative
efficacy of the endogenous descending inhibitory system determined by assessing DNIC
partly predicted patients who developed CPSP after thoracotomy (OR 0.52; 95%CI 0.33 to0.77) (Yarnitsky 2008 Level IV, n=62). Widespread pressure pain sensitivity was correlated withworse functional outcome following TKA (Wylde 2013 Level III-3, n=51). Sensitivity to noxious
heat and mechanical stimuli did not correlate with CPSP in an unselected surgical population,
whereas cold sensitivity correlated both with CPSP and comorbid chronic pain conditions(Johansen 2014 Level IV, n=12,981 ). Prior to herniotomy, high pain scores from a 47°C
temperature probe were predictive of postherniotomy pain (OR 1.34; 95%CI 1.15 to 1.57)(Aasvang 2010a Level IV, n=464 ).
It is also likely that genetic and epigenetic factors influence both the sensitivity of
individuals to analgesics and their risk of CPSP ( Mauck 2014 NR; Buchheit 2012 NR). For example,
different haplotypes of the gene for the enzyme catechol-O-methyltransferase (COMT),
involved in the modulation of pain responses, were associated not only with differences inexperimental pain sensitivity but also with the development of chronic temporomandibular
joint disorder (TMD) ( Nackley 2007 Level IV). In women undergoing hysterectomy thepolymorphism rs4818 within the COMT gene was associated with the presence of CPSP at
3 mth but not 12 mth postoperatively (Hoofwijk 2019 Level III-2, n=345). However, opioid
receptor mu-1 (OPRM1) genotype, but not COMT genotype, was associated with thedevelopment of CPSP after abdominal surgery ( Kolesnikov 2013 Level IV, n=102). One prospective
study of patients undergoing various surgical procedures did not reveal any correlation
between 90 genetic markers and the incidence or severity of CPSP ( Montes 2015 Level IV,
5th Edition | Acute Pain Management: Scientific Evidence25n=2,929). Overall, heritability estimates suggest that about 50% of the variability in CPSP rates

is attributable to genetic variability. In order to apply these findings to individual patients, verylarge studies analysing tens of thousands of genetic samples will be needed to characteri sepatients at risk (Clarke 2015 NR) (see also Section 1.7).
To date, clinical risk factors remain the most reliable tools for the prediction of CPSP (Althaus2012 NR). Attempts have been made to generate predictive models of CPSP but these do not yet
have sufficient sensitivity and specificity to prove clinically useful. Using a training set of 150
patients with an incidence of CPSP of about 50%, five factors were independently predictive ofdeveloping CPSP, of which four can be assessed pre-operatively: pain in the surgical field,
comorbid chronic pain at other sites, capacity overload and comorbid stress. Moderate to severe
postoperative pain at POD 5 was the only significant postoperative factor. Patients with three tofive risk factors were more likely to go on to develop CPSP than were those with zero to two
factors (sensitivity 74%, specificity 65%).
Screening tools based on specific types of surgery have demonstrated better specificity,
but identify many false positives. For example, for breast cancer surgery four factors werepredictive of CPSP: preoperative pain at the site of surgery, high body mass index, axillary
lymph node dissection and severity of acute pain on the 7th d after surgery (Meretoja 2017
NR). At the 20% risk level, the model had 32.8% and 47.4% sensitivity and 94.4% and 82.4%
specificity in two cohorts from Denmark and Scotland, respectively. A predictive model for
CPSP after inguinal hernia repair, hysterectomy or thoracotomy has been developed ( Montes
2015 Level IV, n=2,929 ). The model included six clinical factors: surgical procedure, age,physical health, mental health, preoperative pain in the surgical field, and preoperative pain
in another area. This model was a good fit (c-statistic 0.731; 95%CI 0.705 to 0.755).
Interestin gly, the same study found that 90 genetic markers did not predict CPSP.
The trajectory of daily pain scores after surgery has also been investigated as a predictor of
CPSP (Chapman 2011 Level IV, n=502). Following TKA, 4 distinct acute pain trajectories wereidentified. Patients with a constantly high acute pain trajectory were at higher risk of CPSP ( Page
2015 Level IV, n=173). Subacute pain after orthopaedic surgery at 10 d and 6 wk also predicted
CPSP at 12 mth in one study (Andersson 2015 Level IV). Trajectories of anxiety and depression overtime have also been assessed as a potential risk factor for CPSP, and patients with unremittinghigh levels of anxiety, but not depression were found to be more likely to experience CPSP
following cardiac surgery (Page 2017 Level IV, n=173).
A summary of risk factors identified for the development of CPSP is presented in Table 1.3.

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Table 1.3 | Risk factors for chronic postsurgical pain
Preoperative factors

Pain, moderate to severe, lasting >1 mth
Repeat surgery
Psychological vulnerability (eg catastrophising)
Preoperative anxiety
Female sex
Younger age (adults)
Workers’ compensation
Genetic predisposition
Inefficient diffuse noxious inhibitory control
Opioid use (particularly if ineffective)

Intraoperative factors

Surgical approach with risk of nerve damage

Postoperative factors

Pain (acute, moderate to severe and subacute)
Radiation therapy to area
Neurotoxic chemotherapy
Depression
Psychological vulnerability
Neuroticism
Anxiety
Pain and anxiety trajectories

Sources: Adapted from Page 2017; Schug 2017; Johansen 2014; Wylde 2011; Hinrichs-Rocker 2009;
Macrae 2008; Kehlet 2006.

1.4.5 | Mechanisms for the progression from acute to chronic pain
Central and peripheral sensitisation are the most likely underlying factors in the development of
CPSP (Richebe 2018 NR; Lavand'homme 2017 NR). There is limited trial data to infer mechanisms
and therefore most evidence relating to likely mechanisms is based on laboratory animal or
epidemiological data (Peirs 2016 NR BS). Initiation of these processes is most likely in a situation
where an individual is “primed” (eg by pre-existing pain) or susceptible (eg inefficient DNIC,
psychological state or genetic predisposition) (Lavand'homme 2017 NR; Denk 2014 NR;
Lavand'homme 2011 NR). The imposition of an intense surgical stimulus induces both central andperipheral changes (Baron 2013 NR). Maintenance of these intense nociceptive inputs by poorly
controlled postoperative pain, peripheral nerve damage (D'Mello 2008 NR) and complications (egwound infection) then lead on to a chronic pain state. It is proposed that these all lead toneuroplastic processes such as peripheral and central sensitisation. Such processes include
inflammation at the site of tissue damage as well as ectopic discharges after nerve injury andlead to a barrage of afferent input that produces changes in the peripheral nerves, spinal cord,higher central pain pathways, somatosensory cortex and the sympathetic nervous system (seeSection 1.1). Evidence for sensitisation includes the presence of larger area of secondary
hyperalgesia at 48 h (88 vs 33 cm2) in patients having iliac crest bone harvesting who developed
CPSP with higher neuropathic pain scores on the Doleur Neuropathique 4 (DN4) questionnaire(4.3/10 vs 2.3) (Martinez 2012 Level IV). Similarly, following abdominal surgery, patients with
analgesic regimens resulting in smaller areas of wound hyperalgesia (indicating less sensitisation)
had a lower incidence of CPSP (Lavand'homme 2005 Level II, n=85, JS 5). Punctuate hyperalgesia

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27around a surgical incision could be shown in a large area, suggesting central sensitisation, which
was suppressed by IV ketamine injection (Stubhaug 1997 Level II, n=20, JS 5).
The relative degree of ongoing inflammation or intraoperative nerve injury resulting inperipheral and central sensitisation may explain the variation in risk and, to an extent, thecharacteristics of CPSP for different operations (Simanski 2014 Level IV).
Psychological factors (depression, psychological vulnerability and stress) are important in thedevelopment of CPSP (Hinrichs-Rocker 2009 Level IV SR, 50 RCTs, n≈25,000) and cortical processingof nociceptive information and descending inhibitory and excitatory pathways provides aplausible mechanism for some of these effects. Functional connectivity and anatomicaldifferences of corticolimbic structures involved in emotion and motivation predict chronic pain
in some circumstances (Vachon-Presseau 2016 Level IV EH; Baliki 2012 NR).

1.4.6 | Prevention of chronic postsurgical pain
Effective prevention of CPSP is limited by an incomplete understanding of the mechanisms thatgenerate it. However, some recognised risk factors are modifiable in the perioperative period.
These include, body mass index, opioid use, preoperative pain and some psychological factors.
In the postoperative period, attention to effective management of acute pain, limiting exposure
to opioids and psychological support in rehabilitation and recovery of normal functioning are all
likely to play a role.
Interventions evaluated thus far are divided into four broad groups and include regional andneuraxial analgesia, pharmacotherapy, surgery and multidisciplinary nonpharmacologicalinterventions. Analgesic strategies for which the clinical efficacy outlasts the pharmacologicalactivity are described as “preventive analgesia” (defined as analgesia that persists more than 5.5
half-lives of the medicine) and most likely rely on reducing peripheral and central sensitisation(Katz 2011 NR) (see also Section 1.5).
1.4.6.1 | Regional or neuraxial analgesia
Meta-analysis on the prevention of CPSP by regional anaesthesia found benefits for three
procedure types: thoracotomy, breast cancer surgery and Caesarean section ( Weinstein 2018
Level I (Cochrane), 63 RCTs, n=3,027 ). Following open thoracotomy (7 RCTs, n=499 ), epiduralanaesthesia reduces the incidence of CPSP 3 to 18 mth following surgery compared tosystemic analgesia (OR 0.52; 95%CI 0.32 to 0.84) (number-needed-to-treat [NNT] 7). For
breast cancer surgery any form of regional anaesthesia ( 18 RCTs, n=1,297 ) reduces CPSP 3 to
12 mth after surgery compared with systemic analgesia (OR 0.43; 95%CI 0.28 to 0.68) (NNT7); specifically paravertebral block (PVB) ( 6 RCTs, n=419 ) is effective (OR 0.61; 95%CI 0.39 to0.97) (NNT 11). For Caesarean section (4 RCTs, n=551 ), a mixture of regional analgesia
techniques, reduces CPSP from 3 to 8 mth (OR 0.46; 95%CI 0.28 to 0.78) (NNT 19). There isinsufficient data to make clear recommendations regarding the timing of various local
anaesthetic interventions (21 RCTs) and the impact on CPSP, but earlier administration of
epidural prior to incision vs post amputation (4 RCTs, n=334) may provide benefit (Humble
2015 Level I, 32 RCTs, n=2,834 ).
For many procedures, studies investigating the effect of regional anaesthesia and analgesia
on chronic pain outcomes are limited in number and have differing designs, which prevents
meta-analysis due to high levels of heterogeneity. In patients undergoing open colonic resection,
continuous perioperative epidural analgesia led to a lower risk of developing chronic pain up to
1 y after surgery compared with IV analgesia (Lavand'homme 2005 Level II, n=85, JS 5). In a casecontrol study, epidural anaesthesia reduced chronic pain at 6 mth after surgery (OR 0.19; 95%CI
0.05 to 0.76) (Bouman 2014 Level III-2). Spinal anaesthesia in comparison to general anaesthesia

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reduced the risk of CPSP after Caesarean section (Nikolajsen 2004 Level III-2) and hysterectomy(OR 0.42; 95%CI 0.21 to 0.85) (Brandsborg 2007 Level III-2). The latter study found no difference inrisk between abdominal and vaginal hysterectomy.
A systematic review on phantom limb pain prophylaxis showed that perioperative (pre, intra
and postoperative) epidural analgesia reduced the incidence of severe phantom limb pain
12 mth after surgery (NNT 5.8) (Gehling 2003 Level III-2 SR, 9 studies, n=836). The use of epidural
analgesia to prevent the development of phantom pain or CPSP following limb amputation may
be a useful component of multimodal therapy in patients with severe preoperative pain
(Karanikolas 2011 Level II, n=65, JS 5). See also Section 8.1.5.
The use of IV lidocaine for prevention of CPSP is discussed in Section 1.4.6.3 below.
1.4.6.2 | Local anaesthetic infiltration
Meta-analysis on the prevention of CPSP by local infiltration finds benefits for breast cancer
surgery and iliac crest bone graft (ICBG) harvest (Weinstein 2018 Level I [Cochrane], 39 RCTs,
n=3,027). For breast cancer surgery (6 RCTs, n=379), local anaesthetic infiltration reduces CPSP
3 to 12 mth after surgery vs systemic analgesia (OR 0.29; 95%CI 0.12 to 0.73) (NNT 7). For ICBG
harvest (4 RCTs, n=159), continuous local anaesthetic infiltration reduces CPSP 3 to 12 mth after
surgery vs systemic analgesia (OR 0.1; 95%CI 0.01 to 0.59) (NNT 3).
Local anaesthetic wound infiltration reduced the proportion of patients with chronic pain andneuropathic pain 2 mth following intracranial tumour resection (Batoz 2009 Level II, n=52, JS 3).
1.4.6.3 | Pharmacotherapy
Ketamine
Ketamine is commonly used to treat both acute and chronic pain. When used as a preventive
analgesic, perioperative ketamine compared to placebo significantly reduces CPSP at 3 mth(5 RCTs, n unspecified) but only when administered for >24 h (OR 0.37; 95%CI 0.14 to 0.98)(Chaparro 2013 Level I [Cochrane], 14 RCTs [ketamine], n=1,388). At 6 mth (10 RCTs, n=516),
perioperative ketamine reduces CPSP (OR 0.63; 95%CI 0.47 to 0.83), which remains significant
when infused for <24 h (OR 0.45; 95%CI 0.26 to 0.78). These effects were predominantly in
abdominal surgery. Another meta-analysis found a benefit of perioperative IV ketamine vsplacebo in reducing the incidence of CPSP at 3 mth (RR 0.74; 95%CI 0.60 to 0.93) (NNT 12), 6 mth(RR 0.70; 95%CI 0.50 to 0.98) (NNT 14) but not at 12 mth postoperatively (McNicol 2014 Level I,
14 RCTs [IV route], n=1,586) (11 RCTs overlap); such beneficial effects were not found with epiduraladministration of ketamine (3 RCTs, n=302).
A network meta-analysis investigating multiple pharmacological interventions to reduce
CPSP identified ketamine as the highest ranked in terms of efficacy and safety ( Ning 2018 Level I[NMA], 24 RCTs, n unspecified). In thoracic surgery, low dose ketamine infusion (0.1 mg/kg/hr)
reduced opioid use for 24 h and pain at 48 h, but did not affect CPSP at 3, 6 or 12 mth ( Chumbley
2019 Level II, n=70, JS 5).
Opioids
High dose intra-operative opioids, particularly remifentanil, have been shown to result in opioid
induced hyperalgesia, increased pain and 24 h opioid use in the postoperative period which may
be associated with CPSP (Fletcher 2014 Level I, 27 RCTs, n=1,494). The intra-operative use of
remifentanil in cardiac surgery also resulted in a higher incidence of CPSP at 1 y (OR 8.9; 95%CI
1.6 to 49.0) (van Gulik 2012 Level III-2, n=90).

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Alpha-2-delta ligands (gabapentinoids)
Two previous parallel meta-analyses (10 RCT overlap) and a correction of one of these investigated
the use of perioperative gabapentin or pregabalin in reducing CPSP across a diverse range ofprocedures (Chaparro 2013 Level I [Cochrane], 15 RCTs [gabapentin and pregabalin], n=1,300; Clarke 2012
Level I [PRISMA], 11 RCTs, n=930; Clarke 2013 Level I, 5 RCTs, n=875). The overall conclusion was that
there was limited or no benefit in the setting of significant heterogeneity.
In addressing the issue of potential bias due to unpublished data, a meta-analysis ofpregabalin and CPSP included 79% unpublished trials ( Martinez 2017 Level I [PRISMA], 18 RCTs,
n=2,485). There was no benefit with pregabalin use in the prevention of CPSP overall at 3, 6 or
12 mth postoperatively, in cardiac, visceral or orthopaedic surgery (OR 0.87 [at 3 mth]; 95%CI
0.66 to 1.14). There was, however, a reduction in chronic postsurgical neuropathic pain in four
published trials (4 RCT, n=451) (OR 0.16; 95%CI 0.04 to 0.73). These results reflect weakevidence due to the small size of most included studies, the variability in existing study design,
doses used, duration of treatment and measured outcomes, and positive publication bias.
IV lidocaine (lignocaine)
IV lidocaine has preventive effects on acute postoperative pain (Barreveld 2013 Level I, 16 RCTs
[lidocaine], n=847) (see Section 1.5) and reduces CPSP following breast cancer surgery at 3 mthcompared to systemic analgesics alone (OR 0.24; 95%CI 0.08 to 0.69) (Weinstein 2018 Level I[Cochrane], 2 RCTs, n=97 [IV lidocaine]) (1 RCT overlap). A meta-analysis of IV lidocaine versus
placebo in the prevention of CPSP at 3 mth across a range of surgeries (predominantly
mastectomy), identified a significant benefit (OR 0.29; 95%CI 0.18 to 0.48) (NNT 5), althoughnumbers were too small to specifically identify safety concerns (Bailey 2018 Level I, 6 RCTs, n=420)(2 RCT overlap with Weinstein 2018).
OthersFollowing mastectomy, 10 d treatment with venlafaxine (37.5 mg/d) commencing preoperatively
was associated with significantly lower burning and stabbing pain after 6 mth ( Amr 2010 Level II,
n=150, JS 3).
Planned subgroup analysis of the intraoperative use of nitrous oxide (ENIGMA-2) revealed
that this intervention prevents CPSP in Chinese patients and those with variants in the methylene
tetrahydrofolate reductase gene (RR 0.70; 95%CI 0.50 to 0.98) suggesting that there may be a
genetic component to vulnerability to CPSP (Chan 2016 Level II, n=674, JS 5); there was no benefit
in non-Chinese patients overall.
1.4.6.3 | Modification of surgical approach
Minimally invasive and laparoscopic surgery has made a significant impact on the severity ofacute postsurgical pain but has resulted in little impact on the prevalence of CPSP ( Aasvang 2010aLevel III-2, n=464). While VATS vs open thoracic surgery reduced the risk of post-thoracotomy pain(aOR 0.33; 95%CI 0.13 to 0.86) and neuropathic pain (aOR 0.18; 95%CI 0.04-0.85), it still carries
a significant risk (35% incidence) (Shanthanna 2016 Level III-3, n=106); this is confirmed in anotherstudy (VATS 13.3% vs thoracotomy 32.2%) (Wang 2017 Level III-2, n=298).
Deliberate neurectomy (of the ilioinguinal nerve) for inguinal hernia repair reduced theincidence of CPSP (from 21 to 6%) in one RCT ( Malekpour 2008 Level II, n=100, JS 4 ) and inanother study ( Smeds 2010 Level III-2), while an earlier no nrandomised multicentre
prospective study found this approach increased CPSP risk ( Alfieri 2006 Level III-2, n=973).
Intraoperative nerve identification of the iliohypogastric, ilioinguinal and genitofemoral
nerves did not reduce the risk of development of sensory loss or postherniotomy pain
syndrome compared with nonidentification ( Bischoff 2012 Level III-3, n=244 ). International30

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guidelines for the reduction in CPSP following inguinal herniorrhaphy have been developed,
recommending preservation of all three nerves ( Alfieri 2011 GL).
Sparing of the intercostobrachial nerve during mastectomy with axillary dissection reduces
the likelihood of a patient having hyposensitivity but not hypersensitivity (Warrier 2014 Level I[PRISMA], 3 RCTs, n=309). Cryoanalgesia of the intercostal (IC) nerves at the time of thoracotomy
results in an increase in chronic pain in comparison to IV PCA or epidural analgesia or in
conjunction with epidural analgesia (Humble 2015 Level I, 6 RCTs [cryoanalgesia], n=186).
1.4.6.4 | Multidisciplinary approaches
The impact of psychological interventions delivered in the perioperative period to prevent CPSP
has been assessed by a systematic review (Wang 2018 Level I [PRISMA], 15 RCTs, n=2,220).
Perioperative education has no effect on CPSP, while perioperative cognitive-behaviouraltherapy and/or relaxation training reduce the severity of CPSP based on evidence of moderatequality (MD -1.06/10; 95%CI -1.56 to -0.55). Preemptive and preventive pain psychoeducation
decrease the length of stay and improve quality of acute postsurgical pain relief (Horn 2020 Level I[PRISMA], 43 RCTs, n unspecified). The authors concluded that preemptive pain psychoeducation
would result in a decreased incidence of CPSP given that severe acute postsurgical pain andcatastrophising were both significant risk factors.
Transitional pain services
New models of acute pain services have been suggested to manage pain and opioid use in
the perioperative period. The ‘Transitional Pain Service’ aims to optimise pain and opioid use
prior to surgery, devise individualised intraoperative opioid sparing analgesic plans andmanage pain postoperatively beyond the time of discharge from hospital ( Katz 2015 NR). Thisapproach is intended to reduce CPSP and inappropriate long-term opioid use. Psychologicalstrategies including Acceptance and Commitment Therapy (ACT) are employed to assist in
rehabilitating patients and treat or prevent CPSP ( Huang 2016 NR). A similar model of ‘AcutePain Service Outpatient Clinic’ has been established in Finland ( Tiippana 2016 Level III-3). Of thefirst 200 high risk patients referred to the clinic, 70% had evidence of neuropathic CPSP. The
median time to referral to the clinic from surgery was 2 mth and patients were followed up
for a median of 2.8 mth. At discharge from hospital, half the patients were using weak
opioids, one third strong opioids and 70% were taking gabapentinoids. At discharge from theclinic, use of these drugs was approximately halved. One fifth of the patients were referredto the chronic pain clinic for ongoing management.
See also the following Section 1.5 for more examples of the use of preemptive and preventive
analgesic interventions in attempts to reduce the risk of chronic pain after surgery and Sections
8.1.5 to 8.1.6 for more details on prevention of phantom pain after limb amputation and otherpostoperative pain syndromes.

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KEY MESSAGES
1. Perioperative IV ketamine reduces the incidence of chronic postsurgical pain in
selected procedures (S) (Level I [Cochrane Review]).
2. Following thoracotomy, epidural analgesia reduces the incidence of chronic
postsurgical pain (S) (Level I [Cochrane Review]).
3. Following breast cancer surgery, paravertebral block (S), local infiltration (N) (Level I[Cochrane Review]) and IV lidocaine reduce the incidence of chronic postsurgical pain(N) (Level I [PRISMA]).
4. For iliac crest bone graft harvest, continuous local anaesthetic infiltration reduces theincidence of chronic postsurgical pain (N) (Level I [Cochrane Review])
5. Pregabalin reduces the incidence of chronic postsurgical neuropathic pain, but does
not affect non-neuropathic chronic postsurgical pain (N) (Level I [PRISMA]).
6. Sparing of the intercostobrachial nerve during mastectomy does not decrease chestwall hypersensitivity (U) (Level I [PRISMA]).
7. Cryoanalgesia of the intercostal nerves at the time of thoracotomy results in no
improvement in acute pain but an increase in chronic pain (U) (Level I).
8. There is significant association between anxiety, pain catastrophising (U) (Level III-2
SR), depression, psychological vulnerability and stress (U) (Level IV SR) and thesubsequent development of chronic postsurgical pain.
9. Other risk factors that predispose to the development of chronic postsurgical pain
include the severity of presurgical chronic pain and postsurgical acute pain andintraoperative nerve injury (U) (Level IV SR).
10. Spinal anaesthesia in comparison to general anaesthesia reduces the risk of chronic
postsurgical pain after hysterectomy and Caesarean section (U) (Level III-2).
11. Chronic postsurgical pain is common and may lead to significant disability (S) (Level IV).
12. Chronic postsurgical pain often has a neuropathic component (S) (Level IV).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Gabapentin has no demonstrated effect in preventing chronic postsurgical pain;
considerable uncertainty exists regarding efficacy with contradictory meta-analyses ofa few, usually small, studies with a large degree of heterogeneity (Q).
 Implementation of transitional pain services may help manage the complex issues of
prolonged postoperative opioid use and chronic postsurgical pain (N).

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1.5 | Pre-emptive and preventive analgesia
The terms ‘pre-emptive’ and ‘preventive’ analgesia have a highly specific meaning with respect
to pain neurophysiology and sensitisation. The understanding of pre-emptive analgesia has
evolved since the term was first coined in early 1988 (Wall 1988 NR). In laboratory studies,administration of an analgesic prior to an acute nociceptive stimulus more effectively minimised
dorsal horn changes associated with central sensitisation than the same analgesic given after thepain state was established (see Section 1.1) (Woolf 1983 BS). This led to the hypothesis that pain
relief prior to surgery may enhance postoperative pain management when compared with thesame analgesia administered during or following surgery; that is, “pre-emptive preoperative
analgesia” (Wall 1988 NR). However, individual clinical studies have reported conflicting outcomeswhen comparing “preincisional” with “postincisional” interventions. In part this relates tovariability in definitions, deficiencies in clinical trial design and differences in the outcomes
available to laboratory and clinical investigators (Rosero 2014a NR; Katz 2002 NR; Kissin 1994 NR).
Central and peripheral sensitisation affects both the intensity of acute pain and thepersistence of pain well into the postoperative period and beyond (see also Section 1.4). This iscomplex and relates not only to the skin incision but also to the extent of intraoperative tissue
and nerve injury, postoperative inflammation and the nervous system’s response. The research
focus has shifted from the “timing” of a single analgesic intervention to the concept of modifying
sensitisation and thus having a longer-term impact on pain relief. This is termed “preventive”
analgesia (Kissin 1994 NR) rather than pre-emptive analgesia. The differences between these twoterms relate to the timing and outcomes being described, because both aim to minimise
sensitisation. “Pre-emptive” analgesia, as described above, relates to the timing ofadministration of the analgesic intervention prior to the insult and is measured in terms of pain
intensity or related outcomes. “Preventive” analgesia is the persistence of analgesic treatment
efficacy beyond its expected duration of effect (see Table 1.4). This had been defined as analgesiathat persists for >5.5 half-lives of a medicine, to ensure complete washout of any direct
pharmacological effect (Katz 2011 NR). A useful summary of medicines and their criterion valueof 5.5 half-lives has been published (Katz 2008b NR). In clinical practice, preventive analgesia
appears to be the most relevant and, of pharmacological options, holds the most hope forminimising chronic pain after surgery or trauma because it decreases central sensitisation and“wind-up”. An important consideration to maximise the benefit of any analgesic strategy is thatthe active intervention should be continued for as long as the sensitising stimulus persists (iewell into the postoperative period) (Pogatzki-Zahn 2006 NR; Dahl 2004 NR). However, from a“preventive” perspective, the critical aspect is that the effect of the intervention is sufficient tomodify sensitisation and hence longer-term outcomes; the timing and duration for specificinterventions still require clarification.
Table 1.4 | Definitions of pre-emptive and preventive analgesia
Pre-emptive
analgesia

Preoperative treatment is more effective than the identical treatment
administered after incision or during surgery. The key clarification point is
the timing of administration “pre” insult/surgery. A treatment given preemptively can also be preventive if it satisfies the below definition.

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Preventive
analgesia

Postoperative pain and/or analgesic consumption is reduced relative toanother treatment, a placebo treatment or no treatment with the effectobserved at a point in time beyond the expected duration of action of theintervention (eg 5.5 half-lives of the medicine). The intervention may or may
not be initiated before surgery.

Sources: Moiniche 2002; Katz 2002; Katz 2011; Rosero 2014b

1.5.1 | Pre-emptive analgesia
The benefits of pre-emptive analgesia have been questioned (Katz 2008b Level I, 27 RCTs,
n unspecified; Moiniche 2002 Level I, 80 RCTs, n=3,761; Dahl 2004 NR). However, one meta-analysis
provided support for pre-emptive analgesia (Ong 2005 Level I, 66 RCTs, n=3,261). The efficacy ofdifferent pre-emptive analgesic interventions (epidural analgesia, local anaesthetic woundinfiltration, systemic NMDA antagonists, systemic opioids and systemic NSAIDs) was analysed inrelation to different analgesic outcomes (pain intensity scores, supplemental analgesic
consumption, time to first analgesic). The effect size is most marked for epidural analgesia, withimprovements found in all outcomes (13 RCTs, n=653) (overall effect size 0.38; 95%CI 0.28 to 0.47).
Pre-emptive effects of local anaesthetic wound infiltration and NSAID administration were alsosuggested but reanalysis is required as one of the positive studies for each of these treatments
has subsequently been withdrawn (White 2011 NR). As a result of this withdrawal, evidence
supporting the pre-emptive effects of nonselective NSAIDS (nsNSAIDs) and COX-2 inhibitors is
equivocal (White 2009 NR). Reductions in analgesic consumption ranged from 44–58%, which theauthors regarded as clinically significant, but associated changes in adverse effects were notanalysed. Pain score results were equivocal for systemic NMDA antagonists (effect size [ES] 0.00;
95%CI -0.19 to 0.20) (7 RCTs, n=418) and there was no clear evidence for a pre-emptive effect of
opioids (ES -0.24; 95%CI -0.46 to -0.01) (7 RCTs, n=324).
Following thoracotomy, pre-emptive thoracic epidural analgesia (local anaesthetic  opioid
prior to surgery) reduces the severity of acute pain on coughing for up to 48 h, with a marginal
effect on pain at rest compared with the same therapy initiated postoperatively ( Bong 2005
Level I, 6 RCTs, n=458). Acute pain intensity was a predictor of chronic pain at 6 mth in two studies
but there was no statistically significant difference in the incidence of chronic pain between the
pre-emptive epidural (39.6%) vs control epidural (48.6%) groups. Pre-emptive analgesia with
epidural use in thoracotomy identified lower postoperative pain scores, reduced proinflammatory biomarkers and shortened hospital LOS (Yang 2015 Level II, n=90, JS 3).
In single-stage TKA, pre-emptive epidural analgesia was associated with lower postoperative
pain scores, fewer days with pain following surgery (mean ± SD 64.3 d ± 21.3 vs 142.4 d ± 80.0)
and less CPSP at 3 mth (24 vs 56.5%) (Rao 2020 Level II, n=50, JS 3); there were no differences inmorphine consumption or LOS.
A Cochrane review investigated opioids commenced prior to incision compared to thosecommenced following incision; this review uses the term “preventive” to indicate the continued
use of opioids into the postoperative period and so its findings are actually more in line with theabove definition of “pre-emptive” (Doleman 2018 Level I [Cochrane], 20 RCTs, n=1,343). There were
no differences in 6 h or 24 to 48 h pain score outcomes, but a small reduction was found in 24 hmorphine consumption in the pre-incision group (MD -4.9 mg; 95%CI -9.4 to -0.4).
Across a range of procedures, IV paracetamol given before incision is more effective thanpost incision in reducing pain at 1 h (MD -0.50/10; 95%CI -0.98 to -0.02) and 2 h (MD -0.34/10;
95%CI - 0.67 to -0.01), 24 h opioid consumption (SMD 0.52; 95%CI -0.98 to -0.06) and34

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postoperative vomiting (RR 0.50; 95%CI 0.31 to 0.83) ( Doleman 2015 Level I [PRISMA], 7 RCTs,
n=544). IV paracetamol reduces PONV when administered before recovery from anaesthesia(Apfel 2013 Level I [PRISMA], 30 RCTs, n=2,364). This effect is correlated to pain relief achieved but
not to reduced opioid consumption.
In total abdominal hysterectomy, gabapentin given only prior to surgery compared togabapentin given pre- and postoperatively found both interventions decreased 24 h morphine
requirements compared to placebo (preoperatively only SMD -0.69; 95%CI -1.20 to-0.07; pre andpostoperatively -1.45; 95% CI -1.79 to -1.11) (Alayed 2014 Level I SR, 14 RCTs, n=891); the effect ofgabapentin in reducing morphine consumption was stronger in the preoperative only group thanin the preoperative and postoperative group. The design of the studies in this meta-analysis did
not allow for evaluation of a true pre-emptive effect because all active treatments were given
preoperatively.
Dexketoprofen administered 30 min pre- vs 10 min post-incision in patients having abdominal
hysterectomy resulted in lower pain scores for up to 4 h postoperatively and reduced morphine
consumption for up to 24 h ( Gelir 2016 Level II, n=50, JS 3); all patients received intraoperative
ketamine infusions and there was no difference in time to first analgesic request.
A combination of paracetamol, ketoprofen and pregabalin administered 4 h pre-surgery vscontrol, with all drugs being then given to both groups post-incision for at least 48 h, resulted in
improved pain scores for up to 48 h and reduced PCA opioid requirements (Raja 2019 Level II,
n=97, JS 4).
The reason for there being a limited number of valid clinical studies investigating ‘preemptive’ analgesia is that investigators often fail to compare the same technique pre- and postincision or they apply the intervention after sensitisation has occurred eg in trauma or injury.
The variability in clinical trial design coupled with the complexity of clinical pain managementmeans that, with the exception of epidural analgesia, benefits remain unclear regarding preemptive analgesia in a clinical setting.

1.5.2 | Preventive analgesia
A true preventive analgesic effect needs to be assessed many days or even months after the
analgesic intervention has ceased. A large number of studies published use the term ‘preventive’
where the investigation often simply compares the addition of a preoperative dose of ananalgesic to a preoperative placebo (possibly continuing the medications postoperatively) with
analgesic outcomes assessed for a relatively short period – this is not ‘preventive’ in theneurophysiological sense and such studies are not discussed here.
A systematic review analysed dichotomous trial outcomes (overall positive or negative
outcomes) (Katz 2008b Level I, 39 RCTs, n unspecified) and identified overall beneficial acutepreventive effects following the use of a range of different medicines (28 positive RCTs, 11 negative
RCTs). Again, results of this meta-analysis might be affected by the subsequent withdrawal ofsome of the studies included (White 2011 NR). The methodology was unable to identify specifictherapeutic techniques that may be of benefit.
The use of local anaesthetics (neuraxial, perineural or systemic) demonstrates a preventive
analgesic effect in the perioperative period whether given pre- or postincision (Weinstein 2018
Level I (Cochrane), 63 RCTs, n=3,027; Barreveld 2013 Level I, 89 RCTs, n unspecified). Meta-analysis on
the prevention of CPSP by regional anaesthesia found benefits for three procedure types:
thoracotomy, breast cancer surgery and Caesarean section (Weinstein 2018 Level I (Cochrane),
63 RCTs, n=3,027). IV lidocaine versus placebo provides a significant benefit in prevention of CPSP
at 3 mth across a range of surgeries (Bailey 2018 Level I, 6 RCTs, n=420) (2 RCTs overlap with Weinstein
2018 Level I [Cochrane]) 2 RCTs, n=97 [IV lidocaine]) (see Section 1.4 for details).
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35Activation of the NMDA receptor plays an important role in central sensitisation and manystudies have focussed on the ability of NMDA-receptor antagonists to produce pre-emptive or
preventive analgesic effects. A medicine which, when used perioperatively, reduces CPSP has bydefinition a preventive analgesic effect (see Section 1.4). The preventive effects of perioperative
ketamine, dextromethorphan and magnesium on CPSP are described in Sections 1.4 and 4.6.
Analgesic benefit is seen in the acute postoperative period with ketamine following a range ofdoses, timings and procedures (Laskowski 2011 Level I [PRISMA], 70 RCTS, n=4,701) supported by a
network meta-analysis investigating multiple pharmacological interventions to reduce CPSP
which identified ketamine as the highest ranked in terms of efficacy and safety ( Ning 2018 Level I[NMA], 24 RCTs, n unspecified) (see also Section 4.6.1). However, in the immediate postoperative
period, it is difficult to separate persistence of direct pharmacological effects from preventive
actions, as many studies continued treatment for over 24 h. Expanding potential indications for
ketamine in depression have led to exploration of its potential ‘metaplastic’ effects on synaptictransmission whereby a brief exposure may result in persisting changes in neuronal long term
potentiation (Izumi 2014 BS); this may explain in part its effect in CPSP.
The alpha-2-delta ligands, gabapentin and pregabalin, reduce opioid requirements andimprove analgesia when given perioperatively (see Section 4.8). However, even though some ofthese studies used only single-dose therapy, the range of doses, duration of follow-up and long
half-life of gabapentin (6 to 7 h) means that an early preventive benefit is difficult to discern froma direct pharmacological effect. Longer term preventive effects on CPSP are discussed in
Sections 1.4 and 4.8.
In a study of multimodal epidural analgesia (local anaesthetic, opioid, ketamine andclonidine) in four groups of patients having colonic resection, a clear preventive effect on thedevelopment of residual pain up to 1 y after surgery was demonstrated with continuous
perioperative epidural analgesia (Lavand'homme 2005 Level II, n=85, JS 5). Residual pain at 1 y waslowest in patients who received intraoperative vs postoperative epidural analgesia. Epidural
analgesia commenced pre-incision versus post-incision for TKA resulted in less CPSP at 3 mth(24 vs 56.5%) (Rao 2020 Level II, n=50, JS 3) indicating a possible preventive effect (see Section
1.5.1 above for other details).
Epidural calcitonin, bupivacaine and fentanyl versus epidural bupivacaine and fentanyl alone
reduced phantom pain, allodynia and hyperalgesia at 6 and 12 mth following proximal or distal
amputation in the lower limb (Yousef 2017 Level II, n=60, JS 3).

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Pre-emptive analgesia
1. The timing of opioid administration (preincision rather than postincision) may reduce
further opioid consumption over 24 h, but has no effect on pain scores (N) (Level I[Cochrane Review])
2. Pre-emptive use of paracetamol across a range of procedures reduces pain scores up
to 2 h, opioid consumption for up to 24 h and postoperative nausea and vomiting (N)(Level I [PRISMA]).
3. Pre-emptive epidural analgesia has a significant effect on postoperative pain relief (S)(Level I).
Preventive analgesia
4. Epidural, regional and systemic local anaesthetic administration shows preventive
analgesic effects in reducing chronic postsurgical pain (S) (Level I [Cochrane Review])
5. NMDA-receptor antagonists (ketamine) reduce the incidence of chronic postsurgical
pain in selected procedures (S) (Level I [Cochrane Review]).
The following tick box represents conclusions based on clinical experience and expert
opinion: In clinical trials assessing acute postoperative pain for many systemic medicines, therange of doses administered, the variable durations of follow-up and variable half-lives
following infusion or repeated dosing means that “early” preventive effects, althoughpossible, are difficult to discern from persistence of direct pharmacological effects (U).

5th Edition | Acute Pain Management: Scientific Evidence371.6 | Adverse physiological and psychological effects of acute pain
1.6.1 | Acute pain and the injury response
Acute pain, and its associated injury and treatment, triggers a complex haemodynamic,
metabolic, neurohumoral, immune as well as somatosensory response (see Figure 1.2) (ManouStathopoulou 2019 NR). Clinically, acute pain is commonly associated with actual tissue damage.
This tissue damage may be due to trauma or surgery. The complete physiological response to
the insult has a quantifiable molecular and cellular response. Importantly, this response isgenerated in a range of anatomical compartments. These include rapid adaptations at the siteof injury, along ascending neuronal projections, within the spinal cord, at higher brain centres
and within distal organs. These disparate events are triggered by a coordinated array ofneuronal, autocrine and paracrine signalling events. Many of these events do not result in
nociceptive outcomes but may detrimentally impact an individual’s injury recovery or increaserisk of secondary complications. Importantly, all of these events can occur in a conscious
individual whose prior life experience may prime or protect them from the molecularconsequences and perception-processing of a painful response.
Figure 1.2 | The injury response
Triggers andpredisposing factors

Mediators

Injury response

Surgical trauma or
injuryNeuralPain experience,
primary and secondary
hyperalgesia (peripheral
and central sensitisation)

Preoperative pain

Immune factors
Proteins and other molecules:
growth factors
eicosanoids
nitric oxide
othersInflammation
Haemodynamic

Psychological factors

Endocrine

Catabolism

Social andenvironmental factors

MetabolicPhysical deconditioning

•
•
•
•

Genetic factors

Psychological effects

Anaesthesia andanalgesia, othermedications

Other adaptations
systemic

Source: Modified from NHMRC 1999.

It is difficult to separate the complex array of potential individual or interacting triggers
associated with pain from other aspects of the broader physiological response observed clinically(see Figure 1.2). However, some data have been obtained with experimental pain in the absenceof injury. For example, electrical stimulation of the abdominal wall results in a painful experience38

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(intensity 8/10) and an associated hormonal/metabolic response, which includes increased
levels of cortisol, catecholamines and glucagon, and a decrease in insulin sensitivity (Greisen 2001
Level II EH). A systematic review of the effect of experimental pain on the autonomic nervous
system, assessed by heart rate variability, determined that experimental pain increases
baroreflex activity and decreases parasympathetic activity ( Koenig 2014 Level IV EH SR, 20 studies,n unspecified). Factors such as time of day, possibly owing to nociceptive control by diurnallyactive hormones, contribute to reported differences in thermal pain (both cold and heat) ( Aviram2015 Level II EH, n=48, JS 3). Some of these environmental conditioning factors may change theperception rather than the nociceptive signal itself eg sleep deprivation in healthy controls
causes hyperalgesia which may be caused by a reduction in cortical cognitive or perceptual
mechanisms, rather than sensory nociceptive amplification (Odegard 2015 Level II EH, n=33, JS 4).
Although acute pain is only one of the important triggers of the “injury response” (seeFigure 1.2), as the magnitude and duration of the response is related to the magnitude andduration of the nociceptive stimulus, effective pharmacological pain relief may have asignificant impact on this response ( Moselli 2011 Level II, n=35, JS 3), although this may bevariable (Fant 2013 Level II, n=26, JS 3; Liu 2008 NR; Carli 2008 NR). Beyond pharmacologicalinterventions, mere distraction of attention away from the pain protects against experimental
pain-induced changes in heart rate variability ( Koenig 2014 Level IV EH SR, 20 studies,n unspecified). Importantly, negative expectations in patients created by verbal suggestions canlead to the "nocebo" response, defined as experiencing greater pain to the same nociceptive
stimulus (Petersen 2014 Level III-1 EH SR [PRISMA], 10 studies, n=344 ).
As noted above, the release of systemic factors such as proinflammatory cytokines as a resultof pain and trauma associated with surgery or injury may contribute to multiple physiologicalresponses that hamper the recovery of a patient (Manou-Stathopoulou 2019 NR). Limiting theseeffects by analgesic techniques may affect some surgical outcomes. A group of patients having
abdominal surgery were randomised to receive intraoperative epidural analgesia or IV opioid
analgesia, with both groups receiving postoperative epidural analgesia (Moselli 2011 Level II, n=35,
JS 3). In the intraoperative epidural group, inflammatory markers were lower up to 24 h
postoperatively and minor complications were reduced in number (39 vs 76%), although there
was no difference in major complications or LOS. Postoperative ileus is attenuated in patients
receiving IV lidocaine infusions compared to saline in patients undergoing colonic surgery (Sun2012 Level I [PRISMA], 21 RCTs, n=1,108; Vigneault 2011 Level I [PRISMA], 29 RCTs, n=1,754) (15 RCT
overlap). Analgesic and bowel motility benefits of lidocaine were more marked whenadministered via the thoracic epidural route than by IV infusion ( Kuo 2006 Level II, n=60, JS 5);
however, both lidocaine groups were associated with reduced opioid consumption comparedwith saline. The postoperative decreases in proinflammatory cytokines, such as interleukin (IL)‐6, IL‐8 and IL‐1RA (a competitive inhibitor of IL‐1β), were associated with more rapid return ofbowel function following abdominal surgery. Ketamine, administered intraoperatively, isassociated with reduced IL-6 levels post operatively, suggesting an anti-inflammatory effect inaddition to analgesic benefits (Dale 2012 Level I [PRISMA], 6 RCTs, n=331).
In addition to the stress responses to surgery and analgesia, aberrant neuronal firing during
acute pain creates a state of altered cell function in nociceptive pathways. This may not beperceived as pain by higher brain centres (eg under general anaesthesia) nor acknowledged
consciously by the individual. Cellular adaptations to acute nociceptive inputs in primary andsecondary fibres are well established to drive peripheral and central sensitisation ( Baron 2013 NR;
von Hehn 2012 NR; Woolf 2011 NR; Kuner 2010 NR). Critically, these result in multiple changes togene transcription and protein translation (see also Section 1.1).

5th Edition | Acute Pain Management: Scientific Evidence391.6.2 | Adverse physiological effects
Clinically significant injury responses that are often associated with nociceptive stimuli trigger
diffuse physiological responses such as stress and inflammation, which leads to hyperalgesia,
hyperglycaemia, protein catabolism, increased free fatty acid levels (lipolysis) and changes inwater and electrolyte flux (Manou-Stathopoulou 2019 NR; Carli 2008 NR; Liu 2008 NR) (see Table 1.5).
In addition, increased sympathetic activity has diverse effects on the cardiovascular,
gastrointestinal and respiratory systems and on coagulation, endocrine, immune andpsychological function (Prabhakar 2014 NR; Cardinale 2011 NR; Blackburn 2011 NR).
Table 1.5 | Metabolic immunological and endocrine responses to injury
Catabolic hormones

ACTH, cortisol, ADH, growth hormone,
catecholamines, angiotensin II,
aldosterone, glucagons,

Anabolic hormones

Insulin, testosterone

Mitochondrial initiation

Alarmins (DAMP molecules)

Proinflammatory followed bycompensatory response

IL-1, TNFα, IL-6, IL4, IL8, IL10
Chemokines

Hyperglycaemia, glucose
intolerance, insulin resistance

Glycogenolysis, gluconeogenesis(cortisol, glucagon, growth hormone,
adrenaline, free fatty acids)
Insulin secretion/activation

ProteinMuscle protein catabolism,
synthesis of acute phase proteins

Cortisol, adrenaline, glucagon, IL-1,
IL-6, TNF

Lipid

Lipolysis and oxidation

Catecholamines, cortisol, glucagon,
growth hormone

Water and
electrolyte
flux

Retention of water and sodium,excretion of potassium andfunctional ECF with shifts to ICF

Catecholamine, aldosterone, ADH,
cortisol, angiotensin II, prostaglandins
and other factors

Endocrine

ImmuneMetabolic
Carbohydrate

Note:

ACTH: adrenocorticotrophic hormone; ADH: antidiuretic hormone; DAMP: damage-associatedmolecular pattern; ECF: extracellular fluid; ICF: intracellular fluid; IL: interleukin; TNF: tumour
necrosis factor.

Source: Modified from Manou-Stathopoulou 2019; NHMRC 1999.

1.6.3 | Pain and analgesia: effects on injury-induced organ dysfunction
Pain from injury activates a range of adverse physiological effects (Manou-Stathopoulou 2019 NR;
Prabhakar 2014 NR; Cardinale 2011 NR; Blackburn 2011 NR). Increased sympathetic efferent nerve
activity increases heart rate, contractility and blood pressure. As sympathetic activation
increases myocardial oxygen demand and reduces myocardial oxygen supply, the risk of cardiac
ischaemia, particularly in patients with pre-existing cardiac disease, is increased. Enhanced
sympathetic activity can also reduce gastrointestinal motility and contribute to ileus.
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under-treated pain and associated factors such as stress and inflammation. In patients withfractured neck of femur, delirium was associated with lack of analgesic use ( Thompson 2018 Level
IV, n=688). In elderly patients, postoperative delirium is decreased with the use of multicomponent interventions, which include effective analgesia (Siddiqi 2016 Level I [Cochrane], 39
RCTs, n=16,082).
Severe pain after upper abdominal and thoracic surgery contributes to an inability to coughand a reduction in functional residual capacity, resulting in atelectasis and ventilation-perfusion
abnormalities, hypoxaemia and an increased incidence of pulmonary complications. The injury
response also contributes to a suppression of cellular and humoral immune function and a
hypercoagulable state following surgery, both of which can contribute to postoperativecomplications (Lord 2014 NR). Alterations to glucose metabolism and accelerated protein
breakdown also contribute to the injury response. These factors need to be considered whenevaluating analgesic interventions. Patients at greatest risk of adverse outcomes from unrelieved
acute pain include very young or elderly patients, those with concurrent medical illnesses andthose undergoing major surgery (Liu 2008 NR). Analgesic technique may reduce adverse
physiological impact and improve surgical outcomes. Often a multimodal approach toanaesthesia, pain management, the surgical stress response and perioperative care isundertaken, making it difficult to separate individual factors involved in outcome; especially withmultifaceted strategies such as with enhanced recovery after surgery (ERAS) protocols (Kehlet
2018 NR). The influence of epidural anaesthesia and analgesia on outcome has been evaluated(Popping 2014 Level I [PRISMA], 125 RCTs, n=9,044) (see also Section 5.6).
There is also limited evidence that stress and opioid analgesia in some circumstances may
inhibit immune function, promoting tumour growth or metastasis. Regional anaesthetic andopioid-sparing analgesic techniques might have a beneficial effect on rates of cancer recurrence
after tumour resection but overall study results are still unclear (Meserve 2014 NR; Colvin 2012 NR).

KEY MESSAGES
1. Recognition of the importance of postoperative rehabilitation including
pharmacological, physical, psychological and nutritional components has led toenhanced recovery (U) (Level I [PRISMA]).
The following tick box represents conclusions based on clinical experience and expert
opinion: Acute pain and injury of various types are inevitably interrelated and, if severe andprolonged, the injury response becomes counterproductive and can have adverse
effects on outcome (U).

1.6.4 | Adverse psychological effects
Psychological changes associated with acute pain have received less clinical attention than those
associated with chronic pain, however they have been well-studied in experimental contexts,
especially regarding interference with attention and cognitive processes such as learning andmemory. Clinically, sustained acute nociceptive input, as often occurs after surgery, trauma orburns, can also have a major influence on psychological function, which may in turn increase therisk of progression to chronic pain (Glare 2019 NR). In addition, pre-operative psychologicalcharacteristics, in concert with other factors (eg genetic factors and pre-operative pain), have
5th Edition | Acute Pain Management: Scientific Evidence41also been found predictive of adverse reactions to postoperative pain (Yang 2019 Level III-2 SR, 33
studies, n=53,362; Lindberg 2017 Level IV, n=188; Schug 2017 NR).
Failure to relieve acute pain may result in increasing anxiety, inability to sleep,
demoralisation, a feeling of helplessness, loss of control, and an inability to think and interact
with others; in the most extreme situations, where patients can no longer communicate,effectively they have lost their autonomy ( VanDenKerkhof 2012b Level IV, n=76; Cousins 2004 NR).
In turn, these psychological responses in the acute phase may be major determinants ofprogression to chronic pain conditions, such as chronic postsurgical pain (CPSP), typically in
combination with other known risk factors ( Jenewein 2009 Level III-2, n=90; Williamson 2009 Level
III-2, n=1,290; Schug 2017 NR; Young Casey 2008 NR). In breast cancer surgery patients, anxiety
and low psychological robustness (positive affect and dispositional optimism) emerged as
significant predictors of acute pain with distress being the strongest predictor of chronic pain
(McCowat 2019 Level IV SR, 12 studies, n=3,452). However, the relationship between depression
and CPSP was uncertain
In acute pain, attention has also focussed on perioperative neurocognitive disorders (PND),
including delirium and the research outcome of postoperative cognitive dysfunction (POCD).
Both pain itself and analgesic drugs can exacerbate PND, especially delirium (Scottish
Intercollegiate Guidelines Network 2019 GL). Although the aetiology of PND (and POCD) is unclear,factors include dysregulation of cerebral neurotransmitters, patient factors (age, preoperative
cognitive function), and perioperative pharmacological therapy (Evered 2018 NR).
Neurotransmitters involved in PND include acetylcholine and serotonin, especially in the elderly(Inouye 2014 NR); hence analgesics and adjuvants with anticholinergic or sedative effects should
be avoided where possible in at-risk patients (Scottish Intercollegiate Guidelines Network 2019 GL;
American Geriatrics Society 2015 GL). Effective non-opioid-based acute pain management in older
patients helps reduce delirium (Scottish Intercollegiate Guidelines Network 2019 GL; Mahanna-Gabrielli
2019 NR) (see also Sections 1.2, 1.4, 9.2).

KEY MESSAGES
1. Postoperative delirium is exacerbated by unrelieved acute pain and by overuse of
sedating analgesics, in particular opioids (N) (Level IV).
The following tick box represents conclusions based on clinical experience and expert
opinion: Failure to relieve acute pain can lead to psychological distress (N).

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1.7 | Genetics and acute pain
An increasing number of genetic variants modulating nociception, susceptibility to pain
conditions, as well as response to pharmacotherapy are being discovered.
Pharmacogenomics deals with the influence of variations in the human genome on response(both beneficial and undesirable) to medicines in patients. By correlating gene alterations with a
medicine's efficacy or toxicity, it is possible to gain a better understanding of the causes ofinterpatient variability in response to a specific medicine and so to develop a rational means to
optimise pharmacological therapy with respect to the patient’s genotype and ensure maximum
efficacy with minimal adverse effects. For example, genetic factors regulating opioid
pharmacokinetics (metabolising enzymes, transporters) and pharmacodynamics (receptors andsignal transduction elements, ion channels, enzymes) contribute to the large interpatientvariability in postoperative opioid requirements (De Gregori 2016 NR; Trescot 2014 NR). Informationfrom genotyping may help in selecting the analgesic medicine and the dosing regimen for anindividual patient (Packiasabapathy 2018 NR; Allegri 2010 NR; Lotsch 2006 NR). Nevertheless, given
the complexity of pain pathways, in very few cases is a single gene variant contributing
substantially to response variability, but rather there are a large number of small contributions
from multiple genes.
Although there is increasing information from studies, often small numbers of subjects are
involved and therefore translation into clinical practice is still limited ( Trescot 2014 NR; Stamer
2007b NR). Nevertheless, some preliminary estimates for dose adaptations are possible ( Allegri2010 NR; Lotsch 2006 NR). Importantly however, genetic factors must be considered within thecontext of the multiple interacting physiological, psychological, age-related, cultural, ethnic andenvironmental factors that influence individual responses to pain and analgesia ( Sadhasivam 2014
NR; Searle 2009a NR; Kim 2009 NR).

1.7.1 | Single gene pain disorders
A number of rare pain-related conditions have been identified through family linkage mapping,which are due to single gene mutations (Mendelian gene).
Recognised hereditary syndromes associated with reduced pain sensation include thefollowing.
• Channelopathy-associated insensitivity to pain (CAIP) is caused by variants in the SCN9A
gene, which codes for the alpha-subunit of the voltage-gated sodium channel Nav1.7. Nav1.7
is located in peripheral (dorsal root and sympathetic ganglion) neurones and plays animportant role in action potential generation in these cells. Mutations that result in loss of
Nav1.7 function cause affected individuals to be unable to feel physical pain (Bennett 2014
NR). Patients with a single-nucleotide polymorphism (SNP) in SCN9A (3312T; 5.5%
frequency) had lower postoperative pain sensitivity after pancreatectomy, lower PCA
requirements and a lower likelihood of developing inadequate analgesia than those carrying
the 3312G allele (OR 0.10; 95%CI 0.01 to 0.76) (Duan 2013 Level III-2, n=200).
• Hereditary sensory and autonomic neuropathy (HSAN) I–V syndromes are associatedwith a range of genetic abnormalities and produce varying patterns of sensory
and autonomic dysfunction and peripheral neuropathy (NTRK1 gene) ( Vetter 2017 NR;
Auer-Grumbach 2013 NR; Mogil 2012 NR). These syndromes present as various
combinations of loss or reduced sensitivity to pain accompanied by other autonomic
and sensory deficits. HSAN type IV is also known as congenital insensitivity to pain withanhydrosis (CIPA).
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Recognised hereditary syndromes associated with increased pain sensation include ( Mogil
2012 NR):• Erythromelalgia and paroxysmal extreme pain disorder, also known as familial rectal
disorder, both of which are due to different gain-of-function mutations of sodium channel
Nav1.7 (SCN9A) (Dabby 2012 NR);• Familial hemiplegic migraine;• Hereditary neuralgic amyotrophy;• Hereditary pancreatitis (Rebours 2012 NR).

1.7.2 | Genetic influences on sensitivity to pain
Apart from these rare Mendelian inherited conditions, “pain sensitivity” variability is thought tovary up to 50% in the general population due to genetic differences, with environmental
influences responsible for the remainder of variability (Norbury 2007 Level IV, n=196). Twin studies
have helped identify inheritable traits for development of back pain, postherpetic neuralgia,
fibromyalgia and other common painful conditions (Mogil 2012 NR).
While several hundred genes have been identified as associated with pain expression in mice,
they are not necessarily relevant to humans (LaCroix-Fralish 2011 SR BS) and have been studied inchronic and not acute pain (Kringel 2018 Level IV; Zorina-Lichtenwalter 2016 NR). Evidence for a
genetic association with more common pain conditions has come from association studies,
which require large cohorts (Mogil 2012 NR). Studies often suffer from low sample sizes and therestricted number of potential genotype variants studied. Many findings of an association of aparticular gene allele with pain sensitivity have not been replicated in subsequent studies, so
caution is needed in this area.
Many genetic variants have been associated with pain sensitivity ( Crist 2014 NR); the mostcommonly studied genes include:• Mu opioid receptor (OPRM1);• Catechol-O-methyltransferase (COMT);• Guanosine triphosphate cyclohydrolase 1;• Transient receptor potential (TRPV1);• Melanocortin-1 receptor (MC1R).
Other gene variants that have been associated with alterations in pain sensitivity in acutepain states include ADRB2, HTR2A, IL1RN, KCNJ6, MAOA and MAOB (Mogil 2012 NR), P2RX7(Kambur 2018 Level III-2, n=3,847) and TAOK3 (Cook-Sather 2014 Level III-2, n=617). Often studies haveaddressed postoperative analgesic requirements as the index of pain sensitivity rather than useof experimental pain models.
1.7.2.1 | OPRM1
A variant of the gene encoding the mu opioid receptor OPRM1, A118G SNP, was targeted as avery promising candidate for modulation of analgesia and has been the most studied variant(Crist 2014 NR).
Overall findings on the effects of this SNP remain contradictory (Crist 2014 NR). In a randomeffects meta-analysis in the postoperative setting, OPRM1 118G-allele carriers have higher mean
opioid requirements than OPRM1 118AA homozygotes (SMD -0.18; p=0.003) (Hwang 2014 Level
III-2 SR, 18 studies, n=4,607). These findings were robust in a subgroup analysis of Asian patients,
whose frequency of the G variant is about 40% compared to about 15% for Caucasians (SMD 0.21; p=0.001), morphine users (SMD -0.29; p<0.001) and patients after bowel surgery (SMD 0.20; p=0.008). A preceding systematic review found a similar but smaller effect (SMD 0.096;

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95%CI 0.025 to 0.167) of OPRM1 118G with increased opioid requirements in the perioperativeand postoperative period (Walter 2013 Level III-2 SR, 14 studies, n=3,346); there was no significant
association of OPRM1 118G with opioid requirements, when using the random-effects
environment (Cohen’s d 0.044; 95%CI -0.113 to 0.202). A positive finding was obtained in 1,000
women undergoing breast cancer surgery in which the GG cohort required about 33% more
oxycodone than the AA cohort (Cajanus 2014 Level III-2 SR, n=1,000). For epidural analgesia using
fentanyl during labour however, G-allele (AG+GG) carriers of the OPRM1 118 polymorphism
required lower (not higher) fentanyl doses to achieve adequate pain relief compared to thosewith the AA homozygote (SMD -0.24; 95%CI -0.44 to -0.03) (Song 2013 Level III-2 SR, 6 studies,n=838). OPRM1 304A/G polymorphism did not influence the duration of effect or therequirement for breakthrough analgesia after intrathecal (IT) opioid administration for labour
pain (Wong 2010 Level III-2, n=293). There was also no effect of A118G mu-opioid receptor
polymorphism on duration of analgesia found in a subsequent study, but patients of
Hispanic/African origin had increased duration of analgesia and pruritus vs Jewish/Arabic
patients in labour (Ginosar 2013 Level III-2, n=125).
OPRM1 A118G seems to modulate effects of opioids given in experimental pain; in the clinicalsetting it has limited impact with no clinical relevance in Caucasians, but explains increased
opioid requirements in Asians. Studies that assessed different haplotypes of the OPRM1 andcombinations of genetic variants, eg OPRM1, COMT and ESR1, found greater predictability
suggesting more complexity (De Gregori 2016 Level III-2, n=201; Reyes-Gibby 2007 Level III-2, n=207;
Mura 2013 NR). Overall OPRM1 118 polymorphisms may be too complex to be used as a predictive
tool for individual opioid dosing (Mogil 2012 NR).
1.7.2.2 | COMT
COMT metabolises noradrenaline, adrenaline, and dopamine and has been implicated in themodulation of pain. COMT inhibition or low activity via genetic polymorphisms may lead toincreased pain sensitivity via beta-adrenergic receptor-dependent mechanisms (Nackley
2007 NR). Haplotypes with high COMT activity are associated with low pain sensitivity tomechanical and thermal stimuli (Diatchenko 2005 NR). The Val158Met polymorphism influences
the activity of the COMT enzyme with the Met158 allele associated with low COMT activity andincreased pain sensitivity (Vuilleumier 2012 NR), leading to greater morphine requirements postsurgery in adults (Dai 2010 Level IV, n=69) and children (Sadhasivam 2014 Level IV, n=149).
A large study undertaken to address influence of COMT polymorphism on postoperative pain
in a homogenous ethnic sample of 1,000 women having breast surgery showed no association
with any COMT polymorphism and postoperative oxycodone requirements ( Kambur 2013 Level III2, n=1,000). Furthermore, the most studied COMT mutation, Val158Met, showed no association
with pain levels in these patients, but two previously unstudied mutations did. In contrast, in 152
patients undergoing nephrectomy, the 31 patients with Val/Val genotype consumed more IV
morphine than 61 Met/Met patients (36%; 95%CI 31 to 41) (Candiotti 2014 Level III-2, n=152).
Combinations of several genetic mutations act together to determine pain sensitivity associatedwith COMT (Smith 2014 Level III-2, n=398). Similarly, genetic association studies using COMT
variants have also revealed conflicting results (Belfer 2011 NR).
1.7.2.3 | TRPA1
Emerging evidence suggests that epigenetic variations of the TRPA1 receptor may be responsible
for some of the genetically determined individual differences in pain sensitivity ( Gombert 2017
Level III-2 EH, n=75; Bell 2014 Level III-2 EH, n=100).
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There is considerable complexity associated with genetic mutations influencing pain
sensitivity and much to be unravelled before clear evidenced-based conclusions can be drawn.

1.7.3 | Drug metabolism
Drug-metabolising enzymes represent a major target for identifying associations between an
individual's genetic profile and drug response (pharmacogenetics) (Trescot 2014 NR; Stamer 2007c
NR). The polymorphic cytochrome P450 enzymes metabolise most medicines and showinterindividual variability in their catalytic activity. There are 57 enzymes in this family of which
9 are clinically relevant to drug metabolism: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9,CYP2C19, CYP2D6, CYP2E1, and CYP3A4/3A5, all of which have different and often overlapping
activity. Medicines can be substrates, inhibitors or inducers of metabolism of analgesic
medications.
CYP2D6, CYP2C19, and CYP2C9 are highly polymorphic and are involved in approximately 40%
of CYP-mediated drug metabolism. Of these, CYP2D6 is the most relevant to analgesic
medications. Those who have the genetic variants resulting in poor metabolism by CYP2D6 arelikely to have more severe postoperative pain than those who have other variants (Yang 2012
Level III-2, n=236).
CYP2D6 gene influences the metabolism of many medications including codeine, tramadol,
oxycodone, hydrocodone, dextromethorphan, amitriptyline, nortriptyline, duloxetine,
metoclopramide and venlafaxine. Specifically, CYP2D6 metabolises codeine, dihydrocodeine,hydrocodone, oxycodone and tramadol to their more potent hydroxyl metabolites, which havea higher affinity for the mu receptor (Somogyi 2007 NR). For additional detail related to individual
opioids see Section 4.3.1.
Over 100 allelic variants of CYP2D6 have been identified, resulting in wide variability infunction. Individuals carrying two wild type alleles display normal enzyme activity and are known
as normal metabolisers; intermediate metabolisers are heterozygotes with one reduced function
and one nonfunctional allele; poor metabolisers have no functionally active alleles and haveminimal or no enzyme activity (Crews 2014 NR; Vuilleumier 2012 NR; Zhou 2009a NR; Zhou 2009b NR).
Ultrarapid metabolisers have multiple copies of the wildtype CYP2D6 alleles (Crews 2014 NR;
Vuilleumier 2012 NR; Stamer 2007b NR).
There are large interethnic differences in the frequencies of the variant alleles. For
example, in Caucasian populations, 8–10% of people are poor metabolisers and 1-3% areultrarapid metabolisers (Crews 2014 NR; Vuilleumier 2012 NR; Stamer 2007b NR). The proportion ofultrarapid metabolisers is higher (up to 29%) in Middle Eastern and Northern African
populations and lower (0.5%) in Asian populations ( Stamer 2007c NR). The proportion of poor
metabolisers is lower in Asian and African American populations (Zhou 2017 Level IV SR,
5 population-scale sequencing projects, n=56,945; Yee 2013 Level IV, n=75; Holmquist 2009 NR).
Other genetic factors indirectly affecting the metabolism or effect of analgesics are liver celltransporter proteins: organic cation transporter (OCT1) (Fukuda 2013 Level III-2, n=146); ABCC3(Venkatasubramanian 2014 Level III-2, n=220) and ATP-binding cassette subfamily member B1 (alsoknown as multidrug resistance protein [MDR]1 or p-glycoprotein) (Sadhasivam 2015 Level III-2,
n=263). The latter affects efflux transport of morphine at the blood-brain barrier and thereby
cerebral pharmacokinetics.
Further considerations are the differential risk with genetic differences and varying
prevalence of racial/ethnic phenotypes (Anderson 2014 NR) and consequent variability insensitivity to efficacy and adverse effects (Jimenez 2012 Level III-3, n=68; Fukuda 2013 Level IV, n=146;
Palada 2018 NR).

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1.7.3.1 | Codeine and CYP2D6
In children and adults receiving codeine for postoperative pain, very low or undetectable plasma
morphine levels have been noted in those with poor metaboliser or intermediate metaboliser
genotypes, but with variable impact on analgesia (Williams 2002 Level II, n=96, JS 3; Poulsen 1998
Level IV, n=81; Persson 1995 Level IV, n=11).
CYP2D6 genotypes predicting ultrarapid metabolism resulted in about 50% higher plasma
morphine and its glucuronides concentrations following oral codeine compared with theextensive metaboliser (Kirchheiner 2007 Level IV). Both the impaired renal clearance of thesemetabolites and genetic background (CYP2D6 ultrarapid metaboliser status) have been
implicated in reports of respiratory depression due to codeine in adults and children(Friedrichsdorf 2013 Level IV; Kelly 2012 Level IV; Stamer 2007b Level IV). (See also Sections 4.3.1.3 and10.4.4.5)
1.7.3.2 | Tramadol and CYP2D6
O-demethylation of tramadol by the enzyme CYP2D6 produces the active metabolite (+)-Odemethyltramadol (M1), which has an affinity for mu-opioid receptors that is approximately 200
times higher than the parent drug (Lai 1996 BS). Poor metabolisers have significantly lower plasma
concentrations of M1 compared with both homozygous and heterozygous extensive
metabolisers (Fliegert 2005 Level II, n=26, JS 2; Kirchheiner 2008 Level III-2, n=22; Stamer 2003 Level
III-3, n=300) and experience less analgesia (Stamer 2007a Level III-3, n=174; Stamer 2003 Level III-3,
n=300). As with codeine, impaired renal clearance of metabolites and genetic background(CYP2D6 ultrarapid metaboliser status) have been implicated in cases of respiratory depression
after tramadol (Desmeules 1996 Level II, n=10, JS 3; Stamer 2008 CR) (see also Section 4.3.1.3).
1.7.3.3 | Methadone
Genetic polymorphisms in genes coding for methadone-metabolising enzymes, transporter
proteins (p-glycoprotein) and mu-opioid receptors may explain part of the observed
interindividual variation in the pharmacokinetics and pharmacodynamics of methadone; bloodconcentrations may vary up to 20-fold for a given dose (Somogyi 2014 NR; Li 2008 NR).
Methadone is metabolised primarily by CYP2B6 and to a minor extent by CYP3A4 (Kharasch2017 NR; Kapur 2011 NR). Differing effects for isomers of methadone have also been reported;
genetic variability in CYP2B6 influenced (S)-methadone (less active isomer) and, to a lesser
extent, (R)-methadone (more active isomer) plasma concentrations ( Somogyi 2014 NR). In
addition, genetic polymorphisms in CYP2C19 gene (responsible for a minor role in methadone
metabolism) have effects on methadone-maintenance dosing, (R)-methadone/methadone ratio
and cardiotoxicity of methadone (prolonged QT interval) (Wang 2013 NR) (see also Section
4.3.1.5).
1.7.3.4 | Oxycodone
Oxycodone is metabolised primarily to noroxycodone by CYP3A4 (≈80%) and by CYP2D6 tooxymorphone (Lalovic 2006 Level IV EH). The O-demethylated metabolite oxymorphone has up to
40-fold higher affinity for the mu receptor and eight-fold higher potency than oxycodone andrepresents about 11% of its overall metabolism (Crews 2014 NR). Oxymorphone may contributesignificantly to the overall analgesic effect of oxycodone in experimental pain (Samer 2010 EH);
noroxycodone, the major metabolite, is only a weak mu-receptor agonist (Lalovic 2006 EH; Coluzzi
2005 NR).
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The dependence of oxymorphone concentrations on CYP2D6 activity and its high potency
explains why oxycodone’s pharmacodynamics and pharmacokinetics are dependent on CYP2D6
polymorphism (Soderberg Lofdal 2013 NR), at least in experimental pain (Samer 2010 EH).
However, in acute postoperative pain, CYP2D6 genotype had either no influence on
oxycodone requirements (Zwisler 2010 Level III-2, n=270) or a small difference in dosage that was
not gene-dose related (Stamer 2013 Level III-2, n=121). Overall, the data on the association of
CYP2D6 pheno/genotype and oxycodone response in acute pain are unconvincing ( Huddart 2018
NR) (see also Section 4.3.1.2).
1.7.3.5 | NSAIDs
Wide variability in gene expression and functional polymorphisms in the COX-2 gene (PTGS2)
may explain part of the interindividual variations in acute pain and the analgesic efficacy ofnsNSAIDs and coxibs; this may be useful to predict patient risk and benefit from medicines basedon individual genetic variations (Somogyi 2007 NR; Lee 2006 Level III-2).
NSAIDs such as ibuprofen, diclofenac and celecoxib are metabolised by CYP2C9 (Rollason
2014 NR). Between 1 and 3% of Caucasians are poor metabolisers. Homozygous carriers of the
CYP2C9*3 allele may accumulate celecoxib and ibuprofen in blood and tissues and be at risk ofincreased adverse effects (Kirchheiner 2003 Level III-3, n=26; Kirchheiner 2002 Level IV; Rollason 2014
NR; Stamer 2007b NR), but this is unlikely to affect acute pain response.

KEY MESSAGES
1. CYP2D6 polymorphisms affect plasma concentrations of active metabolites of codeine,
oxycodone and tramadol with variable effects on analgesic efficacy (U) (Level II).
2. The mu opioid receptor OPRM1 polymorphism is unlikely to be clinically relevant as asingle gene mutation in Caucasian populations and is more likely to be of clinicalrelevance in Asian populations (U) (Level III-2 SR).
3. CYP2D6 ultrarapid metabolisers are at increased risk of codeine and tramadol toxicity(U) (Level IV).
The following tick box represents conclusions based on clinical experience and expert
opinion: Genetic polymorphisms contribute to the wide interindividual variability in plasma
concentrations of a given dose of methadone (U).

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2

Assessment and measurementof pain and pain treatment
Section Editor:
Prof David A Scott62

2.1 | Assessment
Contributors: Prof David A Scott, Dr Andrew Stewart

2.2 | Measurement
Contributors: Prof David A Scott, Dr Andrew Stewart

2.3 | Outcome measures in acute pain management
Contributors: Prof David A Scott, Dr Andrew Stewart

5th Edition | Acute Pain Management: Scientific Evidence632.0 | Assessment and measurement of pain and pain treatment
Reliable and accurate assessment of acute pain is necessary to ensure safe and effective pain
management and to provide effective research outcome data. The assessment andmeasurement of pain is fundamental to the process of assisting in the diagnosis of the cause ofa patient’s pain, selecting an appropriate analgesic therapy and evaluating then modifying thattherapy according to the individual patient’s response. Pain should be assessed within asociopsychobiomedical model that recognises that physiological, psychological andenvironmental factors influence the overall pain experience. Likewise, the decision regarding theappropriate intervention following assessment needs to be made with regard to a number offactors, including recent therapy, potential risks and side effects, any management plan for theparticular patient and the patient’s own preferences. A given pain ‘rating’ should not
automatically trigger a specific intervention without such considerations being undertaken ( vanDijk 2012a Level IV, n=2,674; van Dijk 2012b Level IV, n=10,434). Care must be undertaken with pain
assessment to avoid the process of assessment itself acting as a nocebo (see Section 1.3).

2.1 | Assessment
The assessment of acute pain should include a thorough general medical history and physicalexamination, a specific “pain history” (see Table 2.1) and an evaluation of associated functional
impairment (see Section 2.3). In acute pain management, assessment must be undertaken at
appropriate frequent intervals. At these times, evaluation of pain intensity, functional impact
and adverse effects of treatment must be undertaken and recorded using tools and scales thatare consistent, valid and reliable (Scott 2008 NR). In addition, pain assessment must lead tochanges in management and re-evaluation of the patient to ensure improvements in the qualityof care (Gordon 2005 GL).
Although not always possible in an acute setting, a complete pain history provides
important diagnostic information that may help distinguish different underlying pain statessuch as nociceptive (somatic and visceral) or neuropathic pain ( Victor 2008 Level III-2, n=823).
Somatic pain may be described as sharp, hot or stinging, is generally well localised and isassociated with local and surrounding tenderness. By contrast, visceral pain may be describedas dull, cramping or colicky, is often poorly localised and may be associated with tenderness
locally or in the area of referred pain, or with symptoms such as nausea, sweating andcardiovascular changes ( Scott 2008 NR).
While nociceptive pain typically predominates in the acute pain setting, neuropathic pain
may also be present (Guastella 2011 Level IV, n=54) (see also Section 1.1 and 8.1.4). Features in thepain history that may suggest a diagnosis of neuropathic pain include ( Dworkin 2007 Level III-2,
n=618; Haanpaa 2011 GL; Gray 2008 NR):• Clinical circumstances associated with a high risk of nerve injury (eg thoracic or chest wall
procedures, amputations or hernia repairs);• Pain descriptors such as burning, shooting and stabbing;• The paroxysmal or spontaneous nature of the pain which may have no clear precipitating
factors;• The presence of dysaesthesias (spontaneous or evoked unpleasant abnormal sensations),
hyperalgesia (increased response to a normally painful stimulus), allodynia (pain due to a
stimulus that does not normally evoke pain such as light touch) or areas of hypoaesthesia;

64

5th Edition | Acute Pain Management: Scientific Evidence2.0 | ASSESSMENT AND MEASUREMENT OF PAIN AND PAIN TREATMENT• Regional autonomic features (changes in colour, temperature and sweating) andphantom phenomena.
The IASP definition of neuropathic pain is “pain caused by a lesion or disease of thesomatosensory system” (IASP 2019 GL; Jensen 2011 NR). This has been subdivided into ‘central’and ‘peripheral’ neuropathic pain ( IASP 2019 GL). Symptoms consistent with neuropathic pain
may occur without nerve injury (nociplastic pain) ( IASP 2019 GL; Kosek 2016 NR). To determine
if pain is neuropathic, further quantitative sensory testing (QST) may be needed (Haanpaa 2011
GL; Garcia-Larrea 2012 NR).
It is useful to draw the distinction between the different types of pain because the likely
duration of the pain and the response to analgesic strategies may vary. The concept of“mechanism-based pain diagnosis” has been promoted (Woolf 2001 NR) and although thecorrelation between symptoms, mechanisms and response to therapy is not fully defined, specifictherapy targeted at, for example neuropathic pain, may be of benefit (Gray 2008 NR).
Table 2.1 | Fundamentals of a pain history (not necessarily applicable to all settings of acute pain)
1 Site of paina. primary location: description ± body map diagram
b. radiation
2 Circumstances associated with pain onset
including details of trauma or surgical procedures
3 Character of paina. sensory descriptors eg sharp, throbbing, aching (Victor 2008)b. McGill Pain Questionnaire: includes sensory and affective descriptors(Melzack 1987)
c. neuropathic pain characteristics (eg NPQ; DN4; LANSS; PainDETECT; ID Pain)
4 Intensity of paina. at restb. on movementc. temporal factors iduration
ii
current pain, during last week, highest and lowest leveliii
continuous or intermittent
d. aggravating or relieving factors
5 Associated symptoms (eg nausea)
6 Effect of pain on activities and sleep
a. Functional assessment toolsi Acute (eg Functional Activity Scale)ii Recent (eg Brief Pain Inventory – Short Form (BPI-SF))
7 Treatment
a. current and previous medications — dose, frequency of use, efficacy, adverse effects
b. other treatment eg transcutaneous electrical nerve stimulationc. health professionals consulted

5th Edition | Acute Pain Management: Scientific Evidence658 Relevant medical history
a. prior or coexisting pain conditions and treatment outcomesb. prior or coexisting medical conditions
9 Factors influencing the patient’s symptomatic treatment
a. belief concerning the causes of pain
b. knowledge, expectations and preferences for pain managementc. expectations of outcome of pain treatment
d. reduction in pain required for patient satisfaction or to resume “reasonable activities”
e. typical coping response for stress or pain, including presence of anxiety or psychiatricdisorders (eg depression or psychosis)
f. family/cultural expectations and beliefs about pain, stress and postoperative course
Notes:NPQ - Neuropathic Pain Questionnaire; DN4 - Douleur Neuropathique en 4; LANSS - Leeds
Assessment of Neuropathic Symptoms and Signs.

2.2 | Measurement
The definition of pain underlies the complexity of its measurement. As described in Chapter 1,
pain is an individual and subjective experience modulated by physiological, psychological andenvironmental factors such as previous events, culture, prognosis, coping strategies, fear andanxiety. Therefore, most measures of pain are based on self-report. These measures lead tosensitive and consistent results if administered properly (Moore 2003 NR). Self-report measures
may be influenced by mood, sleep disturbance and medications (Scott 2008 NR).
In some instances, it may not be possible to obtain reliable self-reports of pain eg patientswith impaired consciousness or cognitive impairment, young children (see Section 10.3), elderly
patients (see Section 9.2) or where there are failures of communication due to language
difficulties, inability to understand the measures, unwillingness to cooperate or severe anxiety.
In these circumstances, other methods of pain assessment will be needed.
There are no objective measures of “pain” but associated factors such as hyperalgesia(eg mechanical withdrawal threshold), the stress response (eg plasma cortisol concentrations),
behavioural responses (eg facial expression), functional impairment (eg coughing, ambulation)or physiological responses (eg changes in heart rate) may provide additional information.
Analgesic requirements (eg patient-controlled opioid doses delivered) are commonly used as
post hoc measures of pain experienced (Moore 2003 NR).
Regular and repeated measurements of pain and its impact should be made to assess ongoingadequacy of analgesic therapy. An appropriate frequency of reassessment will be determined by
the duration and severity of the pain, patient needs and response, and the type of medicine orintervention (Gordon 2005 GL). Such measurements should incorporate different components ofpain, and assessment for analgesic side effects, especially sedation (Macintyre 2011 NR). For
example, in the postoperative patient this should include assessments of static (rest) anddynamic (on sitting, coughing or moving the affected part) pain. Whereas static measures may
relate to the patient’s ability to sleep, dynamic measures can provide a simple test formechanical hyperalgesia and determine whether analgesia is adequate for recovery of function(Breivik 2008 NR).
Recording pain intensity as “the fifth vital sign” was a program advocated by the USA
Department of Veteran Affairs, which aimed to increase awareness and utilisation of pain

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assessment (Mularski 2006 Level III-3, n=600), with the intention of leading to improved acute pain
management (Gould 1992 Level III-3, n=2,035). However, an over-reliance on sometimes unrealistic
aims (such as “pain free”) and an excessive use of opioids is leading to a more moderate andbalanced approach to intervention (Levy 2018 NR).
Aiming to reduce suffering and improve function rather than targeting ‘zero pain’ is more in
keeping with patient expectations (Lee 2016 NR). In 2018, the USA Joint Commission (JCAHO)
implemented new and revised pain assessment and management standards for accredited
hospitals, emphasising patient engagement, multimodal therapy and improving pain assessment
by concentrating more on how pain affects patients’ physical function (JCAHO 2017 GL).
Uncontrollable or escalating pain should always trigger a reassessment of the diagnosis andconsideration of alternatives such as developing surgical or other complications, or the presenceof neuropathic pain. Review by an acute pain service (APS) or other specialist group should
be considered.

2.2.1 | Unidimensional measures of pain
A number of scales are available that measure either pain intensity or the degree of pain relief
following an intervention. Pain relief scales, although less commonly used, have some advantage
when comparing the response to different treatments as all patients start with the same baseline“relief” score (zero), whereas they may have differing levels of baseline pain intensity ( Breivik
2008 NR; Moore 2003 NR).
2.2.1.1 | Categorical scales
Categorical scales use words to describe the magnitude of pain or the degree of pain relief(Moore 2003 NR). The verbal descriptor scale (VDS) is the most common example (eg using
terms such as none, mild, moderate, severe and excruciating or agonising) typically using fouror five graded descriptors.
These terms can then be converted to numeric scores (eg 0, 2, 5, 8, 10) for charting and easycomparison over time. There is a good correlation between descriptive verbal categories andvisual analogue scales (VAS) (Banos 1989 Level III-2, n=212), but the VDS is a less sensitive measureof pain treatment outcome than the VAS (Jensen 2002 Level IV, n=247). Pain “relief” may also be
graded as none, mild, moderate or complete using a VDS.
Categorical scales have the advantage of being quick and simple and may be useful in theelderly or visually impaired patient and in some children. However, the limited number of choices
in categorical compared with numerical scales may make it more difficult to detect differences
between treatments (Breivik 2000 Level III-2). Other limitations include personal, cultural or
linguistic differences in interpretation of the specific words chosen as descriptors both between
patients and between patients and their clinicians.
2.2.1.2 | Numerical rating scales
Numerical rating scales (NRS) have both written and verbal forms. Patients rate their pain
intensity on the scale of zero to ten where zero represents “no pain” and ten represents “worst
pain imaginable”. The Verbal NRS (VNRS) is typically administered using a phrase such as: “On ascale of zero to ten, with zero being no pain at all and ten being the worst pain you could imagine,where would you rate the pain you are experiencing right now?”. VNRS are often preferredbecause they are simpler to administer, give consistent results and correlate well with the VAS(Karcioglu 2018 Level I, 19 RCTs, n=853; Hjermstad 2011 Level IV SR, 54 studies, n unspecified; Safikhani
2018 NR). Recall of pain intensity using the VNRS over the previous 24 h was a reasonable
5th Edition | Acute Pain Management: Scientific Evidence67indicator of average pain experienced by the patient during that time ( Jensen 2008 Level III-2).
VNRS may reflect pain interference as well as pain intensity (Thong 2018 Level III-3, n=101; Jensen
2017 Level IV, n=807).
It is important that scales are consistent, and it is recommended that the “no pain” point be
represented as zero rather than one (Scott 2008 NR). Pain relief may be measured in the reverse
direction with zero representing “no relief” to ten representing “complete relief”. A visual formof the 11-point NRS with tick marks on a line or boxes with numbers may also be used ( Breivik
2008 NR). Although NRS are widely used, some patients have difficulty representing their pain innumerical terms and are better suited to a categorical scale. A value of four or more is often used
as a threshold to guide clinical intervention (Hartrick 2003 Level IV, n=222).
2.2.1.3 | Visual analogue scales
Visual analogue scales (VAS) consist of a 100 mm horizontal line with verbal anchors at both ends
and no tick marks. The patient is asked to mark the line and the “score” is the distance inmillimetres from the left side of the scale to the mark. VAS are the most commonly used scales
for rating pain intensity in research, with the words “no pain” at the left end and “worst pain
imaginable” at the right. Pictorial versions also exist. VAS can also be used to measure otheraspects of the pain experience (eg affective components, patient satisfaction, adverse effects).
Assessment of pain immediately after surgery can be more difficult and lead to greaterinterpatient variability in pain scores because of transient anaesthetic-related cognitive
impairment and decreases in visual acuity. A “pain meter” (PAULA), which used five coloured
emoticon faces on the front of a ruler and corresponding VAS scores on the back and allowed
patients to move a slider to mark the pain they were experiencing, resulted in less variance thanpain scores obtained from a standard VAS (Machata 2009 Level III-2, n=48).
VAS ratings ≥70 mm are indicative of “severe pain” (Aubrun 2003 Level IV, n=3,045; Jensen 2003
Level IV, n=248) and 0–5 mm “no pain”, 5–44 mm “mild pain” and 45–69 “moderate pain” (Aubrun
2003 Level IV, n=3,045). A reduction in pain intensity by 30–35% has been rated as clinicallymeaningful by patients with postoperative pain (Cepeda 2003 Level IV, n=700; Jensen 2003 Level IV,
n=248), acute pain in the emergency department (ED) (Lee 2003 Level IV, n=143), breakthroughcancer pain (Farrar 2000 Level IV, n=1,268 [episodes of breakthrough pain]) and chronic pain (Farrar
2001 Level IV, n=2,724).
These scales have the advantage of being simple and quick to use, allow for a wide choice ofratings and avoid imprecise descriptive terms (Scott 2008 NR). However, the scales requireconcentration and coordination, need physical devices, are unsuitable for children aged <5 y andmay be unsuitable in up to 26% of adult patients (Cook 1999 NR).
The VAS has been shown to be a linear scale for patients with postoperative pain of mild tomoderate intensity (Myles 1999 Level IV, n=52) and severe pain (Myles 2005 Level IV, n=22).
Therefore, results are equally distributed across the scale, such that the difference in pain
between each successive increment is equal.

2.2.2 | Functional impact of acute pain
Analgesia should be titrated to achieve both decreased pain intensity and the ability toundertake appropriate functional activity (Breivik 2008 NR). This will enable analgesia to optimise
recovery. Most tools for measuring the functional impact of pain are based on chronic pain
assessment and therefore are not routinely applicable to the acute pain environment.
Measurement of pain intensity scores on movement or with coughing is a useful guide;
however, this reflects the subjective pain experience and not the capacity to undertake the68

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specific activity. The Functional Activity Scale (FAS) score is a simple three-level ranked
categorical score designed to be applied at the point of care ( Scott 2008 NR). Its fundamental
purpose is to assess whether the patient can undertake appropriate activity at their current levelof pain control and to act as a trigger for intervention should this not be the case. The patient isasked to perform the activity or is taken through the activity in the case of structured
physiotherapy (eg joint mobilisation) or nurse-assisted care (eg ambulation, turned in bed). The
ability to complete the activity is then assessed using the FAS as:
A — no limitation
B — mild limitation

C — significant limitation

the patient is able to undertake the activity without limitation
due to pain (pain intensity score is typically zero to three);the patient is able to undertake the activity but experiencesmoderate to severe pain (pain intensity score is typically four toten); andthe patient is unable to complete the activity due to pain, or pain
treatment-related adverse effects, independent of pain
intensity scores.

This score is then used to track effectiveness of analgesia on function and trigger
interventions if required. Disadvantages of the FAS score are that it has not been independently
validated and clinical staff need to be educated in its application.
A four-level scale (no interference, interference with some vs most activities vs unable to do
any activity) has been evaluated against NRS in a pilot study and identified a correlation with NRS
in cognitively intact but not impaired patients (Halm 2019 Level III-2, n=68).

2.2.3 | Multidimensional measures of pain
Rather than assessing only pain intensity, multidimensional tools provide further information
about the characteristics of the pain and its impact on the individual. Examples include the Brief
Pain Inventory (BPI), which assesses pain intensity and associated disability ( Daut 1983 Level IV),and the McGill Pain Questionnaire (MPQ), which assesses the sensory, affective and evaluative
dimensions of pain (Melzack 1987 NR). The MPQ also exists in a 15-item short-form (SF-MPQ),
which is well validated and has a VAS item for pain intensity and a VRS for rating the overall pain
experience. The role of the McGill Pain questionnaire (and its Short Form variants) has beenreviewed; with a conclusion that, while still useful, it provides little information regarding
mechanism, nor the broader social and functional impact of the pain and so should not be used
as a single measure to guide research or therapy (Main 2016 NR) . The BPI also exists in a shortform (BPI-SF and -SF2) which includes functional impact of the pain over the previous 24 h
(Dworkin 2009 Level IV, n=1,008).
2.2.3.1 | Neuropathic Pain
Neuropathic pain is not easily identified using unidimensional tools such as the VAS (Haanpaa
2011 GL). Specific scales have been developed that identify (and/or quantify) descriptive factors
specific for neuropathic pain (Dworkin 2007 Level III-2, n=618; Bouhassira 2005 Level III-2, n=160;
Bouhassira 2004 Level IV, n=176; Cruccu 2004 GL; Freynhagen 2006 NR) and may also include sensory
examination (Bouhassira 2005 Level III-2, n=160; Cruccu 2004 GL) and allow evaluation of responseto treatment (Bouhassira 2004 Level IV, n=176).

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69Screening tools in common use for identifying neuropathic pain include:• Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) has five symptom items
and two clinical assessment items — a subjective-only form also exists (Bennett 2001 Level
III-3, n=100);• Douleur Neuropathique en 4 (DN4) has ten items — seven symptomatic and three fromclinical examination (Bouhassira 2005 Level III-3, n=160);• Pain DETECT has nine self-reported items that do not require a clinical examination andgives a likelihood scoring for neuropathic pain (Freynhagen 2006 NR); its use has beenreviewed in over 300,000 patients (Freynhagen 2016 NR)• Neuropathic Pain Questionnaire (NPQ) comprises twelve items and can be self-reported- a three-item short-form also exists (Krause 2003 Level III-2, n=528; Backonja 2003 NR);• ID Pain has six self-reported items (Portenoy 2006 Level IV, n=586).
These scales have similar specificity and sensitivity (except for the ID Pain, which has lower
values than the others), have mostly been validated and are often available in validated
translations in many languages (Haanpaa 2011 GL). In assessing the criterion validity and reliabilityof the above screening questionnaires, the DN4 and NPQ were found to be most suitable forclinical use overall, noting that cross-cultural adaptations had less evidence than the original
versions (Mathieson 2015 Level IV SR, 37 studies, n unspecified).
Clinical questionnaires for neuropathic pain show that subjective pain assessments are
essential for diagnosis and assessment of neuropathic pain, with screening questionnaires being
effective at leading to more formal diagnosis (aided by assessment questionnaires), and also are
valuable in research (Attal 2018 NR).
2.2.3.2 | Global scales and satisfaction
Global scales are designed to measure the effectiveness of overall treatment (see Section 2.3.1).
They are more suited to outcome evaluation at the end of treatment than to modifying
treatment in the acute stage (Moore 2003 NR). Questions such as “How effective do you think thetreatment was?” recognise that unimodal measures of pain intensity cannot adequately
represent all aspects of pain perception.
Satisfaction is often used as a global indicator of outcome; however, patients may report highlevels of satisfaction even if they have moderate to severe acute pain ( Svensson 2001 Level IV,
n=191). Satisfaction may also be influenced by preoperative expectations of pain, effectivenessof pain relief, the patient–provider relationship (eg communication by medical and nursing staff),interference with function due to pain and number of opioid-related adverse effects (Jensen 2004
Level IV, n=191; Carlson 2003 Level IV, n=787; Svensson 2001 Level IV, n=191). Although complete
absence of pain is not required for patients to report high levels of satisfaction, moderate pain
(VAS >50/100) has been associated with dissatisfaction (Jensen 2005 Level III-2, n=207).

2.2.4 | Patients with special needs
Validated tools are available for measuring pain in neonates, infants and children but must be
both age and developmentally appropriate (see Section 10.3). These include behaviouralassessments, pictorial scales (eg faces) and response to treatment. Adult patients who havedifficulty communicating their pain (eg patients with cognitive impairment or who are criticallyunwell in the ED or intensive care unit [ICU]) require special attention as do patients whose
language or cultural background differs significantly from that of their health care team.
Communication aids and behavioural scales such as the modified Faces, Legs, Activity, Cry and70

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Consolability (FLACC) scale (Erdek 2004 Level III-3) can be particularly useful in these situations(see Section 9.2.3).
NRS are considered the best tool for measurement of pain intensity for adult ICU patients
who may be non-verbal, sedated or ventilated. If they are not feasible, then the Behavioural Pain
Scale (BPS) or Critical-Care Pain Observation Tool (CPOT) should be used (Varndell 2017 Level III-3
SR, 26 studies, n unspecified; Barr 2013 GL; Azevedo-Santos 2018 NR; Gelinas 2013 NR). The CPOT has
been validated in neurosurgical patients (Echegaray-Benites 2014 Level III-3, n=43) and in different
countries (Rijkenberg 2015 Level III-3, n=68; Li 2014 Level III-3, n=63). The CPOT appears to be more
specific for pain than the BPS (Rijkenberg 2015 Level III-3, n=68).
In patients with dementia, similar challenges often require the use of non-verbal tools.
Overall, in assessing reviews of multiple tools there is limited evidence about the reliability,
validity and clinical utility of any specific tool (Lichtner 2014 Level IV SR, 23 reviews[28 tools]).
A systematic review of the effect of the use of pain assessment tools in critically ill patientson patient outcomes concluded that it improves pain management, but evidence was tooheterogeneous to draw firm conclusions regarding outcomes such as length of mechanicalventilation or ICU stay (Georgiou 2015 SR Level III-2, 10 studies, n unspecified)Surveys in the UK and Netherlands show that pain assessment tools were underutilised inmany ICUs (Kemp 2017 Level IV, n=750 [patients assessed by 362 UK physicians]; van der Woude 2016
Level IV, n=107 [adult ICUs in the Netherlands]) (see also Section 8.10).

KEY MESSAGES
1. There is good correlation between the visual analogue and verbal numerical rating
scales (S) (Level I).
2. Regular assessment of pain leads to improved acute pain management (U) (Level III-3).
3. Appropriate assessments (including screening tools) are required to determine thepresence of neuropathic pain (N) (Level III-2).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Functional outcomes rather than pain scores alone should be used to guide acute pain
management, including non-pharmacological approaches (N).
 Self-reporting of pain should be used whenever appropriate as pain is by definition a
subjective experience (U).
 The pain measurement tool chosen should be appropriate to the individual patient andthe clinical context (eg intensive care, ward, community). Developmental, cognitive,
emotional, language and cultural factors should be considered (U).
 Scoring should incorporate different components of pain including the functional
capacity of the patient. In the postoperative patient, this should include static (rest) anddynamic (eg pain on sitting, coughing) pain (U).
 Uncontrolled or unexpected pain requires a reassessment of the diagnosis andconsideration of alternative causes for the pain (eg new surgical/ medical diagnosis,
neuropathic pain) (U).

5th Edition | Acute Pain Management: Scientific Evidence712.3 | Outcome measures in acute pain management
What follows is a brief guide to some of the outcome measures used particularly in the acutepain literature. A comprehensive review is beyond the scope of this document and more detail
may be found elsewhere (Breivik 2008 NR). Concerns have been raised regarding trial design
limitations resulting in type II errors (failure to identify a difference when one truly exists) andrecommendations have been made for the design of chronic pain RCTs that include patientnumbers, study site and outcome measurements to reduce this problem (Dworkin 2012 GL).
Similar issues are of relevance to studies in acute pain interventions.

2.3.1 | Outcome measures
2.3.1.1 | Pain
The aim of many clinical trials is to determine whether a medicine or intervention provides
adequate pain relief for the majority of participants or is equivalent or noninferior to an existing
accepted treatment. This can be achieved by repeated single measures at fixed time points,
which may encompass only a proportion of the total illness. When comparison is made with aplacebo, a statistically significant result can be achieved with a relatively small number ofpatients (eg n=40) (Collins 2001 Level I, 11 SRs [151 RCTs], n unspecified). The primary outcome ischosen by the researcher and may not be of direct importance to the individual patient,particularly if it relates to only a proportion of the total time he/she was in pain. It is also
important to consider that statistically significant differences in pain scores may not reflect
clinically significant differences, although these are harder to define (see above).
Data derived from categorical and VAS of pain intensity or relief produce a range of summary
outcomes that can be used to assess (Moore 2003 NR):• the degree of analgesic effect:◦ difference between the baseline and post-intervention score of pain intensity or
pain relief (summed pain intensity difference [SPID]);◦ the area under the time-analgesic effect curve for a given time (total pain relief[TOTPAR]);◦ dose of rescue analgesic consumption required in a given time period (eg PCA use);• the time to analgesic effect:◦ the time to onset of analgesic effect;◦ time to maximum reduction in pain intensity or to peak relief;• the duration of effect:◦ time for pain to return to at least 50% of baseline;◦ time for pain intensity to return to baseline or for pain relief to fall to zero; and◦ time to re-medication/rescue analgesia.
A widely used method of describing the effectiveness of an analgesic intervention is the number
needed to treat (NNT). In this setting it is commonly defined as the number of patients that need
to be treated to achieve at least 50% pain relief (eg at least 50% maximum TOTPAR) in one patientcompared with a placebo over a 4–6 h treatment period (Moore 2003 NR). Analysis at other cut-off
points (30–70% max TOTPAR) has shown the same relative efficacy of different treatments (McQuay
2003 NR).
In acute pain research, using TOTPAR to assess pain relief may be more sensitive to treatment
effects than SPID which is assessing intensity (Singla 2015 Level I [PRISMA], 45 RCTs,
n unspecified).

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The validity of this approach as a true method of comparison may be questioned as there is
no standardisation of the acute pain model or patient and only single doses of the analgesic
agents are used. However, it may sometimes be reasonable to extrapolate estimates of analgesic
efficacy from one pain model to another (Barden 2004 Level I, 160 RCTs, n=14,410).
The use of supplemental analgesic consumption as an outcome measure has beenquestioned in situations where pain scores are not similar (McQuay 2008 Level I, 18 RCTs, n=1,217).
2.3.1.2 | Physical functioning
Measures of physical functioning quantify many aspects of a patient’s life including their ability
to sleep, eat, think, deep breathe, cough, mobilise, perform activities of self-care and daily living,undertake their usual vocation and to enjoy leisure activities and sport ( Williams 1999 NR). In
acute pain, this may be measured by pain intensity scores with movement or other functional
activity scores (see above).
Global or multidimensional measures of function attempt to combine various abilities ordisabilities to derive a summary measure. Scales that employ a large number of items might becomprehensive but risk patient exhaustion or error, while scales with fewer items might bepatient friendly but risk becoming insensitive to state or change (Williams 1999 NR). These scales
have been used in some studies of acute spinal pain and cancer-related pain:• Disability scales — generic scales include the Short Form 36 of Medical Outcomes Study (SF36), the Sickness Impact Profile (SIP) and Roland & Morris Short SIP (Williams 1999 NR);• Quality of life (QOL) measures — these measures are not widely used in acute pain
studies, but have relevance for chronic or cancer-related pain (Higginson 1997 NR).
Disease-specific measures quantify the impact of a specific pain problem on function andcan be used to track changes after an intervention (eg ability to cough after thoracotomy,
ability to lift a baby after Caesarean section) (Garratt 2001 Level IV, n=187). Generic measuresfacilitate comparisons among the functional limitations of different conditions and treatments
and may have advantages for audit of an APS that includes patients with a range of conditions(Patrick 1989 NR).
2.3.1.3 | Emotional functioning
Acute pain is an unpleasant sensory and emotional experience. The unpleasantness of theexperience and its meaning for the individual may have short term (anxiety, depression,
irritability) and long term (lost confidence or self-efficacy or post-traumatic stress disorder)
consequences for the individual’s emotional functioning.
2.3.1.4 | Adverse effects
In trials of efficacy, adverse effects are usually considered to be of secondary importance andinadequate reporting has been found in as many as half of randomised trials reviewed ( Ioannidis
2001 Level I, 192 RCTs, n=130,074; Edwards 1999 Level I, 52 RCTs, n unspecified). If adverse effects are
sufficiently common (eg nausea with opioids), they may be quantifiable in trials of efficacy andspecifically measured using dichotomous (present or absent), categorical (none, mild, moderate,
severe) or interval (analogue or Likert) scales. Analogous to NNTs, the number needed to harm
(NNH) may be used to describe the incidence of adverse effects.
Most efficacy trials will have inadequate power to detect rare adverse effects and therefore
they are also absent from systematic reviews. Large clinical trials specifically designed to detect
adverse effects are required (eg the Vioxx Gastrointestinal Outcomes Research [VIGOR] study
5th Edition | Acute Pain Management: Scientific Evidence73

investigated gastrointestinal toxicity of NSAIDs) (Bombardier 2000 Level II, n=8,076, JS 5). Case
reports and post-marketing epidemiological research and surveillance (eg the Australian Adverse
Drug Reactions Advisory Committee) remain important for detection of delayed effects occurring
after the initial trial period. Results from comprehensive large prospective audits and databasereviews have provided a sufficiently reliable denominator for incidence and risk factor evaluationin rare but serious adverse effects in acute pain management (Wijeysundera 2008b Level IV,
n=259,037; Cameron 2007 Level IV, n=8,210; Wijeysundera 2008a NR).
Besides the adverse effects attributed to acute pain management interventions, another areaof interest is whether the adverse effects of trauma and surgery might be prevented by effective
acute pain management. Outcomes such as mortality, morbidity due to derangements of the
cardiovascular, respiratory, gastrointestinal and coagulation systems and progression to chronic
pain have also been reported (see Chapter 1).

KEY MESSAGE
1. Assessment of pain relief (with total pain relief [TOTPAR]) may be more sensitive totreatment effects than assessment of intensity (with summed pain intensity difference[SPID]) (N) (Level I [PRISMA]).
The following tick box represents conclusions based on clinical experience and expert
opinion: Multiple outcome measures are required to adequately capture the complexity of thepain experience and how it may be modified by pain management interventions (U).

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95(1): 241–49.

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77

3

Provision of safe and effective
acute pain management
Section Editor:
Dr Richard Halliwell78

3.1 | Education
Contributor: Dr Zoe Vella

3.2 | Organisational requirements
Contributor: Dr Richard Halliwell

3.3 | Economic considerations in acute pain management
Contributor: Dr Melanie Zeppel793.1 | Education
3.1.1 | Patients
Patients and carers who learn about assessment of pain, the risks and adverse effects oftreatment, and who are informed that they should communicate both the effectiveness oftreatment and any adverse effects, will have greater control over the quality of their pain relief.
Information on treatment options, goals, likely benefits and probability of success should beavailable; this advice is found in most published recommendations and guidelines. Despite this,many patients still feel uninformed about pain, particularly in the perioperative period(Macintyre 2015 NR; Counsell 2008 NR). A national survey of patients who were undergoing total
hip arthroplasty (THA) revealed that 70% did not believe they had been given adequate
information about their procedure (including pain relief) and those who had higher levels of
education perceived a larger deficit (Johansson Stark 2014 Level IV, n=320). A survey of healthprofessionals acknowledged that perioperative pain management knowledge and otheraspects of colonic surgery were deficient in patients undergoing the procedure ( Sjostedt 2011
Level IV, n=49 [health care professionals]).
3.1.1.1 | General principles
A systematic review of systematic reviews (using the AMSTAR 1 tool) pertaining to methods ofpatient education, in general, concludes that teaching strategies that increase patientknowledge decrease anxiety and improved patient satisfaction (Friedman 2011 Level IV SR, 23
systematic reviews & meta-analyses, n unspecified). This comprised those using computer
technology, audio and videotapes, written materials and demonstrations. While only one
systematic review addressed pain management, the more general results are relevant to this
topic. Educational strategies were better when combined, structured, culturally appropriate andpatient-specific, rather than generic or ad hoc. Verbal teaching and discussions were found to be
the least effective strategies. Web-based teaching improved patient knowledge, anxiety, andsatisfaction, as did audiotapes, videotapes, written materials and lectures, all of which weremore effective than verbal teaching and discussions. Demonstrations had the highest effect of
any of the teaching strategies evaluated. Multiple teaching strategies are better than single
ones, with one systematic review finding that 67% of patients who received patient education
using several different strategies had better outcomes than those who received routine care.
Patient education regarding the procedure or recovery provided a small improvement inpostoperative pain (SMD -0.21; 95%CI -0.02 to -0.39) (12 RCTs, n=1,242), pre-operative anxiety(SMD -0.27; 95%CI -0.10 to -0.44) (12 RCTs, n=1,260) and postoperative anxiety (SMD -0.26;
95%CI -0.08 to -0.43) (11 RCTs, n=921), but had no impact on analgesic use (SMD -0.06; 95%CI
0.13 to -0.24) (10 RCTs, n=860) (Szeverenyi 2018 Level I [PRISMA], 62 RCTs, n=4,908). Pain
psychoeducation undertaken before surgery (pre-emptive) or throughout the perioperative
period (preventive) is an underutilised component of multimodal analgesia with data showing
reduced pain intensity, analgesic use, LOS, return to ED, patient anxiety and possibly chronic
postsurgical pain (Horn 2020 Level IV SR, 33 studies, n unspecified).
There is evidence that written information is better than verbal education. Written
information resulted in more satisfaction, lower pain scores and lower analgesic use after
gynaecological cancer surgery (Angioli 2014 Level II, n=190, JS 2). Knowledge was lower in thosegiven non-standardised verbal information vs those given written information, including
information regarding pain management, at the time of preoperative anaesthetic review

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5th Edition | Acute Pain Management: Scientific Evidence3.0 | PROVISION OF SAFE AND EFFECTIVE ACUTE PAIN MANAGEMENT(Binhas 2008 Level III-3, n=180). Patients receiving education favoured the combination of verbal
plus written information over verbal information alone, as it allowed them to refresh theirmemory (Andersson 2015 Level III-1, n=18). A study of emergency department patients found thatthe provision of patient information leaflets improved doctor-patient communication andpatient satisfaction levels and reduced rates of reattendance for the same condition, as well as
the number of drug prescriptions by doctors (Sustersic 2019 Level III-2, n=324). This aligns withthe findings of a previous systematic review of systematic reviews which determined thatpatient information leaflets improve patient knowledge, satisfaction and adherence totreatment recommendations (Sustersic 2017 Level IV SR, 24 SRs, n unspecified).
A systematic review of studies of postoperative education (conducted between 1986 and2007) which aimed at improvement in self-knowledge and symptom experience (includingpain) evaluated the best type and amount of postoperative education ( Fredericks 2010 Level III-3
SR, 58 studies, n=5,271). All types of surgery were included with 46% assessing cardiac surgery,
26% general surgery, 4% abdominal/ colorectal surgery and 5% hip and knee surgery.
Individualised education with the patient having input into their educational requirements, useof combined media for delivery, provision of one-on-one education and multiple sessions wereassociated with improvement in educational and/or health outcomes. Individuals <50 y andthose with higher educational level showed the highest benefit.
3.1.1.2 | Effects in specific postoperative settings
PCA use
Structured vs brief patient education prior to PCA use resulted in improved patient knowledgeof PCA (Yankova 2008 Level III-1 SR, 5 RCTs & 1 study, n=592). No studies demonstrated thatstructured education about PCA improved postoperative pain scores.
Total joint arthroplasty
Three overlapping reviews draw similar conclusions as to the limited effect of preoperative
patient education in addition to standard care on pre and postoperative outcomes after total
hip and knee arthroplasty (THA/TKA) (McDonald 2014 Level I [Cochrane], 18 RCTs, n=1,463; Aydin
2015 Level I [PRISMA], 12 RCTS, n=1,567; Louw 2013 Level III-1 SR, 12 RCTs & 1 study, n=1,021) (10 &8 RCTs overlap). The included RCTs are heterogeneous in terms of the patient population andteaching methods applied. There is some reduction in preoperative anxiety for THR (MD-5.10/60; 95%CI -7.17 to -3.03) (4 RCTs, n=333) and LOS for TKR (MD -1.86 d; 95% CI -3.40 to-0.32) (2 RCTs, n=183); but little or no evidence for any other outcomes including postoperative
anxiety, mobility, pain, function or postoperative complications.
Preoperative education does not improve postoperative pain scores after either THA (up to
3 mth after surgery) or TKA (up to 12 mth after surgery) (McDonald 2014 Level I [Cochrane],
18 RCTs, n=1,463). However, education has a low risk of adverse effects, and may be beneficial
for certain patients with depression, anxiety or unrealistic expectations about their surgery.
Interviews with focus groups of patients following THA and TKA identified patient requests forincreased education on pain management in the postoperative period ( Kennedy 2017 Level IV,n=32). Patients reported that they would have preferred more information regarding expectedlevels of postoperative pain, the purpose, administration and expected side effects of analgesic
medication, and specific weaning instructions. Among the patients interviewed, there was awide range of preference for content, mode of delivery (web-based or traditional methods),
and timing of education. It is acknowledged in the literature that a more personalised
education program that allows patients to ask questions may translate to improved outcomes
following preoperative education (Aydin 2015 Level I [PRISMA], 12 RCTs, n=1,567). However, arandomised controlled trial that involved personalised preoperative information sessions prior
5th Edition | Acute Pain Management: Scientific Evidence81to TKA did not demonstrate any difference in pain at any time point vs a group receiving
standard care (Wilson 2016 Level II, n=143, JS 4). The authors suggest that this may reflect arequirement for increased education for healthcare providers as well as patients in order toachieve significant benefits in postoperative analgesia. Online resources available for patientsto read about pain control after TKA are generally of limited utility, with more than 90% of
websites containing information directed at patients written in language that exceeds averagereading levels (Schairer 2017 NR). This has the potential to limit patient understanding of
postoperative pain management and highlights an opportunity for orthopaedic, anaesthetistand pain medicine specialists to develop and encourage access to appropriate patient-focused
online resources.
Cardiac surgery
Preoperative education reduces anxiety (6 RCTs, n=829) in patients undergoing mixed types ofcardiac surgery, but there was limited evidence for any effect on pain (4 RCTs, n=704) (Ramesh
2017 Level I [PRISMA], 14 RCTs, n=2,071). This is consistent with a preceding systematic review
which found no effect of preoperative education on pain levels or other outcome measures inpatients after coronary artery bypass graft (CABG) surgery (Guo 2015 Level I, 6 RCTs, n=1,406[2 RCTs pain, n=762]) (2 RCTs overlap).
Spinal surgery
Patients receiving neuroscience education (including a conversation with a physical therapist
for 30 min plus a neuroscience booklet) prior to lumbar spinal surgery for radicular pain had
the same pain levels and function 12 mth following surgery vs controls who received routine
care (Louw 2014 Level II, n=67, JS 3). However, those in the experimental group exhibited 45%
less healthcare expenditure in the 12 mth following surgery and viewed their surgicalexperience more positively. At 3 y follow-up, this reduction in health care costs wasmaintained; the group that received preoperative neuroscience education spent 37% less on
medical expenses (Louw 2016 Level III-2, n=50). The authors postulated this could be a result of
the educational emphasis on neurobiology and neurophysiology (central and peripheral
sensitisation, facilitation and inhibition) as opposed to the pathoanatomical explanation
previously utilised for education in patients undergoing lumbar spinal surgery.
A preoperative educational intervention (provision of a detailed information booklet and 30
to 40 min guided explanation by a nurse) vs control in spinal surgery lowered preoperative
anxiety and postoperative pain scores (6.1/10 to 5.3/10) (Lee 2018 Level II, n=86, JS 3) (see also
Section 7.1.1).
Other types of surgery
The provision of a detailed information sheet to parents after tonsillectomy in children
provided postoperative benefit (Bailey 2015 Level II, n=60, JS 5). The information sheet contained
specific instructions regarding the dose and timing of oxycodone and resulted in higher
parental satisfaction and knowledge and some improvements in pain scores up to POD 7 vsstandard verbal instructions.
After cosmetic day-surgery procedures, preoperative education reduced postoperative
opioid requirements and pain intensity and duration (Sugai 2013 Level II, n=135, JS 2).
Preoperative written and verbal education (two sessions by the same surgeon) on the adverse
and negative effects of opioids resulted in 90% of the treatment group declining an opioidprescription vs 100% filling their opioid prescription in the control group.
Patients undergoing modified radical mastectomy, who had received a specific 20 min
education about their analgesia management and medications, reported less pain andmobilised earlier than those who had not received the education ( Sayin 2012 Level III-1, n=84).

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3.1.1.3 | Effects in other acute pain settings
The effect of patient education has also been studied in patients with acute non-surgical pain.
Education programs, depending on their approach, may not be effective in the prevention
and treatment of neck pain or low back pain in a widely heterogeneous patient and community
groups (including children and at-risk workers) (Ainpradub 2016 Level I, 15 RCTS, n=10,488); thesefindings were cautioned against in a letter (Hurley 2016), because they were based excessively
on a “biomedical education” approach which emphasises “protecting the injured back”. This
type of education has now been supplanted by the effective “biopsychosocial education”
approach, which in contrast, emphasises the robustness of the back, and is in agreement withpain physiology. Another systematic review shows a beneficial outcome from patient educationin the management of acute lumbar back pain when a “biopsychosocial/neuroscience”
education-based approach is used (Traeger 2015 Level I [PRISMA], 14 RCTs, n=4,872). In this review,
the outcomes were “reassurance” (which was a composite of anxiety, fear, worry, distress) andhealthcare utilisation (number of primary care visits for LBP over 12 mth). The effect size for abenefit on reassurance at 4 mth was SMD -0.21 (95%CI -0.36 to -0.07), and the effect on
reduction in healthcare utilisation was SMD -0.14 (95%CI -0.28 to 0.00).
Regarding acute back pain, there is moderate to high quality evidence that patient
education provided by primary care practitioners can reassure patients for up to 12 mth, andlead to reductions in low back pain related healthcare utilisation, with a NNT of 17 to prevent
one subsequent primary care visit (Traeger 2015 Level I [PRISMA], 14 RCTs, n=4,872). Patientreassurance is heightened with education provided by a physician rather than by other healthprofessionals. Conversely, a subsequent RCT found that the addition of two sessions (1 h each)of patient education (focusing on biopsychosocial contributors to pain as well as selfmanagement techniques) to standard practice did not improve pain intensity or disability vs aplacebo educational intervention (Traeger 2019 Level II, n=202, JS 4).
An earlier systematic review of pain education strategies for neck pain was unable to findgood evidence for the benefit of patient education, apart from one RCT (n=348) showing that an
educational video of advice about being active was more beneficial in the medium term ( Gross2012 Level I [Cochrane], 15 RCTs, n=5,305) (3 RCTs overlap with Ainpradub 2016). After acute whiplash
injury specifically, short educational interventions reduce pain and disability and enhancerecovery and mobility (Meeus 2012 Level I [PRISMA], 10 RCTs, n=1,594) (2 RCTs overlap). Educational
interventions for patients with whiplash (neurophysiology content) have demonstrated
improvements in both pain behaviours and pain threshold ( Rebbeck 2017 NR). It is also
recommended that patients receive advice regarding the course of recovery and education
about coping strategies and unhelpful beliefs.
Antenatal education regarding epidural analgesia led to more primigravid women indicatingthat they would request epidural analgesia for pain relief in labour ( Alakeely 2018 Level III-3,n=81). Antenatal teaching about postnatal nipple pain and trauma resulted in reduced nipple
pain and improved breastfeeding (Duffy 1997 Level II, n=70, JS 3).
An emergency department nurse-delivered opioid education intervention (verbal andwritten communication strategies) increased patient understanding of appropriate use ofdischarge opioids (Waszak 2018 Level III-3). However, this relied on nurses’ ability to take extra
steps in their usual discharge routine, including printing information sheets and conducting
verbal ‘teach-back’ sessions.

5th Edition | Acute Pain Management: Scientific Evidence833.1.1.4 | Web-based education for acute pain management
The internet and mobile devices are being increasingly used for pain education. There are few
published studies that have evaluated these types of interventions for patients with acute pain. A
systematic review of web-based pain education included only two RCTs that evaluated educational
websites with information on acute postoperative pain (Bender 2011 Level I, 17 RCTs, n=2,503): one
aimed to prepare adolescents for tonsillectomy and demonstrated improvements in satisfaction
and knowledge, but no difference in pain scores or anxiety (O'Conner-Von 2008 Level II, n=69, JS 3);
the other prepared adults for postoperative self-care after outpatient surgical procedures andfound reductions in postoperative pain intensity the night and day afterwards (Goldsmith 1999 Level
II, n=195 [only 80 at follow-up], JS 2). An innovative web technology used an assessment process toindividualise the content of education and use persuasive educational techniques to effect changes
in response to pain after cardiac surgery (Martorella 2012 Level II, n=60, JS 3). The 30 min web-based
intervention used a virtual nurse to guide the patient, followed by two face-to-face 5-min booster
sessions. In the experimental group, patients did not experience less intense pain, but theyreported significantly less pain interference when breathing/coughing and used more analgesia. A
web-based intervention program providing daily postural advice and exercise instructions withdaily email reminders and personalised log over 9 mth to office workers with sub-acute low-backpain (of 6 wk duration) was effective in improving quality of life, behaviour change, function andpain vs standard care (del Pozo-Cruz 2013 Level II, n=100, JS 2).
A systematic review found no additional benefit for tailored vs standardised web-based
patient education for patients with chronic pain (Martorella 2017 Level I [PRISMA], 16 RCTs
[15 chronic], n=4,304).
The readability of web-based educational materials regarding epidural analgesia was well
above the recommended reading level for patient education, which may limit the ability ofpatients to make informed choices (Patel 2015 Level IV, n=101 [educational materials on 128
websites in English and Spanish]). An assessment of online patient education material about
regional anaesthesia produced by USA teaching hospitals found the mean (SD) Flesch-Kincaid
Grade Level for patient education material was high at hospitals offering and not offering
regional fellowship teaching programs: 13.8 (2.9) vs 10.8 (2.0) ie well above the recommended
sixth-grade level (Kumar 2017 Level III-3, n=32 [websites]). Similarly, a review of patient educationmaterial about safe opioid use after surgery found the online information from the websites of
selected North American academic medical centres to have the reading grade level 7.84
(SD 1.98) (Kumar 2019 Level III-3, n=38 [websites]).

3.1.2 | Staff
Appropriate education of medical and nursing staff is essential if more sophisticated forms ofanalgesia (eg PCA or epidural analgesia) are to be managed safely and effectively and if better
results are to be gained from conventional methods of pain relief ( Macintyre 2015 NR). Medical
and health professional staff education may take several forms; the evidence for any benefit
for the best educational technique is varied and inconsistent. Education may also include
organisational approaches, the provision of guidelines and accompanying changes to practiceto enable good outcomes.
3.1.2.1 | Nursing staff
Improvements in nursing knowledge and ability to manage epidural analgesia followed thereintroduction of an epidural-education program using an audit/guideline/problem-basedteaching approach, accompanied by practical assessments (Richardson 2001 Level III-3). A more84

5th Edition | Acute Pain Management: Scientific Evidence3.0 | PROVISION OF SAFE AND EFFECTIVE ACUTE PAIN MANAGEMENT

recent simulation-based educational workshop (4 h) relating to epidural assessment improved
knowledge and confidence of participating nursing staff and increased the number of correct
procedures performed in a post-workshop assessment (Sawhney 2018 Level III-3). However,translation to practice changes in the clinical environment was not assessed, and educational
workshops of this type require significant time and monetary investments.
Pain
documentation in surgical wards (Ravaud 2004 Level III-1, n=2,278; Karlsten 2005 Level III-2) andintensive care units (ICUs) (Erdek 2004 Level III-3; Arbour 2003 Level IV) was also improved byeducation programs. A quality-improvement system, which included education and guidelines
as well as systems to improve practice, resulted in significant improvements in postoperative
pain, nausea, vomiting and fatigue (Usichenko 2013 Level III-3, n=520). Implementation of aquality-improvement program led to improvements in nurses' knowledge and assessment ofpain using pain-rating scales; however, while the number of patients assessed increased, there
was no improvement in pain relief (Hansson 2006 Level III-2).
There are possible reasons why education programs may not always be successful inimproving nursing staff knowledge or attitudes (Dahlman 1999 Level III-3) or pain relief (Knoblauch1999 Level IV). In rural and remote settings, distance and professional isolation could affect theability of healthcare staff to receive up-to-date education about pain relief. However,similarities between urban and rural nurses’ knowledge and knowledge deficits relating toacute pain management have been reported (Kubecka 1996 Level IV, n=123 [nurses]) and a
tailored education program in a rural hospital improved the management of acute pain (Jones
1999 Level III-3, n=126). An education program delivered to nurses in rural and remote locations
and focusing on acute, chronic and cancer pain improved understanding of pain management(Linkewich 2007 Level III-2). Early attempts at using online education for nurses to improve pain
management were not widely accessed. A proposed model involving e-learning and problembased approaches have had some initial success (Keyte 2011 NR).
A range of didactic and interactive teaching methods have been applied in nursing pain
management education (Drake 2017 Level IV SR [PRISMA], 12 studies, n≈726 [staff] & n≈8,124[patients]). Overall, nurses showed an improvement in pain documentation after participating ina pain management education program. However, there was no assessment of the nurses’
associated behavioural change, and failure to account for the challenges of daily nursing
practice, such as the requirement to frequently shift attention, which may interfere withassessment and ability to empathise with patients in pain). The provision of information andskills has limited ability to improve patient outcomes if these practical barriers to pain
management are not addressed.
3.1.2.2 | Physiotherapists
Physiotherapists have recognised the need for more education about acute and subacute pain
incorporating a biopsychosocial approach to prevent long-term disability and pain. However,an 8 d university course about how to identify and address psychosocial risk factors attended
by practicing musculoskeletal physiotherapists led to no improvement in their patients being
treated for musculoskeletal problems (Overmeer 2011 Level II, n=42, JS 2). The authors suggestthat this type of teaching may be more effective if incorporated at an earlier stage of learning
or by other methods if an impact on practice is to be made.
3.1.2.3 | Medical staff
Education of junior emergency department medical staff improved patient pain relief (Jones 1999
Level III-3, n=126). Additionally, the implementation of an education program with guidelines forpain management improved analgesia and patient satisfaction (Decosterd 2007 Level III-2, n=441).
5th Edition | Acute Pain Management: Scientific Evidence85

A number of studies have shown the benefits of education and/or guidelines on improved
prescribing patterns both in general terms (Ury 2002 Level III-3, n=1,006; Humphries 1997 Level III-3)
and specifically for NSAIDs (Ray 2001 Level II, n=209, JS 2; Figueiras 2001 Level III-2, 495 [doctors innorth-western Spain]; May 1999 Level III-3, n=210 [doctors in South Australia]), paracetamol(acetaminophen) (Ripouteau 2000 Level III-3, n=35 [French anaesthetists and nurses]) and pethidine(meperidine) (Gordon 2000 Level III-3).
A pilot program facilitated within Stanford University’s Clinical Pain Medicine Fellowship
program has implemented simulation as a method of medical education in opioid prescription(Heirich 2019 Level III-3, n=27).
3.1.2.4 | Interprofessional
Interprofessional education programs involving medical and nursing staff may improve
collaboration and communication between health care team members and patients, andtherefore encourage active self-management techniques and limit the implementation ofpassive pain management strategies (Hogans 2018 NR). An educational program (2 h) consistingof an interactive e-learning module and simulation session to both nursing and medical staff
improved knowledge, but did not change analgesic administration or pain reduction forpatients during an emergency department admission (Friesgaard 2017 Level III-3, n=2,140).
The authors suggest that achieving behavioural change in healthcare professionals is complex,
requiring repeated education, changes in workplace attitudes towards pain management,
modification of daily practice environments and continuous support and follow-up.
Junior medical staff education over 3 y in an Australian tertiary hospital reduced
inappropriate oxycodone IR prescriptions from 28% to 10% ( Stevens 2019 Level III-2). The
education package included junior medical and anaesthetic staff group and individual
education (with feedback from audit data on individual prescribing), implementation ofpharmacist-monitored prescription guidelines, an educational patient pamphlet and education
sessions for surgical nursing staff regarding how to discuss opioid weaning and disposal.
3.1.2.5 | Web-based
There is growth in web-based delivery of education programs for health professionals. Online
educational resources improve knowledge and skills, but not confidence and competence,(Liossi 2018 Level IV SR [PRISMA], 13 RCTs & 19 studies, n unspecified). Notably, there was significant
heterogeneity among studies and relevant health outcomes for patients were not assessed.
A survey of clinicians who completed an interactive online learning module regarding opioidprescription determined that clinician knowledge, the likelihood of adherence to prescription
guidelines, and perceived competence in opioid prescription improved following participation(Langford 2020 Level III-3, n=167).
3.1.2.6 | Guidelines
When combined with education, the introduction of medical and nursing guidelines may
contribute to improvements in pain management and prescribing practices (Gould 1992 Level III-2,
n=2,035; Harmer 1998 Level III-3, n=2,738). Several initiatives have been described which employ
guidelines with the aim of safe opioid prescription:• A targeted medical, nursing and patient education initiative significantly reduced the
median quantity of opioid analgesics provided at discharge for trauma patients (Oyler
2018 Level III-3, n=913);

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5th Edition | Acute Pain Management: Scientific Evidence3.0 | PROVISION OF SAFE AND EFFECTIVE ACUTE PAIN MANAGEMENT• An emergency department opioid prescribing guideline reduced the number ofdischarge opioid prescriptions for dental, neck, back or chronic pain presentations from53% (6 to 12 mth prior to introduction) to 34% (12 to 18 mth following introduction) (delPortal 2016 Level III-3, n=13,187);• An Australian tertiary hospital introduced discharge analgesia prescribing guidelines
which initially improved discharge prescribing practices, but diminished over time
(Stewart 2019 Level III-3, n=170 [discharge prescriptions]). Maintaining education of junior
medical staff can be a resource and time intensive proposition and is often maintainedin an informal manner by pharmacists and other healthcare team members.
Advances in pain education require the engagement of healthcare professionals, patients,
stakeholders, and ultimately a better understanding of pain education research ( Hogans 2018
NR). Pain education research continues to present multiple challenges in terms of definition ofcontent, ethical and practical study design, and consideration of appropriate outcome
measures.
The importance of pain medicine education at an undergraduate medical level has also
been recognised. A cross-sectional study of medical school curricula across Europe (Advancing
the Provision of Pain Education and Learning [APPEAL] study) demonstrated that current
undergraduate medical pain education is not consistent with that which would be expected
given the current prevalence of pain conditions and their associated public health burden(Briggs 2015 Level IV, n=242 [curricula of medical schools]). Of 242 medical schools, only 31% offereda dedicated pain module and only 18% of these were compulsory, while 7% lacked any pain
education. In response to the prescription opioid epidemic, American medical schools have
implemented curriculum changes to include pain management and opioid prescribing ( Barth2017 NR). Furthermore, a systematic review of all articles that examined the content of pain
education in medical school curricula found that the number of teaching hours was limited, andmost had no mandatory formal pain medicine program (Shipton 2018 Level IV SR, 14 studies,n=383 [medical schools]); this did not reflect the healthcare needs for pain management in the
population. Anaesthetists and acute pain services are central to the education of junior medical
staff and development of hospital and state-wide prescription guidelines, and thus it isimportant that anaesthetists themselves receive appropriate exposure to acute pain medicine
during their training (Macintyre 2014 NR).

KEY MESSAGES
1. There is no good evidence in favour of general education for acute neck pain having
significant effects on any relevant outcomes (U) (Level I [Cochrane Review]).
2. Short educational interventions in acute whiplash injury reduce pain and disability andenhance recovery and mobility (U) (Level I [PRISMA])
3. There is limited evidence that preoperative education may lead to small improvements
in postoperative outcomes such as pain, preoperative and postoperative anxiety, but
not in analgesic requirements (Q) (Level I [PRISMA]).
4. General “biomedical” education in patients with acute back pain does not reduce pain
or improve other outcomes (S) (Level I); however, education using a “biopsychosocial/
neuroscience” approach reduces a composite of anxiety, fear, worry, distress andhealthcare utilisation (N) (Level I [PRISMA]).
5th Edition | Acute Pain Management: Scientific Evidence875. Targeted reassurance in acute back pain by physicians in primary care can result in
improved changes in psychological factors such as fear, worry, anxiety,catastrophisation and healthcare utilisation (U) (Level I [PRISMA].
6. Preoperative education improves patient or carer knowledge of pain and encourages amore positive attitude towards pain relief (U) (Level II).
7. Specific pain neuroscience education in specific surgical settings may result in lesshealthcare utilisation (U) (Level II).
8. Written information given to patients is better than verbal information given at thetime of the interview (S) (Level II).
9. Educational interventions in cancer pain patients improve knowledge, attitudes andpain control (U) (Level III-1 SR).
10. While evidence for the benefit of patient education in terms of better pain relief isinconsistent, structured preoperative education may be better than routine
information (U) (Level III-2).
11. Staff education and the use of guidelines improve pain assessment, pain relief andprescribing practices (S) (Level III-3).
12. Pain psychoeducation undertaken before surgery (pre-emptive) or throughout theperioperative period (preventive) is an underutilised component of multimodal
analgesia which may reduce pain intensity, analgesic use, length of stay, return to theemergency department, patient anxiety and possibly chronic postsurgical pain (N)(Level IV SR).
13. Pain score documentation improves with various forms of nursing education, but the
impact of this behaviour change has not been adequately assessed (N) (Level IV SR).
14. Pain medicine education in medical school curricula is restricted in scope and content (N)(Level IV SR).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Successful management of acute pain requires close liaison between all personnel
involved in the care of the patient (U).
 More effective acute pain management will result from appropriate education andorganisational structures for the delivery of pain relief rather than the analgesic
techniques themselves (U).

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3.2 | Organisational requirements
It is recognised that patients should be able to access best-practice care, including appropriate
assessment of their pain and effective pain management strategies (ASA 2012 GL; ANZCA 2010
GL). However, effective acute pain management will, to a large extent, depend not only on the
medicines and techniques available, but also on the systems involved in their delivery(Macintyre 2015 NR). Even simple methods of pain relief can be more effective if proper
attention is given to education (see Section 3.1 before), prescribing, administration,
documentation, monitoring of patients and the provision of appropriate policies, protocols andguidelines (Gould 1992 Level III-3, n=2,035). The incorporation of pain measurement into clinicalassessment for all patients, not only those under the care of an Acute Pain Service (APS), willaid pain management for all the patients throughout an institution (Gordon 2008 NR).
Standardised clinical observation charts which include pain, sedation and function scores withother vital signs are an important step in ensuring safe provision of effective analgesia(Macintyre 2015 NR). In many institutions, an APS will assume responsibility for managing
complex patients and more advanced methods of pain relief such as PCA, epidural analgesia
and perineural infusions.

3.2.1 | General requirements
Guidelines to enhance patient outcomes and standardise analgesic techniques (eg selection of
medicines and their concentrations, dose and dose intervals), monitoring requirements, choiceof equipment, and responses to inadequate or excessive analgesic doses or othercomplications lead to consistency of practice. This can potentially improve patient safety andanalgesic efficacy, regardless of the technique used (Macintyre 2015 NR; Counsell 2008 NR). These
guidelines should be evidence-based wherever possible.
Marked improvements in conventional methods of pain relief have followed theintroduction of guidelines for parenteral opioid administration ( Humphries 1997 Level III-3, n=242;
Gould 1992 Level III-3, n=2,035). However, it is the implementation of guidelines, not theirdevelopment that remains the greatest obstacle to their use. Compliance with available
guidelines is highly variable and may be better in larger and university-affiliated hospitals (Nasir
2011 Level IV, n=301 [USA hospitals]; Carr 1998 Level IV, n=400 [USA hospitals]). Resource availability,
particularly staff with pain management expertise, and the existence of formal qualityassurance programs to monitor pain management are positive predictors of compliance withguidelines (Jiang 2001 Level IV, n=220 [USA hospitals]).
Different types of surgery require different types of analgesic regimens. Common andminor surgical procedures often result in high pain scores, which are frequently undertreated(eg laparoscopic appendicectomy, cholecystectomy, and haemorrhoidectomy) (Gerbershagen2013 Level IV, n=70,764). The adoption of procedure-specific methods and the use of analgesic
combinations may help to optimise analgesia and reduce adverse effects ( Joshi 2013 NR) (seeSection 8.1.3). A hospital-wide approach can be incorporated into postoperative enhancedrecovery programs (White 2010 NR) (see Section 3.2.3 below).
Professional bodies in a number of countries have issued guidelines for the management of
acute pain (RCoA 2020 GL; Agency for Clinical Innovation NSW 2016 GL; Faculty of Pain Medicine RCoA2015 GL; ANZCA 2013 GL; ASA 2012 GL).
While there is widespread agreement about the value of clinical guidelines, they do have
limitations. Some of these include reliance on the population-wide aggregation of patient
outcomes, which may not be optimal on an individual patient level. Individual patient
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89variability arises from complex interactions between genetic and environmental exposuresover the life of the patient (Fillingim 2017 NR). A method that can incorporate standardised care
but allow for individual patient variation is the SCAMP approach – Standardised Clinical
Assessment and Management Plans (Beverly 2017 NR). This process is a clinician-engaged
approach that promotes standardisation but accommodates patient preferences, includes
clinician experience and incorporates recent medical knowledge. Benefits include reduced
variability in medical care (Farias 2013 NR).
The success of an APS and patient treatment depends not only on good clinical care but also
on a positive organisational culture(Powell 2009 NR; Bate 2008 NR). This should follow the key
principles of effective change management. A series of semi-structured interviews ofhealthcare professionals identified key areas that need to be addressed for well-organisedcare. These include structural issues, political issues, cultural change, educational challenges,
leadership and motivation, and technological challenges.

3.2.2 | Acute pain services
There is a very wide diversity of APS structures, with no consensus as to the best model and noagreed definition of what might constitute such a service (Counsell 2008 NR). Some are “lowcost” nurse-based (Shapiro 2004 Level IV, n=4,617; Rawal 2005 NR), others are anaesthetist-led but
rely primarily on APS nurses as there may not be daily clinical participation by an anaesthetist(Nagi 2004 NR; Harmer 2001 NR). In contrast, others are comprehensive and multidisciplinary
services with APS nursing staff, sometimes pharmacists or other staff (eg clinical psychologists)(Katz 2015 NR) and daily clinical input from and 24 h cover by anaesthetists (Macintyre 1990
Level IV, n=1,053; Ready 1988 Level IV, n=820; Schug 1993a NR). The development of specificpaediatric pain services has also been described (Kost-Byerly 2012 NR) and is an emerging field(Finley 2014 NR).
Larger hospitals and those with university affiliations are more likely to have a formal APS
and use protocols (Nasir 2011 Level IV, n=301 [USA hospitals]). When advanced modalities such as
epidural analgesia and continuous peripheral nerve block (CPNB) are used, the APS is mostcommonly anaesthetist-led. An economic evaluation of a physician-led APS has shown it to becost-effective even for patients having IV PCA after intermediate grade surgical procedures (Lee2010 Level II, n=423, JS 2).
The degree of medical input varies enormously. A UK survey reported that while 90% of
hospitals reported having an APS, dedicated medical staff sessions did not exist in 37%, werelimited to one or two per wk in 40% and in only 4% were there five or more sessions ( Nagi
2004 NR). In training hospitals in Australia, 91% of hospitals accredited for anaesthetic training
had an APS run from the department of anaesthesia with daily input from medical staff.
Consultant anaesthetist sessions (one session is 0.5 d) varied from zero in 27%, just one or two
a wk in a further 22%, four to six per wk in 22% and ten per wk in 15% ( Roberts 2008 Level IV,
n=67 [AUS and NZ hospitals]). A UK survey of 141 acute pain services found variation in the
structure, function and staffing of the APSs between the responding hospitals ( Rockett 2017
Level IV, n=209 [UK hospitals]). The mean number of consultant hours per wk was only 5.5 h. 35%of the APSs also had other roles in addition to acute pain management. Only half of the teams(49%) had members that also worked in an integrated multidisciplinary pain service. A Dutch
survey showed again that 90% of hospitals have an APS of variable organisational structure;important tasks of the APS were regular patient rounds and checking complex pain techniques(100%), supporting quality improvement of pain management (87%), pain education (100%)and pain research (21%) (van Boekel 2015 Level IV, n=96 [Dutch hospitals]). However, a survey
repeated in Denmark from 2000–2009 showed a surprising decline of APSs in parallel to the90

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increased usage of enhanced-recovery programs (Nielsen 2012 Level IV). In the USA, APSs weremore common in university/academic hospitals (96%) than in Veterans’ Affairs hospitals (69%),
with the lowest rate in private hospitals (47%) (Nasir 2011 Level IV, n=301 [USA hospitals]). Formal
written postoperative pain protocols were more common in hospitals with an APS but overall
only 55% of hospitals had such protocols. In Germany, 81% of the hospitals surveyed statedthat they had an APS; however, only 45% met quality criteria defined by the authors ( Erlenwein
2014 Level IV, n=403 [German hospitals]). In contrast to the USA data above, 97% of the hospitals
had written acute pain protocols for surgical patients, but only 51% on nonsurgical wards.
Some APSs supervise primarily “high-tech” forms of pain relief and/or complex patients,
while others have input into all forms of acute pain management in an institution and will work
towards optimising traditional methods of pain relief so that all patients in that institution
benefit (Macintyre 2015 NR; Counsell 2008 NR; Breivik 2002 NR). Increasingly, APSs are also called
on to deal with much more complex pain management issues (eg acute-on-chronic pain, acutepain after SCI or other major trauma, and resulting from a multitude of medical illnesses) andmore complex patients (eg opioid-tolerant patients, older patients) (Counsell 2008 NR).
Individual publications assessing the benefits of an APS have reported that the presence ofan APS reduced pain scores (Stadler 2004 Level III-3, n=1,975; Bardiau 2003 Level III-3, n=2,283;
Salomaki 2000 Level III-3, n=400; Sartain 1999 Level III-3, n=605; Harmer 1998 Level III-3, n=2,783; Gould
1992 Level III-3, n=2,035; Miaskowski 1999 Level IV, n=5,837) and adverse effects (Sartain 1999
Level III-3, n=605; Stacey 1997 Level III-3, n=40; Miaskowski 1999 Level IV, n=5,837; Schug 1993aLevel IV, n=3,016). A review of publications (primarily audits) looking at the effectiveness of APSs

(77% were physician-based, 23% nurse-based) concluded that the implementation of an APS is
associated with a significant improvement in postoperative pain and a possible reduction in
postoperative neurological symptoms (PONS), but that it was not possible to determine whichmodel was superior (Werner 2002 Level IV SR, 48 studies, n=84,097). The authors comment,
however, that it is not possible to assess the contribution of factors such as an increased
awareness of the importance of postoperative analgesia, the use of more effective analgesic
regimens (eg epidural analgesia), the effects of APS visits and better strategies for antiemetic
therapy. The benefits of an APS can be enhanced when its role is expanded beyond its
traditional postoperative realm and into the entire patient journey – preoperative,
intraoperative, postoperative and posthospital discharge ( Zaccagnino 2017 NR).
Possible benefits of an APS are summarised in Table 3.1.
Given the heterogeneity of APS models and types of patients and pain treated, as well as
variation in the quality of published studies, it is difficult to meaningfully analyse the benefits
or otherwise of an APS. Although systematic reviews have been attempted ( McDonnell 2003
Level III-3 SR, 15 studies, n unspecified; NICS 2003 Level III-3 SR, 32 studies, n unspecified) (4 Studies
overlap), the poor quality of the studies looking at the effectiveness or otherwise of APSs andthe many different types of APSs, means that a meta-analysis cannot be performed.
In addition, the above studies looked at outcome in terms of immediate pain andadverse effects in postoperative patients only. It is possible that an APS may benefit patients inother ways.
Combination of an APS with a physician-based critical-care outreach team, which
systematically reviewed high-risk postoperative patients for 3 d after their return to a generalward, showed a significant improvement in postoperative outcome with a decrease in serious
adverse effects from 23 to 16 events per 100 patients and 30 d mortality from 9 to 3% (Story
2006 Level III-2, n=590). Finally, members of an APS may also be more likely to recognise theearly onset of neuropathic pain associated with surgery, trauma or medical disease andinstitute the appropriate treatment (Counsell 2008 NR).

5th Edition | Acute Pain Management: Scientific Evidence91Table 3.1 | Possible benefits of an acute pain service
Benefit

References

Better pain relief

Stadler 2004; Bardiau 2003; Werner 2002;
Salomaki 2000; Sartain 1999; Gear 1999;
Harmer 1998; Gould 1992

Lower incidence of adverse effects

Werner 2002; Sartain 1999; Miaskowski 1999;
Stacey 1997; Schug 1993b

Lower postoperative morbidity/mortality

Story 2006

Management of analgesic techniques that
may reduce the incidence of persistent pain
after surgery

Gehling 2003; Senturk 2002; Obata 1999

Cost-effective patient care

Lee 2010

Reduced persistent pain and discharge
opioid use after surgery

Tiippana 2016; Katz 2015

The role of an APS can be extended into the pre-admission (elective cases) and post-acutephase of recovery. This approach can bridge the gap between ward-based acute pain care andoutpatient chronic pain management. Descriptions of this type of extended and proactive caresuggests a reduction in the occurrence of persistent pain and excessive opioid use after
hospital discharge, which may also be cost-effective (Tiippana 2016 Level IV, n=200; Katz 2015 NR)(see also 3.3 Economic Considerations).
3.2.2.1 | Safety
Unidimensional management of acute pain can lead to adverse outcomes including opioid induced ventilatory impairment (OIVI) ( Vila 2005 Level III-3; Macintyre 2011 NR). Structuralchanges in an APS can minimise such effects ( Story 2006 Level III-2, n=590). Implementation ofroot-cause analysis for critical incidents improved the safety of patients looked after by an
APS; this approach reduced the overall event rate (1.47% vs 2.35) with specific effects on therate of respiratory depression (0.41% vs 0.71), severe hypotension (0.78% vs 1.34) and PCA
pump programming errors (0.0% vs 0.08) ( Paul 2014 Level III-3, n=35,384) (see also Sections 6.6
and 6.8).
Standardised written documentation of APS treatment can potentially improve the safety ofpatient care. An agreed and consistent format for prescribing, observation and documentationof care can reduce unnecessary clinical variation, which is beneficial ( Agency for ClinicalInnovation NSW 2016 GL). The use of an electronic medical record (EMR) can facilitate thefunction and safety of an institution’s APS. Specifically, these benefits can include clear
documentation, organisation of ward rounds, billing, analysis of patient safety and outcomes,
and integration with research (Goldstein 2014 NR). It is important that the design of an EMR has
features that facilitate usability, efficiency, safety and mobility ( Telenti 2018 NR; Mandl 2012 NR;
Grams 2009 NR). The integration of electronic smart-pumps directly into the EMR greatly
increased the accuracy and completeness of recording PCA episode of care vs paper-based
records (38% to 91) (Suess 2019 Level III-3, n=113).

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5th Edition | Acute Pain Management: Scientific Evidence3.0 | PROVISION OF SAFE AND EFFECTIVE ACUTE PAIN MANAGEMENTKEY MESSAGES
1. Implementation of an acute pain service may improve pain relief and reduce the incidenceof adverse effects (U) (Level III-3).
2. Even “simple” techniques of pain relief can be more effective if attention is given to
education, documentation, patient assessment and provision of appropriate guidelines
and policies (U) (Level III-3).
3. Implementation of root-cause analysis to follow up critical incidents improved the safetyof patients under care of an acute pain service (U) (Level III-3).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Successful management of acute pain requires close liaison between all personnel
involved in the care of the patient (U).
 More effective acute pain management will result from appropriate education andorganisational structures for the delivery of pain relief rather than the analgesic
techniques themselves (U).
 Appropriate institutional support and engagement is important for the effective
implementation of an acute pain service (U).
 Procedure-specific analgesic protocols can help optimise analgesia for the individual
patient while reducing adverse effects (U).
 The adoption of individualised care pathways (eg SCAMPS) can improve patient
outcomes and reduce clinical variation (N).
 The benefit of an acute pain service can be enhanced when acute pain management is
integrated into the pre, intra and postoperative periods (N).
 The recruitment of patients ‘at-risk’ for persistent pain and/or excessive opioid use into a
post-discharge treatment service for early review can improve outcomes (N).
 Appropriately designed, implemented and integrated Electronic Medical Records (EMR)
can improve the standards of clinical care (N).

5th Edition | Acute Pain Management: Scientific Evidence933.3 | Economic considerations in acute pain management
An economic evaluation of healthcare can be described as the “comparative analysis of alternative
courses of action in terms of their costs and consequences” (Drummond 2008 NR). Health economics
aims to maximise health benefits relative to the resources available. This approach is particularly
crucial in a growing and ageing population, with fewer people in the workforce paying taxes, and amore substantial proportion with chronic conditions and aged care, requiring health services. An
economic assessment of acute pain can be of the overall service provision (eg an APS), or a specifictechnique (eg PCA). Areas where acute pain management may affect the economics of healthcare
include: patients, hospitals, and payers/insurers. These impacts may be direct or indirect, where thecosts of delivering pain management may result in savings in other areas of patient treatment.
Limited data indicate potential areas of cost savings arising from improved acute pain care. These
include shorter ICU admissions, decreased cardiac and respiratory adverse events, decreased risk of
postoperative infections, and potentially reduced risk of the development of chronic pain (Gray 2017
NR; Schug 2017 NR).
While the costs of healthcare are relatively easy to measure, the value of healthcare isharder to quantify (Goldman 2014 NR). Often, the benefits of healthcare are limited to thoseoccurring within the healthcare system; however, there may be other significant benefits insociety that should also be included eg return to full employment, long-term disability due topain, or mental health related to ongoing pain (Drummond 2008 NR). The impact on a patients’family and carers in their workforce participation and their psychological well-being are further
considerations (Schofield 2019 Level IV).
There are several types of economic assessment that are commonly used in the literature.
These have important differences; there is a consensus agreement on their definitions(Husereau 2013 GL; Drummond 2005 NR) (see Table 3.2). The most commonly used is costeffectiveness analysis, which examines the cost in dollars per additional life-year gained.
In the literature, these terms may be used interchangeably, without correct adherence totheir definitions. No one assessment measure is superior to another, and health economists
debate the merits of each. In addition, issues of social equity, needs, and priorities should also
be part of the decision making process (Schlander 2009 NR; Phillips 2009 NR; McGregor 2003 NR).
In contrast to most commodities, healthcare is a “credence good” (Emons 1997 NR) ie
patients or consumers/stakeholders find it difficult or impossible to determine the utility of atreatment prior to its consumption. They have to rely on the knowledge of healthcare experts
when choosing a treatment. This situation is also referred to as “asymmetry of knowledge”.
Patients value pain relief highly; a survey of two million USA inpatients found that “howwell their pain was controlled” was the second most important factor in recommending ahospital (PressGaney 2009 Level IV). When healthcare funding occurs without regard to patient’s
values, then funding for formal acute pain services becomes limited (Sun 2010 NR).
A consistent risk factor for the development of chronic postsurgical pain (CPSP) is poorly
controlled postoperative pain (see Section 1.4). CPSP is an economic burden on society. An
economic report in 2019 found that the total cost of chronic pain in Australia was $73.2 billion,
and that much of chronic pain originates as acute pain (Deloitte Access Economics 2019 NR).
Chronic pain interferes with the return to employment, requires ongoing medical treatment
with its inherent costs, and may require carers at an additional cost, or require informal carefrom a family member or friend, influencing their workforce participation (Schofield 2019 IV) .

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Table 3.2 | Definitions of health economic assessment measures
Cost-effectiveness analysis

Consequences are measured in natural units, such as life
years gained, disability days avoided, or cases detected

Cost-utility analysis

Consequences are measured in terms of preference-based
measures of health, such as quality adjusted life years(QALY) or disability adjusted life years (DALY).

Cost-benefit analysis

Consequences are valued in monetary units

Cost-minimisation analysis

Consequences of compared interventions are equivalent(in terms of clinical efficacy and tolerability), and only
relative costs are comparedCost-outcome description

Costs measured in monetary value and health effects
measured in natural units (eg intensive care unit days
saved, patient satisfaction etc.)

Value of statistical life

A method to assign a monetary value to a person’s life (ora proportion if a disability) using a willingness to pay
approach. This is similar to a QALY.
(Office of Best Practice Regulation 2014 GL)

Economic assessment of pain relief requires direct and indirect evaluation of both the costs
and the benefits. Assessment of subjective experiences, such as a reduction in pain scores, canbe assigned a monetary value using techniques such as ‘willingness to pay’, and ‘human capital
approaches’ (Kumar 2006 NR). These monetary values can then be used in performing a costbenefit analysis. Economic analysis needs to include the assessment of a treatment incomparison with the alternatives eg IV PCA vs prn opioid analgesia. Direct costs can include thecost of equipment, drugs and staff. Indirect costs can include the duration of hospital stay, useof ICU, development of persistent pain and treatment of adverse effects. Potential benefits
include: reduction in pain intensity, minimisation of pain-related adverse effects, improved
fast-track recovery and compliance with rehabilitation, as well as earlier return to work of boththe patient and their informal carer (White 2007 NR).

3.3.1 | Economic evaluation of PCA
The direct and indirect costs of PCA for pain relief after three common types of surgery havebeen assessed (Palmer 2014 Level III-3, n=11,805,513). This evaluation used data from a large
administrative healthcare database (Premier 2015 Level IV). Further cost estimates of adverse
events were derived from the literature. The use of PCA after TKA, THA and open abdominal
surgery was evaluated. The costs included PCA pump usage, setup costs, and costs of IV
extension set, drug, fluid for IV co-infusion and the pump. The total of these costs(standardised to US$ in 2012) during the first 48 h after surgery, were US$204, US$196, andUS$243 respectively. Additionally, cost estimates for particular adverse events in the first 48 hof PCA use were calculated. These costs were: phlebitis (US$2.18), healthcare worker needle
stick injury (US$1.67), and IV PCA programming error (US$35.52). The assessment of costs for
PCA programming errors did not include newer pumps that have software for the mitigation ofprogramming errors (ie ‘smart pumps’). The cost of other adverse events, such as respiratory
depression or nausea and vomiting, were not included in this assessment.
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The costs and rates of harmful and non-harmful errors due to the use of IV PCA were
estimated from two large safety-reporting databases in the USA (Meissner 2009 Level IV): thedatasets included medication errors (MEDMARX) and device errors (MAUDE). A costaccounting methodology was used, which included direct, indirect and opportunity costs.
These were estimated from published literature, expert consensus, physician billing-charges
and staff labour-rates (standardised to US$ in 2006). The estimated average cost of a PCA
adverse event in the medication error dataset was US$733, whereas the cost related to a pumperror was US$552. If an error led to patient harm, then the cost was 120 to 250 times morecostly than a non-harmful error. For medication incidents, the most expensive harm-causing
error was due to poor communication (US$8,984 per incident). For pump-related errors, thetwo most expensive were operator error (US$5,756) and those of indeterminate cause(US$6,120). The estimated annual USA error rates per 10,000 patients treated with PCA were
407 for PCA medication errors, and 17 for PCA device errors (see also Section 6.6).

3.3.2 | Economic evaluation of Acute Pain Services
A narrative review (Gray 2017 NR) examined the economic aspects of an APS from within a USA
healthcare perspective. Assessment included the areas of the patient, the hospital and thepayer (insurer). Indirect benefits may include improved outcome over a range of postoperative
measures. This may be relevant for a hospital within an ‘activity-based funding’ agreement. The
use of continuous regional anaesthesia/analgesia techniques can be made more cost-effective
by instigating a single regional block service that covers multiple operating rooms. This service
model could reduce the cost of time delays associated with the initiation of regional
anaesthesia. The treatment options used by a specialised acute pain service could ensure there
is greater use of non-opioids, and mitigation of excess opioid prescribing with that resultant
long-term health cost.
A systematic review of the economic evaluations of APSs has been performed ( Lee 2007
Level IV SR, 9 studies, n=14,774). Five of the studies were of nurse-based, anaesthetist-supervised
services. Out-of-pocket expenses and loss of productivity due to absence from work were notincluded. No study went beyond five d. Monetary values were standardised to $US in 2005. The
cost of an anesthetist-led APS ranged from US$31.73 to US$100.37 per patient per d. The costof a nurse-based/anaesthetist supervised APS ranged from US$3.70 to US$50.77 per patient
per d. The cost-savings from a shorter ICU stay were US$9.90 per patient per d. The costsavings from a shorter duration of hospital stay were US$11.40 per patient per d. Savings fromreduced nursing time were also identified. Data were not available to compare the economics
of a nurse-based/anaesthetist supervised APS with an anaesthetist-led APS. No studies were ofhigh quality or included all costs and benefits associated with APS care.
An RCT for the cost-effectiveness of APS care (anaesthetist-led, nurse-based) compared APS
patient care (IV PCA plus adjuvants) with conventional ward analgesia for patients having major
surgery (Lee 2010 Level II, n=423, JS 2). Regional analgesic techniques were not included. Of
patients in the APS group, 86% had one or more d of highly effective pain relief vs 75% in theconventional care group. Costs were higher in the APS group when compared with theconventional group by US$46/d. Cost-effectiveness was determined using a ‘willingness-to-pay’
methodology which assigns a monetary value to pain relief. This analysis showed that to be
95% certain of obtaining one d of highly-effective pain relief per patient, the benefit was valued
at US$546.
The cost-utility analysis of a nurse-based APS has been performed (Stadler 2004 Level III-3,
n=1,975). The interventions used in this APS were: implementation of guidelines, use ofmultimodal analgesia, optimum use of systemic opioids as well as NSAIDs and paracetamol,96

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along with information pamphlets to patients. In 1.5% of patients, PCA was used; patients
receiving epidural analgesia were not included. The patient population was a large tertiary
hospital that included all surgical subspecialties. Cost-utility was assessed using a measure of‘Postoperative Pain Days Averted (PPDA)’, which is a health state scale conceptually similar toquality adjusted life years (QALY). The PPDA measure summarises treatment outcome in termsof time spent with lower pain scores. A value of “1” represents a state of “no pain”, whereas avalue of “0” represents “worst pain imaginable”. For POD 1 to 3, PPDA values were 0.075(1.8 h), 0.05 (1.2 h) and 0.0375 (0.9 h) respectively. The incremental cost of pain managementby the APS vs no APS, was 19 Euro per patient per d. The effectiveness of the APS may havebeen different if more advanced methods of pain relief had been used. Measuring PPDA
alone may have missed other benefits from improved pain relief (ie quality of life surveys
such as SF-12).

3.3.3 | Economic benefit related to improved patient outcome and reduced
chronic postsurgical pain.
While not intended as economic assessments, there are studies that have measured patient
outcomes, other than pain, which are related to an economic outcome. These are similar to a
cost-effectiveness analysis (see Table 3.2). For example, the mental health issues following
chronic pain, inability to return to the workforce for a patient or informal carers, and theresultant isolation and psychological distress are all non-monetary considerations. Monetaryconsiderations of pain outcomes can be considered either from the health system or patientperspective, depending on whether the issue in question is the impact of pain on the individualor the health systems. From an individual perspective, out-of-pocket costs, travel, parking andaccommodation for rural patients are considerations, particularly for those with chronic pain.
From the health system perspective, cost includes Medicare costs such as the Pharmaceutical
Benefits Scheme (PBS) or Medicare Benefits Scheme (MBS), outpatient visits, as well as otherhospital costs.
The pattern of opioid prescribing (dose, duration and type) while in hospital and after
discharge are significant instigators of opioid misuse and its resultant economic burden (Neuman2019 NR; Lowenstein 2018 NR; Shah 2017 Level IV). This important public health problem can be
mitigated by appropriate acute pain strategies in the hospital setting. These may include
analgesic techniques that minimise the dose and duration of opioid use; this includes using nonopioid analgesic strategies. At the time of patient discharge there needs to be appropriate
limitations on the dose and duration of the prescribed opioids (Lowenstein 2018 NR) (see Sections
8.13 and 10.4.5). The estimated financial cost of prescription opioid misuse in Australia comprises
the costs related to deaths, hospitalisation, and pharmacotherapy. The estimated annual (2018)
costs of these three areas are $4.7 billion, $13.4 million and $60.2 million respectively (Deloitte
Access Economics 2019). These costs may be further mitigated by a real-time prescription
monitoring program which can reduce deaths and the issue of multiple prescribers (“doctor
shopping”) (Finklea 2014 NR; Winters 2013 NR).
A systematic review of patient outcomes after epidural analgesia showed a reduction in theincidence of costly adverse events. These included a reduced risk of atrial fibrillation,
supraventricular tachycardia, deep vein thrombosis, respiratory depression, atelectasis,pneumonia, ileus, postoperative nausea and vomiting and improved recovery of bowel
function (Popping 2014 Level I [PRISMA], 125 RCTs, n=9,044) (see section 5.6). These must bebalanced against the increase in adverse events associated with epidural analgesia such as
hypotension, pruritus, urinary retention and motor block.

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97One study examined the effect on patient outcome when an APS provided additional advice
on patient care during their usual ward round (Story 2006 Level III-3, n=590). Examples of advice
include oxygen therapy, IV fluid management, physiotherapy, analgesia, or calling the medical
emergency team. This APS intervention resulted in a reduction of serious adverse events (from23 to 16 per 100 patients) and reduced 30 d mortality (9% to 3%).
Chronic postsurgical pain (CPSP) has a significant prevalence, which is typically 1 to 10%
at one year after surgery. This is dependent on the nature of surgery. A consistent predictor
for the development of CPSP is the severity and duration of postoperative pain. The
provision of effective acute pain management can reduce this costly public health problem.
Examples include limb amputation, thoracotomy, craniotomy, joint arthroplasty, breast
surgery and inguinal hernia repair. ( Glare 2019 NR). Once CPSP is established, it may bechallenging to treat, resulting in ongoing costs. Additionally, there are indirect costs ,including impairment of return to employment. The annual cost per patient (2018) withchronic pain was estimated at A$42,979 ( Deloitte Access Economics 2019 NR). A potential
strategy to reduce the transition from acute to chronic postsurgical pain, along with its
economic costs, is the use of a transitional pain clinic. Patients at this clinic are reviewed andmanaged in the early period after hospital discharge to prevent the progression from acuteto chronic pain and reduce opioid usage ( Huang 2016 Level IV; Katz 2015 NR) (see also Section
1.4).
Quantifying the health outcomes of patients immediately after surgery as well as over the
longer term will allow improved assessments of cost-effectiveness of new strategies.

KEY MESSAGES
1. Long term economic consequences from the progression of acute to chronic
postsurgical and post-traumatic pain can be significant (S) (Level IV).
2. Strategies to optimise acute and subacute pain management (including involvement oftransitional pain services) may reduce the economic burden of chronic pain andinappropriate prescription opioid use (N) (Level IV).
3. The early pattern of prescription opioid use after surgery may increase the risk ofchronic use with significant direct and indirect economic costs (N) (Level IV).
4. Patients’ willingness to pay for good pain relief is high (S) (Level IV).
5. Costs from PCA errors can be considerable; the most common high cost errors arise
from staff communication error and operator error (S) (Level IV).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: There are different measures of economic assessment and analysis used in healthcare;no one method is the most appropriate (U).
 Prescription drug monitoring may reduce the economic burden through its impact oninappropriate opioid prescribing (N).

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4Analgesic medicines
Section Editor:
Prof Stephan A Schug106

4.1 | Paracetamol
4.2.1 | Systemic nonselective
nonsteroidal anti-inflammatory drugs
4.2.2 | Systemic cyclooxygenase-2
selective inhibitors (Coxibs)

4.7 | Antidepressant medicines
4.8 | Anticonvulsant medicines
4.9 | Alpha-2 agonists
Contributor: Dr A. Reza Feizerfan

Contributor: Dr Jeffrey F Mott

4.10 | Salmon calcitonin andbisphosphonates

4.2.3 | Nonsystemic NSAIDs

Contributor: Dr Noam WinterContributor: Dr Daniel Lee

4.11 | Cannabis, cannabinoids
and cannabimimetics

4.3.1 | Systemic opioids
Contributor: Prof Stephan A Schug4.3.2 | Neuraxial opioids
Contributor: Dr Reginald Edward

4.3.3 | Peripheral opioids
Contributor: Dr Zoe Vella

4.4 | Local anaesthetics and othermembrane stabilisers
Contributor: Prof David A Scott

4.5 | Inhalational agents
4.6 | NMDA-receptor antagonists
Contributor: Prof Stephan A Schug

Contributor: Dr Paul Emery

4.12.1 | Systemic corticosteroids
Contributor: Prof Tomas Corcoran

4.12.2 | Regional corticosteroids
Contributor: Dr Irene Ng

4.13 | Other regional analgesic
medicines
Contributor: A/Prof Laurence
Weinberg

4.14 | Complementary andalternative medicine
Contributors: Dr Phoon Ping Chen,Dr Yin Ling Or, Dr Yee Chi Lee

1074.1 | Paracetamol
Paracetamol and its intravenous prodrug propacetamol are the only remaining aniline derived
drugs used in clinical practice; it is an effective analgesic (see below) and antipyretic. It isabsorbed rapidly and well from the small intestine after oral administration with a bioavailabilityof between 63 and 89% (Oscier 2009 NR). It can also be given rectally and IV (see below andChapter 5).

4.1.1 | Mechanism of action
Despite extensive use since its discovery in the 19th century the mechanism of action ofparacetamol is still not fully understood. In contrast to opioids, paracetamol has no known
endogenous binding sites and, unlike NSAIDs, causes only weak inhibition of peripheral
cyclooxygenase (COX) activity, with apparent selectivity for COX-2 (Graham 2013a NR). Given its
limited peripheral actions the most likely mechanism is a central effect and may involve multiple
pathways:• When paracetamol is de-acetylated to p-aminophenol it can undergo conjugation witharachidonic acid by fatty acid amide hydrolase to AM404 in the CNS ( Ghanem 2016 NR).
AM404 has multiple potential mechanisms of action in the CNS. Firstly, it is a weakcannabinoid receptor agonist as well as a reuptake inhibitor of the endocannabinoid
anandamide. Secondly, it is a potent TRPV1 receptor agonist and a TRPV1 mutation isassociated with paracetamol non-responsiveness in healthy humans volunteers(Pickering 2020 Level II EH, n=47, JS 4);• Paracetamol has been shown to prevent prostaglandin production at the cellulartranscriptional level predominantly in the CNS, independent of COX activity (Mancini
2003 BS). This may also be AM404 mediated as AM404 reduces PGE-2 release from
activated microglia (Saliba 2017 BS). This effect is independent of cannabinoid and TRPV1
receptor effects;• Indirect effects on the serotonergic system appear to be important. In volunteers,
coadministration of tropisetron or granisetron blocked the analgesic effects ofparacetamol (Pickering 2008 EH; Pickering 2006 EH). In children undergoing tonsillectomy
who all received paracetamol, a fixed dose of morphine and betamethasone,
administration of ondansetron was associated with significantly more morphine inrecovery vs droperidol, but no change in codeine over the first 24 h (Ramirez 2015 Level II,
n=69, JS 4).

4.1.2 | Efficacy
For paediatric specific information see 10.4.1.1
Perioperative use
Single doses of paracetamol are effective in the treatment of postoperative pain. The NNTs for avariety of doses, as well as combinations of paracetamol with other analgesic medicines such ascodeine, are discussed in Chapter 5 and listed in Table 5.1.
There is no good evidence for a dose-dependent analgesic effect of oral paracetamol; theeffects of 500 mg (NNT 3.5; 95%CI 2.7 to 4.8), 600/650 mg (NNT 4.6; 95%CI 3.9 to 5.5) and
1,000 mg (NNT 3.6; 95%CI 3.2 to 4.1) show no statistically significant difference (Moore 2015b
Level I [Cochrane], 53 RCTs, n=5,679). Although in clinical practice there is no clear evidence of adose-response relationship, experimental surgical models have shown that the maximal

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4.0 | ANALGESIC MEDICINES

effective dose is 1000 mg. Paracetamol by all routes of administration has an opioid-sparing
effect on PCA-morphine consumption (MD over 24 h -6.3 mg; 95%CI -9.0 to -3.7), although thiseffect is inferior to nsNSAIDs and coxibs (Maund 2011 Level I, 60 RCTs,
n unspecified).
Oral paracetamol given 1 h prior to surgery reduced the pain intensity of propofol injection:
by a median NRS of 2/10(IQR 0 to 3) for 500 mg and 4/10 (2 to 5) for 1,000 mg vs placebo 8/10
(7 to 10) (Nimmaanrat 2019 Level II, n=324, JS 5).
IV paracetamol is also an effective analgesic after surgery with an NNT of 4.0 (95%CI 3.5 to4.8) over 4 h and an NNT of 5.3 (95%CI 4.2 to 6.7) over 6 h (Tzortzopoulou 2011 Level I [Cochrane],
36 RCTs, n=3,896). When paracetamol is used as an adjuvant to opioid analgesia, opioid
requirements are reduced by 30% over 4 h after a single IV dose. For hip and knee arthroplasty,
there is a reduction in pain scores for each of the first 3 PODs (POD 1: WMD -0.95; 95%CI -1.2 to-0.7) and opioid consumption (POD 1: WMD -3.1; 95%CI -4.1 to -2.1) (Yang 2017a Level I [PRISMA],
4 RCTs, n=865).
IV paracetamol given perioperatively reduces PONV when administered before recovery
from anaesthesia (Apfel 2013 Level I [PRISMA], 30 RCTs, n=2,364). This effect is correlated to pain
relief achieved, but not to reduced opioid consumption. IV paracetamol given before incision ismore effective than post incision in reducing pain at 1 h (MD -0.50; 95%CI -0.98 to -0.02) and2 h (MD -0.34; 95%CI - 0.67 to -0.01), 24 h opioid consumption (SMD 0.52; 95%CI -0.98 to -0.06)
and PONV (RR 0.50; 95%CI 0.31 to 0.83) (Doleman 2015b Level I [PRISMA], 7 RCTs, n=544).
Other acute pain indications
Paracetamol is superior to placebo for migraine (NNT 12 for pain-free response at 2 h) andreaches the efficacy of sumatriptan when combined with 10 mg metoclopramide ( Derry 2013aLevel I [Cochrane], 11 RCTs, n=2,942). In episodic tension-type headache (TTH), paracetamol ismildly effective at 2 h (NNT for mild pain or pain free 10; 95%CI 7.9 to 14) (Stephens 2016 Level I[Cochrane], 23 RCTs, n=8,079). Paracetamol is also superior to placebo for postpartum perineal pain
(OR 2.14; 95%CI 1.59 to 2.89) (Chou 2013 Level I, 10 RCTs, n=1,377) but less effective than NSAIDs(Wuytack 2016 Level I [Cochrane], 3 RCTs, n=342). Paracetamol does not appear to be effective for
acute low back pain (Saragiotto 2016 Level I [Cochrane], 3 RCTs, n=1,825).
Paracetamol in combinations
The combination of paracetamol and NSAIDs is more effective than either paracetamol or NSAID
alone (Martinez 2017 Level I [NMA], 2 RCTs, n=85 [paracetamol/NSAID]; 60 RCTs, n=3,259 [NSAIDs]; 20
RCTs, n=699 [paracetamol]; Ong 2010 Level I, 21 RCTs, n=1,909). This in particular is shown for the
combination of paracetamol and ibuprofen in the setting of wisdom tooth removal ( Bailey 2013
Level I [Cochrane], 7 RCTs, n=2,241).
A combination of 1,000 mg paracetamol with 130 mg caffeine is more effective thanparacetamol alone (OR 1.12; 95%CI 1.05 to 1.19) in a range of painful conditions with no safetyconcerns (Palmer 2010 Level I [QUOROM], 8 RCTs, n=2,510).
Combinations of paracetamol with opioids such as codeine, tramadol or hydrocodone show
increased efficacy (see Section 5.1.3.1.).

4.1.3 | Adverse effects
For paediatric specific information see 10.4.1.3
Paracetamol has fewer adverse effects than NSAIDs and can be used when the latter arecontraindicated (eg patients with a history of renal impairment, asthma or peptic ulcers).

5th Edition | Acute Pain Management: Scientific Evidence 109

4.1.3.1 | Hepatic effects
The risk of hepatotoxicity from therapeutic doses (maximum 4 g/24 h) is not supported bycurrent data (Dart 2007 Level IV SR, 791 studies, n=40,202). The higher number of findings in the
retrospective vs the prospective studies suggests that some of these cases may be inadvertent
overdoses. Similar safety has also been shown in a paediatric population with no cases of liverdisease, need for antidote or transplantation, or death (95%CI 0.000 to 0.009) and only 0.031%
of cases (95%CI 0.015 to 0.057) with major or minor hepatic adverse effects ( Lavonas 2010
Level IV SR, 62 studies, n=32,414). In conclusion, hepatotoxicity from therapeutic doses ofparacetamol is extremely rare (Caparrotta 2018 NR; Graham 2013a NR).
Guidelines based on individual case reports only recommend that paracetamol should be
used with caution or in reduced doses in patients with low body weight (<50 kg), active liverdisease, history of heavy alcohol intake, older age, malnutrition, Gilbert’s syndrome and glucose6-phosphate dehydrogenase deficiency (NPS MedicineWise 2015 GL; Queensland Health 2014 GL;
NSW TAG 2008 GL); however, consistent evidence of increased risk in these settings is lacking(Caparrotta 2018 NR; Graham 2013a NR). Therapeutic doses of paracetamol are an unlikely cause ofhepatotoxicity in patients who ingest moderate to large amounts of alcohol. In subjects who
consume alcohol, no elevation of alanine aminotransferase levels was noted with up to 4 g/d ofparacetamol for at least 4 d (Rumack 2012 Level I [PRISMA], 5 RCTs, n=551); no cases of hepatic
failure or death were observed in any published prospective trial of moderate to heavy alcohol
drinkers. In patients newly abstinent after abusing alcohol, therapeutic doses of paracetamol
had no effect on parameters of liver function (Dart 2010 Level II, n=142, JS 5).
There is no evidence that patients who have depleted glutathione stores (eg patients who
are malnourished or who have cirrhosis, hepatitis C or HIV) are at increased risk of liver
dysfunction when exposed to therapeutic doses of paracetamol ( Caparrotta 2018 NR; Graham
2013a NR). However, there is a potential association between acute liver failure and therapeuticparacetamol doses in paediatric patients with myopathies (Ceelie 2011 Level IV, n=2).
Paracetamol overdose is a common cause of acute liver failure ( Caparrotta 2018 NR; Graham
2013a NR); in the USA 30,000 patients are hospitalised every year for paracetamol overdose, of
which >50% are unintentional and 17% result in hepatotoxicity (Blieden 2014 NR). In a multiethnic
Asian population, the hepatotoxicity rate was lower at 7.3% ( Marzilawati 2012 Level IV, n=1,024).
Treatment should be with acetylcysteine; there is no obvious advantage of IV over oral
administration (Green 2013 Level III-3 SR, 16 studies, n=5,164). Treatment delays increase theincidence of hepatotoxicity; a detailed systematic review on interventions for treatment ofparacetamol poisoning (Chiew 2018 Level I [Cochrane], 11 RCTs, n=700) and treatment guidelines
have been published (Chiew 2020 GL).
4.1.3.2 | Renal effects
Newly diagnosed chronic kidney disease patients had an increased risk of end-stage renal disease
with paracetamol use (OR 2.92; 95%CI 2.47 to 3.45) and higher risk with increasing dose exposure(Kuo 2010 Level III-2, n=19,163).
4.1.3.3 | Cardiovascular effects
There is a potential association between premature closure of ductus arteriosus and maternal
paracetamol use in pregnancy (Allegaert 2019 Level IV SR, 12 studies, n=25). Given paracetamol has beenshown to be as effective as ibuprofen for closure of a patent ductus arteriosus in preterm neonates(Ohlsson 2018 Level I [Cochrane], 8 RCTs, n=916), it seems reasonable to recommend that (as with all
medications) use should be limited to the minimum dose and duration that is clinically necessary.

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4.0 | ANALGESIC MEDICINESThe overall effect of oral paracetamol on long term blood pressure remains unclear;observational studies (4 studies, n=155,910) show a variable association between paracetamol use
and increased hypertension, but RCTs (6 RCTS, n=152) have inconsistent results (Turtle 2013
Level III-3 SR, 6 RCTs and 4 studies, n=156,062).
Paracetamol may interact with warfarin to increase the International Normalised Ratio (INR)(Hughes 2011 Level IV SR, 5 studies (& 5 case reports), n=345; Pinson 2013 Level IV SR, 6 studies (& 2 casereports); n=365) (5 studies and 2 case reports overlap).
For information on IV paracetamol and hypotension of see Section 5.2.1.
4.1.3.4 | Respiratory effects
In children, exposure to paracetamol was associated with an increased incidence of asthma(pooled OR 1.63; 95%CI 1.46 to 1.77) (Etminan 2009 Level III-3 SR, 19 studies, n=425,140). There arealso claimed associations between the use of paracetamol in pregnancy and subsequent asthma
in childhood (OR 1.19; 95%CI 1.12 to 1.27) (Fan 2017 Level III-3 SR, 13 studies, n=1,043,109). For
details see Section 10.4.1.3.
4.1.3.5 | Carcinogenic effects
A review of epidemiological studies of paracetamol and cancer found mixed studies with respect
to renal cell carcinoma and very limited positive studies with plasma cell disorders and leukaemia
and otherwise a null effect on other types of cancer (Weiss 2016 NR).
4.1.3.6 | Neurodevelopmental effects
Epidemiological studies show an association between attention deficit disorder and paracetamol
usage in pregnancy: for longer >29 d (HR 2.2; 95%CI 1.50 to 3.24), but not short duration use <8d (HR 0.90; 95%CI 0.81 to 1.00) (Ystrom 2017 Level III-3, n=112,973). For details see Section 9.1.1.1
and 10.4.1.3.
Caution should be used with interpretation of all these retrospective analyses because of thepossible effect of unknown or unmeasured confounding factors; the relevance to use limited toan acute situation is also unclear.

KEY MESSAGES
1. Paracetamol is an effective analgesic for acute pain; the incidence of adverse effects iscomparable to placebo (U) (Level I [Cochrane Review]).
2. Paracetamol given in addition to PCA opioids reduces opioid consumption but does not
result in a decrease in opioid-related adverse effects (U) (Level I).
3. Hepatotoxicity with therapeutic doses of paracetamol is extremely rare (U) (Level IV)
and not associated with alcohol consumption (U) (Level I [PRISMA]).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Emerging evidence suggests that maternal paracetamol use may influence premature
closure of the fetal ductus arteriosus (N).

5th Edition | Acute Pain Management: Scientific Evidence 111

4.2 | Nonselective NSAIDs and coxibs
4.2.1 | Systemic nonselective nonsteroidal anti-inflammatory drugs
The term NSAIDs refers to both nonselective NSAIDs (nsNSAIDs) and coxibs (COX-2 selective
inhibitors). NSAIDs have a spectrum of analgesic, anti-inflammatory and antipyretic effects andare effective analgesics in a variety of acute pain states. Many effects of NSAIDs can be
explained by inhibition of prostaglandin synthesis in peripheral tissues, nerves and the CNS(Botting 2006 NR). However, NSAIDs and aspirin may have other mechanisms of action
independent of any effect on prostaglandins, including effects on basic cellular and neuronalprocesses. Prostaglandins are produced by the enzyme prostaglandin endoperoxide synthase,
which has both COX and hydroperoxidase sites. Subtypes of the COX enzyme have been
identified; the “constitutive” COX-1 and the “inducible” COX-2; COX-3 does not appear to playa significant role in fever or inflammation in humans (Kam 2009 NR; Botting 2006 NR; Gajraj 2005
NR; Simmons 2004 NR).
Prostaglandins regulate many physiological functions including gastric mucosal
protection, bronchodilation, renal tubular function and intrarenal vasodilation. Productionof endothelial prostacyclin leads to vasodilation and prevents platelet adhesion, w hereas
thromboxane, produced from platelets by COX, results in platelet aggregation andvasoconstriction. With the exception of prostacyclin synthesis (mediated largely throughCOX-2), such physiological roles are mainly regulated by COX-1 and this is the basis for manyof the adverse effects associated with nsNSAID use. Tissue damage induces COX -2
production leading to synthesis of prostaglandins that result in inflammation, peripheral
sensitisation of nociceptors and consequently increased pain perception . COX-2 induction
within the spinal cord plays a role in central sensitisation. COX-2 may also be “constitutive”
in some tissues, including the kidney, cardiovascular system and brain and is overexpressedin some cancers ( Kam 2009 NR).
NSAIDs are reversible COX inhibitors with the exception of aspirin, which binds covalently
and acetylates the enzyme irreversibly. In platelets, the enzyme cannot be replenished leading
to prolonged inhibition of platelet function with minimal inhibition of endothelial prostacyclin;
this confers cardiovascular protection at low dosages of aspirin. NsNSAIDs are “nonselective”
COX inhibitors that inhibit both COX-1 and COX-2. The coxibs have been developed to inhibit
selectively, but not specifically, COX-2 (Botting 2006 NR; Gajraj 2005 NR; Simmons 2004 NR).
4.2.1.1 | Efficacy
Single doses of oral nsNSAIDs are effective in the treatment of pain after surgery (Moore 2015b
Level I [Cochrane], RCTs ≈460, n≈50,000). For a list of NNTs for each medicine see
Table 5.1. However, while useful analgesic adjuvants, they are often inadequate as the soleanalgesic agent in the treatment of severe postoperative pain ( Cepeda 2005 Level II, n=1,003,
JS 5).
They are also effective analgesics in chronic low-back pain (Enthoven 2016 Level I [Cochrane],
13 RCTs, n= 4,807), renal colic (Afshar 2015 Level I [Cochrane], 50 RCTs, n=5,734), primarydysmenorrhoea (Marjoribanks 2015 Level I [Cochrane], 80 RCTs, n=5,820), migraine (Rabbie 2013
Level I [Cochrane], 9 RCTs, n=4,473); Derry 2013b Level I [Cochrane], 5 RCTs, n=1,356), acute ankle
sprains (van den Bekerom 2015 Level I, 28 RCTs, n unspecified), biliary colic (Colli 2012 Level I, 11 RCTs,
n=1,076) and acute muscle injury (Morelli 2018 Level I [PRISMA], 41 RCTs, n= 5,343).
For more information on use in migraine see Section 8.6.5.2 and in paediatrics Section 10.9.3.

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Nonselective NSAIDs are integral components of multimodal analgesia ( Young 2012 NR;
Buvanendran 2009 NR; Kehlet 1997 NR). When given in combination with IV PCA morphine after
surgery, nsNSAIDs result in better analgesia, reduced opioid consumption (MD over 24 h -10.2
mg; 95%CI -11.7 to -8.7) and a lower incidence of PONV (OR 0.70; 95%CI 0.53 to 0.88) ( Maund2011 Level I, 60 RCTs, n unspecified). Similar findings were made in the paediatric setting ( Michelet
2012 Level I, 27 RCTs, n=985).
The combination of paracetamol and NSAIDs is more effective than paracetamol or NSAID
alone (Martinez 2017 Level I [NMA], 2 RCTs, n=85 [Paracetamol/NSAID]; 60 RCTs, n=3,259 [NSAIDs]; 20
RCTs, n=699 [paracetamol]; Ong 2010 Level I, 21 RCTs, n=1,909). This is particularly well documented
for the combination of paracetamol and ibuprofen in the setting of wisdom tooth removal ( Bailey
2013 Level I [Cochrane], 7 RCTs, n=2,241).
Administration of ketorolac to patients with rib fractures reduced the incidence ofpneumonia (OR 0.14; 95%CI 0.04 to 0.46) and reduced requirements for ICU admission andventilation (Yang 2014 Level III-2, n=619). The perioperative use of nsNSAIDs, predominantly rectal
diclofenac and indomethacin, for endoscopic retrograde cholangiopancreatography (ERCP)
reduces the risk of post-ERCP pancreatitis vs placebo (RR 0.54; 95%CI 0.45 to 0.64) (Liu 2019 Level I[PRISMA], 19 RCTs, n=5,031).
In cancer surgery, initial data suggested benefits of intraoperative use of nsNSAIDs in
breast cancer patients (reduced recurrence rate and lower mortality) and in lung cancer
patients (lower metastases risk and longer survival) ( Forget 2013 Level III-2, n=720). In breast
cancer surgery, intraoperative administration of nsNSAIDs (ketorolac or diclofenac) was
associated with an improved disease-free survival (HR 0.57; 95%CI 0.37 to 0.89) and betteroverall survival (HR 0.35; 95%CI 0.17 to 0.70) ( Forget 2014 Level III-2, n=720). However, a more
recent case control study found a reduction of distant recurrences with ketorolac, but notdiclofenac (Desmedt 2018 Level III-2, n=1,834). Despite epidemiological associations with NSAIDs
reducing prostate cancer risk, pre-operative courses of celecoxib 400mg BD did not appear toincrease tumor cell apoptosis in surgical specimens (Flamiatos 2017 Level II, n=28, JS 5). NSAID
administration (primarily ibuprofen) after colorectal surgery was associated with reduced
recurrence in a historical case series (aHR 0.84; 95%CI 0.72 to 0.99) (Schack 2019 Level III-3,
n=2,308).
4.2.1.2 | Adverse effects
Adverse effects of nsNSAID are more common with long-term use; the major concerns relate to
the gastrointestinal, renal and cardiovascular systems. In the perioperative and acute period, themain concerns are renal impairment, interference with platelet function, wound and bonehealing and peptic ulceration or bronchospasm in individuals at risk. Certain risks areaccentuated in the perioperative period because of pre-existing comorbidities, concurrent
medications, haemodynamic disturbances, fluid shifts, activation of the neurohumoral stressresponse and deficient enteral feeding.
In general, the risk and severity of nsNSAID-associated adverse effects is increased in elderly
people (Juhlin 2005 Level II, n=14, JS 4; Pilotto 2003 Level III-2, n=2,251). For this reason, opioids are
sometimes used in preference to NSAIDs. A cohort study of elderly patients with arthritis (meanage 80 y) started on nsNSAIDs, coxibs or opioids challenges the assumption that opioids are safer
in that population, showing increased rates of fracture, hospital admission and all-cause
mortality in the opioid cohort and similar or higher rates of cardiovascular, renal andgastrointestinal adverse effects (Solomon 2010 Level III-2; n=12,840). Overall the nsNSAID cohort
appeared to have the lowest risk for adverse effects.

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Gastrointestinal effects
Chronic nsNSAID use is associated with peptic ulceration and bleeding and the latter may be
exacerbated by the antiplatelet effect (Bhala 2013 Level I, 754 RCTs, n=353,809). All long-term
nsNSAID regimens increase the risk of upper gastrointestinal complications (diclofenac RR 1.89;
95%CI 1.16 to 3.09; ibuprofen RR 3.97; 95%CI 2.22 to 7.10; naproxen RR 4.22; 95%CI 2.71 to6.56). The combination of an nsNSAID with an SSRI further increases the risk of uppergastrointestinal bleeding (Anglin 2014 Level III-2 SR, 19 studies, n>393,268). In patients withrheumatoid arthritis, steroids and NSAIDs appear to be additive in increasing gastric ulceration(Tsujimoto 2018 Level III-2, n=1,704).
Acute gastroduodenal damage and bleeding can also occur with short-term nsNSAID use; therisk is increased with higher doses, a history of peptic ulceration, use for >5 d and in patients >75
years of age (Strom 1996 Level III-3, n=10,272 [uses of parenteral ketorolac]). After 6.5 d of naproxen
and 5 d of ketorolac use in healthy elderly subjects (65 to 75 y of age), ulcers were found on
gastroscopy in 18 and 23% of cases respectively (Goldstein 2003 Level II, n=168, JS 4; Stoltz 2002 Level
II, n=94, JS 4; Harris 2001 Level II, n=17 [terminated due to high incidence of gastrointestinal ulcers in bothnsNSAID groups], JS 4). Importantly, such endoscopic findings do not correlate with dyspeptic
symptoms; these consequently cannot be relied upon as an indicator of potential harm ( Dib 2014
Level III-2, n=1,231).
The relative risk of hospital admission for perforations, ulcers and bleeds associated with
nsNSAIDs is estimated as 5.3 vs people not consuming nsNSAIDs ( Lanas 2003 Level III-2, n=3,532).
Use of ketorolac and piroxicam carried the highest risk. Concurrent use of a proton-pumpinhibitor (PPI) significantly reduced the incidence of nsNSAID-related peptic ulcer disease(Targownik 2008 Level III-2, n=35,339). However, concurrent use of a PPI and nsNSAID (diclofenac)
was still associated with an increased risk of clinically significant upper or lower gastrointestinal
adverse effects vs coxib alone (RR 4.3; 95%CI 2.6 to 7.0) (Chan 2010b Level II, n=4,484, JS 5).
Suppression of gastric acid by PPI to reduce nsNSAID-induced gastropathy may increase the riskof enteropathy lower in the gastrointestinal tract (Blackler 2014 NR), possibly from changes in gut
flora (Minalyan 2017 NR).
Colonic diverticular bleeding is also increased by aspirin (RR 1.73; 95%CI 1.31 to 2.30) andother nsNSAIDs (RR 2.24; 95%CI 1.63 to 3.09) (Yuhara 2014 Level III-2 SR, 6 studies, n52,000).
Renal effects
Renal prostaglandins regulate tubular electrolyte handling, modulate the actions of renal
hormones and maintain renal blood flow and glomerular filtration rate in the presence of
circulating vasoconstrictors. The adverse renal effects of chronic nsNSAID use are common andwell recognised. In some clinical conditions, including hypovolaemia, dehydration and major
surgery, high circulating concentrations of the vasoconstrictors angiotensin II, noradrenaline andvasopressin increase production of intrarenal vasodilators including prostacyclin; maintenanceof renal function may then depend on prostaglandin synthesis and thus can be sensitive even tobrief nsNSAID administration (McDowell 2014 NR).
In patients with normal preoperative renal function, NSAIDs vs placebo may slightly increase
serum creatinine (MD 3.23 micmol/L; 95%CI -0.80 to 7.26), however effects on acute kidney
injury and need for renal replacement therapy are uncertain (Bell 2018 Level I [Cochrane], 26 RCTs,
n=8,943). The risk of adverse renal effects of nsNSAIDs and coxibs is increased in the presence offactors such as pre-existing renal impairment, hypovolaemia, hypotension, use of othernephrotoxic agents including angiotensin-converting enzyme (ACE) inhibitors (Juhlin 2005 Level II,
n=14, JS 4), IV contrast media and aminoglycosides (RCA 1998 Level IV). Of note, a trial of naproxen
following cardiac surgery was stopped because of an increased rate of renal failure (7.3 vs 1.3%)(Horbach 2011 Level II, n=161, JS 5). This is confirmed by an analysis of a French pharmacovigilance
database, which showed that acute renal failure caused by drug interactions between NSAIDs

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and ACE inhibitors, angiotensin-receptor blockers or diuretics was a common issue ( Fournier 2014
Level IV, n=11,442 [notifications of adverse drug reactions]).
After nephrectomies, evidence is limited and contradictory with a continuous infusion of
ketorolac for 24 h after laparoscopic donor nephrectomy having no significant effect on renal
function for up to 18 mth postoperatively (Grimsby 2014 Level II, n=111, JS 3), but a retrospective
case series of donor nephrectomies found a reduction in renal function at 12 mth despite lesspain and a shorter LOS (Takahashi 2017 Level III-2, n=251). Another retrospective case series foundno associations at 1 wk, 1 y or 5 y (Tabrizian 2019 Level III-2, n=862).
In the PRECISION trial, long-term use of ibuprofen for treatment of arthritis was associatedwith significantly more serious renal events than celecoxib (HR 0.61; 95%CI 0.44 to 0.85), but notnaproxen (HR 0.79; 95% CI, 0.56 to 1.12) (Nissen 2016 Level II, n=24,081, JS 5).
Overall in the general population, NSAID (including coxib) usage is associated with anincreased risk of AKI (OR 1.73; 95%CI 1.44 to 2.07) as well as exacerbation in patients with CKD(OR 1.63; 95%CI 1.22 to 2.19) (Zhang 2017a Level III-3 SR, 10 studies, n=1,609,163).
For more information on paediatric effects see Section 10.4.2.3.
Cardiovascular effects
Most publications looking at the risk of cardiovascular adverse effects associated with nsNSAID
use also include information relating to risks with coxibs (see the more detailed discussion under
Section 4.3.2 below).
For some years it has been known that ibuprofen may impede access of aspirin to platelet
COX-1 and may abrogate the protective effect of aspirin (Hudson 2005 Level III-2, n=18,503;
MacDonald 2003 Level III-2, n=7,107). Subsequent research indicates that a degree of inhibition may
occur with most nsNSAIDs and even some coxibs; while not blocking COX-1, they may block
aspirin from reaching it (Nalamachu 2014 NR). This is backed up by an ad hoc analysis of PRECISION
trial data which showed worse cardiovascular outcomes of aspirin/ibuprofen vs aspirin/celecoxib(HR 1.27; 95%CI 1.06 to 1.51) (Reed 2018 Level III-2, n=23,953). Impaired aspirin inhibition ofplatelet function is described in multiple studies for ibuprofen, flufenamic acid, mefenamic acid,piroxicam, nimesulide and dipyrone, while there is conflicting evidence with respect to naproxen,celecoxib, rofecoxib and sulindac, and no inhibition was seen with diclofenac, etoricoxib,
ketorolac, ketoprofen, meloxicam or paracetamol (Polzin 2013 Level III-2; Meek 2013 EH; Saxena
2013 EH). The FDA issued a caution specifically about the concomitant use of aspirin andibuprofen, which states that ibuprofen should be “given at least 8 hours before or at least 30
minutes after immediate release aspirin” (FDA 2006 GL).
Platelet effects and bleeding
Nonselective NSAIDs inhibit platelet function on aggregometry with naproxen and ibuprofen
showing a mild antiplatelet effect for up to 72 and 48 h respectively where meloxicam andcelecoxib show essentially no antiplatelet activity (Scott 2014 BS).
More recent studies and meta-analyses seem to show less impact of perioperative nsNSAIDs
on bleeding compared to older ones, perhaps reflecting improvements in surgical technique andreduced total blood loss. A recent meta-analysis found no increased haematoma risk in plastic
surgery (OR 1.39; 95%CI 0.82 to 2.37) (Walker 2019 Level I [PRISMA] 15 studies, n=3,064) and inanother meta-analysis ketorolac did not increase the rate of postoperative bleeding (OR 1.1;
95%CI 0.61 to 2.06) (Gobble 2014 Level I, 27 RCTs, n=2,314). In a cohort study in paediatricneurosurgery, ketorolac was not associated with an increase in clinically significant bleeding
events (OR 0.69; 95%CI 0.15 to 3.1) or radiographic haemorrhage (OR 0.81; 95%CI 0.43 to 1.51)(Richardson 2016 Level III-2, n=1,451). In contrast, in a previous meta-analysis the rate of surgeryrelated bleeding was 2.4% after nsNSAIDs vs 0.4% with placebo (Maund 2011 Level I, 6 RCTs
[bleeding], n=695). In another meta-analysis the use of nsNSAIDs showed a significant increase in
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risk of severe bleeding from 0 to 1.7% vs placebo (NNH 59) ( Elia 2005 Level I, 52 RCTs, n=4,893). A
retrospective analysis using data from 2003 to 2016 looking at transfusion risk for hip fractures
found a small increase in risk of transfusion with preoperative nsNSAID use within 90 d of surgery(RR 1.07; 95%CI 1.04 to 1.10) (Glassou 2019 Level III-2, n=74,791). Other older evidence showing an
increased risk of bleeding includes ibuprofen in total hip arthroplasty (THA) ( Fransen 2006 Level II,
n=902, JS 5), tenoxicam in otorhinolaryngological surgery (Merry 2004 Level II, n=1,001, JS 5) anddiclofenac vs rofecoxib in gynaecological and breast surgery (Hegi 2004 Level II, n=50, JS 5).
Bleeding after tonsillectomy is of clinical significance but occurs infrequently; nsNSAID use
and post tonsillectomy bleeding remains controversial with conflicting evidence. The mostrecent meta-analysis found no statistically significant increase of any outcome related tobleeding with the perioperative use of nsNSAIDs in tonsillectomy ( Riggin 2013 Level I, 36 RCTs,
n=3,193). This was found for most severe bleeding outcome (OR 1.30; 95%CI 0.90 to 1.88),
bleeding requiring reoperation (OR 1.32; 95%CI 0.59 to 2.95), bleeding requiring readmission (OR1.08; 95%CI 0.54 to 2.15), bleeding managed conservatively (OR 1.56; 95%CI 0.91 to 2.66) andsecondary haemorrhage (OR 0.90; 95%CI 0.40 to 2.01). There is also no increased bleeding
outcome in the paediatric subgroup of this meta-analysis (19 RCTs, n=1,747), which is in line withanother meta-analysis in children only (OR 1.69; 95%CI 0.71 to 4.01) (Lewis 2013 Level I [Cochrane],
15 RCTs, n=1,101) (see also Section 10.4.2.3 for details). However, neither of these meta-analyses
include a subsequent multicentre RCT which was unable to show non-inferiority of ibuprofen toparacetamol with respect to bleeding requiring surgery in paediatric patients (1.2% vs 2.9%;
p=0.12 for noninferiority) (Diercks 2019 Level II, n=741, JS 5). The above meta-analysis (Riggin 2013
Level I, 46 RCTs, n=4,878) could not identify a specific risk for any nsNSAID including aspirin (OR4.23; 95%CI 0.64 to 27.66) (3 RCTs, n=1,610) and ketorolac (OR 2.01; 95%CI 0.62 to 6.54) ( 8 RCTs;
n=579). These findings are contradicted by a previous larger meta-analysis on aspirin (OR 1.94;
95%CI 1.09 to 3.42) (Krishna 2003 Level I, 7 RCTs, n=1,368) and a systematic review on ketorolac(Chan 2014 Level III-2 SR [PRISMA], 10 studies, n=1,357). The latter found an overall increased risk of
bleeding post tonsillectomy with ketorolac (RR 2.04; 95%CI 1.32 to 3.15), which was also foundin adults (RR 5.64; 95%CI 2.08 to 15.27) (3 studies, n=246) but not in children (RR 1.39; 95%CI 0.84
to 2.30) (7 studies, n=1,111).
For more information on paediatric effects see Section 10.4.2.3 and on post-tonsillectomy
pain see Sectioin 8.6.7.3.
Hypersensitivity and NSAID-exacerbated respiratory disease (NSAID-ERD)
NSAIDs, especially nsNSAIDs, are one of the most common causes of drug-induced
hypersensitivity reactions. Acute reactions include rhinitis, asthma, urticaria, angioedema andanaphylaxis, while delayed reactions include fixed drug eruptions, Stevens-Johnson syndrome,
toxic epidermal necrolysis, maculopapular reactions, pneumonitis, nephritis or aseptic
meningitis (Kowalski 2019 GL). This guideline advises on classification, diagnosis and management.
NSAID-ERD has a community prevalence of 1.8% and affects 10-20% of adults with asthma
and 5% of children with asthma (Kowalski 2019 GL). Bronchospasm usually occurs within 1 to 2 hof exposure and precipitation is related to COX-1 activity, while both COX-2 selective NSAIDs(eg celecoxib and etoricoxib) and COX-2 preferential inhibitors (eg nimesulide and meloxicam)
being usually well tolerated. See also Section 4.2.2.2 below.
Bone and ligament healing
Ever since the first study in 1976 showed impaired osteoblastic activity with indomethacin inrodent bone models of fracture there has been concern about the effect of NSAIDs on bonehealing. The most recent meta-analysis of cohort studies shows an association between longterm NSAID usage and delayed union or disunion (OR 2.07; 95%CI 1.19 to 3.61), but not with lowdose or short duration (<2 wk) (OR 1.68; 95%CI 0.63 to 4.46) or in paediatric populations (OR116

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0.58; 95%CI 0.27 to 1.21) (Wheatley 2019 Level III-2 SR, 19 studies, n=15,242 bones). Given the nonrandomised cohort nature of this evidence, it may be that patients are taking NSAIDs for longer
for a painful non-healing fracture rather than NSAIDs being a causative agent and a firm
conclusion is unlikely without a large and well-designed randomised control trial.
In a meta-analysis which included primarily anterior cruciate ligament (ACL) reconstructions(93%) no difference in surgical failure was seen (3.6 vs 3.7%) ( Constantinescu 2019 Level III-2 SR,
4 studies, n=4,451)
Anastomotic leakage and colorectal surgery
Rodent models of anastomotic leakage have for some time shown reduced collagen formationin rodents given diclofenac leading to concerns about the effect of NSAIDs on anastomotic leakrate in humans (Klein 2012 BS). The two most recent meta-analyses of primarily cohort studies
show an increased anastomotic leak rate with nsNSAIDs (OR 2.02; 95%CI 1.62 to 2.50 and OR
1.79; 95%CI 1.47 to 2.18 respectively) (Modasi 2019 Level III-2 SR [PRISMA], 8 studies, n=9,835; Huang
2018 Level III-2 SR, 17 studies, n=26,098) (4 studies overlap). Subgroup analysis was unable to show
any increase with either selective COX-2 inhibitors (OR 1.17; 95%CI 0.50 to 2.74) or ketorolac (OR1.36; 95%CI 0.89 to 2.06)). A high risk of publication bias was detected.
NSAIDs do, however, improve recovery of gastrointestinal function with evidence for faster
return of flatus (MD -17.73 h; 95%CI -21.26 to -14.19), stool passage (MD -9.52 h; 95%CI -14.74
to -4.79), and oral feeding tolerance (MD -12.00 h; 95%CI -18.01 to -5.99 h) (Chapman 2019 Level
I [PRISMA], 6 RCTs, n=563). NSAIDs also reduce the recurrence rate of colorectal adenomas afterendoscopic resection (RR 0.68; 95%CI 0.63 to 0.73) (Wang 2015a Level I, 9 RCTs, n=8,521).
Central nervous system effects
CNS effects of NSAIDs are poorly defined, but range from symptomatic adverse effects such as
headache or dizziness through to possible disease modification in conditions such as Parkinson’s
disease and dementia (Auriel 2014 NR). Evidence on effects on cognitive decline is conflicting withlong-term NSAID use showing a small protective effect in one metanalysis of cohort studies (RR
0.87; 95 %CI 0.81 to 0.94) (Wang 2016b Level III-2 SR [PRISMA], 11 studies, n=36,165), but noprotective effect in another looking at low dose aspirin (Veronese 2017 Level III-2 SR [PRISMA],
3 RCTs & 5 studies, n=36,196).

4.2.2 | Systemic cyclooxygenase-2 selective inhibitors (Coxibs)
Coxibs selectively inhibit the inducible COX enzyme, COX-2, and relatively spare constitutive
COX-1 (see above). The coxibs available at present are celecoxib, etoricoxib, polmacoxib andparecoxib (the injectable prodrug of valdecoxib). By sparing physiological tissue prostaglandin
production while inhibiting inflammatory prostaglandin release, coxibs offer the potential for
effective analgesia with fewer adverse effects than nsNSAIDs. However, as noted above, someconstitutive physiological synthesis of prostaglandins is also mediated through COX-2, andcoxibs may still inhibit COX-1 to some extent.
4.2.2.1 | Efficacy
Coxibs are as effective as nsNSAIDs for postoperative pain (Moore 2015b Level I [Cochrane], ≈460
RCTs, n≈50,000), osteoarthritis of the knee (Smith 2016 Level I [PRISMA], 9 RCTs, n= 2,937) and chronic
low-back pain (Chung 2013 Level I [PRISMA], 25 RCTs, n=5,935). NNTs are comparable to those for
nsNSAIDs for the treatment of moderate to severe acute pain. For a list of NNTs for each
mediciation see Table 5.1.

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When given in combination with opioids after surgery, coxibs show reduced opioid
consumption similar to nsNSAIDs (MD over 24 h -10.9 mg; 95%CI -12.8 to -9.1) but no significant
reductions in pain scores or opioid-related adverse effects (Maund 2011 Level I, 60 RCTs,
n unspecified). When given as a single dose preoperatively, coxibs provide a reduction in mean
postoperative analgesic requirements at 24 h (MD -0.68; 95%CI -0.95 to -0.33) (Nir 2016 Level I[PRISMA], 13 RCTs, n=1,079).
After total knee arthroplasty (TKA), use of coxibs in the perioperative period reduces painscores, opioid consumption, PONV and pruritus and improves range of motion without increased
blood loss (Lin 2013 Level I, 8 RCTs, n=571). Continuation of coxibs for 6 wk postoperatively resulted
in ongoing improved analgesia and reduced opioid consumption with improved rehabilitation
conveying benefits on knee flexion for up to 1 y (Schroer 2011 Level II, n=107, JS 5). The risk-benefit
ratio for coxibs as a discharge medication after orthopaedic surgery is superior to that for
nsNSAIDs (Roberts 2012 Level I [PRISMA], 23 RCTs, n unspecified).
Pain relief at rest and on movement and satisfaction were improved when oral celecoxib
was added to thoracic PCEA using local anaesthetic and opioid ( Senard 2010 Level II, n=40, JS 5).
Celecoxib given pre-operatively is effective at reducing 24 h parenteral MED consumption(MD 4.13 mg; 95%Cl 5.58 to 2.67), pain scores at 24 h (MD -1.02/10; 95%CI -1.54 to -0.50) andreducing postoperative nausea and vomiting by 44% and 38% respectively (Khan 2016 Level I,
14 RCTs, n=994).
A meta-analysis of parecoxib in orthopaedic surgery in elderly patients shows a reduction inperioperative cognitive dysfunction up to 7 d (RR 0.32; 95%CI 0.16 to 0.63), but not at 3 mth (RR
0.40; 95%CI 0.16 to 1.02) (Huang 2019 Level I [PRISMA], 2 RCTs, n=200); these results should beviewed with caution as outcome measures were not robust. A similar effect was shown withcelecoxib after arthroplasty (Zhu 2018b Level II, n=178, J 5).
4.2.2.2 | Adverse effects
Gastrointestinal effects
In the PRECISION trial, celecoxib/esomeprazole was associated with significantly lessgastrointestinal events than ibuprofen/esomeprazole (HR 0.43; 95%CI 0.27 to 0.68) andnaproxen/esomeprazole (HR 0.51; 95%CI 0.32 to 0.81) (Yeomans 2018 Level II, n=24,081, JS 5).
Despite a possible dosing inequality this is supported by a trial of naproxen 500 mg BD + PPI vsCelecoxib 100 mg BD + PPI in patients with a recent GI bleed ( Chan 2017 Level II, n=514, JS 5).
Rebleed rates were 5.6% (95%CI 3.3 to 9.2) in the celecoxib group and 12.3% (95%CI 8.8 to 17.1)
in the naproxen group (HR 0.44; 95%CI 0.23 to 0.82). Etoricoxib in osteoarthritis similarly shows
superiority to nsNSAIDs in terms of GI event rates (RR 0.67; 95%CI 0.59 to 0.76) (Feng 2018 Level I[PRISMA], 9 RCTs, n=39,442).
Short-term use (< 7 d) of parecoxib/valdecoxib, as required to treat acute pain, results ingastroscopic ulcer rates similar to placebo in elderly patients (65 to 75y) at increased risk
(Goldstein 2003 Level II, n=168, JS 4; Stoltz 2002 Level II, n=94, JS 4; Harris 2001 Level II, n=17 [terminated
due to high incidence of gastrointestinal ulcers in both nsNSAID groups], JS 4). This contrasts withincreased rates of ulceration with nsNSAIDs in the same setting.
Despite relative safety in comparison to nsNSAIDs, long term usage of COX-2 inhibitors is still
associated with an increased GI event rate in cohort studies of non-use versus etoricoxib (RR
4.85; 95%CI 2.64 to 8.93), rofecoxib (RR 2.02; 95%CI 1.56 to 2.61) and celecoxib (RR 1.53; 95%CI
1.19 to 1.97) (Martin Arias 2019 Level III-2 SR [PRISMA], 28 studies, n=1,255,401). These results might
be unexpected given that both rofecoxib and etoricoxib are more COX-2 selective than celecoxib,
however current understanding of gastrointestinal injury includes multiple mechanisms such as
mitochondrial uncoupling and ion-trapping that may be unrelated to COX inhibition (Bjarnason
2018 NR). In a pooled analysis of COX-2 inhibitor use in osteoarthritis an increase in118

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gastrointestinal events is seen vs placebo (RR 1.19, 95% CI 1.03 to 1.38) (Curtis 2019 Level I[PRISMA], 40 RCTs, n unspecified).
Renal effects
COX-2 is constitutively expressed in the kidney and is highly regulated in response to alterationsin intravascular volume. COX-2 has been implicated in maintenance of renal blood flow,
mediation of renin release and regulation of sodium excretion ( Cheng 2004 NR; Kramer 2004 NR).
A meta-analysis of perioperative parecoxib found no increase in renal failure vs placebo(Schug 2017 Level I, 26 RCTs, n=9,282). In contrast (and as with nsNSAIDs), a statistically significant
increased risk of renal failure was reported following administration of coxibs in cardiac surgery
patients (NNH 73) (Elia 2005 Level I, 3 RCTs [cardiac surgery], n=803).
In the PRECISION trial, long-term ibuprofen was associated with significantly more serious
renal events than celecoxib (HR 0.61; 95%CI 0.44 to 0.85), but naproxen was not worse thancelecoxib (HR 0.79; 95%CI 0.56 to 1.12) (Nissen 2016 Level II, n=24,081, JS 5).
Analysis of the effects of different coxibs on renal function showed heterogeneity within theclass as rofecoxib was associated with increased risk of renal dysfunction, while celecoxib was
not (Zhang 2006 Level I, 114 RCTs, n=116,094).
A subsequent meta-analysis of cohort studies of the general population showed little
evidence of lower AKI incidence with increasing COX-2 selectivity (OR 1.84; 95%CI 1.54 to 2.19
[no COX-2 selectivity] vs OR 1.41; 95%CI 1.07 to 1.87 [≥5 fold COX-2 selectivity]) (Zhang 2017aLevel III-2, 10 studies, n=1,609,163).
Cardiovascular effects
Cardiovascular risk with coxibs seems very dependent on the coxib in question. This may reflect
non-COX dependent effects that NSAIDs may have on the cardiovascular system (Walker 2018
NR).
In acute pain management, short-term use of parecoxib (< 7 d) after noncardiac surgery does
not increase the risk of cardiovascular adverse effects ( Schug 2017 Level I, 26 RCTs, n=9,282).
Similarly, short-term use of other NSAIDs (meloxicam, ketorolac, celecoxib for a mean of 3 d)after lower limb total joint replacement did not increase the risk of myocardial infarction
postoperatively vs nonuse (aOR 0.95; 95%CI 0.5 to 1.8) (Liu 2012 Level III-2, n=10,873). However,an increase in the incidence of cerebrovascular and cardiovascular events has been reported inpatients given parecoxib, then valdecoxib, after CABG surgery (Furberg 2005 Level I, 2 RCTs,
n=2,098). The FDA has contraindicated the use of all NSAIDs in the immediate postoperative
period following CABG surgery (FDA 2007 GL). A subsequent retrospective observational study
with ketorolac has not confirmed these concerns (Oliveri 2014 Level III-2, n=1,309).
Absolute long-term cardiovascular risk with chronic usage of NSAIDs remains unclear as therecent large prospective studies were non-inferiority trials without a placebo arm. Studies areconflicting as to cardiovascular risk with individual drugs.
In a review of epidemiological data, rofecoxib showed increased cardiovascular risks vs othercoxibs and nsNSAIDs (Gunter 2017 Level III-2 SR, 26 studies, n=228,389). In the PRECISION trial inpatients with arthritis, there was no difference in cardiovascular event rates between long-term
celecoxib vs ibuprofen (HR 0.81; 95%CI 0.65 to 1.02) or vs naproxen (HR 0.90; 95%CI 0.71 to1.15) (Nissen 2016 Level II, n=24,081, JS 5). The SCOT trial randomised patients over 60 y witharthritis to either continue their current NSAID or be changed to celecoxib and found nodifference in cardiovascular risk (HR 1.1; 95%CI 0.81 to 1.55) (MacDonald 2017, Level II, n=7,297,
JS 3).
A Bayesian meta-analysis found no increased risk of myocardial infarction for celecoxib (OR1.24; 95%CI 0.91 to 1.82) or ibuprofen (OR 1.48; 95%CI 1.00 to 2.26), but increased risk fordiclofenac (OR 1.50; 95%CI 1.06 to 2.04), naproxen (OR 1.53; 95%CI 1.07 to 2.33) and rofecoxib
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(OR 1.58; 95%CI 1.07 to 2.17) (Bally 2017 Level III-2, n=446,763 [61,460 myocardial infarctions]). Thisdata directly conflicts with a previous meta-analysis that found no increased cardiovascular risk
with naproxen, diclofenac or etoricoxib (Trelle 2011 Level I, 31 RCTs, n=116,429).
Once daily administration of celecoxib eg 400 mg (RR 1.1; 95%CI 0.6 to 2.0) was associatedwith a lower cardiovascular risk than giving 400 mg as divided doses of 200 mg twice daily (RR
1.8; 95%CI 1.1 to 3.1) (Solomon 2008 Level I, 6 RCTS, n=7,950).
All NSAIDs approximately double the risk of congestive heart failure (Bhala 2013 Level I, 54 RCTs,
n=353,809). However, this analysis pooled all coxib data so that data from rofecoxib and celecoxib
was not differentiated. A subsequent meta-analysis of coxibs which looked at heart failure inosteoarthritis found no increase in congestive heart failure (RR 1.18; 95%CI 0.24 to 5.71) (4 RCTs),but increased risk of peripheral oedema (RR 1.61; 95%CI 1.09 to 2.40) (15 RCTs) and generalised
oedema (RR 1.91; 95%CI 1.08 to 3.39) (8 RCTs) (Curtis 2019 Level I [PRISMA], 40 RCTs, n unspecified). Ina nested cohort study which matched 92,163 heart failure admissions with 8,246,403 controls, all
NSAIDs except celecoxib were associated with an increased risk of heart failure (Arfe 2016 Level III-2,
n=8,566,955).
A small increase in the risk of atrial fibrillation with NSAID usage (RR 1.12; 95%CI 1.06 to 1.18)
has been documented (Krijthe 2014, Level III-2, n=8,423).
In comparison with a historical cohort, the use over a subsequent 10 mth period of parecoxib
and valdecoxib 40 mg daily for 2 to 3 wk was associated with an increase in the rate of vascular
free flap failure from 7 to 29%, which fell to 4% after the coxibs were no longer used (Al-Sukhun
2006 Level III-3, n=180). These retrospective data, which are subject to potential confounding
factors, are supported by one study in rats showing a harmful effect of parecoxib on flap survival(Ren 2013 BS), which did not occur with celecoxib (Wax 2007 BS). A retrospective cohort study
using ketorolac after head and neck free flaps found no bleeding complications and no increased
risk of free flap failure (Schleiffarth 2014 Level III-2, n=138 [free flaps]).
Platelet effects and bleeding
Platelets express only COX-1, not COX-2, and as a consequence, coxibs do not impair platelet
function (Munsterhjelm 2006 Level II EH, n=18, JS 4). This is consistent with a study on platelet
aggregometry with meloxicam and celecoxib show essentially no antiplatelet activity (Scott 2014
BS). COX-2 selective NSAIDs show no difference in the risk of postoperative bleeding events (RR
0.92; 95%CI 0.63 to 1.33), intraoperative blood loss (WMD -4.38 mL; 95%CI -14.69 to 5.92),
postoperative blood loss (WMD -13.89 mL; 95%CI -30.24 to 2.47), and 24 h postoperative
haemoglobin loss (WMD 0.47 g/dL; 95%CI 0.14 to 1.09) vs nsNSAIDs, other analgesics, or placebo(Teerawattananon 2017 Level I, 16 RCTs, n=1,704).
Allergic reactions and NSAID-exacerbated respiratory disease
Patients with anaphylactoid reactions to dipyrone and nsNSAIDs (mainly propyphenazone anddiclofenac) tolerated oral challenges with rofecoxib and celecoxib (Quiralte 2004 Level IV, n=33).
Coxibs, administered at analgesic doses, do not produce bronchospasm in patients with
NSAID-exacerbated respiratory disease (Morales 2013 Level I [PRISMA], 14 RCTs, n=426).
Bone and ligament healing
At present, data on the effect of coxibs on bone healing are mainly restricted to animal models,
where they undoubtedly affect bone remodelling (Kurmis 2012 NR BS). Celecoxib after THA
reduced the frequency and severity of heterotopic bone formation (Lavernia 2014 Level III-2, n=170;
Oni 2014 Level III-2, n=214). There is no good evidence of any clinically significant inhibitory effectof coxibs on bone healing (Kurmis 2012 NR; Gerstenfeld 2004 NR; Bandolier 2004 NR).
In a small single centre trial, re-tear rates were increased following rotator cuff repairs incelecoxib(11/30 [37%]) vs ibuprofen (2/27 [7%]) and tramadol treated patients (1/25 [4%])groups (Oh 2018 Level II, n=180, JS 5). This matches animal model data from rabbits (Lu 2015 BS).

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Anastomotic leakage
There is no increased leakage rate with perioperative coxibs (Modasi 2019 Level III-2 SR [PRISMA],
8 studies, n=9,835; Huang 2018 Level III-2 SR,17 studies, n=26,098) (4 studies overlap). See 4.2.1.2 formore detail.

KEY MESSAGES
Efficacy of systemic NSAIDs
1. Nonselective NSAIDs are effective in the treatment of acute postoperative pain, renal
colic, migraine, primary dysmenorrhoea (S) (Level I [Cochrane Review]), acute muscle
injury (N) (Level I [PRISMA]), chronic low-back pain (U) (Level I [PRISMA]) and acuteankle sprain (U) (Level I).
2. Coxibs are as effective as nonselective NSAIDs in the treatment of acute pain (including
postoperative pain) (S) (Level I [Cochrane Review]), chronic low-back pain (U) (Level I[PRISMA]) and osteoarthritis of the knee (N) (Level I [PRISMA]).
3. Nonselective NSAIDs given in addition to paracetamol improve analgesia compared witheither medicine given alone (S) (Level I), in particular ibuprofen combined withparacetamol (U) (Level I [Cochrane Review]).
4. The risk-benefit ratio for coxibs as a discharge medication after orthopaedic surgery issuperior to that for nonselective NSAIDs (U) (Level I [PRISMA]).
5. Nonselective NSAIDs given in addition to PCA opioids reduce opioid consumption andthe incidence of nausea and vomiting (U) (Level I).
6. Coxibs given in addition to PCA opioids reduce opioid consumption but do not result in adecrease in opioid-related adverse effects (U) (Level I), except after total knee
arthroplasty, where they reduce pain scores and adverse effects and improve outcomes(U) (Level I).
7. Celecoxib given as a single pre-operative dose is effective at reducing opioid usage, painscores at 24 hours and postoperative nausea and vomiting (N) (Level I).
Adverse effects of systemic NSAIDs
8. In patients with normal preoperative renal function nonselective NSAIDs slightly increase
serum creatinine, but effects on acute kidney injury and need for renal replacement
therapy are uncertain due to lack of evidence (W) (Level I [Cochrane Review]).
9. Nonselective NSAIDs may increase the risk of any bleeding-related outcome after
tonsillectomy in adults (U) (Level I); however, not in paediatric patients (U) (Level I[Cochrane Review]) except in a large non-inferiority RCT where need for surgicalintervention was increased with ibuprofen versus paracetamol (Q) (Level II). There is anincrease in bleeding complications with aspirin in adults and children (U) (Level I) andwith ketorolac in adults only (U) (Level III-2 [PRISMA]).
10. Nonselective NSAIDS, but not coxibs, may cause bronchospasm in individuals known tohave NSAID-exacerbated respiratory disease (U) (Level I [PRISMA]).
11. Coxibs and nonselective NSAIDs exert individual (non-class) adverse effects on the
cardiovascular system with rofecoxib appearing to be worse than other coxibs andnonselective NSAIDs (N) (Level I). Celecoxib is no worse than naproxen or ibuprofen (N)(Level II) and better than ibuprofen when combined with aspirin (N) (Level II).
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12. Short-term use of parecoxib (S) (Level I) and other NSAIDs (U) (Level III-2) comparedwith placebo does not increase the risk of cardiovascular adverse effects after
noncardiac surgery.
13. Use of parecoxib followed by valdecoxib after coronary artery bypass graft surgery
increases the incidence of cardiovascular and cerebrovascular effects and is therefore
contraindicated (U) (Level I).
14. Perioperative nonselective NSAIDs may increase the risk of minor and major bleeding
after surgery compared with placebo (W) (Level I).
15. Coxibs do not impair platelet function and are not associated with increased
perioperative blood loss (S) (Level I).
16. In patients with normal renal function, parecoxib perioperatively does not increase renal
failure (N) (Level I).
17. NSAIDs hasten bowel recovery after colorectal surgery (N) (Level I).
18. With regard to renal function, celecoxib and naproxen are safer than ibuprofen withlong-term use (N) (Level II).
19. Short-term use (5–7 days) of coxibs results in gastric ulceration rates similar to placeboand lower than nonselective NSAIDs (U) (Level II).
20. The cardiovascular protective effects of low-dose aspirin are reduced by concomitantadministration of some NSAIDs, in particular ibuprofen (S) (Level II).
21. Nonselective NSAIDs, but not coxibs increase the risk of anastomotic leak after colorectal
surgery (N) (Level III-2).
22. Short term use of ketorolac or ibuprofen do not increase bone healing complications inchildren undergoing posterior spinal fusion, osteotomy, or fractures managed
surgically (S) (Level III-3) or conservatively (N) (Level III-3).
23. Chronic administration of nsNSAIDs or coxibs is associated with an increased risk of renal
impairment (N) (Level III-3 SR).
The following tick box represents conclusions based on clinical experience and expert
opinion: The risk of adverse renal effects of nonselective NSAIDs and coxibs may be increased in
the presence of factors such as pre-existing renal impairment, hypovolaemia,
hypotension and use of other nephrotoxic agents including angiotensin-converting
enzyme inhibitors (W).

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4.2.3 | Nonsystemic administration of nonsteroidal anti-inflammatory drugs
Non-systemic (transdermal patch or gel, wound infiltration) for non-ophthalmic (intra- or
abdominal wall, mastectomy and skin graft) surgery as part of multimodal analgesic regimens
may improve pain control and postoperative function vs placebo or systemic administration
based on low to moderate quality evidence (Brubaker 2016 Level I [PRISMA], 9 RCTs, n=532).
4.2.3.1 | Intra-articularFollowing arthroscopy, intra-articular (IA) nsNSAIDs (tenoxicam and ketorolac) result in
improved pain relief (Romsing 2000 Level I, 16 RCTs, n=844 [7 RCTs IA]). Compared with systemic
administration, IA nsNSAIDs (4 RCTs) showed a pain reduction of 20/100 (95%CI 13 to 26) and a
50 to 65% reduction in supplementary analgesic requirements over 24 h. In contrast, when IA
nsNSAIDs were compared with IA placebo, two of three RCTs showed no significant analgesic
benefit. More recent studies do not permit differentiation of the effect of IA NSAIDs from othercomponents in the injected solution.
In human chondrocytes, single-dose equivalent concentrations of ketorolac caused
significant chondrotoxicity (Abrams 2017 BS). Intraarticular ketorolac for THA showed noincreased risk of prosthetic loosening, even with long-term follow-up (mean 7.3 y) (Nizam 2015
Level IV, n=100).
4.2.3.2 | Wound infiltration
Infiltration of the surgical wound with local anaesthetic/nsNSAID vs local anaesthetic and IV
nsNSAID showed no difference in analgesia in three of five RCTs (overall WMD -6/100; 95%CI-19 to 6); similarly, wound infiltration with local anaesthetic/nsNSAID vs local anaesthetic/
placebo showed no analgesic benefit in four of five studies ( Romsing 2000 Level I, 16 RCTs, n=844[10 RCTs wound]). This lack of a local effect was confirmed with lornoxicam after thyroidectomy(Kilbas 2015 Level II, n=80, JS 4).
4.2.3.3 | Local infiltration analgesia
Local infiltration analgesia (LIA) involves the intraoperative periarticular infiltration of large
volumes of local anaesthetic combined with a variety of adjuvants typically including an alpha-2
agonist/vasoconstrictor, an opioid and/or an anti-inflammatory agent. The majority ofinvestigations into the effectiveness of LIA in acute pain management following THA/TKA fail toseparate out the components of the mixture and some protocols also use catheter-based “topup” regimens of varying composition. The lack of appropriate systemic comparators further
complicates analysis of the role of the individual components. Ketorolac is the most frequently
used nsNSAID in the LIA mixture. A systematic review identified no RCTs enabling a comparisonof the efficacy of systemic vs periarticular administration of nsNSAIDs as a component of LIA in
THA (Andersen 2014a Level I [PRISMA], 27 RCTs [THA], n=756).
The peak plasma concentrations of ketorolac after use of 30 mg as a component of LIA werecomparable to those of similar doses administered IM (0.3-2.2 mg/L) (Affas 2014 PK).
4.2.3.4 | Intravenous regional analgesia
Ketorolac 60 mg in combination with local anaesthetic for IV regional analgesia (IVRA)
demonstrated longer time to first analgesia request vs local anaesthetic IVRA with either IV
ketorolac or IV placebo following minor upper limb procedures ( Reuben 1995 Level II, n=60, JS 2).
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However, pain scores were low overall and this study was not blinded. Ketorolac 60 mg added
to local anaesthetic for IVRA or infiltrated into the wound provided superior analgesia for up to
2 h following tourniquet release vs no ketorolac use (Reuben 1996 Level II, n=60, JS 3). Again, painscores were low for all groups and there was no separate parenteral ketorolac arm forcomparison. When varying doses of ketorolac were added to IVRA for hand surgery, a linear
dose-response relationship from 5 to 20 mg was found; between 20 and 60 mg, there appeared
to be no additional analgesic benefit (Steinberg 1998 Level II, n=75, JS 3). With IVRA doses of ≥20
mg vs doses <20 mg, time to first analgesia was prolonged and pain scores were lower for up to
2 h following tourniquet release. There was no comparison with ketorolac administered as aseparate parenteral dose.
Overall, no conclusion can be drawn regarding a specific benefit of adding ketorolac to IVRA
over parenteral administration by a separate route.
4.2.3.5 | Nerve block
Parecoxib/ropivacaine improved quality and duration of brachial plexus block vsplacebo/ropivacaine and ropivacaine/IV parecoxib (Liu 2013 Level II, n=150, JS 5).
4.2.3.6 | TopicalApplication to skin
In adult patients with acute pain resulting from strains, sprains or sports injuries, topical
diclofenac, ibuprofen, ketoprofen, piroxicam and indomethacin are effective vs placebo,
whereas benzydamine is not better than placebo (Derry 2015a Level I [Cochrane]
61 RCTs, n=8,386). Topical compounds with good efficacy are diclofenac with an NNT (for 50% pain
reduction over placebo) of 3.7 (95%CI 3.2 to 4.3), ketoprofen of 3.9 (95%CI 3.0 to 5.3), piroxicamof 4.4 (95%CI 3.2 to 6.9) and ibuprofen of 4.6 (95%CI 3.3 to 8.0). Different formulations may differ
in efficacy; gels seem to be superior to creams with a diclofenac gel preparation having thelowest NNT of 1.8 (95%CI 1.5 to 2.1) and ketoprofen gel one of 2.5 (95%CI 2.0 to 3.4). The rateof systemic adverse effects with the topical NSAIDs is low and does not differ from placebo. The
rate was also lower than with the same NSAID by oral route, although there was limited data on
direct comparison.
Topical NSAIDs were of limited efficacy in lateral elbow pain, providing short-term functional
improvement for up to 2 wk (Pattanittum 2013 Level I [Cochrane], 8 RCTs, n=301). The overall qualityof included studies was poor and findings heterogeneous. No comparisons with oral NSAIDs were
included.
There is insufficient evidence to differentiate between routes of administration of NSAIDs in
the treatment of acute low back pain (Roelofs 2008 Level I [Cochrane], 65 RCTs, n=11,237).
Topical application of diclofenac results in tissue levels that are higher and plasma levels thatare lower vs oral administration (Zacher 2008 Level I, 19 RCTs, n>3,000). Topical NSAIDs wereassociated with fewer gastrointestinal adverse effects but more local skin irritation than systemic
NSAIDs (Klinge 2013 Level I, 6 RCTs, n=600).
Ophthalmological applications
There is no strong evidence for pain reduction with topical NSAIDs for traumatic corneal
abrasions, but some evidence for a reduced requirement for rescue analgesia at 24 h as a proxyfor pain reduction (RR 0.46; 95%CI 0.34 to 0.61) (Wakai 2017 Level I [Cochrane], 9 RCTs, n=637). After
cataract surgery, topical NSAIDs reduce anterior chamber inflammation and thereby provide
postoperative analgesia (Duan 2017 Level I [PRISMA], 19 RCTs, n=7,234); diclofenac, nepafenac,

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ketorolac and bromfenac are in particular effective. After a number of other ophthalmologicalprocedures, multiple studies show contradictory results with topical NSAIDs.
Mucosal applications
Microgranules containing flurbiprofen 8.75 mg provided better pain relief and reductions indifficulty in swallowing for sore throat than placebo, with fast onset (1 min) and long duration(6 h) (Russo 2013 Level II, n=373, JS 5). Flurbiprofen spray (8.75 mg/dose) rapidly reduced symptomsof sore throat after upper respiratory tract infection and provided significantly more relief for up
to 6 h vs placebo, with no difference in adverse effects vs placebo over 3 d (de Looze 2016 Level II,
n=505, JS 5); similar results (non-inferior to the spray) were found with use of a 8.75 mg
flurbiprofen lozenge (Radkova 2017 Level II, n=440, JS 5). Flurbiprofen was also useful in posttonsillectomy pain with reduction in pain scores and reduced requirement for additional
analgesia (Muderris 2016 Level II, n=84, JS 4).

KEY MESSAGES
1. Topical NSAIDs are effective in treating acute strains, sprains or sports injuries withsystemic adverse effects comparable to placebo; gel formulations show superior efficacy
over creams (S) (Level I [Cochrane Review]).
2. Topical NSAIDs are of limited analgesic efficacy for traumatic corneal abrasions, but
reduce rescue analgesia requirements (W) (Level I [Cochrane Review]).
3. Topical NSAIDs reduce anterior chamber inflammation and thereby pain after cataract
surgery (N) (Level I [PRISMA]).
4. The efficacy of NSAIDs for peri- or intra-articular injection as a component of local
infiltration analgesia compared with systemic administration remains unclear (U) (Level I[PRISMA]).
5. Intra-articular nonselective NSAIDs may provide more effective analgesia following
arthroscopy than intravenous administration (U) (Level I).
6. Mucosal administration of flurbiprofen provides long-lasting pain relief for sore throat(N) (Level II).

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4.3 | Opioids
Opioids can bind to receptors in the brain, spinal cord and periphery, and can be administeredsystemically or locally (eg intrathecal, intra-articular).

4.3.1 | Systemic opioids
Opioids remain the mainstay of systemic analgesia for the treatment of moderate to severe
acute pain.
While opioids are conventionally regarded as acting on opioid receptors, some opioids
achieve analgesic effects by additional mechanisms or via alternate interactions with opioid
receptors (Raffa 2014a NR). The first of this class to be labelled as an “atypical opioid” wastramadol with its effects on noradrenergic and serotonergic inhibitory systems on top of a weakmu-agonism (by an active metabolite) (Raffa 1992 BS). The term atypical opioids (althoughanother term “multigesics” has also been suggested) (Pergolizzi Jr 2017 NR) is increasingly used forbuprenorphine, cebranopadol, tapentadol and tramadol ( Schug 2019 NR); of these cebranopadol
is undergoing early clinical investigations (Lambert 2015 NR BS), while the other three areapproved in many countries.
4.3.1.1 | Choice of systemic opioid
All full conventional opioid agonists can produce the same level or analgesia once the dose isappropriately adjusted (McQuay 1991 NR), although accurate determination of equianalgesic
doses is difficult due to interindividual variabilities in kinetics and dynamics ( Gammaitoni 2003 NR).
Equianalgesic conversion dose tables are often used to assist in the change from one opioid toanother. However, such tables are based largely on single-dose studies in opioid-naïve subjects
and may not be as relevant when conversions are made after repeated doses of an opioid havebeen given (either in the acute or chronic pain setting) and do not consider incomplete crosstolerance and patient-specific factors (Weschules 2008a NR). Care must be taken when opioid
rotations are undertaken based on such tables alone without consideration of clinical factors
because this carries a significant risk of toxicity and even fatality (Webster 2012 NR). When
healthcare professionals (physicians, pharmacists, and nurse practitioners/physician assistants)
were surveyed, there was a large variation in mean opioid conversions ( Rennick 2016 Level IV,
n=319). A detailed analysis of equianalgesic doses and suggestions for opioid rotations based onthese calculations has been published (Treillet 2018 Level IV SR, 20 studies, n unspecified).
FPMANZCA provides an opioid calculator including references and background material on a
website (FPMANZCA 2019a GL), which is also available as an app (“Opioid Calculator”) for
smartphones. Opioid rotations to methadone require particular care due to the risk ofaccumulation and subsequent toxicity (McLean 2015 Level IV SR, 25 studies, n=1,229).
In general, there is little evidence, on a population basis, to suggest that there are any majordifferences in efficacy or the incidence of adverse effects between any of the pure agonist
opioids, although the results of individual studies are inconsistent. However, forpharmacokinetic and other reasons, some opioids may be better in some patients ( Woodhouse
1999 Level II, n=82, JS 4). Comparisons of the different opioids are commonly done in patients using
PCA (see Section 6.3.1 for these comparisons).
While the data to support the concept of opioid rotation originate from cancer pain
(Mercadante 2011 Level III-2 SR, 31 studies, n unspecified; Quigley 2004 Level IV SR [Cochrane], 52 studies,n unspecified), it may be a useful strategy in the management of acute pain in patients with126

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intolerable opioid-related adverse effects, who are unresponsive to treatment and in opioidtolerant patients (see also Section 9.7).
The efficacy of various opioids administered by the different routes used in the managementof acute pain is discussed in detail in Chapter 5. The following sections describe other relevant
aspects of selected atypical and conventional opioids.
4.3.1.2 | Conventional opioids
CodeineCodeine is classified as a weak opioid. However, it is only a very weak mu-receptor agonist
and its analgesic action depends on the metabolism of about 10% of the dose to morphine, via
the CYP2D6 cytochrome P450 isoenzyme (Lotsch 2005 NR). The principal metabolite of codeine iscodeine-6-glucuronide, which has a similar low potency to the parent medicine and is renally
excreted.
Over 100 allelic variants of CYP2D6 have been identified, resulting in wide variability inenzyme activity (Somogyi 2007 NR). Individuals carrying two wild-type alleles display normal
enzyme activity and are known as extensive metabolisers; intermediate metabolisers areheterozygotes with two variant alleles known to decrease enzymatic capacity; and poor
metabolisers have no functionally active alleles and have minimal or no enzyme activity (Stamer
2007a NR). In Caucasian populations, 8 to 10% of people are poor metabolisers; however, 3 to
5% are ultrarapid metabolisers (Madadi 2009 Level III-2, n=72; Stamer 2007a NR). Those who areultrarapid metabolisers (carriers of the CYP2D6 gene duplication) have significantly higher levelsof morphine and morphine metabolites after the same dose of codeine (Kirchheiner 2007 Level IV,n=23).
There are large interethnic differences in the frequencies of the variant alleles. For example,
the proportion of ultrarapid metabolisers is higher (up to 29%) in Middle Eastern and Northern
African populations and lower (0.5%) in Asians (Stamer 2007b NR); the proportion of poor
metabolisers is lower in Asians and African Americans (Yee 2013b Level IV, n=75; Holmquist 2009
NR).
A case‐control study including a case of a newborn dying while breastfed by a mother taking
codeine has highlighted that breastfed infants of mothers who are ultrarapid metabolisers areat increased risk of life‐threatening CNS depression (Madadi 2009 Level III‐2, n=72). A numberof similar cases have been reported and health professionals and mothers of breastfeeding
infants should be aware of this risk (Madadi 2008 Level IV, n=35). CYP2D6 genotyping predicts
subjects with reduced or increased metabolism to morphine but must be combined withadditional phenotyping to accurately predict patients at risk of morphine toxicity ( Lotsch 2009
Level III‐2, n=57)
Death or OIVI has occurred after codeine treatment. Although rare, the risk is highest inchildren who are ultrarapid metabolisers, after they have undergone tonsillectomy,
adenoidectomy, or both, as many of these have sleep-disordered breathing and are therefore
more sensitive to opioids (Friedrichsdorf 2013 Level IV, n=3; Kelly 2012 Level IV, n=4; Racoosin 2013
NR). The USA Food and Drug Administration (FDA) now requires a boxed warning of the risk
posed by codeine after a child has undergone tonsillectomy or adenoidectomy (FDA 2013 GL). The
European Medicines Agency has responded similarly (EMA 2013 GL); as has the WHO in removing
codeine from its tiered analgesic ladder for treatment of (persistent) pain in children ( WHO 2012
GL). Guidelines on this issue have been published ( Crews 2014 GL). See also Sections 1.7.3.2 and10.4.4.5.

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Dextropropoxyphene
Oral dextropropoxyphene 65 mg alone is a poorly effective analgesic in postoperative pain (NNT7.7) (Collins 2000 Level I [Cochrane], 6 RCTs [dextropropoxyphene only], n=440). Dextropropoxyphene
is often used in combination with paracetamol but this combination does not lead to better pain
relief vs paracetamol alone and increases the incidence of dizziness (Li Wan Po 1997 Level I,
26 RCTs, n=2,231).
The use of this compound is discouraged, not only because of its low efficacy but also becauseof a number of risks related to its use (Barkin 2006 NR). These include QT-interval prolongationand possibility of Torsades des Pointes (TdP) and cardiogenic death. This is exacerbated bycomplex pharmacokinetics (particularly in the elderly) with the risk of accumulation of
dextropropoxyphene and its metabolite nordextropropoxyphene, leading to CNS, respiratory
and cardiac depression (Davies 1996 NR). However, in therapeutic doses (125±25 mg) no
prolongation of the QT-interval >500 ms was observed (Keller 2018 Level IV, n=92).
In line with many other developed countries including New Zealand, the Therapeutics Goods
Administration (TGA) in Australia decided in November 2011 to remove the registration of
dextropropoxyphene (Buckley 2013 NR). Despite a number of appeals by the manufacturer, themedication has since been withdrawn from sale in Australia.
Diamorphine
Diamorphine (diacetylmorphine, heroin) is rapidly hydrolysed to monoacetylmorphine (MAM)
and morphine (Miyoshi 2001 NR); diamorphine and MAM are more lipid-soluble than morphineand penetrate the CNS more rapidly. It is MAM and morphine that are thought to be responsible
for the analgesic effects of diamorphine.
There was no difference between parenteral diamorphine and morphine in terms ofanalgesia and adverse effects after hip surgery (Robinson 1991 Level II, n=40, JS 4) and between
parenteral diamorphine and pethidine for labour analgesia (Wee 2014 Level II, n=484, JS 4).
Epidurally administered diamorphine resulted in a longer time to first PCA use and lower total
24 h morphine requirements vs the same dose given by intramuscular (IM) injection (Green 2007
Level II, n=60, JS 4). Intranasal (IN) diamorphine has been used as an analgesic for acute pain inchildren attending EDs (Kendall 2015 Level IV, n=226). Here peak morphine plasma concentrations
were higher and occurred earlier when diamorphine was administered IV vs IN ( Kidd 2009
Level III-1, n=24).
Dihydrocodeine
Dihydrocodeine is a semisynthetic derivative of codeine and has similar mu-opioid agonist activity.
However, unlike codeine, inhibition of CYP2D6 by quinine does not alter its analgesic effect, eventhough the CYP2D6-dependent active metabolite, dihydromorphine, has a much higher mu-opioid
receptor affinity than the parent medicine (Lotsch 2005 NR). Orally administered, it has around twice
the potency of codeine and one-sixth the potency of morphine (Leppert 2010 NR).
Fentanyl
Fentanyl is a highly potent phenylpiperidine derivative, structurally related to pethidine. It ismetabolised almost exclusively in the liver to minimally active metabolites. Less than 10% of
unmetabolised fentanyl is renally excreted. Fentanyl is commonly used in the treatment of acutepain, especially when its lack of active metabolites and fast onset of action may be of clinicalbenefit (Grape 2010 NR). The fast onset is the result in particular of its high lipophilicity(octanol:water partition coefficient >700); this leads to a transfer half-life of 4.7 to 6.6 min
between plasma and CNS (Lotsch 2013 NR) (see also Section 5.4.1). The pharmacokinetics offentanyl are influenced by impaired liver function and CYP3A4 inhibitor and inducer use ( Kuip
2017 NR). Data on fentanyl causing opioid-induced hyperalgesia (OIH) are limited and conflicting

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with 4 RCTs supporting the induction and 2 RCTs opposing it ( Lyons 2015 Level I, 6 RCTs,
n=340).
There is insufficient evidence to judge the efficacy of fentanyl in neuropathic pain (Derry 2016b
Level I [Cochrane], 1 RCT, n=163).
There is an increasing rate of fentanyl (and its analogues) abuse, primarily in the USA, butalso now seen in other countries (Jannetto 2019 NR). This is paralleled by an increase in fentanyl
overdose deaths; in the USA there was a 72% increase from 2014 to 2015 reaching 9,580 deaths
caused by synthetic opioids, primarily fentanyl (including illicitly manufactured/nonpharmaceutical). The high mortality is partially due to admixture of fentanyl with other drugs ofabuse, in particular heroin; sources are illegal importation and diversion of fentanyl-containing
medication (Kuczynska 2018 NR). In 2015, a cluster of fentanyl-laced heroin deaths was reported
in Melbourne, Australia, the first report of this nature outside North America ( Rodda 2017
Level IV, n=9 [fentanyl related deaths out of  4,000 deaths investigated]).
Hydromorphone
Hydromorphone is a derivative of morphine that is approximately five times as potent asmorphine. The main metabolite of hydromorphone is hydromorphone-3-glucuronide (H3G), a
structural analogue of morphine-3-glucuronide (M3G). Like M3G (see below), H3G is dependent
on the kidney for excretion, has no analgesic action and can lead to dose-dependent neurotoxic
effects (Smith 2000 NR; Wright 2001 NR; Murray 2005 NR).
Hydromorphone is an effective opioid analgesic with similar efficacy and adverse effects asother strong opioids (Quigley 2002 Level I [Cochrane], 36 RCTs [acute pain], n=2,521). It provides
slightly better clinical analgesia than morphine with similar adverse effects ( Felden 2011 Level I, 8
RCTs, n=1,004). In cancer pain, its efficacy is similar to oxycodone and morphine (Bao 2016 Level I[Cochrane], 4 RCTs, n=504). There is insufficient evidence to judge the efficacy of hydromorphone
in neuropathic pain (Stannard 2016 Level I [Cochrane], 4 RCT, n=604).
Methadone
Methadone is a synthetic opioid commonly used for the maintenance treatment of patientswith an addiction to opioids and in patients with chronic non cancer and cancer pain. It iscommercially available as a racemic mixture of R- and L-enantiomers but it is the R-enantiomerthat is responsible for most, if not all, its mu-opioid receptor-mediated analgesic effects(Fredheim 2008 NR; Lugo 2005 NR).
It has good oral bioavailability (70 to 80%), high potency and long duration of action and a lackof active metabolites (Lugo 2005 NR). It is also a weak NMDA-receptor antagonist and monoamine(5HT and noradrenaline [norepinephrine]) reuptake inhibitor and has a long and unpredictablehalf-life (mean of 22 h; range 4 to 190 h) leading to an increased risk of accumulation (Weschules
2008b NR). Therefore, it is of limited use for acute pain treatment. Its use as an analgesic in general
requires caution and guidelines have been published (ACMT 2016 GL). Recommendations include
that it should not be prescribed on an as-needed basis, that the risk of overdose during the initial
induction period for chronic use is high and that titration should be very slow. A baseline ECG anda follow-up ECG at 30 d should be obtained in patients at risk for QT prolongation (eg on othermedications that prolong QT interval, with structural heart disease or a history of arrhythmias).
Patients need extra education on potential risks of methadone treatment.
Dose conversion is complex and depends on many factors including absolute doses of otheropioids and duration of treatment (McLean 2015 Level IV SR, 25 studies, n=1,229). In cancer pain
management, methadone has similar analgesic effects to morphine ( Nicholson 2017 Level I[Cochrane], 6 RCTs, n=388) (see also 10.4.4.9). There is very limited, very low-quality evidence
supporting the efficacy and safety of methadone for chronic neuropathic pain (McNicol 2017 Level I[Cochrane], 3 RCTs, n=105).
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Methadone is metabolised primarily by the cytochrome P450 group of enzymes, in particular
3A4 and to a lesser extent by CYP 1A2, 2D6, 2D8, 2C9/2C8, 2C19 and 2B6 ( Kapur 2011 NR). Over
50 drug-drug interactions with methadone are described. Concurrent administration of othermedicines that are CYP450 inducers may increase methadone metabolism and lower methadone
blood levels (eg carbamazepine, rifampicin, phenytoin, St John’s wort [Hypericum perforatum]and some antiretroviral agents) leading to potential reduced efficacy or even withdrawal.
Conversely, medicines that inhibit CYP450 (eg other antiretroviral agents, some selective
serotonin-reuptake inhibitors [SSRIs], grapefruit juice and antifungal agents) may lead to raised
methadone levels and an increase in adverse effects or overdose ( Fredheim 2008 NR) See also
Section 8.6.8.2 for interactions in patients with human immunodeficiency virus (HIV).
Methadone use, but not use of other opioids, was associated with an increased incidence of
hypoglycaemia in a dose-dependent fashion (for doses >80 mg/d OR 3.1; 95%CI 2.5 to 3.6) (Flory
2016 Level III-2, n=641). This was also found in an analysis of reports from the USA’s Food and Drug
Administration Adverse Event Reporting System, which showed an association between
methadone use and hypoglycaemia in comparison to all other opioids except tramadol ( Makunts
2019 Level IV, n=12,004,552).
High-dose methadone (eg >100 mg/d) has been associated with prolonged QT intervals andother cardiac complications: Torsade de pointes, changes in QT dispersion, pathological U waves,
Taku-Tsubo syndrome (stress cardiomyopathy), Brugada-like syndrome, and coronary arterydiseases (Alinejad 2015 NR) (see below Section 4.3.1.5).
In the setting of postoperative pain (spinal surgery), low-dose methadone was associatedwith high rates of postoperative complications with the use of a mean dose of 0.14 (±0.07) mg/kg(11.5±4.6 mg) in mostly non opioid naïve patients (72.3%) with BMI 30.3 (±0.9) (Dunn 2018 Level
IV, n=1,478). Respiratory depression was recorded in 36.8%, hypoxemia in 79.8%, naloxone
administered 2.3% and 1.5% required reintubation. QTc prolongation occurred in 58.8% andarrhythmias in 29.9% as well as two in-hospital deaths (0.14%). In contrast, a meta-analysis ofsmall trials in various surgery types (cardiac, abdominal, hysterectomy, day case, orthopaedic,
and spinal) of low to intermediate dose methadone 0.1 to 0.43 mg/kg vs morphine (7 RCTs),
morphine and placebo (1 RCT), hydromorphone (1 RCT) and fentanyl (1 RCT) controls reported
low power and did not detect a difference in risk for sedation (OR 0.62; 95% CI 0.27 to 1.45),
respiratory depression/hypoventilation (OR 1.03; 95% CI 0.20 to 5.25) or hypoxaemia (OR 1.56,
95% CI 0.67 to 3.61) (D'Souza 2020 Level I [PRISMA], 10 RCTs, n=617). Current data
are inadequate to support the routine use of long acting single intraoperative methadone
doses in surgical patients where, as already emphasised, opioid requirements vary and titration
is warranted. Further, large scale randomised trials are needed to overcome detection bias anddefine the efficacy and safety of both single and multiple low-dose methadone use in the
perioperative period, with consideration of opioid naive and opioid tolerant patient groups(Murphy 2019 NR). The ANZCA position paper on the role of slow release (SR) opioid formulationsin acute pain includes methadone due to its long half-life and recommends that its use should
be avoided (ANZCA 2018 GL)
Morphine
Morphine remains the standard against which other opioids are compared. Morphine-6glucuronide (M6G) and M3G, the main metabolites of morphine, are formed by morphine
glucuronidation, primarily in the liver. M6G is a mu-opioid receptor agonist that crosses the
blood-brain barrier more slowly than morphine (De Gregori 2012 NR). It contributes such a large
extent to morphine analgesia in patients with both normal (85% of the effect after parenteraland up to 95% after oral administration) and impaired (98% of the effect) renal function, thatmorphine could be regarded as a prodrug to M6G (Klimas 2014 NR). M6G also has other morphine-130

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like effects including respiratory depression (van Dorp 2006b NR; Dahan 2008b NR). M3G has very
low affinity for opioid receptors, has no analgesic activity and animal studies have shown that it
may be responsible for the neurotoxic symptoms (not mediated via opioid receptors), such as
hyperalgesia, allodynia and myoclonus, sometimes associated with high doses of morphine(Lotsch 2005 NR).
Clinical trials have investigated M6G as an analgesic agent after a variety of different types ofsurgery. It was more effective than placebo (Smith 2009 Level II, n=201, JS 4; Romberg 2007 Level II,
n=42, JS 3) and in some trials as effective as morphine ( Cann 2002 Level II, n=144, JS 4; Hanna 2005
Level II, n=100, JS 3), although withdrawal due to insufficient analgesia was higher in another(Binning 2011 Level II, n=249, JS 5); this is possibly due to a slower onset of effect of M6G. However,in the clinical setting of titration of IV morphine to postoperative analgesia, which is an effective
approach to early postoperative pain (Aubrun 2012 NR), the kinetics of morphine and its
metabolites had only limited value in explaining the analgesic effects of morphine ( Hammoud2011 Level IV, n=214).
Excellent pain relief was also obtained after IT administration of 100 or 125 mcg M6G inpatients after hip replacement surgery, but there was a high incidence (10%) of late respiratory
depression (9 to 12 h after the dose was given) requiring treatment with naloxone, and a highincidence of nausea (76 to 88%) and vomiting (60 to 64%) (Grace 1996 Level II, n=75, JS 5).
The incidence and severity of nausea and vomiting as well as the need for antiemetics wasless with lV M6G than with IV morphine (Binning 2011 Level II, n=249, JS 5; Cann 2002 Level II, n=144,
JS 4). In healthy volunteers, IV morphine 0.15 mg/kg and IV M6G 0.2 mg/kg resulted in similar
reductions in ventilatory response to carbon dioxide (CO2) (Romberg 2003 Level III-1 EH).
Both M6G and M3G are dependent on the kidney for excretion. Impaired renal function, theoral route of administration (first-pass metabolism), higher doses and increased patient age are
predictors of higher M3G and M6G concentrations (Faura 1998 Level IV PK SR, 57 studies, n=1,232;
Klepstad 2003 Level IV, n=300) with the potential risk of severe long-lasting sedation and respiratory
depression.
There is insufficient evidence to judge the efficacy of morphine in neuropathic pain ( Cooper
2017 Level I [Cochrane], 5 RCTs, n=236). Oral morphine is effective in treating cancer pain withsimilar efficacy vs other opioids (Wiffen 2016 Level I [Cochrane], 62 RCTs, n=4,241).
Oxycodone
Oxycodone is a semisynthetic opioid and directly contributes the majority of drug effect itself while
being metabolised primarily to noroxycodone by CYP3A4 (≈45%) and by CYP2D6 to oxymorphone(≈19%) (Kinnunen 2019 NR PK). Oxymorphone is more potent than oxycodone as a mu-receptor
agonist (14 times) and has a higher receptor affinity (40 times) and may contribute to the overall
analgesic effect of oxycodone (Samer 2010b Level II EH, n=10 [5-arm cross over], JS 5); noroxycodone,
the major metabolite, is only a weak mu-receptor agonist (Lalovic 2006 NR; Coluzzi 2005 NR).
The dependence of oxymorphone concentrations on CYP2D6 activity and its high potency
explains the impact of CYP2D6 polymorphism on oxycodone’s pharmacodynamics andpharmacokinetics (Samer 2010b Level II EH, n=10 [5-arm cross over], JS 5). Ultrafast metabolisers
experience better analgesic effects and higher toxicity, while poor metabolisers experience lessanalgesic effect. However, in acute postoperative pain, CYP2D6 genotype had no influence on
oxycodone requirements (Zwisler 2010 Level III-3, n=270; Crews 2014 GL).
These findings mean also that drug-drug interactions can influence the efficacy of oxycodone(Samer 2010a Level II EH, n=10 [cross over], JS 5). This is particularly true for CYP2D6 ultrafast
metabolisers but also can be influenced by CYP3A inhibitors such as ketoconazole, which
increases the efficacy and toxicity of oxycodone. Therefore, use of a CYP3A inhibitor in an
ultrafast CYP2D6 metaboliser is a potentially dangerous combination.
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Animal studies have shown that oxycodone is actively taken up into the brain, resulting in abrain concentration that is up to six times that of free plasma levels ( Bostrom 2008 PK); this may
explain the discrepancies between its poorer mu-receptor affinity compared to morphine but its
higher potency (Olkkola 2013 NR). In general anaesthesia, oxycodone showed a significant dosedependent respiratory depressant effect measured by reduced minute ventilation, which wassignificantly more than that of comparable doses of morphine (Chang 2010 Level II, n=54, JS 4).
Overall oxycodone has a faster onset of action than morphine, better oral bioavailability,
longer duration of action, fewer concerns about metabolites and a lower rate of adverse effects(Olkkola 2013 NR). There is increasing use of oxycodone in the perioperative setting based onthese pharmacological properties (Kokki 2012 NR). With regard to analgesic efficacy in acute pain,
IV oxycodone seems superior to fentanyl (6 RCTs) and sufentanil (2 RCTs) and comparable tomorphine (3 RCTs), but these results may partially reflect use of doses which were notequianalgesic (Raff 2019 Level I, 11 RCTs, n=721). The incidence of adverse effects was lower withoxycodone vs fentanyl (possibly also a reflection of non-equianalgesic doses) and comparable
for oxycodone vs morphine and sufentanil. Patient satisfaction was comparable for all opioids
except for sufentanil, which showed consistently lower patient satisfaction vs oxycodone. Similar
results are reported by a parallel systematic review which also acknowledges similar limitations(Tan 2018 Level I, 8 RCTs, n=506) (6 RCTs overlap). In cancer pain management, oxycodone iscomparable in efficacy and adverse effects to other strong opioids; very low-level evidence
suggests lower risk of hallucinations with oxycodone vs morphine ( Schmidt-Hansen 2018 Level I[Cochrane], 23 RCTs, n=2,144). With regard to adverse effects in the setting of cancer pain
treatment, there were no differences between oxycodone vs other opioids except for lesssleepiness with oxycodone vs morphine (Ma 2016a Level I [PRISMA], 11 RCTs, n=1,211) (5 RCTs
overlap). In neuropathic pain, there is very low-quality evidence that oxycodone is effective in thetreatment of painful diabetic neuropathy (4 RCTs, n=637) and postherpetic neuralgia (1 RCT, n=50)(Gaskell 2016b Level I [Cochrane], 5 RCTs, n=687).
Pethidine
Pethidine (meperidine) is a synthetic opioid with decreasing use worldwide due to multiple
disadvantages compared to other opioids, and equally effective analgesic alternatives. Despite acommon belief that it is the most effective opioid in the treatment of renal colic, it was no better
than morphine (O'Connor 2000 Level II, n=103, JS 5) or hydromorphone (Jasani 1994 Level II, n=73, JS 4).
Pethidine and morphine also had similar effects on the sphincter of Oddi and biliary tract andthere was no evidence that pethidine was better in the treatment of biliary colic ( Latta 2002 NR).
Pethidine induced more nausea and vomiting than morphine when used parenterally in the
ED (Silverman 2004 Level III-3, n=193) and in the first 2 h after gynaecological surgery (Ezri 2002
Level II, n=200, JS4). Pethidine use postoperatively was associated with an increased risk ofdelirium in the postoperative period in comparison to other opioids ( Swart 2017 Level III-2 SR,
3 studies [pethidine], n=877).
Accumulation of its active metabolite, norpethidine (normeperidine), is associated withneuroexcitatory effects that range from nervousness to tremors, twitches, multifocal myoclonus
and seizures (Simopoulos 2002 Level IV, n=355). Impaired renal function increases the half-life of
norpethidine; therefore, patients with poor renal function are at increased risk of norpethidine
toxicity. Naloxone does not reverse and may increase the problems related to norpethidine
toxicity.
Overall, the use of pethidine should be discouraged in favour of other opioids in adults ( Latta
2002 NR) and in the paediatric setting (Benner 2011 NR).

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Remifentanil
Remifentanil is an unusual opioid with a very fast onset of effect (<1 min) and an extremely shortduration of action due to rapid metabolism by nonspecific esterases ( Parashchanka 2014 NR). It ismainly used as a component of anaesthesia and carries a high risk of OIH; its use as an analgesic
has primarily been studied in the setting of labour analgesia (Devabhakthuni 2013 NR) (see Section
9.1.3.1).
Sufentanil
Sufentanil (a derivative of fentanyl with rapid onset, short duration of action and no active
metabolites) was originally used in the anaesthetic setting; its use has been introduced into the
postoperative acute pain setting by the development of SL PCA ( Frampton 2016 NR) (see Section
6.5.3).
4.3.1.3 | Atypical opioids
Buprenorphine
Buprenorphine is a semisynthetic derivative of thebaine, an alkaloid of opium and a potent, but
in vitro partial, mu-opioid receptor agonist (Raffa 2014b NR) with high receptor affinity and slow
dissociation from the mu-receptor and different downstream effects (G protein andadenylcyclase activation) than conventional opioids (Ehrlich 2019 NR; Davis 2012 NR; Pergolizzi 2010NR). Furthermore, buprenorphine is a potent kappa-opioid receptor antagonist, a weak agonistat the nociceptin or opioid-receptor-like 1 (ORL-1) receptor and binds to the delta-opioid
receptor. Buprenorphine, in particular the SL formulation, is increasingly used in the setting ofacute pain management (Macintyre 2017 NR).
Buprenorphine shows biphasic pharmacokinetics with an initial distribution half-life ofaround 2–3 h and a terminal half-life of around 24 h; two-thirds of the medicine is excreted
unchanged, mainly in faeces, while the remaining one-third is metabolised predominantly in theliver and gut wall via glucuronidation to an inactive metabolite, buprenorphine-3-glucuronide,and via CYP3A4 to norbuprenorphine, which has 40 times less analgesic effect thanbuprenorphine (Kress 2009 NR). However, in line with findings in animal experiments, an
exploratory clinical investigation found respiratory depression more strongly associated with
norbuprenorphine than with buprenorphine (Strang 2018 EH PK, n=11). Onset of effect is slower
than for many other opioids; using experimental pain stimuli, the time to peak effect afteradministration of an IV bolus dose of buprenorphine was 70 to 90 min (Yassen 2006 Level III-3 EH).
The debate on buprenorphine being a partial or full mu-opioid receptor agonist in clinicalpractice continues (Holyoak 2019 NR) and is complicated by its multiple mechanisms of action.
While in-vitro experiments have characterised buprenorphine as a partial agonist, clinically it
behaves like a full mu-receptor agonist; in 23 of 24 studies identified in a systematic review,
buprenorphine achieved analgesia comparable to full mu-opioid agonists (morphine, fentanyl,
sufentanil and oxycodone) (Raffa 2014b Level I, 24 studies, n>1,270). The authors conclude that inclinically relevant doses, buprenorphine behaves like a full mu-opioid receptor agonist in-vivo. A
subsequent systematic review found SL buprenorphine comparable to IM or IV morphine inacute pain management without any differences in pain control achieved, need for rescue
analgesia or secondary outcomes (Vlok 2019 Level I [PRISMA], 9 RCTs, n=826) (3 RCTs overlap). This isconfirmed in a paediatric population with IV buprenorphine vs IV morphine showing similaranalgesic effects, but a longer duration of analgesia with buprenorphine ( Murray 2018 Level I, 4
RCTs, n=193). An overarching meta-analysis of buprenorphine vs morphine by any route ofadministration in any population finds no difference in pain intensity at <1 h (WMD 0.18; 95%CI-0.45 to 0.81), conflicting evidence for other points of time (1 to 48 h) and no difference overall
at all time points combined (WMD 0.29; 95%CI -0.62 to 0.03) (White 2018 Level I [PRISMA], 28 RCTs,
5th Edition | Acute Pain Management: Scientific Evidence 133n=2,210) (all 9 RCTs overlap with Vlok 2019 and all 4 RCTs with Murray 2018). All other outcomes for

analgesia and adverse effects (including respiratory depression) are not different except for lesspruritus with buprenorphine (OR.0.31; 95%CI 0.12 to 0.84).
In animals as well as humans, in therapeutic doses there also appears to be no antagonism
of other concurrently administered mu-agonist medicines and combined use should be effective(van Niel 2016 NR; Pergolizzi 2010 NR). In patients on opioid substitution therapy (OST) with daily
SL buprenorphine (12 to 16 mg), high doses of IV hydromorphone (16 and 32 mg) and to a lesser
extent IV buprenorphine (32 mg) achieved analgesic effects in an acute pain model (cold pressortest) (Huhn 2019 Level II EH, n=17, JS 4). In contrast, patients on OST with SL buprenorphine (2 to22 mg/d) achieved no relief of experimental pain (cold pressor or electrical stimulation) with IVmorphine (55 mg achieving plasma concentrations of 92 to 201 ng/mL), but reduced respiratory
rates (Athanasos 2019 Level II EH, n=12, JS 2).
There is a ceiling effect for respiratory depression but not for analgesia in healthy volunteers(in the dose range tested of 200 to 400 mcg) (Dahan 2006 Level III-2 EH; Dahan 2005 Level III-2 EH).
In clinical practice, transdermal (TD) buprenorphine has not been associated with any fatality in
the National Poison Data System of the USA (Coplan 2017 Level IV, n=117 [TD burenorphine]). Whenused for OST, methadone use increased the risk of overdose death vs buprenorphine (RR 6.23;
95%CI 4.79 to 8.10) (Marteau 2015 Level III-2, n=2,418 [overdose deaths] in n=19,935,537[prescriptions]). However, even with buprenorphine the overdose death rate was not zero, but
0.022/1000 prescriptions (vs 0.137/1000 prescriptions of methadone). In an analysis of overdose
deaths, buprenorphine alone can cause fatal respiratory depression, although in most cases(90%) other medications, in particular benzodiazepines and other sedatives, were found ( Selden
2012 Level IV, n=97). Similarly, in elderly opioid-naïve patients acute pain treatment with titrationof SL buprenorphine (200 mcg steps with total doses of 200 to 3,000 mcg) resulted in cases of
OIVI without a fatal outcome; all patients had risk factors such as advanced age, concurrent
comorbidities, or the ingestion of other potential central nervous system depressants ( Richards
2017 Level IV, n=6). A meta-analysis comparing buprenorphine with morphine finds no differencein the incidence of respiratory depression (defined as respiratory rate <8 to 12/min) (OR.2.07;
95%CI 0.78 to 5.51) or sedation (OR.1.44; 95%CI.0.76 to 2.74) (White 2018 Level I [PRISMA], 28 RCTs,
n=2,210).
Should buprenorphine-induced respiratory depression occur, then complete reversal withnaloxone is possible (Pergolizzi 2010 NR), although higher than usual doses and a longer duration
infusion of naloxone are required (van Dorp 2006a Level III-2 EH; Yassen 2006 Level III-3 EH; Boom2012 NR). This is confirmed in the case series referred to above, where naloxone bolus doses up
to 2.2 mg and infusions for up to 20 h were used (Richards 2017 Level IV, n=6).
In animal models of pain, buprenorphine appears to have good efficacy for neuropathic pain
(Hans 2007 NR). In the clinical setting, case reports have suggested that buprenorphine is effectivein peripheral (Licina 2013 Level IV, n=4) and central neuropathic pain (Guetti 2011 Level IV).
However, a specific effect cannot be supported or refuted based on current evidence ( Wiffen
2015 Level I [Cochrane], 0 RCTs, n=0).
Buprenorphine may also have a reduced tendency to cause opioid-induced hyperalgesia(OIH) (Lee 2011 NR). In patients in opioid-substitution programs, buprenorphine reduced pain
thresholds less than methadone ( Compton 2001 Level III-2 EH, n=54). Using experimental pain
stimuli in humans, buprenorphine, unlike conventional mu-opioid agonists, has been shown
to be antihyperalgesic, which may be related in part to its kappa-opioid antagonist activity(Koppert 2005 Level II EH, n=15, JS 4). During major lung surgery under remifentanil infusion,
perioperative buprenorphine infusion (25 mcg/h for 24 h) vs equianalgesic morphine infusion
resulted in less hyperalgesia and allodynia around the incision and longer time until rescue
analgesia requirements, with no long-term benefits at 3 mth ( Mercieri 2017 Level II, n=64, JS 5).

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However, in healthy volunteers, IV infusions of buprenorphine (0.3 mg) and morphine (10 and
20 mg) showed no differences in antihyperalgesic or analgesic effects; only IV buprenorphine(0.6 mg) enhanced the descending nociceptive inhibitory control ( Ravn 2013 Level II EH, n=32,
JS 5). Similarly, patients on OST with SL buprenorphine (2 to 22 mg/d) were hyperalgesic in thecold pressor test vs controls (buprenorphine 172 s vs control 346 s) (Athanasos 2019 Level II
EH, n=12, JS 2).
Withdrawal symptoms, which may be seen if the medicine is ceased after long-term
treatment, are milder and more delayed in onset (≥72 h) than other opioids ( Kress 2009 NR). In a
direct comparison of buprenorphine vs morphine withdrawal, withdrawal symptoms were farless with buprenorphine (subjectively and objectively) (Tompkins 2014 Level III-1, n=7). There is alsoless neonatal abstinence syndrome (NAS) in babies of mothers receiving buprenorphine vsmethadone substitution (Jones 2012 NR). In the USA National Poison Data System, calls describing
intentional abuse of an opioid were lower for TD buprenorphine than any conventional opioid;
specifically, prescription adjusted rates for abuse were much higher for TD fentanyl vs TD
buprenorphine (aRR 10.8; 95%CI 4.46 to 25.9) (Coplan 2017 Level IV, n= 2,687 [calls]).
Buprenorphine can be safely used in patients with renal impairment and has lessimmunosuppressive effect in animal experiments than pure mu-opioid agonists (Davis 2012 NR;
Pergolizzi 2010 NR). However, buprenorphine has the potential to prolong the QT interval (Klivinyi 2018
NR). High doses of buprenorphine patch (above 40mcg/h) may cause QT wave prolongation that isreversible with a MOR antagonist; clinical significance of this is unclear (Merivirta 2015 Level III-1,
n=110).
For use in OST and implications for perioperative management see Section 9.8.3.2
Tapentadol
Tapentadol is a combined mu-agonist and noradrenaline-reuptake inhibitor (Tzschentke
2014 NR). In contrast to tramadol, it has no relevant functional serotonin-reuptake inhibitionand no active metabolites ( Raffa 2012 NR). Therefore, serotonin syndrome with its use alone
has not been reported in 2 systematic reviews ( Channell 2018 Level IV SR, 13 RCTs & 3 studies &8 CRs, n=21,995 [tapentadol-treated]; Gressler 2017 Level IV SR, 13 RCTs & 9 studies, n=12,138 )(significant overlap). However, in spontaneous adverse drug event (ADE) reporting to the TGA,
16 cases consistent with serotonin syndrome were reported (14 with coadministration ofserotonergic medications) ( Abeyaratne 2018 Level IV, n=104 [reports for tapentadol ]). A probableserotonin syndrome in the setting of tapentadol overdose in combination with amitriptyline
and duloxetine has also been published (Walczyk 2016 CR). There is no effect on heart rate or
blood pressure due to noradrenaline-reuptake inhibition in doses up to the maximum
recommended 500 mg/d, even in patients with hypertension and/or on antihypertensives(Biondi 2014 Level I, 3 RCTs [post hoc analysis], n=1,464).
Elimination is by glucuronidation; severely impaired hepatic function may require dose
adjustment (Xu 2010 PK).
Although in humans tapentadol has 18-fold lower affinity for the mu-receptor than morphine,
it is only three times less potent as an analgesic due to its dual mechanism of action with synergy
shown in site-specific administration studies (Christoph 2013 BS). With regard to tapentadol, theconcept of “mu-load” (the % contribution of the opioid component to the adverse effect magnituderelative to a pure/classical mu-opioid at equianalgesic doses) has been discussed, suggesting thatwhile conventional opioids have by definition a mu-load of 100%, atypical opioids have a mu-load<100%; for tapentadol using respiratory depression and constipation the mu-load is
calculated ≤ 40% (Raffa 2018 NR).
The effect of tapentadol as a noradrenaline-uptake inhibitor on descending pathways of pain
inhibition has been confirmed in diabetic neuropathy, where tapentadol use increased
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conditioned pain modulation (Niesters 2014b Level II, n=24, JS 5). This mechanism of action suggests
benefits in neuropathic pain (Vinik 2014 Level II, n=318, JS 5; Freo 2019 NR), but tapentadol also
showed efficacy in nociceptive and inflammatory-pain models (Schiene 2011 NR) including
postoperative pain (Lee 2014b Level II, n=352, JS 5) and cancer pain (Mercadante 2017 Level IV SR,
8 studies, n=792). In the setting of acute pain, tapentadol IR achieves similar analgesia tooxycodone IR, mostly in a 5:1 dose ratio, but with oxycodone resulting in an increased incidenceof the gastrointestinal adverse effects nausea (OR 2.23; 95%CI 1.72 to 2.90), vomiting (OR 2.19;
95%CI 1.09 to 4.42) and constipation (OR 3.16; 95%CI 1.42 to 7.01) ( each in 3 RCTs) (Hartrick 2010
Level I, 5 RCTs, n=2,831). A subsequent systematic review confirmed these results; tapentadol IR
in doses of 50, 75 and 100 mg (with 75 mg being superior to 50 mg) provides similar analgesia tooxycodone IR 10 mg (Xiao 2017 Level I [PRISMA}, 9 RCTs, n=3,961) (4 RCTs overlap). The rate of nausea(RR 0.64; 95%CI 0.48 to 0.85), vomiting (RR 0.37; 95%CI 0.24 to 0.56) and constipation (RR 0.44;
95%CI 0.32 to 0.62) was lower with tapentadol IR 50 mg and nausea (RR 0.41; 95%CI 0.41 to 0.93)
and constipation (RR 0.38; 95%CI 0.25 to 0.54) with 75 mg.
Data in the setting of a number of chronic pain conditions show similar or superior efficacy
to conventional opioids with reduced rates of gastrointestinal adverse effects such as nausea,
vomiting and constipation leading to reduced rates of treatment discontinuation (Riemsma 2011
Level I, 42 RCTs [8 RCTs tapentadol, n=6,698]). In a network meta-analysis of opioids for chronic pain
treatment, tapentadol was identified as top-ranking due to low rates of overall adverse effects,
in particular constipation, and lowest withdrawal rate for adverse effects ( Meng 2017 Level I[PRISMA] [NMA], 32 RCTs, n unspecified).
Despite increasing use of this analgesic in many countries of the world (in particular the USA[approved 2008], Australia [2010] and Europe [2011]), only 4 (possibly 5 as double reporting of
one case could not be excluded) single drug tapentadol overdose deaths could be identified(Channell 2018 Level IV SR, 13 RCTs, 3 studies & 8 CRs, n=21,995 [tapentadol treated]). Relative safety of
tapentadol vs conventional opioids has been confirmed by data from the USA Researched Abuse,
Diversion and Addiction-Related Surveillance (RADARS) System Poison Center Program; there
was no reported death due to tapentadol between 2010 and 2016 and it had the lowest rate ofoverdose deaths, major medical effects, serious adverse events and hospitalisations (datacorrected for amounts dispensed) (Murphy 2018 Level IV, n=64,538 [reports]). Post-marketingsurveillance by the manufacturer could also not identify any overdoses with fatal outcomes(Stollenwerk 2018 Level IV, n=10,758 [case reports]). In an experimental setting, tapentadol (100 mg)
vs oxycodone (20 mg) (equianalgesic doses) had less respiratory depressant effects, but not 150
mg (van der Schrier 2017 Level II EH, n=18, JS 5).
Although a controlled medicine in all countries, tapentadol shows a lower rate of abuse anddiversion than oxycodone and hydrocodone and a rate comparable to tramadol ( Dart 2012
Level IV). Diversion rates of tapentadol in the USA (monitored by RADARS - note that the SR
preparation in the USA is tamper resistant) adjusted for amounts used were lower for tapentadol
IR (0.03/1,000 prescriptions) and tapentadol SR (0.016) than all other scheduled oral opioids(0.172) (Dart 2016 Level III-2, n=38,388 [cases of diversion]). A subsequent analysis by the same
system (adjusted for dosing units dispensed) confirms the lowest rate of diversion (comparable
to tramadol) and lower, but not the lowest, rate of intentional abuse in reports to poison centres(tramadol and hydrocodone being lower) (Vosburg 2018 Level III-3, n multiple denominators). Ratesof doctor shopping (sourcing from multiple providers) were higher for oxycodone vs tapentadol(OR 3.5; 95%CI 2.8 to 4.4) (Cepeda 2013b Level III-2) and rates of abuse lower for tapentadol vs
oxycodone (OR 0.35; 95%CI 0.21 to 0.58) (Cepeda 2013a Level III-2).

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TramadolTramadol is commonly referred to as an atypical centrally acting analgesic because of its
combined effects as an opioid agonist and a serotonin- and noradrenaline-reuptake inhibitor(Bravo 2017 NR; Raffa 2012 NR; Raffa 1992 NR). Although an effective analgesic, it may not provide
adequate pain relief if used as the sole agent for the management of moderate to severe acutepain at the currently recommended doses (Thevenin 2008 Level III-1). However, compared to avariety of strong opioids (morphine, fentanyl, oxycodone, pethidine) when administered by PCA,
tramadol had comparable analgesic efficacy (Murphy 2010 Level I, 12 RCTs, n=782). As discharge
medication after surgery, the risk of prolonged tramadol use was similar, if not slightly higher
than other short acting opioids (Thiels 2019 Level III-2, n= 444,764).
Limited low-quality evidence supports tramadol’s analgesic effect in cancer pain, although it
is not as effective as morphine in this indication (Wiffen 2017b Level I [Cochrane], 10 RCTs, n=958).
Tramadol is an effective treatment for neuropathic pain with NNT of 4.4 (95%CI 2.9 to 8.8)(Duehmke 2017 Level I [Cochrane], 6 RCTs, n=438).
IV tramadol/IV morphine vs IV morphine has a minor opioid-sparing effect (WMD 6.9 mg;
95%CI 211.3 to 22.5), but does not reduce pain intensity (WMD -0.9/100; 95%CI -7.2 to 5.2) nor
adverse effects (nausea, vomiting, sedation) (Martinez 2015 Level I [PRISMA], 14 RCTs, n=713).
The (+) enantiomer of tramadol is the stronger inhibitor of serotonin reuptake and the (-)
enantiomer the more potent inhibitor of noradrenaline reuptake; tramadol is metabolised by
CYP2D6 and the resultant active metabolite O-desmethyltramadol (M1) is a more potent muopioid receptor agonist than the parent drug (Lee 1993 NR). Patients who are poor metabolisers
get less analgesic effect from tramadol (Stamer 2003 Level III-2), while ultrarapid metabolisers may
be at increased risk of opioid-induced adverse effects including OIVI (Desmeules 1996 Level II, n=10,
JS 3; Stamer 2008 CR). See also Section 1.7.3.2.
Coadministration with other medicines that inhibit CYP2D6 may also influence theeffectiveness of tramadol. For example, pretreatment with paroxetine in healthy extensive
metabolisers reduced the hypoalgesic effect of tramadol in an experimental pain model(Laugesen 2005 Level II EH, n=16 [4-way cross over], JS 5). Inhibition of 5HT3 receptors by ondansetron
also decreased the analgesic effect of tramadol, as measured by increased tramadol
requirements, in particular early after ondansetron administration ( Stevens 2015 Level I [PRISMA]
6 RCTs, n=340), although this may also be a pharmacokinetic interaction (Hammonds 2003 NR). Thishas been confirmed in a subsequent RCT in hemithyroidectomy patients; here co-administrationof IV tramadol (1.5 mg/kg) with ondansetron (0.1 mg/kg) vs tramadol alone reduced time torequest for rescue analgesia (76.3 min vs 164.1) and analgesic efficacy at 0 to 60 min
postoperatively (at 60 min: 2.51/10 (SD ± 0.66) vs 1.16/10 (± 0.68), but improved PONV scores(Murmu 2015 Level II, n=134, JS 4)
Tramadol’s adverse-effect profile is different from other opioids. In the RADARS System
Poison Center Program, tramadol had the second-lowest rates of overdose deaths, major
medical effects, serious adverse events and hospitalisations (data corrected for amounts
dispensed) (Murphy 2018 Level IV, n=64,538 [reports]). The risk of respiratory depression is lower
than with conventional opioids at equianalgesic doses (Mildh 1999 Level II EH, n=8 [cross over], JS 5;
Tarkkila 1998 Level II, n=36, JS 4; Tarkkila 1997 Level II, n=36, JS 4) and it does not depress the hypoxic
ventilatory response (Warren 2000 Level II EH, n=20 [cross over], JS 5). However, in a large series oftramadol overdoses in Iran, mainly due to deliberate self-harm or abuse, 3.6% experienced
apnoea and required respiratory support or naloxone use ( Hassanian-Moghaddam 2013 Level IV,
n=525 [overdoses]). The mean time to presentation was 7.7 h (range 1 to 24 h); the mean dose
causing apnoea was 2,125 mg (range 200 to 4,600 mg), significantly higher than in those notexperiencing apnoea (1,383 mg; range 100 to 6,000 mg). One death in each group was reported.
A further series of tramadol overdoses reported hypertension (38.4%), tachycardia (24.8%),
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respiratory depression (20%) (median dose 2,750 mg), seizure (14.5%) and no serotonin toxicity(Habibollahi 2019 Level IV, n=359 [overdoses]). Similar findings are reported from the USA;
respiratory depression with relatively higher doses than other symptoms (median dose 2,500mg) and seizures, tachycardia, mild hypertension, but no serotonin toxicity ( Ryan 2015 Level IV,n=71). Significant respiratory depression has also been described in a patient with severe renal
failure, most likely due to accumulation of the metabolite M1 (Barnung 1997 CR).
There is a risk of inducing serotonin toxicity when tramadol is combined with otherserotonergic medicines, in particular SSRIs (Nelson 2012 Level IV SR, 1 study & 9 CR, n=14). However,despite the widespread use of both medicines, there are only very few case reports (14 cases inabove SR) on this interaction. The interaction might be complex, as SSRIs are often CYP2D6
inhibitors (eg sertraline, paroxetine and fluoxetine) and can thereby increase tramadol
concentrations (Miotto 2017 NR). This might also mean that poor CYP2D6 metabolisers are at anincreased risk of this interaction (Nelson 2012 Level IV SR, 1 study & 9 CR, n=14). Furthermore,administration of tramadol to elderly patients in the postoperative period was a risk factor fordelirium (Swart 2017 Level III-2 SR, 1 study [tramadol]: Brouquet 2010 Level IV, n=133).
Tramadol has less effect on gastrointestinal motor function than morphine ( Lim 2001 Level II,
n=101, JS 5; Wilder-Smith 1999b Level II, n=62, JS 5; Wilder-Smith 1999a Level II, n=30, JS 5; Wilder-Smith
1997 Level II, n=10 [cross over], JS 5). Nausea and vomiting are the most common adverse effects
and occur at rates similar to morphine (Lim 2001 Level II, n=101, JS 5; Radbruch 1996 NR), although

an increased rate in comparison to a variety of strong opioids (morphine, fentanyl, oxycodone,
pethidine) occurs with PCA use (OR 1.52; 95%CI 1.07 to 2.14) (Murphy 2010 Level I, 12 RCTs, n=782).
The incidence of pruritus was reduced with tramadol (OR 0.43; 95%CI 0.19 to 0.98).
Tramadol did not increase the incidence of seizures compared with other analgesic agents in
two observational studies (Gasse 2000 Level III-2, n=11,383; Jick 1998 Level III-2, n=10,916). Seizures
were reported in tramadol intoxication, mainly due to deliberate self-harm or abuse, with recurrent
seizures in 7 and 11.7% of patients (Hassanian-Moghaddam 2013 Level IV, n=525; Shadnia 2012 Level IV,
n=100). Potential risk factors for seizure, other than overdose, were a history of traumatic brain
injury, seizure activity secondary to hypoxia and use in combination with medications that lower
seizure threshold (Miotto 2017 NR). Calls to the National Poison Data System of the American
Association of Poison Control Centers were more likely to report seizures with tramadol vstapentadol (RR 7.94; 95%CI 2.99 to 20.91) (Tsutaoka 2015 Level III-2, n=8,783 [calls]). The low rate ofrecurrence does not justify the prophylactic use of an anticonvulsant after an initial seizure (Shadnia
2012 Level IV, n=100).
An analysis of reports from United States Food and Drug Administration Adverse Event
Reporting System showed an association between tramadol use and hypoglycaemia incomparison to all other opioids except methadone (Makunts 2019 Level IV, n=12,004,552).
Although withdrawal from tramadol is uncommon, abrupt cessation can lead to withdrawal
symptoms, which can have features of classical opioid withdrawal or atypical withdrawal seen with
SNRI antidepressants (similar to those described with venlafaxine withdrawal); gradual tapering is
recommended and treatment with lorazepam and clonidine if necessary (Miotto 2017 NR).
Finally, tramadol has a lower abuse and misuse potential than conventional opioids, asreconfirmed by an expert committee on drug abuse of the German government ( Radbruch 2013
GL); this is in line with previous findings and tramadol’s status as a noncontrolled drug in mostcountries. However, in countries with low availability of conventional opioids, tramadol has ahigher rate of abuse. This has been reported from China ( Wang 2018b Level III-2 SR, 80 studies, n=
118,904) and Africa (Salm-Reifferscheidt 2018 NR): eg Egypt (Bassiony 2018 Level IV, n=1,135), Ghana(Fuseini 2019 NR) and Nigeria (Idowu 2018 Level IV, n=249). A detailed assessment of issues related
to tramadol use and abuse internationally has been released by the WHO (WHO 2018 NR).

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4.3.1.4 | Determinants of opioid doseInterpatient opioid requirements vary greatly (Macintyre 1996 Level IV) and opioid doses therefore
need to be titrated to suit each patient. Reasons for variation include patient age and gender,
genetic differences and psychological factors as well as opioid tolerance.
Patient age
Age, rather than patient weight, appears to be a better determinant of the amount of opioid anadult is likely to require for effective management of acute pain. There is clinical andexperimental evidence of a two-fold to four-fold decrease in opioid requirements as patient age
increases (Gagliese 2008 Level IV, n=246; Coulbault 2006 Level IV, n=74; Gagliese 2000 Level IV, n=99;
Macintyre 1996 Level IV, n=1,010; Burns 1989 Level IV, n=100). The decrease in opioid requirement is
not associated with reports of increased pain (Macintyre 1996 Level IV, n=1,010; Burns 1989 Level IV,
n=100).
This age-related decrease in opioid requirement appears mainly due to differences inpharmacodynamics or brain penetration rather than systemic pharmacokinetic factors (Minto
1997 Level IV, n=65; Scott 1987 Level IV PK; Macintyre 2008b NR). See also Section 9.2.3.
Sex-based differences
In general, females report more severe pain than males with similar disease processes or in
response to experimental-pain stimuli (Hurley 2008 NR). This is more complicated than initiallythought; in experimental-pain settings, women have lower pressure pain thresholds than men
with no difference for cold and ischaemic pain (Racine 2012a Level IV SR, 122 studies, n unspecified).
Temporal summation, allodynia and secondary hyperalgesia may be more pronounced in womenthan in men (Racine 2012b Level IV SR, 129 studies, n unspecified). In acute pain, there is more of adifference in pain perception than pain sensitivity (Ravn 2012 Level IV EH, n=100).
Evidence for differences of opioid responses in the acute pain setting varies. Across all studies
in acute clinical pain with mu-opioids there is no association between sex and opioid response,
however with PCA use there is greater analgesic effect in women (ES 0.22; 95%CI 0.02 to 0.42)(Niesters 2010 Level I, 25 RCTs, n unspecified). The effect is even more pronounced with morphine PCA(ES 0.36; 95%CI 0.17 to 0.56) and is similar in experimental-pain settings (ES 0.35; 95%CI 0.01 to0.69). Likely explanations are interactions between oestrogen and opioid receptors (Lee 2013b NR).
This is supported by preclinical data which show that hormones interact with the opioid systemand that these interactions may produce meaningful sex-based differences in the subjective
experience of opioids, but the direction of effect is variable and inconsistent (Huhn 2018 BS SR).
While response to opioids may differ, both the degree and direction of variation depend on
many variables (Campesi 2012 NR; Dahan 2008a NR). This variation as well as other known andunknown factors involved in the very large interpatient differences in opioid requirements seen
clinically, means that biological sex cannot be used as a basis for opioid-dose alteration andconfirms the need to titrate doses to effect for each patient.
Genetics
Genetic variability may also affect a patient’s response to opioids (see Section 1.7.3).
Psychological factors
The effect of psychological factors such as anxiety on opioid requirements is contradictory (seeSection 1.2). Behavioural and psychological aspects associated with opioid tolerance andaddiction are discussed in Sections 9.7 and 9.8.

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4.3.1.5 | Adverse effects of opioids
Common opioid-related adverse effects are sedation, pruritus, nausea, vomiting, slowing ofgastrointestinal function and urinary retention. A network meta-analysis has assessedfrequencies for the various opioids at equianalgesic doses relative to morphine by PCA ( Dinges
2019 Level I [NMA], 63 RCTs, n unspecified) (for more details see Section 6.3.2). Meta-analysis has
also shown that the risk of adverse effects from opioids administered by PCA is similar to therisks from traditional methods of systemic opioid administration, with the exception of pruritus,
which is increased in patients using PCA (Hudcova 2006 Level I [Cochrane] 55 RCTs, n=3,861).
However, there may be differences in the routine clinical setting (Dolin 2005 Level IV SR, 165
studies, n≈20,000; Cashman 2004 Level IV SR, 165 studies, n≈20,000). The following incidences (means)
were associated with the use of PCA opioids: respiratory depression 1.2 to 11.5% (using
decreased respiratory rate and oxygen desaturation, respectively, as indicators), nausea 32%,
vomiting 20.7%, pruritus 13.8% and excessive sedation 5.3%. The incidences reported for IM
opioid analgesia were: respiratory depression 0.8 to 37% (using the same indicators), nausea
17%, vomiting 21.9%, pruritus 3.4% and excessive sedation 5.2%.
Clinically meaningful opioid-related adverse effects are dose-related. There was an increased
risk of 0.9% for nausea and 0.3% for vomiting for every 1 mg increase in PCA-morphine
consumption after surgery (Marret 2005 Level I, 22 RCTs, n=2,307). In a prospective evaluation ofelderly surgical inpatients (requiring a length of stay (LOS) >2 d and no PONV prophylaxis),
increasing opioid dose also correlated directly with both nausea and vomiting incidence (Roberts
2005 Level IV, n=193). After laparoscopic cholecystectomy, once a threshold dose was reached(≈10 mg MED/d), every further 3–4 mg increase of MED/d was associated with one additional
meaningful adverse effect or patient-day with such an event (Zhao 2004 Level II, n=193, JS 5).
Opioid-related adverse effects in surgical patients were associated with increased LOS in
hospital and total hospital costs; the use of opioid-sparing techniques can be cost-effective(Oderda 2007 Level III-2; Barletta 2012 NR; Philip 2002 NR). Postsurgical patients who experienced an
opioid-related adverse effect had a 55% longer LOS, 47% higher costs, 36% increased risk ofreadmission and 3.4 times higher risk of inpatient mortality ( Kessler 2013 Level III-2, n=37,031).
Similar results were found in the analysis of a large national hospital database ( Oderda 2013
Level III-2, n=319,898). More specific information was reported subsequently where 10.6% ofsurgical patients experienced an opioid-related adverse event (Shafi 2018 Level III-2, n=135,379).
Risk factors were higher opioid doses (MED 46.8 mg vs 30.0 mg) and opioid use for a longer
duration (median 3.0 vs 2.0 d). Opioid-related adverse events were associated with increased
inpatient mortality (OR 28.8; 95%CI 24.0 to 34.5 [2.9% increase in absolute mortality]), prolonged
LOS (OR 3.1; 95%CI 2.8 to 3.4), high cost of hospitalisation (OR 2.7; 95% CI 2.4 to 3.0), higher rateof 30 d readmission (OR 1.3; 95%CI 1.2 to 1.4) and US$ 8,225 per event increase in cost. Similarly,
in previously opioid-naïve patients receiving opioids after surgery, 9.1% experienced opioidrelated adverse effects with an increased risk with prolonged IV administration and resulted in
29% higher costs of hospitalisation, 55% longer postoperative LOS, 29% lower odds of discharge
home and 2.9 times the odds of death (Urman 2019 Level III-2, n= 12,218 [patients receiving opioids]).
Identifying patients at high risk of opioid-related adverse effects using clinical anddemographic parameters is possible (Minkowitz 2014a Level III-2, n=6,285; Minkowitz 2014b Level III-3,
n=3,697); identification of such high-risk patients enabled reduction of adverse effects andhospital costs.
Opioid-induced ventilatory impairment
OIVI is a more appropriate term to describe the effects of opioids on ventilation than respiratory
depression alone (Macintyre 2011 NR). It encompasses the respiratory depression caused by140

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opioids (decreased central CO2 responsiveness resulting in hypoventilation) and elevated partialpressure of CO2 in arterial blood [PaCO2]) (Boom 2012 NR) but also the depressed consciousness(decreased arousal and protection) and the subsequent upper airway obstruction (associatedwith lower airway motor tone) resulting from excessive opioid use. This combination is the mostfeared adverse effect of opioids, potentially with fatal consequences.
The most frequently reported risk factors for OIVI were older age, female gender, sleepdisordered breathing, obesity, renal impairment, pulmonary disease (in particular COPD), cardiac
disease, diabetes, hypertension, neurologic disease, two or more comorbidities, opioid
dependence, concomitant administration of sedatives, different routes of opioid administration
and CYP450 enzyme polymorphisms, but patients without such risk factors can also develop OIVI(Gupta 2018b Level IV SR, 13 studies, n=871,912; Overdyk 2014 Level IV, n=134 [case reports]).
Postoperative OIVI occurred in 5/1,000 cases with 85% in the first 24 h (95% CI 4.8 to 5.1) (Gupta
2018a Level IV SR [PRISMA], 12 studies, n=841,424). Increased risk is linked to cardiac disease (OR1.7; 95%CI 1.2 to 2.5), pulmonary disease (OR 2.2; 95%CI 1.3 to 3.6), OSA (OR 1.4; 95%CI 1.2 to1.7) and higher daily MED (24.7±14 mg vs 18.9±13.0 mg). Age, gender, BMI and ASA status are
not identified as risk factors in this systematic review. In a closed claims study of postoperative
OIVI, 88% of events occurred within 24 h postoperatively; risk factors included multiple
prescribers (33%), concurrent administration of sedating medications (34%), and inadequate
nursing assessments or response (31%) (Lee 2015b Level IV, n=92 [episodes of OIVI]). Other studies
confirm that most postoperative events of OIVI occur in the first 24 h: within 24 h 88% (within
12 h 58%) (Weingarten 2015 Level III-2, n=134 [naloxone administrations]), 81% (34% within 6 h)(Ramachandran 2011 Level IV, n=33 [episodes of OIVI]) and 78% (57% within 12 h) (Taylor 2005
Level III-2, n=62 [episodes of OIVI]).
OIVI can usually be avoided by careful titration of the dose against effect and carefulobservation and monitoring. A variety of clinical indicators have been used to indicate OIVI
caused by opioids; not all may be appropriate or sensitive.
A number of studies investigating hypoxia in the postoperative period in patients receiving
opioids for pain relief have found that measurement of respiratory rate as an indicator of
respiratory depression may be of limited value and that hypoxaemic episodes often occur inthe absence of a low respiratory rate ( Kluger 1992 Level III-2, n=40; Wheatley 1990 Level III-2, n=30;
Catley 1985 Level III-2, n=32; Jones 1990 NR). As respiratory depression is almost always precededby sedation, the best early clinical indicator is increasing sedation ( Jungquist 2017 NR; Macintyre
2011 NR; Vila 2005 NR; Ready 1988 NR). This has also been acknowledged in recommendations ofcurrent guidelines ( Jungquist 2020 GL; Chou 2016 GL).
Introduction of a numerical pain treatment algorithm in a cancer setting was followed bya review of opioid-related adverse effects (Vila 2005 Level III-3, n=25). Use of this algorithm, inwhich opioids were given to patients in order to achieve satisfactory pain scores, resulted in a
two-fold increase in the risk of respiratory depression. Importantly, the authors noted that
respiratory depression was usually not accompanied by a decrease in respiratory rate. Of the
29 patients who developed respiratory depression (either before or after the introduction of
the algorithm), only 3 had a respiratory rate of <12 breaths/min but 27 (94%) had adocumented decrease in their level of consciousness ( Vila 2005 Level III-3, n=29). This study
highlights the risk of titrating opioids to achieve a desirable pain score without appropriate
patient monitoring.
In a review of PCA, case reports of respiratory depression in patients with obstructive sleep
apnoea (OSA) were examined (Macintyre 2008a NR). It would appear that the development of
respiratory depression might have been missed because of an apparent over-reliance on the useof respiratory rate as an indicator of respiratory depression; the significance of excessive
sedation was not recognised.
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In an audit of 700 acute pain patients who received PCA for postoperative pain relief,
respiratory depression was defined as a respiratory rate of <10 breaths/min and/or a sedation
score of 2 (defined as “asleep but easily roused”) or more. Of the 13 patients (1.86%) reportedwith respiratory depression, 11 had sedation scores of at least 2 and, in contrast to thestatements above, all had respiratory rates of <10 breaths/min (Shapiro 2005 Level IV, n=700). In aclosed claims report, 62% of patients with postoperative OIVI (with 77% fatality or severe brain
injury) experienced somnolence before the event (Lee 2015b Level IV, n=92 [events of OIVI]): theauthors emphasise that assessment of sedation levels by nurses needs to be improved; 97% were
judged preventable with better monitoring and response. These studies confirm that assessmentof sedation is a more reliable way of detecting opioid-induced respiratory depression, althoughmonitoring respiratory rate is still important.
Oxygen saturation levels may not be a reliable method of detecting respiratory depression in
the postoperative setting. In addition to the use of supplemental oxygen delaying OIVI diagnosis,
there may be reasons other than opioids for hypoxaemia. For example, when measurement ofoxygen saturation was used as an indicator of respiratory depression, the incidence was reported
to be 11.5% in patients receiving PCA and 37% in those given IM opioids ( Cashman 2004 Level IV
SR, 165 studies, n≈20,000). However, the same authors showed that patients given IM opioids
reported more pain (moderate to severe pain in 67.2% and severe pain in 29.1% vs 35.8% and10.4% respectively in PCA patients), suggesting that these patients received much lower dosesof opioids (Dolin 2002 Level IV SR, 165 studies, n≈20,000). Continuous pulse oximetry (1 RCT, 3 studies)
improves recognition of desaturations (<90%) (OR 15.7; 95% CI 10.6 to 23.2), with no effect ontransfers to the ICU (RR 0.66; 95%CI 0.42 to 1.01) (Lam 2017 Level IV SR [PRISMA}, 2 RCTs & 7 studies,n>6,579).
Increases in PaCO2 are the most reliable way of detecting respiratory depression. Continuous
monitoring of transcutaneous CO2 for 24 h after major abdominal surgery showed that patients
given IV PCA morphine had higher CO2 levels than those receiving epidural local
anaesthetic/fentanyl infusions (McCormack 2008 Level III-2, n=30; Kopka 2007 Level III-2, n=28).
Continuous capnography vs continuous pulse oximetry (1 RCT & 2 studies) identifies more eventsof respiratory depression (OR 5.83; 95%CI 3.54 to 9.63) (11.5% vs 2.8%) ( Lam 2017 Level IV SR[PRISMA}, 2 RCTs & 7 studies, n>6,579).
Alternative monitors include continuous non-invasive respiratory-volume monitoring, which
was described as identifying at-risk patients with a significant drop in minute ventilation or
apnoeic/hypopnoeic episodes with high sensitivity (93%) and specificity (86%) (Voscopoulos 2014
Level IV, n=132).
Pharmacological strategies to reduce OIVI without affecting analgesia, eg by respiratory
stimulants, have been investigated (Kimura 2014 NR; van der Schier 2014 NR).
Cardiac effects
The use of methadone has been linked to the development of prolonged QT interval with a riskof TdP and cardiac arrest (Alinejad 2015 NR; Mujtaba 2013 NR). Methadone has this effect due toinhibition of the cardiac-ion channel KCNH226 and the effect is dose-dependent. Most casereports of TdP in patients taking methadone have identified the presence of at least one otherrisk factor in addition to methadone (Justo 2006 Level IV, n=40 [TdP cases in 14 reports]; Fredheim
2008 NR). Risk factors include female sex, heart disease, other medicines with effects on the QTinterval (eg tricyclic antidepressants [TCAs], antipsychotics, diuretics) or methadone metabolism,
congenital or acquired prolonged QT syndromes, liver impairment and hypokalaemia ( Mujtaba
2013 NR; Fredheim 2008 NR).
Of patients receiving substitution therapy of 60 to 100 mg/d methadone, 23% developed
prolonged QT intervals during treatment vs none of the buprenorphine patients taking 16 to142

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32 mg 3 times/wk (Wedam 2007 Level II, n=165, JS 5). In the methadone group, the QT interval
continued to increase over time, even with stable doses.
There is as yet no consensus regarding the benefits or otherwise of obtaining anelectrocardiogram (ECG) in patients prior to starting methadone, although it may be that thethreshold for doing so should be lower in patients with other concomitant risk factors, including
those receiving higher doses of methadone (Cruciani 2008 NR). Overall, guidelines targeting theprevention of death from methadone can only offer weak recommendations due to lack of gooddata (Chou 2014 GL); a Cochrane review was unable to identify any studies suitable for inclusion(Pani 2013 Level I [Cochrane] 0 RCTs, n=0). No adverse cardiac events related to intraoperative
methadone administration have been reported so far, although methadone (given along withother perioperative medications) has been associated with QT-prolongation in the postoperative period in over 50% of patients (Murphy 2019 NR).
The use of dextropropoxyphene also carries a risk of TdP (Barkin 2006 NR) (see above).
Similarly, higher doses of oxycodone were linked to prolonged QT intervals ( Fanoe 2009
Level III-2). Beside these opioids, buprenorphine and pethidine have also been associated withprolonged QT intervals (Klivinyi 2018 NR).
Nausea and vomiting
Nausea and vomiting are frequent adverse effects of opioid analgesia in a range of settings. PONV
and its prevention have been studied the most extensively; hence the following discussion will
focus on this data. PONV is common and related to opioid administration in a dose-dependent
manner (Marret 2005 Level I, 22 RCTs, n=2,307; Roberts 2005 Level IV, n=193), although many other more
relevant risk factors for PONV have also been identified (Apfel 2012 Level IV SR, 22 studies, n=95,154).
Opioids are a risk factor for PONV (OR 1.39; 95%CI 1.20 to 1.60) but less so than female sex, historyof previous PONV or motion sickness, inhalational anaesthesia and nonsmoking status. The
biological mechanisms of PONV have not yet been completely unravelled (Horn 2014 NR).
Guidelines on the prevention and management of PONV have been published ( Gan 2014 GL).
Medications used as components of multimodal analgesia and that are opioid-sparing may
also reduce PONV. Opioid-sparing effect and PONV reduction occurs with concurrent
administration of gabapentin (Grant 2016b Level I [PRISMA], 44 RCTs, n=3,489) and pregabalin (Grant
2016a Level I [PRISMA], 23 RCTs, n=1,693), nsNSAIDs (Maund 2011 Level I, 43 RCTs [PONV],n unspecified), ketamine (Assouline 2016 Level I [PRISMA], 19 RCTS, n=1,453) and lidocaine (Weibel
2018 Level I [Cochrane], 68 RCTs, n=4,525). See also sections covering these medications.
Opioid-sparing effect with no decrease in PONV is reported for paracetamol and coxibs(Maund 2011 Level I, 43 RCTs [PONV], n unspecified). However, paracetamol given IV preoperatively
or intraoperatively reduces PONV; this effect is associated with improved analgesia, not reduced
opioid requirements (Apfel 2013 Level I [PRISMA], 30 RCTs, n=2,364). Preoperative vs postoperative
paracetamol reduces postoperative vomiting (RR 0.50; 95%CI 0.31 to 0.83) ( Doleman 2015b
Level I [PRISMA], 7 RCTs, n=544) (see also Section 4.1).
Antiemetic medications
Eight antiemetic medications effectively prevent PONV vs placebo: droperidol, metoclopramide,
ondansetron, tropisetron, dolasetron, dexamethasone, cyclizine and granisetron ( Carlisle 2006
Level I [Cochrane], 737 RCTs, n=103,237). The authors conclude that evidence for differences
between the medications was unreliable due to publication bias. Despite limited data tocompare adverse effects, droperidol was more sedative and headache more common after
ondansetron.
Scientific fraud by Yoshitaka Fujii has influenced this meta-analysis on the efficacy ofantiemetics, in particular the efficacy of granisetron and ramosetron is overestimated byinclusion of 168 fraudulent RCTs by his group (Carlisle 2012 Level I, 534 RCTs, n unspecified).
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Ramosetron remains effective vs placebo (but less than reported previously) and maintains astatistical, but clinically questionable, advantage over ondansetron ( Mihara 2013 Level I, 12 RCTs,
n=1,372).
The efficacy of various single compounds in reducing incidence of PONV in the first 24 h has
been confirmed in updated meta-analyses; dexamethasone 4–5 mg IV (NNT 3.7), 8–10 mg IV (NNT3.8) (De Oliveira 2013b Level I [PRISMA], 60 RCTs, n=6,696); droperidol ≤1 mg IV (NNT 3.5 to 5 for highrisk patients) (Schaub 2012 Level I, 25 RCTs, n=2,957); metoclopramide 10 mg IV (NNT 7.8) (De Oliveira
2012b Level I [PRISMA], 30 RCTs, n=3,328); perphenazine (Schnabel 2010 Level I, 11 RCTs, n=2,081); 5HT3antagonists ondansetron, granisetron, tropisetron and dolasetron (Tang 2012 Level I, 85 RCTs,
n=15,269), palonosetron (Singh 2016a Level I [PRISMA], 22 RCTs, n unspecified) and TD hyoscine(scopolamine) (Apfel 2010 Level I, 25 RCTs, n=3,298). All 5-HT3 antagonists are superior to placebo in
reducing incidence of PONV (125 RCTs, n=16,667 patients) (Tricco 2015a Level I [NMA], 450 RCTs,
n=80,410).
NK1 receptor antagonists are also used in treatment and prophylaxis of PONV ( George 2010NR). Aprepitant (80 mg) reduces the incidence of nausea vs placebo (pooled RR 0.60; 95%CI
0.47 to 0.75) (3 RCTs, n=224) and vomiting (pooled RR 0.13; 95%CI 0.04 to 0.37) ( 3 RCTs, n=224)(Liu 2015 Level I [PRISMA], 14 RCTs, n=4,322). However, neither 40 mg (3 RCTs, n=1,171) nor 125
mg (2 RCTs, n=1,085) are superior to ondansetron 4 mg. After craniotomy, IV fosaprepitant 150
mg was significantly more effective than IV ondansetron 4 mg (6 vs 50% vomiting) ( Tsutsumi
2014 Level II, n=64, JS 5) and more effective than IV droperidol 1.25 mg (Atsuta 2017 Level II,
n=200, JS 5).
Propofol (1 mg/kg) close to the end of surgery reduced PONV significantly vs placebo (Kim
2014a Level II, n=107, JS 4). Caffeine 500 mg IV was ineffective in preventing PONV and increased
rates of nausea (Steinbrook 2013 Level II, n=136, JS 3).
Combinations of antiemetics may be more effective than one medication given alone.
Prophylaxis with the combination of a 5HT3-receptor antagonist and dexamethasone wasassociated with lower use of rescue antiemetics than 5HT3-receptor antagonist or
dexamethasone alone (Tricco 2015a Level I [NMA], 450 RCTs, n=80,410; Kovac 2006 Level I, 49 RCTs,
n=12,752), also after strabismus surgery in children (Shen 2014 Level I, 13 RCTs, n=2,006). Similarly,
the combination of droperidol and ondansetron was additive ( Chan 2006 Level II, n=400, JS 5).
Other combinations that were more effective than either medicine given alone werecyclizine/granisetron (Johns 2006 Level II, n=960, JS 5), dexamethasone/haloperidol (Chu 2008 Level
II, n=400, JS 5) and dexamethasone/dolasetron (Rusch 2007 Level II, n=242, JS 5). The addition of
metoclopramide to dexamethasone also led to better PONV prophylaxis but, compared withdexamethasone 8 mg alone, only if doses of 25 mg and 50 mg metoclopramide were used, not
10 mg (Wallenborn 2006 Level II, n=3,140, JS 4). Oral aprepitant 80 mg added to ondansetron
reduced the rate of postoperative vomiting in bariatric surgery patients for 72 h ( Sinha 2014
Level II, n=125, JS 5).
Droperidol and, to a lesser extent, ondansetron may lead to prolonged QT intervals. Concerns
about the potential for serious cardiac arrhythmias secondary to QT prolongation associatedwith droperidol led to a “black box” warning by the USA FDA in 2001. Following this there has
been a significant reduction in the use of this medication, even though the warning was felt by
many to be unwarranted (Habib 2008b NR). Mild QT prolongation can occur with anaesthesia andsurgery. Saline administration vs 0.625 and 1.25 mg IV droperidol were associated with similar
QT prolongation in the postoperative period (White 2005 Level II, n=120, JS 5). Similarly, 1.25 mg
droperidol did not prolong QT interval (Toyoda 2013 Level II, n=72, JS 3). A large review of surgicalpatients in the periods 3 y before (n=139,932) and 3 y after (n=151,256) the FDA black box warning
merged anaesthesia database information with information from ECG and other databases aswell as patients’ case notes, and recorded all patients who had documented prolonged QT

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intervals, TdP or death within 48 h of their surgery (Nuttall 2007 Level III-3). Despite a reduction indroperidol use from 12 to 0% of patients following the warning, there was no difference in theincidence of QT prolongation, ventricular tachycardia, or death within 48 h of surgery and noclearly identified case of TdP related to use of droperidol. The authors concluded that for lowdose droperidol, the “black box” warning was “excessive and unnecessary”. The scientific basisof the decision in favour of a “black box” warning has been questioned as a range of data showthat the incidence of QT prolongation and TdP development is similar for low-dose droperidol
and other compounds used to treat PONV (Halloran 2010 NR). The authors of guidelines for the
management of PONV also express concerns about the FDA caution and state “due to the 2001
black box warning, droperidol is not the first choice for PONV prophylaxis in many countries” (Gan2014 GL).
Haloperidol has also been associated with QT prolongation and TdP (Habib 2008a NR). Using
data from studies published up until 1988, a meta-analysis showed that haloperidol is also aneffective antiemetic (Buttner 2004 Level I, 23 RCTs, n=1,468). Subsequent studies have confirmed its
effectiveness vs placebo (Aouad 2007 Level II, n=93, JS 4), ondansetron (no differences in efficacy,
adverse effects or QT intervals) (Rosow 2008 Level II, n=244, JS 2; Aouad 2007 Level II, n=93, JS 4; Lee2007 Level II, n=90, JS 5) and droperidol (equally effective) (Wang 2008 Level II, n=150, JS 5).
Haloperidol/ondansetron was more effective than ondansetron alone ( Grecu 2008 Level II, n=268,
JS 3) and haloperidol/dexamethasone was also more effective than either medication given alone(Wang 2012 Level II, n=135, JS 3; Chu 2008 Level II, n=400, JS 5), again with no difference in adverse
effects or QT intervals. Compared with droperidol, the only advantage of haloperidol may be“that there is no black box warning” (Ludwin 2008 NR).
Dolasetron (IV and oral formulations) is contraindicated by the Canadian authorities for any
therapeutic use in children and adolescents aged <18 y and the prevention or treatment of PONV
in adults because of the risk of QT prolongation (Health Canada 2006 GL). This age restriction is not
limited to Canada but applies in a number of other countries including the UK. The effect oftherapeutic doses of dolasetron (and ondansetron) on QT prolongation is, however, minimal (6%from baseline) (n=1,429) (Obal 2014 Level III-3, n=1,429); a case of prolonged QT interval has beenreported after overdose (Rochford 2007 CR). More patients receiving granisetron/dexamethasone
experience an arrhythmia vs placebo (OR 2.96; 95 %CI 1.11 to 7.94), ondansetron (OR 3.23; 95%CI 1.17 to 8.95), dolasetron (OR 4.37; 95% CI 1.51 to 12.62), tropisetron (OR 3.27; 95 %CI 1.02
to 10.43), and ondansetron/dexamethasone (OR 5.75; 95% CI 1.71-19.34) (Tricco 2015b Level I[NMA], 31 RCTs, n=6,623).
Other antiemetic interventions
Low-dose naloxone ( 1 mcg/kg/h) reduces opioid-related postoperative nausea (RR 0.80; 95%CI
0.67 to 0.95), but has no effect on vomiting (RR 0.83; 95%CI 0.63 to 1.09) (Barrons 2017 Level I[PRISMA], 9 RCTs, n=946).
Mirtazapine vs placebo reduces PONV (RR 0.44; 95%CI 0.32 to 0.62) ( 3 RCTs) and has similareffects to ondansetron (1 RCT), while it also reduces anxiety (Bhattacharjee 2019 Level I [PRISMA],
7 RCTs, n=581).
Supplemental IV crystalloid infusions reduce the risk of PONV and the need for rescue
antiemetics (Jewer 2019 Level I [Cochrane], 41 RCTs, n=4,424). IV dextrose perioperatively vs control
does not reduce the risk of PONV, but does reduce the need for rescue antiemetics (Kim 2018
Level I [PRISMA], 7 RCTs, n=701).
Supplemental oxygen (FiO2 80%) in the postoperative period does not reduce PONV ( OrhanSungur 2008 Level I, 10 RCTs, n=1,729), but high inspired oxygen concentrations intraoperatively
reduce PONV in patients receiving inhalational anaesthetics without prophylactic antiemetics(Hovaguimian 2013 Level I, 22 RCTs, n=7,001).
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PC6 acupoint stimulation (by any means: acupuncture, electro-acupuncture, transcutaneouselectrical acupoint stimulation, transcutaneous nerve stimulation, laser stimulation, capsicum
plaster, acu-stimulation device and acupressure) reduces the incidence of nausea (RR 0.68;
95%CI 0.60 to 0.77) (40 RCTs, n=4,742), vomiting (RR 0.60; 95%CI 0.51 to 0.71) (45 RCTs, n=5,147)
and rescue antiemetic requirements (RR 0.64; 95%CI 0.55 to 0.73) ( 39 RCTs, n=4,622) based on
low quality evidence (Lee 2015a Level I [Cochrane], 59 RCTs, n=7,667). PC6 acupoint stimulation vsantiemetics (metoclopramide, cyclizine, prochlorperazine, droperidol, ondansetron anddexamethasone) is similarly effective on all three above outcomes. Acupuncture/acupressure is
the only nonpharmacological intervention included in the PONV management guideline
developed by the Society for Ambulatory Anesthesiology, endorsed by ANZCA (Gan 2014 GL).
Ginger (Zingiber officinale) reduces the severity (SMD −0.25; 95%CI −0.46 to −0.04), but not
the incidence of PONV (Toth 2018 Level I [PRISMA], 10 RCTs, n=918).
Aromatherapy vs placebo has no effect on incidence of PONV, but may reduce need for
rescue antiemetic requirements; both statements are based on low-quality evidence (Hines 2018
Level III-1 SR [Cochrane], 16 RCTs and CCTs, n=1,036).
In a pilot RCT, chewing gum was not inferior to ondansetron 4 mg for PONV treatment after
laparoscopic or breast surgery in females (Darvall 2017 Level II, n=94, JS 3).
Impairment of gastrointestinal motility
Opioids are well described as inducing constipation with chronic use (Ahmedzai 2006 NR). Opioids
impair return of bowel function after surgery (Barletta 2012 NR). A daily dose of hydromorphone
IV >2 mg was the most obvious risk factor for postoperative ileus ( Barletta 2011 Level IV, n=279).
Another risk factors was longer IV opioid use and postoperative ileus was a risk factor for
prolonged hospital LOS. After laparotomy and laparoscopic cholecystectomy and colectomy,
patients with postoperative ileus received higher opioid doses (median MED 285 mg vs 95 mg);in postoperative patients with an ileus, opioid doses above the median were associated withincreased LOS (3.8 d to 7.1 d), total costs (US$ 8,458 to 19,562), and readmission after
laparoscopic surgeries (4.8% to 5.2%) (Gan 2015 Level III-3, n= 138,068).
Overall, treatment of opioid-induced constipation due to chronic intake with opioid
antagonists (methylnaltrexone, naloxone, naloxegol, alvimopan, axelopran, or naldemedine)(NNT 3.4 to 7) (23 RCTs) is more effective than laxatives (lubiprostone [NNT 15] or prucalopride)(4 RCTs) (Nee 2018 Level I [PRISMA], 27 RCTs, n=8,881); the effects of the various opioid antagonists
are similar, while the two laxatives are only slightly better than placebo. A network meta-analysis
identified SC methylnaltrexone as the most effective opioid antagonist to treat opioid-induced
constipation (Sridharan 2018 Level I [NMA], 23 RCTs, n unspecified) (17 RCTs overlap).
The peripheral-acting opioid antagonists alvimopan and methylnaltrexone are effective inreversing opioid-induced slowing of gastrointestinal transit time and constipation and alvimopan
is an effective treatment for postoperative ileus (McNicol 2008 Level I [QUOROM], 22 RCTs, n=2,358)(4 RCTs overlap with Nee 2018); insufficient evidence exists about the efficacy or safety of naloxone
or nalbuphine. The efficacy of alvimopan has been confirmed in subsequent studies summarised
in a review (Kraft 2010 NR). After radical cystectomy in an RCT not included in any of the above
systematic reviews, alvimopan resulted in faster gastrointestinal recovery, shorter hospital LOS
and reduced incidence of postoperative ileus (7 vs 26%) with reduced resulting morbidity (8.4 vs29.1%) without increased adverse effects (Lee 2014a Level II, n=280, JS 3).
A combined formulation of controlled-release (CR) oxycodone and naloxone is available inmany jurisdictions. Compared with CR oxycodone alone in patients with chronic non-cancer pain,
the combination formulation resulted in similar analgesic efficacy but less bowel dysfunction(Lowenstein 2010 Level II [pooled analysis of 2 RCTs], n=578, JS 5). It has been suggested that thesebenefits were transferable to acute pain settings ( Kuusniemi 2012 NR). This was not confirmed

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after laparoscopic hysterectomy where oxycodone/naloxone CR had no beneficial effect on
constipation or other opioid adverse effects vs oxycodone CR (Comelon 2013 Level II, n=85, JS 5). IV
administration of the crushed combination resulted in reduced drug liking and other subjective
effects (Colucci 2014 Level II EH, n=24, JS 3).
Urinary retention
Opioids cause urinary retention due to presumed central and peripheral mechanisms. Opioid
antagonists reverse this effect; naloxone reversed opioid-induced urinary retention in 100% of
patients, while the peripheral opioid antagonist methylnaltrexone IV was effective in 42% of
study participants (Rosow 2007 Level III-1 EH, n=13). These data suggest that at least part of the
bladder dysfunction caused by opioids is peripherally mediated.
Premedication with gabapentin reduces urinary retention caused by opioids (NNT 7) ( Tiippana
2007 Level I [QUOROM], 22 RCTs, n=1,909). This effect is most likely related to the opioid-sparing
effect of gabapentin.
Pruritus
The mechanism of opioid-induced pruritus, which is particularly common after neuraxial opioid
administration, is not fully understood but central mu-opioid receptor-mediated mechanisms
are thought to be the primary cause (Ganesh 2007 NR). However, a serotonergic mechanism has
also been suggested (Aly 2018 Level II, n=40, JS 4) (see also Section 4.3.1.5).
Naloxone, naltrexone, nalbuphine and droperidol are effective in the treatment of opioidinduced pruritus, although minimum effective doses remain unknown ( Kjellberg 2001 Level I,
22 RCTs, n=1,477 patients); doses >2 mcg/kg/h of naloxone are more likely to lead to reversal ofanalgesic effects. Low-dose continuous naloxone (0.25–1 mcg/kg/h) has the best evidence (Miller
2011 NR). Nalbuphine specifically is more effective than placebo ( 3 RCTs), control (3 RCTs) anddiphenhydramine (1 RCT) in reducing pruritus (Jannuzzi 2016 Level I, 9 RCTs, n=1,128). Furthermore,
ondansetron reduces the incidence of opioid-induced pruritus after neuraxial administration
only in non-obstetric patients (RR 0.63; 95%CI 0.45 to 0.89) (3 RCTs, n=235) and not in obstetricpatients (RR 0.84; 95%CI 0.69 to 1.03) (7 RCTs, n=576) (Wang 2017b Level I [PRISMA], 10 RCTs, n=811).
Cognitive function and confusion
While opioids can be the cause of cognitive dysfunction, confusion and delirium, it is surprisingthat, after cardiac surgery, IM morphine 5 mg was superior to IM haloperidol 5 mg in treating
delirium (Atalan 2013 Level II, n=53, JS 2). This suggests that undertreated pain is a relevant
consideration. Similarly, in elderly patients after hip fracture repair, opioids were not an
important predictor of postoperative delirium (Sieber 2011 Level IV, n=236).
The risk of delirium and/or changes in cognitive function has been compared in patients
receiving different PCA opioids. There was no statistically significant difference in the rates ofconfusion between morphine and fentanyl (14.3 vs 14.3%) but there was less depression of
cognitive function with fentanyl (Herrick 1996 Level II, n=96, JS 2). No differences in cognitive
function were reported in patients receiving tramadol vs morphine (Silvasti 2000 Level II, n=60, JS 4)
or fentanyl (Ng 2006 Level II, n=30, JS 5) but cognition has been found to be poorer withhydromorphone vs morphine (Rapp 1996 Level II, n=61, JS 4).
Pethidine use postoperatively was associated with an increased risk of delirium in the
postoperative period in comparison to other opioids (Swart 2017 Level III-2 SR, 3 studies [pethidine],
n=877). Tramadol has been identified as a risk factor for postoperative delirium in the elderly
following abdominal surgery (Swart 2017 Level III-2 SR, 1 study [tramadol]: Brouquet 2010 Level III-2,
n=118).

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Tolerance and hyperalgesia
In the absence of disease progression, a decrease in the effectiveness of opioid analgesia has
traditionally been attributed to opioid tolerance. It is now known that administration of opioids
can lead to both opioid-tolerance (a desensitisation of antinociceptive pathways to opioids) and,paradoxically, to opioid induced hyperalgesia (OIH: a sensitisation of pronociceptive pathways
leading to pain hypersensitivity) and that both these phenomena can significantly reduce theanalgesic effect of opioids (Mao 2015 NR; Low 2012 NR; Lee 2011 NR). The mechanisms underlying
the development of tolerance and OIH are still not fully understood but, as with neuropathic
pain, are thought to include activation of the glutaminergic system via the NMDA receptor, GABA
receptors and possibly the innate neuroimmune system ( Arout 2015 BS NR) as well as peripheral
mu-opioid receptors (Weber 2017 NR).
It may be useful here to distinguish “pharmacological tolerance” (ie tolerance, as defined in
Section 9.7.1 “the predictable and physiological decrease in the effect of a drug over time”) and“apparent tolerance”, where both tolerance and OIH contribute to a decrease in theeffectiveness of opioids (Chang 2007 NR; Mao 2008 NR). The clinical significance of this mix, andthe relevant contribution of pharmacological tolerance and OIH to apparent tolerance in any
particular patient is difficult, if not impossible, to determine (Low 2012 NR). However, inadequate
pain relief because of pharmacological tolerance may improve with opioid dose escalation, while
improvements in analgesia in the presence of OIH may follow a reduction in opioid dose ( Mao2008 NR; Chu 2008 NR; Chang 2007 NR).
A formal diagnosis of hyperalgesia may require quantitative sensory testing (QST), that is,serial assessment of the responses to varying intensities of a nociceptive stimulus, in order todetermine pain thresholds (Mitra 2008 NR). QST before and after starting chronic opioid therapy
may assist in the differentiation between OIH and pharmacological tolerance (Chu 2008 NR) but
this is unlikely to become common practice in the acute pain setting. OIH is identified by reduced
pain tolerance to noxious thermal (hot and cold) stimuli, but not electrical stimuli, in patientswith chronic opioid exposure for pain management and for opioid use disorder treatment (heremore evident) (Higgins 2019 Level III-3 EH SR [PRISMA], 26 studies, n=2,706); pain detection thresholds
remain unchanged. However, an attempt to identify a QST method to detect hyperalgesia inchronic pain patients on long-term opioids failed, as none of the measures could be used as adefinitive standard (Katz 2015 Level IV EH SR, 14 studies, n unspecified). The pain types investigatedinclude cold, heat, pressure, electrical, ischaemic and injection; only heat pain sensitivity showedpromise.
Studies of OIH are confounded by factors such as pain modality tested, route ofadministration and type of opioid (Weber 2017 NR). Psychological factors such as pain-related
distress and catastrophising might also affect pain sensitivity in those taking opioids for chronic
pain (Edwards 2011 Level III-2, n=276; Eyler 2013 NR). Illicit substance use, affective characteristics,
or coping styles may also play a role here (Higgins 2019 Level III-3 EH SR [PRISMA], 26 studies,
n=2,706). Additionally, increasing opioid dose will worsen OIH ( Colvin 2019 NR). Practical clinicalchallenges include lack of consensus on “the” diagnostic test, and overlap with tolerance, drug
withdrawal and neuropathic pain.
It is probable that the degree of OIH varies between opioids. Remifentanil in particular (Fletcher
2014 Level I [PRISMA], 27 RCTs, n=1,494; Kim 2014b Level IV EH SR, number of studies unspecified, nunspecified; Rivosecchi 2014 Level IV SR, 35 studies, n unspecified) (significant overlap between all three SRs),

but also morphine, in high doses, may be more likely to result in OIH than some other opioids;
experimental data and a very limited number of case reports have shown an improvement whenmorphine doses were reduced or a change to methadone, fentanyl or sufentanil was made (Angst
2006 NR). Similarly, it appears that opioids differ in their ability to induce tolerance. Medications
such as methadone, fentanyl and sufentanil promote receptor internalisation and thereby receptor

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recycling; in contrast, the activation of opioid receptors by morphine leads to little or no receptor
internalisation and thereby increased risk of development of tolerance (Joo 2007 NR). The difference
between opioids is one reason why opioid-rotation may be a useful strategy in the clinical setting
in attempts to improve pain relief (see Section 9.7.6.4).
In the setting of postoperative pain, high intraoperative doses of opioids resulted in higher
postoperative pain intensity than controls at 1 h (MD 9.4/100; 95%CI 4.4 to 14.5), 4 h(MD 7.1/100; 95%CI 2.8 to 11.3) and 24 h (MD 3/100; 95%CI 0.4 to 5.6) and higher postoperative
morphine use over 24 h (SMD 0.7; 95%CI 0.37 to 1.02) (Fletcher 2014 Level I [PRISMA], 27 RCTs,
n=1,494). These results are mainly influenced by remifentanil due to limited data with otheropioids. Overall, the effect of remifentanil is dose dependent ( Angst 2015 NR).
Compared with abrupt cessation, gradual withdrawal from a target concentration 2.5 ng/mLof a remifentanil infusion for 30 min (by 0.6 ng/mL target concentration every 5 min) induced no
OIH (pain similar to placebo) measured with the heat pain test, but not the cold pressor test
(Comelon 2016 Level II EH, n=19, JS 5). This was confirmed in a clinical setting of thyroidectomy,
where gradual tapering of a remifentanil infusion (from 0.3 to 0.1 mcg/kg/min over at least
30 min) reduced postoperative pain at 1 and 2 h and rescue analgesia requirements ( Han 2015
Level II, n=62, JS 5).
NMDA-receptor antagonists (mainly ketamine [8 RCTs] but also magnesium [5 RCTs] andamantadine [1 RCT]) reduce the development of acute tolerance/OIH associated withremifentanil use (Wu 2015 Level I [QUOROM], 14 RCTs, n=729). Attentuation occurs with pregabalin(Lee 2013a Level II, n=93, JS 5; Jo 2011 Level II, n=60, JS 5), propofol (subgroup analysis: 6 RCTs, n=341)(Fletcher 2014 Level I [PRISMA], 27 RCTs, n=1,494) and N2O (Wehrfritz 2016 Level II EH, n=21, JS 5;
Echevarria 2011 Level II, n=50, JS 4). Low-dose naloxone (0.25 mcg/kg/h intraoperatively) also
reduced postoperative opioid requirements when combined with high dose remifentanil (andimproved time to bowel recovery) (Xiao 2015 Level II, n=75, JS 5). In an experimental setting,propranolol infusion reduced the size of area of secondary hyperalgesia induced by remifentanil
to being not significantly different from baseline (Chu 2012 Level II EH, n=10 [cross over], JS 4). In
animal experiments, the effects of gabapentin and ketamine on fentanyl-induced hyperalgesia
were supra-additive (Van Elstraete 2011 BS).
The challenge faced by the health professional is that if inadequate pain relief is due to OIH,
a reduction in opioid dose may help; if it is due to opioid tolerance, increased doses may provide
better pain relief (Colvin 2019 NR; Huxtable 2011 NR; Mao 2008 NR). There are case reports ofpatients with cancer and chronic noncancer pain taking high doses of opioid who developed OIH
and whose pain relief improved following reduction of their opioid dose ( Chang 2007 CR; Angst
2006 CR); there are no data in the acute pain setting.
When a patient who has been taking opioids for a while (either legally prescribed or illicitly
obtained) has new and ongoing tissue injury with resultant acute pain, a reasonable initial
response to inadequate opioid analgesia, after an evaluation of the patient and in the absenceof evidence to the contrary, is a trial of higher opioid doses (Huxtable 2011 NR; Chang 2007 NR). If
the pain improves, this would suggest that the inadequate analgesia resulted from tolerance; ifpain worsens, or fails to respond to dose escalation, it could be a result of OIH ( Chang 2007 NR).
Fortunately, some of the strategies that may be tried in an attempt to attenuate opioid tolerance
in the acute pain setting may also moderate OIH (see below).
Other reasons for increased pain and/or increased opioid requirements should also be
considered. These include acute neuropathic pain, pain due to other causes including
postoperative complications, major psychological distress and aberrant drug-seeking behaviours(see Sections 9.7 and 9.8) (Edwards 2011 Level III-2; Macintyre 2015 NR; Gourlay 2008 NR).
The clinical relevance of the phenomena of opioid tolerance and OIH in the setting of
perioperative analgesia remains under discussion (Colvin 2019 NR) (See also Section 9.7.2 and 9.8.1).
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Tolerance to adverse effects of opioids
Tolerance to the adverse effects of opioids also occurs; tolerance to sedation, cognitive effects,
nausea and respiratory depression can occur reasonably rapidly but there is little, if any, change
in miosis or constipation (Chang 2007 NR).

KEY MESSAGES
1. Dextropropoxyphene has low analgesic efficacy (U) (Level I [Cochrane Review]).
2. Tramadol is an effective treatment for neuropathic pain (S) (Level I [Cochrane Review]).
3. Droperidol, metoclopramide, ondansetron, tropisetron, dolasetron, dexamethasone,
cyclizine, granisetron (U) (Level I [Cochrane Review]), supplemental crystalloid
infusions (N) (Level I [Cochrane Review]), palonosetron and mirtazapine (N) (Level I[PRISMA]) are effective in the prevention of postoperative nausea and vomiting.
4. PC6 acupoint stimulation by multiple techniques reduces postoperative nausea andvomiting (S) (Level I [Cochrane Review]).
5. Neurokinin-1 receptor antagonists aprepitant (S) (Level I [PRISMA]) and fosaprepitant(U) (Level II) are effective in the prevention of postoperative nausea and vomiting.
6. Intraoperative administration of the long acting opioid methadone reduces
consumption of shorter acting opioids in the 24 hours after surgery (N) (Level I[PRISMA]). Safety data suggest an increased risk of opioid induced ventilatory
impairment due to the long and unpredictable half-life of methadone (N) (Level IV).
7. Opioids in high doses, in particular remifentanil, can induce hyperalgesia and/or acute
tolerance (S) (Level I [PRISMA]).
8. Propofol (U) (Level I [PRISMA]), NMDA-receptor antagonists (U) (Level I [QUOROM]),
pregabalin (U) (Level II), nitrous oxide (N) (Level II) and gradual tapering of remifentanil
dose (N) (Level II) attenuate acute tolerance and/or hyperalgesia induced byremifentanil.
9. NSAIDs, gabapentin, pregabalin, systemic lidocaine and ketamine are opioid-sparing
medications and reduce opioid-related adverse effects (S) (Level I [PRISMA]).
10. Paracetamol given preoperatively and intraoperatively reduces postoperative nausea
and vomiting; this effect is associated with improved analgesia, not reduced opioid
requirements (S) (Level I [PRISMA]).
11. Opioid antagonists (methylnaltrexone, naloxone, naloxegol, alvimopan, axelopran, or
naldemedine) are effective (more so than laxatives) and safe to treat opioid-induced
constipation (S) (Level I [PRISMA]).
12. Alvimopan is an effective treatment for postoperative ileus (U) (Level I [QUOROM]).
13. Haloperidol, perphenazine and transdermal scopolamine are effective in theprevention of postoperative nausea and vomiting (U) (Level I).
14. The incidence of clinically meaningful adverse effects (nausea, vomiting) of opioids isdose-related (U) (Level I).

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15. Paired combinations of 5HT3 antagonists, droperidol or dexamethasone provide
superior prophylaxis of postoperative nausea and vomiting than either compound
alone (U) (Level I).
16. Naloxone, naltrexone, droperidol (U), nalbuphine (S) (Level I) and ondansetron (N)(Level I [PRISMA]) are effective treatments for opioid-induced pruritus.
17. Opioids administered by PCA, in particular morphine, show higher analgesic efficacy infemales than in males (U) (Level I).
18. Tapentadol has similar efficacy to conventional opioids with a reduced rate ofgastrointestinal adverse effects (nausea, vomiting, constipation) (S) (Level I).
19. Tramadol has a lower risk of respiratory depression and impairs gastrointestinal motor
function less than other opioids at equianalgesic doses (U) (Level II).
20. Pethidine is not superior to morphine or hydromorphone in treatment of pain of renal
colic (U) (Level II).
21. Morphine-6-glucuronide is an effective analgesic (U) (Level II).
22. In the management of acute pain, one opioid is not superior to others but someopioids are better in some patients (U) (Level II).
23. High doses of methadone can lead to prolonged QT interval (U) (Level II).
24. Opioid antagonists are effective treatments for opioid-induced urinary retention (U)(Level III-1).
25. Pethidine use is associated with an increased risk of delirium in the postoperative
period compared to other opioids (S) (Level III-2 SR).
26. In clinically relevant doses, there is a ceiling effect for respiratory depression withbuprenorphine but not for analgesia (U) (Level III-2).
27. Tapentadol has lower rates of abuse and doctor shopping than oxycodone (S) (Level III-2).
28. Opioid-related adverse effects in the postoperative period are associated withincreased inpatient mortality, length of hospital stay, costs and rates of readmission (S)(Level III-2).
29. Assessment of sedation is a more reliable way of detecting early opioid-induced
ventilatory impairment than a decreased respiratory rate (S) (Level III-3).
30. The evidence for significant QT prolongation and risk of cardiac arrhythmias following
low-dose droperidol, haloperidol and dolasetron is weak (U) (Level III-3).
31. Opioid-induced ventilatory impairment occurs in particular in the first 24 h after
surgery and important risk factors are cardiac and pulmonary disease, obstructive sleep
apnoea and use of higher opioid doses (N) (Level IV SR [PRISMA]).
32. Continuous pulse oximetry in patients receiving opioids postoperatively increases
detection rate of desaturation, but continuous capnography is superior in identifying
episodes of opioid-induced ventilatory impairment (N) (Level IV SR [PRISMA]).
33. In adults, patient age rather than weight is a better predictor of opioid requirements,
although there is a large interpatient variation (U) (Level IV).
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34. Impaired renal function and the oral route of administration result in higher levels of
the morphine metabolite morphine-6-glucuronide with increased risk of sedation andrespiratory depression (U) (Level IV).
34. CYP2D6 ultrarapid metabolisers are at increased risk of codeine toxicity (N) (Level IV).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Opioid-induced ventilatory impairment is a more appropriate term to describe theeffects of opioids on ventilation as it encompasses the central respiratory depression
caused by opioids and also the depressed consciousness and the subsequent upper
airway obstruction resulting from excessive opioid use (U).
 The use of pethidine and dextropropoxyphene should be discouraged in favour of otheropioids (S).
 Drug interactions relevant for opioids include pharmacodynamic considerations (egcoadministration of sedative agents) and pharmacokinetic effects (eg CYP 450 enzyme
inducers or inhibitors [antidepressants for CYP2D6 and antifungals, antibiotics for
CYP3A4 and complementary medicines for both]) (N).

4.3.2 | Neuraxial opioids
Opioid receptors were described in the spinal cord of the rat in 1976 (Pert 1976 BS) and the same
year a potent analgesic effect of directly applied IT morphine was reported in these animals(Kontinen 2019 NR; Yaksh 1976 BS). Opioid analgesia is spinally mediated via presynaptic andpostsynaptic receptors in the substantia gelatinosa in the dorsal horn ( Yaksh 1981 BS). Spinal
opioid receptors are 70% mu, 24% delta and 6% kappa (Treman 2001 NR); with 70% of all mu anddelta receptors being presynaptic (predominantly small primary afferents) and commonly colocated, with kappa being more commonly postsynaptic. Opioid-mediated antinociception may
be further augmented by descending inhibition from mu-opioid-receptor activation in theperiaqueductal area of the brain, which may be potentiated by neuraxial opioids. In addition tothis, a local anaesthetic action has been described for pethidine (meperidine) that may
contribute to the clinical effect when administered IT (Jaffe 1996 BS). The first clinical use of IT
morphine was for analgesia in cancer patients (Wang 1979 Level IV).
The use of neuraxial opioids has been reviewed in paediatric patients ( Berger 2019 NR) (seesections 10.6.4 for use in paediatric cardiac and general surgery and section 10.6.6 for use inpaediatric scoliosis surgery) and obstetric populations (Armstrong 2016 NR). Its use is widespreadin the obstetric and gynaecological setting for provision of analgesia in labour, Caesarean section
and hysterectomy (Hein 2017 Level IV, n=32 [obstetric units in Sweden]). See also Section 9.1.3.3.
Although dose-response analyses are not always clear, it is suggested that neuraxial opioids
have a ceiling effect for analgesia, with optimal single-injection morphine doses (balancing riskbenefit) of 50 to 150 mcg IT and 2.5 to 3.75 mg via epidural route (Saltan 2011 NR).

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4.3.2.1 | Efficacy of intrathecal opioids
IT opioids have been used for surgical procedures ranging from lower limb orthopaedic surgery
to CABG surgery because of their ability to provide prolonged postoperative analgesia following
a single dose vs systemic administration. IT opioids may be given alone or in conjunction with alocal anaesthetic. In acute pain, the use of continuous subarachnoid infusions of opioids for
postoperative analgesia is uncommon.
The lipid solubility of opioids largely determines the speed of onset and duration of IT
analgesia; hydrophilic opioids (eg oxycodone, morphine, hydromorphone) have a slower onsetof action and longer half-lives in CSF with greater dorsal horn bioavailability and greater cephaladmigration vs lipophilic opioids (eg fentanyl) (Bujedo 2014 NR; Bernards 2003 NR).
Single injection IT opioids
Early clinical studies used very high IT morphine doses (ie ≥500 mcg). However adequate
postoperative analgesia with fewer adverse effects may be obtained with significantly lessmorphine; although at lower doses there is not a clear dose-response relationship for pain relief
or some adverse effects (see below) (Meylan 2009 Level I, 27 RCTs, n=1,205).
Low doses of IT morphine are effective in prolonging local anaesthetic block or reducing thedose of local anaesthetic required for spinal anaesthesia with reduced adverse effects andimproved recovery (Popping 2013 Level I [PRISMA], 28 RCTs; n=1,393; Popping 2012 Level I [PRISMA],
55 RCTs; n=3,338).
When combined with low-dose bupivacaine for Caesarean section, 100 mcg IT morphine
produced analgesia comparable with doses as high as 400 mcg, with significantly less pruritus(Girgin 2008 Level II, n=100, JS 4). A single dose of IT morphine (100 mcg) added to a spinal
anaesthetic for Caesarean section prolongs the time to first postoperative analgesic
administration by 16 to 20 h (Dahl 1999 Level I, 15 RCTs, n=535). Sufentanil (2 RCTs) and fentanyl(8 RCTs) showed little or no analgesic benefit in doses of 25 mcg or less. No differences in pain
reported or analgesia use was detected when comparing 100 mcg to 50 mcg IT morphine for
Caesarean section, although pruritus was more common in the higher-dose group (Carvalho 2013
Level II, n=130, JS 4).
IT morphine 100, 200 and 300 mcg added to bupivacaine for postoperative analgesia
following abdominal hysterectomy reduced IV PCA morphine consumption vs placebo, with noadditional benefit of 300 mcg vs 200 mcg (Hein 2012 Level II, n=144, JS 5).
The addition of IT fentanyl 25 mcg to low-dose spinal bupivacaine for anorectal surgery
resulted in more pruritus but lower mean recovery and discharge times, with fewer analgesic
requests in the fentanyl group (Gurbet 2008 Level II, n=40, JS 3). Tramadol 10 and 25 mg
administered IT with bupivacaine produces extension of spinal analgesia and prolonged
postoperative analgesia similar to comparative doses of fentanyl 10 and 25 mcg for Caesarean
section (Subedi 2013 Level II, n=80, JS 5) and appendectomy (Afolayan 2014 Level III-1, n=186).
Added to hyperbaric bupivacaine 10 mg (2 mL 0.5%), IT sufentanil 5 mcg provided shorter
postoperative analgesia (mean 6.3 h) than IT morphine 200 mcg (mean 19.5 h) with no differencein adverse effects (Karaman 2006 Level II, n=54, JS4).
In a non-blinded comparison, following Caesarean section IT morphine 100 mcg recipients
had longer analgesia and fewer intraoperative adverse effects vs IT pethidine 10 mg recipients
but experienced more pruritus (Kumar 2007 Level II, n=60, JS 2). IT pethidine 25 mg added tolidocaine with adrenaline for spinal anaesthesia had quicker onset with higher sensory block andmore prolonged time to significant pain (≥4/10) (9.6 h) vs IT fentanyl 25 mcg (6.3 h) or placebo(2.1 h) (Farzi 2014 Level II, n=195, JS 5).

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Combination IT opioids
The addition of 10 mcg sufentanil to 400 mcg IT morphine did not potentiate postoperative
analgesia or reduce intraoperative opioid requirements in patients undergoing major colorectal
surgery (Culebras 2007 Level II, n=80, JS 5).
IT opioid infusions
In the ICU, IT infusion of morphine has been reported as a method to control burns pain andthereby avoiding the adverse effects of systemic opioids ( Zuehl 2018 CR). IT morphine has also
been administered in bolus doses via a 22-g IT catheter placed at L 3/4 to provide analgesia after
thoracotomy (mean dose over 48 h 2.56 mg  SD 0.88) with no serious complications or sequelae
at 6 mth follow-up (Ward 2014 Level IV, n=84).
For further details on effectiveness and adverse effects related to the use of IT opioids see
Section 4.3.2.3 below and 5.7.1.2.
4.3.2.2 | Efficacy of epidural opioids
The behaviour of epidural opioids is governed largely by their lipid solubility. The greater
sequestration of lipid soluble opioids into epidural fat and slow rerelease back into the epiduralspace means that elimination from the epidural space is prolonged, resulting in relatively smaller
fractions of medication reaching the CSF (Bernards 2003 NR). Lipophilic opioids (eg fentanyl) havea faster onset but shorter duration of action vs hydrophilic opioids (eg morphine) (Bujedo 2014 NR;
Bernards 2004 NR; de Leon-Casasola 1996 NR).
A meta-analysis of randomised studies involving epidural opioids, mostly in combination withlocal anaesthetics, found no differences in VAS pain scores at any time after surgery between
opioids, although there was a higher rate of nausea and vomiting (OR 1.95; 95%CI 1.14 to 3.18)
with morphine vs fentanyl (Youssef 2014 Level I [PRISMA], 24 RCTs, n=1,513). No studies directlycompare epidural morphine and fentanyl alone for postoperative analgesia.
Epidural diamorphine
Diamorphine (diacetylmorphine, heroin) is rapidly hydrolysed to 6-mono-acetylmorphine (6MAM) and morphine. Diamorphine and 6-MAM are more lipid soluble than morphine andpenetrate the CNS more rapidly, although it is 6-MAM and morphine that are thought to be
responsible for the analgesic effects of diamorphine ( Miyoshi 2001 NR). Epidural administrationof diamorphine is common in the UK and is effective whether administered by intermittent bolus
dose or infusion (McLeod 2005 Level II, n=62, JS 5).
Epidural fentanyl
The evidence that epidural fentanyl acts via a spinal rather than systemic effect is conflicting andit has been suggested that any benefit when comparing epidural with systemic fentanyl alone ismarginal (Bernards 2004 NR; Wheatley 2001 NR). However, the conflicting results may be due todiffering techniques of administration. A lumbar epidural infusion of fentanyl appears to produce
analgesia by uptake into the systemic circulation, whereas a bolus dose of fentanyl produces
analgesia by a selective spinal mechanism (Ginosar 2003 Level IV EH, n=10). Thoracic epiduraladministration does appear to produce greater spinal analgesia, an effect more pronounced withcoadministration with adrenaline, which provides a supra-additive effect possibly via both
pharmacokinetic (via vasoconstriction, increasing the amount of epidural fentanyl available tospinal cord site of action) and pharmacodynamic (via alpha-2 adrenoceptor antinociceptive)
mechanisms (Niemi 2013 NR). Less intraoperative fentanyl is required when administered via athoracic epidural catheter vs IV administration for colon surgery, with longer time to first154

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postoperative analgesia request (Sadurni 2013 Level II, n=30, JS 4). There is no evidence of benefit
of epidural vs systemic administration of alfentanil or sufentanil ( Bernards 2004 NR).
Epidural hydromorphone
The quality of epidural analgesia with hydromorphone is similar to morphine (Chaplan 1992
Level II, n=55, JS 5). In a comparison of epidural and IV hydromorphone, patients required twice
as much IV hydromorphone to obtain the same degree of analgesia (Liu 1995 Level II, n=16, JS 3).
Epidural morphine
Morphine is the least lipid soluble of the opioids administered epidurally; it has the slowest onset
and offset of action (Cousins 1984 NR) and the highest bioavailability in the spinal cord after
epidural administration (Bernards 2004 NR). As morphine has a prolonged analgesic effect, it canbe given by intermittent bolus dose or infusion; the risk of respiratory depression may be higher
and analgesia less effective with bolus dose regimens (de Leon-Casasola 1996 NR). The low lipid
solubility makes level of administration of epidural morphine less relevant after blunt chest wall
trauma with no difference in any outcome between thoracic and lumbar epidural morphine
administration (Hakim 2012 Level II, n=55, JS 3).
Extended-release epidural morphine
An extended-release (ER) suspension of morphine has been developed for epidural use(Depodur™) consisting of morphine molecules suspended in liposome complexes (lipofoam).
ER epidural morphine (EREM) was effective vs placebo after THA (Martin 2006 Level II, n=126, JS 5;
Viscusi 2005 Level II, n=200, JS 5) and, using doses of ≥10 mg, to lead to better pain relief vs standard
epidural morphine (4 or 5 mg) and reduced need for supplemental analgesics up to 48 h after
THA (Viscusi 2006 Level III-1, n=39), lower abdominal surgery (Gambling 2005 Level II, n=541, JS 4) andCaesarean section (Carvalho 2007 Level II, n=70, JS 5; Carvalho 2005 Level II, n=79, JS 3). A pooled
analysis of six clinical studies described consistent prolonged pharmacokinetics vs standard
epidural morphine, with 25% higher peak plasma concentrations in women, mainly explained bydifferences in body weight (Viscusi 2009 PK).
EREM has provided superior analgesia vs continuous femoral nerve block (FNB) after TKA;
however, only at rest at 24 h (Johnson 2011 Level II, n=65, JS 3). There were no differences infunctional outcomes and adverse effects except for more pruritus with EREM but patients
reported greater satisfaction with EREM. In two patients, EREM was used successfully after
multiple rib fractures (Ford 2012 Level IV). After lumbar spinal surgery, EREM provided similaranalgesia with fewer adverse effects than epidural morphine (Vineyard 2014 Level II, n=60, JS 3). IT
morphine 7.5 mcg/kg vs EREM 150 mcg/kg had similar time to first PCA use and similar
postoperative morphine IV use over 0 to 48 h in children (8 to 17 y) undergoing posterior spinal
fusion for scoliosis repair (Cohen 2017 Level II, n=71, JS 4). Pain scores differed relating to thekinetics of the epidural preparation and were lower with IT morphine from 0 to 4 h, similar from
8 to 24 h, and lower with extended release epidural morphine from 28 to 36 h.
OIVI is more likely with EREM than IV PCA opioids (OR 5.74; 95%CI 1.08 to 30.5) (Sumida 2009
Level I, 3 RCTs, n=464). It has been recommended that the liposome preparation of EREM not be
administered while local anaesthetics are present in the epidural space as this may cause early
release of the morphine (Viscusi 2009 PK). When EREM was administered within 3 to 15 min of a
3 mL test dose of 1.5% lidocaine with adrenaline, higher serum morphine maximum
concentration (Cmax) values were reported vs Cmax values when no lidocaine was administered;
there was no difference in morphine Cmax if the interval was >30 min. The Cmax of morphine wasunchanged when EREM doses were given 15, 30 and 60 min after an anaesthetic dose of epidural
bupivacaine 0.25% 20 mL (Gambling 2009 PK) although, in a later study, peak plasma morphine
concentrations were increased when administered 1 h post a high volume anaesthetic dose (2%5th Edition | Acute Pain Management: Scientific Evidence 155

lidocaine with adrenaline, 20 to 35 mL) after Caesarean section, with associated increased
morphine-related adverse effects (Atkinson Rallis 2011 Level II, n=30, JS 3).
Epidural oxycodone
There is limited safety data for neuraxial oxycodone (Lamminsalo 2019 Level III-1 PK, n=30; Olczak
2017 Level IV, n=11; Kokki 2016 BS). After Caesarean section, patients given epidural oxycodone
3 mg vs epidural morphine 3 mg had higher pain scores up to 24 h with slightly less pruritus(Sng 2016 Level II, n=100, JS 4). Epidural oxycodone was superior to IV oxycodone in gynaecologicallaparotomy, resulting in less rescue analgesia up to 4 h (Piirainen 2018 Level II, n=30, JS 5).
The addition of epidural oxycodone to ropivacaine in labour analgesia was superior toropivacaine alone, with lower pain scores for 4 h and longer duration of analgesia ( Zhong 2020
Level II, n=80, JS 5).
Epidural pethidine
Pethidine is effective when administered epidurally by bolus dose, continuous infusion and by
patient-controlled epidural analgesia (PCEA). It is more lipid soluble than morphine (but less thanfentanyl and its analogues); thus its onset and offset of epidural analgesic action is more rapid
than morphine (Ngan Kee 1998 NR). The analgesic effect of smaller doses appears to be spinallymediated but systemic effects are likely after larger doses; in the smaller doses it is not known
whether the local anaesthetic properties of pethidine contribute significantly to pain relief ( Ngan
Kee 1998 NR). Epidural pethidine has been used predominantly in the obstetric setting. After
Caesarean section epidural pethidine resulted in better pain relief and less sedation than IV
pethidine (Paech 1994 Level II, n=45, JS 5) but inferior analgesia vs IT morphine, albeit with lesspruritus, nausea and drowsiness (Paech 2000 Level II, n=144, JS 5).
Epidural sufentanil
Epidural sufentanil has been mainly used in labour analgesia; for details see Section 9.1.3.3.
Epidural buprenorphine
Epidural buprenorphine has been used in a limited number of studies in the past with no recent
publications; a detailed review of the neuraxial use of buprenorphine has been published ( Kosel
2016 NR).
Epidural tramadol
For lumbar epidural analgesia after thoracotomy, tramadol 100 mg vs morphine 4 mg resulted
in comparable analgesia quality of shorter duration with less sedation and less decrease inarterial oxygenation (Turker 2005 Level II, n=40, JS 4). For epidural analgesia in labour, tramadol 5
mg/mL vs fentanyl 3 mcg/mL added to ropivacaine 0.125% had similar efficacy and adverse
effects (Fan 2011 Level II, n=61, JS 5).
For paediatric use see Section 10.4.4.12.
4.3.2.3 | Adverse effects of neuraxial opioids in general
Opioid-induced ventilatory impairment
The prevalence of OIVI (author-reported) with use of neuraxial diamorphine and morphine after
Caesarean section is 61/10,000 (95%CI 51 to 74) (Sharawi 2018 Level IV SR, 78 studies [54 RCTs,
21 studies & 3 case reports], n=18,455). However, when classified as clinically significant OIVI,
highest prevalence with all doses of neuraxial opioids was 8.67/10,000 (95%CI 4.20 to 15.16) andlowest was 5.96/10,000 (95%CI 2.23 to 11.28). These rates dropped even further with the use oflower but clinically relevant doses of neuraxial morphine: IT dose ≤150 mcg 1.63/10,000 (95%CI
0.62 to 8.77) (31 RCTs [IT]) or epidural dose ≤3 mg 1.08/10,000 (95%CI 0.24 to 7.22) (32 RCTs

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4.0 | ANALGESIC MEDICINES[epidural]). No cases were reported for IT diamorphine ≤400 mcg or epidural diamorphine≤5 mg.
Practice guidelines for the prevention, detection and management of respiratory depression
caused by neuraxial opioids have been published (ASA 2016 GL).
Nausea and vomiting
IV dexamethasone reduces the need for rescue antiemetics for PONV caused by long-acting
neuraxial opioids (RR 0.44; 95%CI 0.35 to 0.56) (Grape 2018 Level I [PRISMA], 13 RCTs, n=1,111).
4.3.2.4 | Adverse effects of intrathecal opioids
Depending on type and dose of the opioid, a combination of spinal and systemic (supraspinal)
mechanisms may be responsible for adverse effects associated with intrathecal opioids. Many ofthese effects are more frequent with morphine and are to some extent dose-related (Dahl 1999
Level I, 15 RCTs, n=535; Cole 2000 Level II, n=38, JS 4).
Opioid-induced ventilatory impairment
Late onset respiratory depression (>2 h after administration), which is believed to be a result of
the cephalad spread of opioids to the medulla within the cerebrospinal fluid (CSF), is also seen
more commonly with hydrophilic opioids such as morphine and hydromorphone and appears tomatch the time taken for trigeminal analgesia, which is approximately 6 to 12 h afteradministration (Bujedo 2014 NR; Saltan 2011 NR; Cousins 1984 NR).
A single dose of IT morphine 100 mcg added to a spinal anaesthetic for Caesarean section was
associated with low rate of respiratory depression (Dahl 1999 Level I, 15 RCTs [12 respiratory
depression], n=535). A meta-analysis comparing IT morphine doses <300 mcg, ≥300 mcg and placebo
reported a greater risk of respiratory depression with the higher vs the lower doses of morphine(Gehling 2009 Level I, 28 RCTs, n=1,314). In combination with bupivacaine, IT morphine 50 to
2,000 mcg was associated with more respiratory depression than IT fentanyl 10 to 50 mcg (3.4% vs0.4%) (Popping 2013 Level I [PRISMA], 28 RCTs; n=1,393; Popping 2012 Level I [PRISMA], 55 RCTs; n=3,338).
The incidence of respiratory depression with the lipophilic opioid fentanyl given via theepidural route has been reported to be 1.4% (with 0.4% requiring naloxone) (Scott 1995a Level IV,
n=1,297) but, when given IT, fentanyl or sufentanil are likely to be lower risk than the hydrophilic
opioids morphine and hydromorphone (Horlocker 2009 GL).
Risk factors for respiratory depression include higher doses (>300 mcg morphine), increasing
age, obesity and coadministration of systemic opioids or sedatives ( Saltan 2011 NR). A detailed
analysis of sustained hypercapnia events (transdermal CO2 >50 mm Hg for ≥2 min) after IT
administration of hyperbaric bupivacaine 12 mg , fentanyl 15 mcg and morphine 150 mcg for
Caesarean section revealed an incidence of 32% (Bauchat 2017 Level IV, n=120). Events occurred
at a median of 300 min after IT administration with a median number of 3 events and longest
duration of 26 min.
Nausea and vomiting
A meta-analysis comparing IT morphine doses <300 mcg vs ≥300 mcg and placebo reports
increased nausea (RR 1.4; 95%CI 1.1 to 1.7) and vomiting (RR 3.1; 95%CI 1.5 to 6.4) in the higher
dose group (Gehling 2009 Level I, 28 RCTs, n=1,314). A single dose of morphine 100 mcg added to a
spinal anaesthetic for Caesarean section was associated with nausea (10%) and vomiting (12%)(Dahl 1999 Level I, 15 RCTs [11 nausea & 8 vomiting], n=535).
Pruritus
A meta-analysis comparing IT morphine doses <300 mcg vs ≥300 mcg and placebo reports
increased pruritus (RR 1.8; 95%CI 1.4 to 2.2) in the higher dose group (Gehling 2009 Level I, 28 RCTs,
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n=1,314). A single dose of morphine 100 mcg added to a spinal anaesthetic for Caesarean section
was associated with pruritus (43%) (Dahl 1999 Level I, 15 RCTs [11 pruritus], n=535). For Caesarean

section, IT morphine 50 mcg vs IT morphine 100 mcg resulted in a lower rate of pruritus (70% vs87%) (Carvalho 2013 Level II, n=130, JS 4).
Neurotoxicity
Clinical experience with morphine, fentanyl and sufentanil has shown no neurotoxicity or
behavioural changes at clinically used IT doses (Hodgson 1999 Level IV). Other opioid agonists orpartial agonists do not have animal or human safety data.
Tolerance
Tolerance to spinal opioid analgesia can develop rapidly. Low-dose mu and delta opioid
antagonists can prevent tolerance development and restore morphine IT analgesia in animals(Abul-Husn 2007 BS). In an animal model, bolus doses increased nociceptive thresholds for 3 to 5
h followed by delayed hyperalgesia with a lower threshold lasting 1 to 2 d, an effect prevented
by coadministration of ketamine (Van Elstraete 2005 BS). The clinical implications of single-dose
neuraxial opioid administration in regard to the potential development of OIH or tolerance is
uncertain. IT fentanyl added to bupivacaine and morphine for Caesarean section was associatedwith higher pain scores (the authors suggesting acute tolerance) but no difference in 24 hmorphine consumption (Carvalho 2012 Level II, n=40, JS 5). Adding fentanyl to IT local anaesthesia
for Caesarean section improved anaesthesia conditions but was associated with a 60% increasein morphine consumption between 6 and 24 h (Cooper 1997 Level II, n=60, JS 2). IT sufentanil was
associated with wound hyperalgesia (at 48 h), with a preventive effect demonstrated by additionof 150 mcg IT clonidine (Lavand'homme 2008 Level II, n=96, JS 5). Ondansetron is assumed toameliorate opioid-induced hyperalgesia and tolerance in animal studies; however, IV
ondansetron 8 mg vs placebo administered before spinal anaesthesia for Caesarean section (ITbupivacaine 15 mg, IT fentanyl 20 mcg and IT morphine 100 mcg) had no effect on postoperative
pain scores or opioid consumption (Greer 2017 Level II, n=86, JS 5).
For more details on epidural opioid use see Section 5.6. and in particular 5.6.2.2 and 5.6.2.3.

KEY MESSAGESIntrathecal opioids
1. Intrathecal morphine and intrathecal fentanyl prolong spinal local anaesthetic block,with fentanyl being associated with fewer adverse effects (U) (Level I [PRISMA]).
2. Intrathecal morphine produces better postoperative analgesia than intrathecal fentanyl
or sufentanil after Caesarean section (U) (Level I).
3. Intrathecal morphine doses of 300 mcg or more increase the risk of respiratory
depression (U) (Level I).
Epidural opioids
4. Epidural morphine provides similar analgesia to epidural fentanyl when combined withlocal anaesthetic, although the incidence of nausea is greater with morphine (U) (Level I[PRISMA]).
5. Extended-release epidural morphine provides analgesia for up to 48 hours (U) (Level II),
however it is associated with more respiratory depression than intravenous PCA
following abdominal surgery (U) (Level I).

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6. Epidural pethidine produces better pain relief and less sedation than intravenous
pethidine after Caesarean section (U) (Level II).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: No neurotoxicity has been shown at normal clinical intrathecal doses of morphine,fentanyl and sufentanil (U).
 Neuraxial administration of bolus doses of hydrophilic opioids carries an increased riskof delayed sedation and respiratory depression compared with lipophilic opioids (U).

4.3.3 | Peripheral opioids
Opioid receptors are expressed in peripheral sensory neurons in both animals and humans ( Stein2013 NR; Stein 2011 NR). Multiple mechanisms have been proposed to explain the clinicalobservation that peripheral opioids are more effective in the presence of tissue injury or
inflammation. Further research into the role of peripheral opioids in clinical models of
inflammatory pain is recommended; the acute postoperative period may not allow sufficient
time for the upregulation of peripheral opioid receptors.
Peripherally applied opioids (excluding IA, perineural and mucosal administration) for postoperative pain relief vs placebo or systemic administration do not have any clinically relevant
effects (Nielsen 2015a Level I [PRISMA], 26 RCTs, n=1,531).
However, peripherally applied opioids had an analgesic effect, when injected into areas withpreoperative inflammation (Stein 2013 NR; Stein 2011 NR). Consequently, submucosal injection ofmorphine 2 mg into inflamed tissue after tooth extraction (under a standard local anaesthesia)
resulted in lower pain on swallowing and prolonged post-operative analgesia vs IM injection
and vs injection into non-inflamed tissue of the same dose of morphine (Akural 2016 Level II, n=81,
JS 5).
4.3.3.1 | Intra-articularMorphine
IA administration is the most extensively examined clinical application of peripheral opioid
therapy (Stein 2013 NR). In experimentally induced synovitis in horses, IA morphine reduced
clinical and biological signs of inflammation vs IV administration (Lindegaard 2010 BS).
IA bupivacaine was less effective than morphine in providing analgesia in patients having“high inflammatory arthroscopic knee surgery”, whereas bupivacaine was more effective thanmorphine in those having “low inflammatory surgery” (Marchal 2003 Level II, n=53, JS 5).
IA morphine in a dose of 1 mg is not better than placebo at reducing pain at early, medium
or late stages post arthroscopy (7 RCTs, n=297) (Zou 2016 Level I [Cochrane], 28 RCTs, n=2,564). IA
morphine 1 mg was not more effective than IA bupivacaine, NSAIDs, sufentanil, fentanyl andpethidine. There was no difference in pain relief between IM morphine vs IA morphine at any
time point (2 RCTs, n=73); the latter results are in line with another RCT not included in the metaanalysis (Cepeda 1997 Level II, n=112, JS 5).
Morphine/bupivacaine vs bupivacaine alone leads to reduced pain scores (WMD −1.15/10;
95% CI −1.67 to −0.63) without an effect on time to first analgesic request and requirements for
supplementary analgesia and with no increase in side effects (Yang 2017b Level I [PRISMA], 29 RCTs,
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n=1,116). However following arthroscopy, morphine/bupivacaine increased postoperative
analgesia requirements and side effects vs tenoxicam/bupivacaine (Sanel 2016, Level II, n=240, JS 5).

Other opioids
IA tramadol 50-100 mg administered as an adjunct to bupivacaine reduces postoperative pain
and increases time to breakthrough analgesia requirements without increasing side effects after
arthroscopy (Ryan 2019 Level I, 6 RCTs, n=334). The combination of IA pethidine(meperidine)/bupivacaine had synergistic analgesic effect vs either medication alone (Imani 2015
Level II, n=60, JS 5). IA fentanyl/bupivacaine did not reduce reported pain scores andpostoperative analgesia requirement vs bupivacaine alone or midazolam/bupivacaine in anunderpowered RCT (Nahravani 2017, Level II, n=45, JS 5). IA administration ofmorphine/levobupivacaine/tenoxicam provided superior analgesia to a combination oftramadol/levobupivacaine/tenoxicam or saline placebo (Oral 2015 Level II, n=90, JS 5).
Levobupivacaine 0.25% for arthroscopic knee surgery combined with either fentanyl or tramadol
provided superior analgesia vs levobupivacaine alone for day case arthroscopic knee surgery(Sayin 2015 Level II, n=80, JS 4). The addition of IA sufentanil to a mixture of ropivacaine andclonidine following anterior cruciate ligament repair provided no additional analgesic benefits(Armellin 2008 Level II, n=120, JS 5).
The evidence for IA morphine, tramadol, buprenorphine, fentanyl and NSAIDs wasinconclusive due to a small number of low-quality studies for temporomandibular joint
arthrocentesis (Gopalakrishnan 2018 Level IV SR [PRISMA], 6 studies, n=433 [3 RCTs, n=91]).
There are no comparisons between IA and systemic administration of these opioids alone.
4.3.3.2 | Perineural
An initial meta-analysis found no evidence for analgesic efficacy of peripheral opioids withperineural block by local anaesthetics (Picard 1997 Level I, 26 RCTs, n=952). Since this publication,
more research has been conducted.
Buprenorphine
The addition of perineural buprenorphine 0.1 to 0.3 mg to local anaesthetics prolongs theduration of analgesia provided by nerve blocks vs placebo (MD 8.64 h; 95%CI 6.44 to 10.85)(9 RCTs, n= 510), but is associated with significant increases in PONV (RR 5.0; 95%CI 1.12 to 22.27)(3 RCTs, n=210) (Schnabel 2017 Level I [PRISMA], 13 RCTS, n=685). In comparison to systemic (IM)administration of buprenorphine, perineural administration prolongs duration of analgesia (MD6.87 h, 95%CI 4.02 to 9.71) (5 RCTs, n=294) without increasing PONV. The findings are qualified by
the description of high risk of publication bias and heterogeneity in the results obtained. A
subsequent RCT found no difference in time to first rescue analgesia comparing a femoral nerve
block for TKA with either perineural or SC buprenorphine 0.3 mg (van Beek 2017 Level II, n=65, JS
5). Adjuvant buprenorphine 0.3 mg vs adjuvant dexamethasone 4 mg added to levobupivacaine
0.25% 20 mL transverse abdominis plane block (TAPB) for inguinal hernia repair demonstrated
longer times to rescue analgesia and lower mean postoperative tramadol consumption in thefirst 24 h vs placebo (saline 1 mL) (Seervi 2019 Level II, n=93, JS 4). Perineural administration ofbuprenorphine 0.15 mg and dexamethasone 4 mg vs IV administration of the same doses in
conjunction with sciatic and adductor canal blocks for foot and ankle surgery resulted in longer
block duration, lower scores for ‘worst pain’ and less nausea, but no difference in pain scores at
24 h (YaDeau 2015 Level II, n=90, JS 5).

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Sufentanil
The addition of sufentanil 10 mcg to bupivacaine for ultrasound guided brachial plexus block forupper limb procedures prolonged the duration of both sensory and motor block in chronic opioid
users and non-users (Azimaraghi 2015 Level II, n=120, JS 5). No difference was found inpostoperative pain scores or supplemental analgesic requirements when fentanyl 100 mcg wasadministered with ropivacaine 0.75% in a femoral nerve block and then per perineural catheter
infusion (3 mcg/mL fentanyl/ropivacaine 0.75%: basal rate 10 mL/h) vs ropivacaine alone (Heo2016 Level II, n=82, JS 5).
TramadolTramadol 100 mg as an adjuvant to brachial plexus block vs placebo prolonged analgesia (MD125.5 min; 95% CI 73.3 to 175.8), but also sensory and motor block ( Shin 2017 Level I [PRISMA],
16 RCTS, n=751); there were no comparisons to systemic administration.
Preoperative femoral nerve block for TKA with ropivacaine 0.375% 20 mL and adjuvant
tramadol 100 mg was superior with lower pain scores (from 8 to 72 h), longer sensory and motor
blockade and reduced requirement for postoperative PCA vs no femoral nerve block, femoral nerve
block with ropivacaine only or femoral nerve block with ropivacaine/ tramadol 50 mg (Tang 2016
Level II, n=60, JS 1).
4.3.3.3 | Topical
While opioid receptors have been identified in the cornea and skin, topically applied opioids havenot consistently demonstrated efficacy in pain states such as corneal ulceration (fentanyl) (Zollner
2008 Level II, n=40, JS 4), partial thickness burns (morphine) (Welling 2007 Level II, n=49, JS 5) or chronicskin ulceration (morphine) (Vernassiere 2005 Level II, n=18, JS 4).
The clinical use of topical opioids in palliative care for pain control in cutaneous lesions isreported as beneficial in three of six RCTs (Graham 2013b Level IV SR, 26 studies, n unspecified).
A greater benefit was reported with inflammatory lesions than with vascular ulcers, suggestingan anti-inflammatory role of topical opioids may be as important as a peripheral analgesic
benefit. Topical morphine (0.2% gel) and ointment for mucosal and skin lesions in palliativecancer patients reduced base line pain after 7 d of treatment (NNT50% 1.67) with minimal side
effects (Cialkowska-Rysz 2019, Level II, n=35, JS 4).
In chemotherapy-induced mucositis an analgesic dose-dependent effect was seen in a small
pilot study using 1 mg/mL and 2 mg/mL morphine mouthwash (Cerchietti 2003 Level III-1). Benefit
was also evident for morphine mouthwash 30 mg every 3 h, with a local anaesthetic-based
solution, in mucositis associated with chemoradiotherapy in head and neck cancer patients(Cerchietti 2002 Level II, n=26, JS 3). With oral morphine mouthwash 2% (30 mg in 15 mL) for thetreatment of mucositis pain, the act of mouth washing was beneficial, with early termination due
to recruitment difficulty and indaequate power to detect benefit with morphine vs quinine
placebo solution (Vayne-Bossert 2010 Level II, n=11, JS 5). Topical morphine mouthwash 2% (10 mL)
for patients with severe mucositis associated with head and neck cancer treatment was more
effective than a combination mouthwash (containing viscous lidocaine, magnesium aluminiumhydroxide and diphenhydramine) 10 mL 3 hly over 6 d (Sarvizadeh 2015 Level II, n=30, JS 5). WHO
grading scores for mucositis decreased in both groups at 6 d, but were lower in and withincreased satisfaction in morphine recipients. See also Section 8.6.7.7 and 8.9.8.2.

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KEY MESSAGES
1. Intra-articular morphine (1 mg) following knee arthroscopy does not improve analgesia
compared with placebo (S) (Level I [Cochrane Review]).
2. Intra-articular morphine/bupivacaine following knee arthroscopy compared tobupivacaine alone improves analgesia without increasing adverse effects (N) (Level I[PRISMA]).
3. Perineural buprenorphine/local anaesthetic for peripheral nerve blocks compared to
local anaesthetic and to systemic buprenorphine/local anaesthetic prolongs duration ofanalgesia (N) (Level I [PRISMA]).
4. Perineural tramadol/local anaesthetic for brachial plexus block compared to local
anaesthetic alone prolongs duration of analgesia (N) (Level I [PRISMA]).
5. Peripherally applied opioids (excluding intra-articular, perineural and mucosal
administration) show no clinically relevant analgesic effect (N) (Level I [PRISMA]).
6. Intra-articular tramadol/bupivacaine following knee arthroscopy compared tobupivacaine alone improves analgesia without increasing adverse effects (N) (Level I).
7. Morphine mouthwash may have analgesic effects in chemotherapy-induced mucositis(N) (Level II).
8. Evidence for intra-articular analgesic administration is inconclusive fortemporomandibular joint arthrocentesis (N) (Level IV SR [PRISMA]).

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4.4 | Local anaesthetics and other membrane stabilisers
Local anaesthetics (LA) act primarily by reversibly blocking neuronal voltage-gated sodium
channels (VGSC) and thereby temporarily interrupting nerve impulse propagation. LA also haveadditional systemic effects which may be independent of action on the VGSC due to interaction
with potassium channels, calcium channels, N-methyl-D-aspartate (NMDA) receptors, andG-protein coupled receptors (van der Wal 2016 NR BS; Lirk 2014 BS). The latter, via the Gq/11
subfamily, may contribute to the anti-inflammatory effects of LAs (Hollmann 2000 NR). Thus, theuse of LAs beyond perineural applications is expanding.
Both amide and ester local anaesthetics have been found to have antimicrobial activity inconcentrations used in clinical practice, with tetracaine, bupivacaine and lidocaine having themost marked activity (Razavi 2019 NR BS); these are not primary effects and are modified by arange of factors including the admixture of other drugs.

4.4.1 | Systemic local anaesthetics and other membrane stabilisers
IV lidocaine has analgesic, anti-inflammatory and antihyperalgesic properties and attenuates theneuroinflammatory response in perioperative pain and chronic neuropathic pain (van der Wal
2016 Level IV SR, 36 in vitro studies, 31 animal studies & 21 clinical studies [3 SRs & 7 RCTs in acute pain; 1
SR, 6 RCTs & 4 studies in chronic pain]). The safe dose and duration of perioperative IV lidocaine

infusions has not been clearly established, with only limited total patient numbers and few
adverse reactions having been reported in the literature to date (Bailey 2018 Level I, 6 RCTs, n=420;
Masic 2018 Level IV SR, 13 studies, n= 512).
4.4.1.1 | Acute pain
A Cochrane review on IV lidocaine and analgesia (Kranke 2015 Level I [Cochrane], 45 RCTs, n=2,802)
has been updated with a further 23 RCTs (Weibel 2018 Level I [Cochrane], 68 RCTs [66 vs placebo/no
comparator; 2 vs epidural], n=4,525) finding small effects and uncertain outcomes. Lidocaine
infusions at varying doses (1-5 mg/kg/h) for varying duration in various surgery types ( open
[22 RCTs] or laparoscopic [20 RCTs] abdominal and others [26 RCTs]) vs placebo or no treatment)
reduces pain intensity to a limited extent 1 to 4 h postoperatively (SMD −0.50; 95%CI −0.72 to−0.28; 0.37/10 to 2.48/10) (29 RCTs, n=1,656), at 24 h (SMD −0.14; 95%CI −0.25 to −0.04) (33 RCTs,
n=1,847) and at 48 h (SMD −0.11; 95%CI −0.25 to 0.04) (24 RCTs, n=1,404), noting that the results
for these later time points represent less than a 1 point reduction in a 10 point pain scale. Thereis also a reduction of postoperative ileus (RR 0.37; 95%CI 0.15 to 0.87) (4 RCTs, n=273), time to
first defaecation (MD −7.92 h; 95%CI −12.71 to −3.13) (12 RCTs, n=684), postoperative nausea
0 to 2 h (RR 0.78; 95%CI 0.67 to 0.91) (35 RCTs, n=1,903), opioid requirements (MD −4.52 MME;
95%CI −6.25 to −2.79) (40 RCTs, n=2,201) and LOS (MD −0.37 d; 95%CI −0.60 to −0.15) (32 RCTs,
n=2,077). Vomiting overall was not impacted (OR 0.83; 95% CI 0.63 to 1.08) (19 RCTs, n=1026). IV
lidocaine vs TEA has no effect on pain intensity and other outcomes ( 2 RCTS, n=102). The authors
describe all these results as “uncertain” due to the quality of the evidence being limited byinconsistency, imprecision, and study quality.
In breast surgery, IV lidocaine administered intraoperatively and continued for up to 2 h is
not associated with improved pain scores up to 72 h vs placebo controls, but opioid requirements
were lower in the lidocaine group (Chang 2017 Level I [PRISMA], 3 RCTs, n=167); however, benefit
was found in chronic postsurgical pain prevention. See Section 4.4.1.2 below.

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After colonic surgery, IV lidocaine was associated with improved pain relief vs controls andalso with decreases in proinflammatory cytokines, including interleukin‐6 (IL‐6), IL‐8 and IL‐1RA(a competitive inhibitor of IL‐1β) (Kuo 2006 Level II, n=60, JS 5). For radical prostatectomy, acombination of intraoperative IV and postoperative SC lidocaine for up to 24 h vs saline reduced
pain, morphine consumption and LOS (Weinberg 2016 Level II, n=76, JS 5). Following open
nephrectomy, intraoperative IV lidocaine or IV ketamine continued for 24 h were both superior
to placebo in reducing pain scores and 24 h opioid consumption (lidocaine 27.8 mg ± 5.5 andketamine 32 mg ± 7.0 vs placebo 47.6 mg ± 5.0) (Jendoubi 2017 Level II, n=60, JS 4); IV lidocaine wasassociated with significantly lower pain scores at rest and with movement over 24 h vs IV
ketamine. In radical cystectomy patients, the addition of perioperative IV lidocaine infusion for
6 h resulted in lower pain scores for up to 18 h (Moeen 2019 Level II, n=111, JS 5); recovery of bowel
function was also improved.
Perioperative IV administration of lidocaine also has a preventive analgesic effect (extending
beyond 5.5 half-lives of lidocaine, ie >8 h after cessation of administration) after a wide range of
operations (Barreveld 2013a Level I, 16 RCTs, n=678) (15 RCTs overlap with Weibel 2018). See also
Sections 1.4 and 1.5.
In the emergency department (ED), the efficacy of IV lidocaine in the treatment of nonsurgicalacute pain has been reviewed, noting that dosing was not standardised and individual studies
were small (Silva 2018 Level IV SR, 6 RCTs & 2 studies, n=536; Masic 2018 Level IV SR 4 RCTs & 9 studies,n= 512) (4 RCTs overlap); analgesic benefit is superior to placebo or comparable to active controls
in renal colic (2 RCTs) and limb ischemia (1 RCT), but inconsistently in acute migraine(2 RCTs) and not in acute radicular low back pain (1 RCT). Although most non-randomised studies
demonstrated improved analgesia with IV lidocaine, certainty with these findings is low. Safety
data is limited with 20 adverse events (19 nonserious, 1 classified serious: overall rate 8.9%;
95%CI 5.5% to 13.4%) (6 studies, n=225) reported with IV lidocaine use in the ED (Silva 2018 Level
IV SR, 6 RCTs and 2 studies, n=536).
IV lidocaine has a potentially analgesic effect in procedural pain in burns ( Wasiak 2012 Level I[Cochrane], 1 RCT: Wasiak 2011 Level II, n=45, JS 5), however its role in this indication requires further
investigation.
The use of IV lidocaine in an obese population undergoing laparoscopic gastric reduction
surgery reduced pain scores, opioid consumption and improved quality of recovery ( Sherif 2017
Level II, n=150, JS 5; De Oliveira 2014a Level II, n=50, JS 5).
Results for IN lidocaine are conflicting showing significant benefit ( Maizels 1996 Level II, n=53,
JS 2) and no effect (Blanda 2001 Level II, n=49, JS 4).
Mexiletine improved pain relief and reduced analgesic requirements after breast surgery(Fassoulaki 2002 Level II, n=75, JS 3).
4.4.1.2 | Chronic pain and transition to chronic pain
A meta-analysis found that IV lidocaine reduces chronic postsurgical pain at 3 mth vs placebo(OR 0.29; 95%CI 0.18 to 0.48) (Bailey 2018 Level I [PRISMA], 6 RCTs, n=420). In breast surgery
patients, IV lidocaine administered intraoperatively and continued for up to
2 h has a lower risk for the development of chronic pain at 3 to 6 mth (RR 0.33; 95%CI 0.14 to0.78) (Chang 2017 Level I [PRISMA], 2 RCTs, n=97) (2 RCTs overlap). See also Sections 1.4 and 1.5.
The membrane stabilisers IV lidocaine and mexiletine have a similar analgesic effect onneuropathic pain of various origins, which is superior to placebo (WMD 10.6; 95%CI -14.5 to -6.7)(Tremont-Lukats 2005 Level I, 19 RCTs, n=706) and similar to various comparators (Challapalli 2005
Level I [Cochrane], 30 RCTs, n=1,142). There was strong evidence of benefit for use of membranestabilisers in pain due to peripheral nerve trauma (Kalso 1998 Level I, 17 RCTs, n=450). However, in164

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the guidelines for pharmacotherapy for neuropathic pain by the Special Interest Group on
Neuropathic Pain (NeuPSIG) of the IASP, there is a strong recommendation against the use of
mexiletine because of negative trials on efficacy and safety concerns ( Finnerup 2015 GL Level I[PRISMA], 229 RCTs, n unspecified).
Currently, the use of membrane stabilisers for acute neuropathic pain can only be based on
extrapolation of the above data.

KEY MESSAGES
1. Perioperative intravenous lidocaine reduces pain and opioid requirements to a limited
extent following a range of surgery types, as well as nausea, but not vomiting,incidence and duration of ileus and length of hospital stay (W) (Level I [Cochrane
Review]).
2. In breast surgery, perioperative lidocaine infusion does not improve pain scores for up
to 72 hours, but is associated with lower acute opioid requirements and less chronic
postsurgical pain at 3 to 6 months (N) (Level I [PRISMA])
3. Perioperative intravenous lidocaine has a preventive analgesic effect (extending
beyond 5.5 half-lives of lidocaine, ie > 8 hrs after cessation of administration) after awide range of operations (U) (Level I).
Chronic neuropathic pain and transition to chronic postsurgical pain
4. Both intravenous lidocaine and mexiletine are effective in the treatment of chronic
neuropathic pain (U) (Level I [Cochrane Review]); however, guidelines advise against
the use of mexiletine for this indication (N) (GL Level I [PRISMA]).
5. Perioperative IV lidocaine reduces chronic postsurgical pain at 3 months compared toplacebo (N) (Level I [PRISMA]).
The following tick box represents conclusions based on clinical experience and expert
opinion: The optimal and safe dose and duration of perioperative intravenous lidocaine
infusions has yet to be clearly established (N).
 Based on the experience in chronic neuropathic pain states, it would seem reasonable
to use membrane stabilisers including systemic lidocaine in the management of acuteneuropathic pain (U).
 The role and safety of IV lidocaine for analgesia in the emergency department stillrequires clarification (N).

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4.4.2 | Regional local anaesthetics
LAs exert their effect as analgesics by blocking sodium channels and hence impeding neuronal
excitation and/or conduction. LAs differ predominantly by potency, duration of action andsystemic toxicity.
4.4.2.1 | Short-duration local anaesthetics
Lidocaine is the most widely used short-duration LA in acute pain management. Although theplasma half-life is approximately 90 min, the duration of the LA effect depends very much on siteof administration, dose administered and the presence or absence of vasoconstrictors. Although
lidocaine is hydrophilic, it is delivered in high concentrations and therefore usually diffuses wellinto nerve bundles, resulting in little separation of sensory and motor blocking actions ( Covino
1998 NR).
The use of lidocaine in ongoing acute pain management is usually restricted to the short-term
re-establishment of a LA infusion block. It is generally considered unsuited to long-term (ie days)
use because of the development of tachyphylaxis or acute tolerance, although the existing
literature documenting the phenomenon of tachyphylaxis with neuraxial use of local anaesthetics
is scarce and the mechanisms behind this phenomenon should it occur, is unclear (Kongsgaard 2016
Level III-3 [PRISMA], 6 RCTs & 7 studies, n unspecified). Continuous perineural infusions of lidocaine for
24 h resulted in less effective analgesia and more motor block than infusions of the long-acting LA
ropivacaine (Casati 2003c Level II, n=40, JS 4).
Mepivacaine is a short- to intermediate-duration LA agent, structurally related to bupivacaine
and ropivacaine. Its use is largely restricted to intraoperative anaesthesia.
4.4.2.2 | Long-duration local anaesthetics
The three commonly used long-duration LAs, bupivacaine, levobupivacaine and ropivacaine, arestructurally related (McLeod 2001 NR; Markham 1996 NR). Whereas bupivacaine is a racemic
mixture of S- and R-enantiomers, levobupivacaine is the S(+)- (or levo-) enantiomer ofbupivacaine; ropivacaine is likewise an S-enantiomer.
The issue with relative potency emerges with lower doses and concentrations of LAs. Whendoses are carefully titrated, a minimum local anaesthetic concentration (MLAC) can be found atwhich 50% of patients will achieve a satisfactory analgesic block. In obstetric epidural analgesia,
two separate studies found the MLAC of bupivacaine was 0.6 times that of ropivacaine ( Capogna
1999 Level II, n=87, JS 4; Polley 1999 Level II, n=83, JS 4). The motor-blocking potency showed a similarratio of 0.66 (Lacassie 2003 Level II, n=60, JS 4).
When comparing bupivacaine with levobupivacaine, the “percentage” bupivacaine solution isby weight of bupivacaine hydrochloride, whereas the percentage levobupivacaine solution is forthe active molecule alone. This means that the molar dose of equal “percentage concentration” is
13% higher for levobupivacaine (Schug 2001 NR). The sensory MLAC potency ratio oflevobupivacaine to bupivacaine is 0.98, although if correction is made for molar concentrations thisfalls to 0.87 (neither value being significantly different from unity) (Lyons 1998 Level II, n=60, JS 3).
Levobupivacaine has been shown to have slightly less motor-blocking capacity than bupivacaine
with a levobupivacaine/bupivacaine potency ratio for epidural motor block of 0.87 (95%CI 0.77 to0.98) (Lacassie 2003 Level II, n=60, JS 4). Another labour epidural analgesia study has found nodifference in MLAC between levobupivacaine and ropivacaine with a ropivacaine/levobupivacaine
potency ratio of 0.98 (95%CI 0.80 to 1.20) (Polley 2003 Level II, n=83, JS 4).

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4.4.2.3 | Epidural local anaesthetics
For postoperative analgesia using epidural infusions, dose-ranging studies established that 0.2%
ropivacaine was a suitable concentration (Schug 1996 Level II, n=36, JS 5; Scott 1995b Level II, n=30,
JS 5). Therefore, most investigators compare infusions of bupivacaine or levobupivacaine at 0.1%
or 0.125% with ropivacaine 0.2%, which removes any imbalance in comparative potency. In
obstetric epidural analgesia, lower concentrations of epidural ropivacaine, typically 0.1%, areused in labour to avoid dense sensory and motor block (Zhang 2018 SR Level IV, 30 studies, n=2,851).
The majority of studies find similar analgesic outcomes with postoperative epidural infusions
based on these strengths (Casati 2003b Level II, n=45, JS 5; Macias 2002 Level II, n=80, JS 5; Jorgensen
2000 Level II, n=60, JS 3). Motor block is of clinical relevance in low-thoracic or lumbar epidural
infusions and has been reported to be less intense with epidural ropivacaine than withbupivacaine (Merson 2001 Level II, n=68, JS 4; Muldoon 1998 Level II, n=52, JS 4; Zaric 1996 Level II, n=37,
JS 3). However, this finding has not been supported by another study ( Casati 2003b Level II, n=45,
JS 5).
The relevance of dose, not concentration or volume of LA infused, was confirmed in two
trials. The same dose of a mixture of levobupivacaine in three different concentrations (0.5%,
0.25% and 0.15%) and sufentanil administered during continuous thoracic epidural infusion forthoracotomy resulted in similar efficacy and adverse effects ( Mendola 2009 Level II, n=138, JS 3) as
did two concentrations (0.15 and 0.5%) of levobupivacaine in another RCT ( Dernedde 2006
Level II, n=82, JS 4). Neither infusions of bupivacaine 0.125% nor ropivacaine 0.2% interfered withneurophysiological assessments after scoliosis surgery (Pham Dang 2008 Level II, n=18, JS 4). At
concentrations of ≥0.5%, there were no significant differences in onset time and intensity or
duration of sensory block between bupivacaine, levobupivacaine or ropivacaine used for
epidural analgesia (Casati 2003b Level II, n=45, JS 5; Cheng 2002 Level II, n=45, JS 3).
Local anaesthetic/opioid combinations
The quality of pain relief from low‐dose epidural infusions of plain LA consistently benefits fromthe addition of opioids, most commonly fentanyl ( Walker 2002 Level I, 4 RCTs [epidural local
anaesthetic/opioid combinations], n=226; Curatolo 1998 Level I, 18 RCTs [fentanyl/local anaesthetic],n unspecified); this was confirmed by additional RCTs (Senard 2002 Level II, n=60, JS 3; Hubler 2001
Level II, n=109, JS 4; Crews 1999 Level II, n=64, JS 3; Scott 1999 Level II, n=182, JS 5;). For addition ofother adjuvants see Sections 4.9, 4.12.2 and 4.13.
Potential dose‐sparing benefits are more obvious for LA adverse effects (hypotension andmotor block) than for opioid‐related adverse effects (Walker 2002 Level I, 4 RCTs [epidural LA/opioid
combinations], n=226).
Comparisons of PCEA using ropivacaine 0.2%, ropivacaine 0.125% and levobupivacaine 0.125%,
all with sufentanil 1 mcg/mL (6 mL/h background plus 2 mL bolus), showed no differences in pain
relief or motor block; patients given 0.2% ropivacaine used similar volumes, thus receiving moretotal dose of local anaesthetic and the same amount of sufentanil (Sitsen 2007 Level II, n=63, JS 4).
Similarly, there was no difference in analgesia and no motor block reported in a PCEA comparisonof ropivacaine 0.05%, 0.075% and 0.1%, with fentanyl 4 mcg/mL and droperidol 25 mcg/mL added
to all solutions (Iijima 2007 Level II, n=272, JS 4). In another comparison of PCEA bupivacaine 0.625%
with fentanyl 3 mcg/mL and 0.15% ropivacaine alone, there was no difference in pain relief; patientsatisfaction was lower with PCEA ropivacaine, even though it led to fewer opioid‐related adverse
effects (Pitimana-aree 2005 Level II, n=70, JS 3).
No studies directly compare fentanyl to morphine when added to LA epidural infusions,although a single retrospective audit of the use of high-thoracic epidural following cardiac
surgery suggested improved pain control and lowered infusion rate using ropivacaine 0.2% with
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morphine 20 mcg/mL vs fentanyl 2 mcg/mL (Royse 2005 Level III‐3, n=200). For information relating
to the use of epidural LA or LA/opioid combinations for postoperative pain see Section 5.6.2 andfor labour pain see Section 9.1.3.3.
4.4.2.4 | Peripheral local anaesthetics
A number of studies have compared different LAs or doses of LAs used for peripheral nerve block(PNB) and continuous peripheral nerve block (CPNB). Specific regional and local anaesthetic
techniques are discussed in Section 5.8
In a meta-analysis comparing ropivacaine to levobupivacaine for peripheral nerve block,there was no difference in time to onset of anaesthesia or patient satisfaction, butlevobupivacaine provides longer block (WMD -2.94 h; 95%CI -5.56 to -0.32) and a lower incidenceof postoperative rescue analgesia (OR 2.11; 95%CI 1.18 to 3.74) (Li 2017a Level I [PRISMA], 12 RCTs,
n=556); concentrations included ranged from 0.5% to 1.0% and non-equipotent comparisonswere included.
At concentrations of 0.5% or greater, there were no significant differences in onset time andintensity or duration of sensory block between bupivacaine, levobupivacaine or ropivacaine insciatic (Casati 2002 Level II, n=50, JS 4), interscalene (Casati 2003a Level II, n=47, JS 5) or axillarybrachial plexus blocks (McGlade 1998 Level II, n=61, JS 5). In a comparison of three concentrations(0.1%, 0.2%, 0.3%) of ropivacaine for continuous FNB following TKA, infusions of 0.2% and 0.3%
ropivacaine had equivalent quality of postoperative analgesia ( Brodner 2007 Level II, n=102, JS 4).
After similar surgery, there was no difference in pain relief or motor block between patientcontrolled FNB with levobupivacaine 0.125% and ropivacaine 0.2% (Heid 2008 Level II, n=60, JS 4).
Comparisons of two different patient‐controlled CPNB regimens found different results
depending on the location of the block; the regimens were ropivacaine at 4 mL/h 0.4% (bolus
2 mL) or 8 mL/h 0.2% (bolus 4 mL). For continuous popliteal nerve block, the larger volumes ofthe dilute LA were more likely to cause an insensate limb ( Ilfeld 2008 Level II, n=50, JS 3); forcontinuous interscalene nerve block there was no difference between the two solutions (Le 2008
Level II, n=50, JS 2) and for continuous infraclavicular nerve block the smaller volumes of the moreconcentrated LA were more likely to cause an insensate limb (Ilfeld 2009 Level II, n=50, JS 3).
In another RCT of patient‐controlled continuous interscalene block comparing
levobupivacaine 0.25%, ropivacaine 0.25% and ropivacaine 0.4%, the lower concentration ofropivacaine achieved less effective pain relief (Borghi 2006 Level II, n=72, JS 5).
Continuous popliteal sciatic nerve block using ropivacaine 0.2% vs levobupivacaine 0.2% andlevobupivacaine 0.125% resulted in similar pain relief after foot surgery but fewer patients hadcomplete recovery of motor function at 24 and 48 h with 0.2% levobupivacaine ( Casati 2004
Level II, n=60, JS 5). Many continuous perineural infusion techniques now use low concentrationsof ropivacaine (approx. 0.1%) in order to minimise motor block while still providing effective
analgesia (see Section 5.8).
Skin infiltration
Increasing the pH of commercial lidocaine (to ≥7.35 by the addition of sodium bicarbonate prior
to injection) reduces pain scores on injection for invasive procedures in cross-over studies (WMD
-2/10; 95%CI -2.6 to -1.3) (10 RCTs) and in parallel design studies (WMD -1/10; 95%CI -1.4 to -0.4)(7 RCTs) (Cepeda 2010 Level I [Cochrane], 23 RCTs, n=1,067). The magnitude of the decrease in pain islarger when the solution contains adrenaline (WMD -2.5/10; 95%CI -3.2 to -1.7) (6 RCTs, n=232).
Warming the solution (to 37–43oC), assessed mostly in adults, reduces pain on SC or
intradermal injection overall (WMD -11/100; 95%CI -14 to -7) (18 RCTs, n=831) and when the local
anaesthetic is buffered (WMD -7/100; 95%CI -12 to -3) (8 RCTs, n=412) (Hogan 2011 Level I [PRISMA],
18 RCTs, n=831).

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Local infiltration analgesia
Two main strategies using large volume, low concentration local anaesthetic infiltration
techniques are described: tumescent local anaesthesia and local infiltration analgesia (LIA).
Tumescent local anaesthesia has been described for soft-tissue surgery such as varicose veinsclerosis, liposuction or cosmetic breast surgery.
The term LIA typically refers to the systematic intraoperative injection of LAs in theperiarticular and intra-articular regions. LIA may also be referred to as periarticular infiltration.
A “cocktail” is most commonly used for periarticular LIA comprising a local anaesthetic, an alpha2 agonist/vasoconstrictor, an opioid and an anti-inflammatory agent. The majority ofinvestigations into the effectiveness of LIA in acute pain management following THA or TKA failto separate out the components of the mixture and some protocols use “top-up” regimens ofvarying composition (Andersen 2014a Level I [PRISMA], 27 RCTs, n=1,644). In THA (n=756), multimodal
systemic analgesia or neuraxial techniques (IT morphine or epidural analgesia) have similaranalgesic efficacy vs LIA; however in TKA, LIA provided superior analgesia to placebo (n=328).
Compared with FNB, epidural analgesia or IT morphine, LIA provided similar or improved
analgesia in the early postoperative period, but most trials had a high risk of bias due to different
systemic analgesia regimens between groups. Overall, the use of wound catheters for
postoperative administration of local anaesthetic following LIA was not supported in the
included trials.
Despite the many studies of LIA, final interpretation is hindered by methodologicalinsufficiencies in most studies, especially because of differences in use of systemic analgesia
between groups. For more detail see also Section 5.8.7.1.
There is limited data regarding local anaesthetic systemic toxicity (LAST) in patients receiving
LIA with hip and knee joint surgery. In a case series of 39 patients receiving up to 300 mg
ropivacaine as LIA, there was no clinical toxicity and peak plasma concentrations did not exceed
1.7 mcg/mL; peak concentrations occurred at ≈6 h post administration (Affas 2016 Level IV, n=39).
In volunteers receiving 41 exposures to tumescent subcutaneous infiltration of lidocaine withepinephrine, recommendations were made for up to 28 mg/kg lidocaine without liposuction and
45 mg/kg with liposuction with peak concentrations occurring 8–16 h after infiltration (Klein 2016
Level IV EH, n=14).
Slow-release preparations of local anaesthetics
Encapsulation of bupivacaine within liposomes in clusters of <100 microns diameter (liposomal
bupivacaine) results in drug release into adjacent tissues for a number of days following injection,with peak plasma concentrations occurring 12–36 h after injection (Skolnik 2014 NR). Current
indications from trial data have not raised any specific safety concerns ( Viscusi 2014 Level I, 10
RCTs, n=823).
A limited number of RCTs have been conducted with wound infiltration, periarticular
infiltration, perineural block and epidural administration (see Section 4.3.2.2 for ER epidural
opioid preparations); most RCTs have demonstrated analgesic superiority over placebo for up to
72 h, however benefit over normal formulations of bupivacaine has not been shown (Tong 2014
Level III-2 SR, 5 studies, n unspecified). When comparing wound infiltration with liposomal
bupivacaine to either ropivacaine or plain bupivacaine, no difference was seen with analgesic
outcomes up to 48 h (Kendall 2018 Level I [PRISMA], 9 RCTs, n=779).
A systematic review of liposomal bupivacaine for periarticular infiltration in TKA (Yayac 2019
Level IV SR [PRISMA], 6 SRs & 17 RCTs & 25 studies, n unspecified) finds:• vs conventional LA single injection PNB (3 RCTs, n=555), pain relief is better with PNB(SMD 0.45, 95%CI 0.08 to 0.82), largely driven by benefits on POD 0 and 1; there is no

5th Edition | Acute Pain Management: Scientific Evidence 169••difference in opioid consumption. Differences in complication rates, including falls, aremixed;
vs conventional LA LIA (13 RCTs, n=1,155), slightly lower pain scores are found using AUC
over 5 d (SMD = -0.08, 95%CI -0.14 to -0.03), but not using pain scores by time-point up
to 3 d (-5.21/100; 95%CI -12.1 to 1.65). There are no differences in opioid consumption
nor functional recovery;vs conventional LA IA infiltration (2 RCTs, n=345), only one study included a directcomparison and found no difference in pain outcomes.

Also in TKA, two overlapping meta-analyses compared liposomal bupivacaine by periarticular
infiltration to conventional LA FNB (Liu 2017a Level III-2 SR [PRISMA], 1 RCT & 7 studies, n=2,407; Ma
2016b Level III-2 SR, 1 RCT & 5 studies, n=1,289) (all 6 studies overlap); 2 FNB studies used continuous
infusions. There is no difference between groups in pain scores to 72 h, PONV or range of motion,
but liposomal bupivacaine is associated with decreased LOS (MD -0.43 d; 95%CI -0.60 to -0.27)
and reduced total morphine requirements (MD -29.3 mg; 95% CI -57.6 to -1.1) (Liu 2017aLevel III-2 [PRISMA], 1 RCT & 7 studies, n=2,407).
In THA, LIA with liposomal bupivacaine vs conventional bupivacaine showed no difference up
to 72 h in postoperative opioid consumption, pain scores, opioid-related side effects, time to
first ambulation, or LOS (Perets 2018 Level II, n=107, JS 4).
Following day-case retropubic sling placement, pain scores were low but liposomal
bupivacaine infiltration vs saline improved scores slightly at 4 h post-discharge and the following
morning (Mazloomdoost 2017 Level II, n=109, JS 4).

4.4.3 | Local anaesthetic toxicity
4.4.3.1 | Direct toxicity
Nerve injury following perineural LA injection may be a consequence of many factors including
needle trauma, haematoma, pressure injury, or direct local anaesthetic toxicity (Verlinde 2016
NR). In clinical practice it is difficult, if not impossible to separate out these elements, and thelikely contribution of direct neurotoxicity is small. All local anaesthetics exhibit neurotoxicity ifnerves are exposed to sufficiently high concentrations for a sufficiently long period (Verlinde 2016
NR BS). Lidocaine 5% infused via lumbar subarachnoid microcatheters has been associated withcase reports of cauda equina syndrome (Rigler 1991 Level IV, n=4; Schell 1991 Level IV, n=2). Thissuggested that high local concentrations of lidocaine were potentially neurotoxic and led to thetechnique falling into disfavour. The precise mechanisms of direct LA neurotoxicity remain
unclear, but are concentration-dependent, and may involve the intrinsic caspase-pathway, PI3kpathway, and MAPK-pathways (Verlinde 2016 NR BS).
Transient neurological symptoms (TNS) is a clinical syndrome associated with spinal (IT)anaesthesia. Patients experience pain or muscle spasms in the buttocks or lower limbs following
initial recovery from the spinal anaesthetic. The onset of symptoms is usually within 24 h of theprocedure and it fully resolves spontaneously within a few days. Despite its name, there is noevidence that this condition is associated with actual neurologic pathology. A network metaanalysis showed that the risk of TNS was lower for bupivacaine, levobupivacaine, prilocaine,
procaine, and ropivacaine with RRs in the range of 0.10 to 0.23 vs lidocaine; while 2chloroprocaine and mepivacaine did not differ to lidocaine (Forget 2019 Level I [Cochrane] [NMA],
24 RCTs, n=2,226). The quality of evidence was considered moderate to low, and the overall
incidence of TNS was 10.7%.

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Other tissues are susceptible to direct toxicity from local anaesthetics. Myotoxicity has been
described clinically (Zink 2004 NR) and reproduced experimentally (Yildiz 2011 BS), especially forbupivacaine, but is rare and reversible. Local anaesthetics have chondrotoxic effects on articularcartilage, which are worsened by coadministration of corticosteroids (Jayaram 2019 Level III-2 BS[PRISMA], 16 studies, n unspecified); ropivacaine at concentrations of 0.5% or less was found to be
the least chondrotoxic LA.
4.4.3.2 | Local anaesthetic systemic toxicity (LAST)
There is consistent laboratory data showing that the S-enantiomers of the long-acting amide
LAs exhibit less CNS or cardiac toxicity than the R-enantiomers or the racemic mixtures fordoses resulting in equivalent sensory nerve conduction block. Defining relative toxicities forthese agents is complex because it depends on the parameters measured (eg cardiac, CNS),
the dose, route and species studied. There is lack of scientific data available to determine asafe maximal dose of local anaesthetic. However, the upper limit of a dose should take into
account patient weight, age and comorbidities. There is a pharmacokinetic rationale tosupport fractional dosing by incremental injection of local anaesthetic in addition to
identifying unintended intravascular injection.
The incidence of local anaesthetic systemic toxicity (LAST) has been quantified using registrydatabases at 0.03% or 0.27/1,000 PNBs (95%CI 0.21 to 0.35) (Gitman 2018 Level IV, n=251,325).
Factors associated with increased LAST events were paravertebral (OR 9.20; 95%CI 2.24 to 37.8)
and upper limb blocks (OR 4.80; 95%CI 1.23 to 18.7), the use of lidocaine vs ropivacaine (OR 5.64;
95%CI 2.02 to 15.7) and larger doses of local anaesthetic (Barrington 2013 Level IV, n=25,336 [PNBs
in n=20,021 patients]).
The use of ultrasound and LASTThe use of ultrasound (US) was associated with a reduced incidence of LAST (OR 0.23; 95%CI
0.088 to 0.59) (Barrington 2013 Level IV, n=25,336 [PNBs] in n=20,021 [patients]); this may be due toincreased precision of needle placement with US guidance (minimising intravascular placement)(Neal 2016 Level IV SR, 27 studies, n=1,867), or the use of lower doses of local anaesthetic. A metaanalysis identifies a significantly decreased risk of vascular puncture using US (RR 0.16; 95%CI
0.05 to 0.47) (Abrahams 2008 Level I, 13 RCTs, n=946). These data form the basis for the current
Class I-B ASRA recommendations for the use of US to reduce LAST (Neal 2018 GL). It should be
noted that LAST episodes continue to occur despite precautionary measures, including US use(Gitman 2018 Level IV SR, n=47 [episodes of LAST]).
Seizures related to LAST
The most common presenting feature of LAST was seizure (53% and 61%; from case reports andregistries respectively) (Gitman 2018 Level IV, n=251,325). In blinded human-volunteer studies, CNS
symptoms were detected at IV doses and plasma concentrations that were 25% higher for
ropivacaine vs bupivacaine (Scott 1989 Level II EH, n=12, JS 2) and 16% higher for levobupivacaine
than bupivacaine (Bardsley 1998 Level II EH, n=14, JS 3). Although these data show that CNS toxicity
might
occur
less
frequently
or
be
less
severewith
the
S-enantiomers, all local anaesthetics are toxic. A rapid IV bolus of any of these agents may
overwhelm any of the more subtle differences found at lower plasma concentrations.
Cardiac events related to LAST
Severe myocardial depression and refractory ventricular fibrillation have been described as thehallmark of accidental IV administration of moderately large doses of bupivacaine. This has been
attributed to the slow dissociation of bupivacaine from the myocardial sodium channel, which isless marked with levobupivacaine and ropivacaine (Mather 2001 NR). Animal studies confirm that
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higher systemic doses of ropivacaine and levobupivacaine are required to induce ventriculararrhythmias, circulatory collapse or asystole (Ohmura 2001 BS), with the ranking of toxicity risk being
bupivacaine > levobupivacaine > ropivacaine (Groban 2001 NR).
Controlled human studies are only possible when looking at surrogate endpoints such as ECGchanges or myocardial depression and suggest a similar ranking of adverse effects (Bardsley 1998
Level II EH, n=14, JS 5; Knudsen 1997 Level II EH, n=12, JS 5; Scott 1989 Level II EH, n=12, JS 5), withbupivacaine being the most toxic and levobupivacaine being less toxic and similar to ropivacaine(Stewart 2003 Level II EH, n=14, JS 5).
Successful resuscitation from a massive overdose is of greater relevance in clinical practice.
A canine study investigating resuscitation (not using lipid emulsion) and survival following local
anaesthetic‐induced circulatory collapse showed survival rates of 50%, 70% and 90% withbupivacaine, levobupivacaine and ropivacaine respectively ( Groban 2001 BS).
Case reports of accidental toxic overdose with ropivacaine suggest that outcomes are morefavourable and resuscitation more straightforward (in particular requiring less cardiovascularsupport) than with racemic bupivacaine (Weiss 2014 CR; Hubler 2010 CR; Kimura 2007 CR; Khoo 2006
CR; Soltesz 2003 CR; Chazalon 2003 CR; Huet 2003 CR; Klein 2003 CR; Pham-Dang 2000 CR). This data isprior to the widespread use of guidelines and lipid emulsion therapy, and a review of case-series
and registry data over 33 mth from March 2014 identified only 2 reported deaths out of 47
events, one case having delayed therapy and the other related to lidocaine (Gitman 2018 Level IV
SR, n=47 [episodes of LAST]).
Total plasma concentrations of LAs tend to rise during the first 48 h of postoperative infusion,
although free levels remain relatively low (Scott 1997 Level IV, n=11; Emanuelsson 1995 EH PK). Thus,in published studies, toxicity due to systemic absorption from epidural or perineural infusions
has not been a problem. However, the risk of accidental absolute overdose with postoperative
infusions and the increasing use of fascial plane infusions, suggests that the less toxic agentsshould be used in preference and that the doses administered should be the minimum neededfor efficacy.
Lipid emulsion therapy
Lipid emulsion therapy is advocated for in the treatment of LAST (Neal 2018 GL; AAGBI 2010 GL).
Animal experimental data (Weinberg 2003 BS; Weinberg 1998 BS) has been supported by casereports of successful resuscitation following bupivacaine ( Rosenblatt 2006 CR), ropivacaine (Litz2006 CR), levobupivacaine (Foxall 2007 CR), mepivacaine/prilocaine (Litz 2008 CR) and mepivacaine/bupivacaine (Warren 2008 CR) toxicity and published case series of use of IV lipid emulsion therapy(Gitman 2018 Level IV SR, n=47 [LAST episodes]; Cave 2014 Level IV, n=10 (LAST episodes]; Felice 2008
Level IV, n=4).
The mechanism of action of the lipid emulsion may be due to partitioning of local anaesthetic
within the emulsion itself (acting as a “lipid sink” or “shuttling”) (Fettiplace 2018 NR),mitochondrial substrate enhancement in the myocardium (Weinberg 2000 BS) and/or a direct
inotropic effect (Fettiplace 2014 BS). Uncertainties relating to dosage, efficacy and adverse effects(Cave 2014 Level IV, n=10 (LAST episodes]) still remain, however, lipid administration appears safe.
The ASRA Practice Advisory on Local Anesthetic Systemic Toxicity recommends theadministration of IV lipid emulsion therapy at the first signs of LAST but following airway
management (Class I-B recommendation) (Neal 2018 GL). In suspected LAST, it is also
recommended to administer lipid emulsion immediately after airway support has commenced
and ventilation is controlled (convulsions may or may not need control at this point in order toventilate) (Neal 2018 GL); this prevents hypoxia, hypercapnia, and acidosis which are known topotentiate LAST. It should be noted that local anaesthetic toxicity might recur following

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successful initial resuscitation, suggesting a need for continued intensive observation if a large
dose of local anaesthetic has been administered (Marwick 2009 GL).
The ASRA guidelines are also available as an app for mobile phones and tablets (‘ASRA LAST’)(Neal 2018 GL).
LAST is also discussed in Section 5.8.11.3 and in paediatric patients in Section 10.6.3.5(including adverse effects of lipid emulsion use).

KEY MESSAGES
1. Lidocaine intrathecal is more likely to cause transient neurologic symptoms thanbupivacaine, prilocaine and procaine (S) (Level I [Cochrane Review NMA]).
2. Local anaesthetics have chondrotoxic effects on articular cartilage, with ropivacaine theleast toxic (N) (Level I [PRISMA]).
3. Wound infiltration with liposomal preparations of bupivacaine is no more effective thanropivacaine or plain bupivacaine for analgesic outcomes up to 48 hours (N) (Level I[PRISMA]).
4. The quality of epidural analgesia with local anaesthetics is improved with the addition of
opioids (U) (Level I).
5. Ultrasound guidance reduces the risk of vascular puncture during the performance ofregional blocks (S) (Level I).
6. Local anaesthetic systemic toxicity is reduced by the use of ultrasound guidance forregional anaesthesia (S) (Level I).
7. Continuous perineural infusions of lidocaine result in less effective analgesia and more
motor block than long‐acting local anaesthetic agents (U) (Level II).
8. There are no consistent differences between ropivacaine, levobupivacaine andbupivacaine in terms of quality of analgesia or motor block, when given in low doses forregional analgesia (epidural and peripheral nerve block) (U) (Level II).
9. Cardiovascular and central nervous system toxicity of the stereospecific isomers
ropivacaine and levobupivacaine is less severe than with racemic bupivacaine (U) (Level II).
10. Local anaesthetic systemic toxicity is increased in paravertebral and upper limb blocks,
with the use of lidocaine and higher doses of local anaesthetics (U) (Level IV).
11. Lipid emulsion is effective in resuscitation of circulatory collapse due to local anaesthetic
toxicity (S) (Level IV SR); however, uncertainties relating to dosage, efficacy and adverse
effects still remain; therefore, it is appropriate to administer lipid emulsion only once
ventilatory support has begun and convulsions are controlled (S) (Level IV).
The following tick box represents conclusions based on clinical experience and expert
opinion: Case reports following accidental overdose with ropivacaine, levobupivacaine andbupivacaine suggest that resuscitation is less likely to be successful with bupivacaine (U).

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4.5 | Inhalational agents
4.5.1 | Nitrous oxide
N2O has been used since the inception of anaesthesia for its modest analgesic and sedative
properties. It has minimal respiratory and cardiovascular depression. In many countries it isavailable as a 50% N2O /50% oxygen mixture called Entonox®. While it has a long history of use,
there is a paucity of good studies examining its effectiveness in comparison with other analgesics(Buhre 2019 NR).
In a meta-analysis of inhaled analgesics in labour, subgroup analysis of N 2O shows minimal
analgesic difference vs placebo (RR 0.06; 95%CI 0.01 to 0.34) (MD 3.5/100; 95%CI -3.75 to -3.25)(Klomp 2012 (Level I [Cochrane], 3 RCTs [N2O], n=819). A systematic review shows that N2O in oxygen
has some analgesic efficacy in labour (Likis 2014 Level IV SR, 58 studies, n=20,266). Only two studies
were of good quality. N2O provides less analgesia than epidural analgesia but more thanpethidine, or bath and shower. Maternal satisfaction with the birth experience using N 2O for
analgesia is higher than for pethidine or epidural analgesia. The reports of maternal adverse
effects in this review are nausea, vomiting, dizziness and drowsiness. Apgar scores are nodifferent for N2O vs no analgesia. A subsequent systematic review vs multiple comparators, wasoverall of low quality and did not add to the previous information ( Sheyklo 2017 Level I [PRISMA],
14 RCTs, n=2,158) (See also Section 9.1.3.2).
N2O was effective during painful procedures such as venous cannulation ( Gerhardt 2001
Level II, n=10, JS 5), sigmoidoscopy ( Harding 2000 Level II, n=77, JS 5), dermatological procedures(Brotzman 2018 Level IV SR, 8 studies, n=438), extraction of gauze packing strips after CaldwellLuc operation (Dong 2017 Level II, n=47, JS 4), lumbar puncture (Moisset 2017 Level II, n=66, JS 5),transrectal prostate biopsy (Cazarim 2018 Level II, n=84, JS 4), liver biopsy (Castera 2001 Level II,
n=100, JS 5), in relieving acute ischaemic chest pain ( O'Leary 1987 Level II, n=12, JS 2) and intrauma patients in the prehospital setting (Ducasse 2013 Level II, n=60, JS 4). In elderly patients(median age 84 y), N 2O provided better analgesia than morphine during bed sore and ulcer
care (Paris 2008b Level II, n=34, JS 3). For colonoscopy, there was no difference inpain intensity between continuous and as-required 50% N2O use (Ball 2015 Level II, n=108, JS 5).
While a previous study reported benefits in bone marrow aspiration ( Gudgin 2008 Level III-3,n=16), a subsequent RCT found no difference in pain and anxiety scores between 50% N 2O inoxygen and an oxygen/air mixture ( Kuivalainen 2015 Level II, n=60, JS 3). Similarly, for intrauterine
device insertion, there was no analgesic effect of 50% N 2O vs oxygen (Singh 2016b Level II, n=80,
JS 5) and there was no pain relieving or opioid-sparing effect of 65% N2O vs oxygen for burns
dressing changes (do Vale 2016 Level III-1, n=15).
For lower gastrointestinal endoscopy, there is no difference in pain scores between N 2O andIV opioid/midazolam, or the ability to successfully complete the procedure ( Welchman 2010,
Level I, 11 RCTs, n=623). The N2O group has a shorter time to achieve fitness for discharge. Selfadministration of 50% N2O combined with PO morphine vs the same dose of PO morphine alone
resulted in better pain control of breakthrough pain in cancer patients at 5 and 15 min ( Liu 2018
Level II, n=240, JS 5).
As no RCTs compare N2O and methoxyflurane, an indirect comparison for pain relief in the
ED showed no significant differences in efficacy between the two agents ( Porter 2018b Level I[NMA], 2 RCTs, n=263).
For use in paediatrics see Section 10.7.2 and 10.7.4.
In an experimental setting, a study measuring changes in detection and pain thresholds toelectrical tooth stimulation reported the development of acute and chronic tolerance in174

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response to single and repeated administration of N2O (38% or 35%) for 30 min (Ramsay 2005 EH).
The significance of this finding in the clinical setting is unknown.
A post-hoc analysis of an RCT (ENIGMA) using telephone interviews at a median of 4.5 yfollowing (mostly abdominal) surgery found that the intraoperative use of N 2O reduced the riskof chronic postsurgical pain in an Asian population (OR 0.48; 95%CI 0.33 to 0.93) ( Chan 2011
Level II, n=423, JS 5); factors increasing risk included severity of acute postoperative pain, woundlength, wound infection and anxiety. These findings were confirmed in a planned subgroup
analysis in Asian vs non-Asian patients (RR 0.70; 95%CI 0.50 to 0.98) of a subsequent RCT(ENIGMA II) (Chan 2016 Level II, n=2,924 [phone interviews at 12 mth postop], JS 5).
N2O attenuated remifentanil induced tolerance/hyperalgesia ( Wehrfritz 2016 Level II EH, n=21,
JS 5; Echevarria 2011 Level II, n=50, JS 4).
N2O diffuses more rapidly than nitrogen and can expand enclosed air-containing spaces
within the body. Its use is therefore contraindicated in the presence of a pneumothorax,
obstruction of middle ear and sinus cavities, recent vitreoretinal surgery, pneumocephalus,
bowel obstruction and gas embolism (Shaw 1998 NR).
4.5.1.1 | Toxicity
N2O oxidises the cobalt ion of cobalamin (vitamin B12) preventing it from acting as a coenzyme
for methionine synthetase; methionine synthetase also requires 5-methyltetrahydrofolate as acoenzyme (Sanders 2008 NR). Methionine synthetase is required for the synthesis of
deoxyribonucleic acid and ribonucleic acid and therefore the production of cells in rapidly
dividing tissues such as bone marrow and gastrointestinal mucosa, as well as the synthesis ofmyelin (Sanders 2008 NR). Exposure of young children (median age 11 mth) to N 2O anaesthesia
for more than 2 h leads to a statistically significant but small increase in total homocysteine
plasma concentrations on the first postoperative morning with unclear clinical relevance(Pichardo 2012 Level IV, n=32).
Bone marrow and neurological complications have been reported in patients exposed to N2O.
A systematic review identified 100 cases of neurological toxicity, of which 57% resulted fromrecreational use (Oussalah 2019 Level IV SR, 85 studies, n=100 [cases]). Other reasons for exposure
were surgery in 25%, occupational exposure in 9%, pain control in 6% and procedural sedation
in 1%. Clinical symptoms included paraesthesia in 80%, unsteady gait in 58% and weakness in
43%. The most common diagnoses were subacute combined degeneration (SACD) of the spinal
cord in 28%, myelopathy in 26% and generalized demyelinating polyneuropathy in 23%; a T2
signal hyperintensity in the MRI of the spinal cord was seen in 68%. Pathological haematologicalfindings occurred in 72%. The most relevant factor was possible or probable vitamin B 12
deficiency (diagnosed on the combined indicator of vitamin B 12 status [cB12] scoring system[Fedosov 2015 BS]) in 85%. In a univariate risk analysis, the following risk factors were identified:age 40 y (OR 23.3; 95%CI 6.8 to 79.6), vitamin B12 level 74 pmol/L (OR 6.06; 95%CI 2.05 to17.9) and MCV >100 fL (OR 9.8; 95%CI 1.9 to 49.1). The dose of N2O was not associated with any
outcome.
A parallel systematic review of SACD excluded recreational users (Patel 2018 Level IV SR, 32
studies, n=39 [cases]) (significant overlap). Again in 84% of cases vitamin B12 malabsorption
secondary to a gastrointestinal disorder was the underlying causation. Classical symptoms were
proprioceptive and vibratory sensation loss in 67% and burning or tingling paraesthesia in 59%.
Again, there was no association to exposure duration. Most notably, supplementation withvitamin B12 resulted in complete recovery in 33% and partial improvement in 64%. Mean time tocomplete resolution was 37 wk (4 wk to 3 y).

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The risk may be greater in critically ill patients with increased metabolic demands or poor
nutrition (Amos 1982 Level IV, n=70). N2O-induced bone marrow toxicity leading to megaloblastic
anaemia is usually progressive but reversible. The bone marrow changes were almost completely
prevented by administration of folinic acid (Amos 1982 Level IV, n=70).
The following case reports are included in the systematic reviews above, but highlight specificrisk factors: those at risk of vitamin B12 deficiency include some vegetarians (in particular vegans)(Rosener 1996 CR), the newborns of vegetarian mothers (McNeely 2000 CR), patients withgastrointestinal pathology (Schilling 1986 Level IV) or phenylketonuria (Walter 2011 NR), being
elderly (Nilsson-Ehle 1998 NR), patients taking PPIs (Schenk 1999 Level IV) or H2 blockers andalcoholics (Sanders 2008 NR; Carmel 2000 NR). Cases have also been reported in those abusing the
drug (eg obtained from whipped cream chargers) or being exposed to N 2O for medical purposes
after longer periods of abuse (Lin 2011 Level IV, n=3; Rheinboldt 2014 CR; Hu 2014 CR; Chiang 2013 CR;
Cheng 2013 CR; Ghobrial 2012 CR; Sanders 2008 NR).
The neuropathy appears to be the result of decreased methionine and subsequent defective
myelin formation. Involvement of peripheral, autonomic and central nervous systems may also
lead to incontinence, diplopia, confusion or impaired cognitive function ( Weimann 2003 NR).
Despite the lack of any good data assessing efficacy in humans, and even though the bonemarrow changes are usually reversible, it may be reasonable to give patients repeatedly exposed
to N2O, vitamin B12 and folic or folinic acid supplements (Weimann 2003 NR).
Another consequence of N2O-induced inactivation of methionine synthetase is elevation ofplasma homocysteine (a known risk factor for coronary artery and cerebrovascular disease), thelevels of which rise after anaesthesia using N2O (Myles 2008 Level II, n=59, JS 3; Badner 1998 Level II,
n=20, JS 2; Nagele 2008 Level III-3, n=140). Patients who are homozygous for polymorphisms in thegene encoding the enzyme that is an antecedent to methionine synthetase are at a higher riskof developing abnormal plasma homocysteine concentrations after N2O anaesthesia (Nagele 2008
Level III-3, n=140). However, the large ENIGMA II study, comparing oxygen 30% with or without
N2O (70%) in patients with known or risk factors for ischaemic heart disease, found no difference
in serious adverse effects in the N2O group vs the non-N2O group (Myles 2014 Level II, n=7,112, JS
3). However, as this study examined patients who were undergoing major surgery that lasted forat least 2 h, the applicability to the setting of analgesia may be limited.
Methionine given preoperatively to patients undergoing N 2O anaesthesia improved the rateof recovery of methionine synthetase and prevented the prolonged postoperative rise in plasma
homocysteine concentrations (Christensen 1994 Level IV, n=14). Preoperative administration oforal B vitamins (folate, B6 and B12) (Badner 2001 Level II, n=53, JS 3) and of vitamin B12 infusions(Kiasari 2014 Level II, n=60, JS 5) also prevented the postoperative increase in homocysteine
following N2O anaesthesia.
The information about the complications of N 2O derives from case reports only. There areno controlled studies that evaluate the safety of repeated intermittent exposure to N 2O inhumans and no data to guide the appropriate maximum duration or number of times a patient
can safely be exposed to N 2O. Nevertheless, the potential problems require highlighting. The
suggestions for the use of N2O outlined below are extrapolations only from the information
above.
4.5.1.2 | Suggestions for the use of nitrous oxide as an analgesic
When N2O is to be used repeatedly for painful short procedures, it may be reasonable to:• Exclude patients with persistent vitamin B12 deficiency;• Screen patients at risk of vitamin B12 deficiency by examination of the blood picture andserum B12 concentrations before using N2O repeatedly;176

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Exclude asymptomatic patients with macrocytic anaemia or hypersegmentation ofneutrophils until it is established that vitamin B 12 or folate deficiency is not the cause;• Exclude females who may be in the early stages of pregnancy, although this will dependon the relative harm of any alternative methods;• Limit exposure to N2O to the briefest possible time — restricting the duration of
exposure may require strict supervision and limited access to the gas;
• Administer methionine, vitamin B12 (both with a good safety profile) and possibly folicor folinic acid to patients repeatedly exposed to N2O (doses that may prevent thecomplications of exposure to N2O have not been established);• Monitor for clinical signs and symptoms of neuropathy on a regular basis and start
treatment with vitamin B12 early.

4.5.2 | Methoxyflurane
Methoxyflurane is a volatile anaesthetic agent with analgesic properties. It was first marketed in
1962 and later withdrawn from sale in 2001. The FDA withdrew the medicine because of the riskof nephrotoxicity and hepatotoxicity and stated that it would not consider reintroduction into
the market until new clinical trials were undertaken (FDA 2005). Methoxyflurane is no longer
licensed for anaesthesia in humans.
Although no longer used as an anaesthetic, methoxyflurane has been registered inAustralia and New Zealand (as well as now a number of other countries) for use as ananalgesic in low doses since 1975 for relief of trauma-associated acute pain as well asprocedural pain (Porter 2018a NR; Jephcott 2018 NR; Medical Devices International 2009 ). It isavailable as a self-‐administered “Penthrox®” inhaler, which dispenses 0.2 to 0.4%
methoxyflurane (Medical Devices International 2009 ).
As an analgesic in prehospital and ED settings, methoxyflurane has been reported as
effective (Yeung 2018 Level III-2 SR [PRISMA], 2 SRs & 2 studies, n>43,823 [methoxyflurane recipients];
Grindlay 2009 Level IV SR, 6 studies [analgesia], n=293). Methoxyflurane provided inferior analgesia
to IV morphine and IN fentanyl in the prehospital setting with minimal adverse effects (1 study,n=42,844) (Yeung 2018 Level III-2 SR, 2 SRs & 2 studies, total n unspecified). In ED patients aged ≥12y, it was significantly more analgesic than placebo, with only mild transient adverse effects
such as dizziness and headache ( Wells 2018 Level I [PRISMA, 1 RCT: Coffey 2014 Level II, n=300, JS
4). The median time to onset of analgesia was rapid at 4 min and time to peak analgesia was
15 min. Safety was assessed over 14 d following administration and no significant adverse
effects were found, including no renal impairment. Use of the Penthrox® inhaler in children
reduced pain associated with extremity injuries ( Babl 2006 Level IV, n=15) but did not provide
adequate analgesia for subsequent fracture manipulation ( Babl 2007 Level IV, n=14). It also
provided effective pain relief for adult patients in the prehospital setting, as shown in adults
travelling by ambulance to an urban teaching hospital ( Buntine 2007 Level IV, n=83). Adverse
effects included hallucinations, vomiting, confusion and dizziness, and sedation/drowsiness
was common (26%) in children ( Buntine 2007 Level IV, n=83; Babl 2006 Level IV, n=15).
As an analgesic for painful procedures outside of the ED, methoxyflurane was firstdescribed for obstetric analgesia in 1966 (Bodley 1966 Level IV, n=62) and then used as an analgesic
for burns dressing (Marshall 1972 Level IV, n=60 [procedures in 10 patients]; Firn 1972 Level IV, n=94
[procedures in 36 children]; Packer 1969 Level IV, n=60 [procedures in 11 patients]). Methoxyflurane was
effective for prostate biopsies achieving a low pain score (median 3/10), mild adverse effects andhigh patient acceptance (Grummet 2012 Level IV, n=42). However, methoxyflurane combined with
periprostatic infiltration of local analgesia provided superior analgesia vs methoxyflurane alone(Huang 2016 Level III-1, n=72). In patients having colonoscopies, methoxyflurane vs IV
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fentanyl/midazolam resulted in similar pain scores but shorter recovery and fitness for discharge
times, no respiratory depression, and high degree of patient satisfaction ( Nguyen 2013 Level II
n=250, JS 3). Ten patients in the methoxyflurane group required supplementation with
IV sedation.
In patients having bone-marrow biopsies, local anaesthetic infiltration plus methoxyfluranevs placebo inhaler resulted in lower worst pain scores (4.9 vs 6.0/10) (Spruyt 2014 Level II, n=97, JS
4). Adverse effects were mild and of short duration. The overall efficacy was also confirmed in
an audit of methoxyflurane use for procedural analgesia in a variety of procedures with reported
success in 97% and minimal adverse effects (Gaskell 2016a Level IV, n=173 [procedures in
123 patients]).
As no RCTs compare methoxyflurane and N 2O, an indirect comparison for pain relief in the
ED showed no significant differences in efficacy between the two agents ( Porter 2018b Level I[NMA], 2 RCTs, n=263). In an unblinded comparison between self-administered methoxyfluraneand IV PCA ketamine/midazolam for burns dressing both achieved similar analgesia with patient
preference for methoxyflurane (Gaskell 2016a Level II, n= 8 [cross over], JS 3).
4.5.2.1 | Toxicity
Methoxyflurane causes dose-dependent renal toxicity and, as noted above, renal failure was a
key reason behind the withdrawal of the medicine from use. Use of an analgesic device delivering
higher concentrations of methoxyflurane was reported to have led to two fatalities from renal
toxicity (Toomath 1987 Level IV). However, the amount of methoxyflurane delivered using thePenthrox® inhaler is said to be significantly less than the dose that has been associated with
subclinical nephrotoxicity (Grindlay 2009 NR). There have been no reports of toxicity (Grindlay 2009NR) with dosing limited to 6 mL/d or 15 mL/wk (Medical Devices International 2009). A large
population database study found no long-term (up to 14 y) adverse effects (heart disease, renal
disease, hepatic disease, diabetes, or cancer) in patients who had been given methoxyflurane
by an ambulance service (Jacobs 2010 Level IV; n=17,629). The maximum dose approved (6 mL/dand 15 mL/wk) is calculated to achieve a minimum alveolar concentration (MAC) of 0.59 MAC-h(Dayan 2016 NR). Methoxyflurane ≤2.0 MAC-h results in serum fluoride ≤40 micmol/L, which has
not been associated with renal tubular toxicity, thereby suggesting a safety margin of at least 2.7
to 8-fold of the approved dose limits.
There has been one documented case report of acute hepatitis following threeadministrations of methoxyflurane in an otherwise healthy woman for procedural analgesia(O'Rourke 2011 CR).
Methoxyflurane is contraindicated in patients with known or at genetic risk of malignant
hyperpyrexia as well as in patients with renal impairment (Medical Devices International 2009).

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1. Nitrous oxide has some analgesic efficacy in labour pain (U), increases maternal adverse
effects (nausea, vomiting, dizziness) (U), with no adverse effects on the newborn (U)(Level I [Cochrane Review]) and increases maternal satisfaction compared to pethidine
and epidural analgesia (U) (Level IV SR).
2. Nitrous oxide has equivalent effectiveness and more rapid recovery compared withintravenous sedation in patients having lower gastrointestinal endoscopy (U) (Level I).
3. Methoxyflurane, in low doses, is an effective analgesic with rapid onset in theprehospital setting, and a range of procedures in the hospital setting (U) (Level II) withgood safety data (S) (Level IV); it may have comparable efficacy to nitrous oxide (N)(Level I [NMA]), but is inferior to IV morphine and IN fentanyl (N) (Level III-2 SR).
4. Nitrous oxide is an effective analgesic agent in a variety of other acute pain situations(U) (Level II).
5. Intraoperative use of nitrous oxide reduces the incidence of chronic postsurgical pain in
Asian populations (N) (Level II).
6. Subacute combined degeneration of the spinal cord, myelopathy and generalised
demyelinating polyneuropathy are rare but potentially serious complications of nitrous
oxide use including in those abusing nitrous oxide (S) (Level IV SR).
7. Vitamin B12 deficiency (identified by vitamin B12 level 74 pmol/L and MCV >100 fL) andage 40 years are relevant risk factors in nitrous oxide neurotoxicity; total nitrous oxide
exposure may not be a risk factor (N) (Level IV SR).
8. Early supplementation with Vitamin B12 in subacute combined degeneration of the spinal
cord exacerbated by nitrous oxide use improves neurological recovery (N) (Level IV SR).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: In patients receiving nitrous oxide repeatedly, supplementation with vitamin B12,
methionine and folic or folinic acid is a consideration, in particular in those with risk
factors (Q).
 If nitrous oxide is used with other sedative or analgesic agents, appropriate clinicalmonitoring should be used (U).

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4.6 | NMDA-receptor antagonists
NMDA-receptor/ion-channel complexes are located peripherally and centrally within the
nervous system (Gonda 2012 NR). These ionotropic receptors are an important component ofglutamergic neurotransmission and thereby involved in multiple functions within the nervous
system including learning and memory, cognitive functions, neural development,
neuroplasticity, excitotoxicity, addiction, psychiatric disorders and nociception ( Li 2016a NR).
At the spinal level, NMDA-receptor activation results in the development of central
sensitisation manifested clinically as hyperalgesia and allodynia (Petrenko 2014 NR; Hocking 2007
NR). Activation of NMDA receptors via glutamate release from excitatory synapses augments the
propagation of nociceptive information and is therefore linked to acute and chronic pain states
as well as opioid-induced tolerance and hyperalgesia.
The NMDA-receptor antagonists ketamine, dextromethorphan, amantadine, memantine andmagnesium have been investigated for the management of acute pain ( Kreutzwiser 2019 NR;
Jonkman 2017 NR).

4.6.1 | Systemic NMDA-receptor antagonists
4.6.1.1 | Ketamine
In low (subanaesthetic) doses, ketamine acts primarily as a noncompetitive antagonist of the
NMDA receptor, although it also binds to many other sites in the peripheral and central
nervous systems (Petrenko 2014 NR; Sleigh 2014 NR; Mion 2013 NR). In more detail it is a “hightrapping” antagonist with a slow off-rate, causing a prolonged tonic block; therefore it has
higher adverse effect rates than “low-trapping” antagonists with a fast off-rate such as
memantine (Sleigh 2014 NR). Consequently, ketamine’s main role is as an adjuvant in thetreatment of pain associated with central sensitisation ( Persson 2013 NR), such as in severe
acute pain, neuropathic pain ( Zhou 2011 NR) (see Section 8.1.4) and “opioid-resistant” pain
(Kreutzwiser 2019 NR; Tawfic 2013 NR). See also Section 9.7 and for paediatric use Section 10.4.7.
In experimental pain, low-dose ketamine (<1 mg/kg) reduces the area of hyperalgesia (SMD
0.54; 95% CI 0.34 to 0.74) and pain intensity (MD -1.2/10; 95%CI -0.88 to -1.44) (54 RCTs
[ketamine]: 43 RCTs [IV administration]) (Thompson 2019 Level I EH (PRISMA), 70 RCTs, n=1,069).
In Australia and New Zealand, ketamine is supplied as a racemic mixture (S- andR- enantiomers), although a number of other countries have the more potent pure S-ketamine
enantiomeric form available which has twice the analgesic potency, and slightly less adverse
cognitive effects in adults (Mion 2013 NR).
Perioperative use
Perioperative IV ketamine (IV bolus pooled with IV infusion) used in a large number of operations
performed under general anaesthesia vs placebo reduces postoperative opioid consumption
over 24 h by 19 % (MD 8 mg morphine equivalents; 95%CI 6 to 9) (65 RCTs, n=4,004) and over 48
h by 19 % (MD 13 mg; 95%CI 10 to 15) (37 RCTs, n=2,449) (Brinck 2018 Level I [Cochrane], 130 RCTs,
n=8,341). Pain at rest is reduced by 19% at 24 h (MD -5/100; 95%CI -4 to -7) (82 RCTs; n=5,004) andat 48 h by 22 % (MD -5/100; 95%CI -3 to -7) (49 RCTs, n=2,962). Pain during movement is reduced
in a similar way. Furthermore, PONV is reduced to a minor degree (23 % vs 27 %; RR 0.88; 95%CI
0.81 to 0.96) (NNT 24; 95%CI 16 to 54) (95 RCTs, n=5,965). The incidence of adverse events withketamine (5%) vs placebo (4%) is similar (RR 1.2; 95%CI 0.95 to 1.4) ( 105 RCTs, n=6,538).
A dose-dependent analgesic effect is not apparent.

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Multiple further systematic reviews in subgroups have been performed with significant
overlap of RCTs included.
Adding ketamine to an opioid in the PCA pump has similar benefits to the pooled data aboveon pain at rest at 24 h (WMD 21.1/100; 98%CI 21.8 to 20.39) (9 RCTs, n=595), opioid consumption(-28%) (7 RCTs, n=495) and PONV (-44%) (7 RCTs, n=435) (Assouline 2016 Level I [PRISMA], 19 RCTS,
n=1,453). Respiratory depression (RR 0.31; 98%CI 0.06 to 1.51) (9 RCTs, n=871) and hallucinations(OR 1.16; 98%CI 0.47 to 2.79) (7 RCTs, n=690) are not increased. A parallel meta-analysis on
ketamine added to morphine or hydromorphone PCA confirms these results ( Wang 2016a Level I[PRISMA], 36 RCTs, n=2,502) (12 RCTs overlap).
Morphine/ketamine vs higher doses of morphine alone improves analgesia (MD 2.19/10;
95%CI 1.24 to 3.13) and wakefulness (MD -1.53/10; 95%CI -2.67 to -0.40) and reduces PONV (OR
3.71; 95%CI 2.37 to 5.80) and need for non-opioid rescue analgesia (Ding 2014 Level I, 7 RCTS,
n=492).
Subanaesthetic doses of IM ketamine (escalating from 5 to 25 mg) injected two to three times
17 h to 4 h before cancer surgery reduced postoperative pain and morphine consumption incomparison to a single injection 4 h before surgery and placebo (Rakhman 2011 Level II, n=120, JS 5).
Results with regard to specific types of surgery:• After thoracotomy, addition of ketamine to IV morphine PCA is opioid-sparing andimproved analgesia in all RCTs and increases patient satisfaction in one (Mathews 2012
Level I, 5 RCTs, n=243). Improved respiratory outcomes (oxygen saturations and PaCO 2)
are found in the RCTs assessing these parameters (2 RCTs, n=89). IV ketamine/fentanyl
PCA resulted in comparable analgesia to thoracic epidural analgesia ( Tseng 2019 Level II,
n=70, JS 3);• After knee arthroscopy, IV ketamine reduces pain intensity and opioid requirements aswell as malonaldehyde levels as a measure of reperfusion injury (SMD -0.63; 95%CI 1.05 to -0.2) (2 RCTs, n=90), but not PONV (Pan 2019 Level I [PRISMA], 7 RCTs, n=300);• After laparoscopic cholecystectomy, IV ketamine reduces pain intensity and opioid
requirements at all time points up to 48 h, while reducing the incidence of PONV,
pruritus and ileus (Zhu 2018a Level I, 6 RCTs, n=294; Ye 2017 Level I, 5 RCTs, n=212) (5 RCTs
overlap);• After Caesarean section under spinal anaesthesia (7 RCTs, n=562), but not under generalanaesthesia (5 RCTs, n=391), parenteral ketamine improves pain intensity at 2 h, prolongs
time to first analgesic request and reduces opioid requirements without increasing
adverse effects except for diplopia in one RCT and nystagmus in 2 RCTs ( Heesen 2015
Level I [PRISMA], 12 RCTs, n=953);• After spinal surgery, ketamine reduces pain intensity and opioid requirements for 24 hwithout increased adverse effects (Pendi 2018 Level I, 14 RCTs, n=649). After spinal fusion
surgery, perioperative IV ketamine bolus and infusion vs placebo resulted in improved
long-term outcomes 1 y after surgery with reduced oral morphine (0 mg vs 20 mg) andother analgesic use, better pain relief at rest and on mobilisation (MD -17/100; 95%CI−30 to −3) and higher rate of return to work (43% vs 28%) ( Nielsen 2019 Level II, n=147,
JS 4);• After laparoscopic gastric banding in obese patients, intraoperative ketamine infusion
reduced pain and PCA opioid requirements (Andersen 2014b Level I, 1 RCT: Hasanein 2011,
Level II, n=60, JS 3).
Subsequent to these meta-analyses, multiple further RCTs studying the same issue have been
performed; overall the outcomes from these studies do not affect the existing conclusions andthey are therefore not referenced here.
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Low-dose parenteral ketamine may also improve analgesia in patients with opioid-induced
tolerance or hyperalgesia. After spinal fusion in opioid-tolerant patients, use of a continuous
ketamine infusion resulted in significantly less pain but did not reduce PCA opioid requirements
in one RCT (Urban 2008 Level II, n=24, JS 4), however its use reduced opioid requirements and painscores in the early postoperative period and at 6 wk in another ( Loftus 2010 Level II, n=101, JS 4).
Another trial in the same setting found reduced morphine requirements over 24 h (MD -42 mg;
95%CI -59 to -25), reduced sedation and improved function and disability at 6 mth ( Nielsen 2017
Level II, n=150, JS 5). Similar results were found after noncancer surgery ( Barreveld 2013b Level II,
n=64, JS 5). A preoperative ketamine bolus for extracorporeal shock-wave lithotripsy reduced
opioid requirements in chronic opioid users on low and high doses ( Gharaei 2013 Level II, n=190,
JS 4). However, when opioid-tolerant patients had epidural analgesia and IV PCA after spinal
surgery, the addition of ketamine bolus and 24 h infusion conveyed no further benefit vs placebo(Subramaniam 2011 Level II, n=30, JS 5); the patients in this study also received gabapentin andantidepressants.
After remifentanil based anaesthesia, perioperative systemic ketamine reduces thedevelopment of acute tolerance/OIH associated with remifentanil use ( Garcia-Henares 2018
Level I [PRISMA], 12 RCTs, n=569). This assessment is based on reduced postoperative pain scoresand opioid requirements and increased time to first analgesic request and satisfaction scores in
the ketamine vs the placebo groups but not on QST.
Use of a low-dose IV ketamine infusion 0.05 mg/kg/h for 24 h postoperatively reduced painscores (over 48 h) in patients receiving epidural ropivacaine and morphine analgesia following
thoracotomy (Suzuki 2006 Level II, n=49, JS 5). However, this was not confirmed by a subsequent
study, where the addition of IV ketamine infusion 0.09 mg/kg/h for 48 h to epidural analgesia
added no benefit (Joseph 2012 Level II, n=60, JS 5).
Perioperative ketamine vs placebo reduces the incidence of CPSP at 3 mth (5 RCTs, n unspecified)but only when administered for >24 h (OR 0.37; 95%CI 0.14 to 0.98) (Chaparro 2013 Level I[Cochrane] 14 RCTs [ketamine], n=1,388). At 6 mth (10 RCTs, n=516), perioperative ketamine reduces
CPSP (OR 0.63; 95%CI 0.47 to 0.83), including when infused for <24 h (OR 0.45; 95 %CI 0.26 to0.78). These effects were predominantly in abdominal surgery. Another meta-analysis found abenefit of perioperative IV ketamine vs placebo in reducing the incidence of CPSP at 3 mth(RR 0.74; 95%CI 0.60 to 0.93) (NNT 12), 6 mth (RR 0.70; 95%CI 0.50 to 0.98) (NNT 14) but not at
12 mth postoperatively (McNicol 2014 Level I, 14 RCTs [IV route], n=1,586) (11 RCTs overlap); such
beneficial effects were not found with epidural administration of ketamine ( 3 RCTs, n=302). A
subsequent meta-analysis found a benefit only at one mth, but is based on a much smaller
number of included RCTs and speculates about the potential benefits of ketamine infusion >72
h and the role of epidural administration (Klatt 2015 Level I [PRISMA], 10 RCTs, n=784) (6 RCTs overlap
with Chaparro 2013, all 10 RCTs overlap with McNicol 2014).
Ketamine has an effect on the regulation of inflammation by inhibiting inflammatory cell
recruitment, cytokine production and downregulating inflammatory mediators (Loix 2011 NR).
Intraoperative administration of ketamine has an inhibitory effect on the early postoperative IL-6
inflammatory response (MD -71 pg/mL; 95%CI -101 to -41) (Dale 2012 Level I [PRISMA], 6 RCTs, n=331).
Other acute pain indications
IV ketamine pretreatment reduces pain from propofol injection vs no pretreatment (OR 0.52;
95%CI 0.46 to 0.57) (Jalota 2011 Level I, 7 RCTs, n=910).
Ketamine has also some analgesic efficacy in burns patients ( McGuinness 2011 Level I, 4 RCTs,n=67) (see also Section 8.5).
In the ICU, ketamine acts as a potent analgesic, sedative agent and bronchodilator withpositive effects on haemodynamics (Patanwala 2017 Level IV SR [PRISMA], 6 RCTs, n=223 & 6 studies).

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See also Section 8.10.5.5.
Low dose ketamine 0.1 to 0.3 mg/kg IV is considered a safe and efficacious analgesic in the
ED either as single therapy or in combination with IV morphine 0.1 mg/kg ( Karlow 2018 Level I[PRISMA], 3 RCTs, n=261; Ghate 2018 Level IV SR [PRISMA], 6 RCTs, n=544 & 2 studies, n=65) (2 RCTs
overlap). See also Section 8.11.1.4.
Ketamine is also a safe and effective analgesic for pain due to trauma in the prehospitalsetting (Jennings 2011 Level IV SR, 2 RCTs & 4 studies, n=340). See also Section 8.12.2.4.
Guidelines for the use of ketamine infusions in acute pain support its use in painful surgery,for opioid-dependent or opioid-tolerant patients undergoing surgery or with acute or chronic
sickle cell pain and possibly for patients with sleep apnoea to limit opioid use ( Schwenk 2018 GL).
Adverse effects with short-term systemic administration of ketamine
Overall, CNS adverse events (eg hallucinations and nightmares) were increased vs placebo in 52
studies, while 53 studies reported no increase (Brinck 2018 Level I [Cochrane], 130 RCTs, n=8,341).
Pooled incidence of CNS adverse effects is not increased (RR 1.2; 95%CI 0.95 to 1.4) (105 RCTs,
n=6,538). The incidence of hallucinations is reported as not increased when ketamine is combinedwith the opioid in a PCA pump (OR 1.16; 98%CI 0.47 to 2.79) ( 7 RCTs, n=690) (Assouline 2016
Level I [PRISMA], 19 RCTS, n=1,453).
The incidence can be reduced with a gradual dose increase (Okamoto 2013 Level IV, n=46). For IV
administration, slow IV infusion of 0.3 mg/kg ketamine resulted in lower rates of CNS adverse
effects than IV bolus injection (Clattenburg 2018 Level II, n=62, JS 5; Motov 2017 Level II, n=48, JS 5).
Contrary to common beliefs, IV ketamine does not increase intracranial pressure or reduce
cranial perfusion pressure vs opioids (Wang 2014 Level I, 5 RCTs, n=198). This is also true for patientswith nontraumatic neurological diseases (Zeiler 2014 Level IV SR, 16 studies, n=127 [adult] & n=87
[children]).
Chronic pain
Ketamine has efficacy in treatment of chronic neuropathic pain ( 15 of 23 RCTs positive [ketamine])(Aiyer 2018 Level I [PRISMA], 58 RCTs, n unspecified).
IV ketamine is superior to placebo and comparable to IV lidocaine and IV alfentanil in thetreatment of pain after SCI (Teasell 2010 Level I, 2 RCTs [ketamine], n=19). See also Section 8.2.1.
IV ketamine reduces phantom limb pain short-term with some possible long-term benefit(Alviar 2016 Level I [Cochrane], 2 RCTs [ketamine], n=31; McCormick 2014 Level I, 4 RCTs, n=107) (2 RCTs
overlap). See also Section 8.1.5.2.
Ketamine by various routes of administration (IV, oral, topical) is also a successful treatment
for Complex Regional Pain Syndrome (CRPS) based on limited evidence ( Zhao 2018 Level III-2 SR,
1 RCT & 14 studies, n=258; Azari 2012 Level IV SR, 3 RCTS & 16 studies, n unspecified).
In view of the risks described below, current use of ketamine to treat chronic pain should be
restricted to therapy-resistant severe neuropathic pain (Niesters 2014a NR; Tawfic 2013 NR); recent
evidence-based guidelines outline a cautious approach with possibly best indications in spinal
cord injury pain and CRPS (Cohen 2018 GL). A draft of a practice guideline has been published by
FPMANZCA (FPMANZCA 2020 GL).
Cancer pain
Ketamine is a viable therapeutic option in treating refractory cancer pain despite limitations in
the data available (Bredlau 2013 Level IV SR, 5 RCTs and 6 studies, n=483); however, the largest RCT
included showed no clinical benefit when ketamine was added to opioids for cancer-pain
treatment (Hardy 2012 Level II, n=187, JS 5). A subsequent Cochrane review of ketamine as an
adjunct to opioids in cancer pain excluded most of the RCTs considered above and regards thecurrent evidence as insufficient to assess the benefits and harms of ketamine as an adjuvant to
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opioids for the relief of refractory cancer pain (Bell 2017 Level I [Cochrane] 3 RCTs, n=217). See also
Section 8.9.3.3.
Adverse effects with long-term systemic administration of ketamine
Ketamine has an abuse potential (Morgan 2012 NR) with highest abuse rates in South-East Asia
and China (Liu 2016 NR; Kalsi 2011 NR). Heavy use of ketamine has consequences on cognitive andemotional function (Morgan 2010 NR) and there are increasing consequences including traffic
accidents when under its influence (Liu 2016 NR). Acute toxicity leads to confusion, drowsiness,or transient loss of consciousness, while symptoms of chronic toxicity are “ketamine cystitis” andchronic abdominal pain (Yiu-Cheung 2012 NR) as well as hepatotoxicity. The latter issues need tobe considered when using ketamine in a chronic setting therapeutically ( Bell 2012 NR) and may
limit its indications (Cohen 2018 GL; Niesters 2014a NR).
Other routes of systemic administration and bioavailability
Ketamine is most commonly administered as a continuous low-dose IV infusion, however SC
infusion is also used, especially in palliative care, with a bioavailability (similar to IM) ofapproximately 90% (Clements 1982 PK). Sublingual (SL), IN and TD routes have also been used for
acute pain management (Peltoniemi 2016 NR PK) (see Chapter 5).
A pharmacokinetic study in healthy volunteers calculated the bioavailability of oral ketamine
as 20%, SL 30% and IN 45%; the pharmacodynamic effects of the active metabolite norketamine
were thought to be of potential significance (Yanagihara 2003 PK). The bioavailability of a 25 mg
ketamine lozenge was 24% when given by both SL and oral routes; peak plasma levels were seenat 30 min and 120 min respectively and terminal half-lives were similar at around 5 h (Chong 2009
PK). For both routes, norketamine concentrations exceeded the concentrations of ketamine and,given its pharmacological activity profile, norketamine is therefore likely to be a major
contributor to the overall analgesic effect. A SL ketamine wafer achieved rapid absorption witha bioavailability of 29% (Rolan 2014 PK).
4.6.1.2 | Dextromethorphan
In a meta-analysis of experimental studies (oral administration 11 RCTs; IV administration 1 RCT)
(mean dose 0.92 mg/kg [range 0.17 to 2.71 mg/kg]), dextromethorphan has no effect on area ofhyperalgesia (4 RCTs) nor on pain intensity (SMD 0.07; 95%CI -0.21 to 0.34) (10 RCTs, n=132)(Thompson 2019 Level I EH [(PRISMA]), 70 RCTs, n=1,069). However, PO dextromethorphan 30 mg ina model of primary and secondary hyperalgesia (freeze-injury pain model) had antihyperalgesic
effects on both phenomena, while it has no anti-nociceptive effect in areas of healthy skin (Martin
2019a Level II EH, n=20, JS 5).
In postoperative pain, dextromethorphan reduces pain at 1 h (MD -1.60/10; 95%CI -1.89 to-1.31) (13 RCTs, n=884), 4 to 6 h and 24 h as well as opioid requirements (IV MED MD -10.51 mg;
95%CI -16.48 to -4.53) (14 RCTs, n=848) (King 2016 Level I, 21 RCTs, n=1,520).
As dextromethorphan is metabolised by CYP2D6 to the inactive metabolite dextrorphan, theeffect of the CYP2D6 inhibitor quinidine before PO dextromethorphan 50 mg administration has
been assessed in knee ligament surgery (Ehret 2013 Level II, n=48, JS 4). Dextromethorphan
concentrations were higher after quinidine than after placebo and resulted in lower rescue
analgesia requirements. PO dextromethorphan/quinidine provided superior pain relief vsplacebo in diabetic polyneuropathy (Shaibani 2012 Level II, n=379, JS 3).
PO dextromethorphan 120 to 180 mg reduces chronic phantom limb pain vs placebo (Alviar
2016 Level I [Cochrane], 1 RCT [dextromethorphan]: Ben Abraham 2003 Level II, n=10 [triple phase crossover], JS 3).

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Dextromethorphan may have efficacy in chronic neuropathic pain ( 4 of 6 RCTs), possibly withless benefit in PHN (Aiyer 2018 Level I [PRISMA], 58 RCTs, n unspecified). After IV ketamine treatmentof neuropathic pain, PO dextromethorphan extended treatment effects for one mth vs placebo(Martin 2019b Level II, n=60, JS 4).
PO dextromethorphan therapy (titrated to 480 mg/d) for 5 wk was not effective in reversing
methadone-induced hyperalgesia (Compton 2008 Level III-1).
4.6.1.3 | Magnesium
Magnesium is regarded as an NMDA-receptor antagonist as its primary mechanism of action;
however, magnesium also blocks calcium channels and modulates potassium channels and may
have an antinociceptive effect through the activation of the nitric oxide (NO) pathway ( Srebro
2016 NR). It has also anti-inflammatory effects by reducing IL-6 and TNF-alpha plasma levels in
the postoperative setting, which might contribute to the effects described here ( Aryana 2014
Level II, n=90, JS 4).
Magnesium IV as an adjunct to morphine IV analgesia has an opioid-sparing effect (MED
WMD -7.4 mg; 95%CI -9.4 to -5.4) without reducing PONV but with improved pain scores at 4 to6 h (Murphy 2013 Level I, 22 RCTs, n=1,177). This is in line with two parallel meta-analyses: one also
describes an opioid-sparing effect (MED WMD -10.52 mg; 99%CI -13.50 to -7.54) and reductionof pain at rest (4 and 24 h) and on movement (24 h) ( De Oliveira 2013c Level I [PRISMA], 20 RCTs,
n=1,257) (most RCTs overlap); the second draws similar conclusions and found no significant
adverse effects (Albrecht 2013 Level I, 25 RCTs, n=1,461) (most RCTs overlap).
Subsequent to these three meta-analyses, multiple further meta-analyses and RCTs exploring
the same issues after different types of surgery or anaesthesia with significant overlap ofincluded RCTs conclude:• After orthopaedic surgery, IV magnesium reduces postoperative analgesic
consumption, PONV and shivering (Peng 2018 Level I [PRISMA], 11 RCTs, n=535). Pain
intensity is reduced in 6 of 11 RCTs;• After laparoscopic cholecystectomy, IV magnesium reduces pain intensity at 2 and 8 h
and analgesic consumption (Chen 2018a Level I, 4 RCTs, n=463);• After Caesarean section, a qualitative systematic review showed that IV magnesium
may reduce postoperative pain intensity (McKeown 2017 Level I, 7 RCTs, n=530);• In paediatric tonsillectomy, magnesium administered by local infiltration or IV (bolus 
infusion) has analgesic effects (Xie 2017 Level I [PRISMA], 10 RCTs n=665; Cho 2018 Level I[PRISMA], 10 RCTs, n=615) (9 RCTs overlap). See also Section 10.4.7.2;• After spinal anaesthesia, IV magnesium prolonged the duration of sensory block for
abdominal hysterectomy and reduced postoperative pain scores in the first 4 h after
surgery (Kahraman 2014 Level II, n=40, JS 5). After spinal anaesthesia for umbilical hernia
repair, IV magnesium prolonged time to first rescue analgesia and was opioid-sparing
in the first 24 h after surgery (Kumar 2013 Level II, n=60, JS 5). This was also found after
spinal anaesthesia for THA, where IV magnesium reduced postoperative pain scores andopioid requirements for 48 h, while increasing serum magnesium concentrations(Hwang 2010 Level II, n=40, JS 5). However, IV magnesium did not change magnesium
concentrations in the CSF (Mercieri 2012 Level II, n=45, JS 3).
Subsequent to these meta-analyses, multiple further RCTs studying the same issue have been
performed; overall the outcomes from these studies do not affect the existing conclusions andthey are therefore not referenced here.
Magnesium reduces the development of acute tolerance/OIH associated with remifentaniluse (Wu 2015 Level I [QUOROM], 5 RCTs [magnesium], n=729).
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Combining ketamine with IV magnesium reduced 48 h morphine consumption by 30% vsketamine alone after scoliosis surgery (Jabbour 2014 Level II, n=50, JS 5). While pain scores were
not different, sleep quality and patient satisfaction were improved with the combination
treatment.
IV magnesium may also have other beneficial effects on postoperative recovery; aftersegmental mastectomy in an outpatient setting, patients receiving IV magnesium had better
quality of recovery (QoR) scores at 24 h vs saline (MD 24/40; 99%CI 3 to 33) and reduced opioid
requirements after discharge (De Oliveira 2013a Level II, n=50, JS 5). There were significant linear
relationships between the postoperative systemic magnesium concentrations and 24 h
postoperative QoR scores as well as with pain burden (inverse).
IV magnesium sulphate 4 g attenuated tourniquet pain in healthy volunteers ( Satsumae 2013
Level II EH, n=24, JS 5).
IV magnesium in treatment of acute migraine attacks vs placebo or active comparators is
superior at time points 15-45 min (OR 0.23; 95%CI 0.09 to 0.58) (6 RCTs), 2 h (OR 0.20; 95%CI 0.10
to 0.40) [5 RCTs] and 24 h (OR 0.25; 95%CI 0.10 to 0.60) [4 RCTs] (Chiu 2016 Level I [PRISMA], 11 RCTs,
n=948).
IV magnesium was non-inferior to IV dexamethasone for the prevention of postoperative
sore throat after lumbar spinal surgery in the prone position ( Park 2015 Level II,
n=146, JS 5).
IV magnesium has only at best anecdotal evidence for an effect on any outcome of Irukandji
syndrome, caused by jellyfish sting in Northern Queensland ( Rathbone 2017 Level IV SR 1 RCT & 8
studies, [n=291 Mg recipients]); the only RCT included showed no beneficial effect (McCullagh 2012
Level II, n=39, JS 5).
Oral magnesium daily for 4 wk had no beneficial effect in the treatment of neuropathic pain
(Pickering 2011 Level II, n=45, JS 5). IV or oral magnesium therapy has been shown to have no effecton reducing painful crisis and hospital LOS in treating sickle cell disease (Than 2019 Level I[Cochrane], 5 RCTs, n=386). Oral magnesium (65 mg elemental/d) was also not improving analgesia
when added in cancer pain patients treated with oral morphine ( Baaklini 2017 Level II, n=43, JS 5).
IV magnesium vs IV lidocaine provided inferior analgesia for propofol injection pain; IVmagnesium/IV lidocaine offered no advantage over IV lidocaine alone (Galgon 2015 Level II, n=200,
JS 5).
See Section 5.7.1.4 for magnesium use via the IT route and Section 10.4.7.2 for paediatric use.
4.6.1.4 | Amantadine and memantine
A bolus dose of IV amantadine had no effect on postoperative analgesia after abdominal
hysterectomy (Gottschalk 2001 Level II, n=30, JS 4). However, after radical prostatectomy,
perioperative oral amantadine reduced morphine consumption, wound pain on palpation andbladder spasms (Snijdelaar 2004 Level II, n=24, JS 4). After spinal surgery, premedication with oral
amantadine reduced not only intraoperative fentanyl requirements but also postoperative pain
intensity and opioid requirements in the first 48 h by 25% (Bujak-Gizycka 2012 Level II, n=60, JS 5).
Oral memantine shows analgesic effects in acute [4 studies, n=24], but not in chronic phantom
limb pain [4 RCTs, n=104] (Loy 2016 Level IV SR, 5 RCTs, 2 case series & 1 case report, n=128).
Memantine administered perioperatively was not effective in reducing the incidence of
postmastectomy pain syndrome (Eisenberg 2007 Level II, n=22, JS 5); however, a subsequent trial
showed a reduction in postmastectomy pain, analgesic consumption and better emotional state
at 3 mths (Morel 2016 Level II, n=43, JS 5).
Memantine may have some benefits in neuropathic pain (Pickering 2018 NR).

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4.0 | ANALGESIC MEDICINESKEY MESSAGES
1. Perioperative IV ketamine reduces opioid consumption, pain intensity andpostoperative nausea and vomiting compared to placebo (S) (Level I [Cochrane
Review]); similar outcomes are achieved when ketamine is added to an opioid in a PCA
pump (S) (Level I [PRISMA]).
2. Perioperative IV ketamine reduces the incidence of chronic postsurgical pain in selected
procedures (S) (Level I [Cochrane Review]).
3. NMDA-receptor antagonists reduce the development of acute tolerance/opioidinduced hyperalgesia associated with remifentanil use (S) (Level I [PRISMA]).
4. IV ketamine reduces ischaemic pain intensity in critical limb ischaemia (N) (Level I[PRISMA]).
5. IV magnesium as an adjunct to morphine analgesia has an opioid-sparing effect andimproves pain scores (S) (Level I [PRISMA]).
6. IV magnesium is effective in treatment of acute migraine attacks (N) (Level I [PRISMA]).
7. IV ketamine is effective in the treatment of neuropathic pain following spinal cord
injury (U) (Level I).
8. Morphine/ketamine compared with higher doses of morphine alone improves analgesia
and reduces sedation and postoperative nausea and vomiting in postoperative patients(U) (Level I).
9. IV ketamine does not increase intracranial pressure or reduce cranial perfusionpressure compared to opioids (U) (Level I).
10. Perioperative dextromethorphan reduces opioid consumption and pain intensity
compared to placebo (N) (Level I)
11. Ketamine is a safe and effective analgesic in the prehospital setting (U) (Level II).
12. Ketamine reduces postoperative pain and opioid requirements in opioid-tolerant
patients (S) (Level II).
13. IV magnesium extends the duration of sensory block with spinal anaesthesia andreduces subsequent postoperative pain (N) (Level II).
The following tick box represents conclusions based on clinical experience and expert
opinion: Increasing rates of ketamine abuse are reported, in particular from South-East Asia andChina (S).
 Ketamine toxicity leads to cognitive impairment and abuse to chronic organ toxicity(bladder, liver) (U).

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4.6.2 | Regional NMDA-receptor antagonists
4.6.2.1 | Ketamine
Neuraxial
Some commercially available preparations of ketamine have a low pH (3.5 to 5.5) and contain anuntested preservative (benzethonium chloride) and thus cannot be recommended for IT use in
humans (de Lima 2000 NR; Hodgson 1999 NR). Subarachnoid administration of S(+)-ketamine
without preservative caused histological lesions on the spinal cord and meninges in dogs (Gomes
2011 BS). Concerns of local neurotoxicity in vitro continue to limit the use of neuraxial ketamine,in particular when combined with lidocaine (Werdehausen 2011 NR).
The addition of IT racemic ketamine to bupivacaine did not prolong postoperative analgesia
or reduce analgesic requirements but led to significantly more nausea and vomiting, sedation,dizziness, nystagmus and “strange feelings” (Kathirvel 2000 Level II, n=30, JS 2). IT S(+)-ketaminewith bupivacaine for Caesarean section decreased time to onset and increased spread of theblock but did not prolong duration vs fentanyl (Unlugenc 2006 Level II, n=90, JS 5). However, IT
ketamine/morphine/bupivacine was superior to IT morphine/bupivacaine or IT
ketamine/bupivacaine for major abdominal cancer surgery with regard to pain intensity, opioid
requirements and time to rescue analgesia (Abd El-Rahman 2018b Level II, n=90, JS 3).
The combination of epidural ketamine with epidural opioid-based (local anaesthetic)
solutions improves pain relief and may reduce overall opioid requirements without increasing
the incidence of adverse effects (Subramaniam 2004 Level I, 8 RCTs [epidural], n=513; Walker 2002
Level I, 4 RCTs [epidural], n=211). Ketamine IV may be as effective as epidural ketamine in reducing
hyperalgesia. Epidural racemic ketamine improved early postoperative analgesia when used withbupivacaine for lower limb amputations, although pain at 1 y was not different; perioperative
opioids were not used (Wilson 2008 Level II, n=47, JS 5).
Ketamine 0.25 to 0.5 mg/kg added to caudal local anaesthetic prolongs time to first analgesic
request by a median difference of 5.6 h without prolonged motor block ( Schnabel 2011 Level I[PRISMA], 13 RCTs, n=884); 0.5 mg/kg increases block duration and reduces postoperative analgesic
requirements (Dahmani 2011 Level I [QUORUM], 10 RCTs [caudal], n=686) (6 RCT overlap). Althoughsome adverse effects are more frequent in the ketamine group (eg sedation), there was no
significant difference to placebo. Caudal ketamine prolonged analgesia when administered withcaudal bupivacaine but was less effective than midazolam or neostigmine as caudal adjuvants(Kumar 2005 Level II, n=80, JS 5). See also Section 10.4.7.1 and 10.6.3.3.
Peripheral sites
Use of ketamine alone or with local anaesthesia for PNB or local infiltration shows contradictory
results, possibly due to systemic effects. Systemic comparators are not included in most RCTs.
No analgesic benefit for PNB was shown in brachial plexus block for arm surgery ( Lee 2002
Level II, n=51, JS 4), IA injection (where IV ketamine provided better analgesia) (Rosseland 2003
Level II, n=77, JS 5) or wound infiltration such as following Caesarean section ( Zohar 2002 Level II,
n=50, JS 5) or inguinal hernia repair (Clerc 2005 Level II, n=36, JS 2). Adding ketamine to lidocaine
IVRA did not result in better pain relief vs IV ketamine (Viscomi 2009 Level II, n=36, JS 4). When
added to lidocaine for axillary brachial plexus block, ketamine 50 mg only modestly increased
duration of sensory and motor block vs placebo (114.8  12.5 min v. 106.2  7.9 min), much lessthan dexamethasone (174.4  13.1 min) (Zaman 2017 Level II, n=78, JS 5). Significant nystagmus,
increased heart rate and blood pressure were observed in the ketamine group.
However, in pectoral block for mastectomy, ketamine 1 mg/kg added to bupivacaine 0.25%
30 mL vs bupivacaine alone prolonged time to first analgesic request and reduced opioid

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requirements (Othman 2016 Level II, n=60, JS 3). IA ketamine 1 mg/kg provided analgesia superior
to placebo, but inferior to IA ketamine 0.5 mg/kg in levobupivacaine 0.25% 20 mL after
arthroscopic meniscectomy (Isik 2015 Level II, n=6, JS 3). In circumcision, pain scores were lower
with preincisional ketamine vs saline (Tan 2007 Level II, n=40, JS 4). Adding ketamine 2 mg/kg tobupivacaine 0.25% 40 mL resulted in comparable analgesia to adding dexmedetomidine
2 mcg/kg to local wound infiltration after abdominal hysterectomy; both mixtures were superior
to bupivacaine alone (Mohamed 2018 Level II, n=90, JS 5). Following thyroidectomy, woundinfiltration with ketamine 1 mg/kg provided superior analgesia to IM ketamine 1 mg/kg and bothgroups were superior to placebo (Abd El-Rahman 2018a Level II, n=90, JS 5). After rhinoplasty, theaddition of ketamine 0.5 mg/kg to lidocaine for submucosal infiltration provided superior
analgesia to lidocaine alone with both being superior to placebo (Sanli 2016 Level II, n=90, JS 4).
Topical administration
Ketamine gargle vs placebo or no treatment reduces the incidence of postoperative sore throat
up to 24 h postoperatively (RR 0.42 to 0.52 over time points 0 to 24 h) based on high-quality
evidence (Mayhood 2015 Level I [PRISMA], 5 RCTs, n=291); systemic absorption is an unknown factor.
After mandibular molar extraction, topical administration (to the extraction sockets on
resorbable gelatin sponges) of ketamine 0.5 mg/kg vs tramadol 1 mg/kg and vs saline achieved
the lowest pain scores and rescue analgesic use for the first 24 h after surgery (Gonul 2015 Level
II, n=90, JS 2). In a similar setting, the addition of ketamine 0.3 mg/kg to lidocaine 2% for the local
anaesthesia (Inferior alveolar, lingual and buccal nerve blocks) reduced pain at 1 and 4 h andfacial swelling at 1 d, while improving mouth opening up to 7 d ( Kumar 2015 Level II, n=60, JS 1).
Topical ketamine-amitriptyline did not reduce chemotherapy-induced peripheral
neuropathic pain (Gewandter 2014 Level II, n=462, JS 5).
4.6.2.2 | Magnesium
Magnesium influences neuronal calcium influx and may exert an analgesic effect on NMDA
receptors in the spinal cord (Bailard 2014 NR). The long-term effects of perineural or neuraxial
magnesium have not been clarified.
Neuraxial magnesium for Caesarean section prolongs duration of sensory and motor block,
time to first rescue analgesic requirement and reduces pain intensity and analgesic requirements
without an effect on PONV, pruritus, hypotension, shivering or sedation ( Wang 2017a Level I[PRISMA], 9 RCTs, n=827).
IT magnesium combined with lipophilic opioid, with or without local anaesthetic, prolongs
the duration of spinal analgesia in nonobstetric populations also (SMD 1.38; 95%CI 0.6 to 2.11)(Morrison 2013 Level I, 15 RCTs, n=980). There is no increase in adverse effects. There was a highdegree of heterogeneity, including magnesium dose, making any firm conclusion difficult.
This was supported by a parallel meta-analysis (Pascual-Ramirez 2013 Level I, 12 RCTs, n=817)(9 RCTs overlap).
Epidural magnesium 50 mg added to bupivacaine 12.5 mg/morphine 2 mg improved
analgesia after thoracotomy for the first 4 h and reduced rescue analgesia requirements vsplacebo/ bupivacaine 12.5 mg/morphine 2 mg (Farzanegan 2018 Level III-1, n=80).
Magnesium added to perineural block prolongs analgesia (MD 125 min; 95%CI 65 to 184),
sensory and motor block (Li 2016b Level I [PRISMA], 7 RCTs, n=493). Subsequent RCTs haveconfirmed these findings in femoral nerve block in the prehospital setting ( Jebali 2018 Level II,
n=48, JS 4), TAPB after abdominal hysterectomy (Abd-Elsalam 2017 Level II, n=60, JS 4) and sciatic
nerve block for toe amputation (Sun 2017a Level II, n=70, JS 5). The mechanism of action ofmagnesium at perineural sites is uncertain and safety and outcome data are limited suggesting
caution should be exercised (Bailard 2014 NR).
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Oral topical magnesium reduces postoperative sore throat incidence (RR 0.22; 95%CI 0.12 to
0.39 [at 24 h postoperatively]) and severity after orotracheal intubation ( Singh 2019 Level I[PRISMA] 7 RCTs, n=726).
IA magnesium versus placebo after arthroscopic surgery improves pain control [ 5 RCTs] andprolongs time to first analgesic request [4 RCTs] (Zeng 2016 Level I [PRISMA], 8 RCTs, n=513). The
combination magnesium/bupivacaine versus bupivacaine only prolongs time to first analgesic
request only [4 RCTs]. Magnesium vs bupivacaine results in similar analgesia [3 RCTs]. No relevant
adverse effects were described in any study. Magnesium/levobupivacaine vs levobupivacaine
alone and vs placebo after arthroscopic meniscectomy reduced pain intensity and rescue
analgesic requirements (Kizilcik 2017 Level II, n=96, JS 4).
Magnesium added to lidocaine IVRA improved intra and postoperative analgesia and tourniquet
tolerance (Kashefi 2008 Level II, n=40, JS 4; Turan 2005 Level II, n=30, JS 4).

KEY MESSAGES
1. Neuraxial magnesium reduces pain intensity and analgesic requirements after
Caesarean section (N) (Level I [PRISMA].
2. Oral topical magnesium or ketamine (as gargle or lozenge) reduce the incidence of
postoperative sore throat (N) (Level I [PRISMA].
3. Intra-articular magnesium improves analgesia after arthroscopic surgery compared toplacebo (N) (Level I [PRISMA].
4. Magnesium added to local anaesthetics in peripheral nerve blocks prolongs sensory
block and analgesic effects (N) (Level I [PRISMA].
5. Epidural ketamine (without preservative) added to opioid-based epidural analgesia
regimens improves pain relief without reducing adverse effects (U) (Level I).
6. Caudal ketamine in children, in combination with local anaesthetic or as the sole
medication, improved and prolonged analgesia with few adverse effects (U) (Level I).
The following tick box represents conclusions based on clinical experience and expert
opinion: Variable results for regional and topical administration of ketamine and magnesium
may reflect systemic effects (N).

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4.7 | Antidepressant medicines
4.7.1 | Acute pain
There are limited published data on the use of antidepressants in the management of acutenociceptive and neuropathic pain.
4.7.1.1 | Tricyclic antidepressants
Amitriptyline given to patients with acute herpes zoster reduced the incidence of postherpetic
neuralgia at 6 mth (Bowsher 1997 Level II, n=80, JS 5). Amitriptyline given after orthopaedic surgery
did not improve opioid analgesia vs placebo (Kerrick 1993 Level II, n=28, JS 5).
Desipramine, but not amitriptyline, given prior to dental surgery increased and prolonged theanalgesic effect of a single dose of morphine, but both had no analgesic effect on their own(Levine 1986 Level II, n=30, JS 3). When used for a fortnight in experimental pain, desipramine had
no effect on pain or hyperalgesia (Wallace 2002 Level II EH, n=13, JS 4).
4.7.1.2 | Serotonin–norepinephrine-reuptake inhibitors
After TKA, duloxetine 60 mg (preoperative and on POD 1) had an opioid-sparing effect (35%) vsplacebo (Ho 2010 Level II, n=50, JS 5). In patients with an increased Central Sensitisation Inventory(CSI), duloxetine 30 mg (before surgery and daily for 6 wk thereafter) improved pain control,
physical and emotional functioning and patient satisfaction with analgesia for 2 to 12 wk after TKA
vs control (Koh 2019 Level II, n=40, JS 5). However, duloxetine 60 mg (for 2 wk) had no effect on
subacute pain with ambulation after TKA vs placebo, when used as a component of a multimodal
analgesia regimen (YaDeau 2016 Level II, n=106, JS 5). Venlafaxine 37.5 mg was as effective asgabapentin 300 mg in reducing pain at rest and analgesic requirements, when given perioperatively
for 10 d in mastectomy vs placebo (Amr 2010 Level II, n=150, JS 4). Venlafaxine was inferior togabapentin in reducing pain on movement; however, at 6 mth postoperatively, fewer patients inthe venlafaxine group reported chronic pain or analgesic use.
4.7.1.3 | Selective serotonin-reuptake inhibitors
In patients with high preoperative pain catastrophising scale (PCS) scores, escitalopram 10 mg(preoperatively and for 6 d postoperatively) did not reduce pain on mobilisation at 24 h after
total knee replacement vs placebo (Lunn 2015 Level II, n=120, JS 5). On POD 2 to 6, pain at rest andmobilisation was lower in the treatment group.

4.7.2 | Chronic pain
Treatment guidelines for chronic neuropathic pain recommend TCAs and SNRIs, but not SSRIs,
as first-line treatment in this indication (Finnerup 2015 GL Level I [PRISMA], 229 RCTs,
n unspecified).
4.7.2.1 | Tricyclic antidepressantsWhile TCAs are seen as the first-line therapy in neuropathic pain treatment, data are ofdisappointing quality. None of the supportive studies are of high quality and low risk of bias
(Moore 2015a Level I [Cochrane], 17 RCTs, n=1,342). Adverse events are increased with amitriptyline(RR 1.5; 95%CI 1.3 to 1.8) (NNH 5.2; 95%CI 3.6 to 9.1). Similarly, imipramine (Hearn 2014 Level I
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5
RCTs,
n=168)
andnortriptyline
aresupported
only
by very low-quality evidence in this indication (Derry 2015b Level I [Cochrane],
6 RCTs, n=310). For fibromyalgia, the evidence is also low quality for amitriptyline (NNT 4.1 for≥50% pain relief and NNH 3.3) (Moore 2015a Level I [Cochrane] 9 RCTs, n=649).
In elderly patients, TCAs should possibly be avoided as the use of medications with
anticholinergic activity increases risk of cognitive impairment and even mortality in this patientgroup (Fox 2011 Level III-2, n=13,004).
[Cochrane],

4.7.2.2 | Serotonin–norepinephrine-reuptake inhibitors
Duloxetine 60 to 120 mg/d provides analgesia for diabetic neuropathy ( Lunn 2014 Level I[Cochrane], 8 RCTs, n=2,728; Hossain 2016 Level I [PRISMA], 8 RCTs, n=4,084) (7 RCTs overlap). RCTs
supporting the use of venlafaxine in neuropathic pain have a high risk of bias ( Gallagher 2015
Level I [Cochrane], 6 RCTs, n=460; Aiyer 2017 Level I [PRISMA], 13 RCTs, n=851) (6 RCTs overlap). There isno evidence for an effect of milnacipran in neuropathic pain ( Derry 2015b Level I [Cochrane],
1 unpublished RCT: [NCT01225068], n=40).
SNRIs also have limited analgesic effects in fibromyalgia (NNT 5-11 vs placebo depending on
outcome assessed) (Welsch 2018 Level I [Cochrane], 18 RCTs, n=7,903). This has been confirmed
specifically for milnacipran (Cording 2015 Level I [Cochrane], 6 RCTs, n=4,238). Duloxetine andmilnacipran have comparable efficacy in this indication (Lee 2016 Level I [NMA], 9 RCTs, n=5,140)(4 RCTs overlap).
4.7.2.3 | Selective serotonin-reuptake inhibitors
There is only limited evidence for the effectiveness of SSRIs in neuropathic pain ( Saarto 2007
Level I [Cochrane] 61 RCTs, n=3,293). Similarly, there is only biased evidence that SSRIs are superior
to placebo in treating the key symptoms of fibromyalgia: namely pain, fatigue and sleep
problems (Walitt 2015 Level I [Cochrane], 7 RCTs, n=383).

4.7.3 | Specific pain conditions
In postherpetic neuralgia, TCAs are less effective than pregabalin and 5% lidocaine medicatedplaster (Snedecor 2014 Level I, 28 RCTs, n=4,317). In diabetic polyneuropathy, amitriptyline is theleast effective of the medications studied with the worst benefit-risk balance, while venlafaxineand duloxetine were the superior antidepressants here (Rudroju 2013 Level I, 21 RCTs, n=4,219).
In fibromyalgia, amitriptyline (NNT 4.9) and the serotonin–norepinephrine-reuptake
inhibitors (SNRIs) duloxetine and milnacipran (NNT 10) were the most effective antidepressants(Hauser 2012 Level I, 35 RCTs, n=6,766).
In chronic headaches, antidepressants are effective in treatment and prophylaxis with better
efficacy of TCAs than SSRIs (Jackson 2017 Level I [PRISMA], 21 RCTs, n=2,751; Jackson 2010 Level I[PRISMA], 37 RCTs, n=3,176). Use of SSRIs and SNRIs for migraine prophylaxis ( Banzi 2015 Level I[Cochrane], 12 RCTs, n=585) and prevention of chronic tension type headache is not supported byevidence (Banzi 2015 Level I [Cochrane], 8 RCTs, n=412).
In chronic low-back pain, antidepressants neither improve pain nor depression ( Urquhart 2008
Level I [Cochrane], 10 RCTs, n=706); this was confirmed in a subsequent systematic review ofpharmacological interventions in this indication (Kuijpers 2011 Level I, 5 RCTs, n=303). However,these results are challenged as they did not differentiate between different antidepressants;
SNRIs like duloxetine (Williamson 2014 Level I, 3 RCTs, n=982) and TCAs may be effective, while SSRIs
are not (Staiger 2003 Level I, 7 RCTs, n=440).

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There is only poor evidence for an analgesic effect of any antidepressant in orofacial pain
disorders (Martin 2012 Level I, 6 RCTs, n=208) and for an analgesic effect of TCAs or SSRIs inrheumatoid arthritis (Richards 2011 Level I [Cochrane], 8 RCTs, n=652).
Duloxetine improves WOMAC scores in osteoarthritis to an extent comparable to other firstline treatments for osteoarthritis (eg NSAIDs) (Myers 2014 Level I, 3 RCTs, n=775). Duloxetine results
in a greater reduction in pain, improved function and patient rated impression of improvement
for treatment of osteoarthritis of the knee after 10 to 13 wk of treatment (Wang 2015b Level I,
3 RCTs, n=1,011) (2 RCTs overlap). Therefore, duloxetine is a recommended treatment in updated
guidelines for osteoarthritis (eg McAlindon 2014 GL).
Currently the use of antidepressants for acute neuropathic pain is mainly based on
extrapolation of the above data. Clinical experience in chronic pain suggests that TCAs should bestarted at low doses (eg amitriptyline 5 to 10 mg at night) and subsequent doses increased slowly
if needed, in order to minimise the incidence of adverse effects.

KEY MESSAGES
1. In chronic neuropathic pain and fibromyalgia, tricyclic antidepressants and serotonin–
noradrenaline-reuptake inhibitor are effective analgesics (W) and more effective thanselective serotonin-reuptake inhibitors (U) (Level I [Cochrane Review]).
2. Tricyclic antidepressants are effective in the treatment of chronic headaches (U)(Level I [PRISMA]).
3. Duloxetine is as effective as other first-line treatments for pain and disability ofosteoarthritis (U) (Level I).
4. Some antidepressants, in particular duloxetine, may be effective in the treatment ofchronic low-back pain (U) (Level I).
5. Perioperative serotonin-noradrenaline reuptake inhibitors reduce acute pain andopioid requirements in a limited number of studies (U) (Level II).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Based on the experience in chronic neuropathic pain states, it would seem reasonable
to use tricyclic antidepressants and serotonin–noradrenaline-reuptake inhibitors in the
management of acute neuropathic pain (U).
 To minimise adverse effects, it is advisable to initiate treatment with tricyclic
antidepressants at low doses (U).

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4.8 | Anticonvulsant medicines
4.8.1 | Acute pain
4.8.1.1 | Alpha-2-delta ligands (gabapentinoids)
Efficacy
Gabapentin 250 mg as the sole analgesic reduces the intensity of postoperative pain (NNT 11;
95%CI 6.4 to 35) and requirements for rescue analgesia (NNT 5.8) vs placebo (Straube 2010
Level I [Cochrane], 4 RCTs, n=387 ). This is the only anticonvulsant which has been shown to beeffective in acute postoperative pain on its own; the high NNT, inferior to most analgesics usedin this setting, suggests that gabapentin is clinically not useful as a sole analgesic for
postoperative analgesia.
Single 100 to 1200 mg and multiple 900 to 2400 mg/d doses of gabapentin (similar to pregabalin[see below]) reduce 24 h opioid consumption (MD -7.31 mg; 95%CI -9.74 to -5.98) (73 RCTs,
n=5,630), but less so when analysing only RCTs with a low risk of bias (MD -3.1 mg; 95%CI -5.6 to 0.5) (13 RCTs, n=1,362) (Fabritius 2016 Level I [PRISMA], 132 RCTs, n=9,498). The opioid-sparing effect is
not significant as an add-on to other non-opioids in trials with low risk of bias; in these the risk ofserious adverse events (SAEs) is not significantly increased (RR 1.61; 95%CI 0.91 to 2.86). Similar
results were found in an earlier meta-analysis of all RCTs of prophylactic gabapentin with an opioidsparing effect in the first 24 h (8.44 mg; 95%CI 7.26 to 9.62) and reduced postoperative pain scoresat multiple time points between 1 and 24 h by 0.71/10 to 1.68/10 (Doleman 2015a Level I, 133 RCTs,
n=8,655) (significant overlap). These effects increased with increasing pain scores in the control groupsuggesting more benefit in more painful surgeries. The analysis also identified reduced pre-operative
anxiety, postoperative nausea, vomiting and pruritus, and increased patient satisfaction, but also
increased sedation. The authors acknowledge that the absolute effects may be overestimated bypublication bias and small study effects.
Single 50 to 300 mg and multiple 100 to 600 mg/d doses of pregabalin for postoperative
analgesia reduce 24 h IV morphine consumption (MD 10.8 mg; 95%CI –13.19 to –8.46) (37 RCTS,
n=2,423) across all RCTs assessing this outcome, but less so when analysing only RCTs with a low
risk of bias (MD 5.8 mg; 95%CI -8.5 to -3.2) (11 RCTs, n=705) (Fabritius 2017 Level I [PRISMA], 97
RCTs, n=7,201). In low risk of bias studies, the opioid sparing effect is more pronounced whenno other non-opioids are used (MD -13.7 mg; 95%CI -9.6 to -17.8) (2 RCTs, n=120) and for single
dose (MD -10.1mg; 95% CI -2.4 to -18.0) (6 RCTs, n=399) more so than with multiple dosing (MD2.4mg; 95%CI -0.5 to -4.9) (5 RCTs, n=306).
In a preceding meta-analysis, operations were classified by the authors according toassociation with ‘pronociceptive’ mechanisms (acute hyperalgesia) (eg spine surgery, joint
arthroplasty, amputations) and those without such mechanisms (eg abdominal laparoscopic
surgery, gynaecological procedures) (Eipe 2015 Level I [PRISMA], 43 RCTs, n=3,378) (39 RCTs overlap).
Pregabalin 150 to 300 mg reduces pain at rest and on movement more in the pronociceptive
surgical group than in the other surgical group (MD -1.09/10; 95%CI -0.37 to -1.80 vs MD 0.45/10; 95%CI 0.13 to -1.03 and MD -0.94/10; 95%CI -0.65 to -1.23 vs MD -0.31/10; 95%CI 0.15
to -0.77). Across all RCTs, there is a reduction of mean analgesic consumption by 16% (pooled
ratio of means 0.84; 95%CI 0.79 to 0.91). PONV is reduced (NNT 11; 95%CI 7 to 28).
Multiple meta-analyses have looked at perioperative gabapentin and pregabalin (single andmultiple doses) in specific types of surgery with significant overlap with the overarching metaanalyses described above:194

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4.0 | ANALGESIC MEDICINES•In breast cancer surgery, preoperative use of gabapentin or pregabalin reduces acutepostoperative pain and opioid consumption with low to very low quality of evidence ofno effect on the rate of CPSP (Rai 2017 Level I [PRISMA], 12 RCTs, n=516);• After open hysterectomy, gabapentin reduces postoperative opioid consumption andpain scores (Li 2017d Level I [PRISMA], 14 RCTs, n=879);• After Caesarean section, gabapentin improves pain scores on movement at 24 h (MD 11.58/100; 95%CI -23.04 to -0.12) and increases satisfaction scores, with no otherbenefits (Felder 2019 Level I [PRISMA], 6 RCTs, n=656);• After spinal surgery, gabapentin reduces pain scores and morphine consumption overthe first 24 h (Han 2017a Level I [PRISMA], 10 RCTs, n=827);• After laparoscopic cholecystectomy, gabapentin decreases analgesic requirements,
pain scores and PONV (Sun 2016 Level I [PRISMA] 12 RCTs, n=1,192); pregabalin in the samesetting has similar effects, except no effect on PONV (Zhang 2017c Level I [PRISMA], 6 RCTs,
n=434);• After TKA and THA, a number of meta-analyses with significant overlap are published:o After TKA and THA, pregabalin reduces pain scores, opioid consumption and
PONV (Li 2017b Level I [PRISMA], 7 RCTs, n=823);
o Specifically in TKA, meta-analyses identify similar benefits with pregabalin
reducing opioid requirements and PONV and pruritus, but not pain scores ( Han
2017b Level I [PRISMA], 7 RCTs, n=962) and gabapentin reducing opioid
requirements and pruritus (Han 2016 Level I [PRISMA], 6 RCTs, n=859);
o Specifically in THA, gabapentin reduces pain scores and opioid requirements,
but no effect on any adverse effect (Han 2016 Level I [PRISMA] 5 RCTs, n=573).
Pregabalin 150 mg preoperatively and 75 mg BD postoperatively for 7 d
reduced pain and opioid requirements for 7 d with no effects on pain or
physical function at 6 wk or 3 mth (Clarke 2015 Level II, n=184, JS 5);o A combined meta-analysis on the effects of pregabalin and gabapentin foundonly clinically insignificant reductions of pain (pregabalin only) at 24 h (0.5/10;
95%CI 0 to 1.0) and at 48 h (0.3/10; 95%CI 0 to 0.6) and a reduction in
cumulative opioid consumption at 48 h (MD -23.2mg; 95%CI -40.9 to -5.4mg);
the latter effect was only significant with pregabalin (MD -33.14 mg; 95%CI 53.98 to -12.29mg) There was no difference in knee flexion at 48 h, but areduction in the incidence of PONV (RR 0.7; 95%CI 0.6 to 0.9) and an increasein the risk of sedation (only with pregabalin) (RR 1.4; 95% CI 1.1 to 1.9) (NNH
8.7) (Hamilton 2016 Level I [PRISMA], 12 RCTs, n=1,493) (4 RCTs [gabapentin] overlap
with Han 2016 and all 7 RCTs [pregabalin] overlap with Han 2017b).
Used as an adjunct to epidural analgesia, perioperative gabapentin reduced pain scores andepidural analgesic requirements and improved patient satisfaction, despite an increase indizziness (Turan 2006 Level II, n=54, JS 5) but these benefits were not confirmed with thoracic
epidural analgesia for thoracotomy (Kinney 2012 Level II, n=120, JS 5).
Alpha-2-delta ligands were also studied in the setting of acute burns pain (see Section 8.5.2),
acute herpes zoster pain (see Section 8.6.2.2) and acute pain due to Guillain-Barre Syndrome(see Section 8.10.6.7).
The effects of alpha-2-delta ligands on the prevention of CPSP are presented in Section
1.4.6.3.
Dose dependency of effectA network meta-analysis reports a dose-dependent effect of single-dose preoperative pregabalin
and gabapentin on reduction of pain scores and opioid consumption vs placebo (Hu 2018a Level I
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[NMA], 79 RCTs, n=6,201). With regard to pain reduction, pregabalin in a dose ≥150mg andgabapentin ≥900 mg are more effective.

Effects on PONVIn RCTs designed with PONV as a primary endpoint ( 8 RCTs, n=838), preoperative gabapentin
reduces PONV (RR 0.60; 99%CI 0.50 to 0.72), nausea (RR 0.34; 99%CI 0.20 to 0.56), and vomiting(RR 0.34; 99%CI 0.19 to 0.61) at 24 h (Grant 2016b Level I [PRISMA], 44 RCTs, n=3,489). These findings
are similar in an analysis of all 44 RCTs; this is accompanied by an increased rate of sedation (RR
1.22; 95%CI 1.02 to 1.47).
In RCTs designed to report PONV, preoperative pregabalin reduces PONV (RR 0.53; 95%CI 0.39 to0.73), nausea (RR 0.62; 95%CI 0.46 to 0.83), and vomiting (RR 0.68; 95%CI 0.52 to 0.88) at 24 h (Grant
2016a Level I [PRISMA], 23 RCTs, n=1,693). There is no increased sedation reported (RR 0.97; 95%CI 0.71
to 1.33), but an increase of postoperative visual disturbance (RR 3.11; 95%CI 1.34 to 7.21).
Adverse effects
Serious adverse effects (SAEs) in the studies with low risk of bias were rare (22/730) andoccurred more with pregabalin than placebo (RR 2.9; 95%CI: 1.2 to 6.8); nausea, sedation andheadache were not significantly different between the groups (Fabritius 2017 Level I [PRISMA],
97 RCTs, n=7,201).
Adverse effects of perioperative pregabalin include somnolence (RR 1.72; 95%CI 1.08 to2.72), sedation (RR 1.51; 95%CI 1.16 to 1.96; absolute risk 41/1,000) and visual disturbances (RR
3.08; 95%CI 1.91 to 4.96; absolute risk 10/1,000) (Eipe 2015 Level I [PRISMA], 43 RCTs, n=3,378) (39
RCTs overlap). These adverse effects must be weighed against the benefits, which might not beclinically relevant in all postoperative settings. They may also compromise enhanced recovery
strategies as outlined in ERAS guidelines eg for elective colorectal surgery (Gustafsson 2019 GL).
Toxicity
Overdose toxicity from gabapentin or pregabalin alone is rarely fatal, but the risk is increased
when taken in combination with other agents that cause sedation, particularly opioids (thenleading to OIVI). Another contributing factor to the interaction with opioids may be thatpregabalin reversed the tolerance to opioids ( Lyndon 2017 BS).
After laparoscopic surgery, preoperative gabapentin (300 to 600 mg) use as a componentof multimodal analgesia increased the risk of respiratory depression in general (OR 1.47; 95%
CI 1.22 to 1.76) (Cavalcante 2017 Level III-3, n=8,567 [n=1,311 episodes of respiratory depression] ). In
combination with systemic opioids in particular, the risk of OIVI was increased (OR 1.26; 95%CI
1.02 to 1.58) (n=965), in particular in older patients (>50 y) or those having received higher
opioid doses. After joint arthroplasty, preoperative gabapentin (>300 mg) increased the riskof respiratory depression (Weingarten 2015 Level IV, n=11,970 [n=2,836 episodes of respiratory
depression]). Use of alpha-2-delta ligands in combination with opioids was a risk factor forincreased need for naloxone administration in hospital patients ( Minhaj 2020 Level III-2, n=867[n=275 naloxone administrations; n=105 alpha-2-delta ligand exposures]; Weingarten 2015 Level III-2,
n=134 [naloxone administrations; n=15 alpha-2-delta ligand exposures]). This was also shown inpatients after colorectal surgery (OR 1.58; 95%CI 1.11 to 2.26) despite an opioid-sparing effect(Ohnuma 2019 Level III-2; n=175,787 [4,677 alpha-2-delta ligand exposures] ). Continuation of alpha2-delta ligands into the postoperative period in patients receiving this therapy chronically was
associated with increased need for naloxone administration (RR 6.30; 95%CI 2.4 to 16.7) but
not in those receiving this as a new postoperative intervention (Deljou 2018 Level III-2, n=110,019[n=128 naloxone administrations; n=39 alpha-2-delta ligand exposure ). However, in a further study
in hospitalised patients receiving opioids (where >60% received opioid for acute pain
treatment only and 17% had surgery in the preceding 24 h), alpha-2-delta ligand use vs non-196

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use did not increase frequency of naloxone requirement (Savelloni 2017 Level III-2, n=128 [n=153
naloxone administrations; n=36 alpha-2-delta exposures]).
Data from many countries (USA, UK, Germany, Finland, India, South Africa and France)
show that over 75% of deaths attributable to alpha-2-delta ligands also involve opioids ( Smith
2016 Level IV SR, 34 studies & 23 case reports, n unspecified). This is in line with findings that the
combination of gabapentin and opioid vs opioid alone increased the risk of opioid overdose
death (OR 1.99; 95%CI 1.61 to 2.47) ( Gomes 2017 Level III-2, n=5,875).
The combination of alpha-2-delta ligands with conventional opioids in postoperative
patients may be associated with an increased risk of OIVI, in particular in certain patient
subgroups (chronic users, obese patients, patients with OSA, older patients, higher dosing of
opioids and/or alpha-2-delta ligands, combinations with other sedating medications). This is
in line with warnings by regulatory authorities ( FDA 2019 GL; MHRA 2017 GL). More data isrequired to delineate their role in ERAS and multimodal analgesic protocols (Gupta 2018b NR).
Abuse potential
Alpha-2-delta ligands have a potential for misuse, abuse and toxicity in overdose ( Evoy 2017
Level IV SR [PRISMA], 59 studies [24 epidemiological, 3 clinical abuse liability, 16 case series or reports ofabuse or misuse or dependence, 17 case series or reports of acute overdose ]; Bonnet 2017 Level IV
SR [PRISMA], 106 studies [17 rewarding behaviour, 14 clinical, 38 case series or reports on abuse anddependence, 37 on overdose toxicity or fatalities]; Schjerning 2016 Level IV SR [PRISMA], 76 studies[pregabalin only] [17 preclinical, 19 clinical, 13 epidemiological, 27 case series or reports] ) (all withsignificant overlap of studies). Preclinical studies suggest that modulation of the GABA andglutamate systems, with resulting anxiolysis and in particular euphoria, underpin the abusepotential. The prevalence of abuse in the UK general population is 1.1% for gabapentin and 0.5%
for pregabalin; consistently patients with opioid use disorder have higher rates: gabapentin 15
to 22% and pregabalin 3 to 68%. Substance use disorder and psychiatric comorbidities are themost important risk factors. Abuse typically involves the intake of supratherapeutic doses toachieve euphoria, with pregabalin appearing more addictive than gabapentin.
4.8.1.2 | Sodium valproate
A single dose of sodium valproate IV did not improve acute nociceptive pain after surgery ( Martin
1988 Level II, n=39, JS 3). There are conflicting results on IV sodium valproate in treating acutemigraine; it was ineffective in one study (Tanen 2003 Level II, n=40, JS 2) and superior tometoclopramide plus sumatriptan in another (Bakhshayesh 2013 Level II, n=60, JS 3).

4.8.2 | Chronic pain
Among all anticonvulsants, there is good evidence only for the use of alpha-2-delta ligands inchronic pain conditions including neuropathic pain states such as diabetic polyneuropathy,
postherpetic neuralgia and central neuropathic pain as well as fibromyalgia ( Wiffen 2013b Level I[Cochrane], 91 RCTs, n=17,995). For most other anticonvulsants, the evidence was non-existent, so
little or of so low quality that conclusions could not be drawn, or of reasonable quality showing
no or very little effect. This is in line with treatment guidelines for chronic neuropathic pain which
recommend alpha-2-delta ligands, but no other anticonvulsants, as first-line treatment in thisindication (Finnerup 2015 GL Level I [PRISMA], 229 RCTs, n unspecified).

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4.8.2.1 | Alpha-2-delta ligands (gabapentin/pregabalin)
Gabapentin
At doses of 1,800 mg to 3,600 mg/d, gabapentin is effective in treating neuropathic pain, inparticular caused by postherpetic neuralgia (NNT 6.7; 95%CI 5.4 to 8.7) ( 8 RCTs, n= 2,260) anddiabetic polyneuropathy (NNT 5.9; 95% CI 4.6 to 8.3) (6 RCTs, n=1,277) (Wiffen 2017a Level I[Cochrane], 37 RCTs, n=5,914). Withdrawals due to adverse events were more common withgabapentin (NNH 30; 95%CI 20 to 65) (22 RCTs, n=4,346), while serious adverse events were notmore common with gabapentin than with placebo. Pain relief in 20 to 40% of patients isaccompanied by improvement of sleep, fatigue, depression, quality of life and function.
Gabapentin was also effective for the treatment of neuropathic pain caused by traumatic or
postsurgical nerve injury (Gordh 2008 Level II, n=120, JS 5).
Pregabalin
Pregabalin is effective in a dose-dependent fashion in postherpetic neuralgia, painful diabetic
neuropathy, central neuropathic pain due to spinal cord injury (SCI) and mixed or unclassified
post-traumatic neuropathic pain, but only with limited evidence in neuropathic back pain or
sciatica, neuropathic cancer pain or polyneuropathy and no effect in HIV neuropathy (2 RCTs,
n=674) (Derry 2019 Level I [Cochrane], RCTs=45, n=11,906):• Postherpetic neuralgia: 300 mg/d pregabalin (NNT 5.3; 95%CI 3.9 to 8.1) (4 RCTs, n=713)
and 600 mg/d (NNT 3.9; 95%CI 3.1 to 5.5) (4 RCTs, n=732);• Painful diabetic neuropathy: 600 mg/d pregabalin (NNT 7.8; 95% CI 5.4 to 14) ( 5 RCTs,
n=1,015);• Mixed or unclassified post-traumatic neuropathic pain: 600 mg/d pregabalin (NNT 7.2;
95%CI 5.4 to 11) (4 RCTs, n=1,367);• Central neuropathic pain (mainly SCI): 600 mg/d pregabalin (NNT 9.8; 95%CI 6.0 to 28)(3 RCTs, n=562).
In all studies, somnolence and dizziness occurred more in pregabalin than placebo arms in adose-dependent pattern, but serious adverse events were not different between arms:
pregabalin 300 mg (RR 1.2; 95%CI 0.8 to 1.7) (17 RCTs, n=4,112) and pregabalin 600 mg (RR 1.1;
95%CI 0.8 to 1.5) (16 RCTs, n=3,995).
Pregabalin 300 to 600 mg/d has also beneficial effects in fibromyalgia; substantial pain relief
is achieved over 12 to 26 wk of treatment in about 10% more patients than in the placebo arm,
accompanied by improvements of other symptoms, quality of life and function ( Derry 2016aLevel I [Cochrane], 8 RCTs, n=3,283).
Alpha-2-delta ligands are also used in chronic pain due to SCI (see Section 8.2.2.5), phantom
limb pain (see Section 8.1.5.2) and in patients who are opioid-tolerant (see Section 9.7) or havea substance use disorder (see Section 9.8).
4.8.2.2 | Carbamazepine
Carbamazepine for the treatment of chronic neuropathic pain has possibly some analgesic
efficacy in some patients, but the quality of data is insufficient to draw meaningful conclusions
or make comparisons (Wiffen 2014 Level I [Cochrane], 10 RCTs, n=480).

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4.8.2.3 | Oxcarbazepine
Only very-low level evidence supports limited effectiveness of oxcarbazepine in painful diabetic
neuropathy, neuropathic pain from radiculopathy and a mixture of neuropathies ( Zhou 2017
Level I [Cochrane], 5 RCTs, n=862).
4.8.2.4 | Phenytoin
No study supports the use of phenytoin in chronic neuropathic pain or fibromyalgia (Birse 2012
Level I [Cochrane], 0 RCTs, n=0).
4.8.2.5 | Valproate
Valproate may reduce pain in diabetic polyneuropathy based on very small RCTs of poor quality(Gill 2011 Level I [Cochrane] 2 RCTs, n=84). Valproate is effective for the prevention of episodic
migraine (Linde 2013 Level I [Cochrane], 10 RCTs, n=652).
4.8.2.6 | Lamotrigine
Lamotrigine shows no analgesic benefit in neuropathic pain in large, high-quality, long-duration
RCTs (Wiffen 2013a Level I [Cochrane] 12 RCTs, n=1,511).
4.8.2.7 | Lacosamide
Lacosamide is not beneficial for the treatment of neuropathic pain and fibromyalgia ( Hearn 2012
Level I [Cochrane] 6 RCTs, n=2,022).

KEY MESSAGES
1. Alpha-2-delta ligands (gabapentinoids) are the only anticonvulsants with provenefficacy in the treatment of chronic neuropathic pain (S) (Level I [Cochrane Review]).
2. Pregabalin is the only anticonvulsant with proven but limited efficacy in chronic pain
due to fibromyalgia (S) (Level I [Cochrane Review]).
3. Perioperative alpha-2-delta ligands (gabapentinoids) reduce postoperative pain andopioid requirements, in particular after more painful surgery (Q) and reduce theincidence of postoperative nausea and vomiting (S) as well as pruritus (S), but increase
the risk of sedation (S) and visual disturbances (N) (Level I [PRISMA]).
4. Overdose toxicity of alpha-2-delta ligands is increased when taken in combination withother agents that cause sedation, particularly opioids (N) (Level III-2).
5. Alpha-2-delta ligands have the potential for misuse and abuse, in particular in patientswith opioid use disorder or psychiatric comorbidity (N) (Level IV SR).
The following tick box represents conclusions based on clinical experience and expert
opinion: Based on the experience in chronic neuropathic pain states, it would seem reasonable
to use alpha-2-delta ligands in the management of acute neuropathic pain (U).

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4.9 | Alpha-2 agonists
4.9.1 | Systemic alpha-2 agonists
4.9.1.1 | Clonidine
Clonidine is a selective alpha-2 agonist with an alpha-2 to alpha-1 ratio of 200:1 (Chan 2010a NR).
Systemic perioperative administration of clonidine 1 to 5 mcg/kg vs placebo does not reduce
pain scores, but has an opioid-sparing effect at 24 h (MD 24%; 95%CI 16 to 32) (4 RCTs, n=313)
and reduces incidence of PONV (RR 0.35; 95%CI 0.25 to 0.51]) (6 RCTs, n=412) (Sanchez Munoz 2017
Level I [PRISMA], 57 RCTs, n=14,790 [PO 29 arms, IM 4 arms, IV 24 arms, TD 2 arms]).
After non-cardiac surgery, PO clonidine 200 mcg given preoperatively and continued as 200
mcg/d transdermal clonidine patch for 72 h did not reduce pain scores or opioid consumption vsplacebo over these 72 h (Turan 2016 Level II, n=624, JS 5). An updated meta-analysis adding thisand two further RCTs to a preceding one (Blaudszun 2012 Level I [PRISMA], 30 RCTs [clonidine
19 RCTs], n=1,792 [clonidine n=1,156]) confirms no effect of clonidine vs placebo on pain scores at
24 h (7 RCTs, n=802) or 48 h (4 RCTs, n=562) (Turan 2016 Level I, 7 RCTs, n=802).
Alpha-2 agonists such as clonidine are more effective than placebo in the management of
opioid-withdrawal symptoms (Gowing 2014 Level I [Cochrane], 25 RCTs, n=1,668).
4.9.1.2 | Dexmedetomidine
Dexmedetomidine is a highly selective alpha-2 adrenoceptor agonist with an alpha-2 to alpha-1
ratio of 1,620:1 (Chan 2010a NR). Systemic intraoperative only administration of dexmedetomidine
vs placebo reduces pain intensity at 6 h (WMD −0.93/10; 95%CI −1.34 to −0.53) and at 24 h
(WMD=−0.47/10; 95%CI −0.83 to −0.11) as well as opioid consumption (WMD −6.76 mg; 95% CI−10.16 to −3.35) (Wang 2018c Level I [PRISMA], 40 RCTs, n=2,401). Dexmedetomidine also reduces theneed for rescue analgesia (7 RCTs, n=290) and extends the time to first rescue analgesia (4 RCTs,
n=220), without impact on PONV (5 RCTs, n=262). Dexmedetomidine used perioperatively (12 RCTs
[intraoperative use only]) in spinal surgery reduces postoperative pain at 2 h postoperatively andreduces analgesic requirement at 12 h (2 RCTs) and 48 h (3 RCTs), but not 24 h (3 RCTs) (Tsaousi 2018
Level I [PRISMA], 15 RCTs, n=913) (4 RCTs overlap).
Findings in paediatric RCTs are similar, see Section 10.4.8.
4.9.1.3 | Effects of systemic dexmedetomidine on neuraxial and peripheral blocks
The use of IV dexmedetomidine in patients receiving spinal anaesthesia prolongs time to firstanalgesic request by at least 60% as well as duration of sensory and motor block by 34%
respectively 17% (Abdallah 2013 Level I [PRISMA], 7 RCTs, n=364). These results were in principle
confirmed by a subsequent systematic review, which separately analysed 8 RCTs published since
the previous review (Johnson 2016 Level I, 8 RCTs, n=480) and by one subsequent RCT (Kumari 2017
Level II, n=60, JS 5). Most of the RCTs utilised an initial bolus dose and a subsequent maintenanceinfusion for the duration of surgery (11 of the overall 16 RCTs). IN dexmedetomidine had asignificant opioid-sparing effect after THA (Uusalo 2019 Level III-3, n=120).
IV dexmedetomidine 0.5 mcg/kg but not IV midazolam prolonged spinal bupivacaine sensory
block and also provided sedation and additional analgesia in patients undergoing transurethralresection of the prostate (Kaya 2010 Level II, n=75, JS 2).
IV dexmedetomidine 2 mcg/kg significantly prolonged analgesia and reduced postoperative200

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opioid requirements after single-shot interscalene brachial plexus block vs placebo and lower dosesof dexmedetomidine (0.5 and 1 mcg/kg) (Kang 2018a Level II, n=72, JS 5).
See also Sections 4.9.2.1 and 4.9.2.2 below.

KEY MESSAGE
1. Alpha-2 agonists such as clonidine are more effective than placebo in the managementof opioid-withdrawal symptoms (U) (Level I [Cochrane Review]).
2. The perioperative use of clonidine systemically (excluding transdermal administration)
does not reduce pain intensity (at 24 or 48 hours) (Q) (Level I) but reduces opioid
consumption and postoperative nausea and vomiting versus placebo (Q) (Level I[PRISMA]).
3. The perioperative use of the systemic dexmedetomidine reduces postoperative pain
intensity, opioid consumption and requirements for rescue analgesia (S) without effecton postoperative nausea and vomiting (N) (Level I [PRISMA]).
4. The IV administration of dexmedetomidine combined with intrathecal local anaesthetic
prolongs time to first analgesic request (N) (Level I [PRISMA]).

4.9.2 | Regional alpha-2 agonists
Alpha-2 adrenoceptor agonists act as an analgesic at the level of the dorsal horn of the spinal
cord, although there may be peripheral effects as well (Chan 2010a NR). Systemic adverse effects
are predominantly centrally mediated sedation and hypotension.
4.9.2.1 | Neuraxial
Clonidine
There is no human or animal evidence of neurotoxicity when preservative-free clonidine isadministered IT (Hodgson 1999 NR). Epidural clonidine is approved by the FDA for relief of chronic
cancer pain.
In volunteers, significant analgesia to experimental heat pain was detected with IT doses>25 mcg clonidine: with 50 mcg having similar effects on heat threshold to 5 mg bupivacaine(Ginosar 2013 Level II EH, n=11, JS 4). IT clonidine given in doses from 15 to 150 mcg, combined with
IT local anaesthetic does not affect the rate of onset of a local anaesthetic block, but significantly
prolongs the time to two-segment block regression and prolongs the time to first analgesic
request (median 101 min, range 35–310 min) (Elia 2008 Level I, 22 RCTs, n=1,445). Treatment effects
were noted to be heterogeneous and dose responsiveness could not be demonstrated.
IT clonidine also reduces intraoperative pain, but hypotension was more frequent (RR 1.8; 95%CI
1.4 to 2.3) (Elia 2008 Level I, 22 RCTs, n=1,445).
The addition of IT clonidine to IT morphine causes a small increase in duration of analgesia(MD 1.63 h; 95%CI 0.93 to 2.33) and reduced the amount of systemic morphine consumption
over 24 h (MD 4.45 mg; 95%CI -1.40 to -7.49) (Engelman 2013 Level I, [PRISMA], 7 RCTs, n=503).
Hypotension is also increased (OR 1.78; 95%CI 1.02 to 3.12).
IT clonidine 30 to 150 mcg as an adjuvant to neuraxial anaesthesia during Caesarean section
prolongs the duration of sensory block (MD 128 min; 95%CI 82 to 175) and motor block (MD45 min; 95%CI 9 to 81) (Crespo 2017 Level I [PRISMA], 12 RCTs, n=1,280). IT clonidine increases
sedation (RR 3.92; 95%CI 1.17 to 13.14), but does not increase the risk of hypotension, affect
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pruritus or PONV. Neuraxial clonidine 50 to 150 mcg (epidural and IT) modestly enhances
postoperative analgesia in women having Caesarean section under neuraxial anaesthesia (Allen2018 Level I [PRISMA], 12 RCTs [IT administration] [9 RCT overlap with Crespo 2017] & 6 RCTs [epiduraladministration: 2 RCTs bolus followed by infusion, 2 RCTs repeated bolus, 2 RCTs single bolus], n=1,169).

Neuraxial clonidine reduces morphine consumption (MD -8.7 mg; 95% CI -15.3 to -2.0); this effectis less with IT administration (MD -4.3 mg; 95%CI -7.0 to -1.5) than with epidural administration(MD -18.9 mg; 95%CI -34.8 to -3.0). It also increases the time to first analgesic request (MD 150
min; 95%CI 110 to 190) vs placebo, but does not improve pain scores on movement at 0 to 6 h.
Neuraxial clonidine increases the risk of intraoperative hypotension (49%) vs placebo (33%) andof intraoperative sedation. Risks for bradycardia, nausea/vomiting and pruritus are inconclusive.
There was no case of respiratory depression and neonatal outcome was not different in control
and study group.
In obstetrics patients, the time to achieve highest sensory and complete motor block was lessand duration of analgesia was longer when clonidine and hyperbaric bupivacaine wereadministered sequentially, compared to the mixing of the two medicines in a single syringe(Sachan 2014 Level II, n=60, JS 4).
Low-dose infusion of clonidine alone via thoracic epidural catheters after spinal surgery
reduced systemic opioid requirements and nausea without causing significant sedation or
hypotension (Farmery 2009 Level II, n=65, JS 5). The addition of clonidine to PCEA with ropivacaine
and morphine after TKA decreased opioid requirements and improved analgesia without
increasing adverse effects (Huang 2007 Level II, n=80, JS 3). The addition of clonidine to epiduralanaesthesia with ropivacaine after haemorrhoidectomy improved analgesia without causing
adverse effects (Baptista 2014 Level III-2, n=80).
Dexmedetomidine
Dexmedetomidine is not approved for epidural or IT administration and animal studies on its
neurotoxicity via these routes are contradictory (Ozdamar 2018 BS; Konakci 2008 BS).
Epidural single-shot dexmedetomidine 0.5 to 1.5 mcg/kg as an adjuvant to epidural analgesia
prolongs analgesia (SMD 3.50 h; 95%CI 1.86 to 5.13) (8 RCTs) and reduces rescue analgesia
requirements (SMD -2.00; 95% CI -2.80 to -1.21) (6 RCTs) and pain scores (SMD -0.76; 95%CI -1.46
to -0.06) (4 RCTs) (Zhang 2017b Level I [PRISMA]; 12 RCTs, n=660). It increases sedation scores andreduces heart rate minimally with no other significant adverse effects, and reduces
postoperative shivering. Pain relief was improved with 0.5 mcg/kg epidural dexmedetomidine
versus 0.5 mcg/kg IV administration for open thoracotomy (Zeng 2017 Level II, n=73, JS 5).
IT dexmedetomidine 3 to 100 mcg vs IT clonidine 30 mcg to 2 mcg/kg as adjuvants for IT local
anaesthetics results in a minor prolongation of the sensory block (WMD 24.2 min; 95%CI 12.8 to35.6) and a prolongation of time to first analgesic request (WMD 65.8 min; 95%CI 14.7 to 116.9)
with no difference in incidence of adverse effects (Zhang 2016 Level I [QUOROM], 7 RCTs, n=354).
IT dexmedetomidine 3 to 10 mcg vs IT fentanyl 15 to 25 mcg prolongs the pain free period(SMD 2.98 h; 95%CI 1.69 to 4.27) without increasing the incidence of adverse events, including
hypotension and bradycardia (Sun 2017b Level I, 9 RCTs, n=639). Similarly, after lower limb
orthopaedic surgery, the addition of IT dexmedetomidine 5 mcg vs IT fentanyl 25 mcg to IT
bupivacaine significantly prolonged duration of sensory, motor block and postoperative
analgesia vs saline (Rahimzadeh 2018 Level II, n=90, JS 4). In patients undergoing lower limb surgery,
IT dexmedetomidine 5 mcg was associated with prolonged motor and sensory block,haemodynamic stability and reduced demand of rescue analgesics at 24 h vs IT clonidine 30 mcg,
fentanyl 25 mcg, or saline with bupivacaine (Mahendru 2013 Level II, n=60, JS 4).
In patients having lower abdominal surgery using IT bupivacaine 0.5%, IT dexmedetomidine
5 mcg vs IT buprenorphine 60 mcg prolonged anaesthesia and analgesia with a reduced need for202

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sedation and rescue analgesics (Gupta 2014 Level II, n=60, JS 5). Similarly, in patients undergoing
lower abdominal surgery, the quality of anaesthesia was superior with low-dose
bupivacaine/dexmedetomidine 5 mcg vs bupivacaine/fentanyl 25mcg (Nayagam 2014 Level II,
n=150, JS 4). Dexmedetomidine facilitated the spread of the block and prolonged postoperative
analgesia. For major abdominal cancer surgery, the addition of IT dexmedetomidine 5 mcg to IT
morphine 500 mcg/bupivacaine did not improve analgesia vs IT morphine/bupivacaine (AbdelGhaffar 2016 Level II, n=90, JS 5). Both groups with adjuvants experienced better analgesia thanbupivacaine alone.
Adrenaline (epinephrine)
Adding IT adrenaline to IT local anaesthetics (27 RCTs, n=1,660) prolongs motor block (WMD
64 min; 99%CI 37 to 91), analgesia (WMD 34 min; 99%CI 6 to 62) and time to 2 segments
regression (WMD 20 min; 99%CI 11 to 28) (Tschopp 2018 Level I [PRISMA] [trial sequential analysis],
70 RCTs, n=3,644). For epidural analgesia (37 RCTs, n=1,781), no effects can be identified either due
to lack of an effect (pain intensity, hypotension) or insufficient numbers (motor block, urinary
retention). These findings are in line with those of a preceding meta-analysis which alsopresented dose dependent effects of IT adrenaline ( de Oliveira 2012a Level I [PRISMA], 24 RCTs,
n=1,271) (significant overlap). Doses of ≤100 mcg prolong sensory and motor block duration but
are also associated with more hypotension and PONV than higher doses. IT adrenaline at doses>100 mcg prolongs sensory and motor block more than the lower dose but is not associated witha greater incidence of hypotension and PONV vs IT local anaesthetic alone. The effect of IT
adrenaline in prolonging analgesia duration was not seen when added to IT local
anaesthetic/opioid combinations (de Oliveira 2012a Level I [PRISMA], 24 RCTs, n=1,271).
The influence of caudal adrenaline and/or clonidine on the absorption characteristics of
caudal levobupivacaine were evaluated in children (Chalkiadis 2013 PK, n=240). Adrenaline 5
mcg/mL decreased the rate of levobupivacaine systemic absorption, reducing peakconcentrations by half. Clonidine 2 mcg/mL resulted in faster systemic absorption oflevobupivacaine and a similar concentration time profile to levobupivacaine alone.
In postoperative thoracic epidural infusion, the addition of adrenaline to fentanyl andropivacaine or bupivacaine improved analgesia (Niemi 2003 Level II, n=33, JS 5; Niemi 2002 Level II,
n=12, JS 5; Sakaguchi 2000 Level II, n=77, JS 2). The efficacy of thoracic epidural pethidine infusions
after thoracotomy was not improved by addition of adrenaline ( Bryson 2007 Level II, n=50, JS 5).
With lumbar epidural infusions, no analgesic benefit was seen with added adrenaline at
2 mcg/mL or 4 mcg/mL (Forster 2008 Level II, n=63, JS 3; Forster 2003 Level II, n=46, JS 5).
In labour epidural analgesia, adrenaline 5 mcg/mL added to low-dose bupivacaine infusions
decreased pain scores and resulted in longer redosing intervals with no change in labour duration(Connelly 2011 Level II, n=60, JS 4).
See also Section 5.7.1.4, for obstetric use Section 9.1.3.3 and for paediatric use Sections
10.4.8.1 and 10.6.3.3.
4.9.2.2 | Peripheral nerve blockClonidine
A meta-analysis evaluated the benefits of clonidine as an adjuvant to local anaesthetics forvarious peripheral nerve and plexus blocks (Popping 2009 Level I, 20 RCTs, n=1,054). Clonidine doses
ranged from 30 to 300 mcg with most patients receiving 150 mcg. Clonidine prolongs theduration of postoperative analgesia (WMD 122 min; 95%CI 74 to 169), sensory block (WMD
74 min; 95%CI 37 to 111) and also prolongs motor block. However, clonidine increases the riskof hypotension (OR 3.61; 95%CI 1.52 to 8.55), bradycardia (OR 3.09; 95%CI 1.10 to 8.64) andsedation (OR 2.28; 95%CI 1.15 to 4.51). There was a lack of evidence of dose-responsiveness for
5th Edition | Acute Pain Management: Scientific Evidence 203beneficial or harmful effects. Subsequent studies in supraclavicular blocks report similar findings(Nasir 2017 Level II, n=97, JS 4; Chakraborty 2010 Level II, n=70, JS 4; Singh 2010 Level II, n=50, JS 4).
However, the addition of 150 mcg clonidine to levobupivacaine 0.5% 20 mL in posterior gluteal(Labat) sciatic nerve block did not prolong the duration of analgesia and resulted in more
hypotension vs the control group (Fournier 2012 Level II, n=60, JS 4).
In an experimental setting controlling for systemic effects of clonidine using bilateraladductor canal blocks, the addition of 150 mcg clonidine to ropivacaine for one side resulted in
no difference in block characteristics (quality and duration) on either side ( Andersen 2017 Level II
EH, n=21, JS 5).
Evidence is lacking for the use of clonidine as an adjuvant to local anaesthetics for continuous
catheter techniques, with no studies showing benefit ( McCartney 2007 Level I, 3 RCTs [continuous],
n=110).
Dexmedetomidine
Animal studies suggest potential dose-dependent neurotoxic effects when dexmedetomidine iscombined with ropivacaine for 48 h of continuous FNB in rabbits (Wang 2019 BS) and for brachial
plexus injection in high doses in rats (Kang 2018b BS).
Dexmedetomidine 25 to 150 mcg added to local anaesthetics for various peripheral nerve
and plexus blocks increases duration of postoperative analgesia (MD 4.87 h; 95%CI 4.02 to 5.73)(Schnabel 2018 Level I [PRISMA], 46 RCTs, n=3,149). Dexmedetomidine increases the risk of
intraoperative bradycardia (RR 2.83; 95%CI 1.50 to 5.33) and hypotension (RR 3.42; 95%CI 1.24
to 9.48). Perineural and IV administration of dexmedetomidine results in a similar prolongationof duration of analgesia (MD 0.98 h; 95%CI -0.12 to 2.08) (2 RCTs, n=107). However, for ulnar nerve
blocks, perineural 100 mcg administration was superior to systemic dexmedetomidine inprolonging block duration: perineural 14.4 h (95%CI 13.1 to 15.6) vs systemic administration 9.2
h (95%CI 8.6 to 9.8) vs without dexmedetomidine 7.1 h (95%CI 6.6 to 7.6) (Andersen 2019 Level II
EH, n=22, JS 5).
Meta-analyses of data on specific blocks have significant overlap with the overarching metaanalysis (Schnabel 2018 Level I [PRISMA], 46 RCTs, n=3,149) and show similar results:• For thoracic paravertebral blocks (PVB), dexmedetomidine 1mcg/kg combined with local
anaesthetics reduces pain at rest and with movement; for the latter the results were
(SMD -1.63/10; 95%CI -2.92 to -0.34) and at 24 h (SMD -1.78/10; 95% CI -2.66 to -0.90)(Wang 2018a Level I [QUORUM], 7 RCTs [2 RCTs infusion, 5 RCTs single shot 1 mcg/kg], n=350). It
extends duration of analgesia (202 min; 95% CI 33.5 to 369.6) and reduces postoperative
analgesic consumption, while increasing the incidence of hypotension (OR 4.40; 95% CI
1.37 to 14.17);• For TAPB, dexmedetomidine 0.5 to 1 mcg/kg as an adjuvant increases duration andquality of analgesia, while being opioid sparing (WMD −13.71; 95%CI −17.8 to −9.6)
without increasing adverse effects (Sun 2019 Level I [PRISMA], 20 RCTs, n=1,212);• As part of a brachial plexus block, perineural dexmedetomidine reduces time to onset of
sensory and motor block, and prolongs sensory, motor block and analgesia duration by atleast 57, 58 and 63% respectively (the latter by 266 min; 95%CI 191 to 343) (Vorobeichik
2017 Level I [PRISMA], 32 RCTs, n=2,007; Hussain 2017 Level I, 18 RCTs, n=1,092 [17 RCTs overlap];
Ping 2017 Level I [QUOROM], 18 RCTs, n=1,014 [10 RCTs overlap]). In addition,
dexmedetomidine has an opioid sparing effect (MED 10.2 mg; 95%CI -15.3 to -5.2) in thefirst 24 h, improves pain control and enhances patient satisfaction, but increases theincidence of bradycardia and hypotension.
A dose-finding study for dexmedetomidine as an adjunct to interscalene brachial plexus block
identified 2 mcg/kg as superior over 1 and 1.5 mcg/kg with regard to duration of analgesia

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1,224 min ± 238 min), but with an increased risk of hypotension for the two highest dose groups(Jung 2018 Level II, n=100, JS 5).
Compared with clonidine 1 to 2 mcg/kg, the perineural application of dexmedetomidine ≈1
to 2 mcg/kg as a local anaesthetic adjuvant in single-injection supraclavicular block produces
significant prolongation of sensory block, motor block, and postoperative analgesia (on average
by a factor of 1.2), while increasing the incidence of transient bradycardia (OR 7.4; 95%CI 1.3 to40.8) and postoperative sedation (OR 11.8; 95%CI 1.9 to 73.6) (El-Boghdadly 2017 Level I [PRISMA],
14 RCTs, n=868).
Compared with dexamethasone 1 to 8 mg, dexmedetomidine 30 to 100 mcg as a perineural
adjuvant for supraclavicular plexus block was inferior with regard to duration of analgesia (MD 148 min; 95%CI -259 to -37), while causing more hypotension (RR 6.3; 95%CI 1.5 to 27.5) andsedation (Albrecht 2019 Level I [PRISMA], 49 RCTs, n=3,019).
Adrenaline
Adrenaline added to local anaesthetics for locoregional anaesthesia ( 6 RCTs, n=203) prolongs
analgesia (WMD 66 min; 98%CI 32 to 100) (Tschopp 2018 Level I [PRISMA] [trial sequential analysis],
70 RCTs, n=3,644).
For paediatric use see Section 10.6.2.6.
4.9.2.3 | Intravenous regional anaesthesia
Clonidine
Clonidine 150 mcg was inferior to magnesium sulphate (1.5 g of 50% MgSO4) as an adjuvant to
IVRA with shorter time to first analgesic request (169.5 ± 33.3 vs 193.9 ± 38.4 min) and greater
requirements for rescue analgesia (2.1 ± 0.8 vs 1.6 ± 0.7) (Kaur 2017 Level II, n=40, JS 5). Similarly,
no analgesic benefit was found in a dose-finding study with clonidine (0 to 1.5 mcg/kg) added to
IVRA (Ivie 2011 Level II, n=52, JS 5).
Dexmedetomidine
Addition of dexmedetomidine (most frequently 0.5 mcg/kg) to lidocaine or prilocaine IVRA
increased duration and quality of analgesia (Subramanya 2017 Level II, n=60, JS 5; Kumar 2012 Level
II, n=72, JS 5; Kol 2009 Level II, n=75, JS 5; Esmaoglu 2005 Level II, n=40, JS 4; Memis 2004 Level II, n=30,
JS 4).
In patients having carpal tunnel repairs under IVRA, dexmedetomidine IV was compared withdexmedetomidine added to the local anaesthetic for IVRA and with placebo (Mizrak 2010 Level II,
n=45, JS 5). Both routes of dexmedetomidine had similar effects, with improved postoperative
pain scores up to 30 min.
Dexmedetomidine 1 mcg/kg vs midazolam (50 mcg/kg) as an adjuvant to IVRA resulted insimilar duration of analgesia (Subramanya 2017 Level II, n=60, JS 4).
4.9.2.4 | Intra-articular
Clonidine
Intra-articular (IA) clonidine vs placebo after arthroscopic knee surgery reduces pain scores for
4 h, the need for rescue analgesia and postoperative nausea, but increases the risk ofhypotension (Sun 2014 Level I [PRISMA] 7 RCTs, n=230). Combined femoral-sciatic nerve block
offered better analgesia with fewer adverse effects than IA infiltration withbupivacaine/clonidine/morphine in children undergoing anterior cruciate ligament
reconstruction (Tran 2005 Level II, n=36, JS 2).
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Dexmedetomidine
IA dexmedetomidine 100 mcg when added to ropivacaine resulted in a longer time to analgesic
request than ropivacaine alone (mean 10.8 h [SD 2.6] vs 5.4 h [SD 1.4]) ( Paul 2010 Level II, n=30,
JS 5). Compared with IV route, IA dexmedetomidine resulted in a longer time to first analgesia(IA 312.0 min [SD 120.7]; IV 102.1 min [SD 54.4]; placebo 71.0 min [SD 50.1]) ( Al-Metwalli 2008
Level II, n=60, JS 5). When IA dexmedetomidine 100 mcg, fentanyl 50 mcg and ropivacaine eachalone were compared following knee arthroscopy, time to first analgesia was longest withropivacaine, followed by fentanyl and then dexmedetomidine (mean: 380 min [SD 22], 327 min[SD 17] and 244 min [SD 20] respectively) (Manuar 2014 Level II, n=99, JS 2). Added to bupivacaine,
IA dexmedetomidine 1 mcg/kg resulted in similar prolongation and quality of analgesia as
IA dexamethasone 8 mg vs bupivacaine alone after meniscal surgery (Moeen 2017 Level II, n=60,
JS 5).

KEY MESSAGES
1. Neuraxial clonidine improves duration and quality of analgesia and is opioid sparing
when used as an adjuvant to neuraxial local anaesthetics (in particular after Caesarean
section) (S) (Level I [PRISMA]) or to morphine (U) (Level I [PRISMA]), but increases therisk of hypotension and sedation (N) (Level I [PRISMA]).
2. Neuraxial dexmedetomidine improves duration and quality of analgesia when used as
an adjuvant to neuraxial local anaesthetics (S) (Level I [PRISMA]).
3. Intrathecal adrenaline (epinephrine) when combined with local anaesthetic, but notwith intrathecal opioids, prolongs analgesia duration (U) (Level I [PRISMA]).
4. Dexmedetomidine when added to local anaesthetics for peripheral nerve blocks
improves duration and quality of analgesia, but is associated with increased
hypotension and bradycardia (S) (Level I [PRISMA]).
5. Intra-articular clonidine reduces pain scores for 4 hours, need for rescue analgesia andincidence of nausea, but increases hypotension (N) (Level I [PRISMA])
6. Clonidine improves duration of analgesia and anaesthesia when used as an adjuvant tolocal anaesthetics for peripheral nerve and plexus blocks but is associated withincreased hypotension and bradycardia (U) (Level I).
7. Dexmedetomidine added to intravenous regional anaesthesia improves and prolongs
analgesia (U) (Level II).
8. Epidural adrenaline (epinephrine) in combination with a local anaesthetic improves thequality of postoperative thoracic epidural analgesia (U) (Level II).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: The benefits of perineural adjuvant administration of alpha-2-agonists over systemic
administration remains unclear (N).

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4.10 | Salmon calcitonin and bisphosphonates
4.10.1 | Calcitonin
Calcitonin is a 32-amino acid peptide hormone that regulates calcium homeostasis invertebrates. It also has analgesic properties, primarily through receptor-mediated modulation ofserotonergic activity in pain pathways of the CNS (Visser 2005 NR). Salmon calcitonin has a greater
potency than mammalian forms of the hormone and is therefore reproduced as a synthetic
medicine for pharmaceutical use. The adverse effects of calcitonin therapy such as sedation,
nausea, skin flushing and diarrhoea may reflect increased serotonergic activity. In rodents, the5HT3 antagonist tropisetron reduced its analgesic efficacy, which may be relevant in humans
during the treatment of its adverse effects ─ nausea and vomiting (Visser 2005 NR).
In patients with osteoporotic vertebral compression fractures, salmon calcitonin (IV, SC, IM,
IN or rectal) administered within <10 d reduces acute pain at rest and on movement within 1 wk
and improves mobilisation (in 7 to 28 d); adverse effects are usually minor and mainly
gastrointestinal (Knopp-Sihota 2012 Level I [PRISMA], 13 RCTs, n=589). Weekly IM injections of eel
calcitonin (elcatonin 20 Units) were more effective than NSAIDs in controlling pain and improving
mobility in new (<2 wk) thoracolumbar osteoporotic fractures (Endo 2017 Level II, n=228, JS 3). In
chronic pain (>3 mth) from pre-existing osteoporotic vertebral compression fractures, the effectwas minimal and only statistically significant on movement at 6 mth. In a case series, IN salmon
calcitonin reduced pain due to fracture of the coccyx ( Foye 2014 Level IV, n=8).
In acute phantom limb pain, IV (and likely SC) salmon calcitonin was more effective thanplacebo (Jaeger 1992 Level II, n=21 (cross over), JS 3; Bornemann-Cimenti 2017 CR; Turek 2012 CR).
However, it was not effective for chronic phantom limb pain (Eichenberger 2008 Level II, n=20 [crossover], JS 5). While epidurally administered calcitonin reduced the incidence of chronic phantom
limb pain, allodynia and hyperalgesia at 6 and 12 mth in diabetic patients undergoing lower limb
amputation (Yousef 2017 Level II, n=60, JS 5).
In CRPS, a meta-analysis concluded that salmon calcitonin (IN, IV) is beneficial (Perez 2001 Level I,
5 RCTs [calcitonin], n=260). However, the only two placebo-controlled RCTs in this meta-analysis
produced conflicting results. A subsequent RCT found that calcitonin was no more effective thanparacetamol in improving pain and function in CRPS over a 2 mth period in patients alreadyreceiving physical therapy following upper limb trauma (Sahin 2006 Level II, n=35, JS 2). A network
meta-analysis recommended short term (<2 mth) calcitonin by all routes of administration in CRPS
over 12 mth in duration (Wertli 2014 Level I [NMA], 3 RCTs [calcitonin], n=116); the RCTs included did
not use IASP or Budapest diagnostic criteria for CRPS and the quality of the data have beenquestioned by other authors (Benzon 2016 NR).
Neuropathic pain after SCI was responsive to SC salmon calcitonin (Humble 2011 Level IV, n=3).
In lumbar spinal stenosis, salmon calcitonin (IN, IM, SC) has no effect on pain or walking
distance vs placebo or paracetamol regardless of method of administration ( Peng 2015 Level I,
6 RCTS, n=232).
The limited evidence available does not support the effectiveness of SC salmon calcitonin in
the treatment of acute and persistent metastatic bone pain ( Martinez-Zapata 2006 Level I[Cochrane], 2 RCTs, n=90).
With long-term use of salmon calcitonin for treatment of chronic osteoporosis (withunproven efficacy), there is a suggested association with increased cancer incidence; however,this is based on studies with poor-quality cancer assessment methodology (Overman 2013 NR). A
subsequent meta-analysis further weakened the association and found little biologicalplausibility linking cancer risk and long-term calcitonin use (Wells 2016 Level I, 22 RCTs, n= 11,489).
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The FDA has decided to continue the registration of salmon calcitonin, including for chronic use(FDA 2014b).

4.10.2 | Bisphosphonates
IV pamidronate 30 mg daily (for 3 d) vs placebo, rapidly reduced pain associated with acuteosteoporotic vertebral compression fractures (<21 d after incident) for up to 30 d post treatment(Armingeat 2006 Level II, n=35, JS 5). Pamidronate IV was as effective as IV human synthetic
calcitonin for this indication (Laroche 2006 Level II, n=27, JS 3).
Bisphosphonates reduce subacute and chronic bone pain associated with metastatic
carcinoma of the breast (Wong 2012 Level I [Cochrane], 9 RCTs, n=2,810). In multiple myeloma, there
is high quality evidence for benefit in reduction of vertebral fractures and skeletal related events,and low-quality evidence for pain reduction (Mhaskar 2017 Level I [Cochrane], 24 RCTs, n=7,293). In
advanced prostate cancer, there is no clear benefit to the use of bisphosphonates for reducing
pain, but they may prevent further skeletal related events ( Macherey 2017 Level I [Cochrane],
18 RCTs, n=4,843). Bisphosphonates improve pain control in patients with metastatic bone disease
from lung cancer (Lopez-Olivo 2012 Level I, 12 RCTs, n=1,767). Zoledronate specifically reduces thelikelihood of experiencing a bone pain event in metastatic bone disease in comparison to placebo(RR 0.83; 95%CI 0.76 to 0.89) (Zhu 2013 Level I, 12 RCTs, n=4,450). See also Section 8.9.7.7.
There is poor quality evidence for the use of bisphosphonates outside of the aforementioned
cancer states (breast, multiple myeloma, prostate, lung), nor is it warranted in patients withshort life expectancy (<3 mth) (Porta-Sales 2017 Level I, 40 RCTs, n = 16,105).
Bisphosphonates reduce pain in patients with CRPS Type 1, in particular in the early phasesof the syndrome (<12 mth) (Chevreau 2017 Level I, 4 RCTs, n=181).
In Paget’s disease, bisphosphonate use tripled the proportion (31% vs 9%) of participants
whose bone pain disappeared (RR 3.42; 95%CI 1.31 to 8.90) (NNT 5) (2 RCTs, n=205) (Corral-Gudino
2017 Level I [Cochrane], 20 RCTs [pain], n=3,168). The evidence was limited regarding benefit of
specific bisphosphonates, but zoledronate appeared to have marginally better efficacy vspamidronate and risedronate (2 RCTs, n=436).
In acute pain due to osteoarthritis of the knee, bisphosphonates have no effect on pain,
function or radiological progress (Vaysbrot 2018 Level I, 7 RCTs, n=3,013).

KEY MESSAGES
1. Bisphosphonates reduce bone pain associated with metastatic breast cancer (U),multiple myeloma (S) and Paget’s disease (N) (Level I [Cochrane Review]), but have nobeneficial effect for knee arthritis (N) (Level I).
2. Salmon calcitonin reduces pain and improves mobilisation in the acute phase after
osteoporosis-related vertebral compression fractures (U) (Level I [PRISMA]).
3. Bisphosphonates reduce pain in patients with CRPS Type 1 in the early phase of thedisease (N) (Level I).
4. Salmon calcitonin reduces acute, but not chronic, phantom limb pain (U) (Level II).
5. Pamidronate reduces pain associated with acute osteoporotic vertebral compression
fractures (U) (Level II).

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4.11 | Cannabis, cannabinoids and cannabimimetics
4.11.1 | Pharmacology
Medicinal preparations made from the cannabis plant contain several hundred chemical
substances, which occur in varying concentrations in different plant strains and growthenvironments. Cannabis plants and their extracts are uniquely rich in phytocannabinoids ( Russo
2011 NR), of which delta9-tetrahydrocannabinol (Δ9-THC) is the best characterised substance andinduces most of the psychogenic effects attributed to cannabis. Tetrahydrocannabinolic acid isthe nonpsychotropic phytochemical precursor of THC and is of therapeutic interest for theprevention of nausea (Rock 2013 BS) and the selective inhibition of COX-2 (Takeda 2008 BS). Other
prominent THC congeners include cannabidiol and cannabinol. Cannabidiol (CBD) is of interest
because it opposes the psychotropic activity of THC and is currently being developed for
anticonvulsant therapy (Schubart 2011 Level IV, n=1,877; Devinsky 2014 NR; Borgelt 2013 NR).
Cannabinol is also of interest for possible antitumour actions (Guindon 2011 NR).
“Cannabinoids” refers to both the phytocannabinoid congeners of Δ9-THC and to a wide rangeof synthetic substances that act on a family of G-protein coupled receptors, which are presently
designated subtypes CB1 and CB2. CB1 receptors are predominantly distributed throughout thecentral and peripheral nervous system, where they mediate inhibition of neurochemicaltransmitter release and are associated with analgesic and mood modifying effects. CB2 receptors
predominantly occur on immune cells, including microglia, and are associated with modulation ofcytokine release and have an anti-inflammatory effect (Mackie 2006 NR).
The endogenous cannabinoid system can be considered complementary to the endogenous
opioid system (Wilson-Poe 2013 BS). Endogenous cannabinoid ligands (endocannabinoids) are
derived from arachidonic acid. It is postulated that some (chemically noncannabinoid) analgesic
agents (including paracetamol and various NSAIDs) may act, at least in part, via cannabinoid
receptor mediation, either directly or indirectly via modulation of endocannabinoid metabolism(Graham 2013a NR; Manzanares 2006 NR) although much of this evidence is from pre-clinical dataand some effects may be species-specific (McPartland 2014 BS SR).
It is difficult to group together cannabis-derived preparations and other cannabinoids. This isbecause plant-extract formulations comprise a mixture of active ingredients (eg the oral mucosal
metered-dose spray nabiximols [Sativex®; containing THC:CBD≈1:1] in comparison to pure single
ingredient cannabinoid preparations, such as dronabinol [Marinol®, synthetic THC, oral capsules]
and nabilone [Cesamet®, synthetic analogue of THC, oral capsules]). Nabiximols are registered inAustralia and New Zealand among other countries for treatment of spasticity associated withmultiple sclerosis (MS).
The acute toxicity of phytocannabinoids is extremely low; nevertheless, clinical studies of theeffect-adverse effect profile of cannabis and cannabinoids have demonstrated that desirable
actions may be limited in a proportion of patients due to adverse effects, including dysphoria,
sedation and impaired psychomotor performance, memory and concentration (Robson 2011 NR).
Many patients self-administer cannabis by smoking; the traditional route popularised bynonmedical users (Wilsey 2013 Level II, n=39, JS 4; McQuay 2010 NR). Transpulmonary administeredphytocannabinoids are rapidly and efficiently absorbed; however, newer vaporising delivery
techniques are supplanting smoking with its attendant health risks (Zuurman 2008 Level II, n=12,
JS 4; Eisenberg 2014 Level IV PK; Hazekamp 2006 EH) including emerging concerns regarding severe
pulmonary toxicity and ‘vaping’ (Schier 2019 GL). Oral cannabis and cannabinoid preparations
have a poor and highly variable systemic bioavailability (Huestis 2007 NR). Likewise, theoromucosal spray (of nabiximols) does not achieve a rapid systemic absorption, with a profile
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resembling oral administration (Karschner 2011a Level II PK, n=9, JS 3; Karschner 2011b Level II EH,
n=22, JS 3; Zuurman 2008 Level II EH, n=12, JS 4; Hazekamp 2006 EH).

4.11.2 | Efficacy
4.11.2.1 | Acute Pain
A volunteer study considering acute pain used electrical and heat stimuli in healthy young adultfemale volunteers found 20 mg oral standardised cannabis extract to be no different to 5 mg oral
diazepam (active placebo) in a variety of endpoint measures (Kraft 2008 Level II EH, n=18, JS 4). The
authors concluded that “cannabinoids are not effective analgesics for the treatment of acutenociceptive pain in humans”. The authors determined the plasma concentrations of the Δ 9-THC
and CBD components and found that they varied more than seven-fold between subjects.
Similarly, in the clinical setting, there is no evidence for a role of synthetic or purified
cannabinoids in the management of acute pain (Stevens 2017 Level I [PRISMA], 7 RCTs, n=310). Five
RCTs found cannabinoids to be equivalent to placebo, one inferior and one superior. There wereno synergistic or additive analgesic effects when used in combination with opioids.
4.11.2.2 | Chronic Pain
In a variety of chronic pain conditions, including neuropathic pain, fibromyalgia, arthritis andother mixed groups, the efficacy of all commercially available cannabinoids in all study designs
and considering all IMMPACT recommended outcomes were analysed ( Stockings 2018 Level IV SR[PRISMA], 47 RCTs & 57 studies, n=9,958). Across the RCTs, the pooled event rate for 30% pain
reduction is 29.0% for cannabinoids vs 25.9% for placebo (OR 1.46; 95%CI 1.16 to 1.84) (NNT 30%
24; 95%CI 15 to 61) (8 RCTs, n=1,734); this outcome is achieved in 72% of patients (95%CI 66%78%) in observational studies with no comparison group. Across the RCTs, the benefit is lost for
50% pain reduction with pooled event rate of 18.2% vs 14.4% (OR 1.43; 95%CI 0.97 to 2.11) (5RCTs, n=753). With regard to other outcomes in RCTs, there were no effects on physicalfunctioning, quality of life, overall emotional functioning or depression or anxiety symptoms, butsome low level evidence for reduction in sleep problems (moderate level evidence withnabiximols only) and an improved Global Impression of Change (GIC) (perceived “much” to “verymuch” improved 18.9% vs 11.8%) (OR 1.62; 95%CI 1.34 to 1.96) (NNT 38; 95%CI 27 to 62) (13
RCTs [4 continuous & 9 dichotomous], n=1,896 [1,595 dichotomous]). There is moderate- to high-grade
evidence supporting use of nabiximols to achieve modest reductions in pain as adjuvant therapy
in MS-related pain. Adverse events occurred in 81.2% of cannabinoid-treated patients vs 66.2%of placebo-treated patients (OR 2.33; 95%CI 1.88 to 2.89) (NNH 6; 95%CI 5 to 8) (10 RCTs, n=1,959);
severe adverse events resulting in study withdrawal occurred in 15.8% vs 4.6% (OR 3.47; 95%CI
2.64 to 4.56) (NNH 40; 95%CI 35 to 49) (19 RCTs, n=3,265).
These findings are largely consistent with a preceding meta-analysis with significant overlapof included RCTs (Aviram 2017 Level I [PRISMA], 43 RCTs, n=2,437) and an overview of systematic
reviews not including the above meta-analyses (Hauser 2018 Level I [PRISMA], 10 SRs, unspecified
number of RCTs).
In addition to these meta-analyses of effects on all chronic pain conditions, there are also
assessments of specific conditions published (with significant overlap of included RCTs):• In neuropathic pain, there is no high-quality evidence for the efficacy of any cannabisbased medicine (Mucke 2018a Level I [Cochrane], 16 RCTs, n=1,750). Low quality evidenceshows a 50% or greater pain reduction versus placebo in 21% vs 17% (RD 0.05; 95%CI 0.00
to 0.09) (NNT50% 20; 95%CI 11 to 100) (8 RCTs, n=1,001). Moderate quality evidence shows
a 30% or greater pain reduction in 39 vs 33% (RD 0.09; 95%CI 0.03 to 0.15) (NNT30% 11;

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•

•

•

95%CI 7 to 33) (10 RCTs, n=1,586). For adverse events, evidence is of low quality and shows
an increase in nervous system adverse events 61% versus 29% (RD 0.38; 95%CI 0.18 to0.58) (NNH 3; 95%CI 2 to 6) (9 RCTs, n=1,304) and psychiatric disorders 17% vs 5% (RD 0.10;
95%CI 0.06 to 0.15) (NNH 10; 95% CI 7 to 16) (9 RCTs, n=1,314);
In fibromyalgia, there is no convincing evidence that nabilone (the only cannabinoid in
both RCTs) is of any value in treating this condition (Walitt 2016 Level I [Cochrane], 2 RCTs,n=72);
In cancer pain, very low-quality evidence shows no benefit of nabiximols or THC (theonly cannabinoids in the included RCTs) on any outcome including pain, sleep problems
and opioid consumption with increased adverse events (GI and nervous system) (Hauser
2019 Level I [PRISMA], 5 RCTs, n=1,534). Even for improvement of anorexia or cachexia ina palliative care setting, there is no convincing, unbiased, high quality evidence for aneffect of cannabinoids (Mucke 2018b Level I [PRISMA], 9 RCTs, n=1,561);
In MS, cannabinoids may have modest effects for pain or spasticity based on high quality
evidence (Nielsen 2018 Level III-3 SR [PRISMA], 11 SRs based on 32 studies).

Smoking cannabis has only short-term effects in RCTs of painful HIV associated sensory
neuropathy (Phillips 2010 Level I [PRISMA], 14 RCTs n=1,764 [2 smoked cannabis, n=111]). Specific tosmoked cannabis, the authors caution re potential bias due to difficulties in patient blinding; in
one RCT 92% guessed treatment allocation correctly.
A 4 y prospective cohort study of people with chronic non-cancer pain taking opioids
identified that those using non-prescribed cannabis had increased pain severity, paininterference and generalised anxiety disorder scores and decreased pain self-efficacy scores(Campbell 2018 Level III-2, n=1,514). Cannabis use did not have an opioid-sparing or opioid
cessation effect.

4.11.3 | Adverse effects
Transient adverse effects of cannabis and cannabinoids are variable and include impaired
cognition, dizziness and sedation. In short-term exposure (mean treatment duration of 2 wk)
medical cannabis was not associated with a higher incidence of serious adverse effects vscontrol (RR 1.04; 95%CI 0.78 to 1.39), with dizziness being reported as the most commonly
reported nonserious event in cannabinoid-treated patients (15.5%) (Wang 2008a Level I, 23 RCTs,
n=3,141).
Longer-term studies in patients with MS have indicated no new safety concerns after several
years of administration. Nabiximols (Sativex®) treatment in patients with MS was not associatedwith psychopathology or impaired cognition (Aragona 2009 Level II, n=17, JS 5). Similarly, its adverse
effects were assessed in an open-label study following a trial for treating spasticity in MS patientsfor a mean duration of 334 d (Serpell 2013 Level IV, n=146). Adverse effects typically reported as“dizziness”, “fatigue” and “headache” caused treatment withdrawal in 14% of patients and wereserious (eg psychosis) in 4.3%. A further 9% of these patients withdrew due to lack of efficacy.
There is widespread concern about chronic exposure to cannabis and the development of
psychosis in susceptible individuals. Whilst a causal link is yet to be established, one meta-analysis
concluded that there is a dose-response relationship between the level of cannabis use and the riskfor psychosis (Marconi 2016 Level III-3 [PRISMA], 10 studies, n=66,816). The risk for schizophrenia andother psychosis-related symptoms is highest in the heaviest cannabis users vs non-users (OR 3.90;
95%CI 2.84 to 5.34). Others have argued that there is little evidence that, at a population level,cannabis use is a primary contributing factor in the development of psychiatric illness (Hamilton 2014
Level III-3; Gage 2013 NR; Macleod 2010 NR).
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Rapidly absorbed cannabis (eg by smoking) produces a tachycardia by a beta-adrenergic
mechanism (Beaconsfield 1972 NR). A detailed literature review identifies an increased risk ofacute coronary syndrome and chronic cardiovascular disease associated with cannabis use
through other mechanisms postulated as vascular inflammation, platelet activation andcarboxyhaemoglobin formation (Richards 2019 Level IV SR [PRISMA], 85 studies, n=541,518).
However, in patients surviving acute myocardial infarction there was no association between
cannabis use and mortality (Frost 2013 Level IV, n=519). There are emerging concerns regarding
severe pulmonary toxicity related to “vaping”, with unclear trigger factors but many reports
involve cannabinoids (Schier 2019 GL). Overall, cardiovascular and pulmonary effects ofcannabinoids need to be considered (Pacher 2018 NR).
Acute cannabis intake impairs driving, but the increase in accident risk is of low to medium
magnitude (increase in accident risk pooled OR 1.28; 95%CI 1.16 to 1.40 and in culpable accident riskpooled OR 1.42; 95%CI 1.11 to 1.75) (Rogeberg 2019 Level III-3 SR, 13 studies [culpability], n=78,023).
After trauma, marijuana use, in particular chronic use, leads to higher pain scores and higher
opioid requirements (Salottolo 2018 Level III-2, n=261).
Epidemiological evidence of harms is typically derived from “recreational” users where the“cannabis” is defined neither chemically nor posologically (dose) and its relevance to the medicaluse, particularly of pharmaceutical grade cannabis, in supervised patients, is questionable.

4.11.4 | General considerations
It should be noted that all clinical studies to date have various design limitations, most involving
small numbers of patients and most using only nonselective highly lipophilic cannabinoids, often
of unknown composition. It should also be noted that several RCTs with negative results are yet
to be published. The possible benefits from more selective agonists have yet to be investigatedin the clinical setting, along with more innovative or reliable modes of administration.
Many leading stakeholder institutions world-wide, which hold either scientific, best practiceor regulatory interests in the use of pharmacological agents for the treatment of pain, express auniversal concern for the proliferation of cannabis related products for the indications of acuteor chronic pain (FPMANZCA 2019b GL). This concern is largely underpinned by the current lack ofquality and robust evidence for its efficacy and the significant adverse effects both in the shortand long terms. These same institutions welcome further dialogue within the framework of welldesigned clinical studies to better determine usefulness of cannabinoids and their side-effectprofile.

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1. Adverse effects including dizziness, cognitive changes and psychiatric symptoms(eg psychosis) may limit the usefulness of cannabinoids in pain treatment (S) (Level I[Cochrane Review]).
2. Current evidence does not support the use of cannabinoids in acute pain management(S) (Level I [PRISMA]).
3. Smoking cannabis has short-term efficacy in neuropathic pain in patients with
HIV/AIDS, although potential study bias means that this is not recommended as routine
treatment (Q) (Level I [PRISMA]).
4. Cannabinoids appear to be mildly effective when used in the treatment of pain andspasticity associated with multiple sclerosis and HIV (W) (Level III-2 SR [PRISMA]).
5. Smoked cannabis increases the risk of acute coronary syndrome and chronic
cardiovascular disease (N) (Level IV SR).

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4.12 | Corticosteroids
4.12.1 | Systemic corticosteroids
Surgical tissue trauma leads to the conversion of arachidonic acid to prostaglandins andleukotrienes. NSAIDs inhibit the formation of prostaglandins, whereas corticosteroids also inhibit
the production of leukotrienes and cytokines (Royse 2017 NR; Gilron 2004 NR). The antiinflammatory effects of corticosteroids account for some, but not all, of the antinociceptive
effects of corticosteroids seen in clinical practice. It is likely that the analgesic actions ofsystemically administered corticosteroids are attributable predominantly to rapid-onset
nongenomic mechanisms. However, the well-documented anti-inflammatory actions may
contribute to a more delayed analgesic effect and may be due to genomic effects ( Rijsdijk 2014
NR; Lowenberg 2008 NR). See also paediatric Section 10.4.10.
4.12.1.1 | Efficacy
Perioperative administration of corticosteroids reduces the severity of postoperative pain anddecreases analgesic requirements as discussed below. However, corticosteroids are not only
administered in the perioperative setting for their analgesic effects but also for other reasons.
These include (but are not limited to) a reduction of PONV ( De Oliveira 2013b Level I [PRISMA],
60 RCTs, n=6,696), decreased swelling in dental and maxillofacial surgery ( Dan 2010 Level I,
12 RCTs, n=574) and an improvement in quality of recovery and decreased postoperative fatigue(Yue 2017 Level I, 11 RCTs, n=774; Murphy 2014 Level II, n=200, JS 5; Murphy 2011a Level II, n=120,
JS 5; Murphy 2011b Level II, n=117, JS 5) with facilitation of earlier hospital discharge ( Murphy
2011a Level II, n=120, JS 5).
Corticosteroids have also been shown to have antihyperalgesic effects in animals and humans(Romundstad 2007 NR; Brandsborg 2007 NR). In experimental burn injury pain, bothmethylprednisolone and ketorolac reduced secondary hyperalgesia and increased pain pressure
tolerance threshold vs placebo, although the increase in pain pressure tolerance threshold was
greater with ketorolac (Romundstad 2007 Level II EH, n=12, JS 4). In surgical patients, preoperative
administration of methylprednisolone resulted in significantly less hyperalgesia vs parecoxib andplacebo but there was no reduction in persistent spontaneous or evoked pain ( Romundstad 2006
Level II, n=204, JS 4).
Dexamethasone 1.25–20 mg administration to surgical patients decreases postoperative painscores, opioid consumption, time to first analgesia, requirements for rescue analgesia and PACU
LOS (Waldron 2013 Level I [PRISMA], 45 RCTs, n=5,796). However, the differences are small and, while
statistically significant, unlikely to confer clinically relevant analgesic benefit (eg 13% reductionin postoperative opioid consumption equals 3 mg morphine equivalent over the first 24 h).
Preoperative dexamethasone administration is superior to later administration. When steroid
doses were classified into three levels, an optimal dose of 0.1 to 0.2 mg/kg dexamethasone was
identified (De Oliveira 2011 Level I [PRISMA], 24 RCTs, n=2,751); however, a subsequent
metaregression did not identify any dose-response relationship for an opioid-sparing effect(Waldron 2013 Level I [PRISMA], 45 RCTs, n=5,796).
Systemic dexamethasone 4–40 mg improves quality of analgesia after spinal anaesthesia,
with reduced 24 h morphine consumption (6 RCTs, n=326) and prolonged time to first analgesia
request (Heesen 2019 Level I [PRISMA], 17 RCTs, n=1,133). Systemic 0.5 mg/kg andcaudal dexamethasone 0.1─0.2 mg/kg doubles to triples the duration of analgesia from caudal
blockade after paediatric surgery to a similar extent (Chong 2018 Level I [PRISMA], 14 RCTs, n=1,315).

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Orthopaedic surgery
After THA and TKA, glucocorticoids in a dose greater than 0.1 mg/kg dexamethasone equivalent
seem to be required to achieve reduction of PONV and pain severity within the first 24 h only
(Yue 2017 Level I, 11 RCTs, n=774); in addition, systemic steroids are associated with fasterfunctional rehabilitation and greater inflammation control. This is supported by another parallelmeta-analysis of elective primary THA with perioperative glucocorticoid administration(dexamethasone 8 to 40 mg, methylprednisolone 125 mg or hydrocortisone 200 mg) (Li 2017cLevel I, 6 RCTs, n=449).
In patients undergoing elective TKA, perioperative dexamethasone 5─10 mg
administration decreases postoperative pain scores at 12, 24, and 48 h, and decreases opioid
consumption up to 12 h only vs placebo or control (Zhou 2018 Level I, 6 RCTs, n=576 ). Similareffects are achieved with dexamethasone 10─40 mg in THA (Fan 2018 Level I [PRISMA] 3 RCTs,
n=207 ).
High-dose methylprednisolone (dexamethasone equivalent >10 mg), but not low-dose
systemic perioperative corticosteroid administration improves analgesia in patients undergoing
elective knee or hip surgery (Lunn 2013 Level I [PRISMA], 17 RCTs [15 vs placebo], n=1,081). Afterorthopaedic surgery, there was no difference in the analgesic effect of IV methylprednisolone
125 mg vs IV ketorolac 30 mg, with both being better than placebo; IV methylprednisolone led
to greater opioid-sparing but there was no difference in the incidence of adverse effects(Romundstad 2004 Level II, n=75, JS 5).
Tonsillectomy
Dexamethasone in doses >10 mg over 24 h given to adults undergoing tonsillectomy appears
to decrease postoperative pain, an effect further improved by repeated administration in
the postoperative period ( Diakos 2011 Level I, 7 RCTs, n=580 ). This has been confirmed by asubsequent meta-analysis, which shows pain reduction by 23% at 4 h (MD -1.4/10; 95% CI-1.6 to -1.2) (Tolska 2019 Level I [PRISMA], 10 RCTs [dexamethasone], n=590 ) (6 RCTs overlap ).
In a mixed meta-analysis of tonsillectomy in adults and children, all steroids reduce pain
severity at all time points up to 7 d with a peak benefit on POD 1 (SMD -0.99/10; 95%CI -1.32 to-0.67) (41 RCTs, n=3,477) (Titirungruang 2019 Level I [PRISMA], 64 RCTs, n=6,327) (8 RCTs overlap with
Tolska 2019). These effects are similar for systemic vs local steroid administration. Furthermore,
steroids reduce PONV (OR 0.31; 95%CI 0.24 to 0.40) (46 RCTs, n=4,784), while not increasing therisk of primary (OR 0.96; 95%CI 0.55 to 1.67) (15 RCTs, n=1,736) or secondary haemorrhage (OR1.05; 95%CI 0.74 to 1.51) (23 RCTs, n=2,440).
Thyroidectomy
Dexamethasone in adults undergoing thyroidectomy reduces postoperative pain scores andanalgesic requirements vs control (Chen 2012 Level I [PRISMA], 5 RCTs, n=497) and the need for
rescue analgesia vs placebo (Zou 2014 Level I, 13 RCTs, n=2,180). Only higher dose dexamethasone(8 to 10 mg) appeared to confer this analgesic benefit.
Maxillofacial surgery
Similarly, after maxillofacial surgery, the perioperative administration of corticosteroids(dexamethasone equivalent >5 mg) results in significant analgesic effects vs placebo in addition
to decreased swelling (Dan 2010 Level I, 12 RCTs, n=574).
In rhinoplasty surgery, dexamethasone/pregabalin showed significant analgesic benefits up
to 24 h vs placebo/pregabalin vs placebo/placebo (Demirhan 2013 Level II, n=60, JS 3).

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Other surgery
In lumbar disc surgery, PO dexamethasone 16 mg preoperatively reduced pain with mobilisationin the first 24 h postoperatively vs placebo (Nielsen 2015b Level II, n=160, JS 5).
After mixed ambulatory surgery, ketorolac provided better pain relief than either
dexamethasone or betamethasone in the immediate postoperative period but there were nodifferences in pain relief or analgesic use in the 4 to 72 h period after surgery (Thagaard 2007
Level II, n=179, JS 5).
A combination of dexamethasone/gabapentin provided better pain relief and led to less
PONV than either medicine given alone after varicocoele surgery; both the combination and theindividual medicines were more effective than placebo (Koç 2007 Level II, n=80, JS 5). In contrast,
there was no difference in pain scores or PCA-morphine requirements during the first 24 h
postoperatively in patients given pregabalin, dexamethasone/pregabalin or placebo after
hysterectomy (Mathiesen 2009 Level II, n=116, JS 5).
Nonetheless, not all of the procedure-specific trials demonstrate benefit. Dexamethasone
0.1 mg/kg did not decrease the severity of pain nor opioid consumption up to 72 h in patients
undergoing thoracotomy vs placebo (Joung 2018 Level II, n=40, JS 4). Likewise, in patients undergoing
elective bowel surgery, dexamethasone 8 mg did not improve the quality of recovery, fatigue nor
pain severity at 120 h postoperatively vs control (Dreams Trial Collaborators 2017 Level II, n=1,350, JS
5). When added to a multimodal analgesic combination including intrathecal morphine for
Caesarean section under spinal anaesthesia, dexamethasone 8 mg did not decrease opioid
consumption up to 24 h postoperatively (Ituk 2018 Level II, n=52, JS 4).
After breast augmentation, IV methylprednisolone 125 mg and IV parecoxib 40 mg
provided comparable analgesia; however, PONV and fatigue scores were lower in the patients
given methylprednisolone ( Romundstad 2006 Level II, n=204, JS 4). In cardiac surgery, IV
methylprednisolone 250 mg at induction and repeated immediately prior to cardiopulmonary
bypass did not reduce the incidence of delirium nor improve the quality of recovery vs placebo(Royse 2017 Level II, n=555, JS 5). Oral prednisolone 50 mg preoperatively did not improve pain,
fatigue, nausea or vomiting in patients undergoing laparoscopic cholecystectomy vs placebo(Bisgaard 2008 Level II, n=200, JS 3). In total abdominal hysterectomy, methylprednisolone 125mg
did not confer analgesic benefit vs placebo (Aabakke 2014 Level II, n=49, JS 4).
Sore throat
Corticosteroids administered in a single dose (most commonly PO dexamethasone 10 mg)
provide pain relief for sore throat including pharyngitis more effectively and faster than placebo(8 RCTs, n=907) (Sadeghirad 2017 Level I, 10 RCTs, n=1,426).
Dexamethasone 0.1─0.2 mg/kg decreases incidence (9 RCTs, n=983) and severity (4 RCTs,
n=431) of sore throat after extubation when administered IV at induction vs placebo (Kuriyama
2019 Level I, 15 RCTs, n=1,849).
Acute gout
In acute gout, corticosteroids provide similar analgesic effects to non-corticosteroid treatments(Liu 2017b Level I [PRISMA], 7 RCTs, n=929).
4.12.1.2 | Adverse effects
The principal safety concerns of perioperative corticosteroid administration relate to thedevelopment of hyperglycaemia, increased infection and bleeding risk and the risk of recurrenceof malignancy (Ali Khan 2013 NR; Yee 2013a NR; Turan 2011 NR; Ho 2011 NR).
Two meta-analyses have examined these safety issues with similar conclusions, althoughwith significant methodological differences and including all corticosteroids ( Toner 2017 Level I,

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11 RCTs [hyperglycaemia], n=685; Polderman 2018 Level I [Cochrane], 38 RCTs, n=4,931) (17 RCTs
overlap). However, the RCTs summarised in these meta-analyses are essentially efficacy studiesof the antiemetic and anti-inflammatory effects of dexamethasone. Few trials have examined
long-term effects or patient outcomes and those that have, were not adequately powered to do
so. In consequence, a large RCT (PADDI) has completed recruitment, the results of which willaddress many of the safety issues relating to the administration of intraoperative
dexamethasone (Corcoran 2019 Trial Protocol, n=8,880).
Hyperglycaemia
In non-cardiac surgical patients, glucocorticoids increase blood glucose concentrations (WMD
1.1 mmol/L; 95%CI 0.6 to 1.6) up to 12 h postoperatively (Toner 2017 Level I, 11 RCTs
[hyperglycaemia], n=685 ). When only trials which excluded patients with diabetes were
examined, the observed increase in blood glucose is smaller (WMD 0.7 mmol/L). These findings
are confirmed by the subsequent meta-analysis of dexamethasone only, which finds a similar
increase in non-diabetic patients ( 10 RCTs, n=595) and a more pronounced increase(1.8 mmol/L) in diabetic patients (2 RCTs, n=74) (Polderman 2018 Level I [Cochrane], 38 RCTs,
n=4,931).
A large dose of dexamethasone (1 mg/kg at induction) in cardiac surgery patients, notexcluding diabetic patients, resulted in a higher maximum postoperative blood-glucose
concentration (MD 0.9 mmol/L) vs placebo (Dieleman 2012 Level II, n=4,494, JS 5). As all patients
received glucose-lowering therapy in the ICU postoperatively, the dexamethasone effect may
have been mitigated.
Infection risk
The administration of dexamethasone to patients undergoing surgery is not associated with anincrease in the risk of any infection (OR 1.01; 95%CI 0.80 to 1.27) (Polderman 2018 Level I [Cochrane](27 RCTs [infection], n=4,931]). This is also shown for all corticosteroids (OR 0.9; 95%CI, 0.6 to 1.3)
(Toner 2017 (Level I [PRISMA], 18 RCTs [infection], n=2,138). There is also no increase in impaired
wound healing or anastomotic leakage.
In cardiac surgery, a single intraoperative high dose of dexamethasone (1 mg/kg) did not
significantly increase the incidence of postoperative wound infection; there was actually areduction in total infection complications, due mainly to a reduction in pneumonia (Dieleman 2012
Level II, n=4,494, JS 5).
Bleeding risk
Perioperative corticosteroids do not increase the risk of postoperative haemorrhage in noncardiac surgery (OR, 1.4; CI, 0.7 to 2.7) (Toner 2017 (Level I [PRISMA], 18 RCTs [bleeding], n=2,138).
Specifically, in paediatric tonsillectomy dexamethasone does not increase the overall
bleeding risk; however, its use increases the need for operative intervention for bleeding (Plante2012 Level I, 29 RCTs, n=2,674).
See paediatric section 10.4.10.3 for details of corticosteroid effects on bleeding risk.
Malignancy recurrence
There are limited and contradictory results on recurrence of malignancy; after colorectal surgery
there was an increase in one small RCT (Singh 2014 Level II, n=43, JS 4), while a propensity-matchedstudy failed to confirm such an association following ovarian cancer surgery (De Oliveira 2014b
Level III-2, n=260).

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KEY MESSAGES
1. Mild increase in blood glucose concentration follows perioperative administration of
dexamethasone (S) (Level I [Cochrane Review]) and all corticosteroids (S) (Level I[PRISMA), particularly in patients with diabetes mellitus.
2. Perioperative administration of dexamethasone (N) (Level I [Cochrane Review]) and all
corticosteroids (N) (Level I [PRISMA]) does not increase the risk of infection.
3. Perioperative administration of dexamethasone reduces postoperative pain and opioid
requirements to a limited extent but also reduces nausea and vomiting, fatigue, andimproves the quality of recovery compared with placebo (U) (Level I [PRISMA]).
4. Preoperative dexamethasone appears to be more effective than intraoperative or
postoperative administration (U) (Level I [PRISMA]).
5. Perioperative corticosteroids do not increase the risk of impaired wound healing,
anastomotic leakage or postoperative haemorrhage (N) (Level I [PRISMA]).
6. A single dose of corticosteroids provides more effective and faster relief of pain fromsore throat than placebo (N) (Level I) and decreases incidence and severity of sorethroat after extubation when administered at induction (N) (Level I [PRISMA]).
7. Systemic dexamethasone reduces pain intensity and opioid requirements after spinal
anaesthesia (N) (Level I [PRISMA].
The following tick box represents conclusions based on clinical experience and expert
opinion: As all adverse event data on corticosteroid use in surgical populations are based to dateon efficacy trials (with methodological differences), their long-term safety awaits further
evaluation (N).

4.12.2 | Regional corticosteroids
4.12.2.1 | Neuraxial
Caudal 0.1 to 0.2 mg/kg and IV dexamethasone (mostly 0.5 mg/kg) doubles to triples theduration of analgesia from caudal blockade after paediatric surgery to a similar extent (Chong2018 Level I [PRISMA], 14 RCTs, n=1,315).
Dexamethasone when added to bupivacaine/fentanyl solution in epidural analgesia
prolonged duration of analgesia in abdominal or thoracic surgery (372 min ± 58.1 vs 234.6 min ±24.3) and decreased opioid requirements in the first 24 h ( Naghipour 2013 Level II, n=72, JS 5). In
patients having lower abdominal surgery, single-dose epidural bupivacaine/dexamethasone had
similar prolongation of time to first analgesia, opioid-sparing and antiemetic effects asbupivacaine/fentanyl when compared with epidural bupivacaine alone ( Khafagy 2010 Level II,
n=90, JS 5). Preoperative single-dose epidural administration of dexamethasone, with or without
bupivacaine, reduced postoperative pain and morphine consumption following laparoscopiccholecystectomy (Thomas 2006 Level II, n=94, JS 5). Epidural dexamethasone/ropivacaine reduced
postoperative pain in patients undergoing gastrectomy under epidural analgesia vs ropivacaine
alone in a dose-dependent way with 10 mg superior to 5 mg (Hong 2017 Level II, n=120, JS 5). Use218

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of epidural methylprednisolone resulted in no difference in morphine requirements or painscores following thoracotomy vs epidural saline (Blanloeil 2001 Level II, n=24, JS 4).
Epidural corticosteroids (triamcinolone, methylprednisolone or dexamethasone) applied by
the surgeons intraoperatively for microdiscectomy or laminectomy reduce pain at 24 h and1 mth postoperatively, as well as opioid requirements and hospital LOS vs placebo (Wilson-Smith
2018 Level I [PRISMA], 17 RCTs, n=1,727; Arirachakaran 2018 Level I [PRISMA], 12 RCTs, n=1,006) (10 RCTs
overlap). There is no difference in complications; a meta-analysis looking specifically forcomplications found no significant difference in overall complications (RR 1.94; 95%CI 0.72 to5.26) nor infectious complications (RR 4.58; 95%CI 0.75 to 27.95) (Akinduro 2015 Level III-2 SR, 16
RCTs & 1 study, n=1,933).
Lumbar epidural steroid injections (ESI) for acute sciatica provide small but significant shortterm relief (≤3 mth) from acute radicular pain (MD -6.2/100; 95%CI -3.0 to -9.4) and reduce
disability but do not provide significant longer-term benefits beyond this time (Pinto 2012 Level I,
23 RCTs, n=2,334). Results specifically for transforaminal ESI vs saline or local anaesthetic aresimilar, with modest but significant pain reduction at 3 mth (MD−0.97/10; 95% CI −1.42 to −0.51)
but no benefit on disability or need for later surgery ( Bhatia 2016 Level I [PRISMA] 8 RCTs, n=771)(4 RCTs overlap).
Several meta-analyses overlapping for multiple studies with each other and the above haveanalysed specific questions. ESI is superior to saline (6 RCTs) with regard to improved function
and pain control and superior to local anaesthetic with regard to improved pain control (2 RCTs),
but these findings are only maintained at 1 mth with no significant long-term advantage (Lee2018a Level I, 14 RCTS, n=1,502). Fluoroscopically guided lumbar ESI provide significant short-term
improvement of radicular pain caused by lumbar disc herniation and stenosis, but not for axial
back pain, based on low-quality evidence (Sharma 2017 Level IV SR, 41 studies, n unspecified). Nonimage guided ESI provides inferior short-term improvement based on low-quality evidence andshould only be performed if image-guidance is not available (Vorobeychik 2016 Level IV SR,
39 studies, n unspecified). Transforaminal ESI compared to interlaminar ones result in better shortterm pain control (2 to 4 wk) based on weak evidence with no other significant benefits (Lee2018c Level III-2 SR, 10 RCTs & 2 studies, n=876). There is no significant difference between
transforaminal and caudal ESI based on very weak evidence ( Lee 2018b Level III-2 SR, 4 RCTs &2 studies, n=567). Preganglionic (supraneural, retrodiscal) ESI increases the chance ofeffectiveness vs postganglionic injection (Pairuchvej 2018 Level III-2 SR, 3 RCTs & 1 study, n=412).
Particulate steroids compared to non-particulate ones result in statistically significant, butclinically questionable improved pain control (MD -0.53/10; 95%CI -0.14 to -0.92) (Makkar 2016
Level III-2 SR, 4 RCTs & 3 studies, n=4,398). For fluoroscopically guided cervical transforaminal
epidural steroid injections, the response rate for <50% pain reduction is 48% (95%CI 34 to 61%)
at 1 mth (5 studies, n=164) and 62% (95%CI 49 to 75%) at 3 mth (4 studies, n=259), based on very
low-quality studies with no control group comparison (Conger 2020 Level IV SR [PRISMA], 17 studies,n unspecified).
The FDA issued a warning in April 2014 that injection of corticosteroids into the epiduralspace of the spine may result in rare but serious adverse effects, including loss of vision, stroke,paralysis and death (FDA 2014a GL). These concerns have been subsequently addressed in a
number of consensus statements by multiple organisations (Rathmell 2015 GL; Kennedy 2015 GL).
Recommendations particularly address image-guidance and use of particulate vs non-particulate
steroids and have led to subsequent discussions in the literature.
Furthermore, repeat ESI (mean 1 to 14.7 injections with cumulative methyl-prednisolone
equivalent doses of 80 to 8,130 mg) are associated with reduced bone mineral density andincreased risk of vertebral fractures (Kerezoudis 2018 Level IV SR, 8 studies, n=7,233).

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4.12.2.2 | Perineural sites
When compared with local anaesthetic PNB alone, the addition of dexamethasone 4─10mg tolocal anaesthetic prolongs the duration of sensory block (MD 6.70 h; 95%CI 5.54 to 7.85), andreduces postoperative pain intensity at 12 h (MD -2.08/10; 95%CI -2.63 to -1.53) and 24 h (MD 1.63/10; 95%CI -2.34 to -0.93) (Pehora 2017 Level I [Cochrane], 35 RCTs, n=2,702). Another metaanalysis has similar results for analgesia outcomes and also finds a decrease in PONV (RR 0.36;
95%CI 0.19 to 0.70) (Huynh 2015 Level I [PRISMA], 12 RCTs, n=1,054) (9 RCTs overlap). Specifically inbrachial plexus block, there were similar findings for dexamethasone 1─10 mg, with low quality
evidence of a ceiling effect of dexamethasone at 4 mg (Kirkham 2018 Level I [PRISMA],
33 RCTs, n=2,138) (23 RCTs overlap with Pehora 2017). The effect on duration of sensory block is more
pronounced with bupivacaine (MD 4.0 h; 95%CI 2.8 to 5.2) (4 RCTs, n=429) than with ropivacaine(MD 2.0 h; 95%CI -0.5 to 4.5 h) (5 RCTs, n=357) (Baeriswyl 2017 Level I [PRISMA], 11 RCTs, n=914) (10
RCTs overlap with Pehora 2017).
IV dexamethasone vs placebo (8 RCTs, n=499) increases the duration of sensory block (MD6.21 h; 95%CI 3.53 to 8.88) and reduces postoperative pain intensity at 12 h (MD -1.24/10; 95%CI-2.44 to -0.04) and 24 h (MD -1.26/10; 95% CI -2.23 to -0.29) as well as postoperative opioid
consumption to 24 h (MD -6.58 mg; 95% CI -10.56 to -2.60) (Pehora 2017 Level I [Cochrane], 35 RCTs,
n=2,702).
Perineural vs IV dexamethasone (9 RCTs, n=720) increases the duration of sensory block (MD3.14 h; 95%CI 1.68 to 4.59), but improves analgesia only in a clinically insignificant way and has
no opioid-sparing effect (Pehora 2017 Level I [Cochrane], 35 RCTs, n=2,702). However, a subsequentmeta-analysis using the Hartung-Knapp-Sidik-Jonkman (HKSJ) methodology, which the authors
claim to provide a more conservative estimate of effect, does not confirm the extended durationof sensory block with perineural vs IV dexamethasone 4─10mg (Hussain 2018 Level I, 14 RCTs,
n=1,007) (9 RCTs overlap).
Adding dexamethasone 4 mg perineurally as an adjuvant to saphenous nerve block increased
the duration of analgesia vs placebo (Bjorn 2017 Level II, n=40, JS 5). However, time to first rescue
analgesia was similar with dexamethasone 4 mg perineurally for an ankle block vs IV 10 mg
administration (Marty 2018 Level II, n=100, JS 5). Dexamethasone 8 mg/bupivacaine versus IM
dexamethasone 8 mg for sciatic and ankle blocks improved pain scores at 24 h in the sciatic grouponly, but conferred no other analgesic benefits in either group (Fredrickson 2013 Level II, n=126, JS 5).
Perineural dexamethasone 4 to 8 mg for TAPB prolongs sensory block duration (MD 2.98 h;
95%CI 2.19 to 3.78) and reduces pain scores at 2, 6 and 12 h postoperatively (Chen 2018b
Level I [PRISMA] 9 RCTs, n=575). It also reduces systemic analgesic consumption (SMD -1.29; 95%CI-1.88 to -0.70) and PONV incidence (OR 0.28; 95%CI 0.16 to 0.49) on POD 1.
Dexamethasone 8 mg/bupivacaine vs bupivacaine alone for thoracic paravertebral block
improved analgesia and duration of analgesia in patients undergoing nephrectomy (Tomar 2017
Level II, n=60, JS 4).
Further addition of dexamethasone 8 mg to local anaesthetics for scalp nerve blocks in thesetting of perioperative systemic dexamethasone therapy did not prolong duration of the block(Jose 2017 Level II, n=90, JS 5).
Although perineural dexamethasone has been shown to prolong sensory and motor block ofperineural local anaesthetics, there is little safety data to support its use. Animal data to date arereassuring, with dexamethasone not increasing ropivacaine-induced sensory nerve toxicity atclinically relevant concentrations (Williams 2011 BS) and dexamethasone attenuatingbupivacaine-induced neuronal injury (Ma 2010 BS). In a meta-analysis, although underpoweredfor complications, there is no difference in complications or nerve injury (10 RCTs, n=763) (Hussain
2018 Level I, 14 RCTs, n=1,007). However, given the lack of human safety data, the practice of220

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perineural dexamethasone administration needs to be further evaluated ( Rahangdale 2014 NR).
Furthermore, mixtures of ropivacaine and nonparticulate dexamethasone sodium phosphatedemonstrated a pH-dependent crystallisation and the use of such combinations may be notadvisable (Watkins 2015 BS).
4.12.2.3 | Peripheral sites
Periarticular injection of combinations of local anaesthetic, opioid and anti-inflammatory agentsincluding steroids have been studied (LIA), however the range of mixtures makes determinationof the effect of individual components difficult. In patients having simultaneous bilateral TKAs,
bupivacaine/fentanyl/methylprednisolone were infiltrated by the surgeon around one knee but
not the other (Mullaji 2010 Level II, n=40, JS 4). Pain scores on the infiltrated side were significantly
lower and the joint had greater active flexion up to 4 wk and superior quadriceps recovery up to
2 wk after surgery vs the noninfiltrated knee. Periarticular injection of a mixture ofbupivacaine/morphine/adrenaline/clonidine showed a reduced hospital LOS by 24 h without any
significant effect on pain relief, motion or function following TKA, when methylprednisolone wasadded (Christensen 2009 Level II, n=76, JS 4). In comparing ropivacaine/adrenaline in three groups
with no added steroid, triamcinolone 40 mg and 80 mg, the addition of corticosteroid toperiarticular injection of local anaesthetic did not improve pain relief or range of movement
outcomes for up to 12 wk of follow-up (Chia 2013 Level II, n=126, JS 5).
Intra-articular (IA) corticosteroid injections would be expected to have a direct analgesic
effect in inflammatory arthropathies. Following knee joint arthroscopy, IA steroids were more
effective than placebo in reducing pain, analgesic consumption and duration of immobilisation,either alone (Wang 1998 Level II, n=60, JS 4) or in conjunction with opioids (Kizilkaya 2005 Level II,
n=72, JS 4; Kizilkaya 2004 Level II, n=60, JS 2) and/or local anaesthetics (Moeen 2017, Level II, n= 60,
JS 5; Rasmussen 2002 Level II, n=60, JS 3). Dexamethasone on its own was less effective thanpethidine or fentanyl (Saryazdi 2006 Level II, n=48, JS 3). A single IA injection of methylprednisolone
one wk before TKA did not reduce acute postoperative pain (Luna 2017 Level II, n=48, JS 4). Theremay be a higher risk of septic arthritis with IA steroids (Armstrong 1992 Level IV, n=4,256).
Subacromial injections of corticosteroids have been shown to be effective in treating rotator
cuff tendonitis for up to 9 mth vs placebo (NNT 3.3; 95%CI 1.8 to 7.7) and are superior to oral
NSAIDs (NNT 2.5; 95%CI 1 to 9) (Arroll 2005 Level I [QUOROM], 7 RCTs, n=347). In patients withtendonitis of the shoulder or elbow, steroid injections show similar benefits to NSAIDs for early(up to 1 wk) pain relief (Gaujoux-Viala 2009 Level I, 20 RCTs, n=1,731).
In patients having hand surgery, IVRA using a combination of lidocaine/dexamethasone
resulted in lower pain scores and lower analgesic requirements for 24 h vs lidocaine alone or
lidocaine IVRA with IV dexamethasone in the nonoperative arm (Bigat 2006 Level II, n=75, JS 2). The
addition of dexamethasone to lidocaine/ketorolac IVRA for hand surgery improved
intraoperative tourniquet tolerance and postoperative analgesia vs lidocaine IVRA alone (Jankovic
2008 Level II, n=45, JS 3).

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KEY MESSAGES
1. For brachial plexus blocks, addition of dexamethasone to local anaesthetic prolongs theduration of sensory and motor block and improves postoperative analgesia with only
very limited benefits over systemic administration (S) (Level I [Cochrane Review]).
2. For transverse abdominis plane blocks, addition of dexamethasone to local
anaesthetics prolongs the duration of sensory block, improves postoperative analgesia
and PONV with no comparison to systemic administration (N) (Level I [PRISMA]).
3. After spinal surgery, epidural steroid application intraoperatively by the surgeon
provides analgesic benefit up to 24 hours and reduces length of stay (N) (Level I[PRISMA]).
4. For acute radicular pain, lumbar epidural corticosteroid administration is effective forshort-term relief (S) (Level I [PRISMA]).
5. Subacromial injections of corticosteroids are superior to oral NSAIDs in treating rotator
cuff tendonitis (U) (Level I [QUOROM]).
6. For peripheral nerve blocks, addition of dexamethasone to local anaesthetics prolongs
the duration of sensory block and improves postoperative analgesia with only limited
benefits over systemic administration (N) (Level II).
7. For epidural analgesia, addition of dexamethasone improves postoperative analgesia
and reduces opioid requirements (N) (Level II).
8. Addition of dexamethasone to intravenous regional anaesthesia with lidoocaine
improves analgesia for up to 24 hours (U) (Level II).
9. Addition of corticosteroid to periarticular injection of local anaesthetic does not improvepain relief or range of movement following total knee arthroplasty (U) (Level II).
10. Following knee joint arthroscopy, intra-articular steroids in combination with either
local anaesthetic or opioids reduce pain, analgesic consumption and duration of
immobilisation (U) (Level II).
11. There is a risk of septic arthritis with intra-articular steroids (U) (Level IV).
12. Repeat epiudural steroid injections are associated with reduced bone mineral density
and increased risk of vertebral fractures (N) (Level IV SR).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Concerns have been raised regarding the safety of epidural steroids (U).
 There is little data in humans regarding the neurotoxicity of perineural corticosteroids (N).

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4.13 | Other regional analgesic medicines
4.13.1 | Midazolam
Preservative-free midazolam has been proposed as a spinal analgesic due to its action on GABA A
receptors. Robust safety data for the use of intrathecal (IT) midazolam in humans is lacking ( Yaksh2017 NR), consequently midazolam is currently not licenced for IT use. Several studies in animalmodels have raised concern about IT midazolam toxicity (Williams 2011 BS; Lavand'homme 2006 NR;
Yaksh 2004 NR; Erdine 1999 BS; Malinovsky 1991 NR). However, cumulative experience with IT
midazolam in human trials confirms beneficial analgesic activity with no demonstrable
irreversible side effects vs placebo (Ho 2008 Level I, 13 RCTs, n=672; Yaksh 2017 NR; Staikou 2014 NR).
There is insufficient long-term data to unequivocally exclude long-term neurologicalcomplications, although none have yet been reported.
IT midazolam added to IT local anaesthetic in perioperative and peripartum patients incomparison with IT local anaesthetic alone shows a reduced incidence of nausea and vomiting
and delayed time to request for rescue analgesia (WMD 99 min; 95%CI 76 to 121), but did notaffect the duration of motor block (Ho 2008 Level I, 13 RCTs, n=672). Multiple subsequent RCTs haveconfirmed these findings as well as earlier onset and better quality of analgesia for addition of IT
midazolam to IT local anaesthetics vs IT local anaesthetic alone (Abdollahpour 2015 Level II, n=75,
JS 4; Selvaraj 2015 Level II, n=100, JS 3; Chattopadhyay 2013 Level II, n=90, JS 5; Shadangi 2011 Level II,
n=100, JS 4), compared to addition of IT dexmedetomidine (Shukla 2016 Level II, n=80, JS 3;
Samantaray 2015 Level II, n=60, JS 4) or IT fentanyl (Codero 2016 Level II, n=40, JS 3; Safari 2012 Level II,
n=90, JS 3) and also when added to IT fentanyl (Gupta 2015 Level II, 75 patients, JS 4) or IT sufentanil(Salimi 2014 Level II, n=80, JS2). In addition, IT midazolam decreased the incidence of transientneurologic symptoms with IT lidocaine (Selvaraj 2015 Level II, n=100, JS 3). Overall, an optimum

dose of IT midazolam has not been clearly determined; doses less than 1 mg probably have noeffect on prolongation of spinal blockade or analgesia, and the commonly effective doses
administered in clinical trials range between 1 to 2 mg (Staikou 2014 NR). On the basis of the abovemeta-analyses, reviews and trials, IT midazolam may cause mild, but not excessive sedation, no
additional cardio-respiratory adverse effects or urinary retention.
Specific to the obstetric population, IT midazolam does not seem to have any deleterious
effect on infants' Apgar scores (Abdollahpour 2015 Level II, n=75, JS 4). IT midazolam 1 mg as a partof combined spinal epidural technique in pre-eclamptic parturients undergoing elective
Caesarean section is inferior to IT preservative free magnesium sulphate 50 mg with regard to
prolongation of analgesia (Paleti 2018 Level II, n=50, JS 4; Sapna 2013 Level III-2, n=124).
A single preoperative epidural dose of midazolam combined with ketamine in patients having
a gastrectomy improved analgesia and prolonged the time to rescue analgesia vs epidural
ketamine or placebo, with no significant adverse effects (Wang 2006 Level II, n=44, JS 4). Midazolam
added to bupivacaine for epidural infusion improved analgesia but increased sedation (Nishiyama
2002 Level II, n=100, JS 1).
Midazolam has been added to caudal epidural analgesia in paediatric surgery, although agerelated toxicity issues have not been addressed. In combination with bupivacaine, it prolongs
postoperative analgesia (Kumar 2005 Level II, n=80, JS 5; Ansermino 2003 Level I, 2 RCTs [midazolam],n=60). In infants having hernia repairs, neither midazolam nor fentanyl added to bupivacaine forcaudal anaesthesia improved postoperative analgesia or recovery ( Baris 2003 Level II, n=75, JS 4).

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4.13.2 | Neostigmine
Neostigmine acts as a spinal analgesic by potentiation of muscarinic cholinergic activity. In aliterature review of animal and human studies, there was no evidence of neurotoxicity withspinal neostigmine (Hodgson 1999 NR).
4.13.2.1 | Neuraxial
Adding neostigmine to local anaesthetics (bupivacaine or ropivacaine) ± opioid for neuraxial
administration in labour analgesia and postoperative analgesia after Caesarean section permits
reduction of local anaesthetic doses (MD -4.08 mg/h; 95% CI -6.7 to -1.5) (Cossu 2015 Level I, 16
RCTs, n= 1,186). Only IT neostigmine (5 RCTs), but not epidural neostigmine (11 RCTs), increases riskof nausea (OR 9; 95%CI 4.7 to 17.1). Neuraxial neostigmine reduces risk of pruritus (OR 0.4;
95%CI 0.2 to 0.7) (6 RCTs), but does not increase hypotension, sedation or affect fetal outcome.
4.13.2.2 | Intrathecal
IT neostigmine for perioperative and peripartum analgesia prolongs the time to first analgesia
request and results in a slight improvement in pain scores and a reduced need for rescue
medication, however, it increases nausea and vomiting (OR 5.0; 95%CI 3.4 to 7.3), bradycardia
requiring atropine (OR 2.7; 95%CI 1.4 to 5.4) and anxiety, agitation and restlessness (OR 10.3;
95%CI 3.7 to 28.9) (Ho 2005 Level I, 19 RCTs, n=1,019) (4 RCTs overlap with Cossu 2015). The authors
conclude that the significant adverse effects outweighed any clinical benefit, a conclusion
supported by another systematic review, where a lack of a clear dose-response is also identified(Habib 2006 Level I, 17 RCTs [IT neostigmine], n unspecified) (15 RCTs overlap).
Subsequent RCTs not included in these meta-analyses support their findings in principle. In
patients having various types of surgery under spinal anaesthesia, IT neostigmine prolonged time
to first analgesic request (Kayalha 2015 Level II n=68, JS 4; Akinwale 2012 Level II, n=60, JS 4) and/or
effective postoperative analgesia (Kumari Vasantha 2018 Level II n=100, JS 4) and/or reduced
analgesic consumption (Jain 2012 Level II, n=45, JS 4).
In patients having spinal anaesthesia, IT clonidine 75 mcg had longer time to first analgesic
request (MD 62 min) but more hypotension during surgery vs IT neostigmine 50 mcg(Yoganarasimha 2014 Level II, n=50, JS 3). Both, IT clonidine 30 mcg and IT neostigmine 75 mcg
increased the duration spinal analgesia, but neostigmine caused more nausea and vomiting (Bhar2016 Level II, n=150, JS 4). In patients undergoing orthopaedic surgery under spinal anaesthesia,
IT dexmedetomidine 5 mcg was superior to IT neostigmine 50 mcg due to faster onset ofanaesthesia, better intra- and postoperative analgesia, and prolonged duration of motor andsensory blockade without significant increases in adverse effects (Singh 2017 Level II n=75, JS 4).
After elective gynaecological surgery under spinal anaesthesia, IT neostigmine extended
postoperative analgesia more than IT magnesium (Joshi-Khadke 2015 Level II, n=75, JS 4). After
surgery for tibial fracture under spinal anaesthesia, IT neostigmine 150 mcg/bupivacaine vs IT
fentanyl 25 mcg/bupivacaine and IT magnesium 50 mg/bupivacaine increased the incidence of
hypotension, bradycardia, and nausea and vomiting, and failed to prolong duration of analgesia(Mokaram Dori 2016 Level II, n=210, JS 4).
Adverse events of IT neostigmine seem to be dose-dependent. In patients undergoing lower
abdominal and lower limb surgery, IT neostigmine 150 mcg vs IT neostigmine 50 mcg as an
adjuvant to bupivacaine 12.5 mg caused more nausea and vomiting (Pandey 2016 Level II, n=75, JS 4).
IT neostigmine 75 mcg caused less nausea and vomiting than IT neostigmine 150 mcg when
added to spinal anaesthesia for Caesarean section (Hye 2010 Level II, n=90, JS 4). Very low-dose IT
neostigmine 1 mcg increased the duration of analgesia and decreased the analgesic consumption

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over 24 h post-TKA with no increase in the incidence of adverse effects including nausea orvomiting. (Jain 2012 Level II, n=45, JS 4).
4.13.2.3 | Epidural
Epidural neostigmine in the general surgical and obstetric populations improves postoperative
analgesia in most studies without increasing the incidence of adverse effects ( Habib 2006 Level I,
7 RCTs [epidural neostigmine], n unspecified). Epidural neostigmine combined with an opioid reduces
epidural opioid requirements but may not decrease opioid-related adverse effects vs the opioid
alone (Walker 2002 Level I, 6 RCTs [neostigmine], n=370).
See Section 10.6.3.1 for use of neostigmine in paediatric caudal epidural analgesia.
4.13.2.4 | Other
Intra-articular administration of neostigmine produces a useful analgesic effect in the
postoperative period and is not associated with an increase in the incidence of adverse effects(Habib 2006 Level I, 4 RCTs [intra-articular neostigmine], n unspecified).
Studies investigating the efficacy of adding neostigmine to the local anaesthetics used forbrachial plexus block and IVRA report conflicting results (Habib 2006 Level I, 4 RCTs [perineuralneostigmine], n unspecified).

4.13.3 | Botulinum toxin A
Botulinum toxin (botox) A is an exotoxin produced from clostridium botulinum (Sandrini 2017 NR;
Shilpa 2014 NR). Following direct IM injection, botulinum toxin A irreversibly binds to theacetylcholine receptor inducing chemical denervation with resultant dose-dependent muscularparalysis. The extent and duration of paralysis depends on the dose administered. Systemic
weakness may follow high cumulative doses. Reinnervation occurs over weeks to months.
Botulinum toxin A does not interfere with acute pain perception, nor does it cause local
anaesthesia. The use of botulinum toxin in the treatment of chronic painful conditions is beyond
the scope of this section.
In treating pain and related muscle spasm in a range of conditions, botulinum toxin A is
effective in reducing limb spasm (Son 2019 Level I, 27 RCTs, n=2,793; Dong 2017 Level I, 22 RCTs,
n=1,804), but evidence relating to spasticity-related pain remains uncertain (Baker 2013 Level I,
10 RCTs [in pain], n=971). In a range of neuropathic pain conditions (eg trigeminal neuralgia),
Botulinum toxin A reduces pain at 4 wk (MD -1.6/10; 95%CI -3.2 to -0.1), 12 wk (MD -1.5/10;
95%CI -2.1 to -0.9) and 24 wk (MD -1.6/10; 95%CI -2.8 to -0.4) (Meng 2018 Level I, 12 RCTs, n=495).
In subacute and chronic neck disorders with or without associated cervicogenic headache,
IM botulinum toxin A injections provide no clear benefit ( Langevin 2011 Level I [Cochrane], 9 RCTs,
n=503). There is insufficient evidence for the use botulinum toxin A for the treatment of rarehead and neck pain syndromes (cluster headache, chronic paroxysmal hemicrania, trigeminal
neuralgia) with varying results from only a few small sized trials (cervicogenic headache, chronicneck pain, temporomandibular disorders) (Sycha 2004 Level I, 15 RCTs, n=721).

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KEY MESSAGES
1. Intrathecal midazolam combined with a local anaesthetic improves and prolongs
analgesia and reduces postoperative nausea and vomiting (U) (Level I).
2. Intrathecal neostigmine improves perioperative and peripartum analgesia in
combination with other intrathecal medications (S) (Level I) but is associated withdose-dependent significant adverse effects, in particular nausea and vomiting (Q)(Level I).
3. Epidural neostigmine combined with local anaesthetics improves postoperative andperipartum analgesia without increasing the incidence of adverse effects (U) (Level I).
4. Epidural neostigmine combined with an opioid reduces the dose of epidural opioid thatis required for analgesia (U) (Level I).

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4.14 | Complementary and alternative medicine
Complementary and alternative medicine (CAM) is defined as healthcare practices outside theconventional dominant “orthodox” health system of Western industrialised society (Belgrade 2008
NR). The boundary between CAM and conventional medicine overlaps and changes with time. In
some cultures, these therapies may be considered conventional mainstream practices.
CAM may be classified into two groups: as natural products, including but not limited toherbs, vitamins, minerals and probiotics, vs mind and body practices such as yoga, meditation,
massage, acupuncture, tai chi, qi gong, chiropractic and osteopathic manipulation, hypnotherapy
and others (NCCIH 2018 GL). Ayurvedic medicine, traditional Chinese medicine, homeopathy andnaturopathy are considered CAM. CAM approaches are usually termed “alternative” when usedin place of conventional medical treatments and “complementary” when used together. Thissection covers the use of natural products administered as analgesic medicines for treatment of
acute pain only; good data on their use in this indication are limited.
See Section 10.11 for paediatric specific data.

4.14.1 | Vitamins
Several mechanisms have been described to explain the analgesic effect of Vitamin C (Carr 2017 NR).
Vitamin C reduces acute postoperative pain (Chaitanya 2018 Level IV SR [PRISMA], 4 RCTs &3 studies, n=12,395) and has moderate evidence for a reduction of postoperative morphine
consumption (Chen 2016 Level I [PRISMA], 7 RCTs [postoperative], n=854). In subsequent RCTs, oral
Vitamin C 1 g/d decreased postoperative pain score and rescue analgesia requirements after footand ankle surgery (Jain 2019 Level II, n=60, JS 5) and after major abdominal surgery vs placebo
where Vitamin C 2 g was comparable to melatonin 6 mg (Tunay 2020 Level II, n=165, JS 5). In acuteherpes zoster, concomitant Vitamin C infusion 5 g did not improve pain relief (Kim 2016 Level II,
n=87, JS 2).
Vitamin B complex (comprising of thiamine [B1], riboflavin [B2], pyridoxine [B6] andnicotinamide) reduced pain intensity and analgesic consumption after Caesarean section whencombined with gabapentin vs gabapentin alone (Khezri 2017 Level II, n=128, JS 4). Vitamin B
complex (thiamine, pyridoxine and hydroxo- or cyanocobalamin) when combined with ketorolac
15 mg was as effective as ketorolac 30 mg monotherapy after Caesarean section (Beltran-Montoya
2012 Level II, n=100, JS 3) or more effective when combined with diclofenac 50 mg in relieving
acute low back pain vs diclofenac monotherapy (Mibielli 2009 Level II, n=372, JS 5). Also in acutelow back pain, combination diclofenac/vitamin B complex TPC (thiamine, pyridoxine, andcyanocobalamin) provides greater analgesia vs diclofenac monotherapy (OR 2.23; 95%CI 1.59 to3.13) (Calderon-Ospina 2020 Level I, 4 RCTs, n=1,108). In patients with acute ophthalmic zoster,
Vitamin B 12 1,000 mcg/lidocaine 20 mg SC daily for 12 d into the regions of the affected
innervations of V1 achieved better pain relief vs controls (IM vitamin B 12, local lidocaine) (Xu
2016a Level II, n=98, JS 3; Xu 2016b Level II, n=204, JS 3).

4.14.2 | Herbal Medicines
A meta-analysis on oral homeopathic St John’s wort (Hypericum perforatum) showed nosignificant benefit on dental pain; the meta-analysis was limited by marked heterogeneity andpoor study quality (Raak 2012 Level I [QUOROM], 4 studies, n=325). A subsequent review on topicalapplication of Hypericum perforatum found studies on improved pain relief for acute otitis
media, herpes skin lesions and wound pain after Caesarean section and suggests that this may
be due to its anti-inflammatory effects (Galeotti 2017 NR). Oral Hypericum perforatum affects the
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metabolism of oxycodone through induction of cytochrome P450 3A (CYP3A) and leads to asignificant reduction of plasma concentration and half-life reducing efficacy (Nieminen 2010
Level II, n=12, JS 3).
Homeopathic preparations of Arnica montana (containing sesquiterpenes) in acutepostoperative pain have shown variable results. A systematic review and other studies concluded
that homeopathic arnica vs placebo is not effective for pain relief after orthopaedic surgery(Roberts 2012 Level I [PRISMA], 3 studies (arnica), n=181), hallux valgus surgery (Karow 2008 Level II,
n=88, JS 4) or abdominal hysterectomy (Hart 1997 Level II, n=93, JS 5). In contrast, homeopathic
arnica vs placebo reduced pain after tonsillectomy (Robertson 2007 Level II, n=190, JS 5) (althougha large number of patients in this study were lost to follow-up) and after varicose vein surgery(Wolf 2003 Level II, n=60, JS 5). A subsequent review (covering many of the studies above)
concluded that arnica in homeopathic dilutions has high tolerability and may have effects intreating inflammation (Iannitti 2016 NR). The authors argue that variations in formulation affects
the quantity of active sesquiterpenes and hence result in variable clinical effects. Traumeel S (anover-the-counter homeopathic highly diluted preparation of extracts from a combination ofplants [including arnica] and minerals) was also ineffective following foot surgery ( Singer 2010
Level II, n=80, JS 4).
A systematic review of the efficacy and safety of Damask rose (Rosa damascena Mill) suggests
safe use with some pain relief in acute settings (3 RCTs) (Nayebi 2017 Level I, 12 RCTs, n=748).
Although most of the studies compared topical or inhalational (aromatherapy) applications, one
study used oral extract with greater pain relief after Caesarean section vs placebo. The Damaskrose recipients also experienced a longer time to requesting rescue analgesia, with lower total
analgesic consumption (Gharabaghi 2011 Level II, n=92, JS 3).
Zingiberaceae include turmeric (Curcuma longa), ginger (Zingiber officinale), Javanese
ginger (Curcuma zanthorrhiza) and galangal (Alpinia galanga). Curcumin (diferuloyl methane)is the principal curcuminoid of Indian spice turmeric, while the anti-inflammatory components
of ginger are gingerol and zingerone. Extracts of Zingiberaceae reduce pain intensity in a mixof acute and chronic pain states (SMD -0.67; 95%CI -1.13 to -0.21) (Lakhan 2015 Level I [PRISMA],
8 RCTs, n=734). Curcuminoids are effective in reducing pain vs a pooled control group of placeboor NSAID (SMD -0.57; 95%CI -1.11 to -0.03), but not vs either placebo or NSAID in a mix ofacute and chronic pain states ( Sahebkar 2016 Level I [PRISMA], 8 RCTs, n=606) (2 RCTs overlap). The
effect was greater when a bioavailability enhancer such as piperine was administered (SMD 0.98; 95%CI -1.81 to -0.15); however, only three RCTs in the review evaluated the effectivenessof curcuminoids in acute pain and were not separately analysed. A combination nutritional
supplement containing Boswellia serrata (30% boswellic acid) and Curcuma longa (95%
curcuminoids) lowered pain and tramadol rescue requirements only in the first postoperative
wk after arthroscopic supraspinatus tendon repair vs placebo (Merolla 2015 Level II, n=104, JS 3).
A subsequent RCT found ginger powder 500 mg as effective as ibuprofen 400 mg and superior
to placebo with regard to pain relief and rescue analgesic requirements POD 1 in patients after
wisdom tooth extraction ( Rayati 2017 Level II, n=67, JS 4).
There is weak evidence for a reduction of rescue analgesia requirements (RR 0.5; 95%CI 0.1
to 2.1) with use of Damask rose (Rosa damascena) and ginger vs placebo after laparoscopic andobstetric/gynaecological surgery (Arruda 2019 Level III-1 SR [PRISMA], 10 RCTs & 1 study, n=693).
A transdermal preparation of Fenugreek seeds 10% (Trigonella foenum-graecum L.) applied
topically for open hernioplasty reduced pain intensity and rescue analgesics consumption vsplacebo patch and in the first 6 h vs diclofenac patch (Ansari 2019 Level II, n=90, JS 4).
Saffron (Crocus sativus) 250 mg as a syrup taken together orally with date-juice vs saffron
with artificial sugar and placebo reduced pain intensity and anxiety during labour in primiparous
women (Mohammadierad 2018 Level II, n=96, JS 5).

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Herbal medicines (White willow bark [Salix alba] and Devil’s claw [Harpagophytum
procumbens]) for non-specific low-back pain (a mix of acute, subacute and chronic back pain)
result in short-term improvement vs placebo (Gagnier 2016 Level I [Cochrane], 14 RCTs, n=2,050).
The review also reported on the effectiveness of several topical preparations of herbal plasterand ointment-based applications including Cayenne (Capsicum frutescens), Comfrey root extract(Symphytum officinale) and Brazilian arnica (Solidago chilensis). However, the quality of evidence
was poor. Side effects were usually mild and transient.
Herbal and dietary supplement combinations are commonly prescribed in CAM treatment.
A study using a mixture of homoeopathic preparations (arnica, Bryonia alba, Hypericum
perforatum, Ruta graveolens) did not show any benefit in postoperative pain relief and morphine
consumption after knee ligament reconstruction surgery (Paris 2008a Level II, n=158, JS 4). There isalso no clear evidence that the combination of oral arnica with Hypericum perforatum is effectivein pain relief after dental procedures (Galeotti 2017 NR). Another herbal combination consistingof anise (Pimpinella anisum), celery (Apium graveolens) and saffron (Crocus sativus) (referred toas PAC), had greater pain reduction and faster onset in patients with post-partum pain vsmefenamic acid in a single-blind study (Simbar 2015 Level II, n=108, JS 2).
Puerarin, a Chinese herb extract, was analgesic and anti-inflammatory for burns dressingchanges; however, the control group received no analgesia (Zhang 2013 Level II, n=32, JS 5).
Rhubarb combined with trypsin inhibitor versus trypsin inhibitor alone improved outcomesof acute pancreatitis including abdominal pain (Hu 2018b Level I, 16 RCTs, n=912).
Probiotics reduce the pain and symptom severity in IBS vs placebo (Didari 2015 Level I, 15 RCTs,
n=1,793).
For dysmenorrhoea, a Cochrane review investigated twelve different herbal medicines
German chamomile (Matricaria chamomilla, M recutita, Chamomilla recutita), cinnamon(Cinnamomum zeylanicum, C. verum), Damask rose (Rosa damascena), dill (Anethum
graveolens), fennel (Foeniculum vulgare), fenugreek (Trigonella foenum-graecum), ginger(Zingiber officinale), guava (Psidium guajava), rhubarb (Rheum emodi), uzara (Xysmalobium
undulatum), valerian (Valeriana officinalis), and zataria (Zataria multiflora) and five non-herbal
supplements (fish oil, melatonin, vitamins B1 and E, and zinc sulphate) in a variety of
formulations and doses (Pattanittum 2016 Level I [Cochrane], 27 RCTs, n=3,101). Very limited
evidence of effectiveness vs placebo or no treatment was found for fenugreek (1 RCT, n=101), fishoil (1 RCT, n=120), fish oil plus vitamin B1 (1 RCT, n=120), ginger (4 RCTs, n=335), valerian (1 RCT,
n=100), vitamin B1 alone (1 RCT, n=120), zataria (1 RCT, n=99), and zinc sulphate (1 RCT, n=99). Verylimited evidence was found that chamomile was more effective than NSAIDs (1 RCT, n=160), while
no difference vs NSAIDs was found for dill (1 RCT, n=47), fennel (1 RCT, n=59), guava (1 RCT, n=155),
rhubarb (1 RCT, n=45), valerian (1 RCT, n=99) and Damask rose (1 RCT, n=92). Comparisons between
CAM for dysmenorrhoea showed that Vitamin B1 may be more effective than fish oil(1 RCT, n=120). Subsequent systematic reviews emphasise again the limited quality of theevidence, the high risk of bias and the difficulties to draw definitive conclusions on efficacy. One
systematic review analysed results for fennel (Foeniculum vulgare) (4 RCTs, n=295), chamomile(Matricaria chamomilla) (3 RCTs, n=220) and zataria (Zataria multiflora) (3 RCTs, n=302) (Sharghi
2019 Level I, 17 RCTs, n=1,656). Another identified only one RCT with low risk of bias to beconsidered supportive evidence for use of Damask rose (Rosa damascena) (Pellow 2018 Level I[PRISMA], 22 RCTs, n=1,937).

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4.14.3 | Aromatherapy
Aromatherapy describes the inhalation (or sometimes administration to the skin) of essential oils
as part of herbal medicine, possibly affecting emotions through the neuroendocrine andautonomic nervous system.
Aromatherapy (oil inhalation and oil massage) reduces pain of dysmenorrhoea vs notreatment or placebo treatment; however, there is a high risk of bias weakening these results(Lee 2018d Level III-1 SR, 19 studies, n=1,787; Song 2018 Level III-3 SR [PRISMA], 9 RCTs & 12 studies,
n=1,580) (13 studies overlap).
There is no sufficient evidence to support the use of aromatherapy for the treatment of
postoperative pain (Dimitriou 2017 Level I, 9 RCTs, n=644).
Aromatherapy may reduce pain, anxiety and improve sleep quality in burns patients, but the
low quality of trials with regard to randomisation and bias does not permit a conclusion (Choi2018 Level I [PRISMA], 4 RCTs, n=248). The addition of aromatherapy (lavender) to standard
treatment of renal colic with parenteral diclofenac improved pain scores at 30 min, but only infemale patients (Irmak Sapmaz 2015 Level II, n=100, JS 0).

4.14.4 | Melatonin
An experimental study on volunteers observed a dose dependent effect on pain threshold andpain tolerance after sublingual melatonin 0.15 mg/kg or 0.25 mg/kg vs placebo (Stefani 2013
Level II EH, n=61, JS 5). Two preoperative melatonin doses of 5 mg led to lower pain and anxiety
scores in the first 24 h (NNT 2.20 and 2.53) and reduced IV PCA morphine usage after abdominal
hysterectomy (Caumo 2007 Level II, n=35, JS 5). Melatonin 6 mg vs Vitamin C 2 g both reduced pain
and patient-controlled morphine consumption and supplementary doses of diclofenac inpatients after major abdominal surgery vs placebo (Tunay 2020 Level II, n=165, JS 5). Melatonin
reduced pain during blood taking in children vs placebo (Marseglia 2015 Level II, n=60, JS 5).

4.14.5 | Honey
Oral administration of honey has been associated with improved pain relief ( 3 RCTs, n=201) andreduced need for analgesic intake after tonsillectomy in children vs placebo, especially in theearly postoperative period based on RCTs of poor methodological quality (Lal 2017 Level I[PRISMA], 8 RCTs, n=545; Hwang 2016 Level I, 4 RCTs, n=264) (4 RCTs overlap). An RCT not included in
the meta-analyses found that onset to pain relief was faster, pain severity was lower and theneed for rescue analgesia was less in the honey recipients vs controls (Mohebbi 2014 Level II, n=80,
JS 2).

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4.0 | ANALGESIC MEDICINESKEY MESSAGES
1. White willow bark (Salix alba) and devil's claw (Harpagophytum procumbens) are
effective in treating acute episodes of low back pain (U) (Level I [Cochrane Review])
2. A variety of complementary medicines may show efficacy in prevention and treatmentof primary dysmenorrhoea based on very limited evidence (W) (Level I [Cochrane
Review]), including aromatherapy (N) (Level III-1 SR).
3. Curcuminoids and extracts of Zingiberaceae may reduce pain intensity in acute andchronic pain states compared to placebo (N) (Level I [PRISMA]).
4. Oral administration of honey versus control reduces postoperative pain and analgesic
use after tonsillectomy (N) (Level I [PRISMA]).
5. Vitamin C reduces postoperative opioid requirements (N) (Level I [PRISMA] andpostoperative pain compared to placebo (N) (Level IV SR [PRISMA]).
6. Aromatherapy (N) (Level I), homeopathic preparations of arnica (Arnica montana) (U)(Level I [PRISMA]) and St John’s wort (Hypericum perforatum) are not effective intreating acute postoperative pain (U) (Level I [QUOROM]).
7. St John’s wort (Hypericum perforatum) induces metabolism of oxycodone reducing its
plasma concentrations and efficacy (U) (Level II).
The following tick box represents conclusions based on clinical experience and expert
opinion: There is some evidence that some complementary and alternative medicines may beeffective in some acute pain states. Adverse effects and interactions with medications
have been described with complementary and alternative medicines and must be
considered before their use (U).
 The evidence on complementary and alternative medicines is characterised by small
sample sizes and study designs prone to bias and caution is urged in interpreting
results. Additionally, the safety and potential drug interactions of many complementary
and alternative medicines have not been adequately assessed (N).

5th Edition | Acute Pain Management: Scientific Evidence 231

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5Administration of analgesic medicines
Section Editor:
Prof Stephan A Schug286

5.1 | Oral route5.2 | Intravenous route
5.3 | Intramuscular and subcutaneous routes
Contributor: Dr Jeffrey F Mott

5.4 | Transdermal route
Contributor: Dr Brian Lee

5.5 | Transmucosal routes
Contributor: Dr Brian Lee

5.6 | Epidural analgesia
Contributor: Prof Stephan A Schug

5.7 | Intrathecal analgesia
Contributor: Dr Tuong D Phan

5.8 | Other regional and local analgesic techniques
Contributor: A/Prof Michael Barrington

5.9 | Regional analgesia and concurrent anticoagulant medications
Contributor: Dr Jennifer Curnow287

5.0 | Administration of analgesic medicines
Analgesic medicines can be administered by a number of different routes, either relying on asystemic or local effect or a combination of both. The choice of route may be determined byvarious factors, including the aetiology, severity, location and type of pain, the patient’s overall
condition and the characteristics of the chosen administration technique. Additional factors toconsider with any route of administration are ease of use, accessibility, speed of analgesic onset,
reliability of effect, duration of action, patient acceptability and cost.
The principles of individualisation of dose and dosing intervals apply to the administration of
all analgesic agents, particularly opioids, by any route. A lack of flexibility in dose schedules hasoften meant that intermittent and prn (as needed) methods of pain relief have been ineffective
when the routes of administration discussed below have been used (Bandolier 2003 NR). Frequentassessment of the patient’s pain and their response to treatment (including the occurrence of
any adverse effects) rather than strict adherence to a given dosing regimen is required if
adequate analgesia is to be obtained.
Sections 5.1 to 5.5 below relate to opioids, paracetamol, nsNSAIDs and coxibs. For
information relating to oral, parenteral and regional routes of administration of adjuvant
medicines, refer to Sections 4.6 to 4.12.
Sections 5.6 to 5.9 below relate to routes of administration involving techniques of regional
and local analgesia.

5.1 | Oral and sublingual route
Oral administration of analgesic agents is simple, non-invasive, has good efficacy in most settingsand has high patient acceptability. Other than in the treatment of severe acute pain andproviding there are no contraindications to its use, it is the route of choice for the administrationof most analgesic medicines (Chou 2016 GL).
Limitations to the oral route include vomiting or delayed gastric emptying, when absorption
is likely to be impaired. If multiple doses of an oral analgesic medicine are given before return ofnormal gastric motility, accumulated doses may enter the small intestine at the same time once
emptying resumes (“dumping effect”). This could result in an unexpectedly large systemic uptakeof the medicine and an increased risk of adverse effects.
Rates of absorption will vary according to the formulation of the oral analgesic agent(eg tablet, suspension, slow release [SR] preparation). Bioavailability will also vary between
medications because of the effects of first-pass hepatic metabolism following uptake into theportal circulation. Titration of pain relief with oral analgesic medicines is slower compared withsome of the other routes of administration discussed below.
Direct comparisons between oral opioid and nonopioid analgesics, or between oral and otherroutes of administration, are limited. Indirect comparisons, where the individual medications
have been compared with a placebo, have been used to generate a “league table” of analgesic
efficacy (see Table 5.1). This table is based on randomised, double-blind, single-dose studies ormeta-analyses of such studies in patients with moderate to severe pain and shows the numberof patients that need to be given the active medication to achieve at least 50% pain relief in one
patient compared with a placebo (NNT50%) over a 4 to 6 h treatment period (Moore 2015 Level I[Cochrane], ≈460 RCTs, n≈50,000; Moore 2011 Level I [Cochrane], ≈350 RCTs, n≈45,000; Moore 2003
Level I, unspecified number of RCTs, n unspecified).

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The validity of this approach as a true method of comparison of medicines may be questioned
as there is no standardisation of the acute pain model or patient and only single doses of theanalgesic agents are used. The effects of the analgesics may vary with different pain models (Gray2005 reanalysing Barden 2004 Level I, 43 RCTs [paracetamol], n unspecified). However, it may bereasonable, in some circumstances, to extrapolate estimates of analgesic efficacy from one pain
model to another (Barden 2004 Level I, 43 RCTs [paracetamol], n unspecified). Note for example that
Ketoprofen 25 mg has a better NNT50% of 2.0 (95% CI 1.8 to 2.3) than Ketoprofen 50mg NNT50%
3.3 (95% CI 2.7 to 4.3) suggesting that significant caution should be undertaken comparing datain this way.
Table 5.1 | Table of analgesic efficacy (in all types of surgery)
Analgesic medication*and dose (mg)Number ofpatients incomparison

NNT50%

Lower 95%
confidence
interval

Higher 95%
confidence
interval

Paracetamol + Ibuprofen
1000/400

543

1.5

1.4

1.7

Paracetamol + Ibuprofen
500/200

508

1.6

1.5

1.8

Dipyrone 1,000

113

1.6

1.3

2.2

Etoricoxib 120

798

1.8

1.7

2.0

Ketorolac 20

69

1.8

1.4

2.5

Ketorolac 60 (IM)

116

1.8

1.5

2.3

Oxycodone IR 10 +Paracetamol 1,000

289

1.8

1.6

2.2

Piroxicam 40

30

1.9

1.2

4.3

Ketoprofen 25

535

2.0

1.8

2.3

Diclofenac potassium 50

757

2.1

1.9

2.5

Diflunisal 1,000

357

2.1

1.8

2.6

Ibuprofen + caffeine
200/100

334

2.1

1.9

3.1

Ibuprofen fast acting 200

828

2.1

1.9

2.4

Ibuprofen fast acting 400

1364

2.1

1.9

2.3

Ketoprofen 100

321

2.1

1.7

2.6

Ibuprofen + codeine
400/26-60

443

2.2

1.8

2.6

Paracetamol 800/1,000 +Codeine 60

192

2.2

1.8

2.9

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Number ofpatients incomparison

NNT50%

Lower 95%
confidence
interval

Higher 95%
confidence
interval

Oxycodone IR 5 +Paracetamol 500

150

2.2

1.7

3.2

Diclofenac potassium 100

787

2.3

2.0

2.5

Dipyrone 500

288

2.3

1.9

3.1

Ibuprofen + Oxycodone
400/5

603

2.3

2.0

2.8

Aspirin 1,200

249

2.4

1.9

3.2

Diclofenac fast acting 100

486

2.4

2.0

3.0

Ibuprofen + Caffeine
100/100

200

2.4

1.9

3.1

Ketoprofen 12.5

274

2.4

1.9

3.1

Flurbiprofen 100

416

2.5

2.0

3.1

Ibuprofen 400

6,475

2.5

2.4

2.6

Diclofenac potassium 25

502

2.6

2.2

3.3

Diflunisal 500

391

2.6

2.1

3.3

Celecoxib 400

722

2.6

2.3

3.0

Ketorolac 10

790

2.6

2.3

3.1

Tramadol 75 +Paracetamol 650

679

2.6

2.3

3.0

Flurbiprofen 50

692

2.7

2.3

3.3

Ibuprofen 600

203

2.7

2.0

4.2

Paracetamol 650 +Oxycodone IR 10

1,043

2.7

2.4

3.1

Naproxen 500/550

784

2.7

2.3

3.3

Naproxen 400/440

334

2.7

2.2

3.5

Piroxicam 20

280

2.7

2.1

3.8

Paracetamol 650 +Tramadol 112

201

2.8

2.1

4.4

Etodolac 400

222

2.9

2.3

4.0

Ibuprofen 200

2103

2.9

2.7

3.2

Lornoxicam 8

273

2.9

2.3

4.0

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Number ofpatients incomparison

NNT50%

Lower 95%
confidence
interval

Higher 95%
confidence
intervalMorphine 10 (IM)

946

2.9

2.6

3.6

Pethidine 100 (IM)

364

2.9

2.3

3.9

Tramadol 150

561

2.9

2.4

3.6

Dexketoprophen 20/25

523

3.2

2.6

4.1

Diflunisal 250

195

3.3

2.3

5.5

Etodolac 200

670

3.3

2.7

4.2

Flurbiprofen 25

208

3.3

2.5

4.9

Ketoprofen 50

624

3.3

2.7

4.3

Ketorolac 30 (IM)

359

3.4

2.5

4.9

Naproxen 200/220

202

3.4

2.4

5.8

Paracetamol 500

561

3.5

2.2

13.3

Dexketoprofen 10/12.5

452

3.6

2.8

5.0

Paracetamol 975/1,000

3,232

3.6

3.2

4.1

Paracetamol 1,500

138

3.7

2.3

9.5

Paracetamol 1,000 +Oxycodone IR 5

78

3.8

2.1

20.0

Paracetamol 600/650 +Codeine 60

1,413

3.9

3.3

4.7

Mefenamic acid 500

256

4.0

2.7

7.1

Aspirin 600/650

4,965

4.2

3.8

4.6

Celecoxib 200

705

4.2

3.4

5.6

Ibuprofen 100

396

4.3

3.2

6.4

Lornoxicam 4

151

4.3

2.7

11.0

Oxycodone IR 15

228

4.6

2.9

11.0

Paracetamol 600/650

1,886

4.6

3.9

5.5

Ibuprofen 50

316

4.7

3.3

8.0

Etodolac 100

498

4.8

3.5

7.8

Tramadol 100

882

4.8

3.8

6.1

Aspirin 650 + Codeine 60

598

5.3

4.1

7.4

Analgesic medication*and dose (mg)

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Number ofpatients incomparison

NNT50%

Lower 95%
confidence
interval

Higher 95%
confidence
interval

Tramadol 75

563

5.3

3.9

8.2

Paracetamol 325 +Oxycodone IR 5

388

5.4

3.9

8.8

Ketorolac 10 (IM)

142

5.7

3.0

53.0

Diclofenac sodium 50mg

284

6.6

4.2

17

Paracetamol 300 +Codeine 30

690

6.9

4.8

12.0

Dihydrocodeine 30

194

8.1

4.1

540

Etodolac 50 (dental only)

360

8.3

4.8

30

Tramadol 50

770

8.3

6.0

13.0

Gabapentin 250

327

11.0

6.4

35.0

Codeine 60

2,411

12.0

8.4

18.0

Analgesic medication*and dose (mg)*oral route unless otherwise specified
Source: Compiled with data from Moore 2003 (Level I, unspecified number of RCTs, n unspecified),
Moore 2011 (Level I [Cochrane], ≈350 RCTs, n≈45,000) and Moore 2015 (Level I [Cochrane],≈460 RCTs, n≈50,000). Formulations and doses not approved for use in Australia, New Zealand,
Europe, USA or Canada have been removed from the table.

5.1.1 | Paracetamol
Single doses of paracetamol are effective in the treatment of postoperative pain. The NNTs for avariety of doses, as well as combinations of paracetamol with other analgesic medicines such as
ibuprofen, oxycodone, tramadol and codeine, are listed in Table 5.1.
There is no good evidence for a dose-dependent analgesic effect of oral paracetamol; theeffects of 500 mg (NNT50% 3.5; 95%CI 2.7 to 4.8), 600/650 mg (NNT50% 4.6; 95%CI 3.9 to 5.5) and
1,000 mg (NNT50% 3.6; 95%CI 3.2 to 4.1) show no statistically significant difference ( Moore 2015
Level I [Cochrane], 53 RCTs, n=5,679).
The oral bioavailability of paracetamol is good at between 63 and 89% ( Oscier 2009 NR).
However, rate of absorption and peak concentrations are reduced by factors such as recent foodintake (Moore 2015 SR), pregnancy (Raffa 2014 NR), opioid administration (Raffa 2018 BS) and highaltitude (Idkaidek 2019 EH). Early postoperative oral administration can result in plasma
concentrations that can vary enormously after the same dose and may remain subtherapeutic insome patients (Holmer Pettersson 2004 PK), however there does not appear to be a clinicaldifference of oral vs IV paracetamol in total hip arthroplasty (THA) and total knee arthroplasty(TKA) (Sun 2018 Level I [PRISMA], 2 RCTs, n=236; Westrich 2019 Level II, n=154, JS 5), Caesarean section(Wilson 2019 Level II, n=141, JS 3) or laparoscopic cholecystectomy (Plunkett 2017 Level II, n=60, JS 4).
Paracetamol effervescent tablets are absorbed significantly faster than ordinary paracetamol(Rygnestad 2000 PK).

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5.1.2 | Nonselective NSAIDs and coxibs
A number of nsNSAIDs and coxibs have been shown to be effective as sole therapy in a varietyof acute surgical pain settings. The NNTs of each of these medicines is listed in Table 5.1.
In general, there is no good evidence that NSAIDs given parenterally or rectally are more
effective, or result in fewer adverse effects, than the same NSAID given orally for the treatmentof postoperative pain (Tramer 1998 Level I, 26 RCTs, n=2,225). Only in the treatment of renal colic
do IV NSAIDs result in more rapid analgesia. Only rectal NSAIDs are effective for reducing post
ERCP pancreatitis (Serrano 2019 Level I [PRISMA], 21 RCTs, n=6,854).
The formulation of oral NSAIDs such as diclofenac seems to significantly impact their efficacy(Derry 2015b Level I [Cochrane], 18 RCTs, n=3,714). For the same 50 mg dose, diclofenac sodium has
an NNT50% of 6.6 (95%CI 4.1 to 17) vs diclofenac potassium an NNT50% of 2.1 (95%CI 1.9 to 2.5)
and diclofenac fast acting (dispersible products, solutions, and softgel formulations) an NNT50%
of 2.4 (95%CI 2.0 to 3.0).

5.1.3 | Conventional and atypical opioids
Oral opioids can be as effective in the treatment of acute pain as opioids given by other moreinvasive routes, if equianalgesic doses are administered (Cheung 2017 NR; Chou 2016 GL; Macintyre
2015 NR). Both IR and SR formulations have been used. In a number of postoperative settings
combinations of SR and IR opioids have been used successfully without any parenteral opioids
to treat acute pain after ENT surgery (Pogatzki-Zahn 2013 Level IV, n=275), spine surgery (Rajpal 2010
Level IV, n=200), cardiac surgery (Ruetzler 2014 Level II, n=51, JS 2) and orthopaedic surgery (Lamplot
2014, Level II, n=36, JS 2}).
When opioids are prescribed for the treatment of acute pain, consideration should be given
to duration of therapy. In most cases short-term use only of these medicines is warranted.
Discharge planning must consider the duration of use of opioids prescribed for the short-term
management of acute pain and the weaning of those medicines and, in a small minority ofpatients, the potential for prescribed opioids to be abused or misused (see Section 8.13).
5.1.3.1 | Immediate-release formulations
The NNTs for various IR opioids are listed in Table 5.1.
PO doses of morphine and oxycodone IR have an onset of analgesic effect at around 30 min
with a peak at 1 to 2 h (Hoeben 2012 EH).
The effectiveness of the different PO conventional and atypical opioids may change with theaddition of paracetamol and NSAIDs:• PO codeine in a single dose of 60 mg is not an effective analgesic agent after a variety ofoperations (NNT50% 12) (Moore 2015 Level I [Cochrane], 33 RCTs, n=2,411). The effect waseven smaller in the subgroup after dental surgery (NNT50% 21) (Derry 2010 Level I [Cochrane],
15 RCTs, n=1,146). Combined with PO paracetamol, a significant dose response was seen
with NNT50% of 2.2 for paracetamol 800−1,000 mg/codeine 60 mg, 3.9 for paracetamol
600−650 mg/codeine 60mg, and 6.9 for paracetamol 300 mg/codeine 30 mg, and the
combination extended the duration of analgesia by 1 h compared with paracetamol alone(Toms 2009 Level I [Cochrane] 26 RCTs, n=2,295). There are no data on combinations of PO
paracetamol with low codeine doses <30 mg. A PO combination of paracetamol
500 mg/hydrocodone 5 mg did not provide superior analgesia to paracetamol 300
mg/codeine 30 m for extremity pain after ED discharge (Chang 2014 Level II, n=240, JS 5).

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•

•

•

•

•

•

•

294

However, codeine 25.6 to 60 mg barely improves the analgesic efficacy of 400 mg
ibuprofen in a number of combinations (Derry 2015a Level I [Cochrane], 6 RCTs, n=1,342).
PO oxycodone IR in a single dose of 5 mg shows no benefit over placebo for the treatmentof moderate to severe acute pain (Gaskell 2009 Level I [Cochrane], 3 RCTs [oxycodone 5 mg],
n=317); doses of 15 mg (NNT50% 4.6) (2 RCTs [oxycodone 15 mg], n=228) and in combination
5 mg oxycodone/325 mg paracetamol (NNT50% 5.4) (3 RCTs [combination], n=388), 10 mg
oxycodone/650 mg paracetamol (NNT50% 2.7) (10 RCTs [combination], n=1,043) and 10 mg
oxycodone/1,000 mg paracetamol (NNT50% 1.8) (2 RCTs [combination], n=289) are more
effective than placebo. Similar benefits are achieved by combining 5 mg oral oxycodone
with 400 mg ibuprofen (NNT50% 2.3) (Derry 2013 Level I [Cochrane], 3 RCTs, n=1,303).
PO tramadol IR is an effective analgesic agent for postoperative pain with NNT50% of
7.1 for 50 mg, 4.8 for 100 mg and 2.4 for 150 mg (Moore 1997 Level I, 18 RCTs, n=3,453). The
combination of tramadol 75 mg or 112.5 mg with paracetamol 560 mg or 975 mg is more
effective than either of its two components administered alone (McQuay 2003 Level I,
7 RCTs, n>1,400).
After 3rd molar surgery, a meta-analysis of predominantly PO tramadol showed it is lesseffective and associated with more adverse events (MD 21.8%; 95%CI 13.8 to 29.9) than
predominantly PO NSAIDs (Isiordia-Espinoza 2014 Level I, 4 RCTs, n=426 [oral] &n=51 [IM]).
In women undergoing Caesarean section under single shot spinal anaesthesia with IT
fentanyl, the regular administration of oral paracetamol, ibuprofen and tramadol resulted
in lower pain scores (2.8  0.84 vs 4.1  0.48), higher satisfaction rate (9.1  1.2 vs 8.3 1.5), and more breastfeeds (23.7  6.5 vs 19.2 6.2) vs prn administration (Yefet 2017 Level
II, n=200, JS 3).
PO morphine IR is effective in the treatment of acute pain. Following preloading with IVmorphine, oral morphine liquid 20 mg (initial dose 20 mg; subsequent doses increased by
5 mg if breakthrough doses needed) every 4 h with additional 10 mg doses prn provided
better pain relief after hip surgery than IM morphine 5 to 10 mg prn (McCormack 1993 Level
II, n=47, JS 5).
In comparison with IV PCA morphine alone, administration every 4 h of 20 mg but not
10 mg of PO morphine reduced PCA morphine consumption; however, there were nodifferences in pain relief or adverse effects (Manoir 2006 Level II, n=63, JS 5).
PO tapentadol and PO oxycodone have been compared mostly postoperatively using
total pain relief over 48 h. Tapentadol IR 50 mg (MD -2.83/100; 95% CI-11.8 to 6.14)(3 RCTs, n=1,003 ) and 75 mg (MD -0.92/100; 95% CI -9.15 to 7.32) (2 RCTs, n=885 ) haveefficacy similar to oxycodone IR 10 mg, while 100 mg is superior (MD 9.4/100; 95% CI
2.56 to 16.24) (1 RCT, n=175) (Xiao 2017 Level I [PRISMA], 9 RCTs, n =3,961). Regarding
adverse events, there was less constipation with 50 mg (RR 0.44; 95%CI 0.21 to 0.93)
and 75 mg (RR0.37; 95% CI 0.24 to 0.59), less nausea with 50 mg (RR 0.64; 95%CI 0.48
to 0.85) and 75 mg (0.61; 95%CI 0.41 to 0.93), but more somnolence with 100 mg(RR 1.67; 95%CI 1.08 to 2.58). Overall side effects were only lower in the 75 mg group(RR 0.88; 95%CI 0.83 to 0.94) although the 50 mg group had less discontinuations due
to side effects (RR 0.52; 95%CI 0.35 to 0.77).
SL (11 RCTs, n=1,111) and IV or IM buprenorphine show similar analgesic efficacy overall(pain scores 1─48 h) (23 RCTs) and side effects including respiratory depression (OR 2.07;
95% CI 0.78 to 5.51) (10 RCTs [respiratory rate <8-12 bpm]), sedation (10 RCTs), nausea (21RCTs) and vomiting (13 RCTs) to morphine (IV, IV-PCA, IM, PO), but with less pruritus (6RCTs) (White 2018 Level I, 28 RCTs, n=2,210). See Section 4.3.1.3 for detail.

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IR oral opioids such as oxycodone, morphine and tramadol have also been used as ‘stepdown’ analgesia after PCA, with doses based on prior PCA requirements (Macintyre 2015 NR) andafter epidural analgesia (Lim 2001 Level II, n=101, JS 5).
5.1.3.2 | Slow-release formulations
The role of slow release (SR) formulations (also referred to as controlled-release, extendedrelease or prolonged-release) in acute pain is controversial. ANZCA has published a position
statement indicating their use should be avoided except on a short-term basis for post-operativeand post-traumatic analgesia where pain is prolonged (ANZCA 2018 GL), which has been discussed
extensively in the literature (Stevens 2020 NR; Levy 2019 NR). This recommendation is also in linewith multiple international guidelines (FDA 2012 GL; Webster 2015 GL; Chou 2016 GL; Dowell 2016 GL;
Clarke 2020 GL; Levy 2020 GL). When SR formulations are used, consideration should then be given
to opioids with the least sedative (and therefore respiratory depressant) effect such as theatypical opioids tramadol, tapentadol and transdermal buprenorphine (ANZCA 2018 GL).
Concerns regarding the use of SR formulations include:• SR formulations are not registered for acute pain by most regulatory authorities including
the TGA, the FDA and the EMA.
• SR formulations vary widely in time to peak plasma concentrations with many being inthe 3 to 6 h range. In contrast and in most cases, the analgesic effect of the IR opioid
preparations will be seen within about 40 to 60 min. Rapid titration to effect is therefore
easier and more appropriate with IR formulations.
• There is an increased risk of OIVI with use of SR formulations in an acute setting (Levy 2019NR ). This has been shown specifically for SR oxycodone >10 mg after TKA (Weingarten 2015
Level IV, n=11,970). There is also an increased risk of unintentional overdose with all SR
opioid use (not differentiating conventional from atypical opioids) in chronic pain (Miller
2015 Level III-2, n= 840,606). This risk was particularly high during the first 2 weeks after
initiation of treatment (HR 5.25; 95%CI 1.88 to 14.72), relevant to the acute setting. An
analogy is the increased OIVI incidence with continuous infusions of opioids (Schug 1993
Level IV, n=3,016) and with PCA use with a continuous background infusion (George 2010
Level I, 12 RCTs [adults], n=674) (see also Section 6.4.3). It is of note here that regularly(instead of prn) administered IR opioids would raise similar concerns.
• Where patients are taking SR formulations at home for acute pain there is concern about
the ability of the patient to down titrate medications if their pain resolves faster than
expected by the prescriber, which given the variability of pain is not an unlikely event(Stevens 2020 NR; ANZCA 2018 GL; Macintyre 2015 NR). A retrospective analysis of US
healthcare data found high rates of continued use at 1 y (27.3%) and 3 y (20.5%) in opioidnaïve patients when the initial opioid prescribed was a SR opioid (Shah 2017 Level IV,
n=1,294,247). However, it is unclear how many of these prescriptions were intentional
initiations of medication for chronic pain.
Possible benefits with use of SR formulations (ideally atypical opioids) may exist in certain
settings of acute pain by providing more regular analgesia ie:• Regular analgesia may be more effective than prn only analgesia in some circumstances.
Post LSCS under spinal anaesthesia, patients randomised to receive regular paracetamol,
diclofenac and IR tramadol (note: an atypical opioid with reduced risk of OIVI [see Section
4.3.1.3]) had lower pain, better satisfaction, more breast feeding and less infant formulause than patients prescribed the same medications as prn (Yefet 2017 Level II, n=214, JS3).
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• Some SR formulations may have a better tolerability profile. For example, SR tramadol
formulations have lower adverse events vs IR tramadol in the treatment of chronic pain
due to osteoarthritis (Langley 2010 Level III-II SR, 15 studies, n unspecified).
• Where opioids are being regularly administered due to the severity of the pain caused bysurgery or trauma, SR opioids may have a limited role. Using SR oxycodone in titrated
doses during rehabilitation after TKA improved pain control and functional rehabilitation
and reduced LOS at the rehabilitation hospital. However, it is of concern that SR
oxycodone use in this setting was associated with 4 times higher overall opioid use (total
daily consumption of oxycodone [SR and IR] 54.4 vs 12.9 mg) (Cheville 2001 Level II, n=59,
JS 5). The latter finding highlights reasons for caution with SR opioid use in such a setting,even where possibly indicated (Stevens 2020 NR).
SR opioid preparations should only be used at set time intervals and IR opioids should be usedprn for acute pain exacerbations, and for titration of SR opioids. In this context it is of note, thatthe position paper by ANZCA regards methadone and transdermal fentanyl, due to their long
half-life, as behaving similarly to SR opioids (ANZCA 2018 GL).
SR oxycodone is an effective component in the immediate management of acute pain (Kampe
2004 Level II, n=40, JS 5; Sunshine 1996 Level II, n=182, JS 5). However, IR oxycodone and paracetamol
325 mg given every 6 h led to better pain relief than 10 mg SR oxycodone given every 12 h (Kogan
2007 Level II, n=120, JS 5). In comparison with IV morphine PCA alone, SR oxycodone in addition tomorphine PCA resulted in improved pain relief and patient satisfaction after lumbar discectomy
and a lower incidence of nausea and vomiting, as well as earlier return of bowel function(Blumenthal 2007 Level II, n=40, JS 5). SR oxycodone was found to be effective as ‘step-down’ analgesia
after 12–24 h of PCA morphine (Ginsberg 2003 Level IV, n=189). However after TKA/THA, the additionof SR morphine 30 mg twice daily to usual care resulted in only minimally improved analgesia but
increased adverse effects (Musclow 2012 Level II, n=200, JS 5). Similarly, addition of preoperative SR
oxycodone to a multimodal analgesia regimen increased pain intensity and opioid requirements
and impaired early mobilisation on POD 1 (Cooper 2019 Level III-3, n=550).
The addition of oral naloxone to oral opioids results in less constipation in the setting ofchronic pain (Nee 2018 Level I [PRISMA], 5 RCTs, n=838). While it was suggested that these benefits
were transferable to acute pain settings (Kuusniemi 2012 NR), a difference was not found after
laparoscopic hysterectomy (Comelon 2013 Level II, n=85, JS 5) or TKA (Oppermann 2016 Level III-2,n=80) but time to first bowel motion was improved after colorectal surgery (Creamer 2017 Level II,
n=82, JS 3).
Comparing PO SR tapentadol 50 mg with SR oxycodone 10 mg/naloxone 5mg after
orthopaedic trauma surgery found similar quality of analgesia (3.8 ± 1.9 vs 3.8 ± 2.1) and minor
adverse effects (51% vs 49%; 95%CI for difference −8 to 14%) (Haeseler 2017 Level II, n=266, JS 2).
In non-breastfeeding women undergoing Caesarean section with IT morphine, SR tapentadol 50
mg was inferior to SR oxycodone 10 mg in terms of summed pain intensity difference (SPID) at
36 h (MD -13.77; 95%CI -26.1 to -1.42) but not at 48 h, and with no difference in other analgesic
outcomes or patient satisfaction at 36 or 48 h (Ffrench-O'Carroll 2019 Level II, n=68, JS 3). There wasan increased time to rescue medication with SR oxycodone. Side effects were common andsimilar in quantity between SR tapentadol and SR oxycodone (70 vs 71%), although more
oxycodone recipients received intraoperative antiemetic prophylaxis vs tapentadol recipients(71 vs 42%) including dexamethasone (43% vs 24%).

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1. Oral combinations of paracetamol/ibuprofen provide superior analgesia toparacetamol/codeine; both combinations are more effective than the individual
medicines and have a dose-response effect (S) (Level I [Cochrane Review]).
2. Oral combinations of paracetamol/tramadol are more effective than the individual
medications and have a dose-response effect (U) (Level I).
3. NSAIDs given parenterally or rectally are not more effective and do not result in fewer
adverse effects than the same medicines given orally (U) (Level I).
4. The formulation of oral NSAIDs (eg fast acting [dispersible, solution or gel], sodium
versus potassium salt) can greatly affect their efficacy (N) (Level I).
5. Early postoperative oral administration of paracetamol results in highly variable plasma
concentrations that may remain subtherapeutic in some patients (U) (Level II).
However, no difference in clinical efficacy to intravenous administration is seen in hipand knee arthroplasty (N) (Level I), Caesarean section (N) (Level II) or laparoscopiccholecystectomy (N) (Level II).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Other than in the treatment of severe acute pain, and providing there are nocontraindications to its use, the oral route is the route of choice for the administrationof most analgesic medicines (U).
 Slow-release opioid preparations (particularly conventional opioids includingtransdermal fentanyl and methadone) are not recommended in general for the
management of acute pain in opioid-naïve patients due to difficulties in short-term
dose adjustments needed for titration, an increased risk of opioid-induced ventilatory
impairment and risk of initiating long-term use (S). In some patients with prolonged
postoperative and post-traumatic acute pain states, the use of slow-release opioid
preparations may be appropriate on a short-term basis with preference for use of
atypical opioids (N).
 Slow-release oral opioid preparations should only be given at set time intervals (U).

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5.2 | Intravenous route
Analgesic medicines given by the IV route have a more rapid onset of action compared with mostother routes of administration.

5.2.1 | Paracetamol
IV paracetamol 1,000 mg is an effective analgesic after surgery with an NNT50% of 4.0 (95%CI 3.5
to 4.8) over 4 h and an NNT50% of 5.3 (95%CI 4.2 to 6.7) over 6 h (Tzortzopoulou 2011 Level I[Cochrane], 36 RCTs, n=3,896). As an adjunct to opioid analgesia, opioid requirements are reduced
by 30% over 4 h after a single IV dose. For orthopaedic surgery specifically, IV paracetamol has
similar benefits (Jebaraj 2013 Level I [PRISMA], 8 RCTs, n unspecified). After Caesarean section,
IV paracetamol reduces opioid consumption (SMD -0.46; 95%CI -0.83 to -0.09) and pain (SMD 0.72; 95%CI -1.31 to -0.13) (Ng 2019 Level I [PRISMA], 7 RCTs, n=467).
IV paracetamol perioperatively reduces PONV when administered before incision and to alesser extent before recovery from anaesthesia (Apfel 2013 Level I [PRISMA], 30 RCTs, n=2,364). Thiseffect is correlated to pain relief achieved but not to reduced opioid consumption.
IV paracetamol given within 1 h prior to incision is more effective than post incision in reducing
pain at 1 h (MD -0.50; 95%CI -0.98 to -0.02) and 2 h (MD -0.34; 95%CI - 0.67 to -0.01), 24 h opioid
consumption (SMD of -0.52; 95% CI -0.98 to -0.06) and PONV (RR 0.50; 95%CI 0.31 to 0.83)(Doleman 2015 Level I [PRISMA], 7 RCTs, n=544).
Dosing of IV paracetamol in bariatric patients remains undefined; in a study of adolescentsand young adults undergoing bariatric surgery (mean BMI 46) plasma concentrations ofparacetamol were undetectable 2 h after 1,000 mg dosing (Hakim 2019 Level IV PK).
The use of IV propacetamol and IV paracetamol has been associated with hypotension (withvariable definitions: systolic vs MAP change ─ absolute value or 15-20% decrease) in mostly
critically ill (often cardiac) patients (14/19 studies) (Maxwell 2019 Level IV SR, 5 RCTs & 14 studies,
n=3,470). Hypotension may be more prevalent with IV vs NG paracetamol in critically ill patients(Kelly 2016 Level II, n=50, JS 3). Clinically significant hypotension appears to be an issue when
patients have cardiovascular compromise prior to administration; importantly regular qid dosingwith IV paracetamol exposes the patient to 0.23 mg/kg/d mannitol (with its diuretic andsecondary hypotensive effect) (Chiam 2015 NR). Within the above SR, IV paracetamol (withmannitol excipient) vs mannitol vs placebo reduced MAP by only 1.8 mmHg in healthy adultvolunteers (Chiam 2016 Level II, n=24, JS 5).
Due to the good bioavailability and tolerability of oral paracetamol, the use of the IV formshould be limited to clinical circumstances where use of the enteral route is not appropriate.
There does not appear to be a clinically significant difference in efficacy between IV and oral
paracetamol (see Section 5.1.1 above).

5.2.2 | Nonselective NSAIDs and coxibs
Compared with PO NSAIDs, there are only a relatively limited number of nsNSAIDs or coxibs
available for IV injection at present, although this number is growing.
IV/IM Ketorolac is an effective adjuvant of multimodal analgesia with more beneficial effectof 60 mg than 30 mg and a greater opioid-sparing effect with IM than IV administration (MD -2.13
mg; 95%CI -4.1 to -0.21 mg) (De Oliveira 2012 Level I [PRISMA] 13 RCTs, n=782).
IV Ibuprofen in doses of 400 and 800 mg every 6 h postoperatively as an adjuvant to IV PCA
morphine resulted in improved analgesia, but only the 800 mg dose showed an opioid-sparing298

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effect (Southworth 2009 Level II, n=406, JS 3). IV Ibuprofen 800 mg has also shown efficacy after
orthopaedic surgery (Singla 2010a Level II, n=185, JS 3), abdominal hysterectomy (Kroll 2011 Level II,
n=319, JS 3) and laparoscopic cholecystectomy (Ekinci 2019, Level II, n=90, JS 4). IV ibuprofen at 800
mg was more effective at relieving renal colic pain at 15, 30 and 60 min than IV ketorolac 30 mg(Forouzanfar 2019 Level II, n=240, JS 4).
In single doses as the sole analgesic agent, the COX-2 selective IV/IM parecoxib has beenshown to be effective in a dose-dependent way (Lloyd 2009 Level I [Cochrane] 7 RCTs, n=1,446);
NNT50% vs placebo are for 10 mg 3.1 (95%CI 2.4 to 4.5), 20 mg 2.4 (95%CI 2.1 to 2.8) and 40 mg
1.8 (95%CI 1.5 to 2.3).
A single dose of IV diclofenac is effective for postoperative pain after a variety of surgeries(McNicol 2018 Level I [Cochrane], 8 studies, n=1,756).
IV dexketoprofen 50 mg vs IV diclofenac 75 mg resulted in less IV PCA morphine usage after
laparoscopic cholecystectomy over 24 h (18 vs 46mg) (Anil 2016, Level II, n=60, JS 2).
IV meloxicam used as a rescue for moderate-severe pain after bunionectomy reduced pain
intensity and need for further rescue opioids vs placebo (Pollak 2018, Level II, n=201, JS=5).
IV meloxicam 15, 30 and 60 mg had faster onset of and then longer-lasting analgesia vs a single
dose of PO ibuprofen 400 mg after dental impaction surgery but IV meloxicam 15mg did notprovide superior analgesia to PO ibuprofen 400 mg from 2 to 8 h post administration (Christensen
2018 Level II, n=230, JS 5).
Both IV and IM administration of lornoxicam were similarly effective for the treatment of
acute renal colic pain (with no placebo comparator) (Soylu 2019, Level II, n=51, JS 2).
IV flurbiprofen (given 15 min before mastectomy and 6 h post) reduced pain at 2 h but not atlater points of time, nor did it reduce overall opioid consumption. The number of patients withchronic postsurgical pain at 6 mth was reduced vs placebo (3.3 vs 26.7%) (Sun 2013, Level II, n=60,
JS 5).
IV indomethacin is only approved for use in closure of a patent ductus arteriosus in neonates
and there are no recent trials in humans for acute pain.
In most cases, the route of administration does not seem to alter efficacy. IV NSAIDs or
COX-2 selective inhibitors are more expensive than oral or rectal NSAIDs, although theirefficacy and likelihood of adverse effects is similar ( Tramer 1998 Level I, 26 RCTs, n=2,225). For
renal colic, the onset of action of NSAIDs is faster when administered IV vs IM, PO or PR. A
comparison of rectal diclofenac and IV parecoxib showed no difference in pain relief, adverse
effects or rescue analgesic requirements after laparoscopic sterilisation (Ng 2008 Level II, n=55,
JS 5). Efficacy and times to onset of analgesia are similar with IV and IM parecoxib after oral
surgery (Daniels 2001 Level II, n=304, JS 5).

5.2.3 | Conventional and atypical opioids
5.2.3.1 | Intermittent intravenous bolus doses
Titration of opioids for severe acute pain is best achieved using intermittent IV bolus doses as itallows more rapid titration of effect and avoids the uncertainty of medicine absorption by otherroutes. The optimal doses and dose intervals for this technique have not yet been established.
In a postoperative care unit, bolus doses of morphine 2 mg or 3 mg, given at 5 min intervals
prn and with no limitation on the number of bolus doses administered, was more effective
and resulted in no greater incidence of adverse effects than the same doses given at 10 min
intervals or when a maximum of five doses only was allowed (Aubrun 2001 Level III-3, n=1,600;
Aubrun 2012 NR).

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In prehospital care, an initial dose of IV morphine 0.1 mg/kg was more effective than
0.05 mg/kg followed by half the initial dose at 5 min prn (VAS ≤30/100: 40% vs 17% at 10 min)(Bounes 2008 Level II, n=106, JS 5). In a comparison of IV fentanyl and morphine bolus doses every
5 min as needed for prehospital analgesia over a period of just 30 min, no difference was foundin pain relief or incidence of adverse effects (Galinski 2005 Level II, n=54, JS 5).
A single dose of IV morphine 10 mg vs IV paracetamol 1,000 mg in moderate to severe
traumatic limb pain had a similar analgesic effect with significantly more adverse effects in themorphine arm; approximately one-third of patients in each group required rescue analgesia of
titrated IV morphine (Craig 2012 Level II, n=55, JS 4).
Titration of IV bolus doses of an opioid is frequently accomplished using a treatment
algorithm to guide management, which includes age-based bolus doses of opioid given at 3- or
5-min intervals prn (Macintyre 2015 NR).
Approximately one-third of patients given a 1 mg single bolus dose of hydromorphone(followed by another dose at 15 min if needed) desaturated below 95% ( Chang 2009 Level IV,
n=269). As a standardised therapy, a single 2 mg dose of IV hydromorphone in adults <65 y old
resulted in more patients (11.6%; 95%CI 1.8% to 21.1%) not requiring further pain relief after
30 min vs standard care (any IV opioid in any dose) ( Chang 2013 Level II, n=350, JS 4). Adverse
effects of pruritus and nausea were more common in the hydromorphone group, who received
double the morphine equivalent dose; however, all patients received oxygen via nasal prongs
to prevent desaturation. Comparing the 2 mg hydromorphone bolus to a “1+1” titration
protocol, both showed similar efficacy and safety with an opioid-sparing effect noted in thetitration group, where 42.3% required only the first bolus ( Chang 2013 Level II, n=350,
JS 4).
For acute traumatic pain in an ED setting, sufentanil given as an IV bolus of 0.15 mcg/kg
followed by 0.075 mcg/kg every 3 min was not more effective than IV morphine 0.15 mg/kg
followed by 0.075 mg/kg and less effective at 6 h (Bounes 2010 Level II, n=108, JS 5).
IV tramadol was found to be more effective than the same dose given PO after dental surgery,however it was recognised that the difference in bioavailability of a single dose of tramadol may
be up to 30% (Ong 2005 Level II, n=72, JS 5). Large IV bolus doses of tramadol can result in a highincidence of nausea and vomiting. This effect can be reduced by slowing delivery of the medicine
or, in the surgical setting, by giving it before the patient emerges from general anaesthesia (Pang2000 Level II, n=60, JS 5).
Comparing intermittent oxycodone with other opioids reveals oxycodone is more effective
than fentanyl (5 of 6 RCTs) and sufentanil (1 of 3 RCTs) and equivalent to morphine (Raff 2019
Level I, 6 RCTs, n=466 [vs fentanyl]; 3 RCTs, n=287 [vs sufentanil]; 2 RCTs, n=135 [vs morphine] ). There wasmore nausea (3 of 6 RCTs) and vomiting (1 of 6 RCTs) reported in individual RCTs with oxycodone
vs fentanyl.
5.2.3.2 | Continuous infusions
A continuous infusion of opioids results in constant blood levels after approximately four to fivehalf-lives of the opioid used. The aim of an infusion is to avoid the problems associated with thepeaks and troughs of intermittent administration techniques. However, the variation in patient
response, the changing intensity of acute pain with time and the delay between any alterationof the infusion rate and its subsequent effect, may result in inadequate treatment of incident
pain or delayed onset of adverse effects, such as respiratory depression. Very close monitoringis therefore essential with continuous infusions of opioids.
Compared with PCA, continuous IV opioid infusions alone in a general ward setting resulted
in a five-fold increase in the incidence of respiratory depression ( Schug 1993 Level IV, n=3,016).

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Furthermore, morphine infusion 0.5 mg/h vs PCA alone after abdominal hysterectomy resulted
in higher opioid requirements, pain intensity and adverse effects including POV and dizziness(Chen 2011 Level II, n=60, JS 4).
PCA with a continuous background infusion increases the risk of respiratory events incomparison to PCA alone in adults only (OR 10.2; 95%CI 3 to 35) ( George 2010 Level I, 12 RCTs
[adults], n=674). Despite these safety concerns, PCA with a continuous background infusion of
low-dose oxycodone (0.01 mg/kg/h) vs PCA alone reduced VAS at 1, 6 and 24 h after laparoscopic
radical cervical surgery without altering satisfaction, PONV or FAS (Zhu 2019 Level II, n=90. JS 4).

KEY MESSAGES
1. Intravenous paracetamol is more effective in reducing pain, opioid consumption and
PONV when given prior to versus after surgical incision (U) (Level I [PRISMA]).
2. The onset of analgesia is faster when NSAIDs are given intravenously for the treatmentof renal colic (U) (Level I).
3. Continuous intravenous infusion of opioids in the general-ward setting is associatedwith an increased risk of respiratory depression compared with other methods ofparenteral opioid administration (U) (Level IV).
The following tick box represents conclusions based on clinical experience and expert
opinion: Titration of opioids for severe acute pain is best achieved using intermittent
intravenous bolus doses as it allows more rapid titration of effect and avoids theuncertainty of medicine absorption by other routes (U).

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5.3 | Intramuscular and subcutaneous routes
IM and SC injections of analgesic agents (usually opioids) are still commonly employed for thetreatment of moderate or severe pain. Absorption may be impaired in conditions of poor
perfusion (eg in hypovolaemia, shock, hypothermia or immobility), leading to inadequate earlyanalgesia and late absorption of the medication depot when perfusion is restored.

5.3.1 | Nonselective NSAIDs and coxibs
Compared to oral NSAIDs there are only a relatively limited number of NSAIDs or COX-2 selective
inhibitors available for IM injection at present and fewer still where Level I evidence forindividual efficacy is available; IM ketorolac (Lloyd 2009 Level I [Cochrane], 7 RCTs, n=1,446) and IM
parecoxib are effective analgesic agents (De Oliveira 2012 Level I [PRISMA], 13 RCTs, n=782).
IM diclofenac administration has been associated with rare soft tissue necrosis, particularlyin obese patients where the needle may not be long enough to reach the muscle (Dadaci 2015
Level IV, n=17 [mean BMI 42]).

5.3.2 | Conventional and atypical opioids
5.3.2.1 | Intramuscular
IM injection of opioids has been the traditional mainstay of postoperative pain management
despite the fact that surveys have repeatedly shown that pain relief with prn IM opioids isfrequently inadequate. Although IM opioids are often perceived to be safer than opioids given
by other parenteral routes, the incidence of respiratory depression reported in a review ranged
from 0.8% (0.2 to 2.5) to 37.0% (22.6 to 45.9) using respiratory rate and oxygen saturation,
respectively, as indicators (Cashman 2004 Level IV SR, 165 studies, n20,000). For comparisons with
PCA and epidural analgesia see Chapter 6; for comments on respiratory rate as an unreliableindicator of respiratory depression see Section 4.3.1.5.
Single doses of IM morphine 10 mg (McQuay 1999 Level I, 15 RCTs, n=1,046) and IM pethidine(meperidine) 100 mg (Smith 2000 Level I, 8 RCTs, n=364) have been shown to be effective in theinitial treatment of moderate to severe postoperative pain.
The use of an algorithm allowing administration of IM morphine or pethidine hourly prn andrequiring frequent assessments of pain and sedation, led to significant improvements in pain
relief vs longer dose interval prn regimens (Gould 1992, Level III-3, n=235).
The quality of pain relief is lower with intermittent IM regimens vs IV PCA (McNicol 2015
Level I [Cochrane], 49 RCTs, n=3,412).
5.3.2.2 | Subcutaneous
The placement of SC plastic cannulae or ‘butterfly’ needles allows the use of intermittent
injections without repeated skin punctures. In healthy volunteers, median time to reachmaximum serum concentration (Tmax) after SC injection of morphine was 15 min ( Stuart-Harris
2000 PK). In elderly adults, mean Tmax after a single SC injection of morphine was 15.9 min andthe rate of absorption and the variability in the rate of absorption were similar to those reported
after IM injection (Semple 1997 Level IV PK, n=22). In patients given a second and same dose of SC
morphine 5 h after the first, it was shown that there can also be significant within-patientvariations in absorption (Upton 2006 PK). The absorption rate of SC fentanyl was found to be
similar to that of SC morphine with a significantly longer terminal half-life for fentanyl (10 h vs302

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2.1 h) (Capper 2010 Level IV PK). For SC oxycodone, peak venous concentrations were seen after
22.10 min (±18.0) in healthy controls however, despite similar onset, peak plasma
concentrations were markedly reduced in critically ill ICU patients vs these healthy volunteers(Krishnamurthy 2012 Level IV EH PK). Similarly, SC tramadol in healthy volunteers had a time to peakvenous concentration of 20.6 min (±18.8), however, unlike oxycodone, plasma concentrations
were not reduced in critically ill patients vs healthy controls (Dooney 2014 Level IV EH PK).
In children, there was no difference in rate of onset, analgesic effect and adverse effects withuse of morphine SC vs morphine IM and there was a significantly higher patient preference for
the SC route (Cooper 1996 Level II, n=55, JS 4; Lamacraft 1997 Level IV, n=220 [paediatric]). Also, IM and
IV administration of morphine (along with IN fentanyl) were found to be equally effective withno significant differences in FLACC scores for postoperative pain in children (Hippard 2012 Level II,
n=171, JS 5). A comparison of IM and SC morphine in patients after Caesarean section reported
no significant differences in adverse effects, patient satisfaction or pain relief at rest, but lower
pain scores after SC administration at 12, 16 and 20 h after surgery ( Safavi 2007 Level II, n=60,
JS 3).
A comparison of the same dose of morphine given as either a single SC or IV injection, showedthat use of the IV route resulted in more rapid onset of analgesia (5 min IV vs 20 min SC) andbetter pain relief between 5 and 25 min after injection but also led to higher sedation scores up
to 30 min after injection and higher PaCO2 (Tveita 2008 Level II, n=40, JS 5). However, a comparisonof intermittent IV and SC doses of hydromorphone (the doses adjusted in a similar manneraccording to the patients’ pain scores and given at intervals of no less than 3 h) showed nodifferences in pain relief or adverse effects over a 48 h period after surgery; pain relief was thesame but the incidence of pruritus lower vs PCA hydromorphone (Bell 2007 Level II, n=130, JS 3).
Continuous infusions of opioids via the SC route were as effective as continuous IV infusions(Semple 1996 Level II, n=30, JS 2).
Treatment algorithms for intermittent SC morphine, oxycodone and fentanyl using age-based
dosing are published (Macintyre 2015 GL).

KEY MESSAGE
1. Intermittent subcutaneous morphine injections are as effective as intramuscular
injections and have better patient acceptance (U) (Level II).

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5.4 | Transdermal route
Not all medications applied topically have a local, peripheral action. The term ‘transdermal’ will
be used to describe medications that, while applied to the skin, have predominantly central
effects that are the result of systemic absorption of the medicine. The term ‘topical’ will be usedin the discussion of medications – primarily NSAIDs – that are applied topically (including to skin)
but have a predominantly peripheral effect. See Sections 5.4.2 and 5.5 below.

5.4.1 | Opioids
The stratum corneum of the epidermis forms a major barrier to the entry of medications.
However, medications such fentanyl (Sathyan 2005 PK) and buprenorphine (Skaer 2006 NR) areavailable as TD preparations. The analgesic effects are a result of systemic effects rather thanlocal peripheral opioid analgesia (Worrich 2007 Level IV EH, n=12).
5.4.1.1 | Transdermal fentanyl
TD fentanyl is commonly used in the management of cancer and chronic pain. Due to theformation of a significant intradermal reservoir, onset and offset times of this preparation are
slow and this makes short-term titration impossible. The time to first analgesic effect is generally
between 12 and 24 h after initial patch application and after the patch is removed, serum
fentanyl concentrations decline with a mean terminal half-life of 17 h (Lotsch 2013 NR).
TD fentanyl patches are currently specifically contraindicated for the management of acuteor postoperative pain in many countries and for use in opioid naïve patients ( FDA 2019a GL; MIMS
2019 GL; emc 2014 GL).
Nevertheless, TD fentanyl patches have been trialled in the management of postoperative
pain. For example after THA (Minville 2008 Level II, n=30, JS 2), TKA (Sathitkarnmanee 2014 Level II,
n=40, JS 5; Abrisham 2014 Level II, n=40, JS 5), foot surgery (Merivirta 2015 Level II, n = 60, JS 5) andhysterectomy (Sandler 1994 Level II, n=120, JS 4), preoperative use reduced postoperative painscores and supplementary opioid or other analgesic requirements. However, the wide variabilityof clinical effect (Peng 1999 NR) and the high incidence of respiratory depression that can occur
in the postoperative setting (Bulow 1995 Level II, n=24 [then terminated for safety concerns], JS 4;
Sandler 1994 Level II, n=120 [9 patients withdrawn due to severe respiratory compromise], JS 4 ) make TD
fentanyl preparations unsuitable for acute pain management. In line with these concerns andreported fatal outcomes with perioperative use, guidelines advise against the use of transdermal
fentanyl in acute pain management (ANZCA 2018 GL). There are concerns that studies in thisindication are still undertaken and published (Nair 2017 NR).
Transdermal fentanyl by an iontophoretic PCA device for the management of acute pain isalso available. See Section 6.5.5.
5.4.1.2 | Transdermal buprenorphine
TD buprenorphine patches are available for the management of chronic and cancer pain (Plosker
2011 NR). After application of the patch, steady state is achieved by 3 d; after removal of thepatch, buprenorphine concentrations decrease with a terminal half-life of 12 h (range 10 to 24h). High doses of buprenorphine patch (above 40 mcg/hr) may cause QT wave prolongation thatis reversible with mu-opioid antagonists; clinical significance of this is unclear (Merivirta 2015 Level
III-1, n=110). As with other chronic preoperative opioid use, patients on TD buprenorphine304

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preoperatively and continued through the perioperative period show higher opioid
requirements and report worse pain than opioid-naïve controls (Martin 2019 Level-III 2, n=19).
TD buprenorphine showed a dose-dependent analgesic effect with no serious adverse effects
in gynaecological postoperative patients (Setti 2012 Level II, n=47, JS 4). Use of TD buprenorphine
for acute pain management in spinal surgery was noninferior to oral tramadol ( Kim 2017 Level II,
n=48, JS 3) and superior to placebo (Niyogi 2017 Level II, n=70, JS 5). TD buprenorphine in abdominal
surgery was associated with superior analgesia but comparable adverse effect profile to placebo(Kumar 2016 Level II, n=90, JS 5). After surgical repair of hip fractures, TD buprenorphine 10 mcg/hvs PO tramadol 50 mg tds provided better analgesia from 24 h to POD 7 with lower rescue
requirements and less PONV and higher patient satisfaction ( Desai 2017 Level II, n=5, JS 3).
After hallux valgus repair, TD buprenorphine 10 mcg/h provided superior analgesia vs celecoxib
400 mg/d and comparable analgesia to IV flurbiprofen 50 mg twice daily with highest patientsatisfaction (Xu 2018 Level II, n=90, JS 3).
Inherent difficulty in titrating the dose according to changing analgesic requirement should
be considered when using TD buprenorphine for acute pain management.

5.4.2 | Other medicines
There is no basis to recommend routine use of TD nicotine patches for acute pain managementin view of no demonstrable effect on analgesia (Matthews 2016 Level I [Cochrane], 9 RCTs, n=666).
TD administration of ketamine as a patch delivering 25 mg over 24 h reduced rescue analgesic
consumption after gynaecological surgery (Azevedo 2000 Level II, n=52, JS 4).
TD melatonin 7 mg patch for perioperative pain management in lumbar laminectomy was
superior to placebo in analgesia and reduced supplementary analgesia consumption, but was
associated with significant sedation (Esmat 2016 Level II, n = 75, JS 5).
TD diclofenac patches have been applied in nonsurgical settings for systemic (non-topical)
analgesia. They have been trialled for acute pain management after dental surgery and 75 mg
and 200 mg patches were comparable in effect to oral diclofenac 75 mg and 100 mg twice daily(Krishnan 2015 Level II, n = 40, JS 2; Diwan 2019 Level III-1, n=20, JS 2). Another study found TD
diclofenac patch 100 mg applied preoperatively to be noninferior to IM diclofenac 75 mg at
surgical cessation but with a longer duration of action (Perepa 2017 Level III-1, n=60, JS 2).

KEY MESSAGES
1. Transdermal buprenorphine reduces postoperative pain with a low rate of adverse
effects (N) (Level II).
2. Transdermal fentanyl (except for iontophoretic patient-controlled transdermal devices)
should not be used in the management of acute pain because of safety concerns anddifficulties in short-term dose adjustments needed for titration (S) (Level IV).
The following tick box represents conclusions based on clinical experience and expert
opinion: Transdermal fentanyl preparations should not be used in opioid-naïve patients or inacute pain settings because of safety concerns and, in most countries, the lack ofregulatory approval for use in other than chronic pain in opioid-tolerant patients (S).

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5.5 | Transmucosal routes
Medications administered by transmucosal routes (rectal, IN, SL, buccal and pulmonary) are
rapidly absorbed directly into the systemic circulation, thus bypassing hepatic first-passmetabolism. The medications most commonly administered by transmucosal routes in acutepain management are the more lipid-soluble opioids.

5.5.1 | Rectal route
Rectal administration (PR) of medications is useful when other routes are unavailable. It results
in uptake into the submucosal venous plexus of the rectum, which drains into the inferior, middle
and superior rectal veins. Medication absorbed from the lower half of the rectum will pass into
the inferior and middle rectal veins and then the inferior vena cava, bypassing the portal system.
Any portion of the medicine absorbed into the superior rectal vein enters the portal system,
subjecting it to hepatic first-pass metabolism.
Potential problems with the administration of medication by the rectal route relate to thevariability of absorption, possible rectal irritation and cultural factors. Some suppositories should
not be divided as the medicine may not be evenly distributed in the preparation.
Contraindications to the use of this route include pre-existing rectal lesions, recent colorectal
surgery, severe thrombocytopaenia and immune suppression. Whether the medication isadministered to a patient who is awake or under anaesthesia, it is important to obtain priorconsent from the patient or guardian.
5.5.1.1 | Paracetamol
Paracetamol is effective when given by the rectal route (Romsing 2002 Level I, 8 RCTs, n=640), althoughabsorption is slower and less predictable than after oral administration with bioavailability
between 24 and 98% (Oscier 2009 NR). In children, it is also less effective than the same dose
administered by the oral route (Anderson 1996 Level II, n=100, JS 4; Anderson 1999 Level IV, n=120).
However, in children aged 3 to 36 mth, there were no differences in Tmax, Cmax and total medicine
exposure between rectal and oral administration, possibly due to slower gastric emptying in thisage group (Walson 2013 Level II, n=30, JS 2).
Doses of 1 g PR after cardiac surgery (Holmer Pettersson 2006 Level II, n=48, JS 2), hysterectomy(Kvalsvik 2003 Level II, n=60, JS 4) and 2 g PR for laparoscopic gynaecological surgery (Hahn 2000
Level IV, n=23) resulted in subtherapeutic plasma concentrations, although these may increase towithin the therapeutic range after repeat administration (Holmer Pettersson 2006 Level II, n=48, JS
2). When available, the oral route is therefore preferable.
Higher doses may be more effective. Plasma concentrations in the therapeutic range havebeen reported in adults after PR doses of 40 mg/kg but not 20 mg/kg (Beck 2000 Level IV, n=65)
and sustained therapeutic levels followed the PR use of 35 mg/kg and 45 mg/kg, but not
15 mg/kg and 25 mg/kg (Stocker 2001 Level IV PK, n=10).
In children, initial PR doses of 40 mg/kg followed by 20 mg/kg also provided therapeuticplasma concentrations without evidence of accumulation (Birmingham 2001 Level IV PK, n=16). In
children after ophthalmic surgery, 20 and 40 mg/kg PR were equally effective and superior toplacebo (Gandhi 2012 Level II, n=135, JS 4). PR paracetamol 30 mg/kg provided equivalent analgesia
postoperatively vs peritonsillar infiltration of bupivacaine ( Dahi-Taleghani 2011 Level III-1, n=110).
For inguinal herniorrhaphy in children, administration of PR paracetamol appeared to be aseffective as IV paracetamol, both in postoperative analgesia and reduction in nausea and306

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vomiting (Khalili 2016 Level II, n=120, JS 3). However, addition of PR paracetamol to caudal epidural
block did not result in a meaningful improvement vs caudal block alone for the same procedure(Nnaji 2017 Level II, n=87, JS 4).
5.5.1.2 | NSAIDs
Rectal administration of nsNSAIDs provides effective analgesia after a variety of surgicalprocedures (Tramer 1998 Level I, 26 RCTs, n=2,225). This continues to be supported by a number ofsubsequent studies (Karaman 2016 Level II, n=82, JS 5; Nadeem 2016 Level II, n=60, JS 3; Pazouki 2015
Level III-1, n=130). A study comparing PR diclofenac vs PR indomethacin for postepisiotomy pain
found both to be similarly effective but diclofenac appeared to have a shorter duration of action(Rezaei 2014 Level II, n=90, JS 3).
Local effects such as rectal irritation and diarrhoea have been reported following use of therectal route but other commonly reported adverse effects such as nausea, vomiting, dizzinessand indigestion are independent of the route of administration ( Tramer 1998 Level I, 26 RCTs,
n=2,225). Rectal NSAIDs may be particularly useful as a part of multimodal analgesia in cases
where an enteral route cannot be established, such as immediately after upper GI surgery(Bameshki 2015 Level II, n=90, JS 2).
In comparison to PR paracetamol, PR NSAIDs were more efficacious (Nikooseresht 2016 Level
II, n=102, JS 1; Ubale 2016 Level II, n=60, JS 2). The synergistic benefit of combining paracetamol with
an NSAID was also confirmed for the rectal route. After abdominal hysterectomy, PR
paracetamol/PR diclofenac vs PR diclofenac only or vs placebo resulted in superior analgesia andsignificantly reduced rescue opioid requirements (Samimi Sede 2014 Level II, n=90, JS 4). PR NSAIDs
showed superior analgesic effect when combined with paracetamol in adults (Bakhsha 2016 Level
III-1, n=90) and children (Yallapragada 2016 Level II, n=60, JS 2), and also with other analgesics suchas pentazocine (Olateju 2016 Level II, n=116, JS 5).
To provide analgesia after gynaecological procedures, PR indomethacin was superior toplacebo, but inferior to intrauterine lignocaine for hysteroscopy (Senturk 2016 Level II, n=206, JS 4),
and conferred no advantage over placebo after endometrial biopsies ( Kaya 2015 Level II, n=90,
JS 2; Telli 2014 Level II, n=151, JS 4).
For inguinal herniorrhaphy in children, addition of PR diclofenac to caudal epidural block did
not result in improved analgesia vs caudal block alone (Nnaji 2017, Level II, n=87, JS 4).
For periprocedural analgesia in US-guided prostate biopsy, PR diclofenac is superior toplacebo (3 RCTs), but inferior to the gold standard of periprostatic nerve block (2 RCTs) (Lee 2014aLevel I, 106 RCTs, n unspecified). Administration 45 to 60 min prior to procedure is recommended.
While the same systematic review found some benefit in combining PR diclofenac with
periprostatic block (2 RCTs), a subsequent RCT failed to find additional benefit with this approachvs periprostatic block alone (Ooi 2014 Level II, n=96, JS 4).
For acute renal colic in the Emergency Department (ED), PR indomethacin 100 mg provided
analgesia slightly inferior to PR morphine 10 mg at 20 min but was equivalent afterwards (Zamanian2016 Level II, n=158, JS 5) and was inferior to IM tramadol 50 mg, with significantly higher need for
rescue analgesia (Shirazi 2015 Level II, n=120, JS 3).
5.5.1.3 | Opioids
In most instances, similar doses of rectal and oral opioids are administered, although there may
be differences in bioavailability and the time to peak analgesic effect for the reasons outlined
above; rectal opioids play primarily a role in cancer-pain management (Kestenbaum 2014 NR).
Here, no differences in either pain relief or adverse effects were found in a comparison of oral
and rectally administered tramadol (Mercadante 2005 Level II, n=60, JS 5). Analgesic effects of rectal
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opioids in acute procedural pain settings have been demonstrated ( Imani 2018 Level II, n=90, JS 2;
Rahimi 2016 Level II, n=70, JS 4); advantages of this approach are unclear if oral or parenteral routes
are available.
5.5.1.4 | Ketamine
Rectal ketamine is advantageous for the paediatric population, when parenteral access may not
be feasible and a degree of sedation in addition to analgesia is desirable. PR ketamine 2 mg/kg
provided comparable analgesia to IV ketamine 0.5 mg/kg when delivered intraoperatively during
tonsillectomy in children (Yenigun 2015 Level II, n=120, JS 1). Higher doses of PR ketamine (4 mg/kg,
6 mg/kg and 8 mg/kg) were trialled in addition to 0.5 mg/kg midazolam for analgo-sedation for
outpatient burns dressing changes in children, and it was noted that the higher dose of 8 mg/kg
was associated with prolonged recovery time and adverse events ( Grossmann 2019 Level II, n=90,
JS 5); a dose of ketamine 6 mg/kg with midazolam 0.5 mg/kg appeared to provide the bestbalance between the degree of analgo-sedation and adverse effects.

5.5.2 | Intranasal route
A variety of different medications can be administered by the IN route, including analgesics. The
human nasal mucosa contains medication-metabolising enzymes but the extent and clinicalsignificance of human nasal first-pass metabolism is unknown (Dale 2002 NR). It is suggested thatthe volume of a dose of any medication given IN should not exceed 150 microL in order to avoid
run-off into the pharynx (Dale 2002 NR). Absorption through the nasal mucosa depends on boththe lipid solubility and degree of ionisation of the medication (Shelley 2008 NR).
5.5.2.1 | NSAIDs
IN ketorolac has also been shown to be effective vs placebo. After major surgery, ketorolac IN
31.5 mg (Singla 2010b Level II, n=321, JS 5) but not 10 mg IN resulted in significant opioid-sparing
and better pain relief (Moodie 2008 Level II, n=127, JS 5). This was also found for IN 31.5 mg after
oral surgery (Grant 2010 Level II, n=80, JS 5). For acute migraine, IN ketorolac 31.5mg was superior
to placebo and at least as effective as IN sumatriptan 20 mg (Rao 2016 Level II, n=72, JS 5).
5.5.2.2 | Opioids
Single-dose pharmacokinetic data in healthy volunteers for a number of opioids administered by
the IN route have been published (Dale 2002 NR; Grassin-Delyle 2012 NR). The mean bioavailabilities
and Tmax reported were fentanyl 71% and 5 min; sufentanil 78% and 10 min; alfentanil 65% and9 min; butorphanol 71% and 49 min; oxycodone 46% and 25 min; and buprenorphine 48% and
30 min. An analysis of multiple trials for IN fentanyl showed a bioavailability of 89% with an onsetof analgesia at 2–5 min (Lotsch 2013 NR). Hydromorphone, when given to volunteers in doses of
1 mg or 2 mg IN vs 2 mg IV, had median Tmax after the 1 mg and 2 mg IN doses of 20 min and 25
min respectively and an overall bioavailability of only 55% (Coda 2003 PK).
Clinical data exist for the effectiveness of several opioids administered via the IN route. IN
fentanyl must be provided in a sufficient concentration to deliver an analgesic dose in a volume
that does not exceed the nasal capacity. It is an effective treatment for breakthrough pain incancer patients (Zeppetella 2013 Level I [Cochrane] 15 RCTs [4 INF], n=1,699) and has similar analgesic
efficacy to IV administration in the ED and prehospital settings (Hansen 2012 Level I [PRISMA], 3
RCTs, n=301). IN fentanyl spray vs oral transmucosal fentanyl, fentanyl buccal tablet and oral
morphine for the treatment of breakthrough cancer pain provides the greatest and fastest

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improvement (Vissers 2010 Level I, 6 RCTs, n=594) (see also Section 8.9.3.2). It provides also similaror better analgesia than other opioids or routes of administration in children withoutcompromising safety (Mudd 2011 Level IV SR, 12 studies, n=1,743). Effectiveness of IN fentanyl for
paediatric acute pain management is confirmed by two systematic reviews (Murphy 2014 Level I[Cochrane], 3 RCTs, n=313; Setlur 2018 Level I [PRISMA], 10 RCTs, n=5,945) (2 RCTs overlap) (see also
Section 10.9.1.2). When IN fentanyl was used in the prehospital setting, there was no differencein effectiveness vs IV morphine (Rickard 2007 Level II, n=258, JS 3) and it was also effective for burns
dressing changes (Nederveld 2017 Level III-2, n=64) (see Section 8.5.3.1). In paediatric sickle cell
crisis, it was superior to placebo at 20 min, but not earlier or later (Fein 2017 Level II, n=49, JS 5).
Adding IN fentanyl to nitrous oxide 70% for paediatric procedural sedation does not confer any
advantage for short duration procedures (Seiler 2019 Level II, n=399, JS 5).
Two studies have examined the role of IN fentanyl delivered via postoperative nasal packing
foam soaked in fentanyl solution after nasal passage operation (Kim 2018b Level II, n=152, JS 5) andnasal fracture repair (Kim 2019c Level II, n=65, JS 5). In both cases superior analgesia vs placebo
lasting for up to 24 h was achieved without an increase in adverse events. The authors postulate
a significant local analgesic effect in addition to systemic absorption.
Analgesic efficacy has also been shown for IN butorphanol (Wermeling 2005 Level II, n=60, JS 4;
Abboud 1991 Level II, n=186, JS 5), IN pethidine (Striebel 1995 Level II, n=44, JS 2; Striebel 1993 Level II,
n=60, JS 5), IN morphine (Stoker 2008 Level II, n=187, JS 5), IN hydromorphone (Wermeling 2010 Level
IV, n=99) and IN sufentanil (Mathieu 2006 Level II, n=40, JS 4; Stephen 2012 Level IV, n=15; Steenblik
2012 Level IV, n=40).
Butorphanol (Abboud 1991 Level II, n=186, JS 5) and morphine (Christensen 2008 Level II, n=225,
JS 5) had similar efficacy when given by IN or IV routes. IN butorphanol was similarly effective toIV butorphanol, and provided advantages of reduced postoperative cognitive decline vs IV
fentanyl, when given to patients aged over 65 y for palate-pharyngoplasty (Yang 2015 Level II,
n=260, JS 2). IN pethidine was more effective than SC injections of pethidine ( Striebel 1995 Level II,
n=44, JS 2). IN sufentanil has been trialled in the ED setting and was superior to placebo at 0.4
mcg/kg (Lemoel 2019 Level II, n=144, JS 5) and superior to IV morphine 0.1 mg/kg at 0.7 mcg/kg (Sin2019 Level II, n=60, JS 5). In both studies adverse event profiles were minor and transient.
Patient-controlled IN analgesia (PCINA) using diamorphine (bolus doses of 0.5 mg) was lesseffective than PCA IV morphine (1 mg bolus doses) after joint replacement surgery ( Ward 2002
Level II, n=52, JS 2) but provided better pain relief in doses of 0.1 mg/kg than 0.2 mg/kg IM
morphine in children with fractures (Kendall 2001 Level II, n=404, JS 3). PCINA fentanyl (54 mcg
4 min lockout) provided better postoperative analgesia vs regular IM pethidine in women after
Caesarean section (Fleet 2015 Level II, n=156, JS 3).
Adverse effects can be related to the medication itself or to the route of administration.
Systemic effects appear to be no higher for IN administration than for other routes withequivalent efficacy; nasal irritation, congestion and bad taste have been reported (Grassin-Delyle
2012 NR; Dale 2002 NR).
Technical problems with pumps have been reported in up to 10% of cases and dispensing
issues for techniques such as PCINA, which could allow ready and unauthorised access to the
medications, have not been addressed (Dale 2002 NR).

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5.5.2.3 | Ketamine
IN ketamine has been shown to provide relatively rapid onset of effective pain relief within
15 min (peak effect 30 min) with estimated bioavailability of 45% (Farnia 2017 Level II, n=53, JS 4);
any adverse effects were mild and transient (Andolfatto 2019 Level II, n=120, JS 5; Christensen 2007
Level II, n=40, JS 4). Its use in the adult ED setting has been validated for orthopaedic trauma(Mohammadshahi 2018 Level II, n=91, JS 5), general trauma (Shimonovich 2016 Level III-1, n=90) and in
the prehospital setting with demonstrated efficacy over placebo and analgesia comparable to
IN/parenteral opioid (Andolfatto 2019 Level II, n=120, JS 5).
IN ketamine for acute headache was not found to be superior tometoclopramide/diphenhydramine (Benish 2019 Level II, n=53, JS 4). In adult renal colic, IV fentanyl
was superior in both analgesic and adverse effect profiles to IN ketamine ( Mozafari 2019 Level II,
n=130, JS 5).
As well as a premedication in paediatric patients, IN ketamine has been studied for paediatric
ED pain management and was similarly effective to the usual treatment of IN fentanyl, althoughassociated with higher rate of mild transient adverse events (Frey 2019
Level II, n=90, JS 5; Reynolds 2017 Level II, n=82, JS 5; Graudins 2015 Level II, n=73, JS 5). See also Section
10.4.7.1.
IN ketamine for postoperative analgesia in paediatric tonsillectomy was similarly effective to
IN fentanyl (Yenigun 2018 Level III-1, n=63). IN S(+)-ketamine combined with midazolam delivered
on demand provided analgesia comparable to IV morphine PCA for patients who underwent
spinal surgery (Riediger 2015 Level II, n=22, JS 4).
5.5.2.4 | Alpha-2 agonists
There is no data for use of clonidine via this route for analgesia in adults or children. The
analgesic effect of IN dexmedetomidine has been shown in adult populations such as after
hysterectomy (Wu 2016 Level II, n=120, JS 3) and endoscopic sinus surgery (Tang 2015 Level II, n=60,
JS 5). IN dexmedetomidine is used in children for preoperative sedation, and may also confer
additional analgesic benefits. IN dexmedetomidine 2 mcg/kg, but not 1 mcg/kg, was associatedwith clinically significant postoperative analgesia vs placebo (Li 2018b Level II, n=90, JS 5). IN
dexmedetomidine had a similar analgesic effect to IN fentanyl after myringotomy whenadministered intraoperatively ( Dewhirst 2014 Level II, n=100, JS 2). IN dexmedetomidine
provided persistently better analgosedation for IV cannulation (as evidenced by FLACC score)when given through a mucosal atomization device (MAD) vs IN administration of drops ofsolution (Xie 2017 Level II, n=106, JS 3). See also Section 10.4.8.
5.5.2.5 | Others
IN lignocaine has shown poor efficacy in the treatment of acute headaches with significant
adverse effects vs placebo (Dagenais 2018 Level I, 6 RCTs, n unspecified).
While IN nicotine may have a small analgesic effect, this has been inconsistently
demonstrated and is associated with significant increase in PONV (Matthews 2016 Level I[Cochrane], 9 RCTs, n=666).
IN desmopressin relieved subacute pain after orthopaedic surgery for up to 24 h (Yang 2019
Level II, n=653, JS 3).

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5.5.3 | Sublingual and buccal routes
When analgesic medicines are administered by the SL or buccal routes, their efficacy will in part
depend on the proportion of medication swallowed.
5.5.3.1 | Opioids
A number of different SL fentanyl preparations are currently on the market world-wide; theseinclude oral transmucosal fentanyl citrate (OTFC), fentanyl buccal tablets (FBT), SL fentanyl
citrate orally disintegrating tablet (ODT) and fentanyl buccal soluble film (FBSF); in addition,
buccal or SL sprays and a wafer are under development ( Schug 2017 NR; Paech 2012 NR).
The only registered indication of these preparations (commonly called ‘Transmucosal
Immediate-Release Fentanyl (TIRF) medicines’) in all countries is the treatment of break-throughpain in opioid-tolerant cancer patients. SL and buccal fentanyl are effective treatments forbreakthrough pain in cancer patients vs placebo, oral or IV opioid (Zeppetella 2013 Level I[Cochrane], 15 RCTs, n=1,699). In this indication, OTFC, FBT and ODT provide more efficacious
analgesia than oral morphine (Jandhyala 2013 Level I, 5 RCTs, n=415) (5 RCTs overlap). However, as
outlined above, IN fentanyl was superior to OTFC and FBT here (Vissers 2010 Level I, 6 RCTs, n=594)(5 & 6 RCTs overlap). See also Section 8.9.4.
In many countries, regulatory authorities have specifically noted that SL preparations mustnot be used in opioid-naïve patients or in the management of acute and postoperative pain:
OTFC has been the suspected primary cause of death in 226 USA fatalities between 2004 and2011 (Paech 2012 NR). As a consequence, warnings regarding the use of all TIRF formulations havebeen issued (FDA 2019b GL) and specifically for OTFC (MIMS 2019 GL; emc 2014 GL).
Oral transmucosal fentanyl citrate
OTFC incorporates fentanyl into a flavoured solid lozenge on a stick and is available in a range ofdoses from 200 to 1,600 mcg. Overall, the bioavailability of OTFC is about 50% vs IV fentanyl,with Cmax achieved in 23 min (Lotsch 2013 NR); the time to onset of analgesia is about 4.2 min. The
relative potency vs IV morphine is 1:8 to 1:14 (200 mcg OTFC≈2 mg IV morphine) (Lichtor 1999
Level II, n=133, JS 5).
Only a few studies have investigated the postoperative use of OTFC. It was found to be aneffective analgesic after orthopaedic surgery vs placebo (Ashburn 1993 Level II, n=38, JS 5),
abdominal surgery vs IV morphine (Lichtor 1999 Level II, n=133, JS 5), retinal photocoagulation vsplacebo (Hillier 2009 Level II, n=35, JS 5) and during burns wound care in paediatric patients vs PO
opioids (Sharar 2002 Level II, n=22, JS 3; Sharar 1998 Level II, n=14, JS 3). Pain relief at 15 min inchildren with lower extremity injuries was the same with IV bolus doses of morphine and OTFC,
but lower with OTFC after that until the end of the 75-min study period (Mahar 2007 Level II, n=87,
JS 3). However, because of the risk of achieving high peak plasma levels with unsupervised
administration, the limited data available, and the specific lack of approval for use in opioid-naïve
patients, OTFC cannot be recommended for the management of acute pain.
Fentanyl buccal tablets
FBTs use an effervescent medicine delivery technology that enables more rapid absorption anddelivers a larger proportion of the fentanyl dose vs OTFC (Grape 2010 NR); bioavailability is 65%
with time to onset of effect 10 min (Lotsch 2013 NR). FBTs are effective in opioid-tolerant cancer
patients for breakthrough pain (Zeppetella 2013 Level I [Cochrane] 15 RCTs [2 FBT], n=1,699; Jandhyala
2013 Level I, 5 RCTs, n=415; Vissers 2010 Level I, 6 RCTs, n=594) (full overlap between all three SRs).
Although only indicated for this usage, FBTs have been studied in the ED. Here, a 100 mcg FBT
had faster onset of analgesia (10 vs 35 min) than an oxycodone 5 mg/paracetamol 325 mg
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combination tablet, with no other advantages (Shear 2010 Level II, n=60, JS 4). FBT 200 mcg was
noninferior to oxycodone 10 mg/paracetamol 650 mg in an ED setting, but again without obvious
advantage in terms of onset, efficacy or adverse effect profile (Arthur 2015 Level II, n=50, JS 2). FBT
was also trialled for treatment of sickle cell crisis (De Franceschi 2016 Level III-2). Use of FBT for
non-cancer pain in opioid-naïve patients cannot be recommend given significant safety concerns.
Sublingual fentanyl citrate orally disintegrating tablets
SL fentanyl citrate ODTs consist of a mixture of carrier particles coated with fentanyl and a
mucoadhesive agent and are left under the tongue to dissolve, leading to rapid fentanyl
absorption (Paech 2012 NR). This leads to a bioavailability of around 70% and a time to onset of
effect of 15 min (Lotsch 2013 NR). They are effective in opioid-tolerant cancer patients forbreakthrough pain (Zeppetella 2013 Level I [Cochrane] 15 RCTs [2 ODT], n=1,699) and one subsequent
RCT (Shimoyama 2015 Level II, n=37, JS 3). They have also been used with effect in breakthroughnoncancer pain (Guitart 2013 Level IV, n=182).
Fentanyl buccal soluble film
FBSF consists of a small soluble disc-shaped film containing fentanyl in doses of 200–1,200 mcg,
proportional to the film surface area (Grape 2010 NR); bioavailability is 71% and time to onset of
effect 15 min (Lotsch 2013 NR). FBSF is effective in opioid-tolerant cancer patients forbreakthrough pain (Zeppetella 2013 Level I [Cochrane] 15 RCTs [1 FBSF], n=1,699).
Other transmucosal fentanyl preparations
Fentanyl buccal spray has a bioavailability of 76% and a time to onset of effect of 5 min ( Lotsch2013 NR). It is effective in opioid-tolerant cancer patients for breakthrough pain ( Zeppetella
2013 Level I [Cochrane], 15 RCTs [1 SL spray], n=1,699 ). Fentanyl SL wafers showed a bioavailabilityof 79% (Lim 2012 PK).
Sublingual buprenorphine
SL buprenorphine, given as a tablet, has an overall bioavailability of 30–50% and a long durationof action (mean half-life 28 h) (Mendelson 1997 NR; Kuhlman 1996 NR). SL buprenorphine 0.4 mg
was found to be as effective as 10 mg morphine IM after abdominal surgery (Cuschieri 1984
Level II, n=89, JS 2) and 75 mg pethidine IM after gynaecological surgery (Moa 1990 Level II, n=96,
JS 4). For adults with acute fractures in the ED, SL buprenorphine 0.4mg is as effective and safeas IV morphine 5 mg (Jalili 2012 Level II, n=49, JS 4). A much higher dose of SL buprenorphine 2 mg
for renal colic achieved comparable analgesia and adverse event to IV morphine 0.1 mg/kg(Payandemehr 2014 Level II, n=69, JS 5).
First pass metabolism of buprenorphine is dependent on cytochrome P450-3A4. Concurrent
administration of enzyme inhibitors such as voriconazole more than posaconazole significantly
elevated plasma concentrations after SL buprenorphine in healthy volunteers (Fihlman 2016 Level
II PK, n=12, JS 3). Similarly, co-administration of rifampicin, an enzyme inducer, reduced plasma
concentration of buprenorphine after SL administration by up to 25%, but had no effect whenbuprenorphine was given IV (Hagelberg 2016 Level III-2 PK, n=12).
SL buprenorphine is at least as effective as parenteral morphine for treatment of acute painwith a comparable safety profile (Vlok 2019 Level I [PRISMA], 9 RCTs, n=826).
Sublingual sufentanil
Sufentanil is a lipophilic drug which rapidly crosses the blood-brain barrier (t1/2keo 6 min), resulting
in a faster onset of action than morphine (Melson 2014 NR). Bioavailability of SL sufentanil isestimated at 60%; and vs IV administration, SL sufentanil has a blunted peak and prolonged plasma
half-life (Ringold 2015 NR). A sublingual sufentanil tablet system (SSTS) has been developed
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radiofrequency ID tag linked to an individual patient, and dispenses SL sufentanil 15 to 30 mcg
tablets in a patient-controlled manner with a 20 min lockout (Frampton 2016 NR). See Section 6.5.3.
SSTS has been trialled in both postsurgical and other acute pain settings. Compared to IV
morphine PCA for analgesia after major abdominal or TKA/THA surgeries, SSTS 15 mcg provided
analgesia that was noninferior with similar rate of adverse effects and superior satisfaction
ratings from patients and nursing staff (Melson 2014 Level II, n=357, JS 2). Specifically post TKA/THA,
SSTS 15 mcg was superior to placebo but associated with a higher rate of nausea and vomiting(Jove 2015 Level II, n=419, JS 5). While for open abdominal surgery, the analgesia from SSTS wassuperior to placebo, with similar adverse events profiles for SSTS 15 mcg (Ringold 2015 Level II,
n=172, JS 5) and SSTS 30 mcg, and rapid onset of reported analgesic effect within 15 min ofadministration (Minkowitz 2017 Level II, n=161, JS 5). SSTS 30 mcg was also trialled for acute pain
management in the ED setting (Miner 2018 Level III-3, n=76).
5.5.3.2 | Ketamine
A pharmacokinetic study in healthy volunteers calculated the bioavailability of oral ketamine as20%, SL 30% and IN 45%: the pharmacodynamic effects of the active metabolite norketamine
were thought to be of potential significance (Yanagihara 2003 PK). The bioavailability of a 25 mg
ketamine lozenge was 24% when given by both SL and oral routes; peak plasma levels were seenat 30 min and 120 min respectively and terminal half-lives were similar at around 5 h (Chong 2009
PK). For both routes, norketamine concentrations exceeded the concentrations of ketamine and,given its pharmacological activity profile, norketamine is therefore likely to be a major
contributor to the overall analgesic effect. A wafer preparation of ketamine showed an oral
bioavailability of 29% (Rolan 2014 PK).
5.5.3.3 | Others
Sublingual nsNSAIDs have been used in a variety of acute pain settings. One study found SL
piroxicam to be noninferior to IM diclofenac for renal colic (KandaSwamy 2015 Level II, n=100, JS 5),
and another found SL ketoprofen to have similar efficacy to oral naproxen for acute lower backpain (Plapler 2016 Level II, n=83, JS 3). A novel formulation of buccal paracetamol 125 mg was noted
to provide analgesia similar to IV paracetamol 1 g for limb trauma in ED (Pickering 2015 Level II,
n=40, JS 5). Advantages of above formulations over their oral equivalents are not clear.
Sublingual desmopressin vs IM ketorolac for renal colic was found to be similarly effective(Pricop 2016 Level II, n=249, JS 2).

5.5.4 | Pulmonary
5.5.4.1 | Opioids
Opioids are rapidly absorbed after nebulised inhalation, reflecting the high blood flow, surface
area and permeability of the lungs.
Clinical data exist for the effectiveness of several opioids administered via the pulmonary
route including morphine (Thipphawong 2003 Level II, n=89, JS 5; Dershwitz 2000 Level IV PK, n=15)
and fentanyl (Miner 2007 Level II, n=41, JS 3; Worsley 1990 Level II, n=30, JS 3).
For post-traumatic thoracic pain, there was no difference in the pain relief obtained fromnebulised morphine and PCA morphine (Fulda 2005 Level II, n=44, JS 4). Nebulised morphine 20 mg
every 10 min vs nebulised morphine 10 mg or IV morphine 2 mg every 5 min for ED trauma pain
provided superior analgesia while being associated with a lower rate of adverse events than the
IV group (Grissa 2015 Level II, n=300, JS 5). Cmax following administration of morphine via a standard
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nebuliser occurred within 10 min but bioavailability was low with a mean of only 5% ( Masood
1996 PK). Bioavailability may be improved (up to 59–100%) with Cmax occurring at 2 min using
specific pulmonary-medication delivery systems (Dershwitz 2000 PK; Ward 1997 PK).
Bioavailability of inhaled fentanyl is significantly higher and may approach 100% (Mather 1998
PK). The pharmacokinetic profiles of inhaled and IV fentanyl showed similar peak arterial
concentrations and areas under the curve (Macleod 2012 Level II, n=10, JS 5). The time to Cmax was
slightly shorter for inhaled vs IV fentanyl (20.5 vs 31.5 s). As is with other nebulised medications,mode of delivery and specifically achieving a particle size small enough to reach the pulmonary
alveoli, but large enough to not be expired, is important for absorption (Thompson 2016 Level I[PRISMA], 7 RCTs, n=583). Use of breath actuated atomisers may reduce the leak of drug to thegeneral environment while allowing the clinician to establish total dose delivered.
Nebulised fentanyl provides analgesia comparable to IV morphine for acute pain
management in a variety of settings with the advantages of lower adverse effect profile,noninvasive delivery and rapid onset (Thompson 2016 Level I [PRISMA], 7 RCTs, n=583). Nebulised
fentanyl in the ED setting for adults provided analgesia for acute limb trauma that was
noninferior to IV morphine (Farahmand 2014 Level II, n=90, JS 5). Using a breath actuated inhaler
delivering atomised fentanyl provided faster onset of and superior analgesia to IV morphine for
acute abdominal pain (Deaton 2015 Level II, n=40, JS 5). For renal colic, IV fentanyl provided better
analgesia than nebulised fentanyl (Imamoglu 2017 Level II, n=117, JS 5).
In children requiring pain relief in an ED, nebulised fentanyl was as effective as IV fentanyl(Miner 2007 Level II, n=41, JS 3). See also Section 10.4.4.4.
5.5.4.2 | Other analgesic medications
Nebulised ketamine and dexmedetomidine have been trialled for paediatric pre-medication andmay contribute to improved postoperative analgesia (Zanaty 2015 Level II, n=60, JS 5).
See Section 4.5 for inhaled N2O and methoxyflurane.

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5.0 | ADMINISTRATION OF ANALGESIC MEDICINESKEY MESSAGES
1. Intranasal, sublingual and buccal fentanyl preparations are effective treatments forbreakthrough pain in cancer patients (U) (Level I [Cochrane Review]) with similar
efficacy to IV administration (U) (Level I [PRISMA]) and superiority to oral morphine (U)(Level I).
2. Intranasal fentanyl is an effective treatment for paediatric acute pain management,with an acceptable adverse effect profile and ease of delivery (N) (Level I).
3. Intranasal fentanyl provides faster and better analgesia for breakthrough pain in cancer
patients than oral transmucosal fentanyl and fentanyl buccal tablets (U) (Level I).
4. Sublingual sufentanil delivered by a PCA device provided analgesia comparable to IV
PCA opioids in a number of acute pain settings (N) (Level II).
The following tick box represents conclusions based on clinical experience and expert
opinion: Neither transmucosal immediate-release nor transdermal fentanyl preparations should
be used in the management of acute pain in opioid-naïve patients because of safetyconcerns and, in most countries, the lack of regulatory approval for use in other than
opioid-tolerant patients (U).

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5.6 | Epidural analgesia
Epidural analgesia (ie the provision of pain relief by continuous administration ofpharmacological agents into the epidural space via an indwelling catheter) is an important
technique for the management of acute pain in adults and children, particularly after surgery(Weiss 2018 NR) and in women in labour (see Section 9.1.3.3). For epidural and caudal analgesia
in children see Sections 10.6.3.1 and 10.6.3.2.

5.6.1 | Efficacy
The difficulty with interpretation of available data is that epidural analgesia is not a single entity
but can be provided by a number of pharmacological agents administered into different levelsof the epidural space for a wide variety of operations.
5.6.1.1 | Efficacy and outcomes in general
The universal efficacy of epidural analgesia has been well demonstrated. Regardless of analgesic
agent used, location of catheter, type of surgery and type or time of pain assessment, epidural
analgesia provides better pain relief than parenteral opioid administration ( Guay 2019 Level I[Cochrane], 69 RCTs, n=4,680; Salicath 2018 Level I [Cochrane], 32 RCTs, n=1,716; Guay 2016a Level I[Cochrane], 15 RCTs [8 TEA, 2 LEA, 4 mixed, 1 unspecified], n=1,498; Popping 2014 Level I [PRISMA],
125 RCTs, n=9,044) (significant overlap of multiple RCTs).

One meta-analysis of epidural analgesia vs systemic opioids via PCA concludes that epidural
analgesia provides better pain relief at rest and with movement after all types of surgery; withthe exception of epidural analgesia using hydrophilic opioids only (Wu 2005 Level I, 50 RCTs,
n=3,208). The epidural group has a lower incidence of nausea/vomiting and sedation but a higher
incidence of pruritus, urinary retention and motor block than IV PCA. A meta-analysis of epidural
analgesia provided with local anaesthetics for at least 24 h vs systemic analgesia after surgery(performed under general anaesthesia) shows reduced mortality with epidural analgesia (3.1 vs4.9%) (OR 0.60; 95%CI 0.39 to 0.93) (Popping 2014 Level I [PRISMA], 125 RCTs, n=9,044), as did a large
matched-cohort retrospective audit of administrative data (30-d mortality: 1.7 vs 2.0%) (RR 0.89;
95%CI 0.81 to 0.98) (Wijeysundera 2008 Level III-2, n=144,744). The meta-analysis also reports
benefits of epidural analgesia on perioperative morbidity with decreased risk of atrial fibrillation,
supraventricular tachycardia, deep vein thrombosis, respiratory depression, atelectasis,pneumonia, ileus, PONV, and time to return to normal bowel function. A preceding meta-analysis
reported similar results (Guay 2006 Level I, 70 RCTs, n unspecified). However, adverse effects of
epidural analgesia include hypotension, pruritus, urinary retention and motor block ( Popping 2014
Level I [PRISMA], 125 RCTs, n=9,044).
With regard to pulmonary outcomes specifically, epidural analgesia vs systemic analgesia
reduced rate of pneumonia (OR 0.54; 95%CI 0.43 to 0.68), but also the need for prolonged
ventilation or reintubation, improved lung function and blood oxygenation ( Popping 2008 Level I,
58 RCTs, n=5,904); however, notably a decrease of relative benefit has occurred over time wherefrom 1971 to 2006 the baseline risk of pneumonia in the opioid group has decreased from 34 to
12%, but remained 8% in the epidural group.
5.6.1.2 | Cancer surgery outcomes
Current data do not support a benefit for cancer recurrence or survival through addition of
epidural anaesthesia/analgesia to general anaesthesia/systemic analgesia following cancer

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surgery; neither overall survival (HR 1.03; 95%CI 0.86 to 1.24) nor progression-free survival(HR 0.88; 95%CI 0.56 to 1.38) are improved (Cakmakkaya 2014 Level I [Cochrane], 4 RCTs, n=746).
Evidence was graded low to very low and all four studies are secondary data analyses ofpreviously conducted RCTs. In a much larger systematic review including not only RCTs, overall
survival was improved by epidural anaesthesia (HR 0.84; 95%CI 0.74 to 0.96), in particular after
surgery for colorectal cancer (HR 0.65; 95%CI 0.43 to 0.99) (Chen 2013 Level III-3 SR, 14 studies,n≈47,000). However, epidural anaesthesia did not improve recurrence-free survival (HR 0.88;
95%CI 0.64 to 1.22). For gastroesophageal cancer surgery, there is no evidence in favour oragainst an effect of epidural anaesthesia or analgesia on cancer outcomes ( Perez-Gonzalez 2018
Level I, 6 RCTs, n=263).
5.6.1.3 | Procedure-specific efficacy
Open abdominal surgery
For intra-abdominal surgery of any kind (including hysterectomies, radical prostatectomies,
Caesarean section, colorectal and upper gastrointestinal procedures), epidural analgesia (bycontinuous infusion [16 RCTs, n=418] or PCEA [16 RCTs, n=451]) vs IV PCA opioids improves pain
relief at rest to 6 h by 5.7/100 (95%CI 1.9 to 9.5) (7 RCTs, n=384), 7 to 24 h by 9.0/100 (95%CI 4.6
to 13.4) (11 RCTs, n=558) and beyond 24 h by 5.1/100 (95%CI 0.9 to 9.4) (7 RCTs, n=393) (Salicath
2018 Level I [Cochrane], 32 RCTs, n=1,716). There is limited evidence for improvement of pain on
movement and coughing based on few RCTs, but no evidence for differences in other outcomessuch as mortality, venous thromboembolism, sedation, nausea and vomiting, and respiratory
parameters. However, in the epidural group, risk of failure of the analgesic technique is increased(RR 2.48; 95%CI 1.13 to 5.45) (10 RCTs, n=678) as is hypotension requiring intervention (RR 7.13;
95%CI 2.87 to 17.75) (6 RCTs, n=479) and pruritus (RR 2.36; 95%CI 1.67 to 3.35) (8 RCTs, n=492).
Epidural local anaesthetics vs systemic or epidural opioids after abdominal surgery reduce
pain on movement (SMD -0.89; 95%CI -1.08 to -0.70; equivalent to 2.5/10) (35 RCTs, n=2,731)(Guay 2016b Level I [Cochrane], 128 RCTs, n=8,754). Outcomes with regard to gastrointestinal transit
time are improved: time to first flatus (SMD -1.28; 95%CI -1.71 to -0.86; equivalent to 17.5 h)(22 RCTs, n=1,138) and to first stool (SMD -0.67; 95%CI -0.86 to -0.47; equivalent to 22 h) (28 RCTs,
n=1,559). There is no effect on vomiting within 24 h (22 RCTs, n=1,154) and gastrointestinal
anastomotic leakage (17 RCTs, n=848), but very low-quality evidence on reduced LOS for open
(not laparoscopic) surgery (SMD -0.20; 95%CI -0.35 to -0.04; equivalent to 1 d) (30 RCTs, n=2,598).
For a wide range of open and laparoscopic abdominal surgery in adults (6 RCTs, n=310) andchildren (4 RCTs, n=195), epidural analgesia vs TAPB provides similar analgesia (MD 0.3/10; 95%CI-0.1 to 0.6), but TAPB reduces the risk of hypotension (RR 0.13; 95%CI 0.04 to 0.38) (4 RCTs) andLOS (MD -0.6 d; 95%CI -0.9 to -0.3) (3 RCTs) (Baeriswyl 2018 Level I [PRISMA], 10 RCTs, n=505).
After open abdominal surgery in the setting of enhanced-recovery programs (ERAS), TEA vsother analgesic approaches results in no more complications (OR 1.14; 95%CI 0.49 to 2.64) but
better analgesia (7 RCTs) and earlier recovery of bowel function (4 RCTs[flatus]; 6 RCTs [stool])
without reducing LOS (7 RCTs) (Hughes 2014 Level I [PRISMA], 7 RCTs, n=378).
A large retrospective cohort study after elective colectomy reported that postoperative
epidural analgesia significantly reduced mortality at 7 d (OR 0.35; 95%CI 0.21 to 0.59) and 30 d
(OR 0.54; 95%CI 0.42 to 0.70) (Wu 2006a Level III‐2, n=12,817). In patients with COPD undergoing
major abdominal surgery, TEA added to general anaesthesia vs general anaesthesia alone did
not reduce the incidence of postoperative pneumonia (11 vs 16%), but was associated withdecreased 30 d mortality (5 vs 9%) and with improved outcome for postoperative pneumonia(OR 0.5; 95%CI 0.3 to 0.9) (van Lier 2011 Level III-2, n=541 [324 epidural]). The beneficial effect of
TEA increased with increasing COPD severity.
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After major upper abdominal surgery, TEA in combination with NSAIDs and IV nutritional
support prevented protein loss vs epidural analgesia alone or PCA with and without nutritional
support (Barratt 2002 Level II, n=57, JS 3). Similarly, after colonic surgery, epidural analgesia
increased the anabolic effect of amino acid infusions in diabetic patients ( Lugli 2008 Level II, n=12,
JS 3) and reduced whole body protein breakdown ( Lattermann 2007 Level II, n=20, JS 2). Epiduralanaesthesia/analgesia vs general anaesthesia/systemic analgesia reduced insulin-resistanceonly in patients who were insulin-resistant preoperatively (Donatelli 2007 Level II, n=60, JS 2).
After abdominal cancer surgery, continuous TEA vs continuous IT thoracic analgesia resulted
in similar efficacy and adverse effects (Mercadante 2008 Level II, n=60, JS 3). After open
gastrectomy, TEA (PCEA) was superior to IT morphine combined with IV PCA opioids for all
relevant outcomes including analgesia, mobilisation, bowel recovery and pulmonary
complications (Lee 2014b Level II, n=64, JS 3) and was superior to IV PCA morphine with regard topain control, gastrointestinal recovery and hospital LOS (Zhu 2013 Level II, n=67, JS 2). Compared
to continuous wound infiltration with local anaesthetics in fast-track open colectomy, epidural
analgesia reduced pain scores on mobilisation until hospital discharge, reduced time to return ofbowel function and tolerance of a complete diet, improved sleep quality and reduced hospital
LOS (4 vs 5.5 d) (Jouve 2013 Level II, n=50, JS 5). These benefits were not demonstrated in another,similar RCT (Bertoglio 2012 Level II, n=106, JS 3).
Laparoscopic colectomy
After laparoscopic colectomy, TEA is rarely used in the USA (2.14%) ( Halabi 2014 Level III-2,
n=191,576). After laparoscopic colectomy, TEA vs IV PCA opioids improves pain at rest (2 RCTs,
n=110) and on walking at POD 1 and 2 (2 RCTs, n=110) and time to first bowel opening (4 RCTs,
n=190), but increases LOS (WMD 0.73 d; 95%CI 0.24 to 1.23) (8 RCTs) and total complication rate
(OR 1.57; 95%CI 1.07 to 2.29) (8 RCTs) (Perivoliotis 2019 Level I [PRISMA], 8 RCTs, n=492).
Similarly, in a large case-matched analysis, TEA increased LOS by 0.6 d, hospital charges by
USA$ 3,732.71 and higher rates of urinary tract infection without any clinical benefits (Halabi 2014
Level III-2, n=191,576). Outcomes were inferior with epidural vs IT analgesia or IV PCA ( Levy 2011
Level II, n=99, JS 3). TEA also did not improve long-term survival in this setting, but increased LOS(median length 5 d vs 3 d with IV PCA) (Day 2012 Level III-2, n=424).
Hepatic surgery
For hepatic surgery, there is ongoing debate on the value of epidural analgesia. A large USA
survey showed the technique is infrequently used in 5.9% of cases (Rosero 2014 Level IV, n=68,028).
Epidural analgesia vs IV PCA after open hepatectomy improves pain control at rest at 24 h
(MD 0.59/10; 95%CI 0.30 to 0.88) (3 RCTs, n= 243) and with movement at 48 h (MD 0.95/10; 95%CI
0.31 to 1.60) (2 RCTs, n=98) with no difference in LOS (2 RCTs), complications (overall andanalgesia-related) (2 RCTs) nor effect on transfusion (2 RCTs) (Li 2019 Level I [PRISMA], 4 RCTs, n=278).
However, wound catheters vs epidural analgesia for open hepatectomy result in similar pain
intensity on POD 1 and only slightly worse on POD 2 (WMD 0.29; 95%CI 0.09 to 0.49) (3 RCTs)
with less opioid requirements (WMD -6.29; 95%CI -7.92 to -4.65) (2 RCTs, n=176) and fasterfunctional recovery (WMD −0.73; 95%CI −1.13 to −0.32) (3 RCTs) and no other differences incomplications (Gavriilidis 2019 Level I [PRISMA], 3 RCTs, n=240).
Applying propensity-score matching techniques to a cohort of patients after hepatectomy,
there was an association of epidural anaesthesia/analgesia with higher need for bloodtransfusion and slightly longer hospital LOS (Rosero 2014 Level III-2, n=1,604).
Compared to IT morphine with subsequent IV PCA fentanyl, TEA was not superior with the
exception of pain at 12 h postoperatively and reduced blood loss ( Kasivisvanathan 2014 Level III-2,n=73). However, an RCT found significantly improved analgesia and a 50% opioid-sparing effect318

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5.0 | ADMINISTRATION OF ANALGESIC MEDICINES(Mondor 2010 Level II, n=44, JS 5). Similarly, after live liver donation, TEA vs IV PCA opioids improved
analgesia but no other outcomes (Clarke 2011 Level III-2, n=228).
Abdominal aortic surgery
After open abdominal aortic surgery in comparison with systemic opioid administration ( Guay
2016a Level I [Cochrane], 15 RCTs [8 TEA, 2 LEA, 4 mixed, 1 unspecified], n=1,498 ), epidural analgesia
reduces:• Pain scores on movement POD 1 (MD -1.78/10; 95%CI -2.32 to -1.25) (3 RCTs, n=162), POD
2 (3 RCTs, n=155) and POD 3 (2 RCTs, n=105);• Time to tracheal extubation (SMD -0.42; 95%CI -0.70 to -0.15; equivalent to 36 h mean
reduction) (8 RCTs, n=975);• Time spent in the ICU (SMD -0.23 (95% CI -0.41 to -0.06); equivalent to 6 h mean
reduction) (3 RCTs, n=523);• Acute respiratory failure (RR 0.69; 95%CI 0.56 to 0.85); NNT 8 [95%CI 6 to 16]) (6 RCTs,
n=861);• Myocardial infarction (RR 0.54; 95%CI 0.30 to 0.97; NNT 28 [95%CI 19 to 1423]) (3 RCTs,
n=503);• Gastrointestinal bleeding (OR 0.20; 95% CI 0.06 to 0.65); NNT 32 [95%CI 27 to 74]) (4 RCTs,
n=487).
However, the reduced morbidity does not translate to a difference in mortality between
epidural vs systemic opioids use (RR 1.06; 95%CI 0.60 to 1.86) (14 RCTs, n=1,383).
Studies not included in this meta-analysis support these results: TEA vs systemic opioids
improved pain, mobility and time to oral intake ( Salman 2013 Level III-1, n=80) and pain andpostoperative respiratory function in COPD patients (Panaretou 2012 Level III-2, n=30). After
endoluminal aortic aneurysm repair, TEA provided better analgesia than IV opioids (Sen 2014
Level III-2, n=32). However, in a fast-track setting for abdominal aortic aneurysm repair, TEA was
similarly effective vs continuous local anaesthetic wound infiltration with no effects on overalloutcome (Renghi 2013 Level II, n=60, JS 3).
Gynaecological surgery
In gynaecological surgery, epidural ropivacaine infusion provided only slightly better analgesia in
the first 8 h postoperatively vs wound infiltration/infusion of ropivacaine with no other clinically
relevant improvements (Ammianickal 2018 Level II, n=102, JS 3; Fassoulaki 2014 Level II, n=80, JS 3).
After abdominal hysterectomy (midline incision), epidural analgesia increased duration of
postoperative analgesic use, nonserious postoperative complications and LOS vs parenteral
opioids (Belavy 2013 Level III-2, n=257). Similarly, after uterine artery embolisation for uterine
fibroids, epidural analgesia increased complications but reduced pain scores at high costs (179Euro for 1/10 pain score reduction) (van der Kooij 2013 NR). After abdominal hysterectomy, TAPB
(bupivacaine 0.25% 15 mL bilaterally)/placebo/placebo provided the best pain relief and thelowest rescue morphine requirements vs placebo/epidural analgesia/placebo (bolus injectionsof 8 mL bupivacaine 0.125% every 6 h) and vs placebo/placebo/parenteral (alternating
diclofenac, tramadol) analgesia (Mathew 2019 Level II, n=60, JS 4). In contrast, single bolus TAPB
was inferior to single bolus epidural analgesia in the same setting with higher pain intensity 6 to
24 h and higher rescue tramadol requirements (68.8 mg [SD 25.5] vs. 5.3 mg [SD 11.6])(Raghvendra 2016 Level II, n=60, JS 3).
After abdominal hysterectomy, epidural analgesia and IT morphine 200 mcg provided
acceptable analgesia over 24 h, but IT morphine resulted initially (0 to 16 h) in better pain relief
and lower opioid requirements (Hassan 2017 Level II, n=32, JS 3).

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Urologic surgery
After radical retropubic prostatectomy, TEA vs patient-controlled local anaesthetic woundinfusion reduced pain scores upon coughing and opioid requirements, with better preservationof expiratory muscle strength (Fant 2011 Level II, n=50, JS 5). However, a cohort study found anincreased median hospital LOS with use of epidural analgesia for this operation (6 vs 7 d), which
remained significant after adjusting for complications (Mir 2013 Level III-2, n=239). Malignancy
recurrence based upon prostate-specific antigen change was more common in the epiduralgroup (14.8 vs 4.8%). TEA had no effect on blood loss or transfusion rates ( Baumunk 2014 Level II,
n=235, JS 2).
Thoracic surgery
Following thoracotomy, there is moderate-quality evidence that shows comparable analgesic
efficacy at rest and after coughing over 24 (6 RCTs, n=365) and 48 h (5 RCTs, n=346) with TEA vsPVB (Yeung 2016 Level I [Cochrane], 14 RCTs, n=698). There is low to very low-quality evidence thatshows no significant difference in mortality and major complications. There is moderate-quality
evidence that PVB has a superior minor complication risk vs TEA including hypotension (RR 0.16;
95%CI 0.07 to 0.38) (8 RCTs, n=445), nausea and vomiting (RR 0.48; 95%CI 0.30 to 0.75) (6 RCTs,
n=345), pruritus (RR 0.29; 95%CI 0.14 to 0.59) (5 RCTs, n=249) and urinary retention (RR 0.22;
95%CI 0.11 to 0.46) (5 RCTs, n=258). These results are consistent with a parallel meta-analysis
showing that continuous PVB reduces the incidence of nausea, vomiting, hypotension andurinary retention vs thoracic epidural analgesia, wound infiltration or IV opioids with comparable
post-cardiothoracic surgery analgesia (Scarfe 2016 Level I [PRISMA], 23 RCTs, n= 1,120) (10 RCTs
overlap with Yeung 2016).
For oesophagectomy, TEA vs systemic analgesia does not improve pain relief at 24 h (MD0.89; 95%CI −0.47 to 2.24) (2 RCTs & 2 studies) or 48 h (MD 0.15; 95%CI −0.60 to 0.91) (2 RCTs &2 studies) nor does it reduce the rate of pulmonary complications (RR 1.69; 95%CI 0.86 to 3.29)(2 RCTs & 2 studies) (Visser 2017 Level III-2 SR, 5 RCTs & 5 studies, n=891). Technical failure with TEA
occurs in 17 to 22%. These findings are supported by a subsequent systematic review ( Hughes
2018 Level I [PRISMA], 3 RCTs [oesophagectomy], n=93) (2 RCTs overlap).
After lung resection, postoperative TEA reduced mortality at 7 d (OR 0.39; 95%CI 0.19 to 0.80)
and 30 d (OR 0.53; 95%CI 0.35 to 0.78) in a retrospective cohort study (Wu 2006b Level III-2,
n=3,501). TEA in patients after lobectomy resulted in better pain relief and pulmonary function
vs IV morphine (Bauer 2007 Level II, n=93, JS 5).
After video-assisted thoracic surgery (VATS), PCEA achieved similar pain control as IV fentanyl
PCA/low-dose ketamine with no difference in analgesia-related adverse effects (Tseng 2019
Level II, n=74, JS 3).
Following open thoracotomy, epidural anaesthesia reduces the incidence of CPSP three to18 mth following surgery vs systemic analgesia (OR 0.52; 95%CI 0.32 to 0.84; NNT 7) (7 RCTs,
n=499) (Weinstein 2018 Level I (Cochrane), 63 RCTs, n=3,027).
Cardiac surgery
A meta-analysis of epidural analgesia vs multiple comparators for cardiac surgery with or without
cardiopulmonary bypass finds insufficient evidence to show an effect of epidural analgesia vsperipheral nerve blocks (4 RCTs), interpleural analgesia (1 RCT) or wound infiltration (1 RCT) (Guay2019 Level I [Cochrane], 69 RCTs, n=4,680). In comparison to systemic analgesia, there is a reductionof pain at rest and on movement for the first 72 h eg from 6 to 8 h (SMD -1.35/10; 95%CI -1.98
to -0.72) (10 RCTs, n=502) and an increase in hypotension (RD 0.21; 95%CI 0.09 to 0.33) ( 17 RCTs,
n=870) not leading to increased need for inotropes or vasopressors (RD 0.00; 95%CI -0.06 to 0.07)(23 RCTs, n=1,821). With regard to other outcomes, there is no difference in mortality,
cerebrovascular accidents or pneumonia, there may be a reduction in myocardial infarction at320

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0 to 30 d, respiratory depression (RD -0.03; 95%CI -0.05 to -0.01) (21 RCTs, n=1,736) and risk of
atrial fibrillation or atrial flutter at 0 to 2 wk (RD -0.06; 95%CI -0.10 to -0.01) (18 RCTs, n=2,431).
A difference in mortality is reported in a meta-analysis including RCTs and case-matched studies;
here epidural anaesthesia/analgesia reduces mortality (59/3123 [1.9%] vs 108/3260 [3.3%])(RR 0.65; 95%CI 0.48 to 0.86; NNT 70) and rate of myocardial infarction (67/2785 [2.4%] vs
108/2933 [3.7%]) (RR 0.68; 95% CI 0.51 to 0.90]; NNT 78) (Landoni 2015 Level III-2 SR, 57 studies,
n=6,383) (40 RCTs overlap).
In smaller studies, high TEA improved left ventricular function (Schmidt 2005 Level III‐3, n=37)
and increased stroke volume index and central venous oxygenation in elderly cardiac surgery
patients, without an increase in heart rate or mean arterial pressure (Jakobsen 2012 Level II, n=60,
JS 3). Prior to CABG surgery, high TEA improved myocardial oxygen availability in patients withischaemic heart disease (Lagunilla 2006 Level II, n=52, JS 4) and partly normalised myocardial bloodflow in response to sympathetic stimulation (Nygard 2005 Level III‐3, n=20). After CABG surgery,high TEA postoperatively reduced insulin requirements and hyperglycaemia ( Greisen 2013 Level II,
n=42, JS 3) (included in Guay 2019). However, TEA did not reduce the ICU LOS or improve the qualityof recovery in the ICU (Nielsen 2012 Level II, n=60, JS 3). The discussion on the overall value of
epidural analgesia after cardiac surgery continues, with concerns regarding anticoagulation risk
being a key factor (Ziyaeifard 2014 NR).
Rib fractures
Compared to thoracic epidural analgesia, systemic IV analgesia provides inferior analgesia for rib
fractures (2 RCTs & 2 studies, n=205) (Peek 2019 Level III-2 SR [PRISMA], 8 RCTs & 11 studies, n=2,081).
There was no significant difference in secondary outcomes such as duration of mechanicalventilation (3 RCTs & 1 study), ICU LOS (4 RCTs & 4 studies), hospital LOS (4 RCTs & 4 studies) andpulmonary complications (4 RCTs & 6 studies). Thoracic epidural analgesia provides similaranalgesia to continuous intercostal (1 RCT & 1 study) and paravertebral blocks (1 RCT & 1 study)
with no significant difference in duration of mechanical ventilation, ICU LOS, hospital LOS andpulmonary complications (2 to 3 studies per outcome).
In patients with multiple traumatic rib fractures, provision of TEA with local anaesthetic
reduces the duration of ventilation vs other forms of analgesia (including LEA) (Carrier 2009 Level I,
8 RCTs, n=232) (2 RCTs overlap with Peek 2019); however, mortality and ICU LOS is not different inpooled analysis of all routes of epidural administration vs parenteral opioids and hypotension
was more frequent in the epidural groups when TEA with local anaesthetic was used.
After blunt chest trauma with three or more rib fractures, the use of TEA was more common
in USA trauma centres than in nontrauma centres; the use of TEA vs other methods of analgesia
reduced adjusted mortality at 30 d (OR 0.08; 95%CI 0.01 to 0.43), 90 d (OR 0.09; 95%CI 0.02 to0.42) and 365 d (OR 0.12; 95%CI 0.04 to 0.42) (n=100 [TEA]) (Gage 2014 Level III-2, n=836). See also
Section 8.3.
Orthopaedic surgery
Spinal fusion
After spinal fusion, patient controlled epidural analgesia (PCEA) vs IV PCA opioids provides better
analgesia on POD 1 (MD −0.47/10; 95%CI −0.74 to −0.20) and POD 2 (MD −0.66; 95%CI −1.14 to−0.19), but not on POD 3 (Tian 2015 Level I, 8 RCTs, n=482). There are no differences in PONV rates,
but PCEA increases rates of pruritus (RR 1.53; 95%CI 1.08 to 2.6) and paraesthesia (RR 3.34;
95%CI 1.12 to 9.98). A parallel meta-analysis not differentiating results as detailed as theprevious one finds similar results for analgesia overall, and no differences in all pooled adverse
effects (Lu 2015 Level I, 9 RCTs, n=436) (7 RCTs overlap).
In RCTs not included in these meta-analyses, epidural analgesia with levobupivacaine
reduced pain scores, opioid consumption, nausea, blood loss and time to first stool vs IV opioid
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analgesia (Servicl-Kuchler 2014 Level II, n=81, JS 5). Similarly, after major spinal surgery, epidural
analgesia (levobupivacaine/fentanyl/ adrenaline) vs systemic opioids reduced pain and nausea,
permitted earlier mobilisation and increased satisfaction with less intraoperative andpostoperative blood loss and reduced stress response markers (glucose, cortisol, IL-1beta, IL-6,
and IL-10) (Ezhevskaya 2013 Level II, n=85, JS 2). However, when added to systemic multimodal
analgesia, TEA did not provide a significant opioid-sparing effect (Choi 2014 Level II, n=39, JS 5).
Lower limb arthroplasty (TKA and THA)
After THA and TKA, lumbar epidural analgesia (LEA) provides better pain relief than parenteral
opioids, in particular with movement (Choi 2003 Level I [Cochrane], 13 RCTs, n unspecified). A
subsequent study showed that epidural analgesia vs systemic opioids reduced inflammatory
response measured by a number of parameters after TKA (Chloropoulou 2013 Level II, n=56, JS 3).
However, in comparison to peripheral nerve blocks (FNB and ACB by single-injection orcatheter), LEA does not improve pain following TKA for 0 to 48 h (7 & 8 RCTs), but is associatedwith increased PONV (RR 1.65; 95 %CI 1.20 to 2.28) (9 RCTs, n=433), hypotension (RR 1.76; 95 %CI
1.26 to 2.45) (9 RCTs, n=551) and urinary retention (RR 4.51; 95%CI 2.27 to 8.96) (7 RCTs, n=331)(Gerrard 2017 Level I [PRISMA], 12 RCTs, n=670). In comparison to local infiltration analgesia (LIA) bysingle-injection or via catheter for TKA and THA, LEA has similar analgesic effects at rest for<24 h (9 RCTs), but LIA achieves better analgesia at 48 h (MD −1.08/10; 95%CI −1.86 to −0.29))
and 72 h (MD −0.82/10; 95%CI −1.24 to −0.4) more so in TKA (6 RCTs, n=446) (Yan 2016 Level I, 9
RCTs [6 TKA & 3 THA], n=537) (0 RCT overlap). Pain on movement was similar overall at <24 h (4 RCTs),but better controlled by LIA at 48 h for TKA with better range of knee movement at all time points(3 RCTs).
For comparisons with other regional analgesic techniques, see also Section 5.8.
Vascular surgery of the lower limbs
Used in vascular surgery of the lower limbs, LEA improved outcome by reducing incidence ofgraft occlusion (Christopherson 1993 Level II, n=100, JS 3; Tuman 1991 Level II, n=80, JS 1). However,these findings have not been confirmed by other investigators in retrospective reviews (Schunn
1998 Level III-2, n=294; Pierce 1997 Level III-1, n=423), although a subsequent data base analysis of
the USA National Surgical Quality Improvement Program (NSQIP) showed a number of outcome
advantages (re graft failure, cardiac events, postoperative pneumonia) with epidural (and spinal)
over general anaesthesia (Singh 2006 Level III-2, n=14,788).
For effects of epidural analgesia on pain after amputation, see Section 8.1.5.1.
5.6.1.4 | Level of administration
TEA is widely used for the treatment of pain after major abdominal and thoracic surgery.
Administration of local anaesthetics into the thoracic epidural space resulted in improved bowel
recovery after abdominal surgery, while these benefits are not consistent with lumbar
administration (Jorgensen 2000 Level I [Cochrane], 22 RCTs, n=1,023). In a direct comparison between
TEA and LEA for thoracotomy, TEA vs LEA reduced pain scores and opioid requirements as wellas hypotension, bradycardia, atelectasis and need for ICU treatment (Sagiroglu 2014 Level II, n=134,
JS 4). Benefits of epidural analgesia after abdominal aortic surgery were found with impact on
nonanalgesic outcomes significant for TEA, but not LEA (see above) (Nishimori 2012 Level I[Cochrane], 15 RCTs, n=1,297). In patients with multiple traumatic rib fractures, provision of TEA
with local anaesthetic reduced the duration of ventilation vs other forms of analgesia including
LEA (Carrier 2009 Level I, 8 RCTs, n=232). In gynaecological surgery, TEA provided better pain relief
vs LEA only when the incision extended above the umbilicus; TEA led to less motor block but
more pruritus (Richman 2007 Level II, n=103, JS 5). Motor block with epidural analgesia (mainly by322

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infusion of bupivacaine 0.1%/fentanyl 2 mcg/mL) occurred in 36.5% of patients with the highest
incidence when the catheter was placed at levels L2/3 and L 3/L4 (Ahmed 2016 Level IV, n=123).
TEA permits early removal of urinary catheters in many patients vs LEA; rates of urinary
retention are variably reported as 6.6% (Tripepi-Bova 2013 Level IV, n=61), 11.9% (vs 2.2% after TEA
was discontinued) (Stubbs 2013 Level III-2, n=118) and 26.7% (vs 12.4% in historic controls) (Hu 2014
Level III-3, n=101). Post removal of the urinary catheter, effective bladder emptying took hours tonormalise (defined as post-void volumes <200 mL) in patients who received TEA, however
without need for recatheterisation; this effect was prolonged when the urinary catheter was
removed early on the morning after surgery rather than remaining in situ for the duration of TEA
therapy (345 min  169 vs 207 min  122) (Zaouter 2012 Level II, n=205, JS 2). TEA for thoracotomy
did not change the post-void volume from the preoperative findings in men and women(Wuethrich 2011b Level III-3, n=26); only three men >50 y with prostrate hypertrophy had post-voidvolumes >100 mL. However, in women undergoing nephrectomy, early removal of the urinary
catheter under TEA led to an increase in post-void residual volume (median 5 vs 220 mL) andnegatively affected other parameters of bladder emptying (detrusor pressure, maximum flow
rate, voided volume) (Wuethrich 2011a Level III-3, n=13); the authors suggest that this necessitates
indwelling or intermittent catheterisation or monitoring.
5.6.1.5 | Patterns of administration
Routinely, epidural analgesia is maintained by continuous infusion. More recently, programmed
intermittent epidural bolus (PIEB) has been suggested as a superior technique, based on data inlabour analgesia (see Section 9.1.3.3). After TKA, PIEB vs continuous infusion (both delivering 3
mL/h of 0.125% bupivacaine/0.005% morphine) reduced pain scores and rescue analgesia
requirements (Kang 2013 Level II, n=53, JS 2). After major abdominal or gynaecological surgery,
PIEB TEA vs continuous TEA infusion (both techniques delivering 6 mL/h ropivacaine 0.2%)
resulted in reduced PCEA requirements in the first 48 h postoperatively (median 10 mL [IQR 2 to28] vs 28 mL [12 to 64]) without any other clinically relevant benefits (Wiesmann 2018 Level II,
n=110, JS 5). In a similar RCT following open gynaecological surgery, PIEB TEA vs continuous TEA
infusion (both delivering 4 mL/h ropivacaine 0.2%/fentanyl 2 mcg/mL) resulted in slightly
reduced PCEA requirements, but also improved pain control from 3 to 48 h (Satomi 2018 Level II,
n=57, JS 5).

5.6.2 | Medicines used for epidural analgesia
Differences in analgesic effect, duration and adverse effects depend upon the various local
anaesthetic, opioid and adjuvant medicines used in epidural analgesia.
5.6.2.1 | Local anaesthetics
For epidural infusions, dose‐ranging studies established that 0.2% ropivacaine was a suitableconcentration (Scott 1995 Level II, n=40, JS 3; Schug 1996 Level II, n=50, JS 4). Therefore, mostinvestigators compare infusions of bupivacaine or levobupivacaine at 0.1 or 0.125% withropivacaine 0.2%, which removes any imbalance in comparative potency. For more information
on differences in efficacy and adverse effects between the local anaesthetics used for epidural
analgesia see Section 4.4.

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5.6.2.2 | Opioids
Opioids alone via the epidural route appear to be of limited benefit. In particular, whenadministered via TEA, opioids fail to demonstrate any advantage over parenteral opioids except
for a slight reduction in the rate of atelectasis (Ballantyne 1998 Level I, 48 RCTs, n unspecified) withno benefit with regard to bowel recovery (Jorgensen 2000 Level I [Cochrane], 22 RCTs, n=1,023). On
the basis of the available studies, the benefits of administering lipophilic opioids alone by the
epidural route appear to be marginal, or unproven in the case of upper abdominal surgery, andin many situations will not outweigh the risks of the more invasive route of administration. Fora detailed discussion see (Wheatley 2001 NR) and Section 4.3.2.
For information on the epidural use of morphine, ER morphine, pethidine, fentanyl,
alfentanil, sufentanil, diamorphine and hydromorphone see also Section 4.3.2.
5.6.2.3 | Local anaesthetic-opioid combinations
Combinations of low concentrations of local anaesthetic agents and opioids provide consistently
superior pain relief vs either of the medications alone (Curatolo 1998 Level I, 18 RCTs [fentanyl],
n unspecified). Addition of fentanyl to a continuous epidural infusion of ropivacaine reduced therate of regression of sensory block after orthopaedic (n=80) and abdominal gynaecologicalsurgery (n=39) (Kanai 2007 Level II, n=119, JS 3) and decreased the discontinuation of postoperative
epidural infusion due to lack of efficacy (Scott 1999 Level II, n=244, JS 4).
Addition of 4 mcg/mL of fentanyl to levobupivacaine 0.125% improved quality of analgesia andreduced the stress response (ACTH, cortisol and prolactin levels) after TKA vs plain levobupivacaine(Bayazit 2013 Level II, n=40, JS 4). Addition of 0.5 mcg/mL sufentanil to 0.1% ropivacaine vs higher
sufentanil concentrations and 4 mcg/mL fentanyl resulted in no difference in quality of analgesia
after arthroplasty and had the lowest rate of pruritus (Jeon 2011 Level II, n=80, JS 3). The MLAC of
epidural lidocaine of 0.785% (95%CI 0.738 to 0.864) was reduced by 2 mcg/mL fentanyl to 0.596%(95%CI 0.537 to 0.660) and by 3 mcg/mL to 0.387% (95%CI 0.329 to 0.446) (up-down sequential
titration) (Zhang 2012 Level III-1, n=120).
5.6.2.4 | Adjuvant medicines
The efficacy of adding of adjuvant medicines such as adrenaline (epinephrine), clonidine,dexmedetomidine, ketamine, midazolam, neostigmine and magnesium to solutions used for
epidural analgesia has also been investigated (see Chapter 4).

5.6.3 | Patient-controlled epidural analgesia
The use of PCEA is based on similar concepts as for other patient-controlled techniques. It has
been shown to be safe and effective in standard ward settings ( Golster 2014 Level IV, n=4,663; Kim
2013 Level IV, n=2,276; Tan 2011 Level IV, n=928; Liu 2010 Level IV, n=3,736).
5.6.3.1 | Comparison with continuous epidural infusions
A systematic review comparing PCEA, continuous epidural infusions and IV PCA opioids after
surgery showed that both forms of epidural analgesia (with the exception of hydrophilic opioid‐
only epidural regimens) provide better pain relief with rest and with activity than PCA opioids(Wu 2005 Level I, 50 RCTs, n=3,208). However, analgesia with a continuous epidural infusion issuperior to PCEA, countered by higher incidence of nausea, vomiting and motor block.

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For specific procedures, results of PCEA vs continuous infusion are conflicting. After colonicresection, PCEA was superior to continuous epidural infusion with regard to pain control,
requirements for top‐ups and systemic analgesia as well as patient satisfaction ( Nightingale 2007
Level II, n=205, JS 5). In contrast, comparisons of PCEA and continuous epidural infusions for pain
relief after thoracotomy using both high (0.5%) and low (0.15%) concentrations oflevobupivacaine showed no differences in quality of analgesia, morphine consumption orsatisfaction; more patients in the high concentration continuous epidural infusion group had
significant motor block (Dernedde 2008 Level II, n=82, JS 3).
5.6.3.2 | Concurrent background (continuous) infusions
The addition of a continuous background infusion to PCEA using bupivacaine and fentanyl
following gastrectomy resulted in better dynamic pain scores, with higher total doses and agreater incidence of pruritus than PCEA-bolus dose only (Komatsu 1998 Level II, n=40, JS 2). The
use of a night-time-only background infusion with PCEA bupivacaine-fentanyl, also post
gastrectomy, resulted in better sleep, but total cumulative doses were similar and pain scores
were only better in the morning of postoperative d 2 ( Komatsu 2001 Level II, n=40, JS 2). A
Swedish case series over 7 y ( Golster 2014 Level IV, n=4,663) and a USA case series (Liu 2010
Level IV, n=3,736) describe successful and safe use of PCEA with a background infusion.
Other studies have found no improvement in pain relief with background infusions. After
lower abdominal surgery there was no difference in pain scores but higher total cumulative
doses and incidence of adverse effects when a background infusion was added to PCEA withropivacaine and fentanyl (Wong 2000 Level II, n=42, JS 2). The addition of a background infusion tobupivacaine-fentanyl PCEA did not improve pain relief after pelvic reconstruction ( Nolan 1992
Level II, n=23, JS 5).
5.6.3.3 | Medications used in postoperative patient-controlled epidural analgesia
The medications used for PCEA are typically the same as those used for continuous epidural
infusions. Conclusions about the efficacy of different medications and medication combinations
administered via PCEA are difficult to make because of the wide variety of analgesic agents andconcentrations used in the various studies.

5.6.4 | Adverse effects
5.6.4.1 | Neurological injury
Permanent neurological damage is the most feared complication of epidural analgesia.
A systematic review identified 647 cases of epidural haematoma (n=387) and abscess (n=260)
after neuraxial anaesthesia (Bos 2018 Level IV SR, n=409 [reports]). Epidural anaesthesia was related
to 58% of haematomas and 83% of abscesses. After epidural haematoma, 28% had partial and
25% no recovery. After epidural abscess, 21% had partial and 11% no recovery. Persistentneurological deficits were correlated with the severity of the initially presenting neurology.
A retrospective survey from Sweden put the risk of a severe neurological complication after
obstetric epidural analgesia at 1 per 25,000 and for all other patients at 1 per 3,600; 67% of
events resulted in permanent neurological deficit (Moen 2004 Level IV, n=450,000). It also
identified osteoporosis as a previously neglected risk factor. A review of data from publications
reporting adverse effects after obstetric epidural analgesia reported a risk estimate of 1 per
240,000 for persistent neurological injury and 1 per 6,700 for transient (resolution within 12 mth)
neurological symptoms (Ruppen 2006a Level IV SR, 27 studies, n≈1.37 million).
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A review of data from published studies of the risk of neurological injury associated with
epidural and other regional anaesthesia and analgesia techniques differentiated between therisk of permanent neurological injury (deficit lasting >12 mth) and transient neuropathy ( Brull2007 Level IV SR, 32 studies, n unspecified). This review focussed on adverse neurological sequelae
associated with the various regional techniques and did not address the overall risk of epidural
haematoma or abscess. The incidence of transient neuropathy (radiculopathy) after epiduralanaesthesia was estimated to be 2.19 per 10,000 (95%CI 0.88 to 5.44) ( Brull 2007 Level IV SR,
4 studies [epidural], n unspecified). The risk of permanent neurological injury was lower and theincidences reported in the studies included in this review ranged from 0 to 7.6 per 10,000. The
rates of paraplegia and cauda equina syndrome associated with epidural anaesthesia were
estimated to be 0.09 per 10,000 (95%CI 0.04 to 0.22) and 0.23 per 10,000 (95%CI 0.14 to 0.39)
respectively.
A project in the UK (NAP3) assessed the incidence of neurological complications in an
estimated 97,925 adult patients with perioperative epidural catheters ( Cook 2009 Level IV).
Depending on the inclusion or exclusion of cases with unlikely causation, pessimistic andoptimistic assessments were published. The incidence of permanent injury was pessimisticallyassessed as 17.4 per 100,000 (95%CI 7.2 to 27.8; 1 in 5,800) and optimistically as 8.2 per 100,000(95%CI 3.5 to 16.1; 1 in 12,200). Laminectomy was performed with an incidence of 12.3 per
100,000 cases (95%CI 6.3 to 21.4; 1 in 8,100). Paraplegia was caused in 6.1 per 100,000 (95%CI
2.2 to 13.3; 1 in 16,400) in the pessimistic vs 1.0 per 100,000 (95%CI 1.0 to 5.7) in the optimistic
model.
Audit data from a single (nonobstetric) tertiary institution of epidural catheters inserted overa 16 y period for postoperative pain relief found two spinal haematomas and six epiduralabscesses; only one patient (with an epidural abscess) required surgical decompression and nopatient suffered any long-term neurological deficit (Cameron 2007 Level IV, n=8,210 [epidural
catheters]). The largest published audit of patients undergoing arthroplasty with epidural
analgesia at one institution described no persistent neurologic deficit despite four patientsdeveloping epidural haematoma and two requiring surgical compression ( Pumberger 2013 Level
IV, n=62,856). Another audit at a single institution reported 1 epidural haematoma, but 57
postoperative neurologic deficits, which resolved within 3 mth except for one being permanent(unilateral lower limb paraesthesia) (Kang 2014 Level IV, n=5,083).
The incidence of transient neuropathy after epidural analgesia in large case series was in therange of 0.013 to 0.023% (Auroy 1997 Level IV, n=30,413; Tanaka 1993 Level IV, n=40,010; Xie 1991
Level IV, n=1,304,214).
5.6.4.2 | Epidural haematoma
A major concern is the development of an epidural haematoma with subsequent, potentiallypermanent, SCI. A review including case series involving over 1,335,000 patients with epidural
analgesia reported seven cases of haematoma (1 per 191,000) (Wulf 1996 Level IV). On the basisof this case series, the possible incidence is in the order of 1 per 100,000 at the upper limit of the
95%CI. The Swedish case series quoted above puts the overall risk of epidural haematoma after
epidural blockade at 1 per 10,300 (Moen 2004 Level IV, n=450,000). A Finnish closed-claims study
calculated a risk of 1 per 26,400 (Pitkanen 2013) Level IV, n=216 [claims]). An even higher incidenceof epidural haematoma (1 per 3,100) has been estimated for epidural analgesia in association
with inappropriate low molecular weight heparin (LMWH) dose regimens (Horlocker 2003 GL) (seeSection 5.9).
A systematic review of the risks of epidural haematoma and neurological injury associatedwith epidural anaesthesia/analgesia in cardiac, vascular and thoracic surgery patients concluded

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that the maximum risks of epidural haematoma were 1 per 1,700, 1 per 1,700 and 1 per 1,400
respectively (Ruppen 2006b Level IV SR, 12 studies, n=14,105). However, this was a calculated risk
only; there were actually no cases of epidural haematoma reported in the studies used in thisanalysis and the maximal calculated expected rate of permanent neurological injury associatedwith epidural haematoma was 1 per 4,600.
In a large USA case series of patients having epidural analgesia perioperatively, seven patientsdeveloped haematoma requiring surgical evacuation (1 per 8,921; 95%CI 1/4,330 to 1/22,189)(Bateman 2013 Level IV, n=62,450)). In four of the seven patients, management of anticoagulation
was not in line with the guidelines of American Society of Regional Anesthesia and Pain Medicine(ASRA) discussed later (see Section 5.9). In a similarly large case series of patients having
arthroplasty with an indwelling epidural catheter at one institution, four epidural haematomas
occurred (1 per 15,714), of which two required emergency decompression and none resulted inpersisting neurological deficits (complete recovery at 6 wk) (Pumberger 2013 Level IV, n=62,856). It
is of note that all four patients had combined spinal and epidural anaesthesia, took at least one
medication affecting coagulation (aspirin, TCA, NSAIDs, clopidogrel) and had preoperative
hypertension. Additional risk factors were clopidogrel only discontinued for 4 d in one,thrombocytopenia (70,000/microL) at day of insertion and removal in one and excessive alcohol
consumption in two.
In a case series after cardiac surgery, the risk of epidural haematoma was calculated at 1 per
12,000 (95%CI 1 per 2,100 to 1 per 68,000); comparable to an obstetric population ( Bracco 2007
Level IV, n=1,293). It was described as being in the same risk range as receiving a wrong blood
product (or the yearly risk of having a fatal traffic accident in a Western country). A subsequent
study including a survey in cardiac surgery identified a risk of epidural haematoma of 1 per 3,552(95%CI 1 per 2552 to 1 per 5841) (Landoni 2015 Level IV, n=88,820 [estimated epidural catheters]).
A review of data from publications reporting adverse effects after obstetric epidural analgesia
reported a risk estimate of 1 per 168,000 for epidural haematoma ( Ruppen 2006a Level IV SR,
27 studies, n≈1.37 million). In a large USA series of obstetric epidural analgesia, no epidural
haematoma was found (Bateman 2013 Level IV, n=79,837); the haematoma rate in this setting was
significantly lower than in the perioperative data from the same series.
Case reports of epidural haematoma after neuraxial blockade (spinal and epidural) haveincreased from 1994 to 2015, primarily due to increased rates in elderly women (Lagerkranser
2017a Level IV SR, n=166). Anticoagulants, in particular heparins, remain an important risk factor,
but epidural haematomas occur also in patients with no risk factors and despite following
guidelines. 80% present with paresis or paralysis, early MRI scan is the best diagnostic measureand over the period studied, outcomes have improved (Lagerkranser 2017b Level IV SR, n=166).
Early diagnosis and, if indicated, immediate decompression (<8 h after the onset ofneurological signs) increases the likelihood of partial or good neurological recovery ( Horlocker
2003 GL). This is confirmed by a case series of epidural haematomas (n=163), which showed worse
outcome with decompression delayed >12 h vs earlier decompression (OR 4.5; 95% CI 2.1 to 9.9)
(Bos 2018 Level IV SR, n=409 [reports]). This is confirmed by a further case series, although somepatients operated >24 h regained full motor function (Lagerkranser 2017b Level IV SR, n=166).
5.6.4.3 | Infectious complications (including epidural abscess)Serious neuraxial infections following epidural anaesthesia have previously been reported as
rare. However, prospective studies have found rates in the range of 0.015 to 0.05% (Wang 1999
Level IV, n=9,232; Rygnestad 1997 Level IV, n=2,000; Kindler 1996 Level IV, n>13,000). It is of note thatin the studies with these high incidences, patients had long durations of epidural catheterisation;
the mean duration in patients with an epidural space infection was 11 d, no infection occurred
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in any patient whose catheter was in situ for <2 d and the majority of patients were
immunocompromised (Wang 1999 Level IV, n=9,232).
Only 5.5% of 915 cases of epidural abscess published between 1954 and 1997 developed
following epidural anaesthesia and analgesia; 71% of all patients had back pain as the initialpresenting symptom and only 66% were febrile (Reihsaus 2000 Level IV, n=915). The classic triad ofsymptoms (back pain, fever and neurological changes) was present in only 13% of patients with
an epidural abscess (in a study unrelated to epidural catheterisation); diagnostic delays occurredin 75% of these patients and such delays led to a significantly higher incidence of residual motor
weakness (Davis 2004 Level IV, n=63 [epidural abscesses]).
Audit data showed that of 8,210 patients with epidural catheters over a period of 16 y, sixdeveloped epidural abscesses (Cameron 2007 Level IV). Only one of these required surgicaldecompression and they did not suffer any long‐term neurological loss. The authors stress theimportance of appropriate patient monitoring and early diagnosis using MRI. In five of the six
patients diagnosed with an epidural abscess, both fever and epidural insertion site infection were
present. They therefore suggested that MRI investigation may be warranted if this combination
is present and that urgent investigation is especially indicated if there is a third sign that could
indicate an abscess, such as back pain or neurological change ( Cameron 2007 Level IV, n=8,210). If
the diagnosis of epidural abscess can be made before the onset of any neurological deficit,
conservative treatment (antibiotics only) may be effective. The presence of severe or increasing
back pain, even in the absence of a fever, may indicate epidural space infection and should be
investigated promptly.
Thoracic epidural abscesses have been analysed; most common presentations were
neurological deficits (68%) (paraparesis 48% and paraplegia 20%), back pain (64%), fever (24%)
and loss of bowel or bladder control (16%) (Howie 2018 Level IV SR [PRISMA], 25 studies, n=25
[thoracic epidural abscesses]). Recommended diagnostic measures are early MRI scans, laboratory
tests (ESR, CRP, blood count and sedimentation rate/C-reactive protein, complete blood count),
empiric antibiotics (until abscess culture) and immediate surgical decompression in neurologicaldeficits as immediate surgical compression achieves better recovery than a failed antibiotic
course before surgical decompression.
A review of data from publications reporting adverse effects after obstetric epidural analgesia
reported a risk estimate of 1 per 145,000 for epidural space infection (Ruppen 2006a Level IV SR,
27 studies, n≈1.37 million).
Septic meningitis has also been associated with neuraxial anaesthesia and analgesia,
although most cases were associated with spinal or combined techniques; only 25 of 234 cases
identified were linked to epidural techniques (Zorrilla-Vaca 2018 Level IV SR, n=234). Not using
surgical masks was the most common association and staphylococcus aureus the most common
bacterium. Time to onset of meningitis was longer with epidural than spinal techniques (96 h;
IQR 84 to 240 vs 24 h; IQR 8 to 72) and mortality rate 13.3%.
5.6.4.4 | Diagnosis and prevention of Infectious complications
Bacterial colonisation of epidural catheter tips is reported to occur in 0 to 28% of patients (Yuan
2008 Level IV, n=205; Mishra 2006 Level IV, n=466; Steffen 2004 Level IV, n=502; Simpson 2000 Level IV,
n=1,442). The most common organism cultured from the catheter tips was coagulase‐negative
staphylococcus.
Experimental data suggest that after accidental epidural catheter disconnection, cutting thecatheter 2 cm distal to the level of contamination left all such treated catheters sterile, while
spray-wipe disinfection or employing ropivacaine 0.75% as flushing solution or a combination of328

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these measures were not as effective (Scholle 2014 BS). The authors suggest spray-wipe
disinfection and cutting as the safest strategy.
An in vitro comparison of the antibacterial activity of medications used in epidural solutions
showed that the minimal inhibitory concentration of bupivacaine for Staphylococcus aureus,
Enterococcus faecalis and Escherichia coli was between 0.125% and 0.25% (growth of
Pseudomonas aeruginosa was not affected at any of the concentrations investigated) (Coghlan
2009 Level III‐2 BS). Levobupivacaine and ropivacaine showed no activity against S aureus,
E faecalis and P aeruginosa, even at the highest concentrations tested, and minimal activity
against E coli (minimum inhibitory concentrations 0.5 and 1% respectively). The addition offentanyl, clonidine and adrenaline did not improve antibacterial activity
Chlorhexidine-impregnated dressings of epidural catheters in comparison to placebo or
povidone-iodine-impregnated dressings reduced the incidence of catheter colonisation ( Ho 2006
Level I, 8 RCTs, n=2,588). Chlorhexidine was also the superior skin disinfectant prior to regional
catheter insertion with a positive skin culture immediately after skin disinfection of 10% vs 35%
of povidone-iodine treated (NNT 4) (Krobbuaban 2011 Level II, n=100, JS 4). Chlorhexidine istherefore the recommended skin disinfectant before insertion of regional catheters ( Campbell
2014 GL). However, chlorhexidine is neurotoxic and skin preparation solutions must be allowed
to dry before instrumentation of the epidural space. For this reason, chlorhexidine must also be
kept clearly identified and separate from all solutions used for injection. As 2% chlorhexidine is
not superior to 0.5% for skin disinfection, UK guidelines recommend the use of 0.5% to reduce
neurotoxicity (Campbell 2014 GL).
Comprehensive reviews of infectious complications associated with central neuraxial and
PNB, including epidemiology, factors affecting bacterial colonisation of the epidural catheter aswell as use in febrile, infected and immunocompromised patients are published ( Hebl 2011 NR;
Horlocker 2008 NR).
Guidelines for skin antisepsis prior to neuraxial block (Association of Anaesthetists of GreatBritain and Ireland, Obstetric Anaesthetists’ Association, Regional Anaesthesia UK, Associationof Paediatric Anaesthetists of Great Britain and Ireland) recommend thorough handwashing withsurgical scrub solution, the use of barrier precautions, including the wearing of a cap, mask,sterile gown and gloves, and of a large sterile drape (Campbell 2014 GL). Chlorhexidine in alcohol(0.5%) should be used for skin preparation, but meticulous care must be taken to avoid thisreaching epidural space or CSF.
5.6.4.5 | Respiratory depression
The incidence of respiratory depression with epidural opioid analgesia depends on the criteria
used to define respiratory depression. In a review of published case series and audit data, thereported incidence of respiratory depression ranged from 1.1% (95% CI 0.6 to 1.9) using
respiratory rate to 15.1% (95%CI 5.6 to 34.8) using oxygen saturation (see Section 4.3.1.5 forcomments on respiratory rate as an unreliable indicator of respiratory depression); this was very
similar to the incidence reported for PCA (Cashman 2004 Level IV SR, 165 studies, n20,000).
5.6.4.6 | Hypotension
The incidence of hypotension depends on the dose of local anaesthetic and criteria used todefine hypotension. In the same review as above, the reported incidence of hypotension was
5.6% (95% CI 3.0 to 10.2) (Cashman 2004 Level IV SR, 165 studies, n20,000). In the large metaanalysis quoted above, incidence of hypotension is increased by epidural analgesia (OR 4.92;
95%CI 3.11 to 7.78) (Popping 2014 Level I [PRISMA], 125 RCTs, n=9,044). Hypotension requiring
intervention is increased in another meta-analysis after abdominal surgery (RR 7.13, 95%CI 2.87
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to 17.75) (6 RCTs, n=479) (Salicath 2018 Level I [Cochrane], 32 RCTs, n=1,716); a subsequent metaanalysis shows an increase in hypotension (RD 0.21; 95% CI 0.09 to 0.33) ( 17 RCTs, n=870) notleading to increased need for inotropes or vasopressors (RD 0.00; 95%CI -0.06 to 0.07) (23 RCTs,
n=1,821) (Guay 2019 Level I [Cochrane], 69 RCTs, n=4,680) (significant overlap between all three SRs).
But while TEA was associated with arterial hypotension after thoracic or abdominal surgery,this did not predict inability to walk (Gramigni 2013 Level IV, n=161); early mobilisation may be
carefully attempted despite hypotension or orthostatic changes.
5.6.4.7 | Treatment failure with epidural analgesia
Epidural analgesia may not always be successful due to a number of factors including catheter
malposition or displacement, or technical and patient factors resulting in an inability to achieveeffective analgesia (Hermanides 2012 NR). Intolerable adverse effects may also be an indication
for premature discontinuation. In a large prospective audit, 22% of patients had prematuretermination of postoperative epidural infusions (Ballantyne 2003 Level IV, n=5,628): the mostcommon causes were dislodgement (10%), inadequate analgesia (3.5%) and sensory or motor
deficit (2.2%). Most of these failures occurred on or after POD 2. The rate of technical failures ina meta-analysis of epidural analgesia is 6.1% (Popping 2014 Level I [PRISMA], 125 RCTs, n=9,044) andrisk of failure of the analgesic technique is increased in another meta-analysis (epidural vs IV
PCA) (RR 2.48; 95%CI 1.13 to 5.45) (10 RCTs, n=678) (Salicath 2018 Level I [Cochrane], 32 RCTs, n=1,716)(siginificant overlap of RCTs). After oesophagectomy, technical failure with TEA occurred in 17 to
22% (Hughes 2018 Level I [PRISMA], 3 RCTs, n=93) (0 RCT overlap).
Tunnelling and then suturing the epidural catheter subcutaneously vs fixation with adhesive
tape without tunnelling reduced incidence of clinically relevant dislocation of epidural catheters(>20 mm; 1/60 vs 9/61) (Sellmann 2014 Level II, n=121, JS 3). Bacterial contamination rates did not
differ (8/59 vs 14/54). Length of the catheter in the epidural space may also influence rate ofdislocation; in an RCT of 3 vs 5 vs 7 cm insertion, one patient in the 7 cm group had unilateral
sensory block and four patients in the 3 cm group had epidural catheter dislodgement ( Afshan
2011 Level II, n=102, JS 5). The authors suggest that 5 cm is the ideal depth of insertion.
5.6.4.8 | Anastomotic leakage
There has been concern among surgeons about increased risk of anastomotic leakage after
bowel surgery due to the stimulating effects of epidural administration of local anaesthetics; so
far there is no evidence to support these claims in colorectal surgery. This is supported by a large
meta-analysis which shows no difference in the incidence of gastrointestinal anastomotic
leakage (RR 0.74, 95%CI 0.41 to 1.32) (17 RCTs, n=848) (Guay 2016b Level I [Cochrane], 128 RCTs,
n=8,754). An audit of patients undergoing surgery for colorectal cancer in one centre showed that
epidural analgesia had no influence on occurrence of anastomotic leakage ( Lai 2013 Level III-2,
n=1,312). After oesophagectomy, TEA reduced the risk of anastomotic leakage (OR 0.13;
95%CI 0.02 to 0.71) (Michelet 2005 Level III-2, n=207).

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1. For all types of surgery, epidural analgesia provides better postoperative pain relief
compared with parenteral (including PCA) opioid administration (S) (Level I [Cochrane
Review]); except epidural analgesia using a hydrophilic opioid only (U) (Level I).
2. Thoracic epidural analgesia for open abdominal aortic surgery reduces pain intensity,
time to tracheal extubation, time spent in the intensive care unit, rate of acuterespiratory failure, myocardial infarction and gastrointestinal bleeding when comparedwith intravenous opioids (S) (Level I [Cochrane Review]).
3. High thoracic epidural analgesia used for coronary artery bypass graft surgery reduces
postoperative pain, risk of dysrhythmias, pulmonary complications and time to
extubation when compared with intravenous opioid analgesia (Q) (Level I [Cochrane
Review]).
4. Thoracic epidural analgesia for thoracotomy reduces the risk of chronic postsurgical pain(S) (Level I [Cochrane Review]).
5. Thoracic epidural analgesia improves bowel recovery after abdominal surgery (includingcolorectal surgery) (S) (Level I [Cochrane Review]).
6. Epidural analgesia is not associated with increased risk of anastomotic leakage after
bowel surgery (S) (Level I [Cochrane Review]).
7. Epidural analgesia provided with local anaesthetics for at least 24 hours compared tosystemic opioid analgesia reduces perioperative mortality and multiple morbidities(including ileus, pneumonia, respiratory depression and arrhythmias) but increases
hypotension (U) (Level I [PRISMA]).
8. After laparoscopic colectomy, thoracic epidural analgesia compared to intravenous PCA
reduces initial pain scores and time to first bowel opening, but length of hospital stay,
total rate of complications (S) (Level I [PRISMA]), urinary tract infection rates andhospital costs are increased (U) (Level III-2).
9. Combinations of low concentrations of local anaesthetic agents and opioids for epidural
analgesia provide consistently superior pain relief compared with either of the
medications alone; epidural opioids alone have no advantage over parenteral opioids (U)(Level I).
10. Epidural local anaesthetic administration improves oxygenation and reduces pulmonary
infections and other pulmonary complications compared with parenteral opioids (U)(Level I).
11. Chlorhexidine‐impregnated dressings of epidural catheters in comparison to placebo‐ or
povidone‐iodine‐impregnated dressings reduce the incidence of catheter colonisation(U) (Level I).
12. In patients with multiple rib fractures, thoracic epidural analgesia improves pain relief
versus parenteral opioids (N) (Level III-2 SR), but does not reduce incidence ofpneumonia and mortality (U) (Level I) and may not reduce need for ventilation (Q)(Level III-2 SR).

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13. The combination of thoracic epidural analgesia with local anaesthetics and nutritional
support leads to preservation of total body protein after upper abdominal surgery (U)(Level II).
14. The incidence of permanent neurological damage in association with epidural analgesia
is extremely low, especially in the obstetric population, but increases with various
comorbidities and risk factors; the incidence is higher where there have been delays indiagnosing an epidural haematoma or abscess (S) (Level IV SR).
15. Immediate decompression of an epidural haematoma (within 8 hours of the onset ofneurological signs) increases the likelihood of partial or good neurological recovery (S)(Level IV SR).
16. Epidural abscesses present mainly with neurological deficits and back pain; they are
best diagnosed with early MRI and best treated with empiric antibiotics (until abscessculture) and immediate surgical decompression when neurological deficits are present(S) (Level IV SR).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: The provision of epidural analgesia by continuous infusion, programmed intermittent
bolus or patient-controlled administration of local anaesthetic-opioid mixtures is safeon general hospital wards, as long as supervised by an anaesthesia-based pain service
with 24-hour medical staff cover and monitored by well-trained nursing staff (U).
 Prior to insertion of an epidural catheter, thorough handwashing with surgical scrub
solution, the use of barrier precautions including the wearing of a cap, mask, sterile
gown and gloves and use of chlorhexidine in alcohol for skin preparation arerecommended; but meticulous care must be taken to avoid the chlorhexidine solution
from reaching epidural space or cerebrospinal fluid (U).

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5.7 | Intrathecal analgesia
5.7.1 | Medicines used for intrathecal analgesia
5.7.1.1 | Local anaesthetics
IT local anaesthetics provide short-term postoperative analgesia. The use of spinal
microcatheters (<24 G) for postoperative infusions of local anaesthetics became controversial
when multiple cases of cauda equina syndrome were reported (Bevacqua 2003 NR). See also
Section 5.7.1.1. above.
5.7.1.2 | Opioids
Morphine is the most frequently studied IT opioid followed by fentanyl ( Popping 2012 Level I[PRISMA], 65 RCTs, n=3,338; Meylan 2009 Level I, 27 RCTs, n=1,205) (0 RCT overlap). Reported IT use ofother opioids includes pethidine (meperidine), hydromorphone, diamorphine, pentazocine,sufentanil, tramadol and buprenorphine (Staikou 2014 Level I, 105 RCTs, n unspecified). Some clinicalstudies used very high IT morphine doses (ie 500 mcg or more) without additional benefit. Lower
doses (<300 mcg) should be used as there is no clear dose-response relationship with IT
morphine for duration of analgesia nor for adverse effects (Popping 2012 Level I [PRISMA], 65 RCTs,
n=3,338; Meylan 2009 Level I, 27 RCTs, n=1,205)
For patients having procedures amenable to spinal anaesthesia alone (orthopaedic, urologic,
gynaecologic), the addition of IT morphine (50 mcg to 2 mg) consistently provides an increase induration of analgesia (as time to first requirement of additional opioid analgesia) (WMD 503 min;
95%CI 315 to 641) vs IT local anaesthetic alone (13 RCTs) (Popping 2012 Level I [PRISMA], 65 RCTs,
n=3,338). IT fentanyl (10 to 50 mcg) prolongs the duration of analgesia (WMD 114 min; 95%CI 60
to 168). When IT morphine is used, cumulative morphine consumption is reduced (WMD -12 mg;
95%CI -18 to -5) (7 RCTs). There is considerable heterogeneity in the study data and no doseresponsiveness could be identified.
For major abdominal or thoracic surgery, IT opioids are typically combined with a generalanaesthetic technique. In patients having abdominal, cardiothoracic or spinal surgery,IT morphine (100 to 500 mcg, without local anaesthetic) reduces pain scores at rest and withmovement by 1/10 and 2/10 respectively at both 12 h (7 RCTs, n=353) and 24 h time points (8RCTs, n=393) (Meylan 2009 Level I, 27 RCTs, n=1,205). Morphine-sparing is evident for up to 48 h
postoperatively (11 RCTs, n=482), being more pronounced at 24 h after abdominal (5 RCTs, n=272)
than cardiothoracic surgery (6 RCTs, n=210).
IT fentanyl is inferior to IT dexmedetomidine which prolongs the pain free period (SMD 2.98;
95%CI 1.69 to 4.27) (7 RCTs, n=491) without increasing the incidence of adverse events including
hypotension and bradycardia (8 RCTs each) (Sun 2017 Level I, 9 RCTs, n=639).
Lower limb arthroplasty (TKA and THA)
In comparison to IT morphine 100─200 mcg for THA and TKA, local infiltration analgesia (LIA:
local anaesthetic, ketorolac 30 mg and adrenaline) results in a small reduction of pain scores atrest and at mobilisation at 24 h, but not at 48 h ( Jia 2017 Level I, 4 RCTs, n=242). There is nodifference in the rescue opioid consumption (4 RCTs) or LOS (3 RCTs). Nausea, vomiting andpruritus are increased in the IT morphine group (4 RCTs).
IT morphine 100─300 mcg vs FNB for TKA shows similar pain scores at 6 h (SMD -0.09; 95%CI-1.62 to 1.43) as well as at 12 h and 24 h, with no difference in morphine consumption for thesame time points or PONV (Li 2016 Level I, 4 RCTs, n=185). The risk of postoperative pruritus is
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reduced with FNB (RD 0.41; 95%CI 0.29 to 0.54). Another overlapping meta-analysis of the same
issues shows significant inconsistencies in representing trial results, which makes it difficult tobe confident of the conclusions drawn (Tang 2017 Level I [PRISMA], 5 RCTs, n=225) (4 RCTs overlap).
Thus only the results of the previous meta-analysis are considered (Li 2016 Level I, 4 RCTs, n=185).
Several RCTs and studies have shown that the use of low-dose IT morphine has analgesic
benefit. One RCT included in both meta-analyses had a third group combining continuous FNB
with IT morphine 175 mcg, with no advantage of the combination over the continuous FNB,
which was superior to IT morphine alone (Olive 2015 Level II, n=81, JS 4). In contrast, a small IT
morphine 35 mcg dose improved pain scores when added to a continuous FNB, although theauthors noted a higher rate of severe pain in both groups than in comparable studies of FNB(Sundarathiti 2016 Level II, n=70, JS 4). For TKA under spinal anaesthesia, where all patients had LIA,
addition of IT morphine 100 mcg to adductor canal block [ACB] achieved the lowest pain scoresand morphine requirements vs ACB alone and sham ACB (Biswas 2018 Level II, n=201, JS 5).
However, there was no difference in the primary outcome ‘Timed Up and Go (TUG)’ test on POD
2 and any other short- or long-term functional outcomes. IT morphine >100─200 mcg in addition
to systemic multimodal analgesia for THA and TKA (and a continuous femoral nerve block (FNB)
or adductor canal block (ACB) for TKA until POD 1) achieved better analgesia, reduced opioid
consumption, better mobilisation and less nausea (Cheah 2018 Level III-2, n=598 [467 ITM]). When
compared to an US-guided fascia iliaca block for THA under spinal anaesthesia, IT morphine 100
mcg reduced the cumulative morphine consumption at 48 h and time to mobilisation (by 2 h)without a significant difference in adverse side effects (Kearns 2016 Level II, n=108, JS 5). Compared
to a continuous lumbar plexus catheter technique for THA, IT morphine 100 mcg added to spinal
anaesthesia resulted in similar pain scores and opioid supplementation rates, but higher rates ofpruritus (Fredrickson 2015 Level II, n=50, JS 2).
Caesarean section
IT opioids have been used as a component of the spinal anaesthetic for Caesarean section formany years. The addition of IT morphine 50─250 mcg increases the median time to first analgesia
from 2 h (range 1 to 4 h) to 27 h (range 11 to 29 h) (Dahl 1999 Level I, 15 RCTs, n=535). Higher dosesof IT morphine (>100─250 mcg) vs lower doses (50─100 mcg) for analgesia after Caesarean
section lead to a longer time to first analgesic request (MD 4.49 h; 95%CI 1.85 to 7.13), but withno significant difference in pain scores or morphine consumption ( Sultan 2016 Level I, 11 RCTs,
n=480) (3 RCTs overlap). The high-dose IT morphine group has higher incidence of PONV andpruritus (NNH 5.9; 95%CI 3.4 to 20.0) with no effect on Apgar scores.
IT morphine in a dose of 50 mcg had similar analgesic effects to 100 and 150 mcg whenused with a spinal block and ketorolac with a similar side effect profile (with the lowest dose
having a slightly reduced incidence of pruritus) ( Berger 2016 Level II, n=144, JS 5). IT morphine
50 mcg had similar analgesic effects to 100 mcg, but the higher dose resulted in a significantly
higher rate of pruritus (64 vs 40%) ( Mikuni 2010 Level II, n=75, JS 3). Using an up–down sequential
allocation the ED90 was determined to be 75 mcg (95%CI 46 to 93) for IT hydromorphone and
150 mcg (95%CI 145 to 185) for IT morphine with no difference between both for analgesia,side effects and patient satisfaction ( Sviggum 2016 Level II, n=80, JS 5).
IT fentanyl 12.5 to 50 mcg added to spinal anaesthesia leads to a longer time to first analgesic
request (MD 91 min; 95%CI 69 to 113) (12 RCTs, n=574) and reduces the incidence ofnausea/vomiting (RR 0.41; 95%CI 0.24 to 0.70) (NNT 6.5) (12 RCTs, n=580), but increases theincidence of intraoperative pruritus (RR 5.89; 95%CI 2.07 to 16.79) (NNH 13.5) (13 RCTs, n=604)(Uppal 2020 Level I [PRISMA], 17 RCTs, n=1,064).

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IT fentanyl 25 mcg/morphine 100 mcg combination vs morphine alone improved
intraoperative analgesia and did not affect 24 h postop opioid requirements, but increased 12 h
opioid requirements and PONV rates (Weigl 2017 Level II, n=60, JS 5).
Compared to a transversus abdominis plane (TAP) block, IT morphine 100 mcg resulted inlower pain scores, but only at 10 h, while causing more PONV and pruritus (Loane 2012 Level II,
n=66, JS 5). This study failed to achieve full recruitment. IT morphine 100 mcg vs ropivacaine 0.2%
via wound catheter had the same efficacy with no difference in median time to first morphinerequest (Lalmand 2017 Level II, n=192, JS 5). Both techniques were superior to the control groupwith spinal anaesthesia by bupivacaine/sufentanil only.
LabourAdding IT morphine 50 to 250 mcg to single-injection IT bupivacaine/fentanyl 12.5 or 25 mcg or
bupivacaine/sufentanil 5 or 10 mcg prolongs pain relief during labour by 61 min (range 3 to 155min) with no effect on SMD of pain intensity (Al-Kazwini 2016 Level I [PRISMA], 5 RCTs, n=286).
Spinal surgery
IT morphine (100 mcg to 1 mg; 3.5─20 mcg/kg) vs placebo (6 RCTs) or control after spinal surgery
results in reduced pain scores (7 RCTs) and postoperative opioid consumption (8 RCTs) during thefirst 24 h postoperatively with a higher rate of pruritus; respiratory depression only occurred in
the IT morphine group (6/231) (8 RCTs) (Pendi 2017 Level I, 8 RCTs, n=393). This review includes
abstract data for a later peer reviewed publication (Yen 2015 Level II, n=32, JS 4).
Cardiothoracic surgery
IT morphine 7 mcg/kg prior to surgical aortic valve surgery had a better analgesic effectpostoperatively vs titrated systemic fentanyl, with reduced parenteral opioid requirements andincreased time to first opioid rescue (Elgendy 2017 Level II, n=44, JS 5). In addition, the IT morphinegroup had a slightly earlier extubation and shorter ICU LOS. There were no reports of increasedside effects. In minimally invasive cardiac surgery, IT morphine 1.5 mcg/kg reduced PCA-opioid
requirements and pain scores (Mukherjee 2012 Level II, n=62, JS 3). For open thoracotomy
procedures, the combination of IT morphine 4 to 5 mcg/kg (max 500 mcg) and sufentanil 0.2−0.3
mcg/kg (max 25 mcg) with a continuous PVB offered slightly higher but acceptable pain scoresvs epidural analgesia (Dango 2013 Level II, n=84, JS 4).
Hepatic surgery
After liver resection, IT morphine 500 mcg/fentanyl 150 mcg resulted in better analgesia andlower opioid requirements than morphine PCA up to 18 h postoperatively (Roy 2006 Level II, n=20,
JS 3). IT morphine 200 mcg vs epidural analgesia in liver resections showed comparable painscores, although epidural recipients had lower opioid consumption and intubation duration (DePietri 2006 Level II, n=50, JS 2). Similarly, in patients for liver resections, IT morphine 500 mcg andfentanyl 15 mcg was inferior to epidural bupivacaine infusion, with twice as much morphine
consumption (123 mg vs 59 mg) and more pain (Mondor 2010 Level II, n=44, JS 5).
Urological surgery
IT morphine 50 to 200 mcg (± clonidine) after prostatic surgery resulted in better analgesia andlower opioid requirements vs morphine PCA up to 18 h postoperatively (Brown 2004 Level II, n=99,
JS 5). For transurethral resection of the prostate under spinal anaesthesia, low-dose IT morphine
25 and 50 mcg resulted in similar pain scores for up to 24 h, but the higher-dose group had morepruritus (15 vs 0%) (Duman 2010 Level II, n=70, JS 4).

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Other surgery
IT hydromorphone 5 or 10 mcg in addition to spinal anaesthesia for knee arthroscopic surgery
reduced pain scores for up to 12 h vs 2.5 mcg dose or placebo (Lee 2012 Level II, n=60, JS 3). Nausea
was more frequent (46%) in the 10 mcg group.
After open nephrectomy, IT morphine 330 mcg plus IV PCA versus IV PCA alone resulted inbetter analgesia and reduced systemic opioid requirements with similar adverse effects except
for increased pruritus (77 vs 26%) (Kim 2016 Level II, n=45, JS 4).
IT morphine at three different doses (100, 200 and 300 mcg) for abdominal hysterectomy
was superior to placebo for analgesia up to 24 h, with the 200 mcg dose equivalent to 300 mcg
and superior to 100 mcg in rescue analgesia requirements ( Hein 2012 Level II, n=144, JS 5). For
inguinal hernia repair, IT morphine 100 mcg had similar analgesia to 400 mcg with increased
PONV in the higher dose group (Meco 2016 Level II, n=48, JS 4).
For endovenous laser ablation in lower extremity venous insufficiency/varicose vein disease,
the addition of IT morphine 100 mcg versus IT fentanyl 25 mcg to bupivacaine spinal anaesthesia
reduced shivering vs placebo control as well as increased time to first analgesia use similarly (Onk2016 Level II, n=90, JS 4).
5.7.1.3 | Adverse effects
Typical adverse effects of IT opioids include nausea and vomiting, pruritus and delayed
respiratory depression (Popping 2012 Level I [PRISMA], 65 RCTs, n=3,338; Meylan 2009 Level I, 27 RCTs,
n=1,205) (0 RCT overlap).
Opioid-induced ventilatory impairment
The definition of respiratory depression in different investigations often lacks uniformity, withmany studies using respiratory rate as the primary marker and others using desaturation todifferent levels and a few others using the need for opioid antagonists. This significantly
compromises interpretation of reported event rates. OIVI is a more appropriate term ( Macintyre
2011 NR). Patients may be hypoxic or hypercapnic with a normal respiratory rate ( Bailey 1993 Level
IV EH, n=20), while others may be able to maintain normocarbia with a lower respiratory rate
(Boezaart 1999 Level II, n=60, JS 5). In a volunteer study, clinical signs or symptoms including
respiratory rate, sedation and pupil size did not reliably indicate hypoventilation or hypoxaemia,
unlike peripheral pulse oximetry (Bailey 1993 Level IV EH, n=20); although desaturation itself is alate indicator when supplemental oxygen is being administered ( Shapiro 2005 Level IV, n=1,524).
Very large numbers of patient exposures are needed to adequately quantify risk of infrequent
events (eg OIVI), thus most studies and meta-analyses will have a limited capacity to reportmeaningfully on such adverse effects (see also Section 4.3.1.4).
When measured in opioid-naïve volunteers, respiratory depression peaked at 3.5 to 7.5 hfollowing IT morphine at 200 to 600 mcg doses (Bailey 1993 Level IV EH, n=20). Volunteers given
600 mcg had significant depression of the ventilatory response to CO 2 up to 19.5 h later.
In patients following major surgery, a 7.6% incidence of respiratory depression was reported
for IT morphine >300 mcg vs IV PCA morphine (OR 7.86; 95%CI 1.54 to 40.3) (3 RCTs, n=172)(Meylan 2009 Level I, 27 RCTs, n=1,205). In patients having spinal surgery, IT morphine only resulted
in respiratory depression (6/231) vs placebo (0/162) (RR 3.48; 95%CI 0.41 to 29.32) (Pendi 2017
Level I, 8 RCTs, n=393). In patients having minor surgery, major respiratory depression (endpoint“SpO2 85 to 90%” in addition to respiratory rate <12) occurred in 3 of 290 (1.0%) patients
receiving IT bupivacaine alone and 15 of 410 (3.7%) receiving IT bupivacaine/morphine (OR 3.49;
95%CI 1.25 to 9.73) (Popping 2012 Level I [PRISMA], 65 RCTs, n=3,338). In the same analysis, theincidence of OIVI in patients receiving IT fentanyl (0.4%) was no different to control (0%). Thus,

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indirect comparisons suggest that the risk of OIVI is more pronounced with IT morphine thanwith IT fentanyl.
A meta-analysis for a range of procedures, comparing IT morphine doses of <300 mcg,
≥300 mcg and placebo reported a greater risk of respiratory depression (respiratory rate
<8 to 12) with the higher doses (9%) with no increased risk with lower morphine dose (1%) vssystemic opioids (2%) (Gehling 2009a Level I, 28 RCTs, n=1,414). This difference was not statisticallysignificant but this may reflect the relatively small number of patients in the higher dose group(n=87). The incidence of pruritus was increased for all doses (low dose RR 1.8; 95%CI 1.4 to 2.2
vs high dose RR 5.0; 95%CI 2.9 to 8.6); the risk of nausea and vomiting was increased only inthose patients given <300 mcg morphine.
For Caesarean section, when IT opioids (all types of opioids and all doses) were combinedwith local anaesthetic for analgesia, the rate of respiratory depression was low and not
significantly different from controls (Dahl 1999 Level I, 15 RCTs, n=535). In a large case series,
clinically detected respiratory depression in the 24 h following IT morphine 150 mcg was noted
in 0.26% of patients (Kato 2008 Level IV, n=1,915). In a closed claims study from the USA, a maternal
death from IT opioid overdose is reported (Clayton 2018 CR).
A prospective audit of IT morphine 200─800 mcg for pain relief following a range of surgicalprocedures reported a high degree of patient satisfaction and effective analgesia in the first
24 h (Gwirtz 1999 Level IV, n=5,969). The incidence of pruritus was 37%, nausea and vomiting 25%
and respiratory depression 3% (PaCO2 >50 mmHg and/or respiratory rate <8).
Overall, considering the increased risk of OIVI with IT morphine, the lowest effective dose of
IT opioid should be used and surveillance for OIVI should continue for at least 18 to 24 h following
a single dose (Bailey 1993 Level IV; Bujedo 2012 NR). A current ASA guideline recommends a
minimum monitoring period of 24 h after administration of single-injection IT morphine, with
monitoring of at least once per hour for the first 12 h and then at least once every 2 h for the
next 12 h (ASA 2016 GL). The monitoring should consist of level of consciousness, adequacy ofventilation (rate and depth of respiration) and pulse oximetry. Higher risk patients may require
additional monitoring and for a longer period of time. This document also discusses in further
detail identification of at-risk patients and strategies for prevention, detection and management
of OIVI in patients with neuraxial opioids.
A similar guideline has been published by the Society for Obstetric Anesthesia and Perinatology(SOAP) for the use of neuraxial opioids in Caesarean section patients (Bauchat 2019 GL).
Pruritus
Pruritus is a frequent adverse effect of opioids by all routes. The rate following IT morphine ishigher than that for patients receiving IV PCA morphine (OR 3.85; 95%CI 2.40 to 6.15) ( Meylan
2009 Level I, 27 RCTs, n=1,205) and is dose-dependent (Sultan 2016 Level I, 11 RCTs, n=480). The itchis thought to be caused by stimulation of spinal and supraspinal mu-opioid receptors which
includes the trigeminal nucleus and explains the frequency of facial itch ( Kumar 2013 NR). The
incidence of pruritus with IT morphine 50 mcg to 1 mg was 29.2% vs 4.4% with bupivacaine alone(OR 6.92; 95%CI 4.51 to 10.6; NNH 4) (17 RCTs) (Popping 2012 Level I [PRISMA], 65 RCTs, n=3,338). IT
fentanyl 10─40 mcg had an incidence of pruritus of 27.3% vs 0% with bupivacaine alone (13 RCTs).
Incidence following IT opioids for Caesarean section
Pregnant women report greater rates of pruritus of 60 to 100%, which may be due to aninteraction of oestrogen with opioid receptors (Kumar 2013 NR). While the incidence of pruritus
is consistently high, the number requiring treatment is lower; in post-Caesarean section patients
receiving 100 mcg IT morphine, 64% of patients reported pruritus with the proportion requiring
treatment being 18% (Mikuni 2010 Level II, n=75, JS 3). In patients having Caesarean section underspinal anaesthesia, IT morphine 100 mcg was vs oral opioid (oxycodone CR), the IT morphine
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group had similar overall pain scores but reported better satisfaction at 24 h and fewer high painscores but experienced more pruritus (87 vs 56%) (McDonnell 2010 Level II, n=111, JS 5).
5HT3-receptor antagonists
There may be a connection between serotonin (5-HT) levels and pruritus, as IT morphineincreases serotonin plasma concentrations in a dose-dependent fashion by 283% (10 mcg) vs
556% (200 mcg), with pruritus rates of 55% and 75% respectively (Aly 2018 Level II, n=40, JS 5).
5HT3-receptor antagonists decrease the incidence of pruritus related to IT opioids with an NNTof 6 (OR 0.44; 95%CI 0.29 to 0.68) (Bonnet 2008 Level I, 15 RCTs, n=1,337). This analysis included ahigh number of Caesarean section patients, who reported higher rates of pruritus. In a subgroup
analysis, the antipruritic effect is seen in the morphine (9 RCTs) but not fentanyl/sufentanil
recipients (5 & 1 RCTs). A similar analysis based purely on Caesarean section patients receiving IT
morphine does not identify a decrease in incidence in pruritus overall with prophylactic 5HT 3
antagonists, but use does reduce the incidence of severe pruritus with an NNT of 3 forestablished pruritus (George 2009 Level I [PRISMA], 9 RCTs, n=1,152) (6 RCTs overlap with Bonnet 2008).
Ondansetron 4 to 8 mg reduces pruritus after IT morphine in non-obstetric cases (RR 0.63; 95%CI
0.45 to 0.89) (7 RCTs [1 RCT epidural morphine], n=576) (Wang 2017 Level I (PRISMA), 10 RCTs, n=811).
However, the result for Caesarean section was not significant with a high degree ofheterogeneity (3 RCTs, n=253). Reasons for an inconclusive result in the obstetric grouphighlighted by the authors include the co-administration of a lipid soluble opioid fentanyl, thedelay in administration of ondansetron until after IT morphine because of concerns of placental
transfer and altered pharmacokinetic handling of ondansetron in parturient women. Specifically,in pruritus caused by IT fentanyl 10 to 25 mcg and IT sufentanil 10 mcg, IV ondansetron 8 mg
does not reduce the incidence of pruritus, but does reduce the need for rescue medication (RR
0.57; 95%CI 0.35 to 0.91) (Prin 2016 Level I, 6 RCTs, n=555).
Opioid antagonists
There is limited data and conflicting results regarding the use of opioid antagonists in treating
pruritus following IT opioids. However, with parenteral opioids, overall IV naloxone reduces theincidence of pruritus (OR 0.40; 95%CI 0.21 to 0.79) and nausea (OR 0.62; 95%CI 0.43 to 0.89) but not
vomiting (Murphy 2011 Level I, 8 RCTs, n=800). Other methods that have been described for prevention
include nalbuphine (Tubog 2019 Level I [PRISMA}, 17 RCTs, n=1,052), mirtazapine (a noradrenergic andspecific serotonergic antidepressant [NaSSA]) and dopamine antagonists such as droperidol (Kumar
2013 NR). SC methylnaltrexone 12 mg (a mu-opioid receptor antagonist that works peripherally anddoes not cross the blood brain barrier) reduced nausea, but had no effect on pruritus or urinary
retention (Zand 2015 Level II, n=72, JS 5). Similarly, SC methylnaltrexone 12 mg versus placebo did not
reduce pruritus from IT morphine 100 mcg after Caesarean section (84% vs 88%) (Paech 2015 Level II,
n=37, JS 5).
Other treatments
Other treatments for established pruritus include pentazocine (a mixed opioid agonistantagonist with kappa receptor effects) which was more effective in treating pruritus post
Caesarean section than ondansetron 4 mg (Tamdee 2009 Level II, n=208, JS 5). IV pentazocine
15 mg had a prophylactic effect on pruritus after IT opioids for Caesarean section vs placebo (RR
0.69; 95%CI 0.52 to 0.90) (Hirabayashi 2017 Level II, n=122, JS 5). Diphenhydramine 25 mg has also
been reported to be as effective as ondansetron 4 mg (Siddik-Sayyid 2010 Level II, n=113, JS 5).
Preoperative acupuncture vs sham acupuncture maintained for 48 h postoperatively wasineffective in reducing pruritus caused by IT morphine for Caesarean section (Mazda 2018 Level II,
n=30, JS 5).

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Nausea and vomiting
Postoperative nausea is common after IT morphine, especially in obstetrics. Consensus
guidelines exist for PONV management; however, these do not address IT opioids specifically(Gan 2014 GL). Following minor surgical procedures, the addition of IT morphine significantly
increased the risk of nausea from 29.4% to 39.4% (OR 1.66; 95%CI 1.05 to 2.64) (NNH 9.8) (10
RCTs, n=361) and vomiting from 16.6% to 26.2% (OR 1.88; 95%CI 1.20 to 2.94) (NNH 10) (14 RCTs,
n=505) vs IT local anaesthetic with systemic analgesics (Popping 2012 Level I [PRISMA], 65 RCTs,
n=3,338). Following major surgery, comparing IT opioids to systemic opioids there was anonsignificant increase in the incidence of nausea (30.5 vs 24.2%; OR 1.22; 95%CI 0.77 to 1.95)
and no difference in the incidence of vomiting (23.8 vs 22.6%; OR 1.05; 95%CI 0.63 to 1.73)(Meylan 2009 Level I, 27 RCTs, n=1,205). A low dose of IT morphine 100 mcg caused no vomiting vs
400 mcg (23%) for inguinal hernia repair (Meco 2016 Level II, n=48, JS 4).
Following Caesarean section with IT morphine and fentanyl, ondansetron and transdermal
scopolamine were equally effective in reducing emesis from 59.3% (control) to 41.8%(ondansetron) and 40% (scopolamine), although scopolamine use was associated with more
anticholinergic adverse effects (Harnett 2007 Level II, n=240, JS 4). The combination of ondansetronwith either dexamethasone or droperidol had a better antiemetic effect after gynaecologicalsurgery with IT morphine vs droperidol/dexamethasone (Sanchez-Ledesma 2002 Level II, n=90, JS 4),
although this latter combination was superior vs either alone (Wu 2007 Level II, n=120, JS 5).
Urinary retention
The incidence of urinary retention is not increased in patients receiving IT morphine for major
surgery (Gehling 2009b Level I, 28 RCTs, n=1,414; Meylan 2009 Level I, 27 RCTs, n=1,205); however, inpatients having spinal anaesthesia for minor surgery, IT morphine increases the risk of urinary
retention (OR 3.9; 95%CI 1.94 to 7.86) (NNH 6.5) (7 RCTs, n=225) (Popping 2012 Level I [PRISMA],
65 RCTs, n=3,338).
Other adverse effects
In women in labour, reactivation of oral herpes simplex labialis was more frequent following IT
morphine for labour analgesia than IV PCA morphine (38 vs 16.6%) (Davies 2005 Level II, n=98, JS 4).
Cardiovascular effects of IT opioids have generally not been reported. In a retrospective cohort
study, IT hydromorphone 50 to 80mcg used in patients having elective colorectal resection withrestricted fluid therapy found a higher rate of hypotension (mean arterial blood pressure <60
mmHg or systolic blood pressure <110 mmHg) in those receiving hydromorphone (4.3%) vs thecontrol group up to 12 h (Hubner 2013 Level III-2, n=163). This normalised by 24 h and was not
associated with any identified adverse outcomes. IT morphine 7 mcg/kg in surgical aortic valve
replacement decreased mean arterial pressure and heart rate while preserving cardiac output,
pulmonary capillary wedge pressure and central venous pressure (Elgendy 2017 Level II, n=44, JS 5).
Caution has been advised regarding the use of IT opioids in patients who are at risk of spinal
cord ischaemia (eg thoracic aortic stenting/surgery) (Fedorow 2010 NR), although its use has been
described (Chaney 1996 Level IV). Such caution is based primarily on laboratory data, although acase report is published (Kakinohana 2003 CR).
5.7.1.4 | Adjuvant medicines
A variety of adjuvant medicines have been used with IT analgesia, including clonidine,dexmedetomidine, ketamine, neostigmine and midazolam. Many medicines are not licensed foruse as spinal analgesic agents; however adequate evidence from the literature may make theiruse acceptable (for more detail see Chapter 4).

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Clonidine and Dexmedetomidine
The addition of clonidine 30 to 150 mcg to IT morphine 100 to 500 mcg causes a small increasein analgesia duration (1.63 h; 95%CI 0.93 to 2.33) (5 RCTs, n=464) and reduces the amount ofsystemic morphine consumption over 24 h (4.45 mg; 95%CI 1.40 to 7.49) (7 RCTs, n=629)(Engelman 2013 Level I [PRISMA], 7 RCTs, n=503). Incidence of hypotension was also increased (OR1.78; 95%CI 1.02 to 3.12).
For major abdominal cancer surgery, IT dexmedetomidine 5 mcg added to IT morphine
500 mcg and bupivacaine did not improve analgesia vs the IT morphine/bupivacaine group(Abdel-Ghaffar 2016 Level II, n=90, JS 5). Both groups with adjuvants experienced better analgesia
than bupivacaine alone.
Magnesium
Magnesium most likely contributes to analgesia by acting as a noncompetitive NMDA-receptor
antagonist in the spinal cord. There was no benefit with IT versus intraperitoneal magnesium inanimal experiments (Messeha 2016 BS). Magnesium 1.67─50% with opioid with or without local
anaesthetic prolongs the time to first analgesia requirement in non-obstetric populations (SMD
1.38; 95%CI 0.6 to 2.11) but not obstetric patients (Morrison 2013 Level I, 15 RCTs, n=980). This may
be an effect of fewer studies in the obstetric group. There is no increase in incidence of
hypotension. There was a high degree of heterogeneity making any firm conclusion difficult.

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5.0 | ADMINISTRATION OF ANALGESIC MEDICINESKEY MESSAGES
1. Intrathecal morphine improves analgesia and is opioid-sparing for up to 24 hours after
major surgery including abdominal (S), orthopaedic (N), spinal (N) (Level I [PRISMA])
and cardiothoracic surgery (N) (Level II).
2. Adding intrathecal morphine to intrathecal bupivacaine/fentanyl or intrathecal
bupivacaine/sufentanil prolongs pain relief after labour (N) (Level I [PRISMA]).
3. The addition of intrathecal fentanyl (N) (Level I [PRISMA]) and morphine to spinal
anaesthesia prolongs time to first analgesic request after Caesarean section (N) (Level I).
4. Intrathecal morphine in comparison to peripheral regional analgesia techniques offers
similar analgesic benefits, but increases adverse effects (nausea, vomiting, pruritus)
after lower limb arthroplasty (N) (Level I).
5. The incidence of opioid-induced ventilatory impairment, pruritus and postoperative
nausea and vomiting is higher with intrathecal morphine compared with intravenous
PCA opioids (S) (Level I).
6. Pruritus with intrathecal opioids is dose-dependent (N) (Level I) and can be effectively
prevented and treated with 5HT3 antagonists in non-obstetric patients, but only
treated but not prevented in obstetric patients (Q) (Level I)
7. The addition of intrathecal magnesium to opioids and/or local anaesthetics results inslightly longer analgesia in non-obstetric patients (U) (Level I).
8. The addition of intrathecal clonidine to intrathecal morphine results in slightly longer
analgesia and reduced opioid requirements (U) (Level I).
9. Pruritus with intrathecal opioids cannot be treated with methylnaltrexone (N) (Level II).
The following tick boxes represent conclusions based on clinical experience and expert opinion: The absence of consistent dose-responsiveness to the efficacy of intrathecal opioids
and the increase in adverse effects with higher doses suggests that the lowest effective
dose (typically 50-200 mcg morphine) should be used (Q).
 Patients receiving intrathecal opioids should be monitored for opioid-induced
ventilatory impairment for the anticipated duration of opioid effects, eg 18 to 24 hours
after intrathecal morphine (S).
 Clinical experience with morphine, fentanyl and sufentanil has shown no neurotoxicity
or behavioural changes at normal clinical intrathecal doses (U), however caution isrecommended in patients who are at risk of spinal cord ischaemia (U).

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5.8 | Other regional and local analgesic techniques
Regional and local analgesic techniques have evolved recently, with a large number of new
ultrasound-guided blocks. There have been developments in our understanding of anatomy andproof-of-concept studies on neuromodulation for acute pain management. Regional and local
analgesic techniques should be used in conjunction with oral multimodal analgesic techniques.
Adjuvant agents to local anaesthetics are considered in other sections: eg alpha-2-agonists in
Section 4.9.2 and corticosteroids in Section 4.12.2 and opioids in Section 4.2.3.

5.8.1 | Needle and catheter localising techniques
Techniques used to precisely identify correct needle location and hence local anaesthetic andcatheter placement include anatomic landmarks, peripheral nerve stimulation (PNS) andultrasound (US) guidance. Radiologic imaging and direct vision during surgery have also beenused. In comparison with PNS, blocks performed using US-guidance are more likely to be
successful (RR 0.41 [for block failure]; 95%CI 0.26 to 0.66) (9 RCTs), faster to perform (WMD 1.1 min less to perform with US; 95%CI -1.7 to -0.4) (7 RCTs), have faster onset (29% shorter onset
time; 95%CI 45 to 12%) (8 RCTs), longer duration (SMD 25%; 95%CI 12 to 38) (5 RCTs) and reduced
vascular puncture (RR 0.16; 95%CI 0.05 to 0.47) (4 RCTs) (Abrahams 2009 Level I, 13 RCTs, n=941).
US-guidance is associated with an increase in success rate of nerve blocks vs all non-US
techniques (RR 1.11; 95%CI 1.06 to 1.17) and vs PNS alone (RR 1.11; 95%CI 1.05 to 1.17) (Gelfand
2011 Level I, 16 RCTs, n=1,264) (8 RCTs overlap with Abrahams 2009). US-guided techniques vs PNS (17RCTs) and other needle-localisation techniques (2 RCTs) are associated with higher success rates,
faster onset of block and lower vascular puncture rate (McCartney 2010 Level I, 25 RCTs, n=2,187) (8RCTs overlap with Abrahams 2009 & 9 RCTs overlap with Gelfand 2011).
These findings are also confirmed for placement of catheters, where US- vs PNS-guidance
results in a higher success rate (9 RCTs, n=530) and a lower rate of accidental vascular puncture(RR 0.13; 95% CI: 0.04 to 0.38) (15 RCTs) vs PNS guidance (Schnabel 2013 Level I [PRISMA], 15 RCTs,
n=977). Stimulating catheters have been compared with nonstimulating catheter techniques inestablishing continuous FNBs for postoperative analgesia following TKA. There was no differencein quality of postoperative analgesia between these two insertion techniques ( Barrington 2008
Level II, n=82, JS 5; Morin 2005 Level II, n=141, JS 3). Stimulating catheters have also been comparedwith nonstimulating catheter techniques at other anatomical locations with inconclusive results(Stevens 2007 Level II, n=43, JS 4; Dauri 2007 Level II, n=70, JS 3; Rodriguez 2006 Level II, n=48, JS 3).
US-guidance has been compared with stimulating and non-stimulating techniques forcontinuous infraclavicular brachial plexus block. The combination of US- and PNS-guidance (withstimulating catheters) resulted in the highest primary success and reduced secondary catheter
failure (McCartney 2010 Level I, 1 RCT: Dhir 2008 Level II, n=66, JS 3). In the placement of popliteal
sciatic nerve catheters, US-guidance alone resulted in similar analgesic outcomes for up to 48 h
vs US- and PNS-(stimulating catheter) guidance (Robards 2013 Level II, n=21, JS 3). In patients having
TKA, the combination of US-guidance and PNS (needle and/or stimulating catheter) was notdifferent to US-guidance alone in analgesic efficacy over 48 h (Farag 2014 Level II, n=437, JS 4);
stimulating catheter use was associated with a longer procedural time.
An analysis of the German Network of Regional Anaesthesia database between 2007 and2012 reveals the effects of being awake (n=25,004), sedated (n=15.121) or anaesthetised (n=2,529)
on complications of regional anaesthesia (Kubulus 2016 Level III-2, n=42,654). There are nodifferences in the rates of LAST or pneumothorax. For peripheral nerve blocks, both sedation(aOR 1.82; 95%CI 1.50 to 2.21) and general anaesthesia (aOR 1.33; 95%CI 1.01 to 1.78) are342

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associated with an increased risk of a bloody tap. The risk for multiple skin puncture is lower insedated (aOR 0.78; 95%CI 0.71 to 0.85) and higher in anaesthetised patients (aOR 1.28; 95%CI
1.12 to 1.46).

5.8.2 | Continuous and single-injection peripheral nerve blocks
Percutaneous perineural catheter placement enables an infusion of local anaesthetic increasing
the duration of analgesia and associated benefits. Continuous peripheral nerve blockade (CPNB)
is indicated for treatment of acute postoperative pain, vascular insufficiency, chronic pain
conditions and cancer-related pain. CPNB is used in hospital, ambulatory and in trauma settings(Ilfeld 2017a NR; Ilfeld 2011a NR).
5.8.2.1 | Continuous peripheral nerve block compared to single-injection techniques
Compared with single-injection techniques, CPNB improve pain control, decrease opioid
requirements, reduce nausea and improve patient satisfaction postoperatively ( Bingham 2012
Level I, 21 RCTs, n=702). CPNBs after ambulatory upper and lower limb surgery vs single-injection
blocks reduce pain at rest (5 RCTs) and during movement (in 4 of 5 RCTs) and opioid requirements
for the first 24 h (1 RCT), but not consistently sustained beyond this time frame (Saporito 2017
Level I [PRISMA], 5 RCTs, n=160); the quality and size of the RCTs included limits these statements.
These findings are consistent with some but not all recent studies.
Following TKA, various analgesic modalities have been compared:• There were no differences between continuous FNB, single-injection FNB and LIA bysurgeon in pain scores on the morning of POD 2 (primary outcome) or 48 h opioid
consumption (Choi 2016 Level II, n=120, JS 5). However, both continuous FNB and LIA
resulted in superior pain control vs the single-injection group on POD 1;• There were no differences between continuous FNB infusion of ropivacaine 0.2%,
ropivacaine 0.1% vs placebo (sodium chloride 0.9 %) for the primary outcome ‘time todischarge readiness’ (Albrecht 2014 Level II, n=99, JS 5). This RCT was terminated earlybecause of changes in institutional pathways;• Continuous FNB was not superior (pain scores at 48 h) to single-injection FNB with nodifference in opioid consumption and functional recovery (Dixit 2018 Level II, n=85, JS 4).
• Single-injection ACB (combined with sciatic nerve block and posterior capsule LIA bysurgeon) provided comparable early analgesia for 32 h vs continuous ACB, but
continuous ACB improved pain scores beyond 42 h (Turner 2018 Level II, n=60, JS 5). The
local anaesthetic adjuvants included clonidine 33.4 mcg, buprenorphine 150 mcg,
dexamethasone 2 mg, and adrenaline;• Single-injection ACB ropivacaine 0.5% 20 mL vs ropivacaine/IV dexamethasone 8 mg
similarly reduced 24 h opioid consumption vs continuous ACB (ropivacaine 0.5% 20 mL
then 0.2% 5 mL/h for 48 h) where all patients received periarticular infiltration withropivacaine 0.5% 30 mL at surgery (Lee 2018, Level II, n=180, JS 3). Possible reasons forsuperiority over catheter technique include catheter migration or poor placement andsuperior injectate spread of the single-injection technique.

5.8.3 | Upper limb blocks
5.8.3.1 | Interscalene and suprascapular nerve block
Compared with a single-injection interscalene block, continuous interscalene block withropivacaine 0.2% following shoulder surgery (rotator cuff surgery, arthroplasty) improved pain
outcomes, sleep, patient satisfaction, time to discharge readiness and achieved a greater degreeof shoulder movement (Salviz 2013 Level II, n=71, JS 3; Yang 2013 Level II, n=56, JS 4; Mariano 2009
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Level II, n=32, JS 5; Ilfeld 2006 Level II, n=32, JS 3). Because of close proximity to the neuraxis, a test

dose of local anaesthetic through an interscalene catheter should precede a continuous infusion.
Performing interscalene blockade in adults under general anaesthesia is controversial with casereports of block-related mechanical injury to the spinal cord (Benumof 2000 CR). Phrenic nerve
block is the most common adverse effect of interscalene block. Strategies to reduce thelikelihood or magnitude of phrenic nerve block include reducing local anaesthetic dose, using USguidance, injecting at the C7 vertebral level and use of suprascapular or axillary block ( Verelst
2013 NR). Suprascapular block resulted in reduced pain vs placebo or subacromial local
anaesthetic infusion (Jeske 2011 Level II, n=45, JS 4). For shoulder arthroscopy, interscalene blockvs combined suprascapular and axillary block resulted in superior analgesia in PACU, but inferior
analgesia at 24 h (Dhir 2016 Level II, n=60, JS 5). Suprascapular nerve block (anterior approach deep
to omohyoid muscle) was compared with interscalene block for shoulder arthroscopy using acomposite outcome of pain and grip strength (Wiegel 2017 Level II, n=336, JS 5). Different
ropivacaine dose used in the two study groups (interscalene 150 mg vs suprascapular 100 mg)
resulted in reduced motor block with the suprascapular block and non-inferiority for pain
outcomes. Following shoulder arthroplasty, vital capacity at 24 h (primary outcome) was reduced
more with continuous interscalene (by 991 mL) vs supraclavicular (by 803 mL) block ( Auyong 2017
Level II, n=75, JS 5). However, anterior suprascapular block had the least effect on vital capacity(reduced by 464 mL) indicating a potential advantage in using this approach in patients withpulmonary disease, while there were no differences in analgesic outcomes.
5.8.3.2 | Other brachial plexus blocks
For surgery in the area of the forearm, infraclavicular block offers advantages due to a lower
likelihood of tourniquet pain during surgery, more reliable blockade of the musculocutaneous
nerve when compared to a single-injection axillary block, and a significantly shorter block
performance time compared to multi-injection axillary and mid-humeral blocks (Chin 2013 Level I[Cochrane], 22 RCTs, n=1,732). The incidence of insensate limb with continuous infraclavicularbrachial plexus block was higher when the same total dosage of 0.4% ropivacaine was comparedwith 0.2% ropivacaine (Ilfeld 2009 Level II, n=50, JS 3). There was no difference in analgesia but
satisfaction scores were higher in patients who received the 0.2% infusion. Following handsurgery, continuous brachial plexus block (axillary approach) (0.1 or 0.2% ropivacaine) did not
improve pain outcomes vs single-injection technique with a long‐acting local anaesthetic (Salonen
2000 Level II, n=60, JS 4). This was also true in comparison with continuous infraclavicular blocks(Mariano 2011 Level II, n=20, JS 3).

5.8.4 | Lower limb blocks
Patient falls following major surgery is a key concern. After TKA, inpatient falls occurred in 1.6%
and this event was associated with increasing age and higher comorbidity burden, whereas PNB
did not increase the risk (OR 0.85; 95%CI 0.71 to 1.03) (Memtsoudis 2014 Level IV, n=191,570).
Following TKA, continuous lumbar plexus block was associated with an increased risk of inpatient
falls vs single-injection block or no block (OR 3.85; 95%CI 1.52 to 9.72) (NNH 59) (5 RCTs, n=1,595)(Johnson 2013 Level III-3 SR, 10 studies, n=4,014). The risk of falls with FNB was not different from
ACB following total knee arthroplasty, but patients receiving ACB had significantly increased
quadriceps motor strength (Elkassabany 2016 Level II, n=62, JS 5).

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5.8.4.1 | Femoral nerve block
Femoral nerve block (FNB) either as a continuous (7 RCTs) or single-injection (6 RCTs [FNB alone] &2 RCTs [FNB and sciatic PNB]) technique vs IV PCA analgesia alone is associated with improved
analgesia on movement, reduced morphine consumption and decreased incidence of nausea
following TKA (Paul 2010 Level I, 23 RCTs, n=1,016). Compared with periarticular infiltration of local
anaesthetic (LIA), continuous FNB for TKA reduced opioid consumption and improved functional
indicators at 6 wk (Carli 2010 Level II, n=40, JS 4). A similar study (infiltration vs continuous FNB)
reported no significant difference in opioid consumption; however, 37% of patients who
received the FNB experienced quadriceps weakness vs 0% in the infiltration group (Chaumeron2013 Level II, n=60, JS 5). Continuous FNB combined with single-injection sciatic block resulted inbetter pain relief vs IT morphine (Alvarez 2017 Level II, n=40, JS 2). For more information on any
differences between the local anaesthetics used for FNBs see Section 4.4.2.
5.8.4.2 | Fascia iliaca compartment and lateral femoral cutaneous nerve block
Single-injection fascia iliaca compartment block (FICB) provided similar postoperative analgesia
to FNB following anterior cruciate ligament repair (Farid 2010 Level II, n=23, JS 3); and to ‘3-in-1’
nerve block following knee joint arthroscopy and meniscal repair (Wallace 2012 Level II, n=60, JS 3).
Suprainguinal FICB was opioid-sparing following THA vs no block (Desmet 2017 Level II, n=88, JS 5).
However, effect on mobilisation was not recorded, which is relevant because FICB may haveresulted in motor block delaying early mobilisation. Following a posterior approach to THA underspinal anaesthesia, US-guided lateral FNB with ropivacaine 0.75% 8 mL had no effect on analgesic
outcomes at 4 h vs placebo (Thybo 2016 Level II, n=100, JS 5). All patients received paracetamol andibuprofen.
Continuous FICB provided similar postoperative analgesia to continuous FNB over 48 hfollowing TKA (Brisbane 2010 Level II, n=98, JS 2).
5.8.4.3 | Adductor canal and distal femoral triangle block
Recent anatomical studies point to the importance of the nerve to vastus medialis innervating theanteromedial knee capsule (Burckett-St Laurant 2016 BS). Research into the anatomy of the adductor
canal and femoral triangle has supported the development of US-guided motor-sparing techniques.
Since 2014, there has been a vast literature published on adductor canal block (ACB) compared todifferent combination therapies. However, interpreting the results of RCTs with ACB as anintervention is confounded by lack of consistency in how the block is implemented. It is likely inmany RCTs that the ACBs were performed in the femoral triangle and not in the adductor canal.
There has been extensive dialogue on this topic with one group describing how the apex of thefemoral triangle (and hence the adductor canal which is located between the femoral triangle apex
and the adductor hiatus) can be defined using US (Wong 2017 BS). The apex of the femoral triangle
can be identified using US as where the medial borders of the adductor longus and sartoriusintersect. This knowledge permits block placement at a consistent location where the nerve to
vastus medialis and saphenous nerve are closely located. In contrast, but also to maintainconsistency, other investigators perform ACB exactly halfway ‘mid-thigh’ between the anterior iliac
spine and the cephalad border of the patella (Jaeger 2012 Level II, n=42, JS 5). Subsequent studies
have defined the optimal anatomical location further. ‘Mid-thigh’ placement has been comparedto the more distal true adductor canal catheter location, where the superficial femoral arterydescends towards the adductor hiatus in 2 RCTs with contrasting results post TKA. One found the
median pain score on POD 1 was reduced with the proximal vs the distal catheter placement(0.5/10 vs 3.0/10); however the worst pain scores were not different (Sztain 2018 Level II, n=50, JS 4).
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While the second concluded continuous distal ACB provided noninferior analgesia to mid-thighpositioning (Meier 2018 Level II, n=73, JS 5). Combined distal femoral triangle/obturator blockade wassuperior to LIA in patients having TKA (Runge 2018 Level II, n=74, JS 5). The median 20-h morphine
consumption was 6 mg (IQR 2 to 18) vs 20 mg (12 to 28) respectively with no difference in LOS.
Adductor canal block compared to placebo
ACB reduced opioid consumption and pain scores vs placebo after TKA (Hanson 2014 Level II, n=80,
JS 5; Grevstad 2014 Level II, n=50, JS 5; Jenstrup 2012 Level II, n=75, JS 4; Jaeger 2012 Level II, n=42, JS 5).
Single-injection ACB with bupivacaine 0.25% 10 mL vs 0.9% saline in addition to LIA withropivacaine 0.2% 100 mL resulted in clinically relevant improvements in analgesia outcomes(opioid consumption, pain scores) at 36 h (Nader 2016 Level II, n=40, JS 5).
Adductor canal compared to femoral nerve blockade
In volunteer studies, ACB produced less loss of quadriceps strength vs FNB (8 vs 49%) (Jaeger 2013
Level II EH, n=12, JS 5); with minimal impact on balance (Kwofie 2013 Level II EH, n=16, JS 5).
Following TKA, ACB vs FNB results in similar control of postoperative pain (no differences inpain at rest and with mobilisation, rescue opioid requirements and patient satisfaction) with
reduced likelihood of quadriceps weakness and improved mobilisation leading to better
functional recovery (Kuang 2017 Level I [PRISMA], 9 RCTs, n=609; Hussain 2016 Level I, 6 RCTs, n=447)(6 RCTs overlap).
Studies published subsequent to the meta-analyses or not included confirm these findings.
Pre-block maximum voluntary isometric contraction (MVIC) of the quadriceps increased at
60 min in patients who received ACB 24 h after TKA with ropivacaine 0.75% 30 mL vs placebo(median 170% vs 93%) (Sorensen 2016 Level II, n=64, JS 5). Despite overall better motor function
associated with ACB, decrease in MVIC (defined as MVIC <75% of pre-block values) occurred in
5/64 patients and 4 of these were unable to perform the ‘Timed Up and Go’ test. This
underscores the importance of a thorough functional assessment and falls prevention program.
Continuous FNB vs continuous ACB showed no difference in analgesic outcomes and earlyrecovery, although quadriceps motor strength with ACB was increased (Seo 2017 Level III-1, n=43).
Time to discharge did not differ with continuous ACB vs continuous FNB following
unicompartmental knee arthroplasty despite more patients satisfying discharge criteria on POD
2 in the ACB group (Sztain 2015 Level II, n=30, JS 3). More ACB recipients, despite significantly worse
dynamic pain scores on day of surgery and POD 1, ambulated >30 m than FNB recipients.
Adductor canal block compared to LIA
There was no difference in the ‘Timed Up and Go’ test (46, 45 and 52 s) on POD 2 (primary
outcome) with LIA/placebo blocks vs LIA/ACB vs LIA/ACB/IT morphine (Biswas 2018 Level II, n=201,
JS 5). However, pain control was improved in patients randomised to LIA/ACB/IT morphine.
Combined ACB/LIA reduced pain on walking on POD 1 vs ACB block alone or LIA alone (Sawhney2016 Level II, n=151, JS 5). ACB vs LIA following TKA reduced opioid consumption at 24 h (6 vs 13mg) and at 48 h (10 vs 25 mg) and pain scores at 6 to 16 h (by 1.2 to 1.5/10) (Kampitak 2018 Level
II, n=60, JS 5). See also Section 5.8.2.1 below.
Adductor canal block compared to other peripheral nerve block combinations
Patients received continuous ACB and LIA for TKA and were randomised to receive in addition:
obturator, tibial or both nerve blocks (Kampitak 2019 Level II, n=90, JS 4). Patients who received all
three blocks had superior analgesia and mobilisation outcomes, and reduced opioid use (2 mg
vs 4 mg and 6 mg morphine at 24 h). Continuous ACB vs sham catheter inserted on POD 1
decreased opioid consumption and pain scores at 0─20 h following insertion (ie on POD 2) and
improved function at 3 wk (Leung 2018 Level II, n=165, JS 4). Epidural analgesia was used as theanalgesic technique in the first 24 h and multimodal analgesia (eg NSAID or Cox II inhibitors) was346

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not used. Due to withdrawals only 70 patients completed the study which may have introduced
bias.
Adductor canal block – single-injection dose and infusion considerations
There was no meaningful difference in quadriceps strength to 4 h with 10 mL vs 30 mL
ropivacaine 0.1% for ACB (Jaeger 2015b Level II EH, n=26, JS 5). Both volumes produced
meaningfully reduced tonic heat pain response indicating successful saphenous block. The ED 95(minimum effective anaesthetic volume in 95% of the subjects) to fill the distal adductor canalestimated on MRI was 20 mL (Jaeger 2015a Level III-2 EH, n=40). The ED50 (minimum effective
anaesthetic volume in 50% of the subjects) needed for a 30% decrease in quadriceps strength
was determined used the Dixon-Massey up-and-down method in patients having arthroscopic
knee surgery as being 46.5 mL (95% confidence interval, 45.01-50.43 mL) (Johnston 2017 Level III2, n=26). This volume is significantly higher than standard doses used in clinical practice.
Bilateral continuous ACB was established in volunteers with one limb of each subject
randomly assigned to a continuous infusion of 8 mL/h or automated hourly boluses of 8 mL
(Monahan 2016 Level II EH, n=24, JS 5). Tolerance to transcutaneous electrical stimulation in the
territory of the anterior branch of the medial femoral cutaneous nerve was evaluated at 8 hwith equivalent cutaneous analgesia (non-inferiority). There were no differences in secondary
endpoints such as cutaneous analgesia at later time points or motor blockade. Continuous
infusion 7 mL/h was compared to intermittent boluses (23 mL/3 h) with no difference in opioid
consumption and other analgesic outcomes following TKA ( Jaeger 2018 Level II, n=110, JS 5).
5.8.4.4 | Sciatic nerve block
After lower extremity surgery (Ilfeld 2002 Level II, n=30, JS 4) and foot surgery (White 2003 Level II,
n=24, JS 5), continuous popliteal sciatic nerve analgesia resulted in better pain relief, lower opioid
requirements and fewer adverse effects compared with opioids alone. The benefit of sciatic
nerve block in addition to single-injection and continuous FNB for analgesia following TKA
remains unclear (8 RCTs [various comparators]) (Paul 2010 Level I, 23 RCTs, n=1,016).
Interspace between the Popliteal Artery and the Capsule of the Posterior Knee (iPACK) block
iPACK block is a motor sparing block following TKA. It is likely iPACK results in blockade of a plexus
formed by the posterior division of the obturator nerve and the tibial nerve that innervates theposterior knee capsule (Tran 2019 BS). ACB and iPACK block when added to periarticular injection
had lower pain scores on ambulation on POD 1 (Kim 2019a Level II, n=86, JS 5). ACB/iPACK block vs
ACB resulted in improved pain scores from 8 h to POD 2 (Sankineani 2018 Level III-2, n=120).
5.8.4.5 | Lumbar plexus
Following THA, there was no difference for continuous posterior lumbar plexus block vscontinuous FNB in postoperative pain scores, however FNB recipients had more motor block
impairing ambulatory function (Ilfeld 2011b Level II, n=50, JS 3). Lumbar plexus block resulted in amodest improvement in pain in the early postoperative period following hip arthroscopy (YaDeau
2012 Level II, n=84, JS 5). Lumbar plexus block vs ACB provided similar analgesia following
unicondylar knee arthroplasty at 6 h (Henshaw 2016 Level II, n=150, JS 5). There were also no other
differences in analgesia outcomes at other time points to 24 h. Quadriceps motor strength wasbetter in the ACB group.

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5.8.5 | Truncal blocks
Truncal blocks are increasingly used to provide analgesia after surgery; the number of techniques
for these blocks is continuously increasing and most are performed with US-guidance; a detailed
systematic review on the current developments of these techniques with regard to anatomy (10studies [cadaver], 6 [volunteer/imaging], 2-4 technical descriptions), clinical outcomes andcomplications has been published (3 SRs, 4 RCTs, 12 studies, 4 CR) (Abrahams 2016 Level IV SR, 42
manuscripts, n unspecified).
5.8.5.1 | Paravertebral blocks
Paravertebral block (PVB) is a technique that is likely to benefit from US-guidance because thelandmark technique has been associated with a high proportion of misplaced catheters (Luyet
2012 Level IV, n=31), and US-guidance can improve the needle trajectory (Abdallah 2014a NR). Allforms of PVB combined (single-injection, multi-level injection and continuous infusion)
demonstrate superior analgesia for up to 48 h following breast surgery vs systemic analgesia,
with a lower incidence of PONV (RR 0.26; 95%CI 0.13 to 0.5) and few specific adverse effects(Schnabel 2010 Level I [PRISMA], 15 RCTs, n=877). PVBs with general anaesthesia or propofol
sedation reduce pain scores at rest and movement (22 RCTs, n=1,714) and reduce opioid
consumption (16 RCTs, n=1,406) up to 72 h after breast surgery (Terkawi 2015 Level I [PRISMA], 24
RCTs, n=1,822) (14 RCTs overlap). Addition of fentanyl (11 RCTs) and multilevel injection (5 RCTs)
improve quality of analgesia. Reduced nausea (OR 0.44; 95%CI 0.31 to 0.61) (12 RCTs) andvomiting (OR 0.42; 95%CI 0.25 to 0.71) (9 RCTs) and small decrease in hospital LOS (SMD -0.60; 1.13 to -0.06) (6 RCTs) are also observed. A further study confirmed an improved quality ofrecovery (Abdallah 2014b Level II, n=64, JS 5).
For breast cancer surgery, PVB (6 RCTs, n=419) reduces CPSP (OR 0.61; 95%CI 0.39 to 0.97)(NNT 11) (Weinstein 2018 Level I (Cochrane), 63 RCTs, n=3,027). See also Section 1.4.6.1.
For thoracotomy, paravertebral or epidural techniques provide superior analgesia vs IT,
interpleural, IC and systemic opioid techniques; PVBs cause less hypotension than epidural
analgesia and reduce the incidence of pulmonary complications vs systemic analgesia (Joshi 2008
Level I, 74 RCTs, n unspecified). Following thoracotomy, there is moderate-quality evidence thatshows comparable analgesic efficacy at rest and after coughing with PVB vs epidural analgesia (3to 6 RCTs [2-6, 24 & 48 h]) (Yeung 2016 Level I [Cochrane], 14 RCTs, n=698). There is low to very lowquality evidence that showed no significant difference in mortality and major complications.
There is moderate-quality evidence that PVB has a superior minor complication risk vs thoracic
epidural analgesia including hypotension (RR 0.16; 95%CI 0.07 to 0.38) ( 8 RCTs, n=445), nausea
and vomiting (RR 0.48; 95%CI 0.30 to 0.75) (6 RCTs, n=345), pruritus (RR 0.29; 95%CI 0.14 to 0.59)(5 RCTs, n=249) and urinary retention (RR 0.22; 95%CI 0.11 to 0.46) (5 RCTs, n=258). These results
are consistent with a parallel meta-analysis showing that continuous PVB reduces the incidenceof nausea, vomiting, hypotension and urinary retention vs thoracic epidural analgesia, woundinfiltration or IV opioids while providing comparable post-cardiothoracic surgery analgesia (Scarfe2016 Level I [PRISMA], 23 RCTs, n= 1,120) (12 RCTs overlap).
Paravertebral block for sternotomy and open liver resection
Most of the evidence for PVB is following breast surgery or thoracotomy, but there are a limited
number of studies following sternotomy for cardiac surgery (eg 2 of 18 RCTs comparing PVB and
TEA in Scarfe 2016 Level I, 23 RCTs, n=1,120). A comparison of continuous bilateral thoracic PVB withbilateral continuous SC lidocaine infusions in patients undergoing cardiac surgery found nodifference in postoperative morphine requirements ( Lockwood 2017 Level II, n=50, JS 5).
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continuous bilateral PVBs in patients with ischaemic heart disease and extensive medicalcomorbidities. The risk of LAST is confirmed in patients having coronary artery bypass surgery(CABG) with continuous bilateral thoracic PVB, where plasma ropivacaine concentrations
consistent with toxicity and one case of toxicity occurred with dosages in the range
recommended by manufacturers (Ho 2016 Level IV PK, n=8).
Following elective open liver resection, patients were randomised to receive either TEA or
bilateral T7 or T8 PVB with ropivacaine 0.2% infused for 3 d (Schreiber 2016 Level II, n=87, JS 3).
There was a statistically significant, but clinically modest reduction in pain score in the epiduralgroup.
Paravertebral block for breast cancer surgery
For mastectomy, PVB reduces the risk of CPSP at 12 mth postoperatively (OR 0.43; 95% CI 0.28
to 0.68) (18 RCTs, n=1,297) (Weinstein 2018 Level I (Cochrane), 63 RCTs, n=3,027).
5.8.5.2 | Intercostal and interpleural block
Following a single intercostal block (ICB) using 0.5% bupivacaine, segmental analgesia can last up
to 20 h (Perttunen 1995 Level II, n=45, JS 2). Multilevel ICBs improve analgesia vs systemic opioids
alone, particularly during POD 1 (Detterbeck 2005 Level I, 12 RCTs [ICB vs systemic opioids], n=477);
pulmonary function tests are better preserved, although pulmonary complications are notconsistently reduced. There are no consistent differences in analgesia outcomes for multilevel
ICBs in comparison with epidural analgesia (Detterbeck 2005 Level I, 5 RCTs [ICB vs epidural], n=140),
although duration of follow-up was not specified and individual studies were small. Following
thoracotomy, surgically delivered ICBs with liposomal bupivacaine provided improved analgesia
on POD 1 and 3 vs TEA (technique unspecified) with hydromorphone PCA used as rescue in bothgroups (Khalil 2015, Level III-2, n=85).
Analgesia can be achieved using a subpleural catheter placed in the space posterior to theparietal pleura alongside the paravertebral area, or more laterally in the IC region. Following
posterolateral thoracotomy, patients receiving TEA had superior pain control vs continuous
subpleural analgesia (Kanazi 2012 Level II, n=42, JS 4; Debreceni 2003 Level II, n=50, JS 5). However,similar analgesia was achieved for up to 5 d with epidural vs IC catheter local anaesthetic
infusions (Luketich 2005 Level II, n=91, JS 3).
Multilevel US-guided IC nerve blocks provided superior pain relief for 24 h vs systemic
analgesics alone after percutaneous nephrolithotomy (Ozkan 2013 Level II, n=40, JS 5).
The incidence of pneumothorax following multilevel ICBs has been estimated at 0.07% basedon data from approximately 100,000 injections (Moore 1975 Level IV, n=10,941 [patients]).
Interpleural local anaesthetic infusion has not been found to be superior to systemic opioid
analgesia in thoracotomy patients (Detterbeck 2005 Level I, 11 RCTs [interpleural], n=287).
Interpleural analgesia (intermittent bolus injection technique) was compared to continuous TEA
following minimally invasive thoracoscopic surgery (Ishikawa 2012 Level II, n=40, JS 1); pain scores
were not different between the groups. Interpleural analgesia is superior to systemic analgesia
following open cholecystectomy but not following laparoscopic cholecystectomy ornephrectomy (Dravid 2007 NR).
5.8.5.3 | Erector spinae plane block and retrolaminar block
The erector spinae plane block (ESPB), an US-guided technique with plane of injection between
the thoracic vertebral transverse process (often mid-thoracic) and the erector spinae muscle wasdescribed in 2016 for a chronic pain indication (Forero 2016 CR). The premise of erector spinae
plane block and retrolaminar blocks are that spinal ventral and posterior rami are accessed with
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local anaesthetic injected posterior to, instead of injection anterior to the costotransverse
ligament. For retrolaminar blocks, the local anaesthetic is injected between erector spinae
muscle and the thoracic lamina. It is debated whether the ESPB is a paravertebral variant
involving nerve roots (Tsui 2019a Level IV, n=242) vs a myofascial plane block. Paravertebral spreadof 15 mL radiocontrast was demonstrated during fluoroscopic study through continuous ESPB
(Ueshima 2018 Level IV, n=3). In unembalmed cadavers, US-guided 20 mL injectate into ESP at T5
involved dorsal rami in 80%, ventral rami in 20%, but dorsal ganglion in only 10% (Ivanusic 2018
Level IV BS, n=10 [cadavers]). A second cadaver study assessed an injection on opposite sides into
ESP and retrolaminar space with 20 mL injectate at T5; spread to the epidural and neuralforaminal spaces over 2 to 5 levels was demonstrated with MRI and anatomical dissection(Adhikary 2019 Level IV BS, n=3 [cadavers]).
For ESPB studies, single-injection techniques are used in 80.2%, intermittent boluses in 12%
and continuous infusions in 7.9% (Tsui 2019a Level IV SR, 85 studies, n=242). Multimodal analgesia
is used in 91% of cases. Sensory changes are reported in 35% of cases; 35% report reduced opioid
use. ESPB versus systemic analgesia after breast (1 RCT: Gurkan 2018 Level II, n=50, JS 2), cardiac
surgery (1 RCT: Krishna 2019 Level II, n=106, JS 4) and laparoscopic cholecystectomy(1 RCT: Tulgar 2018 Level II, n=30, JS 1) improves analgesia and/or reduces rescue requirements (DeCassai 2019 Level I [PRISMA], 4 RCTs, n=242) (2 of 4 RCT overlap with Tsui 2019a). Following sternotomy(for midline cardiac surgery), continuous bilateral ESPB vs TEA resulted in similar pain scores forthe first 12 h and improved pain scores between 24 h and 48 h (1 RCT: Nagaraja 2018 Level II, n=50,
JS 3).
Subsequent RCTs not included in these SRs are in line with these results. For modified radical
mastectomy, similar results were demonstrated for ESPB vs routine pain management (Singh2019 Level II, n=40, JS 4). Following open epigastric hernia repair, ESPB vs sham block reduced painscores and decreased perioperative analgesic requirements (Abu Elyazed 2019 Level II, n=60, JS 3).
Following abdominal hysterectomy, bilateral ESPB vs sham block did not result in a clinicallysignificant reduction in postoperative fentanyl consumption, but achieved clinically significant
pain reduction for 12 h (Hamed 2019 Level II, n=60, JS 4).
ESPB vs TAP block following laparoscopic cholecystectomy leads to reduction of opioid
requirements and pain intensity (Ciftci 2020 Level II, n=60, JS 3; Altiparmak 2019a Level II, n=68, JS 4).
For video-assisted thoracoscopic surgery (VATS), EPSB vs serratus plane block reduced pain
intensity from 4 to 6 h and increased time to rescue analgesia (Gaballah 2019 Level II, n=60, JS 4).
5.8.5.4 | Pectoralis nerves and serratus plane blocks
US-guided pectoralis nerves (PECS) blocks and serratus anterior plane (SAP) blocks are regional
analgesia techniques of the thorax (Battista 2020 NR). PECS and SAP blocks were developed as aless invasive alternative to PVB for breast surgery. In PECS I blocks the injectate is injected
between pectoralis major and minor only. PECS II blocks refer to an US-guided block of the medial
and lateral pectoral nerves (target plane between pectoralis major and minor muscles) combinedwith lateral cutaneous branch of the intercostal nerves (target plane between the pectoralis
minor and serratus anterior muscles).
PECS I blocks vs placebo in the setting of multimodal analgesia did not reduce pain scores in
PACU following tissue preserving breast cancer surgery (Cros 2018 Level II, n=128, JS 5).
Combined PECS I and PECS II blocks vs control reduced postoperative pain scores for 24 h anddecreased morphine consumption for 12 h following modified radical mastectomy surgery(Bashandy 2015 Level II, n=120, JS 3). After mastectomy, PECS II block vs placebo resulted in lesspain and reduced opioid requirements during PACU stay (Versyck 2017 Level II, n=140, JS 5).
Similarly, for breast cancer surgery, PECS II blocks vs control had an opioid-sparing effect andresulted in better mobilisation of the shoulder and patient satisfaction (Neethu 2018, Level II, n=60,

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JS 2). Following radical mastectomy, PECS II block provided superior analgesia to ESPB (tramadol
requirements as primary outcome) (Altiparmak 2019b Level II, n=38, JS 3).

Postoperative insertion of combined bilateral PECS II blocks and drain site infiltration (35 mL
bupivacaine 0.25%) vs no block (all participants received paracetamol/tramadol) following
sternotomy for cardiac surgery reduced pain scores and requirement for intensive care resources(Kumar 2018, Level II, n=40, JS 3). After paediatric cardiac surgery via thoracotomy, PECS II and SAP
blocks vs IC blocks resulted in statistically significant, but clinically modest, improvement inanalgesia (Kaushal 2019 Level II, n=108, JS 3).
SAP block was superior (opioid consumption and first request for analgesia) to no block formastectomy (Rahimzadeh 2018 Level II, n=60, JS 2). SAP block vs PVB for modified radical
mastectomy was inferior with regard to time to commence PCA use (245 min vs 346 min) andopioid requirements, but with similar pain scores (Gupta 2017 Level II, n=50, JS 5). Similarly,
following modified radical mastectomy, PVB vs SAP block prolonged analgesia (11 vs 6 h) (Hetta
2016 Level II, n=64, JS 3).
Following VATS, SAP block vs placebo improved 40-item Quality of Recovery (QoR-40) scoreat 24 h after surgery (Kim 2018a Level II, n=90, JS 5). SAP block vs systemic multimodal analgesia
reduced pain scores following thoracoscopic surgery for 8 h (Semyonov 2019 Level II, n=104, JS 1).
SAP block vs TEA had reduced effects on blood pressure (primary outcome) following
thoracotomy (Khalil 2017 Level II, n=60, JS 3).
5.8.5.5 | Sternal bed blocks
PECS blocks will not block the anterior cutaneous branch of the intercostal nerves. However,transversus thoracis block, a sternal bed block with local anaesthetic injected into theneurovascular plane superficial to the transversus thoracis muscle, will result in anterior
cutaneous branch block. Injections of ropivacaine 0.5% (total dose <5 mg/kg) into the 2nd to 6thparasternal intercostal spaces were superior vs placebo (same volume of sodium chloride 0.9 %)for treatment of postoperative pain in pediatric patients undergoing midline cardiac surgery(Chaudhary 2012 Level II, n=30, JS 4). PECS block combined with transversus thoracis block vs PECS
block alone reduced pain intensity following mastectomy ( Ueshima 2017a Level II, n=70, JS 3).
Surgeon administered sternal bed blocks combined with systemic analgesia vs systemic
analgesia alone resulted in clinically relevant reduced pain scores for 24 h following CABG (DoganBaki 2016 Level II, n=81, JS 4). This study included a 6 mth follow-up, where there was no differencein the incidence of chronic pain
5.8.5.6 | Transversus abdominis plane blockTransversus abdominis plane block (TAPB) is used to provide analgesia following abdominal
surgery. TAPB by US-guidance has generally replaced use of landmark technique. Independentof the type of surgery (abdominal laparotomy, abdominal laparoscopy, and Caesarean section)
US-guided TAPB vs sham or no block reduce IV morphine consumption at 6 h (MD -6 mg; 95%CI−7 to −4) and 24 h (MD −11 mg; 95%CI −14 to −8) vs control or placebo (Baeriswyl 2015 Level I[PRISMA], 31 RCTs, n=1,611). In addition, pain scores are reduced at rest (MD −10/100; 95%CI −15
to −5) and on movement (MD −9/100; 95%CI −14 to −5) at 6 h, but not PONV or pruritus. These
effects are not seen in patients receiving long-acting spinal opioid, and were independent oftiming of injection, approach used or the use of systemic multimodal analgesia. A parallelsystematic review in all types of surgery describes similar effects; TAPB vs placebo reduces pain
intensity at 6 h (SMD -1.4/10; 95%CI -1.9 to -0.8) (23 RCTs, n=1,092), at 12 h (SMD -2.0/10; 95%CI-2.7 to -1.4) (18 RCTs, n=930), at 24 h (SMD -1.2/10; 95%CI -1.6 to -0.8) (33 RCTs) and opioid
requirements at 24 h (MED -14.7 mg; 95%CI -18.4 to -11.0) (28 RCTs) (Brogi 2016 Level I [PRISMA],
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51 RCTs, n unspecified) (significant RCT overlap). These results remain consistent across surgicaltypes, but analgesic efficacy of TAPB is inferior to IT morphine. These results are also in line withtwo preceding meta-analyses specifically looking at effects of TAPB in Caesarean section (Mishriky2012 Level I, 9 RCTs, n=524) (4 RCTs overlap with Baeriswyl 2015) and in laparoscopic surgery (DeOliveira 2014 Level I, 10 RCTs, n=633) (all 10 RCTs overlap with Baeriswyl 2015). RCTs not included inthese meta-analyses have shown contradictory results (Soltani Mohammadi 2014 Level II, n=67,
JS 5; Rao Kadam 2013 Level II, n=42, JS 3).
For a wide range of open and laparoscopic abdominal surgery in adults and children, epidural
analgesia vs TAPB provides similar analgesia (MD 0.5/10; 95%CI -0.1 to 1.0) (6 RCTs [adult], n=310),
but TAPB reduces the risk of hypotension (RR 0.13; 95%CI 0.04 to 0.38) (4 RCTs, n=191) and LOS(MD: -0.6 d; 95%CI: -0.9 to -0.3) (3 RCTs, n=146) (Baeriswyl 2018 Level I [PRISMA], 10 RCTs, n=505).
After abdominal hysterectomy, TAPB vs sham block or no block reduce 24 h opioid
consumption (3 RCTs, n=126), pain scores at 2 h (6 RCTs, n=274) and 24 h (5 RCTs, n=228), PONV
(6 RCTs, n=345) and prolong time to analgesic request (4 RCTs, n=238) (Zhou 2018 Level I [PRISMA],
13 RCTs, n=841) (3 RCTs overlap with Baeriswyl 2015). After abdominal hysterectomy, TAPB provided
the best pain relief and the lowest opioid rescue requirements vs epidural analgesia and vsparenteral analgesia (Mathew 2019 Level II, n=60, JS 4).
In adults undergoing lower abdominal surgery, TAPB vs local anaesthetic infiltration provided
superior analgesia at 24 h, although pain scores at 2 and 4 h postoperatively were similar ( Yu
2014 Level I, 4 RCTs, n=196) (3 RCTs overlap with Baeriswyl 2015). TAPB vs local anaesthetic infiltration
reduces 24 h morphine consumption (MD -3.85 mg; 95%CI -7.47 to -0.22) (Guo 2015 Level I, 5 RCTs,
n=127) (3 RCTs overlap with Baeriswyl 2015).
Both landmark and US-guided TAPB have been complicated by liver trauma (Lancaster 2010
CR; Farooq 2008 CR). For paediatric use, see Section 10.6.2.3.
5.8.5.7 | Quadratus lumborum block
Quadratus lumborum block (QLB) has been proposed as a superior alternative to US-guided TAPB(Elsharkawy 2019 NR; Ueshima 2017b NR). With QLB, local anaesthetic is injected anterior, posterior
or lateral to the posterior abdominal wall muscle quadratus lumborum. Posterior QLB vs placebo
or control reduced morphine requirements and pain intensity after Caesarean section (Krohg
2018 Level II, n=40, JS 5; Mieszkowski 2018 Level II, n=58, JS 3; Blanco 2015 Level II, n=50, JS 5). Posterior
QLB vs TAP block reduced morphine requirements while providing comparable analgesia after
Caesarean section (Blanco 2016 Level II, n=75, JS 4).
Following laparoscopic gynaecological surgery posterior QLB vs control improved pain relief
at rest and on movement (Ishio 2017 Level II, n=70, JS 2). QLB was not superior to systemic IV
lidocaine for the reduction of morphine requirements 24 h after laparoscopic colorectal surgery(Dewinter 2018 Level II, n=125, JS 5).
For paediatric use see Section 10.6.2.3.
5.8.5.8| Other abdominal wall blocks
Ilioinguinal and iliohypogastric nerves innervate the lower abdominal wall and groin region (Chin2017 NR). These nerves can be blocked using landmark or ultrasound-guided techniques in theimmediate vicinity of the anterior superior iliac spine. Anatomical variability likely contributes tothe variable success rate of the Ilioinguinal-iliohypogastric nerve blocks. This variability together
with the heterogeneity of published trials, means that there are no specific evidenced-based
recommendations for this procedure. The clinical efficacy of rectus sheath blocks in the generalsurgical (open and laparoscopic) and obstetric populations is unclear. Transversalis fascia plane
has been described in case reports.

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5.8.6 | Head and Neck Blocks
5.8.6.1 | Sphenopalatine ganglion block
After endoscopic sinus surgery, sphenopalatine ganglion block vs placebo or control improved
pain intensity and PONV (Kim 2019b Level I [PRISMA], 8 RCTs, n=441). Topical sphenopalatine
ganglion block was associated with improved results for treatment of postdural puncture
headache (PDPH) vs epidural blood patch (Cohen 2018 Level IV, n=81).

5.8.7 | Periarticular and intra-articular analgesia
The use of intra-articular (IA) infusions of bupivacaine with adrenaline has been cautioned
against because of reports of glenohumoral chondrolysis following shoulder arthroscopy (Hansen
2007 Level III-3, n=189 [shoulders operated on]; Bailie 2009 Level IV, n=23). Chondrotoxic effects havebeen shown for all local anaesthetics in in-vitro studies of human knee cartilage (Jayaram 2019
Level III-2 BS [PRISMA], 16 studies, n unspecified). Chondrotoxicity is worsened by coadministrationof corticosteroids; ropivacaine at concentrations ≤0.5 % was the least chondrotoxic LA. See also
Section 4.4.3.1.
IA NSAIDs have demonstrated analgesic efficacy over systemic administration in some studies
but the overall benefit is less clear (see Section 4.2.3.1). An analgesic effect for IA morphine
following arthroscopy vs placebo cannot be shown (Rosseland 2005 Level I, 46 RCTs, n=3,166).
5.8.7.1 | Local infiltration analgesia
LIA refers to the systematic intraoperative injection of local anaesthetics in the periarticular andIA regions; LIA may also be referred to as periarticular infiltration. There have been methodology
issues in LIA studies: lack of blinding, lack of placebo, lack of supplemental agents in controls(eg ketorolac), variable use of ‘top-up’ catheters, inferior results with established techniques(peripheral nerve or epidural block) compared to the literature, the use of traditional recovery
programs with low activity (limiting the assessment of therapies on early functional recovery)
and inadequate pain assessment (Andersen 2014 Level I, 27 RCTs, n=1,644). Other limitations of LIA
studies have included non-uniform use of both non-opioid and opioid analgesia across treatmentgroups, poorly defined multimodal analgesia therapies and mobilisation pathways ( Kehlet 2011NR). The role of NSAIDs introduced via LIA vs systemic administration is also unclear (see Section
4.2.3.3). Similarly, there seems to be little benefit of adding opioids such as morphine; morphine
0.1 mg/kg as a component of LIA with ropivacaine/ketoprofen/methylprednisolone/adrenaline
in one side vs no morphine in patients having bilateral TKA had no effect on pain, swelling or
ROM (Iwakiri 2017 Level II, n=53, JS 4).
Total knee arthroplasty: LIA compared to placebo or no injection
Compared to placebo or no injection in TKA, LIA (with local anaesthetics in various combinations
with NSAID, steroids, opioids and adrenaline) was associated with reduced pain scores andreduced opioid consumption for up to 32 h (Andersen 2014 Level I, 7 RCTs [LIA in TKA vs placebo/no
injection], n=328); there was a high risk of bias with unbalanced systemic analgesic regimens
between groups. In patients having bilateral TKA, LIA improved pain outcomes vs periarticularplacebo on the opposite side (Fajardo 2011 Level II, n=30, JS 2; Mullaji 2010 Level II, n=40, JS 5; Andersen
2008 Level II, n=12, JS 4). Reviews comparing LIA with placebo or no injection report that following

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TKA LIA achieves superior analgesia and reduced opioid consumption, however the source RCTs
were at high risk of bias because of lack of blinding (Xu 2014 Level I, 18 RCTs, n=1,858).
Total knee arthroplasty: LIA compared to epidural analgesia
In comparison to LIA in TKA, LEA has similar analgesic effects at rest for <24 h, but LIA achieves
better analgesia at 48 h (MD −1.08/10; 95%CI −1.86 to −0.29) and 72 h (MD −0.82/10; 95%CI−1.24 to −0.4) (Yan 2016 Level I, 9 RCTs [TKA], n=537). Similarly, pain on movement was similar at<24 h, but better controlled by LIA at 48 h and LIA enabled a better range of movement at alltime points.
Total knee arthroplasty: LIA compared to peripheral nerve blockade
When comparing FNB to LIA in TKA, most RCTs report either equal analgesic efficacy or a shortterm benefit of LIA (Andersen 2014 Level I, 5 RCTs [LIA vs FNB in TKA], n=307; Fan 2016 Level II, n=157,
JS 2; Ashraf 2013 Level II, n=50, JS 3; Ng 2012 Level II, n=16, JS 4). Interpretation of results is hinderedby the multitude of techniques, leaving the analgesic benefit of LIA per se unclear.
LIA achieved similar time to readiness for discharge from hospital (mean 3.2 d) vs combined
PCEA/FNB (Yadeau 2013 Level II, n=90, JS 3). A single-injection FNB when combined with epidural
analgesia resulted in reduced pain vs LIA during the first 24 h (Reinhardt 2014 Level II, n=94, JS 5).
LIA has superior analgesic outcomes vs epidural analgesia (Andersen 2014 Level I, 3 RCTs [LIA vs
epidural in TKA], n=204); these trials had high risk of bias because of incomplete blinding and highheterogeneity due to different systemic analgesic regimens between groups. In patients
receiving epidural analgesia, there was no added analgesic or functional benefit from LIA vsplacebo in the contralateral side for up to 14 d (Joo 2011 Level II, n=572, JS 5). When LIA was added
to combined FNB and sciatic block (with spinal anaesthesia for the surgery), improved pain relief
was only found at one time point postoperatively (0.6/10 ± 1.5 vs 1.7/10 ± 2.3) (Hinarejos 2016
Level II, n=50, JS 5). As there were no other differences in analgesic outcomes, the authors
concluded that adding LIA to their regimen was not necessary.
Total hip arthroplasty
In THA, no additional analgesic benefit of LIA vs placebo LIA (5 RCTs) or no injection (2 RCTs)(added to systemic multimodal analgesia) is identified (Andersen 2014 Level I, 10 RCTs [THA], n=756).
Compared with IT morphine (1 RCT) and epidural analgesia (1 RCT), LIA was reported to have
similar or improved analgesic effects.

5.8.8 | Wound catheter infusion, instillation and wound infiltration
5.8.8.1 | Wound catheter local anaesthetic infusions and intermittent injection
Wound catheter local anaesthetic continuous infusion (21 RCTs) or intermittent injections (9 RCTs)
provide minor analgesic benefits up to 48 h in obstetric and gynaecological surgery (6 RCTs), but
do not improve analgesic outcomes following abdominal (7 RCTs) or other non-orthopaedic(urological, reconstructive or thoracic) surgery (Gupta 2011 Level I, 32 RCTs, n=1,999). LOS is not
reduced (pooled for all surgery) (17 RCTs). Continuous wound infiltration with ropivacaine vsplacebo leads to a reduction in pain scores and opioid consumption (Raines 2014 Level I, 14 RCTs,
n=756) (4 RCTs overlap with Gupta 2011). Following Caesarean section, local anaesthetic woundinfiltration (by infusion) reduces opioid consumption (MD −10.29 MME; 95%CI −18.36 to −2.21)(8 RCTs, n=441), but has limited effects on pain scores with movement at 24 h (MD −0.83/10;
95%CI −1.90 to −0.23) (7 RCTs, n=434) (Adesope 2016 Level I, 21 RCTs, n=1,435) (5 RCTs overlap with
Gupta 2011). Local anaesthetic infusions (6 RCTs [continuous]), 2 RCTS [intermittent], 1 RCT [PCA]) via
abdominal wound catheter vs epidural analgesia have equal analgesic efficacy for up to 48 h (7354

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RCTs, n=425) with a lower incidence of urinary retention (3 RCTs, n=160) (Ventham 2013 Level I[PRISMA], 9 RCTs, n=505); there was however considerable heterogeneity with variability inanalgesic regimens, especially in the epidural arms. Epidural analgesia provided better pain relief
than continuous wound infiltration at rest at 72 h (4 RCTs, n=289) (Li 2018a Level I, 16 RCTs, n=1,345)(8 RCTs overlap with Ventham 2013). There were no differences in pain score at rest or on
mobilisation at 2 h, 12 h, 24 h and 48 h. Hypotension is more common in epidural vs woundinfusion recipients (14 RCTs, n=1,350).
Continuous preperitoneal local anaesthetic infiltration is superior vs continuous
subcutaneous infiltration (1 RCT, n=60) and vs placebo (9 RCTs, n=537), with similar analgesia vsactive control (epidural analgesia or PCA) (13 RCTs, n =887) (Mungroop 2019 Level I [PRISMA], 29 RCTs,
n=2,059). Preperitoneal wound catheter infusion of ropivacaine following colorectal surgery
resulted in improved pain relief, opioid-sparing and earlier recovery of bowel function (Beaussier
2007 Level II, n=49, JS 5).
5.8.8.2 | Intraperitoneal instillation
Early postoperative abdominal pain is improved after laparoscopic cholecystectomy by the useof intraperitoneal local anaesthetic; the effect is better when given at the start of surgery vsinstillation at the end of surgery (Boddy 2006 Level I, 24 RCTs, n=1,256). In laparoscopic gastricsurgery, intraperitoneal local anaesthetic reduces postoperative abdominal pain intensity, theincidence of shoulder pain and opioid consumption (Kahokehr 2011 Level I [PRISMA], 5 RCTs, n=273).
5.8.8.3 |Local anaesthetic infiltration
Local anaesthetic infiltration vs a variety of controls for mastectomy did not improve analgesic
outcomes (Tam 2015 Level I [PRISMA] 13 RCTs, n=1,150).
Infiltration of local anaesthetic into the scalp is used to treat postoperative pain following
craniotomy. Preoperative scalp infiltration provides improved pain scores for up to 8 hpostoperatively, with postprocedural infiltration improving analgesia for up to 12 h ( Guilfoyle
2013 Level I [PRISMA], 7 RCTs, n=325).

5.8.9 | Topical application of local anaesthetics
Topical EMLA® cream (eutectic mixture of lignocaine and prilocaine) is effective in reducing thepain associated with venous ulcer debridement (Briggs 2012 Level I [Cochrane], 6 RCTs, n=343).
When compared with EMLA® cream, topical amethocaine provides superior analgesia forsuperficial procedures in children, especially IV cannulation ( Lander 2006 Level I, 6 RCTs, n=534).
Topical tetracaine, liposome-encapsulated tetracaine and liposome-encapsulated lignocaine areas effective as EMLA® cream for dermal instrumentation analgesia in the ED (Eidelman 2005 Level I,
25 RCTs, n=2,096). See Sections 10.6.3.5 and 10.6.6 for use in penile surgery, 10.7.1 to 10.7.3 and10.8.2 for procedures involving skin puncture use in children and Section 8.11.2 for use in the ED.
Topical local anaesthetic provides no analgesic benefit when performing flexible diagnostic
nasoendoscopy, either alone or in combination with a vasoconstrictor (Conlin 2008 Level I, 8 RCTs,
n=818; Nankivell 2008 Level I, 18 RCTs, n=1,356). Intraurethral instillation of lidocaine gel provides
superior analgesia to lubricating gel during flexible cystoscopy (Aaronson 2009 Level I, 4 RCTs,
n=411). Following tonsillectomy, local anaesthetics provide a modest reduction in posttonsillectomy pain; administering the local anaesthetic on swabs appeared to provide a similarlevel of analgesia to that of infiltration (Grainger 2008 Level I, 13 RCTs [6 adult & 7 paediatric], nunspecified). Topical local anaesthetic gel and/or nebulised local anaesthesia of the nose and5th Edition | Acute Pain Management: Scientific Evidence 355

pharynx reduced pain associated with nasogastric tube insertion in adults (OR 0.42; 95%CI 0.20
to 0.88) (Kuo 2010 Level I, 5 RCTs, n=212). See also paediatric Section 10.7.2.6.
The lignocaine 5% patch may reduce acute pain intensity following herpes zoster once lesions
have healed (McCarberg 2013 NR).

5.8.10 | Neuromodulation
There is some emerging evidence that percutaneous peripheral nerve stimulation may be a
promising alternative to infusions of local anaesthetics through a perineural catheter (Gabriel 2019
NR). In this technique, small gauge insulated electrical leads are placed percutaneously throughneedle that is placed remotely 0.5 to 3.0 cm from a peripheral nerve using US-guidance. The leadis connected to an external stimulator and narrow pulse duration electrical stimulation is applied
to selectively activate pain-relieving fibres in a peripheral nerve trunk. This technique does not
activate fibres that would result in muscle contractions, loss of strength or loss of proprioception.
US-guided percutaneous peripheral nerve stimulation has been used successfully for analgesia
following pain refractory to standard therapy following knee arthroplasty (Ilfeld 2017b Level IV, n=5).
Following ambulatory rotator cuff repair, although initial pain control was inadequate, the later
postoperative quality of analgesia (POD 1 to 14) was considered excellent (Ilfeld 2019a Level II, n=11,
JS 5). Proof of concept studies have used percutaneous femoral nerve stimulation for ambulatory
anterior cruciate ligament reconstruction (Ilfeld 2019b Level II, n=10, JS 5) and percutaneous sciatic
nerve stimulation for ambulatory foot surgery (Ilfeld 2018 Level II, n=10, JS 5). Development issues
with this technique include optimal lead location and insertion technique, the stimulating protocol
and prevention of lead fracture/dislodgement.

5.8.11 | Safety
Regional anaesthesia techniques when performed with vigilance and professionalism areassociated with a high degree of safety ( Barrington 2013 Level IV, n=25,336 [PNBs in 20,021
patients]; Orebaugh 2012 Level IV, n=14,498 [PNBs]; Barrington 2009 Level IV, n=8,189 [PNBs in 6,950
patients]). Simple strategies such as preprocedural checklists, including a pre-block “time-out”(‘Stop Before You Block’) and a “pause”, may help reduce the incidence of events such as
wrong-site blockade (Barrington 2015 GL; ANZCA 2015 GL).
For paediatric data see Sections 10.6.1.3, 10.6.3.5 and Table 10.10.
5.8.11.1 | Anticoagulation
Caution should be used when considering and performing some peripheral nerve or plexus blocks
in patients with impaired coagulation (see Section 5.9.2). This particularly applies to where the PNB
is performed at a deep location that prevents external compression, should bleeding occur.
5.8.11.2 | Nerve injury and postoperative neurologic symptoms
A new onset postoperative nerve injury regardless of severity is of concern to patients andhealthcare providers. Methods used to capture, define and report neurologic outcomes varyconsiderably. A multicentre registry using systematic postoperative contact with all patients
reported the incidence of block-related nerve injury as 4/10,000 blocks (95%CI 0.8 to 11)(Barrington 2009 Level IV, n=8,189 [PNBs in 6,950 patients]). A large single-institution database
identified four cases of peripheral nerve injuries with sensory loss persisting for 6 to 12 mth, whichwere not able to be attributed to nonblock causes (≈3/10,000) (Orebaugh 2012 Level IV, n=14,498[PNBs]). A single-centre study reported the incidence of postoperative neurologic symptoms

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5.0 | ADMINISTRATION OF ANALGESIC MEDICINES(PONS) >6 mth duration as 9/10,000 (95%CI 5 to 17) (Sites 2012 Level IV, n=12,668). Nerve injury
may follow surgery independently of nerve block procedures. The baseline risk of nerve injury risk
inherent to common elective orthopaedic surgical procedures is now better understood (Neal 2015
GL). Awareness of the mechanism, location, and frequency of nerve injuries associated withelective orthopedic surgery may facilitate diagnosis and treatment of peripheral nerve injury.
After TKA, the all-cause incidence of perioperative nerve injury was 0.79%; however, this outcome
was not associated with PNB (Jacob 2011b Level III-3, n=12,329). Similarly, PNB following THA (Jacob
2011a Level III-3, n=12,998) and shoulder arthroplasty (Sviggum 2012 Level III-3, n=1,569) was not
associated with perioperative nerve injury. Observational studies consistently report that PONS
or postoperative neurologic dysfunction may be related to patient and surgical factors and thatthe incidence of neuropathy directly related to peripheral regional anaesthesia is infrequent orrare (Sviggum 2012 Level III-3, n=1,569; Jacob 2011a Level III-3, n=12,998; Jacob 2011b Level III-3, n=12,329;
Sites 2012 Level IV, n=12,668; Orebaugh 2012 Level IV, n=14,498; Barrington 2009 Level IV, n=8,189 [PNBs
in 6,950 patients]). However, distinguishing between contributing surgical, anaesthetic, and patient

factors is often difficult. Differential diagnosis should include use of a pneumatic tourniquet (>120min), which has been associated with nerve injury. These injuries often present as diffuse
sensorimotor deficits. Delaying placement of regional blocks if assessment of postoperative nerve
function is important for the surgeon is a consideration. Mechanical, ischaemic or neurotoxic
injury of the neuraxis or peripheral nervous system associated with regional anaesthesia and pain
medicine interventions has been summarised into a practice advisory (Neal 2015 GL).
5.8.11.3 | Local Anaesthetic Systemic Toxicity
US-guidance has been associated with a reduced incidence of local anaesthetic systemic toxicity(LAST) following PNB, with an incidence of 8.7/10,000 PNBs and no related deaths (Barrington 2013
Level IV, n=25,336 [PNBs in 20,021 patients]). This result is consistent with an analysis of block
outcomes over 10 y period, which revealed higher LAST incidence with landmark vs US-guided
technique: 7 of 5,932 vs 0 of 16,858 respectively (Melnyk 2018 Level IV, n=22,790 [PNBs]). A review ofcase reports and registries estimates LAST incidence to be 2.7/10,000 PNBs (95%CI 2.1 to 3.5)
(Gitman 2018 Level IV n=251,325). Seizure was the most common presenting feature (53% [CRs] and61% [registries]). It is important to note that presenting features of LAST may not comply withclassic descriptions and be overlooked or disguised by perioperative processes and interventions.
There is a trend toward delayed presentation, which may mirror the increased use of US-guidance(fewer intravascular injections), local infiltration techniques (slower systemic uptake), andcontinuous local anaesthetic infusions. Small patient size, sarcopenia and patient co-morbidities
potentially increase the risk of LAST. An increasing number of reported events occur outside of the
traditional hospital setting and involve non-anaesthetists. Caution must be exercised with all
regional techniques as case reports of adverse outcomes, including death, continue to occur (Vadi2014 CR & NR), even with local anaesthetic infusion catheters placed under direct vision (Calenda
2014 CR). This caution also applies to fascial plane techniques such as TAPB that tend to involve
large doses (Hessian 2013 Level IV PK, n=20; Griffiths 2013 Level IV PK, n=8) (see also Section 4.4.3.2). Of
note, an analysis from the Pediatric Regional Anesthesia Network database indicates that TAPB has
a low risk of local anaesthetic systemic toxicity in this patient population (Long 2014 Level IV,
n=19,994).
Treatment of LAST should be directed towards importance of the airway and oxygenation (avoiding
hypercarbia and acidosis), seizure control and lipid emulsion therapy (100 mL lipid emulsion 20%
for patient 70 kg or over; 1.5 mL/kg for patient less than 70 kg). Mechanisms of lipid emulsion
reversal of LAST include rapid partitioning, direct inotropy, and post ischaemic conditioning (Neal2018a GL). The American Society of Regional Anesthesia and Pain Medicine (ASRA) has updated its
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checklist for the management of LAST (Neal 2018b GL). Exact volume and flow rate of lipid emulsion
are not essential; however recommendations include avoiding administration of >10 to 12 mL/kg
of lipid emulsion, calling for help early, and use of electronic decision support tools. The
pharmacological treatment of LAST is different to other cardiac arrest scenarios. It is recommended
to reduce individual doses of adrenaline to less than 100 mcg, avoiding vasopressin, calcium
channel blockers, beta-blockers and use of other local anaesthetics. A guideline for managementof severe LAST has been developed by the AAGBI and is endorsed by ANZCA (AAGBI 2010 GL).
5.8.11.4 | Infection
The strongest recommendations for infection-prevention are effective hand hygiene and skinpreparation with alcohol-based chlorhexidine solution; as per the UK epic2 National Guidelines(Pratt 2007 GL). These guidelines recommend full barrier precautions for central venous catheter
placement (cap, mask, sterile gown and gloves; and large drape). Although specific data for
aseptic technique in CPNB is lacking, advisories have been developed which advocate similar
practices (Hebl 2011 NR). In a review of infections associated with CPNB, the use of full surgicaltype aseptic technique for CPNB procedures was supported ( Capdevila 2009 NR). Identified risk
factors for local CPNB catheter inflammation include ICU stay, duration of catheter use >48 h,lack of antibiotic prophylaxis, axillary or femoral location and frequent dressing changes(Capdevila 2009 NR). The use of a chlorhexidine-impregnated patch designed to inhibit bacterial
growth for days as a dressing after femoral nerve catheter insertion did not reduce the low rateof bacterial colonisation, nor reduce local skin inflammation (2.1 vs 10.6%) in an underpowered
RCT (Schroeder 2012 Level 2, n=100, JS 3). Chlorhexidine was also the superior skin disinfectant prior
to regional catheter insertion vs povidone iodine (Krobbuaban 2011 Level II, n=100, JS 4); a positive
skin culture immediately after skin disinfection occurred in 10 vs 35% (NNT 4).
The implications of catheter-related sepsis in patients with implanted prosthetic devices(eg joint arthroplasty) are significant and therefore all reasonable measures should be taken tominimise the risk of infection. The widespread use of US-guidance has introduced a potential risk
related to contamination. The use of a sterile disposable sheath reduces the risk of contaminationof the aseptic field by the transducer. Decontaminating US transducers with 70% isopropyl alcohol
was effective at removing pathogenic organisms (Chuan 2013 Level IV, n=120 [swabs]).

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5.0 | ADMINISTRATION OF ANALGESIC MEDICINESKEY MESSAGES
1. Topical EMLA cream (eutectic mixture of lignocaine [lidocaine] and prilocaine) is
effective in reducing the pain associated with venous ulcer debridement (U) (Level I[Cochrane Review]).
2. Transversus abdominis plane blocks provide pain relief superior to local anaesthetic
infiltration for a range of abdominal surgeries (N) (Level I [PRISMA]).
3. Intraperitoneal local anaesthetic instillation after laparoscopic gastric surgery (N) (Level I[PRISMA]) and laparoscopic cholecystectomy (U) (Level I) improves postoperative pain
outcomes.
4. Adductor canal block results in similar postoperative pain outcomes following total knee
arthroplasty versus femoral nerve block with less quadriceps weakness, earlier
mobilisation and better functional recovery (S) (Level I [PRISMA]).
5. Following thoracotomy, thoracic paravertebral block provides comparable analgesia tothoracic epidural analgesia (U) (Level I).
6. Continuous peripheral nerve block, compared with single-injection peripheral nerve
block, results in improved pain control, decreased need for opioid analgesics, reduced
nausea and improved patient satisfaction in some settings, in particular in the first 24
hours postoperatively (W) (Level I).
7. Femoral nerve block, either single-injection or continuous, provides better analgesia anddecreased nausea compared with parenteral opioid-based techniques after total knee
arthroplasty (U) (Level I).
8. Compared with opioid analgesia, continuous peripheral nerve block (regardless ofcatheter location) provides better postoperative analgesia and leads to reductions in
opioid use as well as nausea, vomiting, pruritus and sedation (U) (Level I).
9. Blocks performed using ultrasound guidance are more likely to be successful, faster toperform, with faster onset and longer duration compared with localisation using aperipheral nerve stimulator (U) (Level I).
10. Morphine injected into the intra-articular space following knee arthroscopy does not
improve analgesia compared with placebo (U) (Level I).
11. Following total knee arthroplasty, local infiltration analgesia reduces postoperative pain
for up to 32 hours when compared to systemic analgesics alone; however, there islimited benefit in comparison to femoral nerve block (U) (Level I).
12. Following total hip arthroplasty, there is no additional analgesic benefit for local
infiltration analgesia over conventional multimodal analgesia (S) (Level I) and peripheral
nerve blocks have limited or no effect on postoperative pain (Q) (Level II).
13. Following either knee or hip arthroplasty, there is insufficient evidence to support
postoperative administration of local infiltration analgesia via catheter (U) (Level I).
14. Local anaesthetic infusions or intermittent injections through wound catheters provide
analgesic benefits following gynaecological and obstetric surgery, but not otherabdominal or nonorthopaedic surgery (Q) (Level I).

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15. Intraurethral instillation of lignocaine gel provides analgesia during flexible cystoscopy(U) (Level I).
16. The benefit of routine sciatic nerve block in addition to femoral nerve block for analgesia
following total knee joint arthroplasty remains unclear (U) (Level I).
17. Continuous interscalene analgesia provides better analgesia, reduced opioid-related
adverse effects and improved patient satisfaction compared with intravenous PCA or
single-injection interscalene block after open shoulder surgery (U) (Level II).
18. Erector spinae plane blocks provide postoperative analgesia superior to systemic
analgesia after cardiac surgery (N) (Level II) and to transverse abdominis blocks after
laparoscopic cholecystectomy (N) (Level II).
19. Quadratus lumborum block reduces pain scores and opioid requirements following
Caesarean section compared to placebo or control (N) (Level II).
20. Intra-articular bupivacaine infusions have been associated with chondrolysis and theiruse has been cautioned against (U) (Level IV).
21. Postoperative neurologic symptoms or dysfunction is often related to patient andsurgical factors and the incidence of neuropathy directly related to peripheral regional
anaesthesia is rare (S) (Level III-3).
22. Ultrasound guidance of regional blocks is associated with a reduced risk of local
anaesthetic systemic toxicity in adults (N) (Level IV).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Continuous peripheral nerve blocks carry a risk of infection; skin preparation withalcohol-based chlorhexidine and full barrier precautions (including face masks) arerecommended for insertion of peripheral nerve catheters (U).
 Ultrasound-guided techniques should be practiced with a high degree of skill and care,including aseptic techniques, as they do not eliminate the risks of injury to tissues andstructures, local anaesthetic systemic toxicity or site contamination (U).
 Caution should be used when considering and performing some peripheral nerve or
plexus blocks in patients with impaired coagulation, in particular where the PNB is
performed at a deep location that prevents external compression, should bleeding
occur (N).

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5.9 | Regional analgesia and concurrent anticoagulant medications
5.9.1 | Neuraxial block and anticoagulant medication
The low event rate of epidural haematoma means that evidence cannot be based on RCTs but
must rely on data from case reports, case series and large audits. An American Society of Regional
Anesthesia and Pain Medicine (ASRA) Practice Advisory publication provides a good overview ofand guidance on neurological complications of regional anaesthesia (Neal 2008 GL).
The population incidence of epidural haematoma following neuraxial block is possibly smaller
than that of spontaneous epidural haematoma, however the rate in patients exposed to epiduralanaesthesia is more appropriate for comparison. Between 1962 and 1992, 326 case reports of
spontaneous epidural haematoma were published (Schmidt 1992 Level IV), while between 1906
and 1996 only 51 cases of epidural haematoma following epidural anaesthesia or analgesia werereported (Wulf 1996 Level IV).
Anticoagulation (present in 48% of cases) was the most important risk factor for epidural
haematoma following insertion of an epidural needle/catheter, followed by coagulopathy(present in 38% of cases) (Wulf 1996 Level IV, n=51). This was confirmed by the series of epidural
haematomas that followed epidural anaesthesia/analgesia in combination with inappropriate
LMWH regimens in the USA, where the incidence was reported to be 1 in 3,000 ( Horlocker 2003
Level IV).
In view of the increased risk with anticoagulation, ASRA (Horlocker 2010 GL) and the European
Society of Anaesthesiology (ESA) (Gogarten 2010 GL) published a number of consensus statements
and recommendations on regional anaesthesia in patients receiving antithrombotic or
thrombolytic therapy. Such statements should be viewed as “a panel of experts” best faith efforts
to offer reasonable pathways to provide safe and quality patient care while allowing for clinicaldifferences based on individual situations (Bergqvist 2003 NR). It is recognised that variances fromrecommendations outlined in the ASRA guidelines “may be acceptable based on the judgementof the responsible anesthesiologist” (Horlocker 2010 GL). That is, these guidelines will not
substitute for an individual risk/benefit assessment of every patient by the individualanaesthetist.
The ASRA guideline was updated in 2018 (Horlocker 2018 GL), but the ESA (Gogarten 2010 GL)
recommendations have not been updated since 2010, despite the fact that new information on
both established and newly introduced anticoagulants has become available. Subsequentguidelines developed for interventional spine and pain procedures jointly by ASRA, European
Society of Regional Anaesthesia and Pain Therapy (ESRA), the American Academy of Pain
Medicine (AAPM), the International Neuromodulation Society (IMS), the North American
Neuromodulation Society and the World Institute of Pain (WIP) in 2015 ( Narouze 2015 GL) were
updated in 2018 (Narouze 2018 GL). These guidelines classify pain procedures according topotential risk of serious bleeding and emphasise the importance of assessing both procedureand patient-specific risk factors, such that concurrent use of anticoagulant or antiplatelet agentsincreases the potential procedural risk.
The Society for Obstetric Anesthesia and Perinatalogy (SOAP) published a consensus
statement in 2018 also (Leffert 2018 GL), in the context of increased use of thromboprophylaxis
in obstetrics and differences in pharmacokinetics of anticoagulants in the obstetric population,
as well as the competing risks to the fetus and from general anaesthesia, which were issues notdirectly addressed in the aforementioned guidelines.

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Table 5.2 summarises recommendations from these guidelines for timing of antithrombotic
or antifibrinolytic administration in relation to neuraxial blockade including epidural catheter
insertion and removal.
Recommendations aim to minimise anticoagulant presence during both insertion and removalof an epidural catheter due to associated risk of spinal haematoma formation. Time intervals
between discontinuation of therapeutic anticoagulation and neuraxial block are predominantly
pharmacologically based. After 5 half-lives (adjusted for renal impairment, if the anticoagulant isrenally excreted), the residual anticoagulant activity will be 3%. Prophylactic doses of parenteral
anticoagulants are interrupted for 2 half-lives due to lower levels of anticoagulation, although thismay not be the case for non-vitamin K oral anticoagulants (NOACs) as discussed below.
Time intervals for subsequent dosing are based on the time to reach peak effect for eachanticoagulant which is subtracted from the 8 h required for platelet plug stabilisation (Rosencher
2007 GL; Bouma 2006 NR BS).
Pregnancy-related physiological changes may impact unfractionated heparin (UFH) and/or
LMWH pharmacokinetics. Increased maternal plasma volume may increase their volume of
distribution with decreased peak and steady-state concentrations, more rapid renal clearance
due to increased blood flow and glomerular filtration rate (GFR) and the free fraction of highly
protein bound drugs may be increased due to lower serum albumin concentration in pregnancy(Leffert 2018 GL). Consequently, recommendations for the range of drug doses, includingintermediate and high doses have been included in the SOAP guideline and Table 5.2.
For some anticoagulants there is a role for coagulation studies and use of anticoagulant
reversal agents may be relevant if urgent neuraxial block is required.
• Unfractionated heparin SC or IV— Thromboprophylaxis with SC UFH given twice‐daily is
not a contraindication to neuraxial block after an appropriate time interval (see Table 5.2).
IV UFH administration results in immediate anticoagulant activity. SC administration has
lower bioavailability than IV UFH administration with a 1 to 2 h delay in onset of
anticoagulant activity. Offset of action is also slower when higher SC doses are used. To
identify heparin‐induced thrombocytopenia (HIT), a platelet count should be checked
during therapy continued for more than 5 d and specifically prior to removal of an
epidural catheter in patients who have had more than 4 d of heparin therapy. In patientswith prior heparin exposure, pre-formed heparin-platelet factor 4 antibodies may exist
and the onset of HIT may occur by 2 d. The anticoagulant activity of unfractionatedheparin, administered IV or SC can be fully reversed with protamine (1 mg per 100 IU
heparin, max dose 50 mg).
• Low molecular weight heparin — Routine use of anti-Xa monitoring is not recommended
and a safe level of residual anti-Xa activity for neuraxial block has not been determined.
Concurrent administration of other medicines that may affect haemostasis (eg antiplatelet
medicines) should be avoided. Renal impairment prolongs the effect of LMWH (for dosing
recommendations in renal impairment see Table 5.3), although only one of the guidelines
suggests determination of antifactor Xa activity in patients with renal insufficiency (Narouze2015 GL). Protamine reverses approximately 60% of LMWH activity.
• Fondaparinux – This parenteral synthetic pentasaccharide with antiXa activity has aplasma half-life of 21 h and is not reversed by protamine. Neuraxial anaesthesia is notrecommended outside of the context of clinical trials and an alternative VTE prophylactic
agent should be utilised (Horlocker 2018 GL).
• Oral warfarin — Established warfarin therapy should be discontinued 5 d prior toneuraxial block and the INR normalised. Preoperative initiation of warfarin therapy
requires an INR check prior to neuraxial block if a single dose of warfarin 5 mg was given>24 h preoperatively or a second dose was given. The INR should also be checked prior to362

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removal of indwelling epidural catheters if warfarin was administered >36 h before. An
INR <1.5 is estimated to be a safe level for removal, while an INR >3 requires withholding
warfarin and waiting for normalisation or actively reversing warfarin to allow earlier
catheter removal. Specific advice on warfarin reversal is available in an updated Australianand New Zealand guideline (Tran 2013 GL).
Non-vitamin K oral anticoagulants (NOACs)
Neuraxial techniques should be avoided whilst patients are anticoagulated with NOACs.
• Rivaroxaban and apixaban are oral direct factor Xa inhibitors with partial renal
excretion. They require cessation at least 3 d prior to neuraxial blockade (see Table 5.2
for details) and may be recommenced 6 h post epidural catheter removal or at least
24 h post-surgery. Andexanet alpha partly reversed the anti-Xa activity of these agentsin patients with major bleeding but is not currently available for use in Australia or New
Zealand and has not been trialled in a surgical or procedural setting ( Connolly 2019 Level
IV, n=352).
• Dabigatran is an oral direct thrombin inhibitor with 80% renal clearance. It also requires
cessation at least 3 d prior to neuraxial anaesthesia and longer periods of interruption forvarious degrees of renal impairment and it may be recommenced 6 h post epidural
catheter removal or at least 24 h post-surgery. Idarucizumab is a direct specific reversal
agent for dabigatran and is widely available in Australia and New Zealand. A 5 g dose
rapidly and completely reverses dabigatran in patients with major bleeding and 92%
patients requiring urgent surgery or procedures had normal haemostasis post
administration of idarucizumab including some patients requiring urgent neuraxial
anaesthesia (Pollack 2017 Level III-1, n=503). A dilute thrombin time assay can quantify the
dabigatran concentration in plasma and should be tested 24 h after administration of
idarucizumab as a minority of patients may show rising dabigatran concentrations
potentially requiring a further dose of idarucizumab.
• The timing of NOAC interruption was standardised for the particular anticoagulant, renal
function and surgical bleeding risk (Douketis 2019 Level III-2, n=3,007). Patients did not receive
bridging anticoagulation. Rates of major bleeding (2%) and arterial thromboembolism (<1%)
were low. A subgroup of 230 patients received neuraxial anaesthesia and were managed
according to the ‘high-bleeding risk’ protocol in which patients received their last NOAC dose
3 d prior to surgery or 5 d prior for patients on dabigatran with creatinine clearance less than
50 mL/min. Almost all patients (98.8%) had a residual anticoagulant level less than 50 ng/mL.
The proportion of these patients with residual anticoagulant level less than 30 ng/mL was
93.1% in the apixaban cohort, 98.9% in the dabigatran cohort and 85.4% in the rivaroxaban
cohort. The optimal preoperative anticoagulant level has not been established and someassays show increased result variability below 50 ng/mL. No spinal haematomas werereported in this study. The same NOAC interruption protocol was used for different doses ofeach NOAC and there was no significant difference in drug levels preoperatively. NOACs havea wide therapeutic index and consequently shorter periods of interruption are not currently
recommended for the lower drug doses.
Antiplatelet medications
NsNSAIDs and other antiplatelet therapies
NsNSAIDs including aspirin alone do not significantly increase the risk of spinal haematoma but
should be regarded as a risk factor if combined with other classes of anticoagulants. In suchsituations, coxibs should be preferred. Recommended time intervals between discontinuation or
recommencement of nsNSAIDs and other antiplatelet medications (eg prasugrel) and neuraxial
5th Edition | Acute Pain Management: Scientific Evidence 363

block are given in Table 5.2. There are significant changes in the updated guidelines with wide
variation in recommendations for different agents. For some agents, the post-operative timeinterval to recommencement is longer than the recommendation for neuraxial procedures
without surgery.
Herbal therapy
Although garlic (Allium sativum), ginkgo (Ginkgo biloba), ginseng (Panax spp), dong quai (Angelica
sinensis) and danshen (Salvia miltiorrhiza) have effects on haemostasis, there are currently no
specific concerns about their use alone with neuraxial block. However, their combination withother anticoagulants or antithrombotics increases the risks. Patients taking dong quai and danshen
combined with warfarin require an INR check.
Fibrinolytics and thrombolytics
Patients receiving fibrinolytic or thrombolytic medicines should not undergo neuraxial block
except in exceptional circumstances; no data are available on a safe time interval after use ofsuch medicines but at least 48 h and normalisation of fibrinogen level are recommended. No
definite recommendations are given for the removal of neuraxial catheters after initiation ofsuch therapy, although fibrinogen level might be a useful guide in such situations.

5.9.2 | Plexus and other peripheral regional block and anticoagulant medication
Significant blood loss or haematoma formation, rather than neurological deficit, seems to be themain risk when plexus or other regional blocks are performed in patients taking anticoagulant
medications (Horlocker 2010 GL). Technical and anatomical considerations are different for paininterventions with both patient-specific and procedure-specific risk factors requiring assessment(Narouze 2018 GL).
In a series of peripheral nerve blocks for joint replacement (continuous lumbar plexus,
continuous femoral and continuous or single sciatic block), with removal of the catheters at POD
2 or 3, no perineural haematoma was found despite use of warfarin (50.0%), fondaparinux(12.8%), dalteparin (11.6%), enoxaparin (1.8%) and aspirin (23.8%) (Chelly 2008a Level IV, n=6,935).
A case series of patients receiving rivaroxaban 10 mg with a femoral catheter for TKA
replacement in situ and removal 20 h after intake reported no cases of haematoma formation(Idestrup 2014 Level IV, n=504). However, a case series of bleeding complications after removal offemoral and sciatic catheters under LMWH suggests that caution is appropriate ( Bickler 2006
Level IV, n=3; Horlocker 2010 GL).
For obvious reasons, deep blocks may be more at risk of bleeding complications thansuperficial blocks, where external compression is possible. Case reports of retroperitoneal
haematoma after lumbar plexus block in conjunction with anticoagulation are published witheither no neurological sequelae (Weller 2003 CR) or plexopathy (Klein 1997 CR). However, in a caseseries where lumbar plexus catheters were removed in warfarinised patients (36.2% with an
INR >1.4 [range 1.5–3.9]), only one superficial bleeding event occurred (in a patient with INR 3.0)
(Chelly 2008b Level IV, n=670).
The updated guidelines developed for interventional spine and pain procedures classify
procedure–related risks, then upgrade the risk for patients on anticoagulants such thatpreoperative recommendations are similar to other guidelines but the post-operative
resumption of anticoagulants is aligned with postsurgical recommendations of at least 24 h delay(Narouze 2018 GL). An expert panel of the Regional Anesthesia and Acute Pain Section of theCanadian Anesthesiologists Society (CAS) published a practice advisory on the bleeding risks forperipheral nerve and interfascial plane blockade, which categorises blocks into low, moderate
and high risk (Tsui 2019b GL).

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5.0 | ADMINISTRATION OF ANALGESIC MEDICINESKEY MESSAGES
1. Anticoagulation and coagulopathy are the two most important risk factors for thedevelopment of epidural haematoma after neuraxial block (U) (Level IV).
The following tick box represents conclusions based on clinical experience and expert
opinion: Consensus statements of experts guide the timing and choice of regional anaesthesia
and analgesia in the context of anticoagulation but do not represent a standard of careand will not substitute the risk/benefit assessment of the individual patient by theindividual anaesthetist (S).
 Caution should be used when considering and performing some peripheral nerve or
plexus blocks in patients with impaired coagulation, in particular where the peripheral
nerve block is performed at a deep location that prevents external compression,
should bleeding occur (S).

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Table 5.3 | Dosing of prophylactic LMWH in renal impairment
Normal dosing(CrCl greater than 30 mL / min)

Renal impairment(CrCl =10 to 30 mL / min)

Renal impairment(CrCl less than
10 mL / min)

TWICE a day regimen:
Enoxaparin (Clexane®):
1 mg / kg TWICE a day(max. 150 mg TWICE a day
Dalteparin (Fragmin®):
100 units / kg / TWICE a day

Enoxaparin (Clexane®)*:(max. 15,000 units TWICE a day)

1 mg / kg ONCE daily

ONCE daily regimen:

Dalteparin (Fragmin®)*:Enoxaparin (Clexane®):100 units / kg ONCEdaily

Use unfractionatedheparin

1.5 mg / kg ONCE daily(max. 180 mg ONCE daily)
Dalteparin (Fragmin®):
200 units / kg ONCE daily(max. 25,000 units ONCE daily)*The determination of an tiXa levels is recommended for optimal dosing(adapted from Sanofi-Aventis Australia 2018; Pfizer Australia 2019370

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6

Patient-controlled analgesia
Section Editor:
Dr Richard Halliwell402

6.1 | Efficacy of intravenous PCA
6.2 | Cost of PCA
6.3 | Medicines used for parenteral PCA
6.4 | Program parameters for IV PCA
6.5 | Efficacy of PCA using other systemic routes of administration
6.6 | Safety and complications related to PCA
6.7 | Equipment
6.8 | Patient and staff factors
Contributor: Dr Richard Halliwell403

6.0 | Patient-controlled analgesia
Patient-controlled analgesia (PCA) refers to all methods of pain relief that allow a patient toself-administer small doses of an analgesic agent as required. Most often, the term PCA refers
to programmable infusion pumps that deliver opioid medications IV. However, many othermethods and routes of delivery using opioids as well as other analgesic agents have been
described (SC, epidural, IT, SL, IN, oral, pulmonary, and TD). In addition to treating
postoperative pain, PCA is used for pain following trauma and with cancer.
For epidural PCA see Section 5.6.3; for PCA use in labour see Section 9.1.3.1 and in children
see Sections 10.5.2 to 10.5.4.

6.1 | Efficacy of intravenous PCA
6.1.1 | Analgesia, patient preference and outcomes
An updated Cochrane review is published (McNicol 2015 Level I [Cochrane], 49 RCTs, n=3,412); thisincludes only four RCTs since 2005, which may reflect the adoption of PCA into usual clinicalpractice. The meta-analysis compares IV PCA using full mu-opioids with intermittent full muopioids (usually IM morphine), and also includes the use of supplemental NSAIDs orparacetamol. The most frequently used opioid is morphine (33/49 RCTs); the most common
bolus size is 1 mg and the most common lockout intervals are 5 to 10 min. There was a lack ofhead-to-head trials comparing different opioids via PCA so no comparison of opioids could be
made. IV opioid by PCA for treatment of postoperative pain provides better analgesia thanconventional (IM, SC) opioid regimens, although the magnitude of the difference in analgesia issmall (MD 9.7/100; 95%CI 12.5 to 7 [0 to 48 h]). PCA use increases opioid consumption at 0 to
24 h (7 MME; 95%CI 1.4 to 13) and 25 to 48 h (5 MME; 95%CI 3 to 8). PCA improves number ofpatients satisfied (80% vs 61) (RR 1.32; 95%CI 1.12 to 1.53) (11 RCTs, n= 547) and satisfaction
scores (SMD 0.55; 95%CI 0.13 to 0.97) (7 RCTs, n=427). This benefit may relate to the increased
autonomy that PCA confers. None of the studies measured ‘readiness for discharge’. LOS does
not differ (10 RCTs), but this outcome may have been dependent on other factors. Serious
adverse event rates (including death, wound infections, atelectasis and adhesions) do not differ
between the two groups (19 RCTs, n=1,284). However, as death is a rare event, larger patientnumbers are required to reliably evaluate this outcome. Other adverse events occur similarly:
sedation (15 vs 16%), respiratory depression (Sa02 ≤ 90% or RR <10/min or need for naloxone)(2.3 vs 2%) and nausea and/or vomiting (30 vs 32%), while pruritus was more frequent in the
PCA group (15 vs 8%) (RR 1.8; 95%CI 1.1 to 2.8).
In an ED setting, IV PCA was as effective as nurse-administered IV bolus doses of opioid(Evans 2005 Level II, n=86, JS 3). In two other RCTs in the ED setting, PCA morphine provided more
effective analgesia with more rapid onset and higher patient satisfaction than nurseadministered IV morphine (Rahman 2012 Level II, n=96, JS 3; Birnbaum 2012 Level II, n=211, JS 3).
Other information obtained from published RCTs as well as cohort studies, case-controlled
studies and audit reports suggests that IV PCA may be appreciably more effective thanintermittent IM opioid analgesia in a “real world” clinical setting; patients given IM opioid
analgesia were more than twice as likely to experience moderate to severe pain and severe
pain than those given PCA (Dolin 2002 Level IV SR, 165 studies, n≈20,000).

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In settings where there are high nurse:patient ratios and where it might be easier toprovide analgesia truly on-demand, conventional forms of opioid administration may be aseffective as IV PCA. A comparison of PCA vs nurse-administered analgesia following cardiac
surgery found no difference in analgesia at 24 h (a period when nursing attention is likely to behigher) but significantly better pain relief with PCA at 48 h (Bainbridge 2006 Level I, 10 RCTs,
n=666).
The enormous variability in PCA parameters (bolus doses, lockout intervals and maximum
permitted cumulative doses) used in many studies indicates uncertainty as to the ideal PCA
program and may limit the flexibility, and thus the efficacy, of the technique. Individual PCA
prescriptions may need to be adjusted if patients are to receive the maximal benefit ( Macintyre
2015 NR; Macintyre 2008 NR; Macintyre 2005 NR).
A number of studies have shown that PCA provides less effective pain relief vs epidural
analgesia. See Section 5.6.1.1 .

6.2 | Cost of PCA
The use of any analgesic technique, even if it is known to provide more effective pain relief,
requires consideration of the cost involved. There is limited data on the economic assessmentof PCA vs conventional opioid analgesic techniques; information that is available often does notinclude the full scope of costs (eg cost of adverse effects or failure of an analgesic technique, as
well as the more obvious costs of pumps, disposables and nursing time). However, in general,
PCA comes at a higher cost because of the equipment, consumables and medicine preparation;
nursing time needed is much less (Chang 2004 Level II, n=125, JS 3; Choiniere 1998 Level II, n=126,
JS 3; Rittenhouse 1999 Level III-2; Jacox 1997 NR). PCA was more cost-effective than epidural
analgesia after major abdominal surgery (LOS and morbidity excluded) (Bartha 2006 Level III-2,
n=644). In a subsequent assessment, PCA costs were estimated by analysis of a large
administrative database covering 500 USA hospitals (Palmer 2014 Level III-3, n=11,805,513). The
direct and indirect cost estimates (US$ in 2012) were assessed for the first 48 h after major
surgery (TKA, THA and open abdominal procedures). The cost estimates range from US$196 to
243 per patient. Further estimates, adding in the costs of adverse effects of PCA programming
errors, phlebitis and bacteraemia due to IV access, increased the costs to US$342 to 389 per
patient. See also Section 3.3.

6.3 | Medicines used for parenteral PCA
6.3.1 | Opioids
In general, there is little evidence, on a population basis, to suggest that there are any majordifferences in efficacy or the incidence of adverse effects between morphine and other opioids
commonly used in PCA, although the results of individual studies are inconsistent (for moredetails see 6.3.1.10 below). Most studies are not powered adequately to make conclusions
about comparative safety, especially for respiratory depression.
On an individual patient basis, one opioid may be better tolerated than another and achange to an alternative opioid may be beneficial if the patient is experiencing intolerable
adverse effects (Woodhouse 1999 Level II, n=82 [cross over], JS 4).

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6.3.1.1 | Morphine
Morphine is still a commonly used opioid for IV PCA ( Palmer 2014 Level III-2, n=11,805,513).
Compared with other opioids, morphine has a long equilibration half-life between plasma
and the CNS effect site (2 to 3 h) (Aubrun 2012 NR; Lötsch 2005 NR). Furthermore, morphine
has an active metabolite, M6G, which has opioid effects, with an equilibration half-life of 7 h
and a long elimination half-life (Lötsch 2005 NR). Simulated peak effect-site concentration formorphine occurs 8 to 24 h after the commencement of PCA ( Sam 2011 Level III-3 PK, n=10).
These pharmacokinetic features may make morphine less suitable for IV PCA use than otheropioids. Limited clinical data suggest that morphine may have a higher incidence of sedation
and respiratory depression than fentanyl ( Hutchison 2006 Level III-2, n=241).
6.3.1.2 | Fentanyl
In general, there is limited evidence to show a difference between morphine and fentanyl interms of pain relief or the incidence of most adverse effects ( Woodhouse 1996 Level II, n=50, JS 5;
Howell 1995 Level II, n=37, JS 3); pruritus was more common with morphine (Woodhouse 1996
Level II, n=50, JS 5). A retrospective cohort study of patients having hip or knee surgery foundthose receiving PCA fentanyl, when compared with morphine or hydromorphone, had lower
pain scores and fewer opioid-related adverse effects (PONV, sedation, pruritus or urinary
retention) (Hutchison 2006 Level III-2, n=241). Fentanyl PCA vs morphine PCA after cardiac surgery
had a lower incidence of nausea (32 vs 52%) (Gurbet 2004 Level II, n=75, JS 3).
6.3.1.3 | Tramadol
Tramadol by IV PCA has similar analgesic efficacy vs other opioids by IV PCA, mainly vsmorphine (7 RCTs) (Murphy 2010 Level I, 12 RCTs, n=782). However, the adverse-effect profile isdifferent with the tramadol group experiencing more PONV (OR 1.52; 95%CI 1.07 to 2.14) but
less pruritus (OR 0.43; 95%CI 0.19 to 0.98). There was no difference in sedation or fatigue. Data
were insufficient to assess safety. Tramadol also has a lower risk of respiratory depression andless effect on gastrointestinal motor function compared with other opioids. See also Section
4.1.1.2.
6.3.1.4 | Hydromorphone
There is limited data examining the use of hydromorphone when delivered by IV PCA. A surveyof a large USA inpatient database found that hydromorphone was the second most commonlyused opioid for PCA after morphine (Palmer 2014 Level IV, n=11,805,513). When compared withmorphine in patients having general surgery, there was no difference in adverse effects, pain
relief or satisfaction (Hong 2008 Level II, n=50, JS 4). Hydromorphone and morphine IV PCA had
similar rates of opioid-induced adverse effects, with fentanyl having the lowest in a
retrospective comparison of patients after hip or knee surgery ( Hutchison 2006 Level III-2, n=254).
In a comparison of IV PCA morphine with hydromorphone in patients having open abdominal
surgery, analgesia was equivalent and there were similar adverse effects (Rapp 1996 Level II,
n=61, JS 3). The morphine group had less cognitive impairment and the hydromorphone group
had better mood. A study of patients having IV PCA for oral mucositis pain after bone marrowtransplantation found that hydromorphone vs morphine was equally effective for analgesia buthydromorphone had more frequent adverse effects (Coda 1997 Level II, n=119, JS 4). Comparing
PCA hydromorphone with PCA sufentanil in patients having surgery for colorectal cancer foundthat postoperative mood assessment differed, with ‘anger’ being lower in the hydromorphone406

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group (Yang 2018 Level II, n=80, JS 5). This may be due to differences in opioid receptor typeaffinity.
Safety issues have occurred due to confusion about the name of the medicine and its highpotency (5 times that of morphine) (NSW Health 2011 GL). See also Section 9.5.5.
6.3.1.5 | Oxycodone
Oxycodone, unlike morphine, has a rapid equilibration with the CNS which might make it moresuited to PCA use (Sadiq 2013 BS & PK [rodent]). Oxycodone IV PCA vs morphine IV PCA resulted
in similar pain relief and adverse effects during the first 24 h after surgery (breast or spinal)(Silvasti 1998 Level II, n=50, JS 3). The dose requirements were similar. After laparoscopic
hysterectomy, IV PCA oxycodone dose requirements were lower than with morphine ( Lenz 2009
Level II, n=91, JS 4) with less sedation in the oxycodone group; pain scores were lower but only inthe first h after surgery and thereafter were similar. After maxillofacial surgery, IV PCA
oxycodone vs IV PCA tramadol provided equivalent analgesia (Silvasti 1999 Level II, n=54, JS 3).
In patients having laparoscopic gynaecological surgery, IV PCA oxycodone and PCA fentanyl
produced equivalent analgesia and satisfaction. Dizziness was more common in the oxycodone
group, whilst nausea and vomiting were the same (Park 2015 Level II, n=74, JS 4). In laparoscopic
hysterectomy patients (who received ketorolac and ramosetron), IV PCA oxycodone improved
pain relief vs PCA fentanyl, but increased adverse effects of PONV, dizziness, and drowsiness(Kim 2017 Level II, n=130, JS 5).
Trials to date are not adequate in sample size to assess if IV PCA oxycodone confers
superiority over other opioids.
6.3.1.6 | Pethidine
Compared with morphine, IV PCA pethidine (meperidine) may lead to less effective pain
relief on movement ( Plummer 1997 Level II, n=102, JS 4; Sinatra 1989b Level II, n=75, JS 4; Bahar
1985 Level II, n=48, JS 1), no difference in nausea and vomiting ( Plummer 1997 Level II, n=102,
JS 4; Woodhouse 1996 Level II, n=50, JS 5; Stanley 1996 Level II, n=40, JS 5; Bahar 1985 Level II, n=48,
JS 1) and less sedation (Sinatra 1989a Level II, n=75, JS 4) and pruritus (Woodhouse 1996 Level II,
n=50, JS 5; Sinatra 1989b Level II, n=75, JS 4). IV PCA pethidine may cause more cognitive
impairment than morphine ( Plummer 1997 Level II, n=102, JS 4). Pethidine has a neurotoxic

metabolite (norpethidine) that can accumulate during PCA administration and can cause
adverse effects (Simopoulos 2002 Level IV, n=355; Stone 1993 Level IV, n=3; McHugh 1999 NR).
6.3.1.7 | Methadone
Methadone by IV PCA, in comparison to morphine, provided more effective pain relief at restand during movement for the first 24 h after surgery, with no difference in adverse effects(Neto 2014 Level II, n=34 [trial discontinued prematurely], JS 4). It should be noted, that thepharmacokinetics of methadone are complex (and are not suited to IV PCA use in acute pain
management) (Weschules 2008 NR). (See also Section 4.3.1.2)
6.3.1.8 | Other opioids
Remifentanil IV PCA provided at least equivalent analgesia vs morphine or fentanyl PCA andmay be associated with less nausea and vomiting (Kucukemre 2005 Level II, n=69, JS 4; Gurbet 2004
Level II, n=75, JS 3). See also Section 9.1.3.1 for discussion of use of IV PCA remifentanil during
labour.
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6.3.1.9 | Opioid combinations
The combination of two opioids in the PCA syringe has been investigated.
There was no difference in pain scores and adverse effects between fentanyl/morphine andfentanyl by PCA, apart from slightly less nausea with the combination (Friedman 2008 Level II,
n=64, JS 5).
Beneficial effects on pain relief and the incidence of pruritus in a comparison of morphine,
nalbuphine and varying combinations of the two medicines were dependent on the ratio of
medicines used (Yeh 2007 Level II, n=311, JS 5). The combination, when compared to morphine
alone, provided improved analgesia and reduced nausea.
The combination of alfentanil/morphine IV PCA resulted in no differences in pain relief oradverse effects vs morphine alone, although patients who received alfentanil/morphine rated
speed of onset and adequacy of analgesia as better ( Ngan Kee 1999 Level II, n=80, JS 5). There
was no improvement in pain-related sleep disturbance with this combination vs fentanyl alone
but analgesia, both at rest and movement, was better in the first 24 h after surgery (Lee 2013
Level II, n=212, JS 5).
Compared with IV PCA tramadol alone, remifentanil added to tramadol improved pain relief
but increased total opioid doses used (Unlugenc 2008 Level II, n=62, JS 4).

6.3.2 | Adverse effects of PCA opioids
As noted in Section 6.1.1 above, meta-analyses and individual studies have shown that, ingeneral, the risk of adverse effects is similar for all opioids administered by PCA, regardless ofthe opioid used. However, individual patients may be intolerant of specific opioids but tolerantof others (Woodhouse 1999 Level II, n=82 [cross over], JS 4). In a network meta-analysis, adverse
effects occur at differing frequencies for the various opioids at equianalgesic doses (Dinges 2019
Level I [NMA], 63 RCTs, n unspecified). Results are reported as a relative risk (with morphine as thecomparator):• Nausea and vomiting are most frequent with buprenorphine (RR 1.37; 95%CI 1.05 to1.8) and least with fentanyl (RR 0.82; 95%CI 0.67 to 1.0). Other opioids are not different
to morphine (39 RCTs, n=4,614);• Pruritus is the most frequent with morphine, and the least frequent with methadone(RR 0.17; 95%CI 0.03 to 0.90) and pethidine (RR 0.47; 95%CI 0.25 to 0.87). Other opioids(including oxycodone, tramadol, fentanyl, hydromorphone and remifentanil) are notsignificantly different to morphine (39 RCTs, n=3,480);• Sedation is least frequent with fentanyl, oxymorphone and pethidine. Other opioids are
not different to morphine (31 RCTs, n=1,528);• Satisfaction is highest with oxycodone, alfentanil, remifentanil, fentanyl, and pethidine.
Tramadol has the least satisfaction. Other opioids are not different to morphine (17RCTs, n=1,476).
OIVI is rare with 22 cases reported (n=2,452); sufentanil, alfentanil, remifentanil andmorphine have the highest reported rates here.
Two reviews of published RCTs, cohort studies, case-controlled studies and audits reported
the following incidences associated with IV PCA use: respiratory depression 1.2 to 11.5%(depending on whether respiratory rate or oxygen saturation were used as indicators), nausea
32%, vomiting 20.7% and pruritus 13.8% (Dolin 2005 Level IV SR, 183 studies [PONV] & 89 studies[sedation] & 166 studies [pruritus], n100,000; Cashman 2004 Level IV SR, 165 studies, n20,000).
Excessive sedation was not used as an indicator of respiratory depression in any of the studies
included in these reviews (see importance of sedation score in Section 4.3.1.4).

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The incidence of respiratory depression (<10 breaths/min) with PCA morphine was 0.06%
and no patient required naloxone (Cheung 2009 Level IV, n=5,137). The incidence of nausea was
47.4% and vomiting was 18.5%; these were most common in female patients and those having
gynaecological surgery. The incidence of pruritus was 8%.
In 1.86% of patients who received PCA for postoperative pain relief, respiratory depression(defined as a respiratory rate of <10 breaths/min and/or a sedation score of 2; defined as“asleep but easily roused”) was identified; of these 13 patients all had respiratory rates of<10 breaths/min and 11 also had sedation scores of 2 (Shapiro 2005 Level IV, n=700).
Impact of adjuvants on IV PCA adverse effects
The combination of NSAIDs with IV PCA morphine reduces adverse effects vs IV PCA morphine
alone:• PONV is reduced by 30% (OR 0.70; 95%CI 0.53 to 0.88) (Maund 2011 Level I, 60 RCTs,
n unspecified);• Sedation is reduced by 29%, while respiratory depression, pruritus and urinary retention
are not reduced (Marret 2005 Level I, 22 RCTs, n=2,307).
These benefits are most likely due to the opioid-sparing effect of concurrent NSAIDs, rather
than a direct effect of NSAIDs themselves. Similar beneficial effects have also been found forthe addition of IV ketamine via various regimens (Assouline 2016 Level I [PRISMA], 19 RCTS,
n=1,453; Wang 2016 Level I [PRISMA], 36 RCTs, n=2,502) (12 RCTs overlap), gabapentin (Fabritius 2016
Level I [PRISMA], 132 RCTs, n=9,498), pregabalin (Fabritius 2017 Level I [PRISMA], 97 RCT, n=7,201), IV
lidocaine (Weibel 2018 Level I [Cochrane], 68 RCTs, n=4,525) and the alpha-2 agonists clonidine(Sanchez Munoz 2017 Level I [PRISMA], 57 RCTs, n=14,790) and dexmedetomidine by various
administration regimens (Wang 2018 Level I [PRISMA], 40 RCTs, n=2,401).

6.3.3 | Adjuvant medicines
Discussion of adjuvant medicines in this section will be confined to those added to the PCA
opioid solution. For additional information see Chapter 4.
6.3.3.1 | Antiemetics
Droperidol added to the PCA morphine solution is effective in preventing nausea (NNT 2.7;
95%CI 1.8 to 5.2) and vomiting (NNT 3.1; 95%CI 2.3 to 4.8) with no apparent doseresponsiveness (Tramer 1999 Level I, 6 RCTs [droperidol], n=642). Adverse effects were notincreased when the dose of droperidol was <4 mg/d. However, in a subsequent comparison of
0.5 mg, 1.5 mg and 5 mg droperidol added to 100 mg PCA morphine, the smallest dose had no
significant antiemetic effect and the 1.5 mg dose was effective against nausea (NNT 6.3; 95%CI
3.3 to 100) but not vomiting (Culebras 2003 Level II, n=340, JS 4). The 5 mg dose significantly
reduced both nausea and vomiting but at the cost of unacceptable sedation (NNH 6.4; 95%CI
4.1 to 15), which was not seen at the other doses. The 1.5 mg and 5 mg doses also reduced
pruritus. There was no difference in dysphoric effects. In another RCT, droperidol 5 mg added
to morphine 100 mg by PCA resulted in morphine-sparing and, in the first 24 h after surgery,
reduced the frequency of PONV (Lo 2005 Level II, n=179, JS 5). While, droperidol given as a single
dose at the end of surgery was as effective as adding droperidol to PCA morphine ( Gan 1995
Level II, n=82, JS 3). The cost-benefit and risk-benefit of the routine addition of droperidol to PCA
opioids must therefore be considered, because all patients receive the medication when not all
will need it and some patients might receive inappropriately high doses of droperidol.

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Evidence of benefit from the addition of 5HT3 antagonists to IV PCA is unclear.
Ondansetron, given both as a bolus at the end of surgery and mixed with morphine in the PCA
solution, reduced the incidence of nausea and the need for additional antiemetics but not thepatients’ perception of their overall satisfaction with care ( Cherian 2001 Level II, n=81, JS 4).
Adding ondansetron to PCA opioids reduces nausea and/or vomiting (NNT 2.9; 95%CI 2.1 to4.7) (Tramer 1999 Level I, 2 RCTs [ondansetron], n=184). A later study showed that ondansetron
given as an initial dose of 4 mg followed by 0.2 mg/1 mg morphine PCA morphine could reduce
nausea and vomiting; although pain scores were higher ( Boonmak 2007 Level II, n=160, JS4). The
combination of ondansetron plus prochlorperazine to IV PCA morphine was more effective
than ondansetron alone (Jellish 2009 Level II, n=150, JS 4).
Dexamethasone 8 mg given at the start of surgery reduced the incidence of severe nausea
and vomiting only vs ondansetron at the end of surgery in patients receiving PCA fentanyl withadded ondansetron (12 mg added to 2 mg fentanyl) ( Song 2011 Level II, n=130, JS 4). The additionof midazolam to PCA morphine had a similar antiemetic effect to that of ondansetron but was
associated with an increase in mild sedation (Huh 2010 Level II, n=90, JS 3).
6.3.3.2 | Ketamine
Two systematic reviews evaluated the effect of peri- and postoperative ketamine (subanaesthetic doses) coadministered as an adjuvant to PCA (morphine 15 RCTs and 1 RCT each inadults for tramadol & fentanyl and in adolescents for fentanyl & hydromorphone) (Assouline 2016 Level I[PRISMA], 19 RCTs, n=1,453) and to PCA morphine (33 RCTs, n=2,374) or PCA hydromorphone(3 RCTs, n= 128) (Wang 2016 Level I [PRISMA], 36 RCTs, n=2,502) (12 RCTs overlap).
Adding ketamine to an opioid in the PCA pump in various ratios has benefits to pain scoresat rest at 24 h (WMD 21.1/100; 98%CI 21.8 to 20.39) (9 RCTs, n=595) and opioid consumption(-28%) (7 RCTs, n=495) and PONV (-44%) (7 RCTs, n=435) (Assouline 2016 Level I [PRISMA], 19 RCTs,
n=1,453). Respiratory depression (RR 0.31; 98%CI 0.06 to 1.51) (9 RCTs, n=871) and hallucinations(OR 1.16; 98%CI 0.47 to 2.79) (7 RCTs, n=690) are not increased. A parallel meta-analysis on
ketamine added to morphine or hydromorphone PCA confirms these results (Wang 2016 Level I[PRISMA], 36 RCTs, n=2,502) (12 RCTs overlap). There was no dose-response effect found and the
optimum analgesic/sub-anaesthetic dose is uncertain.
IV ketamine PCA vs hydromorphone PCA reduced supplemental analgesia and need forsupplemental oxygenation, but was associated with more hallucinations (Takieddine 2018 Level II,
n=20, JS 5).
The stability and compatibility of mixtures of tramadol with ketamine in polyolefin bags
were satisfactory over a test period of 14 d at 4° and 25°C (Gu 2015 BS).
For more details see also Section 4.6.
6.3.3.3 | Naloxone
There was no analgesic benefit of adding naloxone to the PCA morphine solution ( Cepeda 2004
Level II, n=265, JS 5; Sartain 2003 Level II, n=96, JS 5; Cepeda 2002 Level II, n=166, JS 5); with “ultra-low
doses” only (naloxone 0.6 mcg per morphine 1 mg), the incidence of nausea and pruritus wasdecreased (Cepeda 2004 Level II, n=265, JS 5).
6.3.3.4 | Other adjuvants
Ketorolac added to morphine (Chen 2009 Level II, n=102, JS 5; Chen 2005b Level II, n=79, JS 5) ortramadol (Lepri 2006 Level II, n=60, JS 3) by PCA did not improve pain relief or alter the incidence

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of adverse effects; however, it was opioid‐sparing and led to an earlier return of bowel function
after colorectal surgery (Chen 2009 Level II, n=102, JS 5).
The addition of lidocaine to morphine conferred no benefit in terms of pain relief oradverse effects (Cepeda 1996 Level II, n=195, JS 5).
The addition of clonidine to IV PCA morphine resulted in significantly better pain relief forthe first 12 h only, and less nausea and vomiting vs morphine alone; there was no reduction inmorphine requirements (Jeffs 2002 Level II, n=60, JS 5).
Dexmedetomidine/morphine by IV PCA resulted in better pain relief (at rest andmovement), significant opioid-sparing (29%) and a lower incidence of nausea vs IV PCA
morphine alone (Lin 2009 Level II, n=100, JS 5). Adverse cardiovascular effects, sedation or
respiratory depression were not increased in the dexmedetomidine/morphine group.
Dexmedetomidine/sufentanil IV PCA sufentanil IV PCA alone in patients having elective
abdominal surgery (laparoscopic and open) improved pain relief at rest and with movement,
nausea (25% vs 12.5%) and vomiting (18.2% vs 6.25%) (Gao 2018 Level II, n=210, JS 4).
Magnesium added to morphine was opioid-sparing and led to better pain relief ( Unlugenc
2003 Level II, n=90, JS 3); added to tramadol, it was opioid-sparing but only provided better pain
relief for the first 2 h (Unlugenc 2002 Level II, n=66, JS 4).
Midazolam/morphine IV PCA after spinal surgery reduced anxiety and provided a small
reduction in the pattern of morphine consumption over time vs IV PCA morphine (Day 2014
Level II, n=29, JS 4). Sedation scores were not reported.
The addition of nalbuphine to PCA morphine resulted in reduced pruritus without affecting
pain relief (Yeh 2008 Level II, n=311, JS 5).

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6.4 | Program parameters for IV PCA
6.4.1 | Bolus dose
While the optimally sized bolus dose should provide good pain relief with minimal adverse
effects, there are only limited data available concerning the effects of various dose sizes. In
patients prescribed 0.5 mg, 1 mg and 2 mg bolus doses of morphine, most of those who wereprescribed 0.5 mg were unable to achieve adequate analgesia, while a high incidence of
respiratory depression was reported in those who received 2 mg (Owen 1989a Level II, n=21, JS 3).
It was concluded that the optimal PCA bolus dose for morphine was therefore 1 mg.
Similarly, in patients prescribed 20, 40 or 60 mcg bolus doses of fentanyl, the larger dose
was associated with an increased risk of respiratory depression and a conclusion was madethat the optimal dose of fentanyl for use in PCA was 40 mcg ( Camu 1998 Level II, n=150, JS 4).
However in this study, each dose was infused over 10 min, which could alter the eff ect ofthat dose.
Four different demand doses of fentanyl (10, 20, 30 and 40 mcg) were assessed for the
management of pain during changes of burns dressings. Pain relief was significantly better withthe 30 mcg and 40 mcg doses; no patient became sedated or experienced nausea and vomiting(Prakash 2004 Level II, n=60, JS 2).
Rigid adherence to an “optimal” dose may not, however, lead to the best pain relief for all
patients. If the prescribed dose is not “optimal” and not too small, the patient will be able tocompensate to some degree by changing their demand rate. However, they will only
compensate to a certain degree. Even if uncomfortable, patients may only average fourdemands/h, even though they could press the PCA button more frequently (Owen 1989a Level II,
n=21, JS 3).
Initial orders for bolus doses should take into account factors such as a history of prioropioid use (see Section 9.7) and patient age (Macintyre 2015 NR; Macintyre 2008 NR). PCA
morphine requirements are known to decrease as patient age increases (Gagliese 2008 Level IV,
n=246; Macintyre 1996 Level IV, n=1,010) (see also Section 9.2.4.2). Subsequent bolus doses may
require adjustment according to patient pain reports or the onset of any adverse effects.
The number of demands a patient makes, including the number of “unsuccessful” demands,
is often used as an indication that the patient is in pain and as a guide to adjusting the size ofthe bolus dose. However, there may be a number of reasons for a high demand rate other thanpain. For example, excessive PCA demands may correlate with anxiety, poor perioperative
adaptation to surgery involving avoidance behaviour and intrusive thoughts, as well as highpain scores (Katz 2008 Level IV, n=117). See also Section 1.2.2 for additional information on therelationship between pain relief and psychological factors in PCA.

6.4.2 | Lockout interval
The lockout interval is a safety mechanism that limits the frequency of doses delivered to thepatient. For maximum safety, it should be long enough to allow the patient to feel the full
effect of one opioid dose before another dose can be delivered. However, if it is too long theeffectiveness of PCA could be reduced. There were no differences in pain relief, adverse effects
or anxiety when lockout intervals of 7 or 11 min for morphine and 5 or 8 min for fentanyl wereused (Ginsberg 1995 Level II, n=78, JS 4).

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6.4.3 | Concurrent background (continuous) infusions
When a background infusion is used, opioid will continue to be delivered regardless of thepatient’s sedation level or respiratory status. The addition of a continuous background infusion
significantly increases the risk of respiratory depression (OR 4.68; 95%CI 1.20 to 18.21) ( George
2010 Level I [Cochrane], 14 RCTs, n=769); in 12 of the 14 RCTs, morphine was used. The risk wasincreased in adults in comparison to children (OR 10.2; 95%CI 3 to 35) (11 adult, 1 mixed,
2 paediatric). The definition of respiratory depression in this meta-analysis was either
respiratory rate ≤10, saturation ≤90% or PaCO2 ≥50.
There is no good evidence to show that the addition of a background infusion to IV PCA
improves pain relief or sleep or reduces the number of demands (Dal 2003 Level II, n=35, JS 3;
Parker 1992 Level II, n=156, JS 2; Parker 1991 Level II, n=230, JS 3; Owen 1989b Level II, n=22, JS 2). In
adults, the routine use of a background infusion is therefore cautioned against, although it may
be useful in opioid-tolerant patients (see Section 9.7).
Limited data found that the use of time-scheduled decremental continuous infusion of
opioid added to the PCA program provided better pain relief than bolus only PCA in women
having laparoscopic gynaecological surgery (Zhu 2019 Level II, n=90, JS 5; Kim 2013 Level II, n=99,
JS 4). The use of PCA with a variable rate feedback background infusion in patients having spinal
fusion surgery showed equivalent analgesia, and less total opioid dose than PCA with aconstant rate background infusion (Lee 2019 Level II, n=78, JS 5). Estimating the risk of respiratory
depression with these techniques from small studies is not possible.

6.4.4 | Dose limits
Limits to the maximum amount of opioid that can be delivered over a certain period(commonly 1 or 4 h) can be programmed into most PCA machines. There is no good evidenceof any benefit that can be attributed to these limits (Macintyre 2015 NR).

6.4.5 | Loading dose
There is enormous variation in the amount of opioid a patient may need as a “loading dose”,
and there is no good evidence of any benefit that can be attributed to the use of the loadingdose feature that can be programmed into PCA machines. PCA is essentially a maintenancetherapy; therefore adequate pain relief should be established before PCA is started byadministration of individually titrated loading doses (Macintyre 2015 NR; Macintyre 2008 NR).
IV opioid loading improved the analgesic efficacy of subsequent oral and PCA opioid therapy inthe treatment of acute sickle cell pain (Rees 2003 GL).
When administering IV loading doses of opioids, lipophilic medicines such as fentanyl are
more appropriate than morphine for titrating analgesia because they equilibrate more quickly
with the brain. While plasma and CNS fentanyl levels equilibrate within minutes, morphinetakes many hours, which can lead to OIVI occurring well after a patient has been deemed“comfortable” and discharged from a high acuity area to a lower level area (eg PACU or ED to
the ward) (Aubrun 2012 NR; Lötsch 2005 NR).

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6.5 | Efficacy of PCA using other systemic routes of administration
6.5.1 | Subcutaneous PCA
Data on the effectiveness of SC PCA vs IV PCA are variable and inconsistent. Both similar ( Bell2007 Level II, n=130, JS 3; Munro 1998 Level II, n=80, JS 3; White 1990 Level II, n=24, JS 5; Urquhart 1988
Level II, n=30, JS 1) and significantly better (Keita 2003 Level II, n=40, JS 3; Dawson 1999 Level II,
n=100, JS 2) pain relief has been reported, as well as the same (Keita 2003 Level II, n=40, JS 3;
Dawson 1999 Level II, n=100, JS 2; Munro 1998 Level II, n=80, JS 3; Urquhart 1988 Level II, n=30, JS 1) or
higher incidence of nausea and vomiting (White 1990 Level II, n=24, JS 5) or pruritus (Bell 2007
Level II, n=130, JS 3). SC PCA vs IV PCA may result in higher opioid use (Bell 2007 Level II, n=130,
JS 3; Dawson 1999 Level II, n=100, JS 2; White 1990 Level II, n=24, JS 5; Urquhart 1988 Level II, n=30, JS 1)
or may not (Munro 1998 Level II, n=80, JS 3).

6.5.2 | Oral PCA
Oral PCA, using a modified IV PCA system, is as effective as IV PCA ( Striebel 1998 Level II, n=64,
JS 2). An oral PCA device has been developed that uses radiofrequency identification (RFID)
technology to allow patients in an oncology ward access (subject to a lockout interval) to a
medication-dispensing system at the bedside (Rosati 2007 Level IV, n=20).
The use of a computer-controlled oral PCA dispensing device (the PCoA® Acute Device) was
compared to conventional nurse-administered on-request oral opioid analgesia in patients
having a variety of elective surgical procedures (Wirz 2017 Level II, n=70, JS 3). This device allowed
secure patient access to bedside oral opioid analgesia (oxycodone or morphine) via RFID
technology with higher use of opioid analgesia.

6.5.3 | Sublingual PCA
A sublingual sufentanil tablet system (SSTS) has been trialled in both postsurgical and otheracute pain settings. When compared to IV morphine PCA for analgesia after major abdominalor arthroplasty surgeries, SSTS 15 mcg provided analgesia that was noninferior to IV PCA with asimilar rate of adverse effects and superior satisfaction ratings from patients and nursing staff(Melson 2014 Level II, n=357, JS 2). Specifically for postarthroplasty pain management, SSTS
15 mcg was found to be superior to placebo but with a higher rate of nausea and vomiting ( Jove2015 Level II, n=419, JS 5). For abdominal surgeries, the analgesia from SSTS was superior toplacebo with similar adverse events profiles for 15 mcg (Ringold 2015 Level II, n=172, JS 5) and30 mcg, with rapid onset of reported analgesic effect within 15 min of administration(Minkowitz 2017 Level II, n=161, JS 5). SSTS 30 mcg was also trialled for acute pain management in
the ED setting (Miner 2018 Level III-3, n=76). See also Section 6.7.2.2 below.

6.5.4 | Intranasal PCA
IN PCA fentanyl can be as effective as IV PCA (Paech 2003 Level II, n=24, JS 3; Manjushree 2002
Level II, n=40, JS 4; Toussaint 2000 Level II, n=57, JS 3; Striebel 1996 Level II, n=50, JS 2), as is IN PCA
butorphanol (Abboud 1991 Level II, n=186, JS 2). As would be expected from the data on IN
bioavailability of opioids (see Section 5.5.2), higher doses are needed via the IN route(Manjushree 2002 Level II, n=40, JS 4; Striebel 1996 Level II, n=50, JS 2). IN PCA pethidine is aseffective as IV PCA pethidine, although larger doses are needed ( Striebel 1993 Level II, n=112, JS
3), and more effective than SC injections of pethidine ( Striebel 1995 Level II, n=44, JS 2).

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Diamorphine IN PCA (bolus doses of 0.5 mg) is less effective than IV PCA morphine (nonequivalent higher bolus doses of 1 mg were used) after joint arthroplasty surgery (Ward 2002
Level II, n=52, JS 2). It provided better pain relief in doses of 0.1 mg/kg vs 0.2 mg/kg IM
morphine in children with fractures (Kendall 2003 NR). See also Section 6.7.2.3 below.

6.5.5 | Transdermal PCA
Iontophoretic TD fentanyl PCA provided analgesia superior to placebo but significantly morepatients in the TD group withdrew because of inadequate analgesia vs IV PCA morphine (Poon2009 Level I [QUOROM], 6 RCTs, n=2,866). There was no difference in patient global assessment.
Maximum blood concentrations of fentanyl were the same if the fentanyl patientcontrolled TD patch was placed on the chest or upper outer arm, but less if placed on the lower
inner arm; the pharmacokinetics were not affected by gender, ethnicity, age or weight ( Gupta
2005 Level IV PK). See also Section 6.7.2.4 below.

6.6 | Safety and complications related to PCA
Complications related to the use of PCA can be divided into operator or patient-related errors,
and problems due to the equipment, practice environment or opioid used.
A large case series of PCA use (by IV, epidural and regional routes) including various device
types (elastomeric, CO2 driven, semiprogammable disposable and programmable electronic)
reported an incidence of adverse events related to with human error (0.74%), and devicerelated errors (0.19%) (Son 2019 Level IV, n=82,685). Human error in this study included theprocess of PCA solutions prepared by clinical staff rather than prepared commercially. The
highest device error-rates occurred in the programmable electronic device group. Adverse
events were associated with 63% of the errors and two patients had severe respiratory
depression requiring ICU admission; there was no PCA-related death.
An early prospective study of patients given PCA postoperatively found nine cases of
respiratory depression (Looi-Lyons 1996 Level IV, n=4,000). These were associated with druginteractions, continuous (background) infusions, nurse- or physician-controlled analgesia, andinappropriate use of PCA by patients. A similar sized prospective study showed that use of PCA
was associated with 14 critical events: 8 programming errors (all associated with the setting ofa continuous infusion); 3 family members activating PCA; 1 patient tampering; and 3 errors inclinical judgment (Ashburn 1994 Level IV, n=3,785).
Analysis of data from the USA FDA's Manufacturer and User Facility Device Experience(MAUDE) database shows that 76.4% of adverse effects related to IV PCA were attributed totechnical problems with devices (eg frayed wires or cracks in syringes/ cartridges) and 6.5%
were caused by operator error (Schein 2009 Level IV, n=2,009 [events]). Of these operator errors(n=131 events), most (81%) related to pump misprogramming and 48% were associated withpatient harm. In contrast, only 0.5% of technical device problems resulted in patient harm.
A later retrospective analysis (from July 2000 to June 2005) reported to a national voluntary
medication error-reporting database (MEDMARX), showed that PCA-related medication errors
continue where 9,571 (1%) were related to PCA use (Hicks 2008 Level IV, n= 919,241 [errors]). Of
these, 624 (6.5%) were associated with patient harm. By comparison, only 1.5% of medication
error reports in general led to harm. The majority of PCA errors occurred during theadministration of the medication. Of these, 38% were errors in dose or quantity, 17.4%
involved an omission and 17.3% were related to an unauthorised or wrong medicine; human
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factors were the main cause of errors; distractions (37.8%) and inexperienced staff (26.3%)
were the leading contributing factors. Overall, human factors were the leading cause of PCA
errors. A postmarketing surveillance program (2011 to 2016) by the FDA identified 1,430
events with use of IV PCA, of which 11% were associated with an unfavorable clinical outcome;device related issues, which were mostly identified as preventable, occurred in 87% of these(Lawal 2018 Level IV, n=1,430 [events]). The authors suggest that education, training anddevelopment of improved safety features for PCA devices are needed to improve the overall
safety of PCA use.
The implementation of “smart pump” technologies may reduce the incidence and severityof PCA pump programming errors (Ohashi 2014 Level IV SR [PRISMA], 22 studies, n unspecified; Mai
2012 Level III-3). These technologies include the adoption of standardised and preselected
medicine concentrations and dosages. Additionally, the extent of dose sizes is limited to safe
ranges through the use of “soft” and “hard” limits.
The safety of PCA can be improved by the use of a hospital-wide safety improvement
program (Paul 2010 Level III-3, n=25,198). A large prospective survey initially found that theincidence of errors with the use of PCA was 0.25%. Following the introduction of a safety
improvement initiative, the incidence of PCA errors was reduced to 0.09% (OR 0.28; 95%CI 0.14
to 0.53).
The costs and rates of errors due to the use of IV PCA were estimated from two large
safety-reporting databases in the USA (Meissner 2009 Level IV). The datasets included
medication errors and device errors. The estimated average cost of a PCA adverse effect in the
medication error dataset was US$733, whereas the cost related to a pump error was US$552.
An error which lead to patient harm cost 120–250 times more than a non-harmful error. The
estimated annual error rates per 10,000 patients in the USA using PCA were 407 for PCA drug
errors and 17 for PCA device errors.
The safety of PCA prescribing and patient observation may be improved by the adoption of
a common and standardised form and process that incorporates human factors and safety
triggers (Agency for Clinical Innovation 2014 GL).
PCA safety can be addressed through a variety of strategies including the adoption of new
and emerging technologies such as bar-code scanning of prefilled syringes, computer provider
order entry (electronic medication management), and feedback using continuous capnography
in combination with pulse oximetry (Ocay 2018 NR).
For more detail on adverse effects due to the opioid administered, equipment used or
operator and patient-related factors, see Sections 6.3, 6.7 and 6.8 respectively.

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6.7 | Equipment
Both programmable PCA pumps and disposable PCA devices are available.

6.7.1 | Programmable PCA pumps
These types of pumps allow significant flexibility of use. Adjustments can be made to the dosedelivered and lockout intervals, background infusions can be added and accurate assessments
can be made of the total dose of medicine delivered. In addition, access to the syringe (or othermedicine reservoir) and the microprocessor program is only possible using a key or accesscode.
All require disposable items eg generic or dedicated syringes or cartridges, antisiphon
valves (to prevent siphoning of medicine from the medicine reservoir) and anti-reflux valves (toprevent backflow of medicine into the IV infusion line). See Section 6.7.3 below.

6.7.2 | Disposable PCA devices
6.7.2.1 | Parenteral PCA devices
Disposable PCA devices are often based on the same physical principle; the volume ofpressurised fluid delivered (dependent upon spring or elastomer technology) is determined bymechanical restrictions within the flow path and the speed of filling of the bolus dose reservoir
determines the lockout interval (Skryabina 2006 NR). Advantages include small size and weight,
freedom from an external power source, elimination of programming errors and simplicity ofuse. Disadvantages include an inability to alter the volume of the bolus dose delivered or add abackground infusion, difficulties accurately determining the amount of medicine the patient
has received, the possibility of inaccurate flow rates, and long-term costs (Skryabina 2006 NR).
There may also be security issues as the medicine reservoirs for these devices are more readily
accessible.
6.7.2.2 | Sublingual PCA devices
A sublingual sufentanil tablet system (SSTS) has been developed commercially and incorporates
a hand-held computerised dispenser which is activated by an RFID tag linked to an individual
patient, and dispenses SL sufentanil 15 mcg tablets in a patient-controlled manner with a 20
min lockout (Frampton 2016 NR).
6.7.2.3 | Intranasal PCA devices
Metered-dose PCINA devices are available. The medicines must be administered in small
volumes to avoid significant run-off into the pharynx.
Initial PCINA devices delivered sprays of a reasonable dose but a large volume (eg 25 mcg
fentanyl/0.5 mL) (Striebel 1996 Level II, n=50, JS 2; Striebel 1993 Level II, n=112, JS 3) or smaller
volume but with smaller doses than commonly used with IV PCA (eg 9 mcg fentanyl/0.180 mL)(O'Neil 1997 Level IV, n=10). A specially formulated solution of 300 mcg/mL fentanyl has beenused in a device that enables fentanyl doses of 54 mcg to be delivered in just 0.18 mL (Paech
2003 Level III-1, n=21).

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6.7.2.4 | Transdermal PCA devices
The iontophoretic TD PCA fentanyl system uses a low-intensity electric current to drive themedicine from the reservoir through the skin and into the systemic circulation ( Scott 2016 NR).
The IONSYS device, which is applied to the chest or upper outer arm, delivers a fixed dose of
40 mcg fentanyl over a 10-min period following a patient demand and allows delivery of up to 6
doses/h, up to a maximum of 80 doses in 24 h (Power 2008 NR). This device must be replaced
every 24 h and is designed for in-hospital use only.
After initial technical difficulties related to corrosion, the device was reapproved by the FDA
for short-term use in hospitalised patients in 2015; however, the manufacturer discontinued
sale and distribution for business reasons in June 2017 (The Medicines Company 2017).

6.7.3 | Equipment-related complications
In general, modern PCA pumps have a high degree of reliability. However, problems continue
to be reported as well as problems related to the disposable items required. Information
regarding complications due to equipment problems is mainly case-series or report-based.
While the number of reports of “run-away” pumps, where the PCA pump unexpectedly
delivers an unprescribed dose of medication (Notcutt 1990 Level IV, n=1,000), has decreased
following changes made to pump design, they continue to occur, including a report ofspontaneous triggering (Christie 1998 CR) and of a frayed wire in the demand apparatus leading
to triggering as a result of an electrical short circuit (Doyle 2001 CR).
Uncontrolled siphoning of syringe contents when the PCA machine was above patient levelhas been reported following cracked glass PCA syringes (ECRI 1996 CR; Thomas 1988 CR), failureof a damaged drive mechanism to retain the syringe plunger ( Kwan 1995 CR), improperly
secured PCA cassettes (ECRI 1995 CR) and broken medication cartridge syringe (Doyle 2008 CR).
To minimise the risk of siphoning, the use of antisiphon valves is recommended ( ECRI 1996 CR).
Antireflux valves are essential if the PCA infusion is not connected to a dedicated IV line.
The non-PCA infusion tubing should have an antireflux (one-way) valve upstream from theconnection with the PCA line to prevent back-flow up the non-PCA line should distal
obstruction occur; otherwise, inappropriate dosing can occur ( Rutherford 2004 CR; Paterson
1998 CR)

In response to concern about problems with infusion pumps, including PCA pumps, in 2010
the FDA commenced the Infusion Pump Improvement Initiative. Areas for improvement
included software, design of user interface, and mechanical and electrical defects ( FDA 2010 GL).
Device-related errors occurred in 0.19% of patients in a large series (Son 2019 Level IV, n=82,685).
The highest device error-rates occurred in the programmable electronic device group. See also
Section 6.6 above.

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6.8 | Patient and staff factors
6.8.1 | Patient factors
Patient factors play a role in the effectiveness of PCA as well as complications that can arise
from its use; as for equipment issues, much of the information regarding complications due topatient factors is case-based. Psychological factors that may affect PCA use and efficacy are
discussed in Section 1.2.2.
6.8.1.1 | Education
Few controlled studies have evaluated the influence of information provision on PCA use. Of
patients surveyed who used PCA, approximately 20% were worried that they may become
addicted, 20% felt that the machine could give them too much medicine and 30% that they
could self-administer too much opioid ( Chumbley 1998 Level IV, n=200). In a follow-up study,
the same group conducted focus groups with previous PCA users, developed a new
information leaflet and then undertook a randomised study comparing the old and newleaflet. They found that patients wanted more information on the medication in the PCA, thepossible adverse effects and assurance that they would not become addicted ( Chumbley 2002
Level IV, n=100).
Comparisons have been made between different forms of education given to patients
about PCA and results are inconsistent. In an assessment of patient information delivered using
structured preoperative interviews or leaflets vs routine preoperative education, patients given
leaflets were better informed and less confused about PCA and became familiar with using PCA
more quickly but there were no effects on pain relief, worries about addiction and safety or
knowledge of adverse effects; the structured preoperative interview resulted in no benefits(Chumbley 2004 Level III-2, n=225). Another comparison of structured education vs routine
information showed that overall analgesic efficacy, adverse effects and recovery times were
not affected by the education program (Lam 2001 Level II, n=60, JS 2). Patients who were shown avideo on PCA prior to surgery had better knowledge about the technique and reported better
pain control after surgery (Chen 2005a Level III-2, n=60; Knoerl 1999 Level III-2).
6.8.1.2 | Inappropriate use of PCA
The safety of PCA depends on an adequate understanding of the technique by the patient andthe fact that unauthorised persons do not press the demand button.
Oversedation with PCA has followed the patient mistaking the PCA handset for the nursecall button, and family or unauthorised nurse-activated demands (“PCA by proxy”) (Tsui 1997
Level IV, n=2,509; Sidebotham 1997 Level IV, n=6,035; Ashburn 1994 Level IV, n=3,785; Fleming 1992
Level IV, n=1,122; Chisakuta 1993 CR; Wakerlin 1990 CR).
There have been case reports expressing concerns that patients can use PCA to treat
increasing pain and therefore mask problems such as compartment syndrome (Richards 2004
Level IV, n=4; Harrington 2000 CR), urinary retention (Hodsman 1988 CR), pulmonary embolism(Meyer 1992 CR) and myocardial infarction (Finger 1995 CR). However, appropriate routine
patient monitoring should detect changes in pain scores and analgesic consumption enabling
identification of such complications.

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6.8.2 | Nursing and medical staff
The information regarding complications due to nursing and medical staff factors is also casebased.
Of 9,571 PCA-related adverse effects, 69.8% were related to human factors ( Schein 2009
Level IV). Improper dose and quantity was the most common factor in 38.9%.
As noted above, operator error is a common safety problem related to PCA use ( LooiLyons 1996 Level IV, n=4,000; Ashburn 1994 Level IV, n=3,785). Misprogramming of PCA pumps isthought to account for around 30% of PCA errors, be twice as likely to result in injury or
death than errors involving general-purpose infusion pumps and lead to more harm thanerrors in other types of medication administration ( ECRI 2006 NR). Mortality fromprogramming errors has been estimated to range from 1 in 33,000 to 1 in 338,800 patientsprescribed PCA (Vicente 2003 NR).
A number of reports involve the programming of medication concentrations that werelower than the concentration used, with the resultant delivery of an excessive amount of
opioid leading to respiratory depression and sometimes death (ECRI 2002 Level IV; ECRI 1997
Level IV). The use of an incorrect prefilled “standard syringe” for PCA (morphine 5 mg/mL
instead of the prescribed 1 mg/mL) also had a fatal outcome (Vicente 2003 CR). It has beensuggested that medicine concentrations should be standardised within institutions to reducethe chance of administration and programming errors (ECRI 2002 Level IV).
PCA pumps using “smart pump” technology now incorporate dose error reduction systems
described in Section 6.2 above.
Inappropriate prescriptions of supplementary opioids (by other routes) and sedative
medicines (including some antihistamines) can lead to oversedation and respiratory depression(Tsui 1997 Level IV, n=2,509; Ashburn 1994 Level IV, n=3,785; Lotsch 2002 NR).
Human error occurred in 0.74% of patients in a large series, including mistakes with the
preparation of PCA solutions by clinical staff rather than prepared commercially ( Son 2019 Level
IV, n=82,685). Documentation of the management of patient care during PCA use can besignificantly improved with the PCA smart pump transmitting data directly into the electronic
medical record. This automated integration resulted in an increased rate of fully completed
PCA charts from 38% to 91% (Suess 2019 Level III-3, n=113).

6.9 | PCA in specific patient groups
For PCA use in the paediatric patient see Section 10.5.2, the obstetric patient Section 9.1.3.1,,
the elderly patient Section 9.2, the patient with sleep disordered breathing Section 9.4, and theopioid-tolerant patient Section 9.7 respectively.

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1. Intravenous opioid PCA provides better analgesia than conventional parenteral opioid
regimens (S) (Level I [Cochrane Review]).
2. Opioid administration by IV PCA leads to higher opioid consumption, a higher incidence ofpruritus, but no difference in other opioid-related adverse effects, or hospital staycompared with traditional methods of intermittent parenteral opioid administration (S)(Level I [Cochrane Review]).
3. Patient satisfaction with intravenous PCA is higher when compared with conventional
regimens (S) (Level I [Cochrane Review]).
4. The adjuvant use of ketamine with PCA opioid (in varying ratios) improves pain relief andreduces opioid consumption along with nausea and vomiting, with no increase inneurocognitive effects including hallucinations (N) (Level I [PRISMA]).
5. Iontophoretic transdermal fentanyl PCA is not as effective as intravenous morphine PCA,
with more patients withdrawing from studies because of inadequate pain relief (U) (Level I[QUOROM]).
6. In settings where there are high nurse to patient ratios, there may be no difference in theeffectiveness of PCA and conventional parenteral opioid regimens (U) (Level I).
7. Tramadol via intravenous PCA provides effective analgesia comparable to morphine byintravenous PCA (U) (Level I).
8. The addition of a background infusion to intravenous PCA morphine in adults increases theincidence of respiratory depression (U) (Level I) and does not improve pain relief or sleep,or reduce the number of PCA demands (U) (Level II).
9. Different opioids by intravenous PCA show different rates of adverse effects; fentanyl PCA
has the least rates of sedation, nausea and vomiting while pruritus is most frequent withmorphine PCA (N) (Level I [NMA]). Furthermore, on an individual patient basis, one opioid
may be better tolerated than another (U) (Level II).
10. There is no analgesic benefit in adding naloxone to the PCA morphine solution; however,
the incidence of nausea and pruritus may be decreased (U) (Level II).
11. Subcutaneous PCA opioids can be as effective as intravenous PCA (U) (Level II).
12. Intranasal PCA opioids can be as effective as intravenous PCA (U) (Level II).
13. In the emergency department, PCA morphine compared with IV morphine administered bynursing staff, provides more effective analgesia with more rapid onset and with higher
patient satisfaction (U) (Level II).
14. The safety of PCA use can be significantly improved by hospital-wide safety initiatives(equipment, guidelines, education, monitoring) (U) (Level III-3).
15. The adoption of “smart pump” technologies in PCA design can improve documentation ofpatient care (N) (Level III-3), reduce programming errors and improve safety (N) (Level IV SR).
16. Operator-error, in particular programming error, remains a common safety problem with
PCA useoften leading to patient harm (S) (Level IV).

5th Edition | Acute Pain Management: Scientific Evidence 421

The following tick boxes represent conclusions based on clinical experience and expert
opinion: There is insufficient data to compare the risk of rare but serious adverse events with PCA
opioid use to conventionally administered opioid analgesia (N).
 Adequate analgesia needs to be attained prior to commencement of PCA. Initial orders forbolus doses should consider individual patient factors such as a history of prior opioid use andpatient age. Individual PCA prescriptions may need to be adjusted (U).
 The routine addition of antiemetics to PCA opioids is not encouraged, as it is of nobenefit compared with selective administration (U).
 PCA infusion systems must incorporate anti-siphon valves and, in non-dedicated lines,
antireflux valves (U).
 Drug concentrations, prescription and observation forms should be standardised to
improve patient safety (U).
 The pharmacokinetics of morphine (long equilibration half-time and active metabolites)
may make it less suitable for PCA use than other opioids (U).
 Pethidine, when used in PCA, may cause central nervous system toxicity due to theaccumulation of norpethidine (U).
 Improved methods of patient monitoring (eg continuous pulse oximetry, continuous
capnography) may offer opportunities to improve safety in at-risk patient groups (N).

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7Nonpharmacological techniques
Section Editor:
Dr Jeffrey F Mott

430

7.1 | Psychological interventions
Contributor: Prof Michael Nicholas

7.2 | Transcutaneous electrical nerve stimulation
7.3 | Acupuncture and acupressure
Contributors A/Prof Zhen Zheng, Dr Yanyi Wang

7.4 | Photobiomodulation
Contributor: Dr Jeffrey F Mott, Prof Mark Hutchinson

7.5 | Physical therapies
Contributors: Prof Helen Slater, Dr Jared M. Campbell, Dr Carolyn Berryman431

7.0 | Nonpharmacological techniques
7.1 | Psychological interventions
The role of psychological interventions in the management of acute pain is usually as
adjunctive therapies to traditional pharmacological and physical treatment modalities; there isincreasing evidence for their role in pre-emptive and multimodal acute pain therapy as well as
in reducing the risk of chronic postsurgical pain (CPSP) (Horn 2020 NR).
By their very nature, psychological interventions share several common features. Some ofthese features may also apply to effective pharmacological and physical interventions.
Typically, the treatment provider is encouraged to firstly establish a degree of rapport or
acceptance with the patient as well as give some information about the purpose and nature of
the intervention and reasonable expectations the patient should hold for their outcome. These
aspects may be seen as necessary to gain both the informed consent of the patient fortreatment, as well as their active cooperation.
Psychological interventions may be divided into four broad categories:• Information provision (procedural information, description of expected sensory
experience or behavioural instructions) (see also Section 3.1.1);• Stress or tension reduction (relaxation and hypnotic strategies);• Attentional strategies;• Cognitive-behavioural interventions.
It should be emphasised that these are rarely ‘stand-alone’ interventions and elements ofeach may form a single intervention package.
Similar to physical therapies, a lack of clinician blinding and questions as to what constitutes
an adequate psychology placebo arm in an RCT, as well as heterogeneous interventions, limit
the strength of conclusions (Guidi 2018 NR). In the Cochrane meta-analysis presented below,
almost all RCTs were ranked at high risk of performance bias due to lack of clinician blinding(Powell 2016 Level I [Cochrane], 105 RCTs, n=10,302).
When pooled for all pre-procedural psychological interventions in a range of surgery types(including cardiothoracic 10 RCTs and coronary artery bypass surgery [CABG] 17 RCTs) and procedures,
there is a small reduction in postoperative pain scores (SMD -0.2; 95%CI -0.35 to -0.06) (38 RCTs,
n=2,713), length of stay (LOS) (MD -0.52 d; 95%CI -0.82 to -0.22) (36 RCTs, n=3,313) and reduction
in negative affect (SMD -0.35; 95%CI -0.54 to -0.16) (31 RCTs, n=2,496) (Powell 2016 Level I[Cochrane], 105 RCTs, n=10,302). However, multiple pooled psychological interventions for acutepain after open heart surgery do not reduce postoperative pain intensity or PCA usage but doslightly reduce postoperative mental distress over the short and longer term in RCTs of low
quality (Ziehm 2017 Level I [Cochrane], 23 RCTs, n=2,669) (5 RCTs overlap).
For paediatric specific information, see Sections 10.7.5 and 10.11.1.

7.1.1 | Provision of information
7.1.1.1 | Procedural information
Procedural information is information given to a patient before any treatment that summarises
what will happen during that treatment. Here, four information factors were each associatedwith global evaluations of care by patients: surgical information, recovery information, general432

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information and sensory information (Krupat 2000 Level IV, n=3,602). Procedural information(often combined with behavioural instructions, like exercises or body positions) effectively
reduces reported pain in 3 of 7 RCTs and pain medications in 7 of 12 RCTs ( Johnston 1993 Level I,
38 RCTs, n=1,734).
In orthopaedic surgery, patient education regarding the procedure or recovery provided asmall improvement in post-operative pain (SMD -0.21; 95%CI -0.02 to -0.39) (12 RCTs, n=1,242),
pre-operative anxiety (SMD -0.27; 95%CI -0.10 to -0.44) (12 RCTs, n=1,260) and post-operative
anxiety (SMD -0.26; 95%CI -0.08 to -0.43) (11 RCTs, n=921), but had no impact on analgesic use(10 RCTs, n=860) (Szeverenyi 2018 Level I [PRISMA], 62 RCTs, n=4,908).
7.1.1.2 | Sensory information
Sensory information is information that describes the sensory experiences the patient may
expect during treatment. Sensory information given alone has some positive, albeit
inconsistent, effects vs no instruction (Suls 1989 Level III-3 SR, 21 studies, n unspecified). With all
but two studies involving adults, sensory information reduced self-rated pain more thanprocedural information; however, the effect sizes were variable. In contrast, a subsequentmeta-analysis shows a beneficial effect on pain in three RCTs and shows a reduction in the useof pain medication in two of five RCTs (Johnston 1993 Level I, 38 RCTs [7 RCTs sensory information],
n=1,734). A subsequent RCT found sensory only information had no significant effect on
postoperative pain perception (Campbell 1999 Level II, n=63, JS 2).
7.1.1.3 | Combined sensory-procedural preparatory information
Combined sensory-procedural preparatory information, when compared to procedural
information and sensory information given alone, yielded the strongest and most consistentbenefits in reducing negative affect, pain reports and other related distress ( Suls 1989 Level III-3
SR, 21 studies, n unspecified). However, many studies relate to medical procedures such as pelvic
examination or to experimental pain. Subsequent systematic reviews are consistent with thesefindings (Johnston 1993 Level I, 38 RCTs, n=1,734; Devine 1992 Level IV SR, 191 studies, n unspecified).
Interventions investigated include the provision of information about medical procedures andassociated emotional responses and sensations before, during and after surgery, andinstructions about how to adhere to medical advice to support the recovery, with teaching or
instructing patients in different relaxation techniques or helping patients to understand theirthoughts and feelings that influence their behaviour.
In some patients, especially those with an avoidant coping style, giving too muchinformation or asking them to make too many decisions may exacerbate anxiety and pain
(Wilson 1981 Level II, n=70, JS 2). However, later evidence suggested that this may not be a strong
effect (Miro 1999 Level II, n=92, JS 3). Nevertheless, it may be useful to assess a patient's normal
approach to managing stress to identify the best option for that patient. This concept is
supported by the finding in patients undergoing colposcopy where stress related to theprocedure was reduced when information was tailored to individual coping styles ( Kola 2013
Level II, n=117, JS 2).
See also Section 3.1.1 on patient education.

7.1.2 | Relaxation techniques
Relaxation training usually involves teaching a patient ways to reduce their feelings of stressand/or arousal. Techniques used may be taught by audio recording or written or spoken
instructions. The use of audio recording often includes the use of calming music or suitable
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imagery (mental pictures of relaxing scenes). Typically, all methods require the patient topractise the technique regularly, especially when feeling stressed. Some methods focus onaltering muscle tension, often sequentially, while others focus on altering breathing patterns(eg emphasising releasing tension with exhalation). Relaxation techniques are closely related
to, and often indistinguishable from, forms of meditation and self-hypnosis.
A systematic review of relaxation techniques, when used alone for the management ofpain after surgery and during procedures, concluded that there was weak evidence tosupport the use of relaxation in these settings; three of the 7 RCTs reported significant
reductions in pain and distress ( Seers 1998 Level I, 7 RCTs, n=362). Methodologicalshortcomings of the included RCTs meant that a meta-analysis was not possible, limiting thestrength of the findings. Similar conclusions were made in another systematic review, whichfound that 8 of 15 RCTs (again, most had weaknesses in methodology) demonstrated
reductions in pain (Kwekkeboom 2006 Level I, 15 RCTs, n=1,269); the most supported methods
were progressive muscle relaxation for arthritis pain and a systematic relaxation techniquefor postoperative pain. Little evidence was found for autogenic training (another relaxation
technique), and no support for rhythmic breathing or other relaxation techniques. Anotherreview of studies using relaxation techniques for burns pain also found insufficient high quality evidence to draw any conclusions but did recommend further research into the use ofa technique that combined focusing on breathing and jaw muscle relaxation ( de Jong 2006,
Level III-3 SR, 11 studies, n=1,541 ) (1 RCT overlap). The most recent meta-analysis found a
reduction in post-operative pain (SMD -0.45; 95%CI -0.11 to -0.79) (9 RCTs, n=473) but noeffect on analgesic consumption (SMD -0.36; 95%CI 0.25 to -0.98) (7 RCTs, n=183) (Szeverenyi
2018 Level I [PRISMA], 62 RCTs, n=4,908 ) (0 to 1 RCT overlap).
In patients with acute whiplash associated disorder, physiotherapy directed exercises andeducation combined with stress inoculation training (comprising relaxation training, guidanceon problem solving strategies, and their application to stressful situations) reduced painrelated disability vs exercise alone at 6 wk, 6 mth and 12 mth (Sterling 2019 Level II, n=108, JS 3).
Studies of relaxation techniques with cancer patients (in acute pain) provide moderately
strong support for its effectiveness in improving pain, but also nausea, pulse rate and bloodpressure, as well as emotional adjustment variables (depression, anxiety and hostility) ( Luebbert
2001 Level I, 15 RCTs, n=742).

7.1.3 | Mindfulness-based interventions (MBI)
Mindfulness meditation is a type of attentional technique that includes attending to pain
sensations. It has much in common with breathing-based relaxation techniques. This approachencourages the patient to deliberately experience their pain in a calm manner just like any
nonpainful sensation (ie without judging it as good or bad), often while engaging in slowed
breathing styles (Kabat-Zinn 2003 NR). This approach derives from ancient Buddhist methods.
Mindfulness-based approaches have been used to promote adjustment in people experiencing
chronic pain, often in conjunction with a form of cognitive-behavioural therapy (CBT) called
acceptance and commitment therapy (ACT) (McCracken 2007 Level IV, n=105).
MBI/ACT for experimental pain vs other emotion-regulation techniques are superior for
pain tolerance (except for distraction) but not for pain intensity (Kohl 2012 Level I EH [PRISMA],
30 RCTs, n=2,085). Two subsequent RCTs have provided slightly conflicting findings. In healthy
participants undergoing experimental pain (electric shock), both acceptance methods andsuppression were equally effective, and both were superior to a control condition in reducing
pain and anxiety (Braams 2012 Level II EH, n=123, JS 3). In contrast, in healthy students,434

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mindfulness was as ineffective as relaxation training in reducing experimental pain (with thecold-pressor test) (Sharpe 2013 Level II EH, n=140, JS 1).
Brief MBI in mostly healthy volunteers (including adult, some children & adolescent groups)
or patients with chronic pain delivered by either audio/video recorder instruction or provider
delivered instruction is of unclear effectiveness (McClintock 2019 Level IV SR, 18 RCTs & 2 studies,
n=1,740). However, brief MBI delivered by a clinician and lasting more than 5 min may be more
useful than shorter durations and virtual delivery . The single clinical RCT in acute pain includedin this review compared brief MBI vs hypnotic suggestions vs psychosocial education inpatients with pre-existing “intolerable pain” or “inadequate pain control” and found both brief
MBI and suggestion were superior to education for pain relief, anxiety and desire for opioids(Garland 2017 Level II, n=244, JS 3).
A pilot RCT in veterans after major orthopaedic surgery at high risk of CPSP (severe
preoperative pain, moderate postoperative pain, depression or anxiety), found a 1 d ACT
workshop vs standard care did not reduce time to cessation of pain (HR 1.42; 95%CI 0.68 to2.95) or cessation of opioids (HR 1.62; 95% CI 0.82 to 3.21) (Dindo 2018, Level II, n=88, JS 3).

7.1.4 | Hypnosis
Hypnosis shares many features of relaxation with imagery and has a long history of use in acutepain conditions. Techniques vary but they have the common feature of one person responding tosuggestions made by another regarding experiences involving changes in perception, memory andvoluntary actions (Kihlstrom 1985 NR). The variable nature of hypnotic procedures has made itdifficult to compare studies or draw general conclusions (Ellis 1994 NR) although some more
standardised (according to a manual) procedures have been reported (Liossi 2003 Level II, n=80, JS 2).
Preoperative hypnosis was investigated as one of several methods to reduce postoperative
pain in surgical patients; there is no effect on postoperative pain but partial support for
improvements in psychological wellbeing measures (Nelson 2013 Level III-1 SR, 4 studies [hypnosis],n=144). Another meta-analysis looking at women having breast cancer surgery foundpreoperative hypnosis does not reduce postoperative pain but reduces perioperative distress(Holger 2012 Level I, 4 RCTs, n=550). However, a subsequent meta-analysis found that live andrecorded hypnosis both reduce anxiety and live hypnosis reduces pain scores (SMD -0.51;
95%CI -0.06 to -0.96) (8 RCTs, n=669) but both have no effect on analgesic use; while therapeuticsuggestion has no effect on anxiety, pain scores or analgesic use (Kekecs 2014 Level I, 26 RCTs,
n=1,890) (2 RCTs overlap).
Note: reversal of conclusion
This reverses the Level I key message in the previous edition of this document; a precedingmeta-analysis had described no effect of hypnosis on postoperative pain scores.
For labour, hypnosis (eight antenatal and one intrapartum intervention) may reduce
pharmacological analgesic use (RR 0.73; 95% CI 0.57 to 0.94) (8 RCTs, n=2,916) but has no effecton rate of spontaneous vaginal birth (6 RCTs, n=2,361), sense of coping with labour (1 RCT, n=420)
or satisfaction with pain relief when combined with either pethidine ( 1 RCT, n=72) or epidural
analgesia (1 RCT, n=127) (Madden 2016 Level I [Cochrane], 9 RCTs, n=2,954).
Note: reversal of conclusion
This reverses the Level I key message in the previous edition of this document; a precedingmeta-analysis had described no effect of hypnosis in the management of labour pain.
5th Edition | Acute Pain Management: Scientific Evidence435

A reduction is seen with hypnosis in a small majority of study measurements during
procedural pain in paediatric and adult patients vs standard care, attention control or otheractive treatments (Kendrick 2016 Level I [PRISMA], 29 RCTs, n=2,202).
Hypnosis vs control for needle-related procedural pain in children reduces pain scores (SMD
-1.4; 95%CI -2.32 to -0.48) (5 RCTs n=176), distress scores (SMD -2.53; 95%CI -3.93 to -1.12)(5 RCTs, n=176) and behavioural measures of distress (SMD -1.15; 95%CI -1.76 to -0.53) (6 RCTs,
n=193) (Birnie 2018 Level I [Cochrane], 59 RCTs, n=5,550) (6 RCT overlap). Analgesic benefits of
hypnosis are confirmed in children undergoing cancer-related procedures (Tome-Pires 2012
Level I, 10 RCTs [procedural pain], n=394) (5 RCTs overlap). See also Section 10.7.5.

7.1.5 | Attentional techniques
A range of attention-based strategies have been reported, from those involving distraction
from the pain through shifting attention to cognitive tasks, imagined stimuli or external stimuli(such as audio, video, tactile sensations, smells or a combination) (Bascour-Sandoval 2019 NR).
Use of distraction (video, toys, music or stories) is effective in infants, young children andadolescents across a range of procedures eg needle-related pain (Birnie 2018 Level I [Cochrane],
59 RCTs, n=5,550; Birnie 2015 Level III-1 SR, 22 studies, n=1,717 [10 RCTs overlap]; Pillai Riddell 2015
Level III-1 SR, 10 studies, n=1,259 [0 RCT overlap]). See also paediatric sections for vaccine injection(10.7.3.4) and other procedural pain (10.7.5) including that related to paediatric cancer (10.8.2)
and burns (10.9.2).
Some techniques also involve deliberately attending to the pain (or pain site) but in ways
intended to modify the threat value of pain rather than to divert attention from pain. There issome evidence that this method can alter pain perception but possibly mainly among
subgroups of patients (Haythornthwaite 2001 Level II, n=42, JS 1; Logan 1995 Level III-2; Baron
1993 NR).
Attempting to alter the patient’s emotional state, from distress or fear to relative comfort
or peace, is also a common feature of many of these techniques. Commonly, these techniques
are used in conjunction with relaxation methods and at times may be inseparable ( Williams
1996 NR).
Patients may exhibit pre-existing attention bias which prioritises painful sensations or painrelated experiences over other sensory experiences which may be amenable to attention bias
modification); however, results are equivocal, especially when used in isolation (Van Ryckeghem
2019 Level IV SR EH, 52 studies, n=4,466).
7.1.5.1 | Music
Music therapy may be either active or passive: active therapy is when the patient participatesin creating sounds; in passive music therapy, the patient listens to recorded or live music.
When played by medical staff or with music therapists, music reduces acute or procedural pain
(MD -1.11/10; 95%CI -1.45 to -0.77) (67 RCTs, n=5,679) with other beneficial effects in terms ofemotional distress, anaesthetic use, opioid use, non-opioid use, heart rate, blood pressure andrespiratory rate (Lee 2016 Level I, 97 RCTs, n=9,184). Patient, rather than clinician or researcher
selected music, may be most effective (Lunde 2019 NR). In two subsequent RCTs, patient
selected music was of benefit during shockwave lithotripsy (Cakmak 2017 Level II, n=200, JS 3), but
Mozart’s Symphony No. 40 played during colposcopy provided no benefit (Hilal 2018, Level II,
n=215, JS 3).

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Similarly, music reduces pain in cancer patients (SMD -0.59; 95%CI -0.92 to -0.27) (Bradt
2011 Level I [Cochrane], 30 RCTs, n=1,891). In burns patients, music interventions are helpful for
pain alleviation, anxiety relief and heart rate reduction (Li 2017c Level I [PRISMA], 17 RCTs, n=804).
In children, music is effective during dental procedures (see 10.7.2.7), heel lance (see10.7.1.1), burns dressing changes (see 10.7.2.9), vaccination (see 10.7.5) and generalprocedural pain (see 10.7.3.4).
7.1.5.2 | Virtual reality
Virtual reality (VR) has led to reductions in pain unpleasantness and pain-related brain activity
in volunteers using thermal pain stimulation and measuring pain-related brain activity withfunctional magnetic resonance imaging (fMRI): where both opioids and immersive VR reduced
pain and the combination was more effective than opioid alone (Honzel 2019 NR).
VR may be effective at reducing procedural pain eg for needles and burns dressing changes
vs usual care (SMD -0.49; 95%CI -0.83 to -0.41) (Chan 2018 Level III-2 SR [PRISMA], 9 RCTs &7 crossover studies, n=656). However, studies were heterogeneous and inherently unblinded.
In burns patients, VR reduces pain intensity, time spent thinking about pain andunpleasantness (Luo 2019b Level I [PRISMA], 13 RCTs, n=362; Scheffler 2018 Level I [PRISMA], 21 RCTs,
n=660) (4 RCTs overlap).
See 8.5.5 for more information on VR use in burns pain and 10.7.5 on VR use in thepaediatric population.
7.1.5.3 | Smell
Olfaction can induce analgesia and emotional changes in both humans and animals and may
play a role in pain therapy (Lotsch 2016 NR).
See Sections 4.14.3 and 8.5.5 for effects of aromatherapy in adults and 10.11.1 in paediatricpatients.
7.1.5.4 | Tactile sensations
See 10.7.3.4 for information on use of vibration in paediatric vaccine injection pain.

7.1.6 | Cognitive-behavioural interventions
Typically, cognitive-behavioural interventions involve the application of a range of behaviourchange principles, such as differential positive reinforcement of desired behaviours,
identification and modification of unhelpful thoughts and goal setting, in order to achievechange in targeted behaviours. In the context of acute pain this would include encouraging theuse of the techniques outlined above to modify the pain experience, reduce distress, and toprovide alternative, more helpful responses.
Cognitive-behavioural methods focus on both overt behaviours and cognitions (thoughtprocesses) in patients, but interactions with environmental factors are also often addressed.
This means that interactions between patients and others, especially medical and nursing staff
as well as families, may need to be addressed to support the desired responses in the patient.
The latter may entail displaying a calm and reassuring manner and encouragement topersevere with a given task or procedure. Specific training in skills (eg relaxation and othercoping strategies), other behavioural techniques (eg modelling and systematic desensitisation),
information provision and reconceptualisation of the experiences of the patient may also be
provided as part of this approach (as outlined above).
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Cognitive-behavioural interventions are usually aimed at reducing the distressing or threatvalue of pain and enhancing a patient’s sense of his or her ability to cope with pain (pain selfefficacy). Effective coping with pain may be reflected in minimal pain-related distress (egreduced catastrophising) or disability (interference in normal activities). If patients are able toperceive their pain as less threatening, they might also evaluate their pain as less severe.
However, in this context, reduced severity would be seen more as a by-product than as theprimary goal.
Critically, in using cognitive-behavioural methods, the patient must be an active participant
in the process, rather than a passive recipient, as he or she must apply the methods taught
as needed.
7.1.6.1 | Applying pain coping strategies within a cognitive-behavioural intervention
Generally, while some responses by patients to their pain may be helpful, others may not. For
example, those who respond with overly alarmist (or catastrophic) thoughts tend to experience
more pain and distress, vs those who do not respond in this way (eg Haythornthwaite 2001
Level II, n=42, JS 1; Sullivan 2001 NR; Jensen 1991 NR). Identifying unhelpful responses, whether
they are cognitive or behavioural, and changing these responses is a common feature of many
cognitive-behavioural interventions.
Catastrophic thinking has been associated with increased postsurgical acute pain, opioid
use and reduced function ( Darnall 2016 NR) as well as being a risk factor for development of
persistent postsurgical pain (OR 1.55-2.10) (15 RCTs) (Theunissen 2012 Level IV SR, 29 studies,
n=6,628). Thus, identifying and reducing catastrophic thoughts about pain has become acommon intervention within this approach, whether the pain is acute or persistent. A single
preoperative 130 min lecture session was effective at reducing pain catastrophisation (Darnall
2014 Level III-2, n=76). Before breast cancer surgery, delivery of virtual psychoeducation vsgeneral health education reduced time to opioid cessation (5 d vs 13) ( Darnall 2019 Level II, n=68,
JS 3). However, attrition rates were higher in the psychoeducation group vs general education(44% vs 18%). For breast cancer surgery, patients who received stress management training(mainly relaxation and coping skills) had less depression and fatigue up to 3 mth post-surgery,but there were no differences for anxiety, pain and sleep problems vs a usual care control
group (Garssen 2013 Level II, n=70, JS 3).
Perioperative CBT may improve pain and functional outcomes; however, heterogeneity ofinterventions (only in 1 of 6 RCTs delivered by psychologist), outcome measures and timeframes limits firm conclusions (Nicholls 2018 Level I [PRISMA], 6 RCTs, n=578). A previous metaanalysis found that during preparation for surgery or painful medical procedures, training in
cognitive coping methods and behavioural instructions in addition to relaxation training andprocedural information, improves patients’ pain measures and reduces postoperative use ofanalgesics (Johnston 1993 Level I, 38 RCTs, n=1,734). These interventions effectively improvemeasures of negative affect, LOS, and recovery.
It has also been recognised that a given coping strategy may not always be useful and that
this may depend upon circumstances and timing (Turk 2002 NR). For example, ignoring or
denying the presence of pain may be useful when first injured (to reduce distress) but, if itmeans that appropriate help is not sought, it could place the person in danger or at risk oftreatment for complications being delayed.
Details on the psychological management of post-operative pain have been incorporated
into guidelines (Chou 2016 GL).
For information on paediatric cognitive behavioural interventions for procedural pain see 10.7.5.

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7.1.6.2 | Complex psychosocial interventions
Increasingly, researchers are reporting the application of psychologically-based interventions incomplex acute pain settings, especially in relation to work-related injuries and their
management. Instead of employing a single technique (like relaxation), the researchers may
employ strategies aimed at the patient’s responses (eg distress and avoidance) as well as the
responses of key environmental factors, such as in the workplace and in the family.
Injured workers identified within 5 to 15 d of injury as at risk for delayed recovery offered acomprehensive management plan (that included medical/physical treatments, brief CBT-based
intervention by a psychologist, and workplace accommodations) had half the time off work
(32 d vs 67 d) in the following 2 y vs the usual care recipients (Nicholas 2020 Level III-2, n=113).
These results are consistent with those reported by a systematic review of interventions for
return to work (Cullen 2018 Level III-2 SR, 36 studies, n≈195,722).

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KEY MESSAGES
1. Preoperative psychological interventions may be effective at reducing pain, length ofstay and negative affect after various procedures (N) (Level I [Cochrane Review]) but
may not be effective after cardiac surgery (N) (Level I [Cochrane Review]).
2. Distraction (including with video, toys, music or stories) and hypnosis reduces needle
related pain (S) and distress (N) in children and adolescents (Level I [Cochrane Review])
3. Hypnosis may reduce procedural pain and anxiety (N) (Level I [Cochrane Review]),
postoperative pain (R) (Level I), postoperative anxiety (N) and analgesia consumption inlabour (R) (Level I [Cochrane Review]).
4. Listening to music produces a small reduction in postoperative or procedural pain,
analgesic requirements and emotional distress (S) (Level I); patient selected music may
be more effective than clinician selected music (N) (Level II).
5. Patient education regarding the procedure or recovery may reduce postoperative pain
(Q), preoperative anxiety (N) and postoperative anxiety (N) but does not affect analgesia
use (U) (Level I [PRISMA]).
6. Training in coping methods or behavioural instruction prior to surgery reduces pain,
negative affect and analgesic use (U) (Level I).
7. Relaxation techniques may reduce postoperative pain but do not reduce analgesic
consumption (S) (Level I).
8. Immersive virtual reality distraction is effective in reducing pain (S) and anxiety (N) insome clinical situations (Level III-2 SR [PRISMA]).
9. In work injury-related acute pain, psychologically informed and workplace-oriented
interventions may reduce time lost from work (N) (Level III-2 SR).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Pain catastrophisation and anxiety negatively impact the postoperative experience andare risk factors for the development of chronic postsurgical pain and prolonged opioid
use. Interventions aimed at reducing catastrophisation may be useful in improving
patient outcomes, but retaining patient engagement with perioperative
psychoeducation may also prove challenging (N).
 Preoperative psychoeducation may be cost effective from the perspective of reducing
length of stay (N).
 The evidence that sensory and combined sensory-procedural information is effective in
reducing procedure-related pain is equivocal and not sufficient to makerecommendations (U).
 There is insufficient evidence to make a recommendation about the role of brief
mindfulness-based interventions in acute pain (N).

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7.2 | Transcutaneous electrical nerve stimulation
Transcutaneous electrical nerve stimulation (TENS) is the application of pulses of electricalcurrent between two or more transcutaneous electrodes in order to stimulate cutaneous
nerves. Unlike medications which only have dosage and route of administration as variables,
TENS varies by anatomical location of electrodes, duration of usage, pulse amplitude, pulse
frequency, pulse duration and pattern (eg burst, continuous or modulated). The variable ways
in which TENS can be applied and lack of uniform reporting in studies makes pooling of results
and interpretation of conflicting studies challenging. Furthermore, the blinding of such aphysical intervention is difficult. Sham TENS varies in studies between a passive deactivated
box connected to the patient where no stimulus is felt and devices which provide a shortduration of therapeutic TENS. In a trial of inactive sham TENS vs 45 s transient sham TENS vsreal TENS the investigators and patients were blinded 0% and 21% for inactive sham TENS, and100% and 40% for transient sham TENS (Rakel 2010 EH). Thus, for the purposes of applying the
Jadad score to studies we have not considered inactive TENS to be an adequate placebo.
TENS reduces acute pain (procedural and nonprocedural) vs no treatment (MD -19/100;
95%CI -27.3 to -10.8) (6 RCTs, n=413) and sham TENS (MD -24.6/100; 95%CI -31.79 to -17.46)(6 RCTs, n=376), with more participants achieving ≥50% reduction in pain vs sham TENS (RR 3.91;
95%CI 2.42 to 6.32) (4 RCTs, n=157) (Johnson 2015b Level I [Cochrane], 19 RCTs, n=1,346). These
results are limited by a high risk of bias due to inadequate sample sizes in the trials andunsuccessful blinding including the use of non-TENS-naïve patients. Minor adverse effects
reported were mild erythema, itching and participants disliking the TENS sensation ( 7 RCTs).

7.2.1 | Orthopaedic surgery
TENS vs placebo TENS reduces pain after total knee arthroplasty (TKA) at 12 h (SMD -0.26;
95%CI -0.44 to -0.08), 24 h (SMD -0.24; 95%CI -0.43 to -0.06) and 48 h (SMD -0.21; 95%CI -0.40
to -0.03) and opioid consumption at 12, 24, and 48 h ( Li 2017b Level I [PRISMA], 5 RCTs, n=472).
TENS also reduces the incidence of postoperative nausea by 9.8% and vomiting by 9.4%, but
not the hospital LOS. The results are limited by small sample sizes in the trials; however, thequality of evidence is high. Repeated TENS provides long term pain reduction up to 6 mth
postoperatively vs placebo TENS (2 RCTs, n=189) (Tedesco 2017 Level I [PRISMA], 39 RCTs, n=5,509).
However, after anterior cruciate ligament repair, adding high-frequency transcutaneous TENS
to exercise vs exercise alone did not improve pain and function in early rehabilitation ( Forogh
2019 Level II, n=70, JS 4).
After rotator cuff repair TENS for four 45 min sessions/d for the first postoperative wk
reduced pain at 12 h (3.1/10 ± 3.6 vs. 5.8/10 ± 4.4) and 1 wk (3.6/10 ± 2.1 vs. 5.8/10 ± 1.2) withless oxycodone 5 mg/paracetamol 325 mg requirements at 48 h (12.8 tablets ± 4.7 vs. 17.2 ±6.3) and 7 d (25.2 tablets ± 10.0 vs. 33.8 ± 14.3 ) vs placebo TENS (Mahure 2017 Level II, n=37,
JS 5).
Postoperative TENS applied to the surgical site for 15 min/d consecutively for 5 d after
surgery did not reduce pain or analgesic use after Colles’ Fracture vs placebo TENS (Lee 2015b
Level II, n=36, JS 3).

7.2.2 | General and thoracic surgery
After thoracic surgery (thoracotomy or sternotomy), TENS reduces pain intensity vs sham TENS
(thoracotomy -1.3/10; 95%CI -1.9 to -0.7; sternotomy -1.3/10; 95%CI -1.9 to -0.8) (Sbruzzi 2012
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Level I [PRISMA], 11 RCTs, n=570). Subsequent RCT findings are consistent with these results(Sezen 2017 Level II, n=96, JS 1; Engen 2016 Level II, n=40, JS 3; Erden 2015 Level II, n=40, JS 1; Esteban
Gonzalez 2015 Level II, n=50, JS 3). Although TENS was not more effective than a paravertebral(PVB) in relieving pain or reducing PCA usage following thoracotomy procedures, it had fewer
adverse effects (Baki 2015 Level II, n=40, JS 1).
After liposuction, TENS vs placebo TENS reduced pain intensity (0/10 vs 4/10) and need for
rescue analgesia at 6 h (95.2% vs. 47.6%) (da Silva 2015 Level II, n=42, JS 3).
After cessation of epidural analgesia following open colon resection, TENS reduced pain at
24 h post cessation (10/100 vs 23/100) vs placebo TENS, but no differences in quality ofrecovery or opioid use were found (Bjersa 2015 Level II, n=28, JS 5).
TENS (starting 1 h pre-operatively for inguinal hernia repair and ceased on induction)
reduced pain at 2 h (3.5/10 ±1.5 vs 5.1/10 ±1.4) and 4 h (4.0/10 ±1.5 vs 4.8/10 ±1.4) anddiclofenac use at 12 h (15.2% vs 39.4%), with no difference in other time points or anti-emeticuse (Eidy 2016 Level II, n=66, JS 3).

7.2.3 | Procedural pain and prehospital analgesia
TENS reduced procedural pain (MD -2.7/10; 95%CI -1.6 to – 4.0) during carboxytherapy inpatients with cellulite in the gluteal region vs placebo TENS (Sadala 2018 Level II, n=84, JS 1).
TENS used in the prehospital setting reduces pain intensity vs scores before TENS use (MD38/100; 95%CI 28 to 44) and vs sham TENS (MD 33/100; 95%CI 21 to 44), as well as acuteanxiety secondary to pain (Simpson 2014 Level I [PRISMA], 4 RCTs, n=261).

7.2.4 | Gynaecological surgery and obstetrics
In labour, TENS has no effect on pain, interventions or outcomes vs sham TENS (10 RCTs) or
routine care (7 RCTs), when applied to the back (13 RCTs, n=1,150) or cranium (2 RCTs, n=140),
with the exception of a reduction in reports of severe pain when applied to acupuncture points(2 RCTs, n=190) (Dowswell 2009 Level I [Cochrane], 17 RCTs, n=1,466). These findings of no analgesic
effect are confirmed by two subsequent meta-analyses (Bedwell 2011 Level I, 14 RCTs, n=1,456(14 RCTs overlap); Mello 2011 Level I, 9 RCTs, n=1,076 (3 RCTs overlap)).
Three subsequent RCTs not included in the above meta-analyses showed benefit from TENS
in labour. A 30 min session of TENS over thoracic and sacrum area reduced immediate pain
during the active phases of labour vs non-TENS control (Santana 2016 Level II, n =46, JS 3) orplacebo TENS box (Baez-Suarez 2018 Level II, n =63, JS 3). TENS with varying high-frequency (80 to
100 Hz) was more effective than TENS of constant frequency (100 Hz) ( Baez-Suarez 2018 Level II,
n =63, JS 3). TENS produced sustained pain relief 4 h after the intervention and had shortened
first-stage labour vs placebo or no TENS controls (Shahoei 2017 Level II, n=90, JS 1).
High-frequency TENS is effective in primary dysmenorrhoea (Proctor 2002 Level I [Cochrane],
7 RCTs, n=164). A subsequent systematic review did not add new information except for
highlighting that quality of life is not reported in any RCT (Igwea 2016 Level I, 6 RCTs [TENS],
n=247) (2 RCTs overlap). Subsequent RCTs reported similar results of daily TENS during menstrual
bleeding; pain intensity, hours in pain and use of pain medications were reduced withinconsistent results on quality of life improvement vs placebo (Bai 2017 Level II, n=134, JS 3;
Lauretti 2015 Level II, n=40, JS 3). TENS plus thermotherapy reduced period pain and duration inpain vs placebo TENS, without impact on analgesic use or quality of life (Lee 2015a Level II, n=115,
JS 3).

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7.2.5 | Migraine
TENS use in migraine reduces affected days/mth (SMD -0.5; 95%CI -0.7 to - 0.2) andpharmacological treatment intake (SMD -0.8; 95%CI -1.1 to - 0.4) (Tao 2018 Level I [PRISMA],
4 RCTs, n=161). Similarly, TENS over the supraorbital nerve (for 12 wk) reduced days in migraineand days using rescue medications among patients with refractory migraine and not
responding to topiramate (Vikelis 2017 Level IV, n=35).
One 60 min TENS session reduced pain intensity of acute migraine attacks at one and 24 hafter treatment by 50%, and two-thirds of the patients did not require rescue pain medication
at 24 h (Chou 2017 Level IV, n=30).

7.2.6 | Musculoskeletal pain
One 30 min TENS session reduces acute low back pain in an emergency setting (MD – 28.0/100;
95%CI – 32.7 to −23.3) (1 RCT, n=63), whereas a course of TENS for 4-5 wk does not reduce subacute low back pain (MD −2.8/100; 95%CI −11.6 to 6.1) (2 RCTs, n=132) (Binny 2019 Level I, 3 RCTs,
n=192). The evidence is limited by low quality and insufficient sample size.
One TENS session over shoulder myofascial trigger points increased pressure pain thresholdand improved range of motion vs sham intervention (Takla 2018 Level II, n=70, JS 3). Burst‐TENS
was superior to medium‐frequency, low intensity amplitude modulated frequency treatment.

7.2.7 | Neuropathic and phantom limb pain
In patients with herpes zoster, 10 to 15 TENS sessions reduced pain and incidence of PHN vs
anti-viral agent alone and TENS/anti-viral agents (Stepanovic 2015 Level II, n=222, JS 1). However,
the trial reporting quality is very low.
A systematic review of TENS in the treatment of phantom limb pain found no studies(Johnson 2015a Level I [Cochrane], 0 RCTs, n=0). However, a subsequent RCT found TENS vs mirror
therapy equally effective at reducing pain scores from baseline (Barbin 2016 Level I [PRISMA],
1 RCT: Tilak 2016 Level II, n=25, JS 3).

KEY MESSAGES
1. Transcutaneous electrical nerve stimulation compared to sham reduces acute pain(procedural and nonprocedural) (U) (Level I [Cochrane Review]), including pain after
thoracic surgery (U) (Level I [PRISMA), after total knee replacement (N) and in theprehospital setting (N) (Level I [PRISMA]).
2. High-frequency transcutaneous electrical nerve stimulation is effective in primarydysmenorrhoea (U) (Level I [Cochrane Review]).
3. Transcutaneous electrical nerve stimulation has no effect on pain, interventions or
outcomes in labour with the exception of a reduction of reports of severe pain whenapplied to acupuncture points (U) (Level I [Cochrane Review]).
4. Transcutaneous electrical nerve stimulation used preventatively in migraine reduces
attack frequency and medication use (N) (Level I [PRISMA])

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7.3 | Acupuncture and acupressure
Acupuncture, originally a Chinese practice, involves inserting fine needles through the skin at
specific points (acupoints) to cure disease or relieve pain. However, the term acupuncture isoften interpreted broadly in many meta-analyses to incorporate all forms of acupoint
stimulation including by electroacupuncture (EA: where a small electric current is passed
between pairs of acupuncture needles), laser (laser acupuncture), pressure (acupressure),transcutaneous electrical acupoint stimulation (TEAS), chemical (capsicum plaster) or heat(moxibustion). Acupuncture needling or acupressure can be applied to the specific points on
the ears and this form of technique is called auricular acupuncture (AA) or auriculotherapy.
Even for traditional needle-based acupuncture angle, depth, location, rotation, duration andtemperature of needles can all vary between studies.
A significant amount of the literature is published in the Chinese language; these referenceswere excluded from this assessment in line with the agreed methodology, although manyquoted meta-analyses incorporate Chinese language papers.
Similar to other physical therapies, blinding in acupuncture studies is difficult to achieve.
Options such as non-penetrative needles (eg toothpicks) or using real acupuncture needles in
non-acupoint locations might blind the patient, but do not blind the proceduralist and may beunintentionally therapeutic (Langevin 2011 NR). Furthermore, both experienced proceduralists
and patients may expect to feel De qi (the Chinese expression for the sensation of tingling,heaviness and numbness associated with the needle application and rotation). Placebo
acupuncture needles which look identical but retract to a short needle on use may also not foolproceduralists and, similar to using acupuncture in non-acupoint locations, might also be
unintentionally therapeutic (Langevin 2011 NR). In one RCT, 68% of patients and 83% ofproceduralists correctly guessed their allocation (vs an expected 50% if blinding wasappropriate) (Vase 2015 Level II, n=67, JS 5). These blinding issues combined with extremely
heterogeneous methods for heterogeneous conditions and often small sample sizes weaken
the strength of recommendations from pooled results of these meta-analyses.
For paediatric specific acupuncture information see 10.11.2.

7.3.1 | Postoperative pain
The effect of acupuncture on postoperative pain has been examined in different surgicalprocedures, such as cardiac, abdominal, orthopaedic, gynaecological and obstetric surgery.
Overall, acupuncture (excluding AA), compared with sham controls reduces postoperative
pain at 24 h (WMD -1.27/10; 95%CI -1.83 to -0.71) and opioid consumption at 24 h (SMD -0.72;
95%CI -1.21 to -0.22) (Wu 2016 Level I, 11 RCTs, n=682). A subgroup analysis found TEAS (5 RCTs,
n=305) reduces both pain and opioid consumption, needle acupuncture (2 RCTs, n=165) reduces
pain, but EA has no effect (4 RCTs, n=212).
In a prior meta-analysis (9 RCTs overlap), all forms of acupuncture (body or auricular points)
reduce postoperative pain (at 24 h) vs both sham controls (SMD -0.72; 95% CI -1.03 to -0.41)(23 RCTs, n=1,284) and standard treatment (SMD -1.05; 95% CI -1.44 to -0.67) (20 RCTs, n=1,227)(Liu 2015a Level I, 59 RCTS, n=4,578). Opioid analgesia use decreases (ME −4.99mg; 95%CI −7.51 to−2.47) (6 RCTs, n=399) over an unspecified time period.
Similar findings were reported for a number of specific postoperative settings as outlined
below.

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7.3.1.1 | Abdominal and general surgery
After open abdominal surgeries (including Caesarean section, gynaecological and generalsurgical), acupuncture vs sham or no treatment reduces postoperative pain at rest (-7 to 13/100) (18 RCTs, n=1,088), and with movement (-4 to -26/100) (6 RCTs, n=436) at 4 to 48 h, andreduces opioid consumption at 24 h (WMD -9.17 mg; 95%CI -12.47 to - 5.87) (13 RCTs, n=806)(Zhu 2019 Level I [PRISMA], 35 RCTs, n=2,015). Pain scores are less at 4 h in patients who receive
distal acupuncture vs peri-incisional acupuncture. However, reduction of opioids at 24 h is fourtimes more in the peri-incisional acupuncture group than that in distal acupuncture group.
Distal acupuncture reduces the incidence of post-operative nausea and dizziness; however, thisdata was not reported in the studies of peri-incisional acupuncture.
Haemorrhoidectomy
After haemorrhoidectomy, 30 min EA around the surgical site vs sham reduced pain intensity at
6 h, 24 h and during defecation, with no difference in eating, sleeping and anxiety (Wu 2018
Level II, n=72, JS 3).
Hernia repair
Combined pre-emptive acupuncture on body points and intraoperative acupuncture at theincision site for open inguinal hernia repair reduced postoperative pain intensity at 0.5 to 6 hpostoperatively as well as PCA requirements and dizziness (Taghavi 2013 Level II, n=90, JS 1). Preand intraoperative EA resulted in a late reduction in pain scores at POD 4 and 7 only ( Dias 2010
Level II, n=33, JS 5). For inguinal herniorrhaphy under spinal anaesthesia, preoperative
acupuncture on body points enhanced intraoperative sedation and reduced postoperative pain
intensity and opioid requirements (Parthasarathy 2009 Level II, n=50, JS 3). Preoperative and intraoperative EA had similar pain reduction and opioid sparing effect in inguinal hernia (mesh)repair under general anaesthesia (Dalamagka 2015, Level II, n=54, JS 2).
Laparoscopic Surgery
Intraoperative EA for laparoscopic cholecystectomy had no impact on pain, PCA use or PONV vs
no acupuncture (El-Rakshy 2009 Level II, n=107, JS 5). However, one to two sessions of
postoperative acupuncture reduced shoulder pain in patients with established shoulder pain
after laparoscopic abdominal surgery (mostly cholecystectomy) (mean reduction 6.4/10[SD 2.3]) (Kreindler 2014 Level IV, n=25).
Appendicectomy
Sustained acupressure with an ‘acuband’ after open appendicectomy was better than shamcontrol in relieving postoperative pain (Adib-Hajbaghery 2013 Level II, n=70, JS 3).
7.3.1.2 | Orthopaedic surgery
Lumbar spinal surgery
Needle acupuncture after lumbar spinal surgery reduces pain at 24 h (SMD -0.67; 95%CI -1.04
to -0.31) (Cho 2015 Level I [PRISMA], 5 RCTs, n=480). In addition to PCA, postoperative AA and
TEAS improved pain scores vs sham only, and reduced opioid use vs both sham and control
groups (Chung 2014 Level II, n=135, JS 3). During the rehabilitation phase, EA in addition to
standard medical and physiotherapy care, reduced disability at 2 mth postoperatively, but did
not reduce pain or improve quality of life (Heo 2018 Level II, n=39, JS 3).

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Total Knee Arthroplasty
Perioperative acupuncture for TKA reduces pain at POD 2 (WM -1.14/10; 95%CI −1.90 to −0.38)
and delayed time to first PCA use (WMD 46 min; 95%CI 20.8 to 71.5) (Tedesco 2017 Level I[PRISMA], 3 RCTs, n=230), with no effect on opioid consumption within the first 48 h. Acupressure
may improve range of motion vs sham controls (He 2013 Level II, n=90, JS 5; Chang 2012 Level II,
n=68, JS 5). During the rehabilitation phase, acupuncture in addition to exercise was not better
than exercise alone either in reducing pain or improving function at 3 mth post TKA (Petersen
2018 Level II, n=172, JS 3).
Total Hip Arthroplasty
Perioperative AA or acupressure continuing into the postoperative period reduces pain after THA at
12 h, 24 h, 48 h, 72 h, POD 5, POD 7 (1 to 6 RCTs) and intraoperative fentanyl use (SMD -0.73; 95%CI 1.09 to -0.36) (3 RCTs, n=250) (Ye 2019 Level I, 9 RCTs, n=605). There were no differences in the time to
first analgesic request or PONV.
Shoulder Surgery
One session of postoperative acupuncture performed in PACU reduced pain after arthroscopic
shoulder surgery on POD1 and improved sleep quality vs non-acupuncture control (Ward 2013
Level III-1, n=22).
7.3.1.3 | Cardiac & thoracic surgery
Cardiac surgery
For cardiac surgery, EA started 20 to 30 min prior to induction of GA may improve someperioperative outcomes, but has no impact on opioid requirements (Asmussen 2019 Level I[PRISMA], 7 RCTs, n=321).
Preoperative EA administered 12–18 h before cardiac surgery (including myocardial
revascularisation and valve replacement) reduced postoperative pain intensity (2.5/10 ± 1.1 vs
4.0/10 ± 2.0) and PCA fentanyl use by 41% vs placebo (Coura 2011 Level II, n=22, JS 5).
Postoperative acupressure reduced pain intensity after cardiac surgery via median sternotomy
and improved lung function vs acupressure to nonspecific points or no acupressure control(Maimer 2013 Level II, n=100, JS 5). When acupuncture was repeated daily for 7 d, the benefit for
pain and lung function accumulated and improved over time (Colak 2010 Level II, n=30, JS 3).
Thoracic surgery
Repeated postoperative EA (delivered distant to the surgery site over three days) reduced postthoracic pain at 2, 24, 48 and 72 h and breakthrough pethidine consumption (9.2 mg ± 2.8 vs11.5 mg ± 1.8) (Chen 2016 Level II, n=92, JS 3). EA also reduced nausea (21.7% vs 47.8%) but not
vomiting. There was shortened time to first flatus (24.3 h ± 8.2 vs 35.7 h ± 7.76) and
defaecation (42.7 h ± 13.9 vs 59.2 h ± 11.3) n=).
7.3.1.4 | Gynaecological and obstetric surgery
Hysterectomy
After open hysterectomy, EA improved postoperative analgesia over 24 h vs control and shamacupuncture (Lee 2011 Level II, n=47, JS 3). Postoperative auricular EA applied ≈24 h after open
hysterectomy reduced pain at rest and on movement vs control and sham stimulation (Tsang
2011 Level II, n=48, JS 5).
EA during surgery under general anaesthesia provided no benefit vs no acupuncture for
pain, PCA opioid use or PONV after open hysterectomy and laparoscopic cholecystectomy (ElRakshy 2009 Level II, n=107, JS 5).

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Oncological surgery
After open gynaecological surgery for malignancy, EA was superior to traditional acupuncture
in relieving pain initially but not at 48 h (Gavronsky 2012 Level II, n=20, JS 1).
Laparoscopic gynaecological surgery
Auricular EA did not affect pain or opioid requirements after laparoscopic gynaecologicalsurgery (Holzer 2011 Level II, n=40, JS 5); whereas EA to body points delivered 24 h prior tosurgery or during surgery reduced pain and PONV (Li 2017d Level II, n=40, JS 3; Praveena
Seevaunnamtum 2016 Level II, n=64, JS 3).
Oocyte retrieval
For oocyte retrieval, conscious sedation plus EA reduces procedural and postoperative pain
more than sedation plus placebo, or sedation alone (Kwan 2018 Level I [Cochrane], 6 RCTs,
n=1,159). However, a paracervical block achieves lower procedural pain scores than EA(4 RCTs, n=781).
Caesarean section
After Caesarean section, postoperative EA and acupuncture reduced pain scores and PCA
requirements for up to 2 h (Wu 2009 Level II, n=60, JS 3).
7.3.1.5 | Ear, nose and throat surgery
For tonsillectomy, perioperative acupuncture vs sham or no therapy reduces pain for the first
48 h, postoperative analgesia requirements and PONV (Cho 2016 Level I [PRISMA], 12 RCTs,
n=1,025 [11 RCTs in children & adolescents, 1 in adults]).
Battlefield auricular acupressure vs usual care reduces post-tonsillectomy pain in adults atdischarge, with no effect on pain or opioid use at POD 10 (Plunkett 2018 Level II, n=95, JS 3).
7.3.1.6 | Neurosurgery
TEAS vs placebo reduces post craniotomy pain, PCA fentanyl use from 0 to 6 h and reducesdizziness and feelings of “a full head” up to 24 h (Tsaousi 2017 Level I [PRISMA], 2 RCTs [TEAS],
n=176).

7.3.2 | Other acute pain states
7.3.2.1 | Emergency department and acute trauma setting
AA including acupressure improves pain relief vs control treatment for pain due to acute hip
fracture (1 RCT), acute biliary colic (1 RCT) and acute burn and acute emergency conditions(SMD 1.35; 95%CI 0.08 to 2.64) (2 RCTs, n=111) (Asher 2010 Level I [PRISMA], 4 RCTs [acute pain],n=197). These findings were confirmed in a later meta-analysis which found AA vs sham or
standard care reduces pain (WMD -2.6/10; 95%CI -2.00 to -3.22) but had a variable effect onanalgesic use with only 1 of 3 studies reporting a difference (Jan 2017a Level I [PRISMA], 4 RCTs,
n=281) (3 RCTs overlap). Adverse effects of AA were documented in only 2 studies in which minor
pain was experienced in 2 patients. It takes about 2 to 10 min to apply the treatment at thecost of AU$7.50 per patient (Jan 2017b Level I [PRISMA], 4 RCTs, n=281).
Needle acupuncture on the body was faster (16 ± 8 min vs 28 ± 14 min) and more successful(92% vs 78%) at reducing pain by 50% with less nausea and vomiting vs IV morphine control(mean dose 0.17 mg/kg ± 0.08) (Grissa 2016 Level II, n=300 [46% abdominal pain, 54%
musculoskeletal or other pain], JS 3). Similarly, for renal colic a 30 min acupuncture session vs5th Edition | Acute Pain Management: Scientific Evidence447

titrated IV morphine achieved a 50% pain reduction faster (14 min vs 28), with far fewer
patients experiencing side effects (acupuncture 3/54 vs morphine 42/61) (Beltaief 2018, Level II,
n=115, JS 3). An RCT of acupuncture vs acupuncture/pharmacotherapy vs pharmacotherapy
alone for back pain, ankle sprain and migraine found no difference between pain scores at 1 hor satisfaction at 1 h or 24 h (Cohen 2017 Level II, n=528, JS 3). The acupuncture alone grouprequired more rescue analgesia vs the pharmacology alone and combination groups, withlower hospital admission rate in the combination group.
Acupuncture reduced pain (by 2.3/10) and nausea (by 1.2/6) in patients with acute pain vs
retrospectively matched controls, with a high satisfaction rate (98%) (Zhang 2014 Level III-3,
n=400 [59% musculoskeletal, 25% abdominal pain]). Acupuncture treatment provided before
medical consultation reduced the staff time spent managing the patient vs acupuncture given
after medical consultation.
Acupuncture vs sham reduced pain on movement in bed and cough after rib fracture but
not pain on deep breathing (Ho 2014 Level II, n=58, JS 5). Acupressure reduced acutemusculoskeletal pain due to sports injuries vs sham or no acupressure (Macznik 2017 Level II,
n=79, JS 3).
In acute pain due to sports injury, athletes had significant pain reduction (4 to 8/10) after
auricular acupuncture treatment (deWeber 2011 Level IV, n=8).
Acupressure performed during prehospital transport led to better pain relief vs shamacupressure after hip fracture (auricular) (Barker 2006 Level II, n=38, JS 5) and radial fracture (Lang2007 Level II, n=32, JS 5), and after minor trauma vs sham and no acupressure (Kober 2002 Level II,
n=60, JS 5).
7.3.2.2 | Acute back pain
Compared to sham acupuncture, one session of acupuncture reduces pain intensity(MD -9.38/100; 95%CI -17.00 to -1.76) (2 RCTs, n=100) but not function or disability in acuteback pain (3 RCTs, n=148) (Lee 2013 Level I [PRISMA], 11 RCTs, n=1,139). Slightly more patients
improved with acupuncture than NSAIDs (RR 1.11; 95%CI 1.06 to 1.16) (5 RCTs, n=662).
In a large well-designed RCT, five sessions of acupuncture over 14 d were added toconventional treatment for acute low-back pain (Vas 2012 Level II, n=275, JS 5). Acupuncture wasmore effective in reducing pain and analgesic use and improving work readiness vsconventional treatment alone; but there was little difference between real acupuncture, shamacupuncture (penetrating) and placebo acupuncture (nonpenetrating). One session ofacupuncture with concurrent gentle exercise produced better analgesia for severely disabling
acute low-back pain (Oswestry Disability Index [ODI] value ≥60%) than diclofenac (75 mg IM)(Shin 2013 Level II, n=58, JS 3). Patients in the acupuncture group had less pain at 30 min after
treatment (MD 3.12/10; 95%CI 2.26 to 3.98), much improved function (decreased ODI by 33%;
95%CI 27 to 39) and fewer hospital admissions (66 vs 93%). The pain reduction was maintained
at 2 wk and 4 wk follow-up.
Battlefield AA plus standard therapy has better pain reduction for acute low back pain in ED
over standard care alone with no differences in functional recovery (Fox 2018 Level II, n=30, JS 3).
Acupuncture with concurrent lumbar exercise has better sustained pain reduction in acutelumbar sprain than conventional acupuncture, sham intervention or TENS at 24 h ( Lin 2016
Level II, n=60, JS 3). Similar results are shown in a cohort study (Liu 2015c Level III-2, n=74).
Acupuncture plus spinal manipulation has similar pain reduction in sub-acute low back painvs acupuncture alone or spinal manipulation alone (Kizhakkeveettil 2017 Level II, n=101, JS 3).

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7.3.2.3 | Labour and post-partum pain
With regard to use of acupuncture in labour (Smith 2020 Level I [Cochrane], 28 RCTs, n=3,960):• Acupuncture vs sham does not reduce pain scores (2 RCTs, n=325), but does increasesatisfaction with pain relief (RR 2.38; 95%CI 1.78 to 3.19) (1 RCT, n=150) and decrease useof pharmacological analgesia (RR 0.75; 95%CI 0.63 to 0.89);• Acupuncture vs usual care reduces pain scores (4 RCTs, n=495) and use ofpharmacological analgesia (6 RCTs, n=1,059) but does not improve satisfaction (2 RCTs,
n=343).
• Acupuncture vs no treatment reduces pain scores (1 RCT, n=163);• Acupuncture vs water injection did not reduce use of pharmacological analgesia (1 RCT,
n=128);• Acupressure vs sham lowered VAS (MD -1.93/10; 95%CI -3.31 to -0.55) but had no effecton use of pharmacological analgesia (6 RCTs, n=472);• Acupressure vs usual care reduced VAS (SD -1.07; 95%CI -1.45 to -0.69) (8 RCTs, n=620)
and improved satisfaction (1 RCT, n=105);• Acupressure vs both placebo and usual care reduced VAS (-0.42 SD; 95%CI -0.65 to 0.18) (2 RCTs, n=322) and marginally increased satisfaction with analgesia (1 RCT, n=212).
There was no effect on Caesarean section rate for all interventions. No study was at a low
risk of bias on all domains.
Note: reversal of conclusion
This reverses the Level I key message in the previous edition of this document; a precedingmeta-analysis had described a reduction of Caesarean section rate by use of acupuncture.
A critical review (Levett 2014 NR) of the previous iteration of this and another meta-analysis(Cho 2010 Level I, [PRISMA], 10 RCTs, n=2,038) suggests that these meta-analyses may compare
very different approaches in very different settings, in particular by comparing trials of efficacy
with trials of effectiveness.
TEAS provided inferior analgesia in labour vs epidural (SMD -53.00/100; 95%CI -58 to -48) ortramadol/ondansetron PCA but was superior to placebo (Anim-Somuah 2018 Level I [Cochrane],
1 RCT: Liu 2015b Level II, n=120, JS 3).
Patients with mastitis are less likely to have severe symptoms 5 d after acupuncture in 1 of
2 RCTs (Mangesi 2016 Level I [Cochrane], 2 RCTs, n=293).
Auricular acupressure (by taping seeds to the ear) did not reduce acute postpartum
perineal pain in women with 1st or 2nd degree tears or episiotomies (Kwan 2014 Level II, n=266,
JS 3) contrasting with a previous study where wrist-ankle needle acupuncture for perineal pain
after episiotomy reduced requirements for rescue analgesia vs controls (Marra 2011 Level III-1,n=42) (See also section 9.1.3.5).
7.3.2.4 | Dysmenorrhoea
Acupuncture may reduce pain in primary dysmenorrhoea vs NSAIDs (14 RCTs, n=850) or noacupuncture controls (6 RCTs, n=384), but not vs sham or placebo controls (6 RCTs, n=477);
whereas acupressure reduces pain vs sham or placebo control (5 RCTs, n=538), but not vs
NSAIDs (1 RCT, n=136) or no treatment (2 RCTs, n=140) (Smith 2016 Level I [Cochrane], 42 RCTs,
n=4,640). Only one of the 42 RCTs was considered of low risk of bias in all domains and generally
data was unsuitable for pooling due to heterogeneity.
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A subsequent network meta-analysis found acupuncture may be more effective than
NSAIDs in reducing the risk of pain episodes of primary dysmenorrhoea, with EA being the mosteffective (Luo 2019a Level I [NMA], 17 RCTs, n=1,511). Another systematic review found EA more
effective than needle acupuncture or NSAIDs (Woo 2018 Level I [PRISMA], 60 RCTs, n=5,901) (6 RCT
overlap). While, another meta-analysis found acupuncture (pooled all types) reduces symptom
severity scores (6 RCTs, n=621) but not pain scores (2 RCTs, n=168) (Xu 2017 Level I [PRISMA],
19 RCTs, n=1,690) (5 RCTs overlap with Smith 2016).
Acupressure to SP6 (a lower leg acupoint) delivered by trained therapists reduces pain inprimary dysmenorrhoea vs controls and the effect lasts for 3 h (5 RCTs), whereas patient selfadministered acupressure does not reduce pain immediately, and takes 3 mth to be effective(3 RCTs) (Abaraogu 2016 Level III-1 SR [PRISMA], 5 RCTS & 1 study, n=461).
7.3.2.5 | Dental pain
Acupuncture may be useful for pain during dental procedures ( Ernst 1998 Level I, 16 RCTs, n=941).
Acupuncture reduced dental pain from 6.6/10 to ≈1.0/10 in an ED case series, with 119/120
patients responding (Grillo 2014 Level IV, n=120).
7.3.2.6 | Acute neuropathic pain
In severe pain due to acute herpes zoster (NRS >7/10), acupuncture was as effective as
standard pharmacological treatment (pregabalin, local anaesthetics and TD buprenorphine ororal oxycodone) at 4 wk (Ursini 2011 Level II, n=102, JS 3).
7.3.2.7 | Headache
Acupuncture (at least 6 sessions) provides clinically relevant improvement in pain for tension
type headache (TTH) over 3 mth vs standard care (2 RCTs, n=1,472), but only minimal clinicalimprovement vs sham treatment (5 RCTs, n=703) (Linde 2016a Level I [Cochrane], 12 RCTs, n=2,349).
Similarly, acupuncture reduces migraine frequency at 3 mth vs no treatment or routine care
(4 RCTs, n=2,199), but only minor improvements were seen vs sham treatments (14 RCTs,
n=1,825) (Linde 2016b Level I [Cochrane], 22 RCTs, n=4,985). Acupuncture reported fewer adverse
effects (5 RCTs, n=931) vs pharmacological prophylaxis and acupuncture was slightly superior at
3 mth but not at 6 mth (3 RCTs, n=739). A subsequent RCT also found a prophylactic effect of EA(5 sessions per wk for 12 wk) on migraine (Li 2017a, Level II, n=61, JS 3).
In the guidelines for headache by the National Clinical Guideline Centre of the UK, 10
sessions of acupuncture are recommended for TTH treatment and as a prophylaxis, and for
migraine when prophylactic medications are ineffective (NICE 2012 GL).
Acupuncture vs sham as a treatment for acute migraine attacks reduced pain intensity,
but had no impact on pain freedom at or beyond 24 h or risk of recurrence (Wang 2012
Level II, n=150, JS 5).
AA was marginally better than sham acupuncture at 15, 30, 45 and 60 min in reducing
migraine pain and recurrent analgesia usage within 24 h occurred in 1/30 of AA vs 13/30 ofsham patients (Farahmand 2018 Level II, n=60, JS 3).
7.3.2.8 | Other painful conditions
Battlefield AA reduced sore throat vs standard therapy (Moss 2015, Level II, n=54, JS 3).
Acupressure also reduced procedure pain and anxiety related to venipuncture over sham or
standard care (Hosseinabadi 2015, Level II, n=187, JS 2).

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Acupuncture may reduce post-stroke pain (MD −1.59/10; 95%CI −1.86 to −1.32]) when
added to routine rehabilitation (25 RCTs), however with low certainty due to poor study quality(Liu 2019 Level I [PRISMA], 38 RCTs, n=3,184).

KEY MESSAGES
1. Acupuncture and acupressure for labour pain may reduce pain, use of pharmacological
pain relief and increase satisfaction with pain management versus standard care orplacebo (Q) (Level I [Cochrane Review]); Caesarean section rates are unchanged (R)(Level I [Cochrane Review]).
2. For oocyte retrieval, electroacupuncture plus sedation reduced procedural andpostoperative pain compared with sedation plus placebo or sedation alone (U), but
may be inferior to paracervical block plus sedation (Q) (Level I [Cochrane Review]).
3. Acupuncture or acupressure may be effective in the treatment of primarydysmenorrhoea (S) (Level I [Cochrane Review]).
4. Acupuncture may reduce the frequency of tension-type headaches and migraine (U)(Level I [Cochrane Review]); in migraine, it may be better tolerated thanpharmacological prophylaxis (N) (Level I [Cochrane Review]).
5. Acupuncture may be effective in a variety of acute pain conditions in the emergency
department setting (S) (Level I [PRISMA]) including back pain (N) (Level I [PRISMA])
6. Acupuncture by a variety of techniques may reduce postoperative pain and opioid
consumption for a variety of surgical types (S) (Level I); specifically, the benefit may
occur after lumbar spinal surgery (U) (Level I [PRISMA]), total knee arthroplasty (U)(Level I [PRISMA]), total hip arthroplasty (N) (Level I) and craniotomy (N) (Level I[PRISMA]).
7. There is no difference between distant acupuncture and acupuncture at the incisionalsite for open abdominal surgery (S) (Level I [PRISMA]).
8. Acupuncture may reduce post-stroke pain (N) (Level I [PRISMA]).

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7.4 | Photobiomodulation
Photobiomodulation (PBM), previously called low-level laser therapy (LLLT), is the applicationof non-thermal laser in the red and near-infrared light wave lengths (600 to 1,000 nm) to tissue
in order to produce biological effects. Light-matter interactions are well appreciated to occur
where the encounter between a photon (or series of photons) causes the biology to enter analtered energetic state which causes an altered function. Sometimes this is destructive (eg UV
and DNA), other times the effects are transient. PBM has multiple potential mechanisms ofaction including the displacement of inhibitory nitric oxide from cytochrome c oxidase
increasing mitochondrial ATP production as well as interaction with light-sensitive ion channels,
ultimately resulting in reversible inhibition of peripheral nerve conduction (Chow 2011 SR EH BS,
44 studies [18 human, 26 animal]) and reduced levels of prostaglandin E2 and inflammatory
mediators (de Freitas 2016 NR). Studies vary in both total energy (J), energy density (J/cm2) andwavelength of light used.

7.4.1 | Mucositis and stomatitis
A systematic review of PBM for recurrent aphthous stomatitis could not carry out a metaanalysis, but reports pain relief in 5 of 6 RCTs immediately after treatment, and 7 of 9 RCTs in
the days following treatment (Suter 2017 Level I, 10 RCTs, n=512).
PBM may be effective in reducing pain intensity, severity and duration of mucositis basedon moderate evidence (Anschau 2019 Level I [PRISMA], 5 RCTs, n=315). This is in line with findingsof two small low-quality RCTs not included in the meta-analysis (Abramoff 2008 Level II, n=11, JS 2;
Arora 2008 Level II, n=28, JS 2).
PBM used prophylactically reduces the risk of severe mucositis and pain in patients withcancer or undergoing hematopoietic stem cell transplantation (Oberoi 2014 Level I [PRISMA],
18 RCTs, n=1,144). This approach is recommended in a specific clinical practice guideline (Zadik
2019 GL).
For more details see also Section 8.9.8.2 and for paediatric mucositis see Section 10.8.3.1.

7.4.2 | Maxillofacial, ENT and dental surgery
After surgical removal of third molars, PBM reduces postoperative pain on POD 2 (WMD 1.42/10; 95%CI -2.18 to -0.67) (11 studies, n=434) and less on POD 7 (WMD -0.59/10; 95%CI-0.96 to -0.22) (10 studies, n=350) (Dawdy 2017 Level III-2 SR [PRISMA], 11 studies, n=434). However,studies were assessed as high risk of bias in multiple domains and had high heterogeneity.
Similarly, an earlier meta-analysis finds reductions in pain from POD 1 to POD 3 after 3 rd molar
surgery (He 2015 Level III-2 [PRISMA], 4 RCTs, n=150) (3 RCTs overlap). A subsequent study also
showed reductions in postprocedural pain (Singh 2019 Level III-2, n=25).
After Le Fort I osteotomy in patients acting as their own controls, PBM vs no treatment
reduced pain on the irradiated side of the face at 24 and 72 h after surgery, but not during theimmediate post-operative assessment and there was no pain on either side by POD 7(Bittencourt 2017 Level III-2 SR [PRISMA], 1 study: Gasperini 2014 Level III-2, n=10).
After orthodontic treatment with fixed appliances in children and young adults, 11 of 13
studies reported a reduction in acute pain, however, no meta-analysis was performed andstudies were broadly of low quality (Sonesson 2016 Level III-1 SR [PRISMA], 13 studies, n=333).

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5th Edition | Acute Pain Management: Scientific Evidence7.0 | NONPHARMACOLOGICAL TECHNIQUESParacetamol usage in children undergoing secondary palatal surgery was reduced by
PBM (970 nm, 2 W, 35 J/cm2) vs undescribed placebo on POD 2 and POD 3 ( Ezzat 2016 Level II,
n=20, JS 2).
See also orofacial pain in Section 8.6.7.
7.4.2.1 | Tonsillectomy
Immediately after tonsillectomy in 5 to 15 y old children, intraoperative PBM (685 nm, 4 J/cm2)vs no treatment reduced pain scores on POD 1, POD 2, POD 4 and POD 5 as well as the need forbreakthrough non-opioid analgesic on POD 1 (45% vs 100%) (Neiva 2010, Level II, n=18, JS 1).
Intraoperative PBM (980 nm, 4 J/cm2) applied immediately after tonsillectomy in adults vsunpowered probe application reduced mean pain scores in the first 24 h (1.43/4 vs 2.11/4) andneed for rescue opioids (6.6% vs 33.3%) (Aghamohammadi 2013 Level II, n=60, JS 1).
7.4.2.2 | Vascular access
PBM reduces the incidence of needle pain during arteriovenous fistulas access vs placebo(RR 0.08; 95%CI 0.06 to 0.10) (Wan 2017 Level I, 3 RCTs, n=186), however, heterogeneity wasreported as high.
7.4.2.3 | Cardiothoracic surgery
PBM (660 nm, 6 J/cm2, 2.4 J) reduced sternotomy pain after CABG surgery on POD 6 and POD 8
vs both placebo and usual care groups, but all groups had negligible pain 1 mth after surgery(Fernandes 2017 Level II, n=90, JS 4).
After off-pump CABG surgery, pain was reduced post PBM (980 nm, 10 J/cm2, 150 J;
commenced 30 min post-extubation) at 1 h and 24 h vs pre-PBM levels (Karlekar 2015 Level IV,
n=100).
7.4.2.4 | Musculoskeletal pain and orthopaedic surgery
After the first presentation with acute ankle sprain, two sessions of PBM (635 nm, 4.5 and9 J/cm2), in addition to standard care of rest, icing, compression and elevation, did not reduce
pain at 10 d or 6 wk vs standard care (Calin 2019, Level II, n=19, JS 2).
After tibial fracture surgery, PBM (808 nm, 6 J/cm2 and 650 nm, 3 J/cm2) reduced painscores from 2 h to 24 h and IV pethidine administration over 24 h (51.6 mg ± 29.5 vs 89.3 ±35.5) (Nesioonpour 2014b Level II, n=54, JS 1).
In patients undergoing radius fracture fixation under intravenous regional anaesthesia(IVRA) the addition of cervical and affected extremity PBM (808 nm) reduced procedural andpost procedural pain and opioid consumption (Nesioonpour 2014a Level II, n=48, JS 3).
After total hip arthroplasty, PBM (905 nm, 875 nm and 640 nm, total 201.5 J) reduced painscores from baseline more vs placebo, as well as IL-8 and TNF-α concentrations (Langella 2018
Level II, n=18, JS 5). However, pain scores were higher in the PBM group initially and absolute
pain scores were not reported in the study.
7.4.2.5 | Labour, puerperium and Caesarean section
After episiotomy, PBM (780 nm or 660 nm, 8.8 J/cm2, 1.05 J) did not reduce pain immediately
or at 30 min (Santos Jde 2012 Level II, n=114, JS 5). A subsequent RCT had similar findings withPBM (780 nm, 5 J/cm2, 5.4 J) applied 6-10 h postpartum for episiotomy being ineffective forpain (Alvarenga 2017 Level II, n=54, JS 5).
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PBM (650 nm and 804 nm, total 21 to 30 J) after Caesarean section under spinal reduced
pain at 1 h to 24 h and pethidine consumption (57.83 mg ± 29.57 vs 107.78 mg ± 34.28) andprolonged time to first analgesia request (226.5 min ± 14.56 vs 88.5 min ± 15.78) (Poursalehan
2018 Level II, n=80, JS 2).
7.4.2.6 | Other surgery
After breast augmentation, application of pre-incision PBM (630 to 640 nm) reduced painscores at 24 h (21.4/100 vs 36.8) but not at 7 d to 28 d (Jackson 2009 Level II, n=104, JS 2).
Post open inguinal herniorrhaphy, PBM (830 nm, 13 J/cm2, 10.4 J) on POD 1 , POD 3 andPOD 7 did not reduce pain scores at 6 mth (Carvalho 2010, Level II, n=28, JS 3).

KEY MESSAGES
1. Photobiomodulation may be effective for both prophylaxis and treatment of mucositis
in oncology patients (S) (Level I [PRISMA]).
2. Photobiomodulation may reduce pain after 3rd molar extraction (N) (Level I [PRISMA]).
3. Needle related pain after arteriovenous fistula access may be reduced byphotobiomodulation (N) (Level I)
4. After episiotomy, photobiomodulation may not reduce pain (N) (Level II).
The following tick box represents conclusions based on clinical experience and expert
opinion: Photobiomodulation may have a role in acute postsurgical pain management, however
evidence is currently insufficient to make any furrher recommendations (N).

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7.5 | Physical therapies
Physical therapies for acute pain management are typically adjunctive to the psychological andpharmacological treatments discussed elsewhere in this book. The physical therapies coveredin this section include the active therapies of exercise, prehabilitation and rehabilitation as wellas the passive therapies of massage and other manual therapies, warming and cooling. Other
passive physical therapies discussed elsewhere include TENS (see Section 7.2), acupuncture(see Section 7.3) and PBM (low-level laser therapy [LLLT]) (see Section 7.4). Specific conditions
addressed elsewhere include acute back pain (see Section 8.7) and acute musculoskeletal pain(see Section 8.8). Some therapies such as aromatherapy which are not considered core physicaltherapies for acute pain are not covered in this chapter, but in complementary and alternative
medicine (see Section 4.14.3).
Evidence for the benefits and harm of physical therapies in acute pain management isvariable. The use of physical therapies for acute pain management should reflect contemporary
practice guidelines promoting the use of active self-management (including exercise) rather
than a sole focus on passive therapies. Physical therapies typically incorporate contemporary
education on pain, including the provision of clear and meaningful information and advice
about the management of acute pain and this component is covered under education (seeSection 3.1).
The evidence for physical therapies is currently limited by wide heterogeneity ofmultimodal interventions and conditions, limited studies with small sample sizes anddifficulties with consistent blinding leading to a risk of bias.
This section focuses on the effect of physical therapies on pain outcomes; other benefits
may be present but have not been thoroughly reviewed.

7.5.1 | Active exercise-based therapies
7.5.1.1 | Exercise
Total joint arthroplasty
Exercises carried out preoperatively before total knee arthroplasty (TKA) do not improve
postoperative pain at 4 wk (2 RCTs, n=224) or 8 wk (3 RCTs, n=242) vs standard interventions(Umehara 2018 Level I, 27 RCTs, n=2,432). An exercise intervention in addition to standard
postoperative interventions for 8 wk after discharge, reduces pain relative to standard
postoperative interventions alone (SMD −0.65; 95%CI −1.22 to −0.08) and improvement infunction (eg stiffness, extension strength, knee flexion range and gait speed). No differences arefound for implementation of early vs late postoperative exercise for pain outcomes at 4 wk
(2 RCTs, n=573) or 8 wk (2 RCTs, n=318) (Umehara 2018 Level I, 27 RCTs, n=2,432).
After total hip replacement (THA), adding supervised exercise (two 30 to
40 min sessions/wk for 10 wk) did not further increase leg extension, but improved walking
speed and stair climbing speed vs non-supervised exercise alone (Hansen 2019 Level I [PRISMA],
1 RCT: Mikkelsen 2014, Level II, n=60, JS 3).
Meniscal lesions
There is no significant difference in knee pain between exercise therapy and meniscectomy forpatients with a degenerative meniscal lesion in the short term (2 studies, n=125) (Swart 2016,
Level III-1 SR, 12 studies, n=594). Even at two to three mth follow-up, exercise or an exercise-

5th Edition | Acute Pain Management: Scientific Evidence455based physical therapy program vs arthroscopic partial meniscectomy results in no differencein pain (3 RCTs, n=344) (van de Graaf 2016, Level I [PRISMA], 6 RCTs, n=773).
The outcomes of exercise therapy versus no exercise therapy after meniscectomy at <3 mth
are conflicting (2 RCTs, n=125), with one study finding a significant benefit of exercise on knee
pain, while the other did not; however, data could not be pooled due to the measurement ofpain at different time points (Swart 2016 Level I, Level III-1 SR, 12 studies, n=594).
Anterior cruciate ligament (ACL) reconstruction
Immediate postoperative weight bearing significantly decreased the proportion of patients
reporting pain symptoms 2 wk after anterior cruciate ligament (ACL) reconstruction and did notincrease joint laxity vs patients who had 2 wk delayed weight bearing (Secrist 2016 Level I[PRISMA] 1 RCT: Tyler 1998 Level II, n=45, JS 2).
Ankle sprains
Compared with home exercise programs, physiotherapy supervised rehabilitation resulted inless pain and subjective instability at 8 wk after ankle sprain (Feger 2015 Level I, 1 RCT: van Rijn
2009, Level II, n=102, JS 3).
Dysmenorrhoea
Physical activity (single or co-intervention) in any setting or via any mode for the treatment ofprimary dysmenorrhea (non-athlete females with regular menstruation not using hormonal
contraception) reduces pain intensity (MD -1.89/10; 95%CI -2.96 to -1.09) and pain duration (MD-3.92 h; 95%CI -4.86 to -2.97) (Matthewman 2018 Level I [PRISMA], 11 RCTs, n=817 [intensity] & n=469[duration]). Yoga (20 min/day for 14 d/cycle) vs no treatment improved pain intensity fromdysmenorrhea at 1 mth (MD -3.2/10; 95%CI -2.2 to -4.2) (Kannan 2014 Level I, 1 RCT: Rakhshaee 2011,
Level II, n=92, JS 1). Overall quality of this evidence was rated as low due to high risk of bias.
Labour pain
The use of birth ball exercises for labour pain relief improves pain (MD -0.9/10; 95% CI -1.3 to-0.6) (Makvandi 2015, Level I, 3 RCTs, n=205). Overall, the quality of the studies was mixed, withmost providing little information on the exact methods they used.

KEY MESSAGES
1. Following total knee arthroplasty, an exercise intervention in addition to standard postoperative interventions for 8 weeks after discharge may reduce pain and improvefunction (N) (Level I).
2. In primary dysmenorrhoea, exercise may reduce acute pain intensity and pain duration(N) (Level I).
3. Use of a birth ball may improve labour pain (N) (Level I).
The following tick boxes represent conclusions based on clinical experience and expert opinion:
 Clear recommendations on the components of exercise interventions (including time
point of application, frequency, mode, dose and duration) for acute postoperative pain
management cannot be made; different surgical procedures may require different
exercise-based interventions (N).
 Immediate post-operative weight bearing post anterior cruciate ligament reconstruction
may reduce pain and does not appear to result in increased joint laxity (N).

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7.5.1.2 | Prehabilitation
Total joint arthroplasty
Following TKA, despite improvements in function and quadriceps strength, there was no effectof prehabilitation on postoperative pain pooled across heterogeneous time points and scales
nor were significant differences were found at 6 wk (3 RCTs) or 3 mth (9 RCTs) (Moyer 2017 Level
I [PRISMA], 16 RCTs, n=1,178). Multiple systematic reviews and meta-analyses with significant
study overlap come to the same conclusion, with no significant effects demonstrated for:• Pain intensity at 1 mth (2 RCTs, n=297) or WOMAC scores at 3 mth (3 RCTs, n=252) (Cabilan
2016 Level I, 5 RCTs, n=549);• Pain measured variously by WOMAC (5 RCTs), SF-36 (4 RCTs) or VAS (2 RCTs) (Kwok 2015,
Level III-1 SR, 8 studies, n=619);• WOMAC pain intensity between 1.5 and 3 mth (Chen 2018 Level I, 7 RCTs, n=424);• Pain at 6 or 12 wk (Tedesco 2017, Level I [PRISMA], 3 RCTs, n=110).
For THA, in addition to improving function, prehabilitation reduces postoperative painscores vs usual care when pooled across heterogeneous time points (SMD 0.15; 95% CI
0.03 to 0.27) (Moyer 2017, Level I [PRISMA], 13 RCTs, n=905 ). When analysed at specific time
periods, pain scores are reduced at 3 mth vs usual care ( 3 RCTs) (SMD 0.34; 95%CI 0.07 to0.62), but not at 6 wk ( 7 RCTs) or 6 mth (3 RCTs).
When any joint replacement surgery was considered, prehabilitation reduces pain at 4 wk
or less (assessed by multiple scales: WOMAC, VAS, Knee injury and Osteoarthritis Outcome
Score (KOOS) and 10 graded scale, subsequently converted to WOMAC 0-100 subscales) (WMD
-6.1/100; 95%CI -10.6 to -1.6) (Wang 2016 Level I [PRISMA], 2 RCTs, n=105 [THA] & 2 RCTs, n=114[TKA]). The authors noted a low overall quality of evidence in these trials. No significant
difference between prehabilitation and usual care groups for pain is seen at 6 to 8 wk (5 RCTs,
n=488) or 12 wk (10 RCTs, n=806) post-operation.
Anterior cruciate ligament (ACL) reconstruction
For ACL reconstruction, despite improving function and strength, prehabilitation does not
significantly improve patient reported pain vs controls (Alshewaier 2015 Level I [PRISMA], 3 RCTS,
n=291).
Spinal Surgery
For spinal surgery, in spite of earlier discharge times and reduced time to functional
milestones, prehabilitation did not improve pain at one or 3 mth (Cabilan 2016 Level I, 1 RCT:
Nielsen 2010, Level II, n=60, JS 3).
Dosing of prehabilitation
A systematic review looking at prehabilitation duration in TKA, THA and spinal surgery patientsshows no effects of quantity on WOMAC pain scores (Cabilan 2015 Level I [PRISMA], 2 RCTs [<500min], 3 RCTs [500-999 min], 2 RCTs [1,000-1,499 min], 2 RCTs [>= 1,500 min]). A single RCT (n=23) in the
1,000 to 1,499 min range reported an improvement in pain intensity (5.5/10  2.2 vs 7.3/10 2.0), but not WOMAC scores.

5th Edition | Acute Pain Management: Scientific Evidence457

KEY MESSAGES
1. Prior to total hip arthroplasty, prehabilitation may reduce postoperative hip pain at 3
months (N) (Level I [PRISMA]).
The following tick box represents conclusions based on clinical experience and expert
opinion: A recommendation for the specific type of prehabilitation and dosing parameters
cannot be made at this time (N).
7.5.1.3 | Rehabilitation
Spinal Surgery and Injuries
After spinal surgery, physiotherapy commenced within the first 4 wk reduces pain at 12 wk(SMD -0.38; 95%CI -0.66 to -0.10) and 12 to 18 mth (SMD -0.30; 95%CI -0.59 to -0.02) vs no or
sham physiotherapy (Snowdon 2016 Level I [PRISMA], 4 RCTs, n=250). Early comprehensive
physiotherapy (active rehabilitation, education on the performance of daily functional tasks,
functional weight-bearing exercise, cardiovascular endurance exercise, lower limb strengthening
and dynamic proximal stabilisation) does not increase the risk of adverse events (3 RCTs, n=196).
For osteoporotic vertebral compression fractures, spinal orthoses reduce pain (SMD -1.47;
95%CI -1.82 to -1.13) vs no intervention over the medium term (Rzewuska 2015 Level I, 2 RCTs,
n=170). However, there was no difference in pain between a proprietary spinal orthosis(SpinoMed) and a soft lumbar orthosis at short-term follow up (Li 2015 Level II, n=51, JS 1).
Total knee arthroplasty (TKA)
After TKA, accelerated physiotherapy (starting within 24 h) versus standard physiotherapy(after bed rest for 24 h) reduced time to discharge by 2.1 days ( 1.45) and pain at the time ofdischarge (MD −0.96/10; 95%CI −1.21 to −0.71) (Henderson 2018, Level I [PRISMA], 1 RCT: Labraca
2011, Level II, n=273, JS 3). Twice daily vs once daily physiotherapy did not significantly reduce
pain (Henderson 2018, Level I [PRISMA], 1 RCT: Lenssen 2006 Level II, n=43, JS 3).
After TKA, continuous passive motion (CPM) does not improve pain vs standard care overthe short term (< 6 wk) (Tedesco 2017 Level I [PRISMA], 9 RCTs, n=1,025; Harvey 2014, Level I[Cochrane], 8 RCTs, n=414) (7 RCTs overlap). No difference was found for adverse events.
Anterior cruciate ligament (ACL) reconstruction
After outpatient ACL reconstruction, the role of mobilisation strategies was investigated (Secrist2016 Level I [PRISMA], 3 RCTs, n unspecified). Individual trials showed that CPM use for 16 h/d
immediately after surgery did not decrease pain vs controls, but did decrease PCA usage(41 mg  18.9 vs 65 mg  21.4) (Secrist 2016 Level I [PRISMA], 1 RCT: McCarthy 1993 Level II, n=35,
JS 1). A continuous active motion device, in which the patient used the contralateral leg topedal the injured leg, did not decrease VAS scores vs a CPM device (Secrist 2016 Level I [PRISMA],
1 RCT: Friemert 2006 Level II, n=60, JS 1). There was no difference in pain between an unhinged
immobilising brace for 2 wk postoperatively and no immobilisation (Secrist 2016 Level I [PRISMA],
1 RCT: Hiemstra 2009 Level II, n=82, JS 2).
Movement representation
Movement representation (mirror therapy, motor imagery, action observation combinedwith standard physiotherapy or rehabilitation) techniques reduced limb pain acutely458

5th Edition | Acute Pain Management: Scientific Evidence7.0 | NONPHARMACOLOGICAL TECHNIQUES(SMD -0.7; 95%CI -1.24 to -0.15) (Thieme 2016, Level I [PRISMA], 6 RCTs, n=140 ). A sub-analysisof both acute and chronic pain by type found reductions in pain for Complex Regional Pain
Syndrome (CRPS) (SMD -2.23; 95%CI -3.88 to -0.57) (4 RCTs, n=108 ) and nociceptive pain
conditions (ankle sprain, ACL reconstruction, TKA and rotator cuff injury) (SMD -1.26;
95%CI -1.92 to -0.61) (4 RCTs, n=64 ), but not phantom limb pain ( 3 RCTs, n=41 ) or post stroke
pain (3 RCTs, n=116 ).
See also Section 8.1.5.2.

KEY MESSAGES
1. Early comprehensive active physiotherapy in the first 4 weeks post spinal surgery may
reduce pain and does not appear to increase adverse events (N) (Level I [PRISMA]).
2. Movement representation interventions (mirror therapy/motor imagery) may reduce
acute pain after trauma and surgery (N) (Level I [PRISMA]).
The following tick box represents conclusions based on clinical experience and expert
opinion: Accelerated rehabilitation, started within 24 hours post total knee arthroplasty, may
reduce pain at the time of discharge (N).

7.5.2 | Manual and massage therapies
Postoperative pain in general
Massage improves postoperative pain vs routine care (SMD -0.58; 95%CI -0.93 to -0.53)(Kukimoto 2017, Level I [PRISMA], 9 RCTs, n=1,105). Reductions in pain are seen in both single dose
(SMD -0.49; 95%CI -0.64 to -0.34) (6 RCTs, n=757) and multiple doses of massage (SMD -0.53;
95%CI -0.91 to -0.14) (7 RCTs, n=1,031). When analysed for incision type, the beneficial effects ofmassage on postsurgical pain persists for both sternal (SMD -0.68; 95%CI -0.91 to -0.46) (4 RCTs,
n=333) and abdominal incisions (SMD -0.57; 95%CI -1.04 to -0.11) (2 RCTs, n=193).
Cardiac and thoracic surgery
In addition to reducing anxiety, massage reduces pain intensity after cardiac surgery(MD −1.52/10; 95%CI −2.2 to −0.84) (Miozzo 2016 Level I [PRISMA], 10 RCTs, n=409). Different
forms of massage have also been found to have significant beneficial effects on pain post
cardiac surgery: Integrative massage (n=113 [2 sessions]), Swedish massage (n=152 [2 sessions]),
Thai massage (n=74 [one session]) and general massage (n=40 [3 sessions]; n=65 [one session])(Ramesh 2015, Level I [PRISMA], 7 RCTS, n=764). One included RCT showed no effect for generalmassage (n=252 [2 sessions]).
20 to 30 min of healing coach (health care professionals with special training in massage or
touch therapy or massage therapist-administered massage) added to standard analgesia
reduces pain vs standard care alone (MD -0.85/10; 95%CI -1.28 to -0.42) (Boitor 2017 Level I[PRISMA], 7 RCTs, n=1,087); similar results are found in the early period after ICU discharge (MD 0.89/10; 95%CI -1.45 to -0.33) (6 RCTs, n=684). Additionally, 10 to 20 min of massage inconjunction with analgesia administered by a nurse or massage therapist significantly reduces
pain in ICU (MD -0.80/10; 95%CI -1.25 to -0.35) (3 RCTs, n=462), while massage without
analgesia also reduces pain (MD-2.47/10; 95%CI -4.88 to -0.06) (2 RCTs, n=150).

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Labour
Massage reduces pain intensity in first stage labour vs standard care (SMD −0.81; 95%CI −1.06
to −0.56) (6 RCTs, n=362), but not at the second (SMD −0.98; 95%CI −2.23 to 0.26) (2 RCTs, n=124)
or third stage (SMD −1.03/10; 95%CI −2.17 to 0.11) (2 RCTs, n=122) vs standard care (Smith 2018,
Level I [Cochrane], 6 RCTs, n=362). Massage vs a music intervention reduced severe labour pain
(RR 0.40; 95% CI 0.18 to 0.89) (1 RCT, n=101).
An earlier systematic review (including only studies from Iran) found that in labour,
massage reduces labour pain across all phases including: latent (SMD −1.23; 95%CI −1.73 to−0.74) (9 RCTs, n=642), active (SMD −1.59; 95%CI −2.06 to −1.12) (7 RCTs, n=422) and transitional(SMD −1.90; 95%CI −3.09 to −0.71) (6 RCTs, n=362) as well as having an overall effect(SMD −1.52; 95%CI −1.90 to −1.14) (Ranjbaran 2017 Level I [PRISMA], 10 RCTs, n=702) (1 RCT
overlap).
Primary dysmenorrhea
In primary dysmenorrhea, manipulative therapy may reduce pain vs sham (WMD -0.94/10;
95%CI -0.66 to -1.2) (Abaraogu 2017 Level I, 3 RCTs, n=217); however, these studies were
methodologically heterogeneous.
Acute back pain
Manual therapy is also considered with respect to Acute Back Pain in the NICE guidelines NICE
2018 and the older Australian Acute Musculoskeletal Pain Guidelines (Australian Acute
Musculoskeletal Pain Guidelines Group 2003 GL). See also Section 8.7. and 8.8.

KEY MESSAGES
1. Single and multiple doses of massage in the early postoperative period may reduce
pain after surgical procedures, including cardiac surgery (N) (Level I [PRISMA])
2. Massage may decrease pain in the first stage of labour pain compared to standard care(N) (Level I [Cochrane Review])
The following tick box represents conclusions based on clinical experience and expert opinion: The role of manipulative therapy in primary dysmenorrhea is currently unclear (N).

7.5.3 | Warming and cooling interventions
7.5.3.1 | Warming interventions
Dysmenorrhea
In a 4-arm RCT, treatment with heat pads reduced pain vs placebo (unheated pads) (MD
1.8/10; 95%CI 0.9 to 2.7), but ibuprofen plus heat pad was no more effective than ibuprofen
with placebo heat pad (Kannan 2014 Level I 1 RCT: Akin 2001, Level II, n=81, JS 3). Time to noticeable
pain relief was reduced from 2.8 h to 1.5 h with ibuprofen plus heat pad vs ibuprofen withplacebo heat pad.
A subsequent review identified three further studies. Heat therapy interventions including
heat patches (1 study, n=147), hot water (1 study, n=44) and heated red bean pillows (1 study,n=51), improves pain from dysmenorrhoea, however high heterogeneity and a lack of placebo
controls prevent firm conclusions (Igwea 2016 Level III-1 SR, 3 studies, n=242).

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5th Edition | Acute Pain Management: Scientific Evidence7.0 | NONPHARMACOLOGICAL TECHNIQUESLabour pain
Warm packs vs usual care reduce pain intensity in the first stage of labour (SMD −0.59; 95%CI−1.18 to −0.00) (3 RCTs, n=191) and second stage of labour (SMD -1.49; 95%CI −2.85 to −0.13)(2 RCTs, n=128) (Smith 2018 Level I [Cochrane], 14 RCTs, n=1,172). Thermal manual methods resulted
in a reduction in pain intensity vs usual care (MD −1.44/10; 95%CI −2.24 to −0.65) (1 RCT, n=96)
and intermittent hot and cold packs reduced pain in the first phase of labour vs usual care
(MD −1.46/10; 95% CI −2.59 to −0.33) (1 RCT, n=48).
Periocular surgery
Warming the local anaesthetic agent so it is close to body temperature when injected
decreased pain in one of two small RCTs (Gostimir 2019, Level I [PRISMA], 2 RCTs, n=100).
7.5.3.2 | Cooling interventions
All knee surgery
Compression cryotherapy vs cryotherapy alone after any knee surgery improves pain on POD 1(MD -0.94/10; 95%CI -1.63 to -0.26) (7 RCTs, n=420), POD 2 (MD -0.55/10; 95%CI -0.78 to -0.32)(7 RCTs, n=420) and POD 3 (MD -0.46/10; 95%CI -0.87 to -0.05) (2 RCTs, n=100) (Song 2016 Level I[PRISMA], 10 RCTs [2 TKA, 3 arthroscopy, 5 ACL reconstruction], n=662).
Knee Arthroplasty
Cryotherapies reduces pain after TKA (MD -0.51/10; 95%CI -1.00 to -0.02) (8 RCTs, n=1,382)(Tedesco 2017 Level I [PRISMA], 12 RCTs [cryotherapy], n=1,382; Ni 2015 Level I, 13 RCTs [9 TKA, 2 THA,
1 mixed], n=782) (9 RCT overlap). However, when data for POD 1 (7 RCTs, n=529), POD 2 (5 RCTs,
n=422) and POD 3 were considered separately, no effect is seen. Cryotherapy is also not better
than compression therapy (5 RCTs, n=407).
Anterior cruciate ligament (ACL) reconstruction
Cold compress devices improve pain 48 h after ACL surgery vs no therapy (MD -1.41/10; 95%CI-1.66 to -1.17) (2 studies, n=71) (Martimbianco 2014 Level III-1 SR [PRISMA], 10 studies, n=573) (2 RCTs
overlap with Song 2016). There is no effect from cold therapy (3 studies) or cold compression
therapy with cold water vs room temperature water (placebo) (3 studies). Cold compression
therapy vs ice packs reduces pain at 1 wk (1 RCT, n=44) and 6 wk (1 RCT, n=36). Cold compression
devices vs ice packs or no cold therapy reduce the amount of medication taken by patients(6 studies).
A subsequent systematic review of cryotherapy following outpatient ACL surgery shows
superior pain relief in 4 of 8 studies vs no cryotherapy or water at room temperature (Secrist
2016, Level III-1 SR [PRISMA], 10 studies, n unspecified) (8 studies overlap with Martimbianco 2014).
Haemarthrosis of haemophilia
Cryotherapy has been recommended for treatment of pain and swelling in haemarthrosis due
to haemophilia (Rodriguez-Merchan 2018 NR).
Venipuncture
Vapocoolants for pain during IV cannulation vs pooled no or placebo treatments reduce pain
when assessed as a continuous measure (SMD -0.53; 95%CI -0.83 to -0.23) (8 RCTs, n=682) ordichotomised (OR 4.62; 95%CI 1.84 to 11.63) (4 RCTs, n=681) (Zhu 2018 Level I, 11 RCTs, n=1,410).
However, in the paediatric subgroup analysis (2 RCTs, n=172), no effect is seen. A prior metaanalysis also concluded that vapocoolants are superior to pooled no or placebo treatment;
however, with increased discomfort at the time of application (Griffith 2016 Level I [Cochrane],
9 RCTs, n=1,070) (8 RCTs overlap). In contrast, an earlier systematic review including non-RCTs
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461

does not confirm all these findings (Hogan 2014 Level III-I SR [PRISMA], 12 studies, n unspecified)(8 RCTs overlap).
See also Section 10.7.2 for paediatric specific information.
Periocular Surgery
Application of ice for 2 min before injection of local anaesthesia reduced pain ( Gostimir 2019
Level I 1 RCT: Goel 2006 Level II, n=39, JS 2). In a crossover trial, patients received two injections,
one where treatment with ice (for 2 min) occurred prior to unbuffered lidocaine injection vsanother where buffered lidocaine was injected without ice pretreatment; with less pain at thesite of the ice-treated unbuffered injection (Huang 2015 Level III-2, n=60).
Tonsillectomy
Cryotherapy (ice lollipop) over 4 h reduced pain post-tonsillectomy in children (2 to 12 y) at 30
min and 1 h (Keefe 2018 Level I [PRISMA] 1 RCT: Sylvester 2011 Level II, n=87, JS 3). Intraoperative
cryotherapy with a cryotherapy probe (-56°C) (1 RCT) and ice-water cooling (4°C to 10°C)(2 RCTs) reduces post-tonsillectomy pain scores consistently vs no treatment by 21 to 32%(0.9/10 to 1.8/10) (Raggio 2018 Level I [PRISMA], 3 RCTs, n=153).
Dental Surgery
After 3rd molar extraction, cryotherapy is effective at reducing oedema, but mixed results were
found with regard to effect on pain where 5 of 11 studies were positive (Fernandes 2019 Level IV
SR, 11 studies, n=721).
Maxillofacial surgery
Hilotherapy (the application of cold compression at a regulated temperature through a facemask) reduces pain on POD 2 after facial skeletal surgery vs cold compression (MD -2.37/10;
95%CI -3.24 to -1.50) (n=146) and reduces swelling on POD 2 and POD 3, but not POD 28 (Glass
2016 Level I [PRISMA], 6 RCTs, n=286).
Mucositis
Cryotherapy during chemotherapy may have a preventive effect on mucositis see Section
8.9.8.2.
LabourCold packs reduce pain intensity in the first stage of labour (MD −1.43/10; 95%CI −2.56 to−0.30) (Smith 2018 Level I [Cochrane] 1 RCT: Shirvani 2014 Level II, n=64, JS 3).
Puerperium perineal pain
There is only limited evidence to support the effectiveness of local cooling treatments (icepacks, cold gel pads, cold/iced baths) for relieving perineal trauma pain vs various alternatives
or no interventions (East 2012 Level I [Cochrane], 10 RCTs, n=1,825). Ice packs provided superior
analgesia vs no treatment for 24 to 72 h postpartum (RR 0.61; 95%CI 0.41 to 0.91) (1 RCT,
n=208).

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5th Edition | Acute Pain Management: Scientific Evidence7.0 | NONPHARMACOLOGICAL TECHNIQUESKEY MESSAGES
1. Heat packs may reduce labour pain during the first and second stages (N) (Level I[Cochrane Review]).
2. Vapocoolants may reduce the pain of intravenous cannulation in adults but its application
is associated with discomfort (N) (Level I [Cochrane Review]).
3. Cryotherapy may reduce pain after total knee arthroplasty but is not superior tocompression (N) (Level I [PRISMA]).
4. Compression cryotherapy may reduce acute pain and analgesia requirements post
anterior cruciate ligament reconstruction and pain on day one to three post knee surgery(N) (Level I [PRISMA]).
5. Intraoperative cryotherapy may reduce post-tonsillectomy pain (N) (Level I [PRISMA]).
6. Hilotherapy (the application of cold compression at a regulated temperature through aface mask) may reduce pain and swelling after facial skeletal surgery vs cold compression(N) (Level I [PRISMA]).

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8

Specific clinical situations
Section Editor:
Prof Stephan A Schug474

8.1.1 to 1.6 | Postoperative pain
Contributor: Prof Stephan A Schug8.1.7 | Ambulatory or short-stay surgery

8.6.5 | Acute headache
8.6.6 | Acute pain associatedwith neurological disorders

Contributor: Dr Myles Conroy

Contributor: A/Prof Ray Garrick

8.1.8 | Cranial neurosurgery
8.1.9 | Spinal surgery

Contributor: Prof Rob DelcanhoContributors: Dr Charles Kim, Dr Andrew Zacest

8.2 | Acute pain following spinal
cord injury
Contributor: Prof Philip Siddall

8.3 | Acute pain following chest injury
Contributor: Dr Leigh White

8.4 | Acute pain following hip(neck of femur) fracture
Contributor: Dr Chuan-Whei Lee

8.5 | Acute burns injury pain
Contributor: A/Prof Paul Gray

8.6 | Acute medical pain
8.6.1 | Acute abdominal pain
8.6.2 | Herpes zoster-associated pain
Contributor: Dr Frank Buchanan

8.6.3 | Acute cardiac pain
Contributor: Dr A. Reza Feizerfan

8.6.4 | Acute pain associated withhaematological disorders
Contributor: Dr Anna Steer

8.6.7 | Orofacial pain
8.6.8 | Acute pain in patientswith HIV infection
Contributors: A/Prof Catherine
Cherry, Ms Alison Duncan

8.7 | Acute back pain
Contributor: Prof Stephan A Schug

8.8 | Acute musculoskeletal pain
Contributor: Prof Stephan A Schug

8.9 | Acute cancer pain
Contributor: Dr Jeff Kim

8.10 | Acute pain management
in intensive care
Contributor: Dr Benjamin Moran

8.11 | Acute pain management
in emergency departments
Contributor: Prof Tony Celenza

8.12 | Prehospital analgesia
Contributors: Dr Thomas Judd,Dr Dean Bunbury

8.13 | Discharge medication for
acute pain management
Contributor: Dr Christine Huxtable475

8.1 | Postoperative pain
One of the most common sources of acute pain is postoperative pain. A large amount of theevidence presented so far in this document is based on studies of pain relief in the postoperative
setting. However, many of the management principles derived from these studies can be applied
to the management of acute pain in general, as outlined in this and other sections that follow.
The treatment of postoperative pain in specific settings such as day-stay surgery will be
discussed later in this chapter.

8.1.1 | Multimodal postoperative pain management
The concept of multimodal (or “balanced”) analgesia has been advocated as being beneficial forthe management of postoperative pain (Kehlet 1993 NR). This concept suggests that combinationsof analgesics with different modes or sites of action can improve analgesia, reduce opioid
requirements (“opioid-sparing effect”) and thereby reduce adverse effects of opioids in the
postoperative period (Gritsenko 2014 NR). This approach, by reducing the reliance on opioids inthe postoperative setting, also offers opportunities to overcome current concerns about opioid
use in pain management (Savarese 2017 NR). See also Sections 8.13. and 9.7. and for paediatricinformation Section 10.4.5.4.
As outlined in previous chapters, there is Level I evidence to support a large number of
nonopioid analgesics, adjuvants and regional anaesthetic techniques as potential components ofmultimodal analgesia by fulfilling the above criteria: paracetamol, nsNSAIDs and coxibs, local
anaesthetic techniques (local anaesthetic infiltration, peripheral nerve blocks and neuraxial
blocks), systemic local anaesthetics, steroids, ketamine, alpha-2 agonists and alpha-2-delta
ligands (Gabriel 2019 NR; Pitchon 2018 NR; Wick 2017 NR; Rosero 2014 NR).
In this context, depth of general anaesthesia (BIS 30–40 vs 45–60) had no effect on
postoperative pain or opioid requirements (Law 2014 Level II, n=135, JS 4).
Comparative studies of solely opioid-based analgesia with multimodal approaches show
benefits not only with regard to analgesia and patient satisfaction but also for otherpostoperative outcomes:• After total knee joint arthroplasty (TKA), multimodal analgesia (including local
anaesthetic infiltration, nsNSAIDs, tramadol and oxycodone) vs IV PCA
hydromorphone alone resulted in lower pain scores, opioid-sparing, fewer adverse
effects, higher satisfaction scores and earlier achievement of physical therapy
milestones (Lamplot 2014 Level II, n=36, JS 3). For total hip and knee arthroplasty(THA/TKA), adding IV paracetamol to other techniques of analgesia reduces painscores and opioid consumption (Yang 2017 Level I [PRISMA], 4 RCTs, n=865). After
THA/TKA, 85.6% of patients received multimodal analgesia (Memtsoudis 2018 Level
III-2, n=1,318,165). Addition of more modes of analgesia was associated with positiveeffects in a stepwise fashion; for THA patients, more than 2 modes of analgesia vs
opioids only was associated with reduction of respiratory (OR 0.81; 95%CI 0.70 to0.94) and gastrointestinal complications (OR 0.74; 95%CI 0.65 to 0.84), decreased
opioid prescriptions (-18.5%; 95%CI -19.7% to -17.2%) and reduced LOS from median
3 to 2 d (-12.1%; 95%CI -12.8% to -11.5%). NSAIDS and coxibs had the most effecthere. Multimodal analgesia has also been examined in adult OSA patients
undergoing elective THA/TKA (Cozowicz 2019 Level III-2, n=181,182). Assessment of thishigher perioperative risk population demonstrated a step-wise reduction in opioiddose, prescription and PCA use (26.6% in opioid only vs 19.2%, 13.7%, and 7.7%)with increasing modes of multimodal analgesia over 10 y (2006—2016). With
regards to postoperative complications, there were significantly reduced odds for476

5th Edition | Acute Pain Management: Scientific Evidence8.0 | SPECIFIC CLINICAL SITUATIONS

•

•

•

•

•

•

postoperative mechanical ventilation (OR 0.23; 95%CI 0.16 to 0.32) and critical careadmission (OR 0.60; 95%CI 0.48 to 0.75) with the addition of two or more non-opioid
analgesic modes. Of note, the most commonly used components of multimodal
analgesia included paracetamol, coxibs, nsNSAIDs, gabapentin or pregabalin,regional analgesia, ketamine and corticosteroids.
After spinal surgery, the use of multimodal analgesia (paracetamol, NSAIDs,
gabapentin, S-ketamine, dexamethasone, ondansetron and epidural local
anaesthetic infusion or IV PCA morphine) vs historical controls, reduced opioid
consumption, nausea, sedation and dizziness and improved postoperative
mobilisation (Mathiesen 2013 Level III-3, n=85). This was confirmed by a subsequent
RCT in a similar setting (lumbar fusion), where pre- and postoperative multimodal
analgesia (celecoxib, pregabalin, oxycodone CR and paracetamol) with IV PCA
morphine vs IV PCA morphine alone reduced pain and disability (Oswestry Disability
Index) without any difference in adverse effects (Kim 2016 Level II, n=80, JS 3).
After upper extremity orthopaedic surgery, multimodal analgesia (including NSAID
and alpha-2-delta ligand) vs IV PCA opioid alone provided similar quality of analgesia
with reduced incidence of opioid-related complications and greater patientsatisfaction (Lee 2013b Level II, n=61, JS 3).
Introduction of a multimodal protocol for analgesia in laparoscopic sleeve
gastrectomy (preoperative etoricoxib, intraoperative and postoperative
paracetamol with optional postoperative tramadol) vs historic control (previous
standard care) resulted in reduced opioid requirements, reduced adverse effects of
opioids (8.8% vs 33%) with similar analgesic efficacy (Ng 2017 Level III-3, n=158).
Similarly, adding paracetamol to PCEA (thoracic) for open gastrectomy in cancer
patients improved pain control on coughing and reduced PCEA requirements(Kinoshita 2019 Level II, n=120, JS 3).
After cardiac surgery, multimodal analgesia (paracetamol, nsNSAID,
dexamethasone, alpha-2-delta ligand and rescue morphine) vs paracetamol andmorphine resulted in lower pain scores for the first 3 d, reduced PONV and a trend
towards reduced complications (Rafiq 2014 Level II, n=180, JS 3).
In reconstructive pelvic surgery, a multimodal analgesic regimen (preoperative andpostoperative celecoxib, gabapentin, intraoperative and postoperative IV and oral
paracetamol and opioids prn) vs usual care (postoperative ibuprofen and opioidsprn) resulted in reduced opioid requirements in hospital and after discharge (overall
195.5 MME [± 147.2] vs 304.0 MME [ 162.1]; 34.8% vs 10.6% no opioid use after
discharge) with comparable pain relief and no difference in other outcomes ( Reagan2017 Level II, n=138, JS 2).. A multimodal bundle of standardised use of preoperative
paracetamol, postoperative comfort education, simethicone, postoperative gum
chewing, and abdominal binders reduced morphine requirements after Caesarean
section by 61% (Burgess 2019 Level III-1, n=9,313). Furthermore, more women received
less than 20 tablets of oxycodone at discharge (96.7% vs 26.3%).
After rhinoplasty, multimodal analgesia (pregabalin alone and combined withdexamethasone added to IV tramadol and diclofenac IM) vs IV PCA tramadol alone
reduced pain scores, tramadol consumption, rescue opioid use and nausea(Demirhan 2013 Level II, n=60, JS 5).

An additional benefit of a multimodal approach to pain relief after THA/TKA (paracetamol,
pregabalin and celecoxib or ketorolac) was a reduction in postoperative fever incidence (5 vs25%) resulting in fewer patients undergoing tests (1.8 vs 9.8%) (Karam 2014 Level III-3, n=3,901).
A meta-analysis could not identify any RCTs comparing three non-opioids in the setting of
postoperative analgesia after major surgery (Martinez 2017 Level I [NMA], 135 RCTs, n=13,287).
Double combinations with the highest opioid sparing effects over 24 h wereparacetamol/nefopam (-23.9 mg; 95%CI -40 to -7.7), paracetamol/NSAIDs (-22.8 mg; 95%CI -31.5
5th Edition | Acute Pain Management: Scientific Evidence 477

to -14) and an atypical opioid combined with a non-opioid tramadol/metamizole (tramadol beingclassified by the authors as a non-opioid) (-19.8 mg; 95%CI -35.4 to -4.2). In abdominal
hysterectomy, an RCT comparing a triple combination of paracetamol, meloxicam andgabapentin vs the three double combinations was prematurely discontinued for futility, asinterim analysis showed only a minimal chance of showing advantages ( Gilron 2015 Level II, n=87
[terminated], JS 5). In the 8 armed OCTOPUS study, a triple combination of paracetamol, nefopam
and ketoprofen (PCA morphine rescue in all groups) was compared to placebo, the non-opioids
singly and as double combinations (Beloeil 2019 Level II, n=237 [of 1,000 required], JS 5). The study
was discontinued early for logistical and ethical reasons, but showed superiority of the triple
combination over some arms with reduced opioid requirements and pain intensity.
Preemptive or preventive pain psychoeducation is an underutilised component ofmultimodal analgesia despite data showing reduced pain intensity, analgesic use, LOS, return toED, patient anxiety and possibly chronic postsurgical pain ( Horn 2020 Level IV SR, 33 studies,n unspecified).
On the basis of the available evidence, multimodal analgesia regimens are therefore
recommended in the management of postoperative pain, including in the setting of enhanced
recovery after surgery (ERAS) (Dunkman 2018 NR; Beverly 2017a NR) and ambulatory surgery (Kaye2019 NR; Prabhakar 2017 NR). A novel approach to introduce multimodal analgesia into routine
clinical practice are Standardised Clinical Assessment and Management Plans (SCAMPs),
providing an algorithmic approach to standardisation of postoperative analgesic care with theaim of increasing compliance with existing guidelines (Beverly 2017b NR).
Multimodal analgesia is the recommended approach in guidelines for the management of
postoperative pain (Savoia 2010 GL; ANZCA 2013 GL; Chou 2016 GL) including guidelines specificallytargeted at reduction of perioperative opioid use (Wu 2019 GL).

KEY MESSAGES
1. Multimodal analgesia compared to mainly opioid-based analgesia improves pain control
and reduces opioid consumption (“opioid-sparing”) and adverse effects (S) (Level I [NMA]).
The following tick box represents conclusions based on clinical experience and expert
opinion: The concept of multimodal (or “balanced”) analgesia suggests the use of combinationsof analgesics with different mode or site of action (S).

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8.1.2 | Procedure-specific postoperative pain management
In addition to the overall assessment of the efficacy of acute pain management, there is also aneed for information on postoperative pain management that relates to the site of surgery andspecific surgical procedures (Singla 2014 NR; Ward 2014 NR; Kehlet 2005 NR; Rowlingson 2003 NR).
This becomes obvious when considering that even a simple analgesic, like paracetamol, hasdifferent efficacy in different surgical settings; it is significantly less effective after orthopaedic
surgery (RR [of achieving >50% maximal pain relief] 1.87; 95%CI 1.36 to 2.57) than after dental
extraction (RR 3.77; 95%CI 2.80 to 5.07) (Gray 2005 reanalysing Barden 2004b Level I, 43 RCTs
[paracetamol], n unspecified). Although calculation of NNTs requires the pooling of data from atleast 500 patients to be credible (McQuay 2002 NR), pooling of data from different postoperative
pain states may ignore the specific effects of a specific analgesic in a specific postoperative pain
state (Joshi 2013 NR).
Furthermore, different surgical procedures cause different pain states (eg musculoskeletal vsvisceral) of different severity in different locations. On POD 4 after ambulatory surgery,moderate (16.3%) to severe (12.1%) postoperative pain presented with procedurespecific variation; shoulder, anal and dental surgery was associated with the most intense pain
(Vrancken 2018 Level III-2, n=1,123); preoperative pain intensity predicted postoperative pain
intensity, but again related to the procedure performed. Similarly in another study, in addition
to preoperative pain and patient derived expected pain, different types of surgery were thestrongest predictor of moderate to severe pain 4 d after ambulatory surgery ( Stessel 2017
Level III-3, n=1,118). Different surgical procedures influenced the wide range of IV PCA opioid
requirements; open pancreatectomy had the highest (77 mg) and open hysterectomy the lowest
requirements (34 mg) (Lin 2019a Level III-2, n=3,284). The paper presents a table/graph of allprocedures and the respective IV PCA requirements. However, a large cohort study of
postoperative patients reported those with worst pain (NRS > 6/10) on POD 1 included
orthopaedic/trauma procedures on the extremities, while very high pain scores were also
associated with so called "minor" surgery (eg appendectomy, cholecystectomy,
hemorrhoidectomy and tonsillectomy) suggesting insufficient access to analgesia in this group(Gerbershagen 2013 Level III-2, n=50,523).
On the basis of these finding, postoperative pain requires a procedure-specific approach. The
recognition of this need has led to the development of the PROSPECT (PROcedure-SPECificpostoperative pain managemenT) initiative, which aims to provide procedure-specific evidencebased recommendations for the treatment of pain after a wide range of operations ( Kehlet 2007
NR; Lee 2018 NR). Their guidelines can be found at the website of the European Society of Regional
Anaesthesia & Pain Therapy (ESRA) which is supporting the PROSPECT initiative:
https://esraeurope.org/prospect/. The revised methodology underlying this approach isaccessible on the website and has been published (Joshi 2019b NR); it uses an evidence-based
approach including meta-analysis of available procedure-specific data. Surgical factors
contributing to postoperative pain are also considered (eg trocar size in laparoscopiccholecystectomy) (McCloy 2008 Level I, 13 RCTs, n=968).
Procedure-specific evidence for the following operations is currently available at the website
with most of the underlying meta-analyses also published in the peer-reviewed literature;translated PDFs of the recommendations are available in severallanguages (Chinese, French,
German, Japanese, Portuguese and Spanish):• Abdominal hysterectomy;• Caesarean section;• Haemorrhoidectomy (Sammour 2017 Level I [QUOROM], 48 RCTs, n unspecified);• Hernia repair (Joshi 2012 Level I [PRISMA], 79 RCTs, n unspecified);
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•
•
•
•
•
•
•
•
•
•

Laparoscopic cholecystectomy (Barazanchi 2018 Level I [PRISMA], 258 RCTs, n unspecified);
Laparoscopic hysterectomy (Lirk 2019 Level I [PRISMA], 56 RCTs, n unspecified);
Laparoscopic sleeve gastrectomy (Macfater 2019 Level I [PRISMA], 18 RCTs, n unspecified);
Oncological breast surgery (Jacobs 2020 Level I [PRISMA], 9 SRs & 53 RCTs, n unspecified);
Open colorectal surgery;
Radical prostatectomy (Joshi 2015 Level I [PRISMA], 38 RCTs, n unspecified);
Rotator cuff repair surgery (Toma 2019 Level I [PRISMA], 1 SR & 59 RCTs, n unspecified);Thoracotomy (Joshi 2008 Level I, 74 RCTs, n unspecified);
Total hip arthroplasty (Fischer 2005 Level I, 55 RCTs, n unspecified);
Total knee arthroplasty (Fischer 2008 Level I, 112 RCTs, n unspecified).

KEY MESSAGES
1. An analgesic may have different efficacy in different surgical settings (U) (Level I).
2. Different surgical procedures cause different pain states (eg musculoskeletal vs visceral)of different severity in different locations, thereby requiring a procedure-specificapproach (S) (Level III-2).
The following tick box represents conclusions based on clinical experience and expert
opinion: Pooling of data from different postoperative pain states may ignore the specific effects
of a specific analgesic in a specific postoperative pain state (U).

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8.1.3 | Acute rehabilitation after surgery, “fast-track” surgery and enhanced
recovery after surgery (ERAS)
The concept of fast-track surgery is underpinned by a multimodal approach to the perioperative
care of the patient (Nanavati 2014 NR; Kehlet 2008 NR; Wilmore 2001 NR). The approach uses
combinations of perioperative interventions to facilitate the postoperative recovery involving a
multidisciplinary team approach of surgeons, anaesthetists, nutritionists, physiotherapists,
nurses and pharmacists. Management of the surgical stress response, perioperative fluids andpain are key factors of this approach (Kehlet 2011 NR).
Evidence-based approaches following these principles have resulted in a significantly reduced
hospital stay for many operations without increasing, and often reducing, complications andreadmissions. Evidence-based detailed protocols for enhanced recovery after surgery (ERAS) are
published for multiple operations on the ERAS© Society’s website: https://erassociety.org.
For example, application of an ERAS protocol to colorectal surgery results in reduced LOS(WMD -2.55 d; 95%CI -3.24 to -1.85) and complication rates (RR 0.53; 95%CI 0.44 to 0.64)(Varadhan 2010 Level I, 6 RCTs, n=452). However, it is of note that the number of individual ERAS
elements employed ranged from 4 to 12, with a mean of 9 elements targeting perioperative care.
The use of multiple components in enhanced recovery confirms previous findings that provisionof good analgesia alone may have only minimal effects on speed and quality of postoperative
recovery (Kehlet 1997 NR). This is not surprising given the numerous triggers of the injury
response, of which acute pain is only one. This is confirmed in a systematic review of the role ofpain management in recovery from colorectal surgery following ERAS protocols (Chemali 2017
Level I [PRISMA], 21 RCTs, n=1,261). It suggests that the modality for postoperative analgesia has no
impact on the hospital LOS, pain, the time to the first bowel motion or nausea, although data areof limited quality. The authors suggest that as long as pain is reasonably well controlled, choiceof the technique of pain management is of minor relevance.
Even thoracic epidural analgesia (TEA) use, with its superior analgesic effect and faster returnof bowel function, does not shorten LOS or improve morbidity and mortality vs alternative
analgesic techniques when used within an ERAS protocol for open abdominal surgery (Hughes
2014 Level I [PRISMA], 7 RCTs, n=378). This finding highlights the importance of other elements ofthese protocols. Similarly after laparoscopic colectomy, TEA significantly improves time to firstbowel motion (WMD -0.62 d; 95%CI -1.11 to -0.12) and pain scores (WMD -1.23/10; 95%CI -2.4
to -0.07) but does not reduce LOS (WMD -0.47 d; 95%CI; -1.55 to 0.61) (Khan 2013 Level I [PRISMA],
6 RCTs, n=340).
The importance of the various elements of enhanced recovery protocols is welldemonstrated in an analysis of the ERAS register for elective primary colorectal cancer resection(ERAS Compliance Group 2015 Level IV, n=2,352). Elements associated with shorter LOS werelaparoscopic surgery (OR 0.83), increasing ERAS protocol compliance (OR 0.88), preoperative
carbohydrate and fluid loading (OR 0.89) and total IV anaesthesia (OR 0.86). Here, epidural
analgesia increased LOS (OR 1.07). While, risk of complications was reduced with restrictive
perioperative IV fluids (OR 0.35), laparoscopic surgery (OR 0.68) and increasing ERAS protocol
compliance (OR 0.69).
Other analgesic factors that reduced LOS after elective colorectal surgery including avoidanceof oral opioids in the postoperative period (OR 0.39; 95%CI 0.18 to 0.84) and the use of shorter
duration of epidural analgesia (OR 0.44; 95%CI 0.12 to 0.94) (Ahmed 2010 Level IV, n=231). Opioidsparing analgesic techniques reduced postoperative ileus (Barletta 2011 Level IV, n=279; Barletta
2012 NR).
Overall, independent predictors of early recovery after open and laparoscopic colorectal
surgery were enforced advancement of oral intake (normal diet at POD 1 to 3) and early
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mobilisation (Vlug 2012 Level III-2, n=400). Effective analgesia facilitates these elements of ERAS
protocols enabling early enteral feeding and mobilisation/ambulation. It follows that provisionof analgesia by appropriate techniques remains an important component of these protocols(Kehlet 2011 NR; White 2007 NR; Kehlet 2003 NR). Therefore evidence-based and procedure-specificguidelines for pain management need to be incorporated in ERAS protocols for various
operations; goals are not specifically low pain scores, but improved functionality and improved
ambulation (Joshi 2019a NR).
In comparison to conventional care after breast reconstruction, following an ERAS pathway
does not only reduce LOS, but also pain severity and reliance on opioid analgesia as measured
by shortened IV PCA usage and reduced IV, oral and total opioid requirements ( Tan 2019
Level III-2 SR, 10 studies, n=1,838). In an ambulatory setting, implementation of an ERAS protocol
for mastectomy and breast reconstruction included multimodal analgesia (preoperative
paracetamol, gabapentin; regional anaesthesia [PECS type 1 and 2 or PVB] and intraoperative
dexamethasone and ondansetron) (Simpson 2019a Level III-3, n=437). Compared to historicalcontrols prior to implementation of the ERAS protocol, patients in the ERAS group had lower
highest pain scores (median 4/10 [IQR 2,6] vs 6/10 [IQR 4,7]), lower total opioid consumption inoral morphine equivalents (mean 111.4 mg [SD 46.0) vs 163.8 mg [SD 73.2]) and reduced PONV
incidence (28% vs 50%).

KEY MESSAGES
1. Adherence to multimodal enhanced recovery protocols after surgery protocols reduces
hospital length of stay, complication rates (S) (Level I), postoperative pain severity andopioid requirements (N) (Level III-2 SR).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Provision of appropriate analgesia is only one of several elements of enhanced
recovery after surgery protocols (S).
 Analgesic techniques, which permit early mobilisation and early enteral feeding, inparticular those that are opioid-sparing, may contribute to early recovery after surgery
protocols (S).

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8.1.4 | Risks of acute postoperative neuropathic pain
Neuropathic pain has been redefined as “pain caused by a lesion or disease of the somatosensory
nervous system” (Jensen 2011 NR). Although neuropathic pain is often considered a chronic pain
state, it can occur acutely. Acute causes of neuropathic pain can be iatrogenic, traumatic,
inflammatory or infective (Gray 2008a NR). Nerve injury is a risk in many surgical procedures andmay present as acute neuropathic pain postoperatively.
Screening questionnaires for neuropathic pain such as DN4, LANSS or painDETECT are widelyused in the acute setting, but are only validated for chronic neuropathic pain ( Schnabel 2018 NR).
Therefore there is no diagnostic standard for acute neuropathic pain and an attempt has been
made to develop diagnostic criteria in a three-step Delphi process among pain specialists (Searle2012 GL). Besides the usual descriptors of neuropathic pain, the items “difficult to manage pain”,“poor response to opioids” and “good response to anti-neuropathics” were suggested.
The incidence of acute neuropathic pain has been reported as 1 to 3%, based on patientsreferred to an APS, primarily after surgery or trauma (Hayes 2002 Level IV, n=4,888). The majorityof these patients had persistent pain at 12 mth, suggesting that acute neuropathic pain is a risk
factor for chronic pain. These qualitative results were confirmed subsequently (Beloeil 2017
Level III-2, n=593). Using a screening tool (DN-4), 5.6% (95% CI 3.6 to 8.3) screened positive on the
day of surgery and 12.9% (95%CI 9.7 to 16.7) on POD 1. At phone follow-up 2 mth postsurgery,
33.3% of patients screened positively; acute positive screening was a risk factor for later positive
screening (OR 4.2; 95%CI 2.2 to 8.1). Similarly, immediately after thoracotomy or video assisted
thoracic surgery, 8% of patients scored positively on another screening tool for neuropathic pain
(LANSS) and 22% 3 mth later; again acute positive was a risk factor for chronic positive results(RR 3.5; 95%CI 1.7 to 7.2) (Searle 2009 Level III-2, n=100).
The role of acute neuropathic pain as a component of postoperative pain is possibly
underestimated; after sternotomy, 50% of patients had dysaesthesia in the early postoperative
period, which was closely associated with severity of postoperative pain ( Alston 2005 Level IV,n=50). After cancer surgery, a prospective study using the painDETECT screening tool identified
acute neuropathic pain in 10% of cases in the first week postoperatively (Jain 2014 Level IV, n=300).
In a general surgical population, the incidence was 3 to 4.2% (Sadler 2013 Level IV, n=165). Similarly,
a high incidence of acute neuropathic pain in the lower limbs with lumbosacral plexus injury after
pelvic trauma has been reported (Chiodo 2007 Level IV, n=78). In cohort studies, 6 to 13% of
postoperative patients screened positive for acute neuropathic pain ( Searle 2009 Level III-2,
n=100).
Management of acute neuropathic pain is primarily based on extrapolation of data from thechronic neuropathic pain setting (see Sections 4.6 to 4.10). However, selection of a preferredtreatment in the acute setting may be based on a faster onset of effect; tramadol, opioids andalpha-2-delta ligands are suggested (Macintyre 2015 NR; Dworkin 2010 GL). In two small series ofacute neuropathic pain due to SCI, all patients responded positively to IV ketamine followed byoral ketamine (Kim 2013a Level IV, n=13) and salmon calcitonin (Humble 2011 Level IV, n=3).
There is some evidence that specific early analgesic interventions may reduce thedevelopment of chronic pain (often neuropathic pain) after some operations (eg thoracotomy,
amputation). For more details, see Sections 1.4, 1.5, 8.1.5 and 8.1.6.

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KEY MESSAGES
1. Positive screening for acute postoperative neuropathic pain is a risk factor for positive
screening of chronic postsurgical neuropathic pain (N) (Level III-2).
2. Acute neuropathic pain occurs after trauma and surgery (S) (Level IV).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Treatment of acute neuropathic pain should follow guidelines for chronic neuropathic
pain; ketamine, opioids (including tramadol and tapentadol in particular) and alpha-2delta ligands may offer faster onset of effect than other treatment options (U).

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8.1.5 | Acute postamputation pain syndromes
Following amputation of a limb, and also breast, tongue, teeth, genitalia, the eye and even innerorgans such as the rectum, or a deafferentation injury such as brachial plexus avulsion ( Ahmed2014 Level IV, n=80; Boas 1993 Level IV, n=33; Bates 1991 Level IV, n=30; Andreotti 2014 NR), a numberof phenomena can develop which require differentiation:• Residual limb pain (stump pain) is pain localised to the site of amputation. It can be acute(usually nociceptive) or chronic (usually neuropathic) and is most common in theimmediate postoperative period (Jensen 1985 Level IV, n=58; Nikolajsen 2001 NR). The overall
incidence of residual limb pain is uncertain but the risk of early stump pain is increasedby the presence of severe preamputation pain (Nikolajsen 1997 Level IV, n=56).
• Phantom sensation is defined as any sensory perception of the missing body part with theexclusion of pain. Almost all patients who have undergone amputation experiencephantom sensations (Jensen 1983 Level IV, n=58). These sensations range from a vague
awareness of the presence of the missing body part via associated paraesthesia, tocomplete sensation including size, shape, position, temperature and movement.
• Phantom limb pain is defined as any noxious sensory phenomenon in the missing bodypart. The estimated incidence of phantom limb pain is 30–85% after limb amputation andusually occurs in the distal portion of the missing limb (Jensen 1985 Level IV, n=58; Nikolajsen
2001 NR; Perkins 2000 NR). Pain may be early, 75% of patients will report phantom pain
within the first few days after amputation (Nikolajsen 1997 Level IV, n=56), or delayed in
onset. The pain is typically intermittent and diminishes with time after amputation.
Factors that may be predictive of postamputation phantom pain are the severity of
preamputation pain, the degree of postoperative stump pain, and chemotherapy orradiotherapy (see also Sections 1.4. and 1.5.). If preamputation pain was present,
phantom pain might resemble that pain in character and localisation (Katz 1990 Level IV,n=68). The intensity of preamputation pain and acute postoperative pain were strong
predictors of the intensity of chronic pain after amputation ( Hanley 2007 Level III-3, n=57).
Preoperative passive coping strategies, in particular catastrophising, were other strong
predictors of phantom limb pain 6 mth later (Richardson 2007 Level III-3, n=59). Reductionof chronic phantom limb pain intensity by peripheral nerve blocks suggests that afferent
input from the periphery plays a role in maintaining phantom limb pain ( Buch 2019 Level II
EH, n=12 [crossover], JS 5).
There is a strong correlation between phantom limb and residual limb or site pain, and they
may be inter-related (Kooijman 2000 Level IV, n=124; Jensen 1983 Level IV, n=58). All three of theabove phenomena can coexist (Nikolajsen 1997 Level IV, n=56).
A survey identified the high incidence of these pain syndromes after amputation; only 14.8%
were pain-free, 74.5% had phantom limb pain, 45.2% residual limb pain and 35.5% a combinationof both (Kern 2009 Level IV, n=537).
Phantom breast pain has also been described; however, the incidence was low in the range
of 7% at 6 wk and 1% at 2 y (Dijkstra 2007 Level III-3, n=82). Phantom sensations are more common;
reported in 19% of patients more than 5 y after surgery (Peuckmann 2009 Level IV, n=2,000).
Predictive factors of phantom limb pain were longstanding preoperative chronic pain,
subacute postoperative pain as well as psychological factors (depression and anxiety) ( Larbig 2019
Level IV, n=52). Preoperative state anxiety is a risk factor for acute residual and phantom limb
pain (Raichle 2015 Level IV, n=69).

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8.1.5.1 | Prevention of phantom limb pain
Evidence for the benefit of epidural analgesia in the prevention of all phantom limb pain isinconclusive (Halbert 2002 Level III-2 SR, 3 studies [epidural], n=106). However, perioperative (pre,intra and postoperative) epidural analgesia reduced the incidence of severe phantom limb pain
(NNT 5.8; 95%CI 3.2 to 28.6) (Gehling 2003 Level III-2 SR, 9 studies, n=836). In a subsequentsystematic review, chronic pain is reduced by epidural analgesia at 6 mth in 3 of 7 studies,
however with poor study quality (von Plato 2018 Level IV SR [PRISMA], 9 RCTs & 10 studies, n=949).
Epidurally administered calcitonin reduced the incidence of chronic phantom limb pain,
allodynia and hyperalgesia at 6 and 12 mth in diabetic patients undergoing lower limb
amputation (Yousef 2017 Level II, n=60, JS 5).
In a small observational study, the overall incidence of long term phantom limb pain was
similar in regional analgesia recipients given IV ketamine (bolus dose followed by an infusion,
started prior to skin incision and continued for 72 h) vs no ketamine; however the incidence ofsevere phantom limb pain was reduced in the ketamine group ( Dertwinkel 2002 Level III-3, n=28).
An RCT was inadequately powered to show a difference with IV ketamine vs controls in theincidence of phantom limb pain at 6 mth after amputation (47% vs 71%; p=0.28) (Hayes 2004
Level II, n=45, JS 4). Perioperative ketamine/bupivacaine given by the epidural route showed no
preventive effect vs epidural saline/bupivacaine (Wilson 2008 Level II, n=53, JS 5).
Perioperative gabapentin was ineffective in reducing incidence and severity of phantom limb
pain vs placebo (Nikolajsen 2006 Level II, n=46, JS 5). Valproic acid for the duration of the hospital
stay after amputation had no preventive effect on phantom limb pain vs placebo (Buchheit 2019b
Level II, n=128, JS 5).
Infusions of local anaesthetics via peripheral nerve sheath catheters, usually inserted by thesurgeon at the time of amputation, show no benefit in preventing phantom pain or residual limb
pain (McCormick 2014 Level I, 2 RCTs [perineural], n=151; Bosanquet 2015 Level III-2 SR [PRISMA], 2 RCTs
& 5 studies, n=416; von Plato 2018 Level IV SR [PRISMA], 2 RCTs & 8 studies [CPNB], n=949) (2 RCTs overlap[between all 3 SR] & 5 studies overlap Bosanquet 2015 with von Plato 2018). In the latter systematic
review, acute postoperative opioid requirements are reduced (SMD -0.59; 95%CI -1.10 to -0.07)
without any other positive outcomes.
Common peroneal nerve to tibial nerve coaptation and collagen nerve wrapping vs traction
neurectomy only for transfemoral amputation resulted in less neuroma formation and phantom
limb pain respectively at 2 mth (0% vs 36.3% and 0% vs 54.5%) and at 6 mth (0% vs 54.5% and
0% vs 63.6%) (Economides 2016 Level III-2, n=17). Furthermore, pain scores at 6 mth were lower(0.75/10 vs 5.6/10) and more patients were walking with a prosthesis (67% vs 9%).
8.1.5.2 | Therapy for phantom limb pain
A survey in 1980 identified over 50 different therapies used for the treatment of phantom limb
pain (Sherman 1980 NR), suggesting limited evidence for effective treatments. Not a lot ofprogress has been made since then (Urits 2019 NR; Collins 2018 NR).
Pharmacological treatment
With regard to pharmacological treatment, most conclusions are based on studies limited bytheir small sample size (Alviar 2016 Level III-1 SR [Cochrane], 14 studies, n=269). Oral and IV morphine
are effective in the short term (2 RCTs, n=43) as are the NMDA-antagonists ketamine (2 RCTs) anddextromethorphan (1 RCT). Gabapentin also has an analgesic effect (MD -1.16/10; 95%CI -1.94
to -0.38) (2 RCTs, n=43). An earlier meta-analysis of gabapentin specifically in this setting included
a third RCT that showed no benefit (Nikolajsen 2006 Level II, n=46, JS 5) which therefore weakens
this conclusion (Abbass 2012 Level I, 3 RCTs, n=89).

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Amitriptyline may be ineffective in acute phantom limb pain management (1 RCT, n=39) as
well as botulinum toxin A (1 RCT, n=14) (Alviar 2016 Level III-1 SR [Cochrane], 14 studies, n=269).
For memantine no effect is shown in the overarching systematic review ( 4 RCTs and 2 studies,n=81) (Alviar 2016 Level III-1 SR [Cochrane], 14 studies, n=269). Although an overlapping memantine
specific systematic review reports use immediately after amputation reduces phantom limb pain
(1 RCT, n=19; 3 studies, n=5), but lacks efficacy in established chronic phantom limb pain (4 RCTs,n=75) (Loy 2016 Level IV SR [PRISMA], 5 RCTs & 3 studies, n=99) (4 RCTs overlap).
In acute phantom limb pain, IV (and likely SC) salmon calcitonin (within 7 d of amputation)
was more effective than placebo (Alviar 2016 Level III-1 SR [Cochrane], 1 RCT: Jaeger 1992 Level II,
n=21 [cross over], JS 3; Bornemann-Cimenti 2017 CR; Turek 2012 CR). However, it was not effective forchronic phantom limb pain (Alviar 2016 Level III-1 SR [Cochrane], 1 RCT: Eichenberger 2008 Level II,
n=20 [cross over], JS 5).
Systemic lignocaine (1 RCT, n=31) may be ineffective, while contralateral myofascial injectionof bupivacaine (administered once) may reduced phantom limb pain in a very small study (1 RCT,
n=8 [cross-over]) (Alviar 2016 Level III-1 SR [Cochrane], 14 studies, n=269).
A subsequent systematic review reports similar results in a less thorough way ( McCormick
2014 Level III-1 SR, 27 RCTs & 1 study, n=807 [& multiple CRs]). With regard to morphine an additional
RCT (n=12) confirms long term benefits (with a slow-release preparation). An RCT excluded fromthe Cochrane review above due to its complex study design is incorrectly interpreted by thissystematic review; the RCT shows that amitriptyline as well as tramadol provided good controlof phantom limb pain (Wilder-Smith 2005 Level II, n=94 [cross-over], JS 4).
Neurostimulation
Neurostimulation has some effect in case series for the treatment of phantom limb pain in theform of spinal cord (McAuley 2013 Level IV, n=12) and peripheral nerve stimulation (Rauck 2014
Level IV, n=16). Percutaneous peripheral nerve stimulation resulted in more patients achieving≥50% reduction in neuropathic postamputation pain after 4 weeks vs placebo (58% vs 14%)
(Gilmore 2019 Level II, n=28, JS 5). Transcranial magnetic stimulation is also reviewed for treatmentof phantom limb pain and non-painful phantom sensations (Nardone 2019 Level IV SR, 18 studies,n unspecified). However, a systematic review concludes that there /are currently no robust andreliable data on efficacy and safety of any neurostimulation in the setting of postamputation pain
(Corbett 2018 Level IV SR, 7 RCTs & 69 studies, n unspecified); spinal cord stimulation specificallyshows mixed results with some weak evidence for benefit (Aiyer 2017 Level III-3 [PRISMA],
12 studies, n=115)..
Surgery
Targeted muscle reinnervation, originally developed to improve prosthetic tolerance andbioprosthetic outcomes, has been used for the treatment of residual and phantom limb pain
(Bowen 2017 NR). It may even have preventive effects on both types of pain if performed at thetime of amputation (Valerio 2019 Level III-2, n=489).
Nonpharmacological treatment
A systematic review of RCTs excluded low quality RCTs ( Batsford 2017 Level I [PRISMA], 12 RCTs,
n=135). The 5 high to moderate quality RCTs show:• Inconclusive evidence for an effect on phantom limb pain by electromagnetically shielding
limb liner (2 RCTs, n=91);• Graded motor imagery to reduce phantom limb pain and improve function at 6 mth(1 RCT, n=9);• A single session of mirror therapy to be ineffective (1 RCT, n=15);• Hypnosis to reduce phantom limb pain in the short-term vs waitlist control (1 RCT, n=20).
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However, nonpharmacological treatment options for phantom limb pain based on conceptsof cortical reorganisation are widely discussed (Aternali 2019 NR; Andoh 2018 NR). All studies ofmirror therapy, motor imagery, and virtual feedback show an effect on intensity of phantom limb
pain in amputees; however the evidence is weak, as the studies included are of limited quality(Herrador Colmenero 2018 Level III-3 SR [PRISMA], 6 RCTs & 6 studies, n in range of 5 to 41) (2 RCTs overlap
with Batsford 2017). Mirror therapy specifically shows a short-term beneficial effect in 3/4 RCTs
vs controls and similar effects to TENS in 1 RCT and the authors regard the evidence as weak andinsufficient to support its current use as a “first-intention” treatment for phantom limb (Barbin
2016 Level IV SR [PRISMA], 5 RCTS & 15 studies, n=258). An RCT published subsequent to thesystematic review showed that graded motor imagery for 6 wk was superior to routine
physiotherapy in reducing intensity of phantom limb pain and interference with function(Limakatso 2019 Level II, n=21, JS 3).
These findings are supported by even weaker evidence in the form of case reports excluded
from the systematic review above. Maladaptive changes in cortical organisation were reversed
during mirror treatment, which over 4 wk resulted in an average decrease of phantom limb pain
intensity of 27% (Foell 2014 Level IV, n=13); mirror therapy was also effective if self-administeredat the home of patients (Darnall 2012 Level IV, n=40). Use of a hand prosthesis with somatosensory
feedback on grip strength reduced phantom limb pain ( Dietrich 2012 Level IV, n=8). Illusory touch
was another effective approach in this context (Schmalzl 2013 Level IV, n=6).
A technique not included in the systematic review is sensory discrimination training, which was
associated with reduced phantom limb pain and cortical reorganisation (Flor 2001 Level II, n=10, JS 2).
There are only case series and reports describing a beneficial effect on phantom limb pain byuse of virtual or augmented reality treatments (Dunn 2017a Level IV SR, 8 studies, n=45).
A systematic review of TENS in the treatment of phantom limb pain found no studies ( Johnson
2015 Level I [Cochrane], 0 RCTs, n=0). However, a subsequent RCT of TENS vs mirror therapy foundboth were equally effective at reducing pain scores from baseline (Barbin 2016 Level I [PRISMA],
1 RCT: Tilak 2016 Level II, n=25, JS 3).

KEY MESSAGES
1. Morphine, gabapentin, ketamine and dextromethorphan reduce phantom limb pain
compared to placebo (U) (Level I [Cochrane Review]).
2. Calcitonin reduces phantom limb pain in the acute (<7 days post amputation) but not thechronic setting (U) (Level I [Cochrane Review]).
3. Continuous regional block via nerve sheath catheters provides postoperative analgesia
after amputation but has no preventive effect on phantom limb pain (U) (Level I).
4. Treatments aiming at cortical reorganisation such as mirror therapy (W) (Level IV SR),sensory discrimination training and motor imagery may reduce chronic phantom limb
pain (W) (Level III-2 SR).
5. Perioperative epidural analgesia reduces the incidence of severe phantom limb pain (U)(Level III-2 SR).
6. Anxiety may be a predictor of phantom limb pain (N) (Level IV).
The following tick box represents conclusions based on clinical experience and expert opinion: Perioperative ketamine may prevent severe phantom limb pain (U).

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8.1.6 | Other postoperative pain syndromes
Increasing evidence for the development of postoperative chronic pain syndromes has led to themore detailed study of some of them. In the latest revised version of the International
Classification of Diseases (ICD-11), accepted by the WHO, “chronic postsurgical andposttraumatic pain” is a new classification (Schug 2019 GL); a range of postsurgical pain
syndromes are listed (eg chronic pain after thoracotomy, breast surgery, herniotomy,
hysterectomy).
The progression from acute to chronic pain and specific early analgesic interventions to
reduce the incidence of chronic pain after some operations are discussed in Sections 1.4 and 1.5.
8.1.6.1 | Post-thoracotomy pain syndrome
Post-thoracotomy pain syndrome is one of the most common chronic pain states. The incidenceof chronic pain after thoracotomy was 57% at 3 mth (95%CI 51 to 64) (17 studies, n=1,439) and
47% at 6 mth (95%CI 39 to 56) (15 studies, n=1,354) (Bayman 2014 Level IV SR, 17 studies, n=1,439).
The average severity of pain at these time points was respectively 30/100 (95%CI 26 to 35) and
32/100 (95%CI 17 to 46). Quality of life (QoL) was reduced in the SF-36 domains of physicalfunctioning, bodily pain and vitality (Kinney 2012 Level IV, n=110).
Pathophysiology
Post-thoracotomy pain syndrome is thought to be caused primarily by trauma to intercostal
nerves and most patients relate their pain directly to the site of surgery (Karmakar 2004 NR).
Neurophysiological assessments (QST) have revealed that patients with post-thoracotomy pain,
but also pain-free patients after thoracotomy, show increased thresholds suggesting nerve injury
in both groups (Wildgaard 2009 NR). However, only the patients in pain show increased sensitivity
to heat and cold and hyperaesthesia; this suggests that nerve injury by itself is not a predictor
for post-thoractomy pain syndrome and other factors need to be present. Increased or
decreased sensitivity and allodynia were reported more by patients with chronic postthoracotomy pain at 6 and 12 mth; between the 6 and 12 mth assessments, pain resolved insome patients but developed in others (Hetmann 2017 Level IV, n=170). Furthermore, sensory
dysfunction on the nonoperated side was found in patients with post-thoracotomy pain, while
such “mirror-image sensory dysfunction” was not accompanied by mirror pain (Werner 2013 Level
IV, n=28). However, myofascial pain syndromes as a consequence of thoracotomy have also been
described (Hamada 2000 Level IV, n=27).
Predictive factors
As with other postsurgical pain syndromes, poorly controlled acute postoperative pain was astrong predictor of chronic post-thoracotomy pain (Niraj 2017 Level IV, n=504). Other risk factors
were diagnosis of cancer and preceding chronic pain (Shanthanna 2016 Level III-3, n=106). Similarfindings of chronic preoperative and severe acute postoperative pain were confirmed in otherstudies (Kampe 2017 Level III-2, n=174; Wang 2017a Level III-2, n=298). A further study identified
preoperative pain as the major predictor of chronic pain (OR 6.97; 95%CI 2.40 to 20.21) whilefinding dispositional optimism was a protective factor (OR 0.36; 95%CI 0.14 to 0.96) ( Hetmann2015 Level IV, n=170). Surgical approach is relevant where video-assisted thoracoscopic surgery(VATS) vs open thoracic surgery has reduced risk of post-thoracotomy pain (adjusted OR 0.33;
95%CI 0.13 to 0.86) and neuropathic pain (adjusted OR 0.18; 95%CI 0.04 to 0.85), but VATS still
carries a significant risk (35% incidence) (Shanthanna 2016 Level III-3, n=106); this was confirmed inanother study (VATS 13.3% vs thoracotomy 32.2%) (Wang 2017a Level III-2, n=298).

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Preventive strategies
Following open thoracotomy (7 RCTs, n=499), epidural anaesthesia reduces the incidence of CPSP
three to 18 mth following surgery vs systemic analgesia (OR 0.52; 95%CI 0.32 to 0.84) (NNT 7)(Weinstein 2018 Level I [Cochrane], 63 RCTs, n=3,027). A subsequent RCT is in line with these results(Khoronenko 2018 Level II, n=300, JS 3), while a single bolus perioperative PVB had no protective
effect (Li 2018b Level II, n=56, JS 5).
Cryoanalgesia provides pain relief superior to other techniques only in 6 of 12 RCTs in theimmediate postoperative period but increased the incidence of post-thoracotomy pain in 4 of
4 RCTs evaluating this outcome (Khanbhai 2014 Level I, 12 RCTs, n unspecified).
Magnesium (IV bolus and 24 h postoperative infusion) may have a preventive effect onchronic neuropathic pain after thoracotomy (Ghezel-Ahmadi 2019 Level III-2, n=100).
Treatment
Detailed reviews of treatments for acute and chronic pain after thoracotomy have been
published (Doan 2014 NR; Romero 2013 NR).
8.1.6.2 | Post-mastectomy pain syndrome
Chronic pain after mastectomy is common (Kokosis 2019 NR). A consensus document on
suggested diagnostic criteria has been published suggesting the following: “Postmastectomy
pain syndrome is pain that occurs after any breast surgery; is of at least moderate severity;
possesses neuropathic qualities; is located in the ipsilateral breast/chest wall, axilla, and/or arm;lasts at least 6 months; occurs at least 50% of the time; and may be exacerbated by movementsof the shoulder girdle.” (Waltho 2016 NR).
In epidemiological studies, an overall prevalence of 29.8% has been found ( Wang 2018cLevel IV SR, 30 studies [postmastectomy], n=3,746). In this context, it is of interest that the same
systematic review found an incidence of chronic pain after radiotherapy of 27.3% ( Wang 2018cLevel IV SR, 41 studies, n=15,019).
Phantom breast pain has also been described; however, the incidence was low in the range
of 7% at 6 wk and 1% at 2 y (Dijkstra 2007 Level III-3, n=82). Phantom sensations are more common;
reported in 19% of patients >5 y after surgery (Peuckmann 2009 Level IV, n=2,000). Postmastectomy
pain syndrome has a negative effect on many domains of quality of life ( Meijuan 2013 Level IV,
n=225).
Pathophysiology
Sensory testing (thermal thresholds, cold allodynia and temporal summation of repetitive
stimulation) showed that postmastectomy pain is often a neuropathic pain condition ( Vilholm
2009 Level III‐2, n=82); in line with this, 64% of patients after mastectomy describe sensory
disturbances with an increased risk of chronic pain (Meijuan 2013 Level IV, n=225).
Predictive factors
Significant predictors for the development of postmastectomy chronic pain were younger age(Meijuan 2013 Level IV, n=225) and radiotherapy (Henderson 2014 Level III-2, n=272; Peuckmann 2009
Level IV, n=2,000). Other risk factors were higher postoperative pain scores and inclusion of major
reconstructive surgery (Chang 2009 Level IV). Psychosocial factors including catastrophising,
somatisation, anxiety (OR 1.63; 95% CI 1.23 to 2.40) (Nishimura 2017 Level IV, n=64) and sleep
disturbance were significant predictors (Belfer 2013 Level IV, n=611). Type of surgery, axillary nodedissection, surgical complication, recurrence, tumour size and, contrary to above findings,
radiation and chemotherapy were not significantly associated with postmastectomy chronic
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postmastectomy pain vs mastectomy alone (Henderson 2014 Level III-2, n=272). In contrast, a
subsequent study (prevalence of postmastectomy pain 57.3%) identified the risk factors of
postdischarge chemotherapy (OR 2.52; 95%CI 1.13 to 5.82) and postdischarge radiation (OR 3.39;
95%CI 1.24 to 10.41), while reconfirming the importance of severe acute pain (OR 5.39; 95%CI
2.03 to 15.54) and even moderate acute pain (OR 5.31; 95%CI 1.99 to 15.30) (Habib 2019 Level IV,
n=124).
Preventive strategies
PVB reduces postmastectomy pain syndrome at 3 to 12 mth vs systemic analgesia (OR 0.43;
95%CI 0.28 to 0.68) (NNT 5) (Weinstein 2018 Level I [Cochrane], 18 RCTs [breast surgery], n=1,297). A
subsequent RCT has confirmed these findings of reduced chronic postmastectomy pain with PVB
use at 3 mth (OR 0.51; 95%CI 0.28 to 0.94) and at 6 mth (OR 0.48; 95%CI 0.25 to 0.94) (Qian 2019
Level II, n=184, JS 5).
Lidocaine IV infusion vs placebo reduces the risk of chronic postmastectomy pain (OR 0.29;
95%CI 0.18 to 0.48) (Bailey 2018 Level I [PRISMA], 6 RCTs, n=420).
Following mastectomy, 10 d treatment with venlafaxine commencing preoperatively was
associated with significantly lower burning and stabbing pain after 6 mth (Amr 2010 Level II, n=150,
JS=3). A 4 wk course of memantine (5-20 mg/d;started 2 wk before surgery) reduced pain
intensity,neuropathic analgesia requirements and improved emotional state at 3 mth vs placebo(Morel 2016 Level II, n=43, JS 5).
Perioperative use of gabapentin or mexiletine after mastectomy reduced the incidence ofneuropathic pain at 6 mth postoperatively, from 25% in the placebo to 5% in both treatmentgroups (Fassoulaki 2002 Level II, n=75, JS 4). Similar protective results were reported by the samegroup by the use of a eutectic mixture of local anaesthetics alone ( Fassoulaki 2000 Level II, n=46,
JS 4) or in combination with gabapentin (Fassoulaki 2005 Level II, n=50, JS 5).
Treatment
For treatment of chronic postmastectomy pain, amitriptyline (1 RCT, n=15 [crossover]), venlafaxine(1 RCT, n=13 [crossover]), topical capsaicin (0.075%) (1 RCT, n=23) and autologous fat grafting into
the scar area (2 studies [Level III-2], n=209) are effective, while levetiracetam (1 RCT, n=27) isineffective (Larsson 2017 Level III-2 SR, 4 RCTs & 2 studies, n=277).
8.1.6.3 | Post-herniotomy pain syndrome
At 6 mth after herniotomy, 12.4% had “moderate/severe” pain (Aasvang 2010 Level IV, n=442) and
16.0% had substantial pain-related functional impairment (Bischoff 2012 Level III-3, n=244).
Pathophysiology
This syndrome is thought to be mainly neuropathic pain as a result of nerve injury. This
assumption was confirmed in a study that showed that all patients with chronic postherniotomy
pain had features of neuropathic pain (Aasvang 2008 Level IV, n=46). Ejaculatory pain is a featureof this syndrome and occurs in around 2.5% of patients after herniotomy (Aasvang 2007b Level IV,n=10).
Predictive factors
The following risk factors were identified: preoperative Activity Assessment Scale score,preoperative pain to tonic heat stimulation, 30-d postoperative pain intensity and sensory
dysfunction in the groin at 6 mth (nerve damage). An attempt to predict risk also identified openvs laparoscopic herniotomy as an additional intraoperative risk factor (OR 0.45; 95%CI 0.23 to0.87). Furthermore, a genetic risk factor may exist as a homozygous single nucleotide
polymorphism in the TNF-α gene was associated with an increased risk of neuropathic pain after
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herniotomy (Kalliomaki 2016 Level III-2, n=200). Another study suggests that functional variations
in COMT and GCH1 may predict to some extent impairment due to chronic pain after herniotomy(Belfer 2015 Level III-2, n=429).
Very young age may be a protective factor as hernia repair in children <3 mth age did notlead to chronic pain in adulthood (Aasvang 2007a Level IV, n=651).
Preventive strategies
Deliberate neurectomy (of the ilioinguinal nerve) for inguinal hernia repair reduced the incidenceof CPSP (from 21–6%) in one RCT (Malekpour 2008 Level II, n=100, JS 4) and in another study (Smeds
2010 Level III-2, n=525), while an earlier nonrandomised multicentre prospective study found thisincreased CPSP risk (Alfieri 2006 Level III-2, n=973). Intraoperative nerve identification of theiliohypogastric, ilioinguinal and genitofemoral nerves did not reduce the risk of development ofsensory loss or postherniotomy pain syndrome vs nonidentification (Bischoff 2012 Level III-3,
n=244).
Mesh removal and selective neurectomy of macroscopically injured nerves reduced
impairment in patients with postherniorrhaphy pain syndrome ( Aasvang 2009 Level III-3, n=21).
Treatment
Evidence-based consensus guidelines for prevention and management of postoperative chronic
pain following inguinal hernia surgery have been published (Alfieri 2011 GL). Recommended
approaches include to identify and preserve all three inguinal nerves and to perform elective
resection of a suspected injured nerve. Patients with a postherniotomy pain syndrome notresponding to other pain management treatment should be offered surgical treatment (including
all three nerves) after at least 1 y from the previous hernia repair.
8.1.6.4 | Post-hysterectomy pain syndrome
The incidence of chronic post-hysterectomy pain was 27.7% at 3 mth (Han 2017 Level IV, n=870),
32% at 4 mth and 15.7% at 6 mths ( Sng 2018 Level IV, n=216), in line with previous data
(Brandsborg 2012 NR). Incidence at 5 y was 17.1% in another study ( Pinto 2018 Level III-2, n=170).
Predictive factors
In most women pain was present preoperatively; at a 1 to 2 y follow‐up, pain was reported asa new symptom in 1 to 15% of patients (Brandsborg 2008 NR). In an initial small prospective
survey postoperative pain intensity, as well as preoperative nonpelvic pain, were associatedwith the presence of pain 4 mth after surgery ( Brandsborg 2009 Level III‐3, n=90). For pain
reported 1 y after surgery, risk factors were preoperative pelvic and nonpelvic pain andprevious Caesarean section; there was no difference found between vaginal or ab dominal
hysterectomy or the type of incision for abdominal hysterectomy ( Brandsborg 2007 Level IV,
n=1,299). Preoperative pain sensitisation (cutaneous and vaginal hypersensitivity) is associatedwith acute pain after hysterectomy; but only preoperative brush-evoked allodynia wasassociated with chronic pain at 4 mth postoperatively ( Brandsborg 2011 Level IV, n=90).
Subsequent more detailed analyses confirmed most of these risk factors for pain at 4 mth:
preoperative lower abdominal pain (OR 8.55), postoperative itching at 24 h (OR 3.33) andsevere pain in PACU (OR 1.39) ( Sng 2018 Level IV, n=216); presurgical anxiety (OR 1.18),
emotional representation of the surgical disease (OR 1.21), pain catastrophising (OR 1.143),
acute postsurgical pain intensity (OR 1.21) and frequency (OR 3.00) and postsurgical anxiety(OR 1.182), as well as preoperative depression, pre-existing pelvic pain and sexual
dissatisfaction (Han 2017 Level IV, n=870).

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Patients given perioperative gabapentin and a postoperative ropivacaine wound catheter
infusion had lower opioid requirements after surgery and less pain 1 mth later vs placebo,
although there was no difference in pain scores for the first 7 d postoperatively (Fassoulaki 2007
Level II, n=60, JS 5). Perioperative pregabalin (150 mg 3 times/d for 5 d) reduced postoperative
opioid requirements, but had no effect on any pain outcome at 3 mth (Fassoulaki 2012 Level II,
n=80, JS 5).
Spinal anaesthesia in comparison with general anaesthesia reduced the risk of chronic
postsurgical pain after hysterectomy (OR 0.42; 95%CI 0.21 to 0.85) ( Brandsborg 2007 Level IV,
n=1,299). Propofol-based general anaesthesia vs sevoflurane-based anaesthesia reduced theincidence (17.5 vs 52.5%; p<0.01) and severity of posthysterectomy pain (0.78/10 ±0.55 vs
2.23/10 ±0.73; p<0.01) at 3 mth postoperatively (Ogurlu 2014 Level II, n=80, JS 5).

KEY MESSAGES
1. Following thoracotomy, epidural analgesia reduces the incidence of chronic postsurgical
pain (S) (Level I [Cochrane Review]).
2. Following breast cancer surgery, paravertebral block (S) (Level I [Cochrane Review]) andlidocaine IV infusions reduce the incidence of chronic postsurgical pain (N) (Level I
PRISMA]).
3. Cryoanalgesia of the intercostal nerves at the time of thoracotomy results in no
improvement in acute pain, but an increase in chronic pain (U) (Level I).
4. Video-assisted thoracoscopic surgery versus open thoracic surgery resulted in a reduced
rate of chronic post-thoracotomy pain (N) (Level III-3).
5. Post‐thoracotomy, post-mastectomy, post-herniotomy and post-hysterectomy pain
syndromes occur frequently (S) (Level IV) and psychological factors (eg anxiety,catastrophising), chronic preoperative pain and severe acute postoperative pain are
consistently reported risk factors for these pain syndromes (N) (Level IV).

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8.1.7 | Ambulatory or short-stay surgery
Ever increasing numbers of surgical procedure are now performed on an ambulatory or shortstay basis, here defined as hospital LOS <24 h. Adequate postoperative pain management is often
the limiting factor when determining whether a patient can have surgery performed as a daystay procedure.
Provision of effective analgesia after ambulatory surgery remains poor. In two Swedish
nationwide surveys of ambulatory surgery, pain was the most common problem at follow-up
after discharge in a mixed (Segerdahl 2008b Level IV, n=92 [hospitals]) and a paediatric population(Segerdahl 2008a Level IV). Another survey from a single institution found that at 3 and 4 d after
day-stay surgery, 10 and 9% of patients respectively reported moderate to severe pain
(Greengrass 2005 Level IV). Even after cataract surgery in an ambulatory setting, ocular pain wasreported by 10% of patients at 24 h, 9% at 7 d and 7% at 6 wk (Porela-Tiihonen 2013 Level IV, n=201).
Similarly, a French survey identified variable quality and a lack of standardisation of
postoperative analgesia provision after ambulatory surgery across 221 randomly selected healthcare facilities (Aubrun 2019 Level IV, n=7,382).
After paediatric adenotonsillectomy, 52% patients had pain >5/10 at POD 3 (33% had nausea)
and 30% at 7 d (Stanko 2013 Level IV, n=100). Pain scores during the first 24 h were slightly
increased for day-stay tonsillectomy vs overnight inpatient stay, although maximal pain scoresat 24 h and 7 d were unchanged (Norrington 2013 Level III-2, n=60). Differences in parental
attitudes, understanding and access to medications, nausea or fear of adverse effects may
explain some of these differences. Barriers have been summarised as parental, child, medicationand system factors (Dorkham 2014 NR). Neither supplying a discharge medication package (Hegarty
2013 Level II, n=200, JS 2) nor nurse telephone follow-up improved pain relief after ambulatory
tonsillectomy (Paquette 2013 Level II, n=45, JS 2). An audit of children found that pain reports weresignificantly higher at home than in hospital (Shum 2012 Level IV, n=200). Pain scores, functional
limitation and analgesic use are greater after tonsillectomy than after inguinal hernia repair ororchidopexy in children discharged from ambulatory surgery, with the majority requiring at least
one analgesic medication for 7 d after surgery and more than half of the patients requiring visits
to a general practitioner (Stewart 2012 Level IV, n=105).
The best predictive factor of postoperative pain after ambulatory surgery is the presence of
preoperative pain; other factors include high expectations of postoperative pain, anticipation ofpain by clinicians, younger age, and surgery type (particularly orthopaedic, dental, inguinal
hernia, anal, scrotal, and tendon/fascia surgeries) ( Gramke 2009 Level IV, n=648). Not all of thesefactors could be confirmed in a subsequent modelling attempt, which identified preoperative
pain, patient derived expected pain, and different types of surgery as the strongest predictors ofmoderate to severe pain 4 d after ambulatory surgery ( Stessel 2017 Level III-3, n=1,118). Younger
age and orthopaedic surgery were risk factors for severe postoperative pain in wk 1 after
ambulatory surgery and high pain scores predicted more severe nausea for POD 1 to 5 (OdomForren 2015 Level IV, n=248). On POD 4 after ambulatory surgery, moderate (16.3%) to severe(12.1%) postoperative pain presented with procedure-specific variation; shoulder, anal anddental surgery was associated with the most intense pain ( Vrancken 2018 Level III-2, n=1,123);
preoperative pain intensity predicted postoperative pain intensity, but again related toprocedure performed.

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8.1.7.1 | Adverse effects of pain and principles of management
Inadequate analgesia delays patient discharge; pain was the most common cause of delayed
recovery affecting 24% of patients (Pavlin 2002 Level IV, n=150). Uncontrolled pain is also associatedwith nausea and vomiting, extending the patient’s stay in the recovery room ( Eriksson 1996
Level III-1, n=90; Michaloliakou 1996 Level III-1, n=49) and is likely to continue after hospital discharge(Odom-Forren 2015 Level IV, n=248). The most common reason for unplanned hospital admission
across 14 day-stay surgical units in Finland was unrelieved pain (Mattila 2009 Level III-2, n=7,915).
The readmission rate was 5.4% in ambulatory surgery cases with nearly half related toinadequate pain management and half of these potentially avoidable with appropriate
management (Herbst 2017 Level IV, n=28,674). Inadequate pain management may cause sleep
disturbance and limit early mobilisation, which may be crucial for early return to normal function
and work (Strassels 2002 Level IV, n=30).
More complex surgery continues to be performed on an ambulatory or short-stay basis andtherefore the analgesic drugs and techniques required are similar to those used for inpatient
pain relief. Multimodal analgesia is recommended in this setting ( Schug 2015 NR; Elvir-Lazo 2010NR) and seen as an essential part of enhanced recovery in ambulatory surgery settings ( Kaye 2019
NR). Preoperative implementation of multimodal analgesia (various regimens including
paracetamol, gabapentin and celecoxib) for ambulatory breast surgery reduced pain scores andopioid requirements vs no preoperative use and to IV paracetamol alone (Barker 2018 Level III-3,
n=560).
See also relevant sections of this document:• Systemically administered analgesic drugs (Chapter 4);• Regionally and locally administered analgesics drugs (Chapter 4);• Regional and other local analgesia techniques (Chapter 5);• Postoperative pain (Chapter 8);• Paediatric issues (Chapter 10).
8.1.7.2 | Systemic analgesia
Paracetamol, nonselective NSAIDs and coxibs
Following outpatient surgery, ibuprofen (1,200 mg/d) or celecoxib (400 mg/d) for 4 d vs placebo
reduced the need for breakthrough analgesia in the early postdischarge period leading to
improved patient satisfaction and quality of recovery ( White 2011 Level II, n=180, JS 4). A study inminor oral surgery demonstrated equivalent benefit of celecoxib 400 mg to diclofenac 50mg overplacebo for VAS scores and opioid consumption, and while acetaminophen had a similar effectit was not manifest until 5 and 6 h post administration (Hanzawa 2018 Level II, n=128, JS 4).
For ambulatory laparoscopic cholecystectomy, parecoxib preoperatively (30 min prior tosurgery) vs postoperatively or placebo was associated with less pain and analgesic requirements
for up to 24 h leading to shorter times to attain PACU and hospital discharge criteria ( Shuying
2014 Level II, n=120, JS 4). However, for minor day-stay gynaecological surgery, paracetamol orparecoxib, either alone or in combination, did not produce a clinically significant impact on painin the first 24 h after surgery vs placebo (Mohamad 2014 Level II, n=240, JS 4).
In children undergoing ambulatory inguinal hernia repair under general anaesthesia withcaudal bupivacaine, rectal diclofenac provided longer duration of analgesia vs rectal
paracetamol or placebo (Nnaji 2017 Level II, n=90, JS 4).
Afterambulatory
surgery,the
combinationofparacetamol/metamizolevs paracetamol/ibuprofen provided similar acute postoperative pain control at home including
comparable patient satisfaction levels (Stessel 2019 Level II, n=200, JS 5).
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Conventional and atypical opioids (alone or in combination)
Paracetamol/tramadol provided similar analgesia to tramadol alone after ambulatory handsurgery and resulted in a reduced rate of adverse effects ( Rawal 2011 Level II, n=80, JS 5).
Paracetamol/tramadol was also superior to combination paracetamol/codeine with better
analgesia, fewer adverse effects and higher patient satisfaction in a mixed day-stay surgicalpopulation (Alfano 2011 Level II, n=122, JS 2). Paracetamol/codeine provided similar analgesia butwith more discontination due to adverse effects vs paracetamol/ibuprofen after day-stay breast
surgery (Mitchell 2012 Level II, n=145, JS 5).
Morphine vs hydromorphone in patients having ambulatory (including laparoscopic) surgery
showed no difference in analgesic efficacy or side effects (Shanthanna 2019 Level II, n=402, JS 5).
Similarly after pregnancy termination, intraoperative administration of IV oxycodone(0.06 mg/kg and 0.08 mg/kg) vs IV fentanyl (2 mcg/kg) resulted in no clinically relevant differencein pain score at 30 min (Xie 2017 Level II, n=120, JS 2); statistically the higher dose oxycodone group
had the lowest pain scores.
For ambulatory surgery, the use of intraoperative methadone (0.15 mg/kg IBW) resulted insimilar pain control and adverse effects vs conventional prn dosing of short acting opioids (egfentanyl, hydromorphone) (Komen 2019 Level II, n=66, JS 3). Although the authors report reduced
postoperative requirements for other opioids, the potential risks of methadone administration(OIVI, QT prolongation), particularly in an ambulatory setting, were not discussed ( Dunn 2018a
Level IV, n=1,478).
Systemic adjuvant medications
IV dexamethasone 0.1 mg/kg in an ambulatory gynaecological surgery population improved
Quality of Recovery score (QoR-40) and reduced opioid consumption in the first 24 h
postoperatively vs dexamethasone 0.05 mg/kg or placebo (De Oliveira 2011 Level II, n=120, JS 5).
Similarly in a paediatric setting, the addition of systemic dexamethasone (0.5 mg/kg; 10 mg
maximum) to caudal blocks for day-stay orchidopexy improved and extended postoperative
analgesia (Hong 2010 Level II, n=77, JS 5). After ambulatory knee arthroscopy, IV betamethasone(8 mg) vs placebo increased the number of patients with no or minor pain at POD 2 (67 vs 44%)
(Segelman 2016 Level II, n=74, JS 5).
IV dexmedetomidine (0.5 mcg/kg) intraoperatively vs placebo after ambulatory ureteroscopy
and ureteric stenting improved pain control at 1 h and on POD 1 to 3 (at rest and on movement)
and return to daily activities (Shariffuddin 2018 Level II, n=60, JS 5). For outpatient gynaecologicaldiagnostic laparoscopy, dexmedetomidine (0.5 mcg/kg) vs fentanyl (0.5 mcg/kg) on induction
reduced postoperative pain severity, rescue analgesic requirements and PONV ( Techanivate 2012
Level II, n=40, JS 4).
Nebulised dexmedetomidine/ketamine (1 mcg/kg and 1 mg/kg) preoperatively in the settingof outpatient dental surgery was superior to either ketamine (2 mg/kg) or dexmedetomidine(2 mcg/kg) alone with regard to preoperative sedation and recovery and superior to ketamine
alone for postoperative analgesia (Zanaty 2015 Level II, n=60, JS 4).
IV lidocaine infusion intraoperatively until 30 min after arrival in PACU vs placebo forambulatory laparoscopic sterilisation had no effect on postoperative pain and opioid
requirements, increased requirement of PONV rescue, but resulted in earlier readiness fordischarge (Dewinter 2016 Level II, n=80, JS 5).
8.1.7.3 | Local anaesthesia techniques
Certain local and regional techniques offer specific benefits to patients after day-stay or shortstay surgery. There has been increasing interest in the use of single dose (“single injection”) as

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well as continuous peripheral nerve block (CPNB) in patients discharged home ( Ardon 2019 NR;
Schug 2015 NR). See also Section 5.8.
Local and peritoneal infiltration
After day-stay hernia repair, wound infiltration with levobupivacaine provided analgesia for 24 h
(Ausems 2007 Level II, n=120, JS 5) and with bupivacaine reduced pain and tramadol requirementsin the first 4 h (Qureshi 2016 Level II, n=80, JS 3). However, after day-stay laparoscopic
gynaecological surgery, wound infiltration did not significantly reduce pain or opioid
requirements (Fong 2001 Level II, n=100, JS 5).
After ambulatory hallux valgus repair, mid foot infiltration vs sciatic nerve block provided
similar analgesia, but infiltration permitted earlier ambulation (Adam 2012 Level II,
n=40, JS 3).
Three systematic reviews of local anaesthetic interventions for day-stay laparoscopiccholecystectomy have been performed with significant overlap of included RCTs; the two
Cochrane reviews highlight the very low quality of the included RCTs. Local anaesthetic
infiltration provides superior analgesic benefit vs placebo in 6 of 8 RCTs, with preincisional
infiltration being superior to postincisional administration (Ahn 2011 Level I, 8 RCTs [local
infiltration], n unspecified). Pain intensity is lower with local anaesthetic infiltration vs placebo at
4 to 8 h (MD -1.33/10; 95%CI -1.54 to -1.12) (13 RCTs, n=806) and 9 to 24 h (MD -0.36/10; 95%CI-0.53 to -0.20) (12 RCTs, n=756) (Loizides 2014 Level I [Cochrane], 19 RCTs, n=1,263). Intraperitoneal
local anaesthetic is beneficial in 7 of 9 RCTs, with one of the two negative RCTs using local
anaesthesia at the end of the procedure (Ahn 2011 Level I, 9 RCTs [intraperitoneal], n unspecified).
Local anaesthetic is more effective when applied before the commencement ofpneumoperitoneum and use of aerosolised local anaesthetic is more effective than simple
instillation. Two RCTs showed the combination of incisional and intraperitoneal local anaesthesia
is more effective than either intervention alone. Intraperitoneal local anaesthetic vs placebo
lowers pain intensity at 4 to 8 h (MD -0.99/10; 95%CI -1.10 to -0.88) (32 RCTs, n=2,020) and at
9 to 24 h (MD -0.53/10; 95%CI -0.62 to -0.44) (29 RCTs, n=1,787) (Gurusamy 2014 Level I [Cochrane],
48 RCTs, n=2,849).
After laparoscopic cholecystectomy, same day discharge readiness criteria were achieved
after intraincisional ropivacaine in 31% patients, intraperitoneal ropivacaine in 48%, and after
combined intraincisional and intraperitoneal ropivacaine in 89% patients ( Kaushal-Deep 2019
Level II, n=191, JS 5).
Intraperitoneal instillation of local anaesthetic at gynaecological laparoscopy reduced painscores for up to 6 h postoperatively (Marks 2012 Level I, 7 RCTs, n=478). Intraperitoneal local
anaesthetic also reduces shoulder tip pain within 24 h of ambulatory gynaecological laparoscopy(OR 0.23; 95%CI 0.06 to 0.93) (2 RCTs, n=157) (Kaloo 2019 Level I [Cochrane], 32 RCTs, n=3,284).
Single injection peripheral nerve block
PNBs are useful in ambulatory surgery as they provide site-specific anaesthesia with prolonged
analgesia and minimal haemodynamic changes (Salinas 2014 NR).
The decision to discharge ambulatory patients following PNB with long-acting local
anaesthesia is controversial due to the potential risk of harm to an insensate limb. A
prospective study demonstrated that long-acting PNBs were safe and that patients could bedischarged with an insensate limb ( Klein 2002 Level IV, n=1,119 [upper] & 1,263 [lower extremity
blocks] ). Therefore, provided patients are given verbal and written information regarding therisks as well as appropriate follow-up, it would seem reasonable to discharge these patientswith the benefit of prolonged analgesia. Patients may suffer intense pain following resolutionof a PNB, although it maximises pain relief in the first 12 to 24 h (Chung 1997 Level IV, n=10,008).
After outpatient shoulder arthroscopy with single injection interscalene block, 15% of
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patients experienced severe pain at home in the first 3 d and 5% contacted their generalpractitioner for analgesia issues ( Trompeter 2010 Level IV, n=109). After wrist fracture surgery,patients who received a single injection brachial plexus block were 3 times more likely torequire medical attention for pain management within 48 h vs GA (Sunderland 2016 Level IV,
n=419 ). These studies illustrate a major concern with the use of single injection PNBs, inparticular in the ambulatory setting, of ‘rebound’ pain after the regional block wears off(Lavand'homme 2018 NR).
Ilioinguinal and iliohypogastric block
Ambulatory herniorrhaphy performed under ilioinguinal and iliohypogastric nerve block led tosuperior pain relief, less morbidity, less urinary retention and cost advantages ( Ding 1995 Level II,
n=30, JS 4). The analgesic benefit with bupivacaine lasted around 6 h (Toivonen 2001 Level II, n=100,
JS 3). For open inguinal hernia surgery, US-guided ilioinguinal and iliohypogastric blocks withbupivacaine vs saline reduced pain scores at rest and on movement in the PACU, although opioid
consumption and time to discharge did not differ (Baerentzen 2012 Level II, n=60, JS 5).
For paediatric information, see Section 10.6.2.3.
Transversus abdominis plane blocks (TAPB)
After day-stay laparoscopic cholecystectomy, TAPB with ropivacaine vs placebo reduced opioid
requirements for 2 h and pain on coughing, but not at rest, for up to 4 h ( Petersen 2012 Level II,
n=80, JS 5).
After day-stay inguinal hernia repair, local infiltration and TAPB vs local infiltration for surgicalanaesthesia alone reduced the need for intraoperative rescue analgesia (36 vs 8%) and improved
postoperative pain scores for 12 h (Milone 2013 Level II, n=150, JS 3). When blindilioinguinal/iliohypogastric nerve blocks were compared to US-guided TAPB for day-stay open
inguinal hernia surgery, there was a small reduction in pain at rest (but not on movement) in the
TAPB group for up to 24 h (Aveline 2011 Level II, n=273, JS 5). There was also a modest reduction in
postoperative oral morphine requirement over the first 2 d. The primary outcome for this study
was pain at 6 mth, where no difference was found.
For paediatric information, see Section 10.6.2.3.
Paravertebral block (PVB)
For inguinal herniorrhaphy, PVB vs general anaesthesia/systemic analgesia ( 4 RCTS, n=268) orneuraxial anaesthesia (6 RCTs, n=377) reduced PONV, although pain outcomes and hospital LOS
were similar (Law 2015 Level I [PRISMA], 14 RCTs, n unspecified). PVBs provided better analgesia thanmore distal nerve blocks (2 RCTs [ilioinguinal block], n=140; 1 RCT [TAPB], n=60). Successful use after
outpatient lithotripsy has also been reported (Jamieson 2007 Level IV, n=2).
After ambulatory breast augmentation, PVB was superior to direct surgical infiltration withropivacaine with regard to pain scores and requirements for rescue analgesia ( Gardiner 2012
Level II, n=40, JS 3). However, comparing PVB to general anaesthesia for minor breast surgery in a
day-care setting, the benefits were small and may not justify the increased risk ( Terheggen 2002
Level II, n=30, JS 3). After PVB performed for ambulatory breast surgery, complications included
hypotension and/or bradycardia in 2.2%, LAST in 0.17%, and pneumothorax requiring only
conservative management in 0.26% (Kelly 2018b Level IV, n=1,322).
Newer blocks, such as erector spinae plane blocks (ESPB) may prove suitable alternatives to
PVB for abdominal and thoracic surgery (Hannig 2018 Level IV, n=3).
For paediatric information, see Section 10.6.2.3.
Upper and lower limb blocks
Adductor canal blocks (ACBs) offer potential for improved analgesia without significant motor
block for ambulatory arthroscopic knee surgery. For simple arthroscopic procedures, ACBs

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reduced pain scores modestly to 8 h and opioid consumption up to 24 h (4 RCTs, n=247); however,no benefit was demonstrated after anterior cruciate ligament repair from either ACB vs placebo(3 RCTs, n=135) or ACB vs FNB (3 RCTs, n=308) (Sehmbi 2019 Level I [PRISMA], 10 RCTs, n=716).
Interscalene (Bishop 2006 Level IV, n=299; Faryniarz 2006 Level IV, n=133) and supraclavicular (Liu2010 Level IV, n=1,169) plexus blocks provided safe and effective analgesia after ambulatory
shoulder surgery. For hand and wrist surgery, infraclavicular nerve blocks with propofol sedation
vs general anaesthesia followed by local anaesthetic wound infiltration resulted in lesspostoperative pain, less nausea, earlier ambulation and earlier hospital discharge ( Hadzic 2004
Level II, n=52, JS 3). US-guided PNBs with ropivacaine can be added to brachial plexus anaesthesia
with lignocaine to prolong analgesia after hand surgery, while avoiding significant motor block(Dufeu 2014 Level IV, n=125). For day-stay hand surgery (trapeziectomy) performed under anaxillary plexus block, distal nerve blocks (radial and median nerve) with levobupivacaine 0.125%
vs systemic analgesia provided superior pain relief on POD 1 with reduced opioid requirements
and PONV incidence (Rodriguez Prieto 2018 Level II, n=52, JS 4).
For ambulatory shoulder surgery, using 20 vs 40 mL of mepivacaine 1.5%/bupivacaine 0.5%
for US-guided interscalene blocks resulted in similar analgesia and patient satisfaction, but
20 mL had lower incidence of hoarseness and provided better hand grip strength ( Maalouf 2016
Level II, n=154, JS 4). For major day-stay arthroscopic shoulder surgery, the anterior suprascapular
block was non-inferior to the interscalene block and preserved best pulmonary function ( Auyong
2018 Level II, n=189, JS 5).
Pelvic plexus block
Pelvic plexus block provided better intra and postoperative analgesia than periprostatic nerve
block for ambulatory transrectal US-guided prostate biopsy (Cantiello 2012 Level II,
n=180, JS 3).
Gynaecological paracervical block
In awake patients, paracervical local anaesthesia for cervical dilatation and uterine intervention
reduces intraoperative pain vs placebo (10 RCTs), but fails to show a benefit over sedation (6 RCTs)
or other local anaesthesia techniques for postoperative pain (Tangsiriwatthana 2013 Level I[Cochrane], 26 RCTs, n=2,790). Overall, no recommendations regarding benefits could be made.
Specifically, for ambulatory hysteroscopy, paracervical block (SMD -1.28/10; 95%CI -2.22 to 0.35 [vs placebo]) provides superior analgesia vs intracervical injection of LA (SMD -0.36/10;
95%CI -0.61 to -0.10 [vs placebo]) (Cooper 2010 Level I, 20 RCTs, n unspecified); transcervical andtopical application of LA has no analgesic effect.
Adjuvants to single injection peripheral nerve block
Buprenorphine
Buprenorphine added to local anaesthetic for brachial plexus and intraoral blocks increased theduration of analgesia vs local anaesthetic alone (Kumar 2013 Level II, n=100, JS 3; Modi 2009 Level II,
n=50, JS 3; Candido 2001 Level II, n=40, JS 5). However, with infragluteal sciatic block for foot andankle surgery, when buprenorphine was either added to bupivacaine or given IM, there was onlya modest analgesic benefit, with increased vomiting in the groups receiving buprenorphine(Candido 2010 Level II, n=103, JS 5).
Dexamethasone
Caudal dexamethasone improved the quality and duration of caudal epidural ropivacaine
analgesia in a paediatric day-stay orchidopexy population (Kim 2014a Level II, n=80, JS 5). In thesetting of paediatric day-care hernia repair, IV dexamethasone (0.5 mg/kg) also increased
duration of caudal levobupivacaine analgesia (800 vs 520 min) and improved pain control on POD
1 and 2 (Murni Sari Ahmad 2015 Level II, n=64, JS 5).
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For arthroscopic ambulatory shoulder surgery, both systemic and perineural dexamethasone(10 mg) prolonged interscalene block with 0.5% ropivacaine, with both dexamethasone groups
requiring less analgesics in the first 48 h vs placebo (Desmet 2013 Level II, n=150, JS 5). Whendexamethasone 4 mg was added to interscalene ropivacaine for shoulder arthroscopy, median
duration of analgesia was longer than systemic administration (18 h vs 14 h), which was similar
to placebo (Kawanishi 2014 Level II, n=39, JS 3). However, a subsequent RCT found only a minor
prolongation of duration of interscalene block for ambulatory arthroscopic shoulder surgery withperineural vs systemic dexamethasone, which might not be clinically relevant ( Holland 2018
Level II, n=280, JS 5); there was no difference between doses of 4 and 8 mg.
For more details, see Section 4.12.2.
Dexmedetomidine
When added to caudal ropivacaine for paediatric day-stay patients undergoing lower abdominaland perineal surgery, dexmedetomidine (0.5 to 1.5 mcg/kg) prolongs analgesia with minor
prolongation of motor block, time to void and sedation, without increased hypotension or delay
in hospital discharge (Bharti 2014 Level II, n=80, JS 5). For paediatric day-stay orchidopexy, additionof dexmedetomidine (1 mcg/kg) to caudal ropivacaine prolonged time to first analgesic request(Cho 2015a Level II, n=80, JS 4).
For more details, see Section 4.9.2.2
Ketamine
A systematic review of ketamine 0.25 to 0.5 mg/kg added to caudal local anaesthetic prolongs
analgesia (time to first request) by a median difference of 5.6 h, without prolonged motor block(Schnabel 2011 Level I [PRISMA], 13 RCTs, n=884). Of the 13 RCTs, 9 were in the ambulatory paediatricpopulation. Although many adverse effects were more frequent in the ketamine group, there
was no significant difference to placebo. However, concerns of local neurotoxicity in vitro
continue to limit the use of neuraxial ketamine, in particular when combined with lignocaine(Werdehausen 2011 NR).
For more details, see Section 4.6.2.1
Continuous peripheral nerve block
Continuous peripheral nerve blocks (CPNBs) after ambulatory surgery vs single injection blocks
reduce pain at rest and during movement and opioid requirements for the first 24 h, but notconsistently sustained beyond this time frame (Saporito 2017 Level I [PRISMA], 5 RCTS, n=160); thequality and size of the RCTs limits the strength of these conclusions.
Upper and lower limb CPNBCPNB using perineural catheters and continuous infusions of local anaesthetic led to sustained
postoperative analgesia (Zaric 2004 Level II, n=63, JS 5; Ilfeld 2002b Level II, n=30, JS 5; Ilfeld 2002aLevel II, n=30, JS 5), was opioid-sparing (Ilfeld 2003 Level II, n=25, JS 5; Ilfeld 2002b Level II, n=30, JS 5;
Ilfeld 2002a Level II, n=30, JS 5) and resulted in less sleep disturbance (Ilfeld 2002b Level II, n=30, JS 5;
Ilfeld 2002a Level II, n=30, JS 5) and improved rehabilitation (Capdevila 1999 Level II, n=56, JS 2).
Patients achieved discharge criteria significantly earlier in a number of settings approaching
short-stay discharge times: after total shoulder arthroplasty with use of continuous interscalene
blocks (21 vs 51 h) (Ilfeld 2006 Level II, n=29, JS 5); after hip arthroplasty with use of continuous
lumbar plexus block (29 vs 52 h) (Ilfeld 2008a Level II, n=47, JS 5); and after total knee arthroplasty
with the use of continuous FNBs (25 vs 71 h) ( Ilfeld 2008b Level II, n=50, JS 5). Adductor canalcatheters allowed discharge on POD 1 after knee arthroplasty in 12% of patients in one series(Hanson 2016 Level IV, n=512). These benefits have the potential to reduce hospital costs ( Ilfeld
2007 Level III-3, n=20). Similar benefits have been observed with a range of CPNBs in a
predominantly paediatric population (Gurnaney 2014 Level IV, n=1,285).

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A 2 d interscalene infusion at home after shoulder surgery vs a single injection interscalene
block, was opioid-sparing and improved pain relief, sleep and patient satisfaction ( Salviz 2013
Level II, n=70, JS 4; Mariano 2009 Level II, n=32, JS 5). Furthermore at day 7, fewer patients had an
NRS > 4 (26% v. 83%), suggesting a sustained analgesic benefit. Similarly, after arthroscopic
rotator cuff repair, continuous (3 d of 0.125% bupivacaine at 5 mL/h plus a patient-controlled
bolus of 5 mL/h) vs single injection interscalene block provided better analgesia with better sleep
pattern and reduced opioid requirements (Malik 2016 Level II, n=92, JS 4). Patient-controlled bolus
added to continuous infusion of ropivacaine improved analgesia and function more than acontinuous infusion and even more so vs IV morphine PCA (Capdevila 2006 Level II, n=86, JS 4).
Continuous popliteal sciatic nerve block for foot and ankle surgery has a high success rate
and a low rate of complications, with a catheter dislocation rate of 0.2% ( Borgeat 2006 Level IV,
n=1,001). Compared to inpatients, ambulatory sciatic popliteal catheters were not associatedwith increased pain, complications or healthcare interventions in outpatients, allowing asignificant reduction in healthcare costs (Saporito 2014 Level II, n=120, JS 4). For day-case hallux
valgus surgery, placing the tip under US-guidance of the sciatic nerve catheter medial to the tibial
nerve vs between the tibial and peroneal components provides equivalent analgesia with
reduced insensate limb and foot drop and was therefore advantageous in an ambulatory setting(Ambrosoli 2016 Level II, n=84, JS 3).
Paravertebral CPNB
Continuous PVB after short-stay mastectomy with 0.4% ropivacaine vs saline at 5 mL/h for 3 ddemonstrated improved pain scores and less pain-induced physical and emotional dysfunction
for the infusion duration (Ilfeld 2014 Level II, n=60, JS 5). Adding a continuous infusion to maintainthe PVB after a single injection block for outpatient breast cancer surgery did not add further
benefits (Buckenmaier 2010 Level II, n=94, JS 5).
Safety and management of CPNB in an ambulatory setting
The safety and efficacy of CPNBs in an ambulatory setting has been confirmed in adult ( Nye 2013
Level IV, n=281; Fredrickson 2008 Level IV, n=300; Swenson 2006 Level IV, n=620) and paediatricpatients (Gurnaney 2014 Level IV, n=1,285; Ludot 2008 Level IV, n=47; Ganesh 2007 Level IV, n=226[catheters]).
Inadvertent intravascular catheter placement needs to be excluded prior to patientdischarge using a test dose of local anaesthetic and adrenaline (epinephrine) ( Rawal 2002 NR).
Patients and their carers should be given extensive oral and written instructions about
management, adverse effects and care of the local anaesthetic catheter, and have 24 h
telephone access to an anaesthesiologist during the postoperative period while CNPB is in use(Swenson 2006 Level IV, n=620) as 30% of patients make unscheduled phone calls regarding
catheter infusions despite been given adequate written and verbal instructions (Ilfeld 2002aLevel IV, n=30). A review of outpatients with CPNB (including popliteal fossa, fascia iliaca andinterscalene) showed that 4.2% required assistance by the anaesthesiologist after discharge
from hospital for problems relating to issues such as patient education, inadequate anal gesia
and equipment malfunction; only one patient was unable to remove their catheter ( Swenson
2006 Level IV, n=620), although patients may have significant anxiety about catheter removal athome (Ilfeld 2004 Level IV, n=24). While patient satisfaction is high, failure of brachial plexus
catheters within 72 h of insertion in the ambulatory setting may be as high as 26% forsupraclavicular and 19% for infraclavicular approaches ( Ahsan 2014 Level IV, n=207). In anotherseries, approximately one third of patients with brachial plexus catheters (continued for an
average of 4 d) experienced adverse effects or required additional healthcare intervention(King 2019 Level IV, n=501).

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Detailed narrative reviews of the use of CPNBs for ambulatory surgery have been published(Jones 2019b NR; Salinas 2014 NR; Ilfeld 2011 NR).
8.1.7.4 | Nonpharmacological techniques
Nonpharmacological techniques such as TENS, acupuncture, hypnosis, US, laser andcryoanalgesia have also been used in the treatment of acute pain management after ambulatory
surgery. Pressure on acupoints decreased pain following knee arthroscopy ( Felhendler 1996
Level II, n=44, JS 3). TENS resulted in a significant, but clinically trivial reduction of pain after
endometrial biopsy vs placebo TENS (Yilmazer 2012 Level II, n=65, JS 1). Continuous‐flow cold
therapy has been shown to be effective following outpatient anterior cruciate ligament
reconstruction, also reducing analgesic requirements (Barber 1998 Level II, n=100, JS 1).
An educational intervention (individualised education using written and verbal information
as well as two telephone support calls before and after surgery) vs usual care improves multiple
measures of pain intensity and function on POD 2 (Sawhney 2017 Level II, n=82, JS 5). An empathic
patient-centered interview vs standard care prior to ambulatory general surgery resulted inlower levels of pain, preoperative anxiety and higher levels of daily activity and satisfaction with
the information received (Pereira 2016 Level II, n=104, JS 1).
8.1.7.5 | Procedure-specific pain management after ambulatory surgery
Ambulatory arthroscopic anterior cruciate ligament reconstruction
A systematic review finds that arthroscopic anterior cruciate ligament (ACL) reconstruction
preformed as an outpatient vs an inpatient procedure resulted in similar or better outcomes withregard to pain, satisfaction, knee function, strength and complications (Ferrari 2017 Level III-3 SR[PRISMA], 2 RCTs & 5 studies, n=407); included studies were of low methodological quality. In thesame setting, there was no more postoperative discomfort in outpatients vs inpatients andoutpatients had less difficulty sleeping, were less often woken by pain during the first
postoperative night and more often walked regularly on POD 1 ( Lefevre 2015 Level III-1, n=133).
A systematic review of analgesic approaches to ambulatory arthroscopic ACL
reconstruction finds regional nerve blocks and intra-articular LA injections equally effective
analgesic techniques (Secrist 2016 Level III-2 [PRISMA], 77 studies, n unspecified ). Gabapentin,
zolpidem, ketorolac, and ibuprofen have opioid sparing effects and cryotherapy -compression(10 studies) as well as early mobilisation are effective non-pharmacological approaches. Thereis no support for the routine use of FNBs in this setting ( Vorobeichik 2019 Level I [PRISMA], 8 RCTs,
n=716) and ACB is not superior to FNB ( Sehmbi 2019 Level I [PRISMA], 10 RCTs, n=714 ), while useof LIA reduces pain intensity and opioid requirements with minimal complications ( Yung 2019
Level I [PRISMA], 11 RCTs, n=515 ).
Procedure-specific guidelines for pain management after ambulatory arthroscopic ACL
reconstruction have been published (Abdallah 2019 GL).
Ambulatory shoulder arthroscopy
After ambulatory shoulder arthroscopy, interscalene nerve blocks (ISBs) are the most effective
approach to pain management (Warrender 2017 Level I [PRISMA], 40 RCTs, n unspecified); increasing
LA concentrations, continuous infusions, and patient-controlled methods are effective strategies
to improve analgesia. Duration of the analgesic effect can be extended by adding
dexamethasone, clonidine, intrabursal oxycodone, and magnesium. Preoperative oral pregabalinand coxibs improve analgesia and patient satisfaction.

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8.1.7.6 | Discharge analgesia
A survey of day-surgery practices in 100 hospitals in 8 European countries reported takehome analgesics were provided as a "tablet-package" by 69% or as prescription by 80% of
hospitals ( Stomberg 2013 Level IV). Strong opioids on discharge were given or prescribed by
59% of units. Written instructions about management of pain were provided by 69% of units.
Early discharge after day-stay surgery with a prescription of opioids or NSAIDs carries anincreased risk of subsequent long term use of these analgesics. In a population of 391,139 opioidnaïve patients aged >65 y having short-stay surgery, patients receiving an opioid prescription
within the 7 d after surgery were more likely to become long term opioid users within 1 y incomparison to those without a prescription (OR 1.44; 95%CI 1.39 to 1.50) ( Alam 2012 Level III-2,
n=391,139). Discharge NSAID prescriptions were also more likely to be associated with persistentuse (OR 3.74; 95%CI 3.27 to 4.28).
Implementation of multimodal analgesia pathways for same-day thyroid, parathyroid, andparotid surgery (adherence increased from 0% to 87% from 2015 to 2017) resulted in a dramatic
reduction of opioid prescription on discharge (OR 0.13; 95%CI 0.04 to 0.44) ( Militsakh 2018
Level III-3, n=528). After ambulatory surgical procedures, there was a wide range of amounts of
opioids prescribed; only 28% of prescribed opioids were taken and suggestions for more
appropriate prescribing are made (Hill 2017 Level IV, n=642). An educational intervention basedon estimated opioid requirements for specific outpatient procedures resulted in decreased
prescribing rates without increasing patients’ refill requirements ( Hill 2018b Level IV, n=224).
The importance of opioid stewardship specifically in the ambulatory surgery setting has beenemphasised (Roth 2018 NR).
For more details, see Section 8.13 and for paediatric information, see Section 10.4.5.

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KEY MESSAGES
1. Wound infiltration and intraperitoneal instillation with local anaesthetics for short-staylaparoscopic cholecystectomy has good analgesic efficacy, in particular when combined
and administered prior to trocar insertion and at commencement of pneumoperitoneum
respectively (S) (Level I [Cochrane Review]).
2. Intraperitoneal instillation with local anaesthetic provides good analgesia for up to 6
hours after short-stay gynaecological laparoscopy (U) (Level I) and reduces shoulder tip
pain for 24 h (N) (Level I [Cochrane Review]).
3. Ketamine added to caudal local anaesthetic for paediatric day-stay surgery prolongs
analgesia, but not motor block (U) (Level I [PRISMA]); however, concerns regarding
neurotoxicity remain.
4. Continuous peripheral nerve blocks after short-stay surgery provide extended analgesia
for at least 24 h, leading to reduced opioid requirements (S) (Level I [PRISMA]), earlier
achievement of discharge criteria, less sleep disturbance and improved earlyrehabilitation (S) (Level II).
5. Paravertebral block improves pain-related outcomes after short-stay hernia repair (S)(Level I [PRISMA]) and major breast surgery (U) (Level II).
6. After ambulatory anterior cruciate ligament repair, analgesia is superior with local
infiltration anaesthesia versus femoral nerve blocks and adductor canal blocks;
multimodal systemic analgesia, early mobilisation and cooling/compression are also
supported (N) (Level I [PRISMA]).
7. After ambulatory shoulder arthroscopy, interscalene nerve block is superior to otherperipheral nerve blocks; adjuvants to increase block duration and systemic multimodal
analgesia are also supported (N) (Level I [PRISMA]).
8. Gynaecological paracervical block provides superior analgesia to intracervical andtranscervical block and topical local anaesthetic administration (the latter both without
analgesic effect) for ambulatory hysteroscopy (N) (Level I).
9. Dexamethasone added to local anaesthetics in peripheral nerve blocks and for caudal
analgesia or given systemically prolongs duration of analgesia after short-stay surgery(S) (Level I).
10. Single injection peripheral nerve blocks with long-acting local anaesthetics provide longlasting postoperative analgesia after short-stay surgery (S) (Level II).
11. Infiltration of the wound with local anaesthetic provides effective and long-lasting
analgesia after many short-stay procedures (U) (Level II).
12. In the short-stay surgery setting, anti-inflammatories (nonselective NSAIDs, coxibs anddexamethasone) and paracetamol contribute to reduced pain and improved recovery (U)(Level II).
13. Buprenorphine or dexmedetomidine added to local anaesthetics for peripheral nerve
blocks prolong duration of analgesia after short-stay surgery (U) (Level II).

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14. Anterior cruciate ligament repair performed as a short-stay procedure in comparison to
an inpatient setting achieves comparable quality of pain relief and better outcomes (N)(Level III-3 SR).
15. Pain relief after short-stay surgery remains poor (U) (Level IV) and is a common cause of
unplanned re-presentation (U) (Level III-3).
16. Continuous peripheral nerve blocks have been shown to be safe at home after short stay
surgery, if adequate resources and patient education are provided (U) (Level IV).
17. Predictive factors of severe pain after short-stay surgery are preoperative pain, highexpectation of postoperative pain, younger age and certain types of surgery (inparticular orthopaedic surgery) (N) (Level IV).
The following tick box represents conclusions based on clinical experience and expert
opinion.
 Preoperative patient-centered education (verbal and written) and telephone follow-ups
may improve anxiety, pain and functional outcomes and patient satisfaction after
ambulatory surgery (N).

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8.1.8 | Cranial neurosurgery
There is a widespread belief that intracranial surgery does not result in much patient discomfort
and pain. However, surveys have shown that patients have significant pain in the early phase
after intracranial surgery; the incidence of acute post craniotomy pain varies from 27% ( deOliveira Ribeiro Mdo 2013 Level IV, n=91) to 80% of patients (Gottschalk 2007 Level IV, n=187; Nemergut
2007 NR). These findings are in line with other studies that found incidences of 56% moderate
and 25% severe pain (Thibault 2007 Level IV, n=299) and of 87% pain overall in the first 24 h (NRS
1 to 3, 32%; 4 to 7, 44%; 8 to 10, 11%) despite conventional pain management (Mordhorst 2010
Level IV, n=256). In a paediatric population, 35% of patients had moderate to severe pain in theimmediate postoperative setting but this reduced to 8% at POD 1 (Bronco 2014 Level IV, n=206).
Similarly, 42% of children had at least one episode of pain ≥3/10 in the first 72 h after craniotomy(Teo 2011 Level IV, n=52).
However, the pain is not as severe as after other surgical procedures such as extracranial
maxillary/mandibular surgery or lumbar surgery (Klimek 2006 Level III-2, n=649; Dunbar 1999
Level III-2, n=99). The findings that the pain is more severe after an infratentorial rather than asupratentorial approach (Gottschalk 2007 Level IV, n=187) are disputed by another study (Irefin 2003
Level III-2, n=128). Noncraniotomy neurosurgery, for example trans-sphenoidal surgery, seems tobe associated with very limited pain and minimal morphine requirements ( Flynn 2006 Level IV,
n=877).
It is noteworthy that craniotomy can lead to significant chronic headache, defined as
postcraniotomy headache by the International Headache Society (Headache Classification
Committee 2018 GL). At 6 mth after supratentorial craniotomy for aneurysm repair, 40% of
patients reported headache, of whom 10.7% had acute and 29.3% chronic headache ( Rocha-Filho2008 Level IV, n=79). A review of the issues related to postcraniotomy headache has been
published (Molnar 2014 NR).
The management of postoperative pain after intracranial surgery is often poor. The problemsof postcraniotomy analgesia were analysed in a survey of UK neurosurgical centres ( Roberts 2005
Level IV, n=23 [centres]); the principal analgesic was IM codeine, only 3 of 23 centres usedmorphine and only one used PCA. Pain was only assessed in 57% of cases. Similar data arereported in a survey of Canadian neurosurgeons, with 59% describing codeine as their first-line
opioid (Hassouneh 2011 Level IV, n=103 [neurosurgeons responding]). This practice has changed little
since 1995, when IM codeine was the primary analgesic used by 97% of centres ( Stoneham 1995
Level IV, n=110 [neuroanaesthetists responding]).
Concerns about the adverse effects of opioids and their ability to interfere with recovery andneurological assessment contribute to this, as well as the concern that opioid-induced
respiratory depression will lead to hypercarbia and increased intracranial pressure (Nemergut
2007 NR). Similarly, there is a concern that NSAIDs could interfere with haemostasis and increase
intracranial bleeding. Furthermore, there is poor evidence on which to base protocols for theassessment and treatment of pain after cranial surgery (Nemergut 2007 NR); the limited numberof trials are heterogeneous and have many weaknesses in study design and methodology. The
question remains as to whether all craniotomies are the same with regard to analgesic
requirements.
8.1.8.1 | Treatment of acute postoperative pain after cranial neurosurgery
A systematic review of pain treatments after craniotomy identified scalp infiltration/block,opioids and diclofenac as some evidence-based approaches, but could not make firm506

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recommendations due to limited data (Tsaousi 2017 Level I [PRISMA], 19 RCTs, n=1,805 [limited search
period January 2011 to April 2016]).
Paracetamol
A trial comparing paracetamol alone with paracetamol/tramadol or paracetamol/nalbuphine
was stopped early as paracetamol alone gave ineffective pain relief in most patients ( Verchere2002 Level II, n=64, JS 5). Another case series found that oral paracetamol only reduced pain
effectively in 27% of patients post supratentorial craniotomy (Nair 2011 Level IV, n=43).
Nonselective NSAIDs
Ketoprofen was more effective than paracetamol in reducing PCA opioid requirements after
craniotomy, but with minimal benefits in regard to pain scores and no change in adverse
effects (Tanskanen 1999 Level II, n=45, JS 4). Similarly, diclofenac was superior to placebo andcomparable to another nonopioid analgesic, flupirtine, for pain post craniotomy ( Yadav 2014
Level II, n=390, JS 2). Preoperative single dose PO diclofenac 100 mg resulted in improved
analgesia and reduced opioid requirement up to 5 d postoperatively ( Molnar 2015 Level II,
n=200, JS 4). A single-centre, retrospective cohort study over 5 y identified an association
between the development of postoperative haematoma and the use of aspirin or nsNSAIDs(Palmer 1994 Level IV, n=71 [haematomas] in n=6,668 [neurosurgical operations] ).
CoxibsThere was no benefit with a single dose of IV parecoxib (40 mg given at the end of the case) overthe first 24 h postoperatively with regard to pain scores, morphine use and analgesia-related
adverse effects in one study (Williams 2011 Level II, n=100, JS 5), although another study showed
limited benefit over the first 6 h postoperatively (Jones 2009 Level II, n=82, JS 5).
Opioids
IV PCA morphine (with or without ondansetron) was superior to placebo after infratentorial
craniotomy (Jellish 2006 Level II, n=120, JS 5). Morphine was also more effective than codeine
following craniotomy; this was found for IM prn administration of both compounds ( Goldsack
1996 Level II, n=40, JS 3), but also in a comparison of PCA morphine with IM codeine ( Sudheer 2007
Level II, n=60, JS 3). PCA morphine provided better analgesia than PCA tramadol ( Sudheer 2007
Level II, n=60, JS 3). PCA fentanyl was more effective than IV fentanyl prn and did not increase therisk of adverse effects after craniotomy, although more fentanyl was used in the PCA group ( Jalili
2012 Level II, n=80, JS 5; Morad 2009 Level II, n=79, JS 2).
IM codeine 60 mg was more effective than IM tramadol 50 mg or 75 mg (Jeffrey 1999 Level II,
n=75, JS 5). However, the addition of tramadol 100 mg twice daily to a paracetamol and morphineor oxycodone analgesic regimen improved analgesia and reduced opioid requirements vsplacebo (Rahimi 2010 Level II, n=50, JS 2).
The intraoperative use of remifentanil may result in increased pain and/or increased
analgesia requirements postoperatively (see Section 4.3.1.5). This was found vs both fentanyl(Gelb 2003 Level II, n=91, JS 4) and sufentanil (Gerlach 2003 Level II, n=36, JS 3).
Local anaesthetic scalp block
A meta-analysis found that regional scalp block improved pain scores up to 12 h postoperatively
and reduced opioid requirements until 24 h postoperatively vs placebo block (Guilfoyle 2013
Level I [PRISMA], 7 studies, n=325). An RCT performed after this meta-analysis confirmed not only
better analgesia after aneurysm clipping, but also improved outcome (reduced PCA
consumption, requirement for a postoperative antihypertensive agent and PONV incidence) with
scalp block (0.75% levobupivacaine) vs placebo (Hwang 2015 Level II, n=52, JS 5). Preemptive scalp
block vs block at the end of surgery provided improved analgesia up to 6 h postoperatively and5th Edition | Acute Pain Management: Scientific Evidence 507

reduced number of patients requiring opioid and median opioid consumption up to 24 h
postoperatively (Song 2015 Level II, n=52, JS 3). Scalp blocks have also been used in children
following craniosynostosis repair (Pardey Bracho 2014 Level IV, n=32).
Systemic adjuvant medications
Dexmedetomidine given intraoperatively for craniotomy provides superior analgesia in PACU
and up to 12 h postoperatively vs placebo (2 RCTs, n=128) and remifentanil (1 RCT, n=139) (Tsaousi
2017 Level I [PRISMA], 19 RCTs, n=1,805). It also reduces opioid requirements up to 24 h
postoperatively, with inconclusive evidence on effects on PONV and increased risk of delayed
recovery. Clonidine did not improve analgesia after supratentorial craniotomy ( Stapelfeldt 2005
Level II, n=34, JS 3).
Gabapentin improved postoperative analgesia and reduced opioid consumption, but
increased sedation and delayed extubation (by 12 min) vs phenytoin perioperatively forsupratentorial craniotomy (Ture 2009 Level II, n=80, JS 2). This was contradicted by a later study,
which was however inadequately powered with pain relief only as a secondary outcome ( Misra
2013 Level II, n=79, JS 4). Pregabalin showed marginal benefit for postoperative analgesia andreduced number of patients requiring opioids for up to 48 h (Shimony 2016 Level II, n=100, JS 4).
Non-pharmacological techniques
Transcutaneous electric acupuncture stimulation (TEAS) may improve postoperative analgesia
and reduce opioid requirements; however, studies were of poor quality with a high risk of bias
(2 RCTs, n=176) (Tsaousi 2017 Level I [PRISMA], 19 RCTs, n=1,805).
Cryotherapy (cold bags and ice gel packs) improved pain control along with eyelid oedema
and facial ecchymosis after craniotomy (Shin 2009 Level II, n=97, JS 3).

KEY MESSAGES
1. Local anaesthetic infiltration of the scalp provides early analgesia after craniotomy andreduces opioid requirements (S) (Level I [PRISMA]).
2. Intraoperative dexmedetomidine provides early analgesia after craniotomy andreduces opioid requirements compared to placebo or remifentanil (S) (Level I[PRISMA]).
3. Morphine is more effective than codeine and tramadol for pain relief after craniotomy(U) (Level II).
4. Craniotomy leads to significant pain in the early postoperative period (U) (Level IV),
which is however not as severe as pain from other surgical interventions (U) (Level III-2).
5. Craniotomy can lead to significant chronic headache (U) (Level IV).
The following tick box represents conclusions based on clinical experience and expert
opinion: Acute pain following craniotomy is underestimated and often poorly treated (U).

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8.1.9 | Spinal surgery
A considerable number of patients presenting for surgery on the spine have pre-existing
persistent and/or acute pain and some may be on long term analgesic medications. Therefore,
managing acute postoperative pain can be more difficult with an increased risk of persistent
postoperative pain.
8.1.9.1 | Type of Anaesthesia
Propofol/fentanyl TIVA versus desflurane/fentanyl anaesthesia resulted in a minor not clinicallymeaningful reduction of postoperative pain, but also reduces opioid requirement up to 48 h post
spinal surgery (Lin 2019b Level II, n=60, JS 4).
8.1.9.2 | Systemic anlgesics
Use of IV paracetamol vs placebo is associated with better analgesia postoperatively, althoughan opioid-sparing effect was not demonstrated (Cakan 2008 Level II, n=40, JS 4).
NSAIDsConsistent with general postoperative data, nsNSAIDs have demonstrated analgesic benefit andare opioid-sparing in spinal surgery (Zhang 2017 Level I [PRISMA], 8 RCTs, n=408).
A meta-analysis of retrospective studies of spinal fusion concluded that the use of normal
doses of nsNSAIDs or coxibs for <14 d postoperatively was not associated with increased nonunion (Li 2011 Level III-3 SR, 5 studies, n=1,403). However, high-dose ketorolac (>120 mg/d) was
associated with increased rates of nonunion (RR 2.9; 95%CI 1.5 to 5.4).
Opioids
Single IV doses of methadone given at the start of spine surgery provided improved pain control
and reduced analgesic requirements up to 72 h postoperatively ( Murphy 2017b Level II, n=150, JS
5; Gottschalk 2011 Level II, n=29, JS 5). Although no significant adverse effects were noted in these
RCTs, caution is advised re potential OIVI (37%), hypoxaemia (80%) and QTc prolongation (59%)
in a case series of spinal surgery patients, of whom 72% were taking opioids preoperatively (Dunn
2018a Level IV, n=1,478).
8.1.9.3 | Systemic adjuvant medications
Alpha-2-delta ligands (gabapentin and pregabalin)
Both gabapentin and pregabalin given preoperatively reduced postoperative pain and opioid
requirements up to 48 h post spinal surgery vs placebo (Liu 2017a Level I [PRISMA], 16 RCTs,
n=1,112). Although heterogenous in dosing and timing, in all of the RCTs gabapentin or pregabalin
was given 1 to 2 h preoperatively as a single dose and then continued in some up to POD 3. Two
RCTs examined variable doses suggesting that the maximal benefit of gabapentin is achieved
with 600 mg (Liu 2017a Level I [PRISMA] 1 RCT: Pandey 2005 Level II, n=100, JS 5) to 900 mg (Liu 2017aLevel I [PRISMA], 1 RCT: Khan 2011 Level II, n=175, JS 5) with no further benefit in larger doses.
Long term benefits of perioperative gabapentin or pregabalin use beyond the acutepostoperative period after lumbar spine surgery were found in three RCTs. After lumbar
discectomy, pain intensity was reduced and functional outcome improved at 3 mth withperioperative pregabalin administration (Khurana 2014 Level II, n=90, JS 4; Burke 2010 Level II, n=40,
JS 5) and quality of life was improved at 3 mth, but not at 1 y (Gianesello 2012 Level II, n=60, JS 5).
In one of these studies, 75 mg pregabalin every 8 h for 7 d was more effective than 300 mg
gabapentin administered in the same way (Khurana 2014 Level II, n=90, JS 4).
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Alpha-2 agonists
IV dexmedetomidine used intraoperatively (14 RCTs) and intra- and postoperatively for 24 h
(1 RCT) in spinal surgery reduces postoperative pain at 2 h (3 RCTs, n=237) and analgesic
requirements at 12 h (2 RCTs,n=149) and 48 h, but not 24 h (3 RCTs, n=380) (Tsaousi 2018 Level I[PRISMA], 15 RCTs, n=913).
AntidepressantsUse of duloxetine 60 mg given preoperatively for spinal surgery and 24 h postoperatively had
contradictory effects on pain scores in 2 RCTs, but reduced opioid requirements up to 48 h
postoperatively (Attia 2017 Level II, n=60, JS 5; Bedin 2017 Level II, n=57, JS 3).
Corticosteroids
IV corticosteroids given intraoperatively for spinal surgery reduce pain up to 48 h
postoperatively, as well as nausea and length of stay (Wang 2018b Level I [PRISMA], 8 RCTs, n=918).
Epidural corticosteroids (triamcinolone, methylprednisolone or dexamethasone) applied by
the surgeons intraoperatively for microdiscectomy or laminectomy reduce pain at 24 h and1 mth postoperatively as well as opioid requirements and hospital LOS vs placebo (Wilson-Smith
2018 Level I [PRISMA], 17 RCTs, n=1,727; Arirachakaran 2018 Level I [PRISMA], 12 RCTs, n=1,006) (10 RCTs
overlap). The effects on opioid requirements are more pronounced after open laminectomy vsmicrodiscectomy (Arirachakaran 2018 Level I [PRISMA], 12 RCTs, n=1,006). There is no difference incomplications in these two systematic reviews and a further meta-analysis looking specificallyfor complications also found no increase in overall complication (RR 1.94; 95%CI 0.72 to 5.26) or
infectious complication rates (RR 4.6; 95%CI 0.8 to 28.0) ( Akinduro 2015 Level III-2 SR, 16 RCTs &1 study, n=1,933).
Systemic lidocaine
A perioperative IV lidocaine infusion reduced pain scores and postoperative opioid requirements
after complex spinal surgery (Farag 2013 Level II, n=116, JS 5), microdiscectomy (Kim 2014c Level II,
n=51, JS 5) and spinal fusion (Ibrahim 2018 Level II, n=44, JS 4). The latter study showed a clinicallyinsignificant pain reduction even at 3 mth; in this RCT, one participant had a convulsion after theloading dose of lignocaine (2mg/kg). However, a more recent RCT in spinal fusion showed noneof these benefits (Dewinter 2017 Level II, n=70, JS 5).
Ketamine
Ketamine as an adjuvant to PCA fentanyl after lumbar spinal surgery decreased fentanyl
requirements, but increased nausea with no other benefits (Song 2013 Level II, n=50, JS 5). In
children undergoing spinal fusion, there was no benefit of perioperative ketamine continued
until POD 3 (Pestieau 2014 Level II, n=50, JS 5).
Ketamine may have a special role in patients who are opioid tolerant prior to back surgery(Boenigk 2019 Level II, n=122, JS 5; Nielsen 2017 Level II, n=147, JS 5; Loftus 2010 Level II, n=101, JS 4).
Here perioperative ketamine resulted in significantly reduced opioid requirements up to 6 wk
postoperatively with limited benefit on pain intensity in the immediate postoperative period.
However, there was pain reduction as well as functional benefit seen at 6 wk (Loftus 2010 Level II,
n=101, JS 4) and 6 mth follow-up (Nielsen 2017 Level II, n=147, JS 5).
Magnesium
A perioperative magnesium infusion reduced pain scores and analgesic requirements andimproved patient satisfaction (Levaux 2003 Level II, n=24, JS 5). However, this might be due toreduction of OIH associated with perioperative remifentanil infusion rather than an additional
analgesic benefit.

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Muscle Relaxants
Chlorzoxazone, a centrally acting muscles relaxant, used after spine surgery did not improve restor movement pain (Nielsen 2016 Level II, n=110, JS 5).
8.1.9.4 | Neuraxial analgesia
IT morphine vs systemic opioids after spinal surgery results in reduced pain scores andpostoperative opioid consumption during the first 24 h in the IT morphine group; however, witha higher rate of pruritus and respiratory depression only occurring in the IT morphine group(Pendi 2017 Level I, 8 RCTs, n=393).
Patient-controlled epidural analgesia with opioid and/or local anaesthetic vs IV PCA results
in clinically irrelevant improvements of analgesia in the first 2 postoperative days with a higher
incidence of pruritus and paraesthesia (Tian 2015 Level I, 8 RCT, n=405). A subsequent RCT inposterior spinal fusion showed analgesic benefits with reduced opioid requirement for up to
3 days and increased patient satisfaction (Park 2016 Level II, n=94, JS 3). Similarly, in children
undergoing thoraco-lumbar spinal surgery, epidural analgesia reduced pain for up to 72 h
postoperatively vs systemic analgesia (Guay 2019 Level I [Cochrane], 7 RCTs, n=249).
8.1.9.5 | Peripheral regional analgesia
Local infiltration analgesia (LIA) reduces pain at 1 h (but not at 12 and 24 h) postoperatively andanalgesic requirement vs placebo infiltration (Perera 2017 Level I [PRISMA], 11 RCTs, n=438).
Preemptive infiltration with local anaesthetic provided additional benefits vs infiltration at
wound closure; addition of steroid did not improve analgesic efficacy ( Gurbet 2008 Level II, n=100,
JS 1; Ersayli 2006 Level II, n=75, JS 3).
Continuous infusion of local anaesthetics (ropivacaine) after posterior spinal fusion surgery
through wound catheters did not show any further benefit when added to systemic multimodal
analgesia (Greze 2017 Level II, n=39, JS 5).
8.1.9.6. | Non-pharmacological techniques
Acupuncture used postoperatively after spinal surgery reduces pain without reduction of opioid
requirement in the first 24 h postoperatively (Cho 2015b Level I [PRISMA], 5 RCTs, n=480).
Cognitive Behavioural Therapy (CBT) preoperatively (total 9 h group sessions) improved
mobilisation in the early postoperative period after lumbar fusion and reduced analgesic
requirements without changing pain scores suggesting improved coping skills ( Rolving 2016 Level
II, n=96, JS 3); however, there was no longer a benefit at 1 y follow-up (Rolving 2015 Level II, n=90,
JS 3).

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KEY MESSAGES
1. Epidural analgesia compared to systemic analgesia after spinal surgery in children
improves pain up to 72 hours postoperatively (N) (Level I[Cochrane Review]).
2. Perioperative use of gabapentin or pregabalin improves analgesia and reduces opioid
requirements after spinal surgery (S) (Level I [PRISMA]).
3. NSAIDs provide analgesic benefits as well as opioid-sparing effects after spinal surgery(S) (Level I [PRISMA]).
4. Intravenous dexmedetomidine improves early postoperative analgesia and reduces
analgesic requirement up to 48 hours after spinal surgery (N) (Level I [PRISMA]).
5. Intravenous corticosteroids improve analgesia and reduce nausea and length of stayafter spinal surgery (N) (Level I [PRISMA]).
6. Epidural steroid application intraoperatively by the surgeon provides analgesic benefit
up to 24 hours and reduces length of stay after spinal surgery(N) (Level I [PRISMA]).
7. Perioperative pregabalin improves functional outcome after laminectomy at 3 months(U) (Level II).
8. Local infiltration anaesthesia improves analgesia and reduces opioid requirements
after spinal surgery; this benefit is enhanced with preincision infiltration compared toinfiltration at wound closure (U) (Level II).
9. Perioperative systemic lidocaine infusion improves analgesia and reduces opioid
requirements after spinal surgery (W) (Level II).
10. NSAID use for less than 14 days does not increase the risk of nonunion after spinal
fusion, except with high-dose ketorolac (U) (Level III-3).
The following tick box represents conclusions based on clinical experience and expert
opinion: Acute pain management following spinal surgery is often complicated by preoperative
chronic pain and long term medication use (U).

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8.2 | Acute pain following spinal cord injury
Acute pain following spinal cord injury (SCI) is common, with over 90% of patients experiencing
pain in the first 2 wk following injury (Siddall 1999 Level IV, n=100). Acute pain may also develop
during the rehabilitation phase due to intercurrent disease (eg renal calculus) or exacerbation ofa chronic pain syndrome.
Pain associated with SCI usually falls into two main categories: neuropathic pain, either at or
below the level of the injury, and nociceptive pain, from somatic and visceral structures (Bryce
2012 GL). Neuropathic pain associated with a lesion or disease of the central somatosensory
nervous system is termed central neuropathic pain (Jensen 2011 GL). Phantom pain and complex
regional pain syndromes may also develop in patients with SCI.
Table 8.1 | Taxonomy of acute pain associated with spinal cord injury pain
Pain type

Pain subtype

Examples of primary pain source or pathology

Neuropathic pain

At level

Cauda equina compression, nerve root
compression, spinal cord compression

Below level

Spinal cord compression or ischaemia

Other

Trigeminal neuralgia, diabetic neuropathy

Somatic

Musculoskeletal pain (eg vertebral fracture,muscle spasms, overuse syndromes)
Procedure-related pain (eg pressure sore
dressings)

Visceral

Renal calculus, pain due to bowel impaction

Nociceptive pain

Other

Complex regional pain syndrome

Source: Based on the International Spinal Cord Injury Pain Classification (Bryce 2012 GL).

8.2.1 | Treatment of acute neuropathic pain after spinal cord injury
There are only case series specifically examining the treatment of acute neuropathic pain
following SCI.
Three patients with acute neuropathic pain following SCI were administered SC calcitonin
100 IU in addition to other medications with improved pain relief in each person and reduced
analgesic requirements (Humble 2011 Level IV).
Thirteen patients with acute neuropathic SCI pain received IV ketamine (50 mg over 2 h, twice
daily for several days followed by 50 mg orally for up to 3 mth) with a mean pain reduction of
75% at the time of treatment cessation (mean 17 d) with further benefit over the subsequentmonths (Kim 2013a Level IV).
Treatment of acute neuropathic pain must therefore be based on evidence from studies ofchronic central neuropathic pain and other neuropathic pain syndromes (see below). An
algorithm for the treatment of pain in patients with SCI has been promulgated ( Siddall 2006 GL).

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8.2.2 | Treatment of chronic neuropathic pain after spinal cord injury
Clinical practice guidelines have been published which make a number of recommendations forthe treatment of chronic neuropathic pain after SCI (Guy 2016 GL). These guidelines recommend:•

First line: pregabalin, gabapentin and amitriptyline;•

Second line: tramadol and lamotrigine (in incomplete SCI);•

Third line: Transcranial direct current stimulation (tDCS) alone and combined with visual
illusion;•

Fourth line: TENS, oxycodone and dorsal root entry zone lesions.

Further information based on results from individual studies and other systematic reviews is
described below.
8.2.2.1 | Conventional and atypical opioids
Under experimental conditions, IV alfentanil decreased central pain following SCI vs placebo or
ketamine (Eide 1995 Level II EH, n=9, JS 5). IV morphine decreased tactile allodynia but had noeffect on other neuropathic pain components in SCI and poststroke patients ( Attal 2002 Level II
EH, n=21, JS 5). Tramadol was effective for the treatment of neuropathic pain after SCI but theincidence of adverse effects was high (Norrbrink 2009 Level II, n=35, JS 4). A review of animal studies
is concerning here as it shows that high doses of opioids in the acute (<14 d) period following SCI
may be associated with impaired locomotor recovery and increased risk of the development ofpain and infection (Woller 2013 BS). Although these findings have not been verified in clinicalstudies, they suggest the need for caution in administering high doses of opioids in the acuteperiod post injury.
8.2.2.2 | Ketamine
Ketamine infusion decreased acute (see above) and chronic neuropathic pain in SCI patients.
IV Ketamine is superior to placebo and comparable to IV lignocaine and IV alfentanil in thetreatment of pain after SCI (Teasell 2010 Level I, 2 RCTs [ketamine], n=19).
8.2.2.3 | Membrane stabilisers
There is good evidence to support the effectiveness of lidocaine and mexiletine, when data fromneuropathic pain studies done in a variety of conditions including neuropathic SCI pain aregrouped together (Challapalli 2005 Level I [Cochrane], 30 RCTs, n=750). However, the effects in SCI
specifically are mixed. IV lidocaine reduced neuropathic pain in SCI ( Finnerup 2005a Level II, n=24,
JS 5) and reduced spontaneous pain and brush allodynia in central pain ( Challapalli 2005 Level I[Cochrane], 1 RCTs: Attal 2000 Level II, n=16, JS 4). Other trials have found that lidocaine reduced
pain >50% in only one of ten SCI patients (Challapalli 2005 Level I [Cochrane], 1 RCT: Kvarnstrom 2004
Level II, n=10, JS 5) and that mexiletine was ineffective (Challapalli 2005 Level I [Cochrane], 1 RCT:
Chiou-Tan 1996 Level II, n=11, JS 2). Lidocaine is most effective in the treatment of neuropathic pain
due to peripheral nerve lesions (Kalso 1998 Level I, 17 studies, n=450).
8.2.2.4 | Antidepressants
There is lack of evidence to support the effectiveness of antidepressants (amitriptyline,
duloxetine, venlafaxine and trazadone) in people with neuropathic SCI pain, except in those with514

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co-existing depression (Mehta 2016 Level I, 5 RCTs, n=295). There are no studies of SSRIs in thetreatment of central neuropathic pain (Finnerup 2005b Level I, 0 RCTs [SSRIs], n=0). An RCT ofamitriptyline vs lamotrigine found that both medications were effective in reducing neuropathic
SCI pain, with no difference between the two medications (Agarwal 2017 Level II, n=147, JS 3).
8.2.2.5 | AnticonvulsantsAlpha-2-delta ligands (gabapentin and pregabalin) are effective for the treatment of neuropathic
pain after SCI (Mehta 2016 Level I, 10 RCTs, n=567).
Lamotrigine reduced spontaneous and evoked pain in patients with incomplete SCI (Finnerup
2002 Level II, n=30, JS 5). Valproate was ineffective in the treatment of SCI pain ( Drewes 1994 Level II,
n=20, JS 3).
8.2.2.6 | Cannabinoids
The cannabinoid dronabinol did not reduce pain intensity in people with chronic neuropathic SCI
pain (Rintala 2010 Level II, n=7, JS 5). Inhalation of vaporized cannabis (delta 9-THC) vs placebo
reduced neuropathic SCI pain over an 8 h period (NNT30% 4 [95%CI 2.1 to 25.3] for 2.9% and
NNT30% 3 [95%CI 1.6 to 4.2] for 6.7%) although with dose-dependent psychoactive side effects(Wilsey 2016 Level II EH, n=42 [crossover], JS 4).
8.2.2.7 | Intravenous anaesthetics
An IV bolus of low-dose propofol reduced the intensity of central neuropathic pain and allodynia
for up to 1 h in approximately 50% of patients (Canavero 2004 Level II, n=21, JS 4).
8.2.2.8 | Botulinum toxin
SC injection of botulinum toxin type A (200 U total) into the painful area in people withneuropathic SCI pain reduced pain intensity when measured at 4 and 8 wk (VAS -18.6  16.8 and-21.3  26.8 respectively) following injection (Han 2016 Level II, n=40, JS 5).
8.2.2.9 | Baclofen
IT baclofen had an analgesic effect in patients with spinal cord lesions and reduced spasticity(Kumru 2018 Level II, n=13, JS 4).
8.2.2.10 | Palmitoylethanolamide (PEA)
Ultramicronised palmitoylethanolamide (PEA) for 12 wk had no analgesic or other effecton neuropathic pain after spinal cord injury (Andresen 2016 Level II, n=73, JS 5).
8.2.2.11 | Nonpharmacological treatments
There is currently insufficient evidence to support the effectiveness of TENS, acupuncture, selfhypnosis or cognitive behavioural therapy for chronic pain in SCI (Boldt 2014 Level I [Cochrane],
16 RCTs, n=616).
A systematic review found transcranial direct current stimulation (tDCS) reduces chronic
neuropathic SCI pain immediately post treatment, but not at follow-up (Mehta 2015 Level I, 4 RCTs,n=57). A more recent RCT found that significant improvements up to 4 wk post treatment with
tDCS could be demonstrated if the initial 5 d of treatment was followed by a second 10 d periodof treatment 3 mth later (Thibaut 2017 Level II, n=9, JS 3).
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Repetitive transcranial magnetic stimulation (rTMS) of the prefrontal cortex was found toresult in a significant reduction in neuropathic SCI pain, but this was only maintained for one day
following treatment (Nardone 2017 Level II, n=12, JS 2).
Virtual reality techniques to create leg illusions demonstrated a modest and non-significant
reduction in pain intensity (Pozeg 2017 Level II, n=20, JS 2). Virtual walking resulted in a greater
reduction in pain intensity than virtual wheeling, but the pre to post change was not significant(Jordan 2016 Level IV, n=50).
Breathing controlled electric stimulation has an immediate analgesic effect on chronic
neuropathic SCI pain, with no augmentation when combined with tDCS (Li 2018a Level III-2, n=12).

8.2.3 | Treatment of nociceptive and visceral pain after spinal cord injury
There is no specific evidence to guide the treatment of acute nociceptive and visceral pain in SCI
patients. Treatment is therefore based on evidence from other studies of nociceptive andvisceral pain and is usually directed at treating the specific underlying cause of the pain.

KEY MESSAGES
1. Alpha-2-delta ligands (gabapentin/pregabalin) are effective in the treatment ofneuropathic pain following spinal cord injury (S) (Level I).
2. Antidepressants (amitriptyline, duloxetine and venlafaxine) are effective in thetreatment of neuropathic pain following spinal cord injury but only in those with comorbid depression (N) (Level I).
3. Intravenous opioids, ketamine ((U) (Level I), lidocaine and tramadol are effective in thetreatment of neuropathic pain following spinal cord injury (U) (Level II).
The following tick box represents conclusions based on clinical experience and expert
opinion: Treatment of acute spinal cord injury pain is largely based on evidence from studies ofother neuropathic and nociceptive pain syndromes (U).
 There is currently insufficient evidence to support non-pharmacological treatments(TENS, acupuncture, self-hypnosis or cognitive behavioural therapy) for spinal cord
injury pain (N).

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8.3 | Chest trauma (Rib fractures)
Rib fractures occur in approximately 10% of multi-trauma patients (Flagel 2005 Level IV, n=732,823;
Ziegler 1994 Level IV, n=7,147). This is also a common injury in the elderly population, often withserious consequences (Christie 2019 NR). There are multiple complications associated with rib
fractures such as pneumonia, aspiration, atelectasis and acute respiratory distress syndrome(Witt 2017 NR). The prevention of such complications relies on high quality analgesia andaggressive physical rehabilitation. General recommendations are to implement a protocolised
bundled clinical pathway (Witt 2017 GL).

8.3.1 | Paracetamol
A single dose of IV paracetamol 1 g vs IV morphine (0.1 mg/kg) had similar analgesic effects andadverse event rates (Esmailian 2015 Level II, n=54, JS 5).

8.3.2 | NSAIDS
Regular IV ibuprofen reduced pain scores over the 7 d study period and IV morphine
requirements on d 3 to 7 vs control (Bayouth 2013 Level III-3, n=42). Regular IV ketorolac reduced
the incidence of rib fracture related pneumonia vs control (Yang 2011 Level III-3, n=619).

8.3.3 | Adjuvant medications
IV ketamine infusions (0.1-0.15 mcg/kg/hr) reduced pain scores and opioid requirements (Carver
2019 Level II, n=91, JS 5; Walters 2018 Level III-3, n=30). There were no other benefits with regard tooutcome.
IV dexmedetomidine (1 mcg/kg loading followed by 0.5mcg/kg/h infusion) was inferior to thoracic
epidural analgesia in terms of pain and sedation scores (Mahmoud 2016 Level II, n=58, JS 2).
Regular gabapentin (300mg) provided no benefit in terms of pain scores, opioid requirement
and adverse events (Moskowitz 2018 Level II, n=40, JS 5).
Lignocaine patches (5%) showed no difference vs placebo with regard to pain scores, opioid
consumption, LOS or adverse outcomes (Ingalls 2010 Level II, n=58, JS 5). Another study showed areduction in pain scores, but no effect on morphine consumption or adverse events ( Zink 2011
Level III-3, n= 58). A further study showed no benefit in the first 4 d, but then reduced pain scoresfrom the fifth day, reduced opioid requirements and LOS (Cheng 2016 Level II, n=44, JS 3).

8.3.4 | Epidural analgesia
Thoracic epidural analgesia vs systemic IV analgesia (5 RCTs & 6 studies, n=1,057) improves painscores (4 RCTs) (Peek 2019 Level III-2 SR [PRISMA], 8 RCTs & 11 studies, n=2,081). There was no
significant difference in secondary outcomes such as hospital LOS (4 RCTs, n=130 & 4 studies,n=523), ICU LOS (4 RCTs, n=118 & 4 studies, n=501), duration of mechanical ventilation (3 RCTs, n=94
& 1 study, n=165) and pulmonary complications (widely variable rates) (4 RCTs, n=126 & 6 studies,
n=907). Thoracic epidural analgesia achieves similar pain scores vs continuous intercostal (1 RCT,
n=60 & 1 study n=169) and vs paravertebral blocks (1 RCT, n=30 & 2 studies, n=1,224), with nodifference in hospital LOS, ICU LOS, duration of mechanical ventilation and pulmonary
complications (0 to 13.3%) (2 or 3 studies each outcome: 6 studies, n=1,045).
Dexmedetomidine/bupivacaine via thoracic epidural catheters improved pain scores slightly vsbupivacaine alone (Agamohammdi 2018 Level II, n=64, JS 2).
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8.3.5 | Peripheral regional analgesia
Continuous paravertebral and intercostal blocks are effective regional analgesia techniques
providing analgesia superior to IV systemic analgesia (1 study [PVB], n=54; 1 study [ICB], n=90) andequivalent to thoracic epidural analgesia (see above) (Peek 2019 Level III-2 SR [PRISMA], 8 RCTs &11 studies, n=2,081).
Interpleural blocks did not provide analgesia superior to placebo blocks (Short 1996 Level II,
n=16, JS 5) and were inferior to epidural analgesia (Luchette 1994 Level IV, n=19).
Serratus anterior blocks (Iotti 2019 Level IV, n=3; Jadon 2017 Level IV, n=6; Camacho 2019 CR; Fu
2017 CR) and erector spinae plane blocks (ESPB) (Luftig 2018 Level IV, n=3; Nandhakumar 2018 Level
IV, n=2; Hamilton 2017 CR) are described as effective analgesic options after rib fractures. ESPBs
reduced pre to post insertion pain scores in patients with up to seven or more rib fractures(Adhikary 2019 Level IV, n=79).

8.3.6 | Surgical fixation
Surgical fixation vs non-surgical treatment in patients with three or more fractured ribs
reduces duration of ventilation ( Level I, 3 RCTs; Level III-2 SR, 1 RCT & 4 studies), need fortracheostomy (Level I [Cochrane], 2 RCTs; Level III-2 SR, 1 RCT & 6 studies) and intensive care LOS(Level I, 3 RCTs; Level III-2 SR, 1 RCT & 2 studies), pneumonia (Level I [Cochrane], 3 RCTs; Level III-2 SR,
2 RCTs & 6 studies), hospital LOS (Level I, 2 RCTs; Level III-2 SR, 1 RCT & 6 studies ) and mortality(OR 0.28; 95%CI 0.08 to 0.92) ( Level III-2, 3 studies); pain and opioid requirements were notassessed (Cataneo 2015 Level I [Cochrane], 3 RCTs, n=123; Schuurmans 2017 Level I, 3 RCTs, n=123 [all3 RCTs overlap]; Liu 2019c Level III-2 SR [PRISMA], 2 RCTs and 12 studies, n=839 [1 RCT overlap] ). There
was contradictory information on hospital costs; significant reduction ( Level I, 2 RCTs) andsignificant increase (Level III-2, 3 studies) respectively.

8.3.7 | Non-pharmacological therapy
TENS was superior to regular naproxen (275 mg tds) in terms of pain scores for up to 3 d (Oncel
2002 Level II, n=100, JS 4). Acupuncture vs sham acupuncture on top of background ibuprofen
reduced pain on deep breathing and coughing for up to 6 h on each of 3 d of treatment (Ho 2014
Level II, n=58, JS 4).

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1. Surgical fixation in patients with 3 or more fractured ribs improves outcome withregard to incidence of pneumonia and need for tracheostomy (N) (Level I [Cochrane
Review]), duration of ventilation, ICU and hospital stay (N) (Level I) and mortality (N)(Level III-2 SR).
2. Continuous thoracic epidural analgesia and continuous intercostal and paravertebral
blocks provide similar analgesia and are superior to intravenous opioids for rib fracture
related pain (N) (Level I [PRISMA]).
3. Systemic NSAIDs and ketamine are efficacious analgesic adjuvants for rib fracture
related pain (N) (Level III-3)
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Emerging regional techniques such as serratus anterior and erector spinae plane blocks(single shot and continuous infusion) are supported by case series and could beconsidered for rib fracture analgesic management (N).
 Chest trauma with rib fractures carries a high risk of potentially life-threatening
complications; excellent analgesia and aggressive physical rehabilitation, ideallyprovided in a protocolised clinical pathway, can improve outcome (N)

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8.4 | Acute pain after hip (neck of femur) fractures
Hip fractures occur in 199 to 240/100 000 people per year in Australia and New Zealand (AIHW
2018b Level IV; HQSC 2018 Level IV) and cause significant morbidity and mortality largely due topatient age (mean age 84 y), cognitive impairment (39%) and pre-existing co-morbidities(majority ASA 3 or above) (ANZFHR 2018 Level IV, n=9,408). Three mth following a hip fracture,mortality is 10%, and although 71-76% of people have returned home, only 23-26% will haveachieved pre-injury mobility.
Pain is a significant feature of a hip fracture, causing discomfort and distress to the person
and family, thus satisfactory analgesia is a critical aspect of care. Risk factors for severe postoperative pain in the immediate post-operative period include level of education, cognitive
function, preoperative delirium and depression (Radinovic 2014 Level III-2, n=344).
Delirium following hip fracture is common (24% of patients) (Yang 2017 Level III-2 SR, 24 studies,
n=5,364) and is associated with increased 1 y mortality (Ruggiero 2017 Level III-2, n=514; Mitchell2017 Level III-2, n=27,888). Risk factors for developing postoperative delirium are older age, preadmission aged care facility residency, multiple co-morbidities, pre-existing cognitive
impairment and morphine use (Yang 2017 Level III-2 SR, 24 studies, n=5,364; Smith 2017b Level III-2
SR, 32 studies, n=6,704) (17 studies overlap). Effective analgesia provision is an important factor to
reduce the risk of delirium (ANZFHR Steering Group 2014 GL).
Surgical intervention is often the most effective form of analgesia and is one of the main
drivers to timely access to surgery ( ANZFHR Steering Group 2014 GL). Arthroplasty techniques areassociated with less pain and opioid requirements than internal fixation, dynamic hip screw orintramedullary nail (A'Court 2017 Level III-2, n=357; Salpakoski 2016 Level III-2, n=136).
Hemiarthroplasties performed with cement ( Ng 2014 Level III-2, n=197) and minimally invasive
anterior approach (Pala 2016 Level III-2, n=89) have less post-operative pain than non-cemented
or posterolateral approach hemiarthroplasties.
Guidelines to direct care of hip fracture patients are published ( ANZFHR Steering Group 2014
GL); integrated orthogeriatric care, utilisation of care bundles and adherence to clinical carestandards improves outcomes in hip fracture patients (ACSQHC 2016 GL).

8.4.1 | Nerve Blocks
In 2017, on average 36% of patients in New Zealand and 66% of patients in Australia received anerve block before hip fracture surgery, whilst overall 78% had a nerve block during admission(ANZFHR 2018 Level IV, n=9,408). No major complications due to peripheral nerve blocks for hip
fractures have been reported in the literature (Guay 2017 Level I [Cochrane], 31 RCTs, n=1,760).
8.4.1.1 | Pain Relief
Peripheral nerve blocks (pooled data) decrease pain at rest and movement within 30 min of block
placement (SMD -1.41; 95% CI -2.14 to -0.67 [equivalent to -3.4/10]) (8 RCTs, n=373) vs systemic
analgesia (Guay 2017 Level I [Cochrane], 31 RCTs, n=1,760). Femoral nerve blocks (FNB) (Hartmann2017 Level I, 2 RCTs, n=84) and fascia iliaca compartment blocks (FICB) (Steenberg 2018 Level I,
11 RCTs, n=1,062) performed before positioning lead to less pain and shorten time to performing
spinal anaesthesia vs IV opioids alone.
When performed in the emergency department or on admission, FICB ( Hong 2019 Level I[PRISMA], 11 RCTs, n=937; Steenberg 2018 Level I, 11 RCTs, n=1,062) (8 RCTs overlap), FNB (Riddell 2016
Level I, 7 RCTs, n=224) or 3-in-1 blocks (4 RCTs, n=199) (Ritcey 2016 Level I [PRISMA], 9 RCTs, n=547) are520

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superior to systemic opioids in reducing pain on movement, decrease preoperative opioid
requirements and lengthen time to rescue analgesia. These findings are consistent even inpatients with dementia (Unneby 2017 Level II, n=266, JS 2).
Nerve blocks decrease pain at rest 6 to 8 h after surgery and reduce pain at rest, opioid
requirements, time to first mobilisation and lead to higher patient satisfaction up to 24 h after
surgery (Guay 2017 Level I [Cochrane], 31 RCTs, n=1,760). There is no reduction in pain on movement
6 to 8 and 24 h after surgery, or pain on rest or movement 48 to 72 h after surgery.
Single injection PNBs and CPNBs (pooled data) are equivalent in effect 24 h after surgery(4 RCTs, n=195); CPNBs do not improve pain on movement or at rest 48 h (5 RCTs, n=335) and 72 h
(2 RCTs, n=140) after surgery (Guay 2017 Level I [Cochrane], 31 RCTs, n=1,760). However, CPNBs vssystemic analgesia reduced postoperative pain, opioid requirements, opioid adverse effects,
time to mobilisation and resulted in more frequent discharge home (Arsoy 2017a Level III-3, n=265;
Arsoy 2017b Level III-3, n=29; Morrison 2016 Level II, n=161; JS 5).
8.4.1.2 | Prevention of other complications
Moderate quality evidence demonstrates that PNBs (pooled data) reduce the risk of pneumonia
vs systemic analgesia (RR 0.41; 95%CI 0.19 to 0.89) (NNT 7) (3 RCTs, n=131) (Guay 2017 Level I[Cochrane], 31 RCTs, n=1,760). PNBs do not decrease the risk of acute confusional states, acute
myocardial infarction/ischaemia or 6 mth mortality; although evidence was low to very low
quality. FICB led to better abbreviated mental test scores following hip fracture surgery vssystemic analgesia (Odor 2017 Level III-2, n=959).
8.4.1.3 | Nerve Block Technique
There is no evidence for superiority of a particular nerve block or its insertion technique(Steenberg 2018 Level I, 11 RCTs, n=1,062; Riddell 2016 Level I, 7 RCTs, n=224; Ritcey 2016 Level I, 9 RCTs,
n=547) (significant overlap of all 3 SRs). US guided 3-in-1 blocks and landmark guided FICBs areequivalent for pain reduction at 30 and 60 min after intervention (Reavley 2015 Level II, n=178,
JS 3). Nerve stimulator guided FNB reduced pain scores and opioid requirements more thanlandmark guided FIC blocks, but the reduction (-0.9/10) was felt not to be clinically significant(Newman 2013 Level II, n=107, JS 3).
8.4.1.4 | High volume local anaesthesia infiltration
High volume, low concentration (75 mL containing 200 mg ropivacaine [0.266 %]) local
anaesthetic fracture, capsular and tissue infiltration followed by post-operative boluses (20 mL
containing 100 mg ropivacaine [0.5%]) via surgically placed catheter did not reduce
postoperative pain or opioid consumption vs placebo (Bech 2018 Level II, n=74, JS 5).
Periarticular infiltration with bupivacaine (50 mL of 0.25%) followed by liposomal bupivacaine(20 mL diluted into 40 mL) did not result in significantly better pain control or less opioid
requirements vs no local anaesthetic infiltration (Hutchinson 2019 Level III-2, n=178). However, LOS
was lower by 1.1 d and patients were more likely to be ambulatory on discharge (82% vs 69%) if
they had received high volume local anaesthetic infiltration.

8.4.2 | Systemic analgesia
Generally, post-operative analgesia administered on a regular time-based regime leads to lesspain vs prn regimens (Di Filippo 2015 Level III-2, n=131). Choice and dose of analgesia should be
age appropriate with close monitoring for associated side effects (ANZFHR Steering Group 2014 GL).
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8.4.2.1 | Paracetamol
Regular paracetamol should be prescribed every 6 h unless contra-indicated (ANZFHR SteeringGroup 2014 GL); dose adjustments should be considered (older age, malnutrition, low bodyweight) (see Section 4.1.3.). When compared to oral paracetamol, patients administered IV
paracetamol had lower pain scores, less opioid use and shorter hospital LOS ( Sanzone 2016 Level
III-3 SR, n=332). Paracetamol prescribed on discharge is not associated with increased 6 mth
mortality, falls or hospital readmission (Harstedt 2016 Level III-2, n=272)
8.4.2.2 | NSAIDs
Development of acute kidney injury (AKI) following hip fracture surgery ranges from 11 to
24% and is associated with higher mortality. Risk factors for developing AKI include male sex,
older age, number of co-morbid conditions, antihypertensives (particularly ACE-inhibitors
and ATRA2-antagonists), pre-existing renal impairment, hypalbuminaemia and obesity (Shin2018 Level III-2, n=481; Porter 2017 Level III-2, n=2,959; Hong 2017 Level III-2, n=450; Pedersen 2017
Level III-2, n=13,529; Pedersen 2016 Level III-2, n=13,259 ). NSAIDs are not an independent risk
factor for developing AKI in hip fracture patients ( Hong 2017 Level III-2, n=450; Pedersen 2016
Level III-2, n=13,259). In the largest population-based study, NSAIDs were prescribed to 12.3%
of patients who developed AKI vs 14.2% of patients who did not ( Pedersen 2016 Level III-2,
n=13,259).

Caution should be exercised when considering NSAIDs in hip fracture patients, due to thepredominantly older population with co-existent disease; however time limited use of
NSAIDs may be clinically appropriate and relatively safe for short term use in patients withpreserved renal function ( Hong 2017 Level III-2, n=450; ANZFHR Steering Group 2014 GL). A
retrospective analysis using data from 2003 to 2016 looking at transfusion risk for hip
fractures found a small increase in risk of transfusion with preoperative NSAID use within
90 d of surgery (RR 1.07; 95%CI 1.04 to 1.10) ( Glassou 2019 Level III-2, n=74,791 ). There isinsufficient evidence to conclude whether NSAIDs are associated with other complications
in hip fracture patients or to compare analgesic regimes with and without NSAIDs.
8.4.2.3 | Conventional and atypical opioids
Additional opioids should be offered if non-opioids alone do not provide sufficient pain relief(ANZFHR Steering Group 2014 GL). Ninety-five percent of hip fracture patients receive opioids
during their admission ( Lindestrand 2015 Level IV, n=416). Opioid analgesia is part of standard
systemic analgesia in the majority of studies ( Guay 2017 Level I [Cochrane], 31 RCTs, n=1,760 ).
Continuous IV morphine infusion (0.01 mg/kg/h) provides similar pain scores and rescue
analgesia requirements as regular paracetamol, but was associated with more complications
requiring cessation (Di Filippo 2015 Level III-2, n=131). Compared to other patients, hip fracture
patients with dementia and cognitive impairment receive less opioid analgesia (Moschinski 2017
Level I [PRISMA], 17 RCTs, n=4,249; Jensen-Dahm 2016 Level III-2, n=1,507). High prevalence of renal
impairment (11-24%) and association of morphine use with increased risk of postoperativedelirium in hip fracture patients (OR 3.01; 95%CI 1.30 to 6.94) would suggest that if opioids
are required, those not relying on renal elimination should be used in th is cohort (Yang 2017
Level III-3 SR, 24 studies, n=5,364 ).
Pre-existing chronic opioid use occurs in approximately 1 in 4 hip fracture patients(Lindestrand 2015 Level IV, n=416) and is associated with increased risk of hip fracture (RR 1.54;
95%CI 1.34 to 1.77) (Ping 2017 Level I, 10 RCTs, n=697,011).

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Eighty-one percent of hip fracture patients are discharged on opioids with 30% still onprescribed opioids 6 mth later (Lindestrand 2015 Level IV, n=416). Pre-existing opioid use andosteoporosis were the most significant factors associated with continued use at 6 mth.
Conflicting evidence exists regarding opioids and mortality in hip fracture patients. One study
found that discharge opioids were associated with an increased risk (OR 2.95; 95%CI 1.19 to 7.34)
of mortality within 6 mth of surgery (Harstedt 2016 Level III-2, n=272), whereas another study
found that opioids were not associated with increased risk at 30 d, 6 mth or 1 y ( Lindestrand 2015
Level IV, n=416).
Tramadol
Following hip fracture surgery, patients prescribed tramadol on discharge had an increased riskof hospital readmission (OR 2.84) within 6 mth due to falls (Harstedt 2016 Level III-2, n=272). Thereis insufficient evidence to compare perioperative analgesic regimes with and without tramadol.
8.4.2.4 | Acupuncture
Auricular acupressure performed during prehospital transport led to better pain relief after hip
fracture (Barker 2006 Level II, n=38, JS 5).

KEY MESSAGES
1. Lower limb nerve blocks with local anaesthetics reduce pain, analgesia requirements
and lengthen time to rescue analgesia in hip fracture patients compared to systemic
analgesia; there is no advantage of a specific nerve block, insertion technique orcontinuous versus single injection administration (S) (Level I [Cochrane Review]).
2. Lower limb nerve blocks decrease the risk of pneumonia in hip fracture patients, but
do not decrease the risk of delirium, myocardial infarction/ischaemia or mortality (N)(Level I [Cochrane Review]).
3. Morphine should be avoided due to increased risk of delirium in hip fracture patients,
who have a high prevalence of renal impairment (N) (Level III-3 SR).
4. Arthroplasty techniques in hip fracture patients are associated with less pain andopioid requirements than non-arthroplasty techniques (N) (Level III-2).
The following tick box represents conclusions based on clinical experience and expert
opinion: Integrated orthogeriatric care, utilisation of care bundles and adherence to clinical carestandards improve outcomes in hip fracture patients (N).

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8.5 | Acute burns injury pain
Acute pain following burns injury can be nociceptive and/or neuropathic in nature ( Nelson 2019
NR; Gray 2008a NR) and may be constant (background pain), intermittent or procedure-related.
Itch can also be a significant symptom (for details see Section 10.9.2.3). The multifacetedcharacter of burns injury pain requires a broad-based assessment tool for clinical application andresearch, which is currently not available (Mahar 2012 Level I, 25 RCTs, n≈800).
Burns pain is often undertreated, particularly in the elderly ( Choiniere 2001 NR). However,effective pain management after acute burns injury is essential, not only for humanitarian andpsychological reasons but also to facilitate procedures such as dressing changes andphysiotherapy and possibly to minimise the development of chronic pain, which is reported in
18–58% of burns patients ( Browne 2011 Level IV, n=492; Dauber 2002 Level IV, n=358; Choiniere
1989 NR).
More severe acute pain following burns injury leads to a greater risk of post-traumatic stressdisorder (McGhee 2011 Level IV, n=113; Browne 2011 Level IV, n=492). Increased early use of opioids
in children with burns injury reduces post-traumatic stress symptoms up to 4 y after the injury(Sheridan 2014 Level III-3, n=147 [paediatric]).
There is limited evidence for the management of pain in burns injury, and treatment
continues to be largely based on evidence from several randomised clinical trials, case reports
and case series, or data extrapolated from other relevant areas of pain medicine. The use of ahighly protocolised pain management flowchart may be helpful in improving the pain experience(Yang 2013 Level III-3, n=107).
For paediatric information, see also Section 10.9.2.

8.5.1 | Management of background nociceptive pain
Immediately after the injury, simple measures such as cooling ( Davies 1982 NR), covering andimmobilising the burn may provide analgesia (Allison 2004a GL; Gallagher 2000b NR; Kinsella 1991
NR). Cooling under running tap water for ≥20 min or the application of a wet towel (ANZBA 2014
GL) is supported by porcine data (Rajan 2009 BS) and is useful up to 3 h post initial burn injury.
Temporary burns dressings such as thin film plastic “cling” wrap (or clean sheets if unavailable)
reduce pain caused by contact and draft; they should not be applied circumferentially as swellingis inherent (ANZBA 2014 GL; Allison 2004a GL).
In the initial presentation of severe burn, analgesia is best achieved by titration of IV opioids.
Absorption of IM and SC opioids may be unreliable in the presence of hypovolaemia andvasoconstriction associated with burns (Kinsella 2008 NR). PCA with morphine is effective forburns pain in adults (Choiniere 1992 Level II, n=24, JS 4; Lin 2019c Level IV, n=23) and children(Gaukroger 1991 Level IV, n=11).
The addition of dexmedetomidine to an IV PCA (0.5 mcg/kg dexmedetomidine loading 10 min
before induction, then 200 mcg to 100 mcg sufentanil per IV PCA bolus) vs IV PCA sufentanil only
reduced rest and dynamic pain as well as opioid consumption slightly and improved recovery
scores in the first 24 h after burns surgery (Jiang 2019 Level II, n=60, JS 5); however, the bolus doseof sufentanil was quite low and therefore this may have biased towards a positive response in
the combination group.
Conversion to oral opioids is possible once normal gastrointestinal function has returned;even severe burns injury does not affect gastric emptying or the absorption of oral paracetamol(Hu 1993 Level III‐2 PK, n=30).

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5th Edition | Acute Pain Management: Scientific Evidence8.0 | SPECIFIC CLINICAL SITUATIONSMorphine doses do not require adjustment in burns injury, as its pharmacokinetics areunchanged in burns patients (Kinsella 2008 NR; Perreault 2001 PK).
In the ICU, intrathecal (IT) infusion of morphine has been reported as a method to control burns
pain and thereby avoiding the adverse effects of systemic opioids (Zuehl 2018 CR).

8.5.2 | Management of acute neuropathic pain and hyperalgesia
Animal and human volunteer studies in burns injury have shown that secondary hyperalgesia
develops around the injured site. In addition, burns injury results in damage to cutaneous
nociceptors and conducting neurons that may lead to acute neuropathic pain. There is growing
evidence that the addition of antihyperalgesic agents is an important part of multimodal
treatment of burn injury pain. This is also relevant in view of the development of pruritus in thecontext of burns injury. Evidence based guidelines for post-burn pruritus recommend cetirizine
and cimetidine as first line and loratadine as second line peripherally acting agents, gabapentin
as a first line centrally acting agent, and laser therapy and pressure garments as possible
nonpharmacological interventions (Goutos 2010 GL). Combination therapy is commonly used andshould be implemented in a judicious stepwise fashion that includes peripherally acting, centrally
acting and nonpharmacological interventions early.
Gabapentin reduced pain and opioid consumption following acute burns injury ( Cuignet 2007
Level III-3, n=20) and reduced neuropathic pain descriptors in a small case series ( Gray 2008b
Level IV, n=6).
Pregabalin reduced pain in outpatient burns patients ( Wong 2010 Level IV, n=24) and reduced“hot” and “sharp” pain as well as itch and procedural pain in severe burns injury ( Gray 2011
Level II, n=90, JS 5).
Parenteral methylprednisolone or ketorolac reduced secondary hyperalgesia surrounding anexperimental burns injury in human volunteers; however further clinical research is required
prior to recommending these agents (Stubhaug 2007 Level II, n=12, JS 5).
There is also evidence in a burns injury model in human volunteers for beneficial effects ofketamine (McGuinness 2011 Level I EH, 4 RCTs, n=67) and dextromethorphan (Ilkjaer 1997 Level II EH,
n=24, JS 3). Although ketamine is effective as an analgesic and reduces secondary hyperalgesia
without relevant adverse effects, the limitations of the studies (no clinical studies, heterogeneityof results, small study size) preclude any definitive recommendations on clinical use of ketamine
in a burns setting (McGuinness 2011 Level I EH, 4 RCTs, n=67).

8.5.3 | Management of procedural pain
Treatment and rehabilitative procedures for burns patients may be associated with frequent andprolonged periods of pain. It was previously reported that up to 84% of burns patients experienceextreme and intense pain during therapeutic procedures (Ashburn 1995 NR). Analgesic strategies
have more recently improved, but managing procedural pain remains a significant and ongoingchallenge that requires a balance of pharmacological and nonpharmacological approaches.
8.5.3.1 | Opioids
Opioid therapy is the mainstay of analgesia for burns procedures. However, very high doses may
be required (Linneman 2000 Level IV, n=55) and opioid-related sedation and respiratory depression
may develop when the pain stimulus decreases following the procedure.
Short-acting opioids such as fentanyl (Prakash 2004 Level II, n=60, JS 4) or alfentanil (Sim 1996
Level IV) administered via PCA or target-controlled IV infusions (Gallagher 2000a Level IV, n=10)
successfully provide analgesia during burns dressing changes. IN fentanyl was a viable alternative
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to oral morphine in children for burns dressings ( Borland 2005 Level II, n=28, JS 4). In adults, there
was no difference in pain scores or rescue analgesic requirements between IN fentanyl and oral
morphine for burns dressings (total surface less than 26%) ( Finn 2004 Level II, n=26, JS 5). Oraltransmucosal fentanyl provided similar analgesia to oral oxycodone ( Sharar 2002 Level II, n=20,
JS 4) and hydromorphone (Sharar 1998 Level II, n=14, JS 4) with a similar adverse-effect profile inchildren and adolescents. See also Section 10.9.4.
8.5.3.2 | Adjuvant medications
N2O, ketamine and IV lidocaine infusions (Jonsson 1991 Level IV, n=7) have also been used toprovide analgesia for burns procedures (see Sections 4.5.1, 4.6.1 and 4.4.1). However, efficacyof IV lidocaine for procedural pain could not be confirmed in an RCT ( Wasiak 2011 Level II, n=45,
JS 5) and a subsequent Cochrane review found no further trials ( Wasiak 2014a Level I [Cochrane],
1 RCT, n=45; see above).
A systematic review of ketamine in volunteers with a burns injury model has been discussed
above (McGuinness 2011 Level I EH, 4 RCTs, n=67). PCA with a ketamine/midazolam mixture was
effective and well tolerated when used for analgesia and sedation during burns dressings(MacPherson 2008 Level IV, n=44). In children aged 12 to 36 mth with major burns requiring deep
sedation for dressings, a propofol/remifentanil infusion was as effective as a propofol/ketamine
infusion, but had a faster recovery (Seol 2015 Level II, n=50, JS 5). Oral ketamine/midazolam may
provide superior pain reduction vs an oral midazolam/paracetamol/codeine combination forburns dressing changes in children aged 1 to 5 y (Norambuena 2013 Level III-1, n=60).
IM ketamine/tramadol/ dexmedetomidine was found to be more effective thanIM ketamine/tramadol/midazolam or IM ketamine alone in adult burns patients ( Zor 2010 Level
III-1, n=24). In contrast, there was no difference in the pain experience between three groups
receiving ketamine/midazolam, ketamine/dexmedetomidine or ketamine alone in the samesetting (Gunduz 2011 Level II, n=90, JS 3). Oral ketamine was better than oral dexmedetomidine forpain reduction during dressing changes in adult burns patients ( Kundra 2013 Level II, n=30, JS 4).
The heterogeneous nature of the studies and the lack of pain outcome data in a meta-analysis
of dexmedetomidine in burns patients mean no conclusions can be drawn as to its effect on burnpain (Asmussen 2013 Level I, 4 studies, n=266). Only improved sedation is identified.
Sedation and anxiolysis as an adjunct to analgesia can improve pain relief. This has beenshown for lorazepam combined with morphine (Patterson 1997 Level II, n=79, JS 5). However, aretrospective case series of patients receiving midazolam for dressing changes did notdemonstrate a reduction in overall pain or opioid use during the hospital admission ( Bidwell 2013
Level III-2, n=36). Patient-controlled sedation with propofol may also be effective ( Coimbra 2003
Level IV, n=20). A propofol/ketamine combination resulted in less “restlessness” during burns
dressing changes vs a propofol/fentanyl combination, with no difference in emergencephenomena (Tosun 2008 Level II, n=32, JS 5).
Inhaled methoxyflurane may be helpful for dressing changes for burns patients in an
ambulatory setting but further evidence is required prior to recommending routine use ( Wasiak
2014b Level IV, n=15).
Topical analgesic techniques, such as lidocaine as a cream (Brofeldt 1989 Level IV, n=30) or aspray (Desai 2014 Level II, n=29, JS 5) or morphine-infused silver sulfadiazine cream (Long 2001
Level IV, n=4) may be effective; however a topical gel dressing containing morphine was not more
effective than other gel dressing in reducing burns injury pain in the ED (Welling 2007 Level II, n=59,
JS 5). The use of biosynthetic dressings is associated with a reduction in pain during dressingchanges and a decrease in time to healing (Wasiak 2013 Level I [Cochrane], 30 RCTs of various
dressings, n unspecified). The use of a soft silicone wound contact layer on split thickness skin grafts

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reduced pain on dressing changes in comparison to conventional dressings ( Patton 2013 Level II,
n=43, JS 2).
Puerarin, a Chinese herb extract, was found to be analgesic and anti-inflammatory for dressingchanges; however, the control group received no analgesia (Zhang 2013b Level II, n=32, JS 5).

8.5.4 | Regional analgesia for donor site pain management
Traditionally, regional analgesia is often avoided in burns patients due to the high incidence ofbacteraemia and bacterial colonisation. However, recent research suggests that well-selectedpatients may benefit from regional analgesia for donor site pain management.
US-guided local anaesthetic block of the lateral femoral cutaneous nerve in 16 consecutive
patients resulted in no pain 4 h after surgery at the donor site (lateral thigh) ( Shteynberg 2013
Level IV, n=16); however longer-term effects of this intervention are not known. Fascia iliaca
compartment block reduced dynamic, but not rest pain, at the skin donor site and injection of
local anaesthetic through the catheter placed in the compartment reduced pain at the first
dressing change on d 3 following surgery (Cuignet 2005 Level II, n=81, JS 3).

8.5.5 | Nonpharmacological pain management
Numerous non-pharmacological techniques have been described to assist in reducing the pain
and suffering of procedures necessary in burns management
Distraction techniques of virtual reality and hypnosis have the most beneficial effects on
reducing procedural pain, however with high heterogeneity of study effects (Scheffler 2018
Level I [PRISMA], 21 RCT, n=660). Stratified analysis suggest that relaxation alone is insufficient to
reduce procedural pain. Hypnosis provides benefit in pain and anxiety reduction but not
medication use for pain of burn wound care (Provencal 2018 Level I [PRISMA], 6 RCTs, n=234) (4 RCTs
overlap); however, the conclusion states that it may be premature to make hypnosis a generalclinical recommendation in the burn injured population. Indeed, a subsequent RCT found that
hypnosis had no benefit in pain reduction (Chester 2018 Level II, n=64, JS 5).
Virtual reality reduces pain intensity, time spent thinking about pain and unpleasantness (Luo2019 Level I [PRISMA], 13 RCTs, n=362; Scheffler 2018 Level I [PRISMA], 21 RCT, n=660) (4 RCTs overlap).
VR techniques in combination with pharmacological measures reduce the pain experience during
dressing changes and physiotherapy in children (Morris 2009 Level IV SR, 9 studies, n=152) (6 RCTs
overlap). Providing a VR service requires significant physical and staffing resources ( Markus 2009
Level IV, n=10). Simply watching television during burns care may be as effective as VR techniques
in reducing pain scores (van Twillert 2007 Level III-3, n=19) and use of commercially available video
games may be another option (Parry 2012 Level III-2, n=24).
Music interventions are helpful for pain alleviation, anxiety relief and heart rate reduction (Li2017b Level I [PRISMA], 17 RCTs, n=804).
Aroma therapy may reduce pain, anxiety and improve sleep quality, but the low quality oftrials with regard to randomisation and bias does not permit a conclusion ( Choi 2018 Level I[PRISMA], 4 RCTs, n=248).
Transcranial direct current stimulation (Hosseini Amiri 2016 Level II, n=60, JS 1) and whole body
vibration reduce pain and/or anxiety (Ray 2017 Level II, n=31, JS 3).

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KEY MESSAGES
1. The use of biosynthetic dressings is associated with a decrease in time to healing and areduction in pain during burns dressings changes (U) (Level I [Cochrane Review]).
2. Virtual reality distraction, augmented reality techniques and multimodal distraction
methods reduce pain and unpleasantness during burns dressings (S) (Level I [PRISMA]).
3. Music interventions are helpful in reducing pain, anxiety and heart rate in burns
patients (N) (Level I [PRISMA])
4. Opioids, particularly via PCA, are effective in burns pain, including procedural pain (U)(Level II).
5. Pregabalin reduces pain following acute burns injury (U) (Level II).
6. Sedation and anxiolysis with lorazepam improves procedural pain relief in acute burns
injury (U) (Level II).
7. Regional analgesia reduces donor site pain in selected burns patients (U) (Level II).
8. Gabapentin reduces pain and opioid consumption following acute burns injury (U)(Level III‐3).
9. PCA with ketamine and midazolam mixture provides effective analgesia and sedation
for burns dressings (U) (Level IV).
The following tick boxes represent conclusions based on clinical experience and expert opinion: Acute pain following burns injury can be nociceptive and/or neuropathic in nature andmay be constant (background pain), intermittent or procedure-related (U).
 Acute pain following burns injury requires aggressive multimodal and multidisciplinary
treatment and may benefit from protocolised management approaches (S). This isparticularly important as severely burn injured patients require repeated proceduresand frequently have persistent issues of chronic pain, pruritus, post-traumatic stressand other psychological consequences.
 Pruritus is a common symptom following burns injury and alpha-2-delta ligands areuseful in its management (N).

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8.6 | Acute medical pain
Acute pain in medical wards is common (Vallano 2006 Level IV, n=1,675) with a prevalence of 37.7%
to 84% (Gregory 2016 Level IV SR [PRISMA], 11 studies, n=17,705). Comparative rates with surgicalinpatients are variably reported as higher (and less well treated) (Korczak 2013 Level IV SR,
16 studies, n unspecified) or lower (30-56% vs 55-78%) (5 studies, n=5,134), with severe pain
prevalence ranging from 7 to 36% (5 studies, n=7,479) (Gregory 2016 Level IV SR [PRISMA], 11 studies,
n=17,705).

8.6.1 | Acute abdominal pain
Acute abdominal pain may originate from visceral or somatic structures or may be referred;neuropathic pain states should also be considered. Recurrent acute abdominal pain may be amanifestation of a chronic visceral pain disorder such as chronic pancreatitis, pelvic pain or
irritable bowel syndrome and will require a multidisciplinary pain management approach.
8.6.1.1 | Analgesia and the diagnosis of acute abdominal pain
A common misconception is that analgesia masks the signs and symptoms of abdominal
pathology and should be withheld until a diagnosis is established. Pain relief (usually in the formof opioids) does not interfere with the diagnostic process in acute abdominal pain in adults(Manterola 2011 Level I, 8 RCTs, n=922) or in children (Green 2005 Level II, n=108, JS 5; Kim 2002 Level
II, n=60, JS 5) and does not lead to increased errors in clinical management (Ranji 2006 Level I,
12 RCTs, n=1,389).
8.6.1.2 | Renal and ureteral colic/stones
Nonselective NSAIDs, opioids (Holdgate 2005b Level I [Cochrane], 20 RCTs, n=1,613) and metamizole(dipyrone) (Edwards 2002b Level I [Cochrane], 11 RCTs, n=1,053) provide effective analgesia for renal
colic. Nonselective NSAIDs reduce requirements for rescue analgesia and cause less vomiting
than opioids (particularly pethidine [meperidine]) (Holdgate 2005b Level I [Cochrane], 20 RCTs,
n=1,613).
Specifically NSAIDs are superior to placebo and to antispasmodics in reducing pain of renal
colic and requirements for rescue analgesia; indomethacin was less effective than other NSAIDs(Afshar 2015 Level I [Cochrane], 50 RCTs, n=5,734) (7 RCTs overlap with Holdgate 2005b). The
combination of NSAIDs with antispasmodics results in better analgesia than NSAIDs alone, butdoes not show higher responder rates for 50% pain reduction and does not reduce requirements
for rescue analgesia further. NSAIDs show a clinically marginal advantage in early pain reduction
over opioids (MD –5.58/100; 95%CI –10.22 to –0.95) (11 RCTs, n = 1,985) with reduced rescue
requirements and reduced vomiting rates (Pathan 2018 Level I [PRISMA], 36 RCTs, n=4,887) (9 RCTs
overlap). NSAIDs do not differ for early pain relief vs paracetamol, but reduce rescue
requirements.
Onset of analgesia was fastest when nsNSAIDs were administered IV ( Tramer 1998 Level I,
26 RCTs, n=2,225), although suppositories were also effective (Lee 2005a Level II, n=200, JS 3).
IV ibuprofen 800 mg was faster and more effective than IV ketorolac 30 mg in controlling pain
caused by renal colic (Forouzanfar 2019 Level II, n=240, JS 3). Combination IV ketorolac/morphine
provided a greater reduction in pain scores, earlier onset of complete pain relief and reduced
need for rescue analgesia, vs using either analgesic alone (Safdar 2006 Level II, n=130, JS 5).
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An overarching network meta-analysis on early pain management in renal colic concludes
that NSAIDs are superior to opioids, paracetamol, and combination therapy and NSAIDs withIV or IM route ranked first from efficacy and safety perspectives (Gu 2019 Level I [PRISMA] [NMA],
65 RCTs, n=8,633) (many RCTs overlap with previous meta-analyses).
IV paracetamol 1 g provides analgesia for renal colic which is superior to IV morphine(MD -7.5/100; 95%CI -1.99 to -13.00) and comparable to NSAIDs (MD 0.01/100; 95%CI, -0.10 to0.13) (Sin 2017 Level I, 5 RCTs, n=2,020). In contradistinction to their meta-analysed results, theauthors advise against paracetamol as an alternative to opioids or NSAIDs in view of the poor
quality of the RCTs included (ambiguous description of study protocol, incomplete presentationof data, small sample sizes, and/or methodological flaws).
If opioids are used for renal colic in the ED, there is no difference in clinical efficacy between
morphine and pethidine (O'Connor 2000 Level II, n=103, JS 5). SL buprenorphine had similaranalgesic and adverse effects to IV morphine (Payandemehr 2014 Level II, n=69, JS 5). Addition of
IV ketamine (0.15 mg/kg or 0.2 mg/kg) to IV morphine (0.1 mg/kg) increased the effectivenessof pain relief and also decreased the rate of nausea, vomiting and use of rescue medication(Hosseininejad 2019a Level II, n=22, JS 5; Abbasi 2018 Level II, n=106, JS 4). IN ketamine (1 mg/kg) hada slower onset of action vs IV morphine (0.1 mg/kg), but analgesia was comparable after 15 min(Farnia 2017 Level II, n=53, JS 4). Addition of low dose naloxone to IV morphine made no difference
to analgesia (Hosseininejad 2019b Level II, n=150, JS 5).
The smooth muscle relaxant buscopan failed to improve analgesia when combined with
nsNSAIDs (Song 2012 Level II, n=89, JS 5; Jones 2001 Level II, n=59, JS 3), opioids (Holdgate 2005aLevel II, n=192, JS 4) or metamizole (2 RCTs) (Edwards 2002b Level I [Cochrane], 11 RCTs, n=1,053).
IV ketamine 0.6 mg/kg is as effective as IV ketorolac 30 mg in the management of renal colic,but with an increased rate of adverse effects (Sotoodehnia 2019 Level II, n=126, JS 3). IV ketamine
0.15 mg/kg combined with IV NSAID lornoxicam 8 mg achieved better pain control with lessadverse effects and better functional scores than IV pethidine 50 mg ( Metry 2019 Level II, n=120,
JS 3). Combination IV morphine 0.1 mg/kg with ketamine 0.15 mg/kg vs IV morphine alone
improved control of renal colic pain and reduced further opioid requirements in the first 30 min(Abbasi 2018 Level II, n=106, JS 4). IN ketamine 1 mg/kg vs IV morphine 0.1 mg/kg resulted in better
pain relief in the first 15 min (Farnia 2017 Level II, n=40, JS 5).
Papaverine was as effective as IV diclofenac in the initial treatment of renal colic but required
increased use of rescue analgesia (Snir 2008 Level II, n=90, JS 2). However, as a rescue analgesic,
papaverine was of similar efficacy to pethidine and superior to hyoscine in patients who failed
to respond to initial treatment with a diclofenac-hyoscine combination (Yencilek 2008 Level II,
n=110, JS 2).
IV ondansetron produced analgesia in 42% of patients with renal colic but was less effective
than IM diclofenac (Ergene 2001 Level II, n=64, JS 3).
Ureteral calculus expulsive therapy using alpha-blockers (mainly PO tamsulosin) vs standard
therapy reduces the number of pain episodes, the need for analgesic medication and evenhospitalisation (Campschroer 2014 Level I [Cochrane], 32 RCTs, n=5,864; Hollingsworth 2016 Level I[PRISMA] 55 RCTs, n=5,990; Raison 2017 Level I, 67 RCTs, n=6,654) (overlap by a majority of RCTs).
Tamsulosin was more effective in reducing analgesic requirements than nifedipine in this setting(Ye 2011 Level II, n=3,189, JS 2). However, PO tadalafil, a phosphodiesterase-5 (PDE5) inhibitor,
resulted in a higher stone expulsion rate than tamsulosin (Kc 2016 Level II, n=99, JS 3).
IV lidocaine bolus provided superior analgesia to IV morphine in renal colic (2 RCTs and 1 study)(E. Silva 2018 Level IV SR [PRISMA], 6 RCTs & 2 studies, n=536; Masic 2018 Level IV SR [PRISMA], 4 RCTs &9 studies, n=512) (1 RCT overlap). IV lidocaine/ketorolac bolus achieved better analgesia for renal
colic patients vs IV lidocaine alone, but not vs IV ketorolac alone (Motov 2019, Level II, n=100, JS 3).

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The addition of IV magnesium to morphine/ketorolac improved pain control and reduced theneed for rescue analgesics (Jokar 2017 Level II, n=100, JS 5). However, addition of
IV magnesium to ketorolac alone did not improve renal colic pain relief (Maleki Verki 2019 Level II,
n=87, JS 3).
IV fluid therapy has no effect on pain outcomes or stone transition in renal colic (Worster 2012
Level I [Cochrane], 2 RCTs, n=118).
Desmopressin is inferior to NSAIDs in reducing pain of renal colic, but may be a usefuladjuvant therapy to opioids based on weak evidence (Jalili 2016 Level III-1 SR, 9 RCTs & 1 study,
n=1,000).
Intercostal nerve block at T 12 level improved pain vs IM diclofenac from 1 to 45 min(Maldonado-Avila 2017 Level II, n=60, JS 2)
TENS applied over the painful flank during prehospital transport reduced pain scores, anxiety
and nausea in patients with renal colic (Mora 2006 Level II, n=73, JS 4).
The addition of aroma therapy (lavender) to standard treatment of renal colic with parenteraldiclofenac improved pain scores at 30 min, but only in female patients ( Irmak Sapmaz 2015
Level II, n=100, JS 0).
Sexual intercourse (3-4 times/wk) added to standard NSAID therapy prn reduced stone
expulsion time, number of colic episodes and need for rescue analgesia in married male patients(Abdel-Kader 2017 Level II, n=66, JS 3). Similarly, sexual intercourse (3 to 4 times/wk) vs tamsusoline
vs standard medical therapy (control group) increased rate of and reduced time to stone
expulsion (Doluoglu 2015 Level II, n=90, JS 3).
8.6.1.3 | Biliary colic and acute pancreatitis
In the absence of any patient-specific contraindications, a multimodal analgesic regimen isrecommended for the treatment of pain due to biliary colic and acute pancreatitis, including
paracetamol, NSAIDs and opioids (Greenberg 2016 GL).
All opioids increase sphincter of Oddi tone and bile duct pressures in animal and humanexperimental models (Thompson 2001 NR). Morphine increased sphincter of Oddi contractions
more than pethidine during cholecystectomy (Thune 1990 Level IV EH, n=36). However, there is nodifference in the risk of pancreatitis complications or clinically serious adverse effects between
the use of opioids or other analgesic options when treating acute pancreatitis ( Basurto Ona 2013aLevel I [Cochrane], 5 RCTs, n=227). Similarly, a systematic review of parenteral analgesia in acutepancreatitis found mainly RCTs of low (2 RCTs overlap).
NSAIDs for treatment of biliary colic pain result in better pain relief than placebo (5 RCTs) or
spasmolytics (4 RCTs) with no difference to opioids (4 RCTs) (Fraquelli 2016 Level I [Cochrane],
12 RCTs, n=828). NSAIDs reduce cholelithiasis-related complications (eg acute cholecystitis, acutepancreatitis, jaundice, cholangitis) vs spasmolytic drugs (2 RCTs) but not vs placebo (3 RCT), withinadequate power to confirm no difference vs opioids ( 1 RCT).
The perioperative use of rectal indomethacin for ERCP reduces the risk of post ERCP
pancreatitis (OR 0.49; 95%CI 0.34 to 0.71) vs placebo (NNT 17) (Ahmad 2014 Level I, 4 RCTs,
n=1,422). This was subsequently confirmed for NSAID use in general via any route ofadministration with a similar reduction of risk of post ERCP pancreatitis (RR 0.54; 95%CI 0.45 to0.64) vs controls (Liu 2019a Level I [PRISMA], 19 RCTs, n=5,031).
IM atropine was no more effective than saline in the treatment of acute biliary colic (Rothrock
1993 Level II, n= 55, JS 4). There is no difference in outcomes including exacerbation of pain
between nasogastric and nasojejunal feeding in patients with acute pancreatitis ( Chang 2013b
Level I, 3 RCTs, n=151).

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Epidural analgesia improved pain control in severe acute pancreatitis vs IV opioid PCA(Sadowski 2015 Level II, n=38, JS 2)
Rhubarb combined with trypsin inhibitor vs trypsin inhibitor alone improves outcome ofacute pancreatitis including abdominal pain (Hu 2018 Level I, 16 RCTs, n=912).
8.6.1.4 | Irritable bowel syndrome and colic
Bulking agents are not more effective than placebo for treating pain in irritable bowel syndrome(4 RCTs, n=186), while antispasmodics (cimetropium/dicyclomine), peppermint oil, pinaverium
and trimebutine (13 RCTs, n=1,392) and antidepressants (TCAs, but not SSRIs) are effective here
(8 RCTs, n=517) (Ruepert 2011 Level I [Cochrane], 56 RCTs, n=3,725) as well as psychologicalinterventions such as CBT, hypnotherapy, multicomponent psychological therapy, and dynamic
psychotherapy (Ford 2014 Level I, 32 RCTs, n=2,189) (0 RCT overlap for psychological interventions).
5HT3 antagonists (alosetron and cilansetron) significantly improve global IBS symptoms
including abdominal pain and discomfort versus placebo or mebeverine (spasmolytic) ( Andresen
2008 Level I [QUOROM], 14 RCTS, n=3,024). There is an increased risk of constipation and possibly
ischaemic colitis.
Probiotics reduce the pain and symptom severity in IBS vs placebo (Didari 2015 Level I, 15 RCTs,
n=1,793).
8.6.1.5 | Primary dysmenorrhoea
The management of primary dysmenorrhoea embraces both biological and psychosocial aspects
and frequently uses multimodal pharmacological approaches (eg paracetamol, NSAIDs and theoral contraceptive pill). However, there is no evidence base for multimodal intervention withclinical trials restricted to single agents. Women with primary dysmenorrhoea have features of
elevated pain sensitivity and reduced pain tolerance vs controls (Payne 2017 Level III-2 SR EH,
19 studies, n=1,975 [including 110 men]).
The oral contraceptive pill has limited evidence for better pain relief vs placebo (OR 2.01;
95%CI 1.32 to 3.08) (7 RCTs, n=497), with no differences between different preparations (Wong2009 Level I [Cochrane], 10 RCTs, n unspecified).
Nonselective NSAIDs are more effective analgesics in dysmenorrhoea vs placebo, however
withincreased rate of adverse effects (Marjoribanks 2015 Level I [Cochrane], 80 RCTs, n=5,820).
Nonselective NSAIDs are more effective than paracetamol, with no difference between the different
nsNSAIDs with regard to efficacy and safety. Nonselective NSAIDs also reduce bleeding and pain
associated with the use of an intrauterine device (Grimes 2006 Level I [Cochrane], 15 RCTs, n=2,702).
There is no high-quality evidence to support the effectiveness of any complementary
medicine in the treatment of dysmenorrhoea, but there is low quality evidence for effectivenessof some (Pattanittum 2016 Level I [Cochrane], 27 RCTs, n=3,101). See also Section 4.14.3.
High-frequency TENS is effective in primary dysmenorrhoea ( Proctor 2002 Level I [Cochrane],
7 RCTs, n=164). See also Section 7.2.
Acupuncture, acupressure (Smith 2016a Level I [Cochrane], 42 RCTs, n=4,640) and acupoint
stimulation (Chung 2012 Level I, 25 RCTs, n=3,109) reduce pain in primary dysmenorrhoea (vs notreatment or NSAIDs), but the quality of studies is low to very low. See also Section 7.3.
8.6.1.6 | Acute abdominal pain in childrenChildren and adolescents experience all of the above listed medical causes of abdominal pain.
For discussion of the management of recurrent abdominal pain which is mainly a paediatricdisorder (Brusaferro 2018 NR), see Section 10.9.4. For the principles of management of abdominal532

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pain asscociated with vaso-occlusive crises in sickle cell disorder see Section 8.6.4.1 below andfor paediatric issues Section 10.9.5. For CAMT interventions for infantile colic see Section
10.11.3.

KEY MESSAGES
1. Provision of analgesia does not interfere with the diagnostic process in acuteabdominal pain and does not increase the risk of errors in clinical management (U)(Level I [Cochrane Review]).
2. NSAIDs, opioids and intravenous metamizole (dipyrone) provide effective analgesia forrenal colic (S) (Level I [Cochrane Review]).
3. NSAIDs given for renal colic reduce pain (N) (Level I [PRISMA]) and rescue analgesia
requirements with less vomiting compared with opioids, particularly pethidine(meperidine) (S) (Level I [Cochrane Review]).
4. Alpha blockers as expulsive therapy for ureteral stones reduce the number of pain
episodes and analgesic requirements (S) (Level I [Cochrane Review]).
5. Antispasmodics and tricyclic antidepressants, but not bulking agents, are effective forthe treatment of acute pain in irritable bowel syndrome (S) (Level I [Cochrane Review])
as well as psychological interventions (N) (Level I).
6. NSAIDs are effective in primary dysmenorrhoea and superior to paracetamol (S)(Level I [Cochrane Review]).
7. The smooth muscle relaxant buscopan does not add further analgesic benefit whencombined with metamizole (dipyrone) (U) (Level I [Cochrane Review]), opioids or
NSAIDS to treat pain of renal colic (U) (Level II).
9. High-frequency TENS, possibly some dietary supplements andacupuncture/acupressure are effective in the treatment of primary dysmenorrhoea (S)(Level I [Cochrane Review]).
9. NSAIDS are superior to placebo and spasmolytics and as effective as opioids in thetreatment of biliary colic (S) (Level I [Cochrane Review])
10. The perioperative use of NSAIDs for endoscopic retrograde cholangiopancreatography(ERCP) reduces the risk of post ERCP pancreatitis (S) (Level I [PRISMA]).
11. 5HT3 antagonists reduce some of the symptoms of irritable bowel syndrome (S)(Level I [QUOROM).
12. The onset of analgesia is faster when NSAIDs are given intravenously for the treatmentof renal colic (U) (Level I).
13. Intravenous paracetamol is as effective as intravenous morphine and superior to
intramuscular piroxicam for analgesia in renal colic (U) (Level II).
14. There is no difference between pethidine and morphine for analgesia in renal colic (U)(Level II).
15. Low-dose ketamine is an effective analgesic for renal colic pain (N) (Level II).
16. IV lidocaine is an effective analgesic for renal colic pain (N) (Level IV SR).
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8.6.2 | Herpes zoster-associated pain
Herpes zoster (shingles) is caused by reactivation of the varicella-zoster virus (VZV), which lies
dormant in dorsal root and cranial nerve ganglia following primary infection with chickenpox(varicella), usually in childhood (Le 2019 NR). There is a marked increase in the lifetime risk ofherpes zoster with increasing age and with diseases and drugs that impair immunity estimatedat 30%, with 68% of cases occurring in those aged ≥50 y.
Herpes zoster-associated pain occurs in up to 90% of those affected and may occur before
onset of the characteristic rash (during the prodrome), with onset of the rash or following its
resolution (Le 2019 NR). The pain varies in intensity and may be described as “burning”,“throbbing” or “shooting”; itching, dysaesthesias, and allodynia may also be present ( Dworkin2008 ). In the majority of cases, herpes zoster is an acute self-limiting disease, although it may
progress to postherpetic neuralgia (pain that persists for >3 mth after the onset of herpes
zoster). The incidence of postherpetic neuralgia increases with age (>50 y), occurri ng in up to
75% of patients aged ≥70 y who had herpes zoster ( Johnson 2004 NR). Identified risk factors forthe development of postherpetic neuralgia are prodromal pain (RR 2.29; 95%CI 1.42 to 3.69),
severe acute pain (RR 2.23; 95%CI 1.71 to 2.92), severe rash (RR 2.63; 95%CI 1.89 to 3.66), andophthalmic involvement (RR2.51; 95%CI 1.29 to 4.86) ( Forbes 2016 Level III-2 SR, 19 studies,
n=40,238). As previously reported there was an increase with older age; for individual studies,
relative risk estimates per 10-year increase ranged from 1.22 to 3.11.
Early, aggressive treatment of herpes zoster infection and pain may reduce the incidence ofpostherpetic neuralgia, although data on preventive strategies are limited.
Detailed consensus-based guidelines on the treatment of herpes zoster have been published(Werner 2017 GL).
8.6.2.1 | Prevention of herpes zoster
Two vaccines are licensed for the prevention of herpes zoster and post-herpetic neuralgia inolder adults: Zostavax®, a live attenuated vaccine, and Shingrix®, a recombinant subunit
vaccine (Le 2019 NR). Zostavax® is still recommended in Australia for adults aged ≥60 y(Australian Vaccines Handbook GL) in NZ for adults aged ≥65 y (IMAC 2019 GL) and in the UK for
adults aged 70 to 79 y. In the US, the US Advisory Committee on Immunization Practices (ACIP)
updated its guidance and now recommends Shingrix® for adults aged ≥50 y (Dooling 2018 GL).
Zostavax® is effective in the prevention of herpes zoster (and thereby postherpetic neuralgia)
in individuals aged >60 y (Gagliardi 2012 Level I, 8 RCTs, n=52,269). A large, multicentre, randomised
placebo-controlled trial (The Shingles Prevention Study) demonstrated the vaccine’s efficacy,with the incidence of herpes zoster reduced by 51.3%, that of postherpetic neuralgia by 66.5 %and herpes zoster-associated “burden of illness” by 61.1% (Oxman 2005 Level II, n=38,546, JS 4).
The estimated number needed to vaccinate to prevent a case was 11 (95%CI 10 to 13) for herpes
zoster and 43 (95%CI 33 to 53) for postherpetic neuralgia (Brisson 2008 Level III-3). Zostavax is lesseffective with increasing age and its efficacy wanes 10 y after vaccination (Morrison 2015 Level IV,
n=6,867).
Shingrix® is a newer vaccine with substantially higher efficacy than Zostavax® (Syed 2018 NR)
reducing the risk of herpes zoster infection by 97% vs placebo, with mean follow-up duration of
3.2 y (Lal 2015 Level II, n=15,411, JS 5). Unlike Zostavax®, the efficacy of Shingrix® was higher forpatients over 70 y of age and reduced the incidence of postherpetic neuralgia by 88.8%(Cunningham 2016 Level II, n=13,900, JS 5). Protection, however, declines slightly four y after
vaccination with long term efficacy unknown (Morrison 2015 Level IV, n=6,867). As it is not a live
vaccine, Shringrix® should be theoretically safe to administer to immunocompromised534

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patients, unlike Zostavax®, though no recommendations have been made for vaccinating
this group (Le 2019 NR; Syed 2018 NR).
8.6.2.2 | Treatment of acute herpes zoster-associated pain
Around 95% of patients will present with acute pain; processes of neuroinflammation are in part
responsible for the acute pain state (Werner 2017 GL).
Antiviral agents
Antiviral agents should be considered in all patients with acute herpes zoster, in particular those
who have severe disease, are over 50 y of age, immunocompromised, or have evidence oftrigeminal nerve involvement (Werner 2017 GL; Le 2019 NR). Acyclovir (Wood 1996 Level I, 4 RCTs,
n=691), valaciclovir (Beutner 1995 Level II, n=1,141, JS 5) or famciclovir (Tyring 2000 Level II, n=597,
JS 5), given within 72 h of rash onset, accelerated the resolution of acute herpes zoster pain.
Famciclovir, in various doses and frequencies, was as effective as acyclovir for herpes zosterrelated outcomes including acute pain, with fewer adverse effects (Gopal 2013 Level II, n=100, JS 2;
Shafran 2004 Level II, n=559, JS 5; Shen 2004 Level II, n=55, JS 5). Famciclovir or valaciclovir have
replaced acyclovir as the drugs of choice in the treatment of herpes zoster because of morefavourable pharmacokinetics and simpler dosing profiles ( Cunningham 2008 NR). FV‐100, a
prodrug for the bicyclic nucleoside analogue CF‐1743 with high specificity for the VZV showedfaster resolution of clinically significant pain vs valaciclovir (Tyring 2017 Level II, n=450, JS 5).
Systemic analgesics
For mild herpes zoster-associated pain, simple analgesics such as paracetamol and NSAIDs suchas ibuprofen are regarded as sufficient (Le 2019 NR). Multimodal analgesia with regular nonopioids, in addition to an opioid such as oxycodone or tramadol as required, has been
recommended for more severe pain (Werner 2017 GL; Cunningham 2008 NR; Dworkin 2007 NR; Dwyer
2002 NR).
Oxycodone CR, but not gabapentin, effectively reduced the average worst pain during thefirst 14 d of herpes zoster vs placebo, although oxycodone-treated patients had higher
withdrawal rates from the trial, primarily because of constipation ( Dworkin 2009 Level II, n=87,
JS 5).
Corticosteroids
Prednisolone added to acyclovir for acute herpes zoster minimally reduced pain intensity but
improved the rate of skin lesion healing for up to 14 d, with no effect on the overall recovery
rate at 3 wk (Wood 1994 Level II, n=400, JS 4). A later trial showed prednisolone, either as
monotherapy or in combination with acyclovir, increased the likelihood of being “pain-free” at
1 mth by a factor of 2.3 (95%CI 1.4 to 3.5), with no difference in the rate of skin healing vs placebo(Whitley 1996 Level II, n=208, JS 4).
AnticonvulsantsA single dose of gabapentin 900 mg during herpes zoster reduced acute pain intensity by 66%(33% for placebo) and also reduced the area and severity of allodynia, for up to 6 h (Berry 2005
Level II, n=26, JS 5). When given in divided doses between 300 to 900 mg/day within 72 h of onsetof rash, gabapentin reduced pain by 26 to 38% after 4 wk (Kanodia 2012, Level II, n=52, JS 3). This
was also found with pregabalin 150 mg (Jensen-Dahm 2011 Level II, n=8, JS 5). However, one study
showed no analgesic benefit was found when gabapentin up to 1,800 mg daily was administeredfor 28 d (Dworkin 2009 Level II, n=87, JS 5) or with pregabalin 150 to 300 mg daily for 3 wk (Krcevski
Skvarc 2010 Level II, n=29, JS 3).

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Topical lignocaine
Topical lignocaine patches (5%) applied for 12 h twice daily (on intact skin) during acute herpes zoster
reduced pain intensity and improved patients’ global impression of pain relief, vsa vehicle patch: the incidence and severity of adverse effects was low (Lin 2008 Level II,
n=46, JS 5).
Aspirin
Topical aspirin, in either moisturiser or diethyl ether, was an effective analgesic in acute herpes
zoster, vs similar preparations containing indomethacin, diclofenac or placebo ( De Benedittis 1996
Level II, n=37, JS 3) or oral aspirin (Balakrishnan 2001 Level II, n=45, JS 3).
Neuraxial or sympathetic block
Nerve blocks in general for acute herpes zoster vs standard treatment without nerve blocks
reduce duration of acute pain (MD −13.68 d; 95%CI −18.70 to −8.66) (1 RCT [2 stellate ganglion
blocks LA/dexamethasone 1 wk apart]; 1 RCT [continuous PVB]; 1 study [continuous epidural
analgesia]) (Kim 2017a Level I, 8 RCTs & 1 study, n=1,645).
Acupuncture and moxibustion
Based on data from one RCT for each outcome, acupuncture and moxibustion reduces acute painof herpes zoster and its duration with questionable clinical significance (Coyle 2017 Level I, 9 RCTs,
n=945).
8.6.2.3 | Prevention of postherpetic neuralgia
Immunisation of persons aged ≥60 y with live attenuated VZV vaccine reduces the incidence ofherpes zoster and thereby the incidence of postherpetic neuralgia; however there is no evidence
that the immunisation prevents postherpetic neuralgia beyond this effect ( Chen 2011 Level I[Cochrane], 1 RCT, n=38,546).
The use of acyclovir does not significantly reduce the incidence of postherpetic neuralgia at
6 mth (Chen 2014 Level I [Cochrane], 6 RCTs, n=1,211). There is insufficient evidence to determine
the preventive effects of other antiviral agents.
Similarly, systemic corticosteroids (Han 2013 Level I [Cochrane], 5 RCTs, n=787) are ineffective
preventive strategies in postherpetic neuralgia.
Nerve blocks in general for acute herpes zoster vs standard treatment without nerve blocks
reduce the incidence of PHN at 3 mth (RR 0.43; 95%CI 0.25 to 0.7) ( 7 RCTs and 1 study), at 6 mth(RR 0.41; 95%CI 0.2 to 0.83) (6 RCTs) and at 12 mth (RR 0.17; 95%CI 0.1 to 0.28) (2 RCTs) (Kim 2017
Level I, 8 RCTs & 1 study, n=1,645). With regard to specific blocks, stellate ganglion blocks (3 RCTs)
and single epidural block had no preventive effect (1 RCT), while repeated or continuous epidural(2 RCTs, 1 study) and paravertebral analgesia (2 RCTs) have a preventive effect.
During acute herpes zoster, the early administration of amitriptyline (25 mg for 90 d)significantly reduced the incidence of postherpetic neuralgia at 6 mth (Bowsher 1997 Level II, n=80,
JS 4).

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1. Antiviral agents started within 72 hours of onset of the herpes zoster rash accelerate
the resolution of acute pain (U) (Level I) but do not reduce the incidence, severity andduration of postherpetic neuralgia (U) (Level I [Cochrane Review]).
2. Immunisation of persons aged 60 years or older reduces the incidence of herpes zoster
and thereby postherpetic neuralgia with Zostavax® (U) (Level I [Cochrane Review]) and
Shingrix® (N) (Level II).
3. Continuous or repeated paravertebral blocks in the acute phase of herpes zoster
reduce the incidence of postherpetic neuralgia at 3, 6 and 12 months (N) (Level I).
4. Amitriptyline (used in low doses for 90 days from onset of the herpes zoster rash)
reduces the incidence of postherpetic neuralgia (U) (Level II).
5. Topical aspirin, topical lignocaine patch or controlled-release oxycodone provide
analgesia in acute pain due to herpes zoster (U) (Level II).
6. Nerve blocks in the acute phase of herpes zoster reduce the duration of herpes zosterassociated pain (N) (Level III-I SR).
6. Continuous epidural analgesia in the acute phase of herpes zoster reduces theincidence of postherpetic neuralgia at 3 months (N) (Level III-I SR).
The following tick box represents conclusions based on clinical experience and expert
opinion: Provision of early and appropriate analgesia is an important component of the
management of herpes zoster and may have benefits in reducing the incidence ofpostherpetic neuralgia (U).

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8.6.3 | Acute cardiac pain
Acute coronary syndrome refers to a range of acute myocardial ischaemic states including unstableangina and myocardial infarction. Typically, myocardial ischaemia causes central chest pain, which
may radiate into the arm, neck or jaw; nontypical presentations can occur, particularly in the elderly
patient (see also Section 9.2). Reducing ischaemia by optimising myocardial delivery, reducing
myocardial oxygen consumption and restoring coronary blood flow will reduce ischaemic pain andlimit myocardial tissue damage. The mainstay of analgesia in acute coronary syndrome is therestoration of adequate myocardial oxygenation as outlined above.
Inhaled oxygen does not reduce all-cause mortality in acute myocardial infarction and also
does not reduce chest pain measured directly or by surrogate outcome of opioid requirements(Cabello 2016 Level I [Cochrane], 5 RCTs, n=1,172). The meta-analysis could not rule out a potentiallyharmful effect. These findings are confirmed by a subsequent meta-analysis, which showed thatoxygen therapy does not reduce the risk of in-hospital or 30-day mortality, infarct size or chest
pain in patients with suspected AMI (Sepehrvand 2018 Level I [PRISMA], 8 RCTs, n=7,998) (5 RCTs
overlap). Current guidelines by the Australian and New Zealand Cardiology Society (Chew 2016 GL)
and by NICE (NICE 2016b GL) state that the use of supplemental oxygen is not recommended
unless hypoxia (oxygen saturation [SaO2] <94%) is present. In acute coronary syndrome,
hyperbaric oxygen therapy reduced time to relief of ischaemic pain, although insufficientevidence exists to recommend its routine use (Bennett 2011a Level I, 6 studies, n=665).
Nitroglycerine (glyceryl trinitrate) was effective in relieving acute ischaemic chest pain;
however, the analgesic response did not predict the diagnosis of coronary artery disease(Henrikson 2003 Level IV, n=459). During exercise testing, nitroglycerine caused changes in thesystemic and coronary circulation that combine to reduce myocardial oxygen demand and toincrease supply, thereby attenuating exercise induced ischaemia ( Asrress 2017 Level IV EH, n=40).
The Australian and New Zealand Cardiology Society (Chew 2016 GL) and NICE (NICE 2016b GL)
provide recommendations to use nitrates to alleviate symptoms including pain in acute coronary
syndrome.
In patients with suspected acute coronary syndrome, IV morphine significantly reduced pain
within 20 min of administration (Everts 1998 Level IV, n=2,988); morphine doses were low (averageof 7 mg over 3 d) and 52% of patients required no morphine at all. Independent predictors ofincreased morphine requirements included suspicion or confirmation of infarction, ST-segmentchanges on the admission electrocardiogram, male sex and a history of angina or cardiac failure.
After an initial dose of IV metoprolol, IV morphine provided better analgesia than further
IV metoprolol (Everts 1999 Level II, n=265, JS 4). It was associated with better cardiovascularoutcomes during acute hospital admission and later follow-up, vs a fentanyl/droperidol mixture
administered early in the treatment of patients with acute ischaemic chest pain (Burduk 2000
Level II, n=112, JS 2). IV bolus doses of morphine and alfentanil were equally effective in relieving
acute ischaemic chest pain but the onset of analgesia was faster with alfentanil ( Silfvast 2001
Level II, n=40, JS 2). Morphine was similar to buprenorphine (Weiss 1988 Level II, n=76, JS 3) andpethidine (Nielsen 1984 Level II, n=275, JS 4) in terms of analgesia and adverse effects. IN fentanyl
and IV morphine were equally effective in reducing acute cardiac chest pain during prehospitaltransfer (Rickard 2007 Level II, n=258, JS 3).
However regarding impact on antiplatelet therapies, IV fentanyl lowered plasma
concentrations of ticagrelor and delayed its antiplatelet function in patients undergoing PCI(McEvoy 2018 Level II, n=70, JS 3). Similarly, morphine decreased clopidogrel plasma concentrations
and its effect (Hobl 2014 Level II EH, n=24, JS 5) and decreased ticagrelor (Hobl 2016a Level II EH, n=24,
JS 5) and prasugrel plasma concentrations without affecting their antiplatelet effects (Hobl 2016b
Level II EH, n=12, JS 5). On the other hand, morphine co-administered with metoclopramide in538

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patients with unstable angina resulted in significantly higher ticagrelor mean plasma
concentrations within the first one and two h following loading dose (Sikora 2018 Level II, n=32,
JS 3). Overall, morphine administration before loading with P2Y12 inhibitors (prasugrel orticagrelor) possibly decreases their efficacy with regard to platelet inhibition and reduces
ticagrelor plasma concentrations without a negative effect on a composite endpoint of in-hospitalmortality, stroke and reinfarction (Vaidya 2019 Level III-2 SR, 8 studies, n=752).
The Australian and New Zealand Cardiology Society (Chew 2016 GL) and NICE (NICE 2016b GL)
recommend IV morphine (or other IV opioids eg fentanyl) for treatment of chest pain in acutecoronary syndrome. However, a subsequent meta-analysis with high risk of bias identified
concerns with the use of morphine in acute coronary syndrome ( Duarte 2019 Level III-2 SR[PRISMA], 5 RCTs, n=2,237 & 12 studies, n=63,112). The pooled results show associations between
morphine administration and an increased in-hospital mortality (RR 1.45; 95%CI 1.10 to 1.91),
major adverse cardiovascular events (RR 1.21; 95%CI 1.02 to 1.45) and increased platelet
reactivity. However, in two cohort studies, prehospital use of morphine vs non-use was not
associated with worse in-hospital complications or 1 y survival (HR 0.69; 95%CI 0.35 to 1.37)(Puymirat 2016 Level III-3, n=2,438+1,726).
In patients with chest pain due to cocaine-induced acute coronary syndrome, the addition of
IV diazepam or lorazepam to treatment with SL nitroglycerine wasbeneficial (Honderick 2003
Level II, n=36, JS 3) or made no difference to chest pain resolution or cardiac performance(Baumann 2000 Level II, n=43, JS 5).
N2O in oxygen was effective in relieving acute ischaemic chest pain, with a significant
reduction in betaendorphin levels (O'Leary 1987 Level II, n=12, JS 2).
NSAIDs may be useful in the treatment of acute pain in pericarditis (Schifferdecker 2003 NR).

KEY MESSAGES
1. The routine use of oxygen in normoxic patients with acute myocardial infarction does
not reduce pain or mortality (S) (Level I [Cochrane].
2. Morphine is an effective and appropriate analgesic for acute cardiac pain, but may
interfere with pharmacokinetics and pharmacodynamics of some platelet inhibitors (Q)(Level II).
3. Nitroglycerine is an effective and appropriate agent in the treatment of acuteischaemic chest pain (S) (Level IV).
The following tick box represents conclusions based on clinical experience and expert
opinion: The mainstay of analgesia in acute coronary syndrome is the restoration of adequate
myocardial oxygenation, nitroglycerine, beta blockers and strategies to improvecoronary vascular perfusion (U).

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8.6.4 | Acute pain associated with haematological disorders
8.6.4.1 | Sickle cell disease
Sickle cell disease (SCD) includes a group of inherited disorders of haemoglobin production.
Haemoglobin S polymerises when deoxygenated, causing rigidity of the erythrocytes, blood
hyperviscosity and occlusion of the microcirculation with resultant tissue ischaemia andinfarction (Niscola 2009 NR).
Sickle cell disease is a systemic multiorgan disease that most commonly presents with painfulvaso-occlusive crises (VOC), occurring either spontaneously or due to factors such as
dehydration, infection, hypothermia and low oxygen tension. There is considerable
interindividual variability in the frequency and severity of crises. Pain during an acute VOC is
typically severe, in multiple sites and most frequently reported in the arm, shoulder, upper back,sternum, clavicle, chest and pelvis (McClish 2009 Level IV, n=308). Pain may last from hours toweeks. VOCs involving abdominal organs can mimic an acute surgical abdomen. Acute chest
syndrome secondary to SCD may present with chest pain, cough, dyspnoea and fever ( Niscola2009 NR). An evidence-based approach and detailed consensus guidelines to the management of
VOC in SCD are published (NICE 2012b GL; Glassberg 2011 GL; Mousa 2010 GL).
Treatment of pain
Biopsychosocial assessment and multidisciplinary pain management may be required whentreating patients with frequent, painful sickle cell crises. Attendance to a multidisciplinary clinic
specialising in the management of patients with SCD reduced hospitalisations and improved
quality of life (Terry 2018 Level III-3, n=30). A pain management plan in the form of a letter, card or
portfolio carried by the patient is recommended (Rees 2003 GL). The implementation of clinicalpractice guidelines (Morrissey 2009 Level III-3, n=263 [children]) or a clinical pathway (Ender 2014
Level III-3, n=68) for acute pain treatment in VOC leads to more timely and effective analgesia. An
individualised pain management plan results in improved pain control, a higher level of patientsatisfaction and reduced hospitalisations in children (Krishnamurti 2014 Level III-2). Underdosing ofpain medication leads to a higher rate of ED visits for pain (Morrison 2018 Level III-3, n=100). Early
achievement of maximum analgesia improved hospitalisation outcomes (Payne 2018 Level III-3,
n=236).
NSAIDsSingle-dose parenteral ketorolac did not reduce opioid requirements in painful VOC ( Hardwick
1999 Level II, n=41, JS 5; Wright 1992 Level II, n=24, JS 5). Patients who receive ketorolac for pain may
be at risk of acute kidney injury and subsequently require longer periods of hospitalisation(Baddam 2017 Level III-3, n=197).
Opioids
Opioids are an integral component of treatment regimens for patients suffering from debilitating
acute pain from SCD (Rodday 2018 Level III-3, n=449). Pain from a VOC is often undertreated in thehospital setting due to perceived opioid addiction and drug seeking behaviour despite a similar
incidence of opioid addiction in the general population (Pack-Mabien 2001 Level III-3, n=77 [nurses]).
Higher initial doses of opioids in the Emergency Department (ED) along with earlier introductionof oral opioids in a VOC results in significantly shorter hospital LOS and improved outcomes(Brandow 2015 Level II, n=204, JS 4). However, it is important to consider opioid tolerance in thesepatients as a large cohort study reported 40% of patients with SCD were taking regular opioid
analgesics (Han 2018 Level III-2, n=3,882).

540

5th Edition | Acute Pain Management: Scientific Evidence8.0 | SPECIFIC CLINICAL SITUATIONSIn the hospital setting, IV opioids are recommended for severe pain ( NICE 2012b GL). Whentreating acute pain during a sickle cell crisis, IV opioid loading improved the analgesic efficacy ofsubsequent oral and PCA opioid therapy (Rees 2003 GL). PCA only was superior to backgroundinfusions only and PCA with background infusion as it reduced total opioid dose, total time on
PCA , opioid-related adverse effects and hospital LOS (van Beers 2007 Level II, n=19, JS 2). Although
IV opioid PCA is widely accepted in the management of acute pain in sickle cell disease, oral
opioids are also effective. In one paediatric RCT, oral sustained-release morphine for acute pain
was just as effective as a continuous IV morphine infusion ( Jacobson 1997 Level II, n=56, JS 5).
However, in children, the incidence of acute sickle chest syndrome (a severe complication insickle cell crisis) and plasma levels of morphine and M6G, were significantly higher with oral
morphine vs IV infusion (Kopecky 2004 Level II, n=50, JS 4). IN fentanyl was a suitable alternative in
the ED to reduce time to initiation of opioid analgesic therapy, however did not reduce the needfor IV opioid analgesia (Kelly 2018a Level III-2).
Care must be taken when prescribing opioids for the treatment of pain in SCD. In a review of
35 patients who died in hospital following an exacerbation of SCD, 9 received excessive opioids
and “overdose” directly contributed to death in 5 patients ( NCEPOD 2008 Level IV). Inadequate
observations of sedation and respiratory rates after opioid administration was noted as acontributing factor and IM pethidine administration was prevalent.
Corticosteroids
Parenteral corticosteroids reduce the duration of severe pain and analgesia requirements andhospital LOS during VOC without major adverse effects ( Dunlop 2006 Level I [Cochrane], 9 RCTs,
n unspecified). In children, a short course of high dose IV methylprednisolone decreased theduration of severe pain associated with acute sickle cell crises, but patients who received
methylprednisolone had more rebound attacks after therapy was discontinued ( Griffin 1994
Level II, n=36, JS 5).
Ketamine
Low-dose ketamine improved analgesia and reduced opioid requirements ( Puri 2019 Level III-3,
n=4; Tawfic 2014 Level IV, n=9; Uprety 2014 CR). This approach is also suggested for paediatricpatients (Neri 2013a NR); here a single sub-dissociative dose of ketamine given IV over 10 min wasa suitable alternative to morphine for acute exacerbations of pain during a VOC (Lubega 2018
Level II, n=240, JS 5).
Dexmedetomidine
Dexmedetomidine may have a role in the management of recalcitrant pain due to VOC as
infusions for up to 6 d duration reduced opioid requirements and pain scores without adverse
haemodynamic effects (Sheehy 2015 Level IV, n=3).
Inhaled nitric oxide
Nitric oxide deficiency or defective nitric oxide-dependent mechanisms may underlie many ofthe processes leading to VOC. An early paediatric study suggested inhaled nitric oxide may be of
benefit in painful acute VOC (Weiner 2003 Level II, n=25, JS 4); however in young adults admittedwith VOC, there was no difference between inhaled nitric oxide vs nitrogen placebo in time to
VOC resolution or LOS (Gladwin 2011 Level II, n=150, JS 5).
Inhaled nitrous oxide
Inhaled N2O in 50% oxygen used for limited periods may provide analgesia for VOC pain in the
primary-care setting (Rees 2003 GL).

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Oxygen
Although oxygen supplementation is often prescribed during acute sickle cell crises, there wasno difference in pain duration, number of pain sites or opioid consumption in patients treatedwith either air or oxygen (Robieux 1992 Level II, n=66, JS 2; Zipursky 1992 Level II, n=28, JS 3). However,nocturnal oxygen desaturation was associated with a significantly higher rate of painful VOC inchildren (Hargrave 2003 Level IV, n=95). Hyperbaric oxygen therapy was effective in reducing painof VOC rapidly (Stirnemann 2012 Level III-3, n=9).
Rehydration
While commonly practiced, there is no evidence to support fluid replacement therapy to reduce
pain associated with sickle cell crises (Okomo 2017 Level I [Cochrane], 0 RCTs, n=0).
Epidural analgesia
In severe crises, where pain is unresponsive to pharmacological measures, epidural analgesia
has been used effectively in nine paediatric patients (Yaster 1994 Level IV, n=9). Epidural analgesia
has also been described in a pregnant patient with poorly responsive pain from VOC ( Winder 2011CR).
Intravenous lidocaine
IV lidocaine Infusions (1 mg/kg/h to 1.3 mg/kg/h) for treating pain of SCD achieved more than 20%
pain reduction in 53% of patients, while opioid requirements were reduced by 32% (Nguyen 2015
Level IV, n=11). These findings are confirmed in a subsequent study (Puri 2019 Level III-3, n=4).
Magnesium Sulphate
IV magnesium or oral magnesium therapy has been shown to have no effect on reducing
pain during painful crises in SCD or hospital LOS (Than 2019 Level I [Cochrane], 5 RCTs, n=386).
Non-pharmacological management
Yoga in children admitted with VOC has demonstrated significant reduction in pain scores (Moody2017 Level II, n=73, JS 1).
Based on limited evidence, there may be an effect of CBT on pain in SCD (1 RCT, n=59) (Anie2012 Level I [Cochrane], 5 RCTs, n=260). In young adults, CBT reduced the affective (not sensory)component of pain (MD -0.99; 95% CI -1.62 to -0.36) but with no benefit for coping strategies(1 RCT, n=59).
Prevention of painful sickle cell crises
Hydroxyurea acts to increase fetal haemoglobin levels. It has demonstrated efficacy in reducing
the frequency of acute crises, the severity of pain during an acute crisis, the need for bloodtransfusions and the incidence of acute chest syndrome (Nevitt 2017 Level I [Cochrane], 8 RCTs,
n=899). Zinc supplementation reduces the incidence of painful sickle cell crises ( Nagalla 2012
Level I [Cochrane], 3 studies, n=524). Niprisan (an anti-sickling agent) reduces the frequency of crises
with severe pain (Wambebe 2001 Level II, n=82, JS 4) while the evidence for piracetam is insufficient
to support its use (Al Hajeri 2016 Level I [Cochrane], 3 RCTs, n=169).
8.6.4.2 | Haemophilia
Deficiency of Factor VIII (haemophilia A) and deficiency of Factor IX (haemophilia B) are
inherited disorders of coagulation characterised by spontaneous and post-traumatic
haemorrhages, the frequency and severity of which are proportional to the degree of clotting
factor deficiency. Bleeding into joints and muscle is common, although other sites such as
abdominal organs may also be involved. In haemophilic arthropathy, the most frequent sites ofpain are the ankle joints (45%), knee joints (39%), spine (14%) and elbow joints (7%) ( Wallny542

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2001 Level IV, n=71). Pain is significantly associated with age and severity of disease (Rambod 2016
Level III-3, n=154). Patients with haemophilia presenting with acute pain have a background ofchronic pain in 29% of cases (Witkop 2017 Level III-3, n=764 [haemophilia]). Patients withhaemophilia may also have pain syndromes associated with HIV/AIDS (see Section 8.6.8).
Recurrent acute pain may have a significant adverse impact on mood, mobility and QoL in
haemophilia patients; biopsychosocial assessment and treatment should be considered ( Wallny
2001 Level IV, n=71).
The following five features should be considered in the treatment of acute pain resulting fromhaemarthrosis; haematologic treatment, short-term rest of the involved joint, cryotherapy, joint
aspiration and analgesic medication (Rodriguez-Merchan 2018 NR). Many haemophilia patients use
Factor VIII to decrease pain associated with a bleeding episode (Wallny 2001 Level IV, n=71).
Higher-dose Factor VIII replacement reduced the number of patients with restricted joint
movement after an acute haemarthrosis (Aronstam 1983 Level II, n=114, JS 4). Despite this,approximately 30% of patients experience ongoing pain after the infusion of Factors VIII or IX(Rodriguez-Merchan 2018 NR). Joint aspiration may reduce pain and improve joint function ( Baker
1992 NR).
Although there is no good evidence available, simple analgesics, opioids, cryotherapy andbandaging have been used in treating acute pain associated with haemophilia. In a Europe wide survey, the preferred first-line drug was paracetamol for children and paracetamol or
NSAIDs for adults (Holstein 2012 Level IV, n=5,103 [adults] & n=1,678 [children] ). There are no dataon NSAID use in acute haemarthrosis; coxibs may be of benefit due to a lack of platelet
inhibitory effects (see Section 4.2.2.2). Pregabalin and gabapentin are increasingly used as partof a multimodal analgesia approach despite lack of evidence to support their use in this clinicalsetting (Powell 2014 Level IV). IM analgesics should be avoided due to the risk of bleeding.
8.6.4.3 | The porphyrias
The acute porphyrias are a group of inherited disorders of haem biosynthesis. The most common
autosomal dominant forms are acute intermittent porphyria, variegate porphyria and hereditary
coproporphyria. The disorder of haem biosynthesis leads to accumulation of neurotoxic
aminolaevulinic acid and porphyrin metabolites, which can result in peripheral, visceral andautonomic neuropathies (eg clinical features might include motor weakness, abdominal pain andtachycardia) as well as CNS toxicity (neuropsychiatric symptoms, seizures, brainstem andpituitary dysfunction); some patients may have a cutaneous photosensitivity ( Visser 2008 NR).
Pain management in acute porphyria is based on treatment of the disease, including
resuscitation and supportive care, ceasing “triggers”, the early administration of haematin(Herrick 1989 Level II, n=12, JS 4) and possibly high-dose IV dextrose or cimetidine administration(“disease modifying agents”) (Rogers 1997 NR).
Specific evidence for pain management in acute porphyria is limited. Analgesia is basedlargely on the use of IV and (later) oral opioids ( Anderson 2005 NR; Herrick 2005 NR). Analgesics
that lower seizure threshold such as pethidine (Deeg 1990 CR) or tramadol and others (such as
TCAs) should be avoided in acute porphyria because of increased seizure risk.
The safety of NSAIDs or coxibs in acute porphyria has not been established; paracetamol,
buscopan (for colic) or inhaled N2O in oxygen are considered safe (Anderson 2005 NR; Stoelting
1993 NR).
There may be a place for low-dose IV ketamine or regional analgesia, although the safety ofthese approaches has not been established in acute porphyria. Ketamine does not induce
aminolaevulinic acid synthetase in rats (Harrison 1985 BS) and has been used for anaesthesia in
porphyria patients without apparent problems (Capouet 1987 CR). However, one case report
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noted increased porphyrin levels in a patient after induction with ketamine ( Kanbak 1997 CR). A
combined spinal epidural technique has been described in patients with porphyria undergoing
Caesarean section with epidural analgesia continued in the postoperative period minimising IV
opioid requirements (Horvat 2015 Level IV, n=2). As metoclopramide is contraindicated and thesafety of 5HT3 antagonists is as yet unclear, droperidol has been suggested as the antiemetic ofchoice in acute porphyria (Anderson 2005 NR).

KEY MESSAGES
1. Parenteral corticosteroids reduce the duration of severe pain, analgesia requirements
and hospital length of stay, without major adverse effects, during vaso-occlusive crises
in sickle cell disease (U) (Level I [Cochrane Review]).
2. There is no evidence that fluid replacement therapy (S) or intravenous or oral
magnesium reduces pain associated with vaso-occlusive crises in sickle cell disease (N)(Level I [Cochrane Review]).
3. Hydroxyurea decreases the frequency of vaso-occlusive crises, life-threatening
complications and transfusion requirements in sickle cell disease (S) (Level I [Cochrane
Review]).
4. Zinc reduces the incidence of painful vaso-occlusive crises in sickle cell disease (U)(Level I [Cochrane Review]).
5. Intravenous opioid loading optimises analgesia in the early stages of a vaso-occlusivecrisis in sickle cell disease; effective analgesia may be continued with intravenous
opioid therapy, optimally as PCA, or as oral opioids (S) (Level II).
6. Single-dose ketorolac does not reduce opioid requirements in vaso-occlusive crisis in
sickle cell disease (N) (Level II), but may increase the risk of acute kidney injury (N)(Level III-3).
7. Oxygen supplementation does not decrease pain during a vaso-occlusive crisis in sickle
cell disease (U) (Level II), but hyperbaric oxygen may be effective (U) (Level III-3).
8. Intravenous ketamine and intravenous lidocaine reduced pain intensity and opioid
requirements in vaso-occlusive crisis in sickle cell disease (N) (Level IV).

544

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8.6.5 | Acute headache
Headaches are a common cause of acute pain. Headaches may be primary or secondary. There
are many causes of acute headache, some of which involve structures other than the head(eg the neck). Before treating acute headache, it is vital to exclude serious cranial pathologies
such as tumour, infection, cerebrovascular abnormalities, acute glaucoma and temporal arteritis(Silberstein 2000 GL; Steiner 2002 NR).
The most frequent causes of acute primary headache are episodic tension type headaches(TTH) and migraine (Headache Classification Committee 2018 GL). Less common primary headaches
are trigeminal autonomic cephalalgias (episodic cluster headache, episodic paroxysmal
hemicrania and Short lasting Unilateral Neuralgiform headache attacks with Conjunctival
injection and Tearing [SUNCT]) or “secondary headaches”, such as acute post-traumaticheadache, postdural puncture headache (PDPH), headache attributed to substance use or its
withdrawal and cervicogenic headache.
Comprehensive guidelines for the evaluation and treatment of acute headaches
including migraine have been promulgated (Diener 2019 GL; Pringsheim 2016 GL; Marmura 2015 GL;
Beithon 2013 GL; Worthington 2013 GL) including for children and adolescents (see Section 10.9.3).
8.6.5.1 | Tension-type headache
TTH may be episodic (frequent or infrequent) or chronic in nature. The lifetime prevalence of
TTH in the general population is between 30 and 78%. Episodic TTH is usually bilateral and isoften described as mild to moderate “pressing” or “tight” pain (sometimes with pericranial
tenderness), not worsened by movement and not associated with nausea or vomiting.
Photophobia or phonophobia may occasionally be present but not both (Headache Classification
Committee 2018 GL).
The symptoms and pathogenesis of TTH may overlap with migraine and particularly withchronic daily headache, medication overuse headache and cervicogenic headache (NICE
2012a GL). Psychological, physical and environmental factors are important in TTH and should be
addressed during assessment and treatment (Bougea 2013 Level II, n=35, JS 3; NICE 2012a GL;
Bendtsen 2010 GL).
TTHs are frequently self-limiting with total duration under 12 h in many cases. Therefore, theefficacy of various treatments should be assessed against the background of natural history. The
acute adverse effects and the propensity for analgesic medications to transform intermittent
headaches to a chronic daily pattern must be considered in relation to choice of agents (Barbanti
2014 NR). Evidence-based guidelines for TTH treatment are published ( Bendtsen 2010 GL).
Treatment
The NNTs for patients with TTH being pain free at 2 h vs placebo are similar for all oral analgesics
in the range of 8.7 to 9.8 for paracetamol 1,000 mg (5 RCTs, n=1,387), ibuprofen 400 mg (3 RCTs,
n=826) and ketoprofen 25 mg (2 RCTs, n=285) (Moore 2014 Level I [PRISMA], 55 RCTs, n=12,143).
In a meta-analysis of RCTs including a paracetamol arm, the NNT for 1000 mg vs placebo forbeing pain free at 2 h is higher at 22 (95%CI 15 to 40) (8 RCTs, n=5,890) and the NNT for lessfrequent rescue medication was 7.8 (95%CI 6.0 to 11) (6 RCTs, n=1,856) (Stephens 2016 Level I[Cochrane], 23 RCTs, n=8,079) (possible 22 RCTs overlap). Based on limited data, the efficacy ofparacetamol 500 mg to 650 mg was not superior to placebo, and paracetamol 1000 mg was notdifferent from either ketoprofen 25 mg or ibuprofen 400 mg.
A single dose of aspirin between 500 mg and 1000 mg provides some benefit in terms of lessfrequent use of rescue medication (NNT 6.0; 95%CI 4.1 to 12) and more participants satisfied
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with treatment vs placebo (NNT 5.7; 95%CI 3.7 to 12) ( Derry 2017a Level I [Cochrane], 5 RCTs,
n=1,812) (3 RCTs overlap with Stephens 2016). The quality of the evidence is low and was
downgraded because of the small number of studies and events, and because the mostimportant measures of efficacy were not reported.
A paracetamol/aspirin/caffeine combination is superior to paracetamol alone (Diener 2014
Level I, 4 RCTs, n=1,900) (3 RCTs overlap with Stephens 2016).
Parenteral medications are more effective in TTH than oral ones; IV metoclopramide has an
NNT of 2 and IV metamizole and IV chlorpromazine have an NNT of 4 (Weinman 2014 Level I[PRISMA], 8 RCTs, n=486).
IV lidocaine in refractory chronic daily headache was associated with reduced pain intensity
over an 8.5 d treatment period from 7.9/10 to 3.9/10, with low incidence of adverse effects(Rosen 2009 Level IV, n=68).
IV magnesium was ineffective in treating acute TTH in the ED (Frank 2004 Level II, n=42, JS 5).
Acupuncture for TTH (at least 6 sessions) over 3 mth provides clinically relevant improvementin pain vs standard care (2 RCTs, n=1,472), but only minimal clinical improvement vs shamtreatment (5 RCTs, n=703) (Linde 2016, Level I [Cochrane], 12 RCTs, n=2,349). See also Section 7.3.
8.6.5.2 | Migraine
Migraine is common, with a prevalence of 6 to 8% in males and 12 to 14% in females(Evers 2009 GL). Migraine headache is usually unilateral and is often severe, disabling andoften worsened by movement. Either nausea/vomiting or photophobia/phonophobia must bepresent and 20% of migraineurs experience an aura.
Most migraines are successfully managed by the patient and their family doctor, with up to
57% of patients not seeking medical attention for significant attacks (Mitchell 1998 Level
IV). However, a small number of patients fail to respond and present for treatment at EDs;
approximately 80% of patients have tried their usual medications, including simple analgesics or
triptans, before presentation.
Evidence-based recommendations for the treatment of migraine in ED settings are published(Orr 2015 GL). For treatment of migraine in the ED, see Section 8.11.2.6 below.
Treatment
The management of migraine includes avoidance of triggers such as sleep deprivation,
stress, sensory stimulation such as bright lights, exercise, alcohol, foods etc. Management ofassociated symptoms, particularly nausea and vomiting is important, as is the prevention of
acute recurrence.
Environmental modification (quiet dark room) and particularly sleep is integral to successful
migraine treatment (Steiner 2007 NR).
Analgesia outcomes in migraine trials are usually listed as the proportion of patients
who either:• are pain free at 2 h;
• report significant pain relief at 2 h (no headache or mild headache);• report a sustained response over 24 h (migraine stays away for at least 1 d).
Many trials fail to document associated outcomes such as improvement in nausea, vomitingor disability (Moore 2003 NR).

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5th Edition | Acute Pain Management: Scientific Evidence8.0 | SPECIFIC CLINICAL SITUATIONSStrategies for the use of migraine medications
There are three major strategies for the use of analgesics in the treatment of acutemigraine (Lipton 2000 Level II, n=930, JS 5):• Stratified care — where for each attack, the severity and disability caused by the
migraine is assessed and the patient uses simple analgesia for a mild attack and a triptan
for a severe attack;• Step‐up during an attack — for each attack a simple analgesic is always tried first but thepatient “steps up” to a triptan if there is no relief in 2 h;
• Step‐up across attacks — a patient tries simple analgesics exclusively for the first threeattacks; if there has been no benefit from simple analgesia over the trial period then atriptan is used for all further attacks.
The US Headache Consortium (Silberstein 2000 GL) and European Federation of NeurologicalSocieties (Evers 2009 GL) have recommended a “stratified care” approach; Canadian guidelines
recommend this as the most effective and cost-effective approach but also describe the two otherapproaches as suitable in selected patients (Worthington 2013 GL).
Placebo
A significant placebo effect has been observed in migraine trials, particularly if the treatment isadministered by injection (Macedo 2006 Level I [QUOROM], 98 RCTs, n=35,481) and this may be
more relevant in children and adolescents (Evers 2009 Level I, 27 RCTs, n unspecified).
Accordingly, the beneficial effect of specific analgesic mechanisms may be underestimated byprominent placebo responses (Lund 2014 Level II, n=48, JS 5).
Simple analgesics
Patients who experience mild migraine-related headache and disability may be effectively
treated with simple analgesics, either alone or in combination with an antiemetic. European
consensus guidelines recommend the routine, early use of metoclopramide in adults (ordomperidone in children) (Evers 2009 GL).
Paracetamol 1,000 mg is superior to placebo in the treatment of migraine but has a lower
efficacy than other analgesics (NNT 12 for pain free at 2 h) (Derry 2013a Level I [Cochrane], 11 RCTs,
n=2,942). The efficacy of the combination with 10 mg metoclopramide was comparable to oral
sumatriptan 100 mg. Serious adverse effects occurred only with sumatriptan (NNH 32).
Aspirin 1,000 mg is of similar efficacy to sumatriptan 50 or 100 mg orally (NNT 8.1 for pain
free at 2 h) with slightly fewer adverse effects (Kirthi 2013 Level I [Cochrane], 13 RCTs, n=4,222);
adding 10 mg metoclopramide improves nausea and vomiting.
Ibuprofen is also effective here (NNT 7.2 for pain free at 2 h [400 mg]; NNT 9.7 [200 mg]) andsoluble preparations provide faster onset of effect (Rabbie 2013 Level I [Cochrane], 9 RCTs, n=4,473).
Adverse effects are similar to placebo.
Diclofenac has similar efficacy (NNT 6.2 for pain free at 2 h) and low rates of adverse effects
for this indication (Derry 2013b Level I [Cochrane], 5 RCTs, n-=1,356).
Dipyrone is also effective for the treatment of migraine and episodic TTHs
(Ramacciotti 2007 Level I [Cochrane], 4 RCTs, n=636).
Parecoxib IV was similarly effective to oral rizatriptan and SC sumatriptan in an RCT with noplacebo arm (Muller 2011 Level II, n=57, JS 2).
In a network meta-analysis of NSAIDs and triptans for the treatment of migraine, triptans (inparticular eletriptan and rizatriptan) have superior efficacy to NSAIDs; ibuprofen is slightly lesseffective, but has the best tolerability of all medications analysed ( Xu 2016 Level I [NMA], 88 RCTs,
n=9,372). The combination naproxen/sumatriptan in particular has increased efficacy and better
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tolerability than sumatriptan on its own; this is also confirmed by another by systematic review(Law 2016 Level I [Cochrane], 13 RCTs, n=9,334) (4 RCTs overlap).
For paediatric information, see Section 10.9.3.1.
Triptans
All triptans are more effective in the treatment of acute migraine than placebo (Thorlund 2014
Level I, 74 RCTs, n unspecified), particularly in the presence of severe pain and disability where
simple analgesia has failed to provide adequate relief in the past. This must be placed in thecontext of a high placebo response rate and interindividual differences in response to thedifferent triptans, with recommendations for patients to trial a variety of drugs and doses
until the most suitable regimen is found (Worthington 2013 GL; Pringsheim 2014 NR).
In a review of trials with an eletriptan arm, 30–40% of migraine sufferers do not respond to
triptan treatments (Diener 2008 Level I, 10 RCTs, n=8,473). The three clinical variables that predict
poor therapeutic response are: severe pain, photophobia or phonophobia, and nausea; whiletime of dosing following onset of headache has no effect on 2-h pain-free response.
The route of administration of a triptan may affect its efficacy, speed of onset and tolerability.
For sumatriptan, a comparison of different routes of administration showed that SC
administration (in comparison to oral, IN and rectal administration) has the highest efficacy andspeed of onset but also the highest rate of adverse effects (Derry 2014b Level I [Cochrane],
4 Cochrane Reviews, n=52,236). Most effective doses for each route of administration are
PO 100 mg, SC 6 mg, IN 20 mg and rectal 25 mg.
Zolmitriptan is effective in acute migraine with oral doses of 2.5 and 5 mg being comparable
in efficacy to oral sumatriptan 50 mg (Bird 2014 Level I [Cochrane], 25 RCTs, n=20,162).
As most RCTs have compared a single triptan with placebo, it is difficult to determine therelative efficacy of different triptans. A multiple treatment comparison meta-analysis combining
available head-to-head and placebo-controlled trials has been published (Thorlund 2014 Level I[NMA], 74 RCTs, n unspecified). It shows eletriptan followed by rizatriptan, zolmitriptan andsumatriptan having the highest efficacy at 2 h and eletriptan followed by zolmitriptan andsumatriptan at 24 h.
The combination of sumatriptan/naproxen provides a greater headache reduction in theacute treatment of migraine headaches than the same dose of either agent alone, but thedifference in efficacy is small in comparison to sumatriptan alone (Law 2016 Level I [Cochrane],
13 RCTs, n=9,334). The combination and sumatriptan alone causes more adverse effects thannaproxen (3 RCTs) or placebo (10 RCTs).
The most frequent adverse effects associated with triptans are dizziness, fatigue,
sleepiness, nausea, chest tightness and paraesthesiae (Johnston 2010 NR). Triptans may cause anincrease in light touch‐evoked allodynia and thermal sensitivity (Linde 2004 Level III-2 EH, n=24).
Concerns about an increase in cardiovascular events with the use of triptans could not be
confirmed (Roberto 2015 Level III-2 SR, 4 studies, n≈131,000); the pooled OR of serious ischaemic
events was 0.86 (95%CI 0.52 to 1.43).
Frequent use of triptans may lead to triptan‐induced rebound headaches(medication-overuse headache), often described as chronic migraine (Tepper 2012 NR). This riskincreases with increasing days of triptan use, in particular with use on more than 10 d/mth (Lipton
2013 Level IV, n=11,249).
Calcitonin Gene Related Peptide inhibitors
Calcitonin gene-related peptide (CGRP) inhibitors (humanised monoclonal antibodies or small
molecule CGRP receptor antagonists) are useful in migraine management (Edvinsson 2018 NR).
Currently, only two such monoclonal antibodies are registered in Australia, fremanezumab

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5th Edition | Acute Pain Management: Scientific Evidence8.0 | SPECIFIC CLINICAL SITUATIONS(Silberstein 2017 Level II, n=1,130, JS 5) and erenumab (Jain 2018 NR) as preventive treatment, thelatter also in New Zealand. As well, the CGRP pathway may be engaged for emergency
management of acute headache utilising small molecule CGRP receptor antagonists (gepants)
and serotonin 5-HT1F receptor agonists (ditans) may have a major role, but are currently only inPhase III trials and still awaiting registration (Moreno-Ajona 2019 NR).
Ergot derivatives
Ergotamine and dihydroergotamine preparations have been used for many years to treat
migraine, although they have been superseded by the triptans, as they are less effective andhave more adverse effects (Tfelt-Hansen 2008 NR). In particular, oral triptans are superior to oral
ergotamine, because the bioavailability of oral ergotamine is extremely
low (<1%).
IN dihydroergotamine (2 mg) has a NNT of 2.5 for 2 h headache response in migraine (Oldman
2002 Level I, 1 RCT [ergotamine], n=203). As a single agent, parenteral dihydroergotamine may not
be as effective as other migraine treatments (Colman 2005 Level I, 3 RCTs [ergotamine alone], n=423).
However, when dihydroergotamine is combined with an antiemetic such as metoclopramide,
the efficacy of this combination is similar to valproate, ketorolac and opioids ( Colman 2005 Level I,
8 RCTs [ergotamine/antiemetic], n=384).
Importantly, in contrast to the data for triptans, ergot derivatives cause an increased rate ofischaemic events (OR 2.51; 95%CI 1.10 to 5.71) (Roberto 2015 Level III-2 SR, 4 studies, n≈131,000).
Antiemetics and major tranquillisers
Parenteral metoclopramide, as monotherapy or in combination, is effective for the treatment ofheadache and nausea in acute migraine (Orr 2015 Level l [PRISMA], 8 RCTs [metoclopramide],n unspecified; Colman 2004 Level I, 13 RCTs, n=728) (2 RCTs overlap).
Parenteral droperidol is also effective in this indication; the minimum effective dose is 2.5 mg
IM or IV (Thomas 2015 Level I, 5 RCTS, n=685).
Phenothiazines such as chlorpromazine (2 RCTs) and prochlorperazine (3 RCTs) vs placebo
provide better headache relief (OR 15.02; 95%CI 7.57 to 29.82) (4 RCTs, n=303) and achieve moreclinical success (OR 8.92; 95%CI 4.08 to 19.51) (5 RCTs, n=349) (Kelly 2009 Level I, 13 RCTs, n=917).
Phenothiazines achieve also more clinical success than metoclopramide (OR 2.25; 95%CI 1.29 to3.92) (4 RCTs, n=271) and combinations of other active compounds (OR 2.04; 95%CI 1.25 to 3.31)(10 RCTs, n=569), but not better headache relief. The overall clinical success rate of phenothiazines
is high (78%; 95%CI 74 to 82). Butyrophenones achieve similar benefits in an ED setting, howeverwith significant adverse effects (Leong 2011 Level I, 6 RCTs, n=574). IV prochlorperazine was more
effective than IV promethazine for initial ED treatment of migraine (Callan 2008 Level II, n=70, JS 4).
Buccal prochlorperazine was superior to an oral ergotamine/caffeine combination or placebo(Sharma 2002 Level II, n=45, JS 5).
A combination of indomethacin/prochlorperazine/caffeine (Di Monda 2003 Level II, n=112,
JS 3) and a combination of prochlorperazine/diphenhydramine were more effective than SC
sumatriptan (Thomas 2015 Level II, n=68, JS 5).
Conventional and atypical opioids
Opioids are of limited benefit in the treatment of migraine and should not be used ( Casucci 2013
NR; Tepper 2012 NR). IV hydromorphone vs IV prochlorperazine/diphenhydramine was lesseffective for the treatment of acute migraine; the RCT was halted when the primary outcome
was achieved by 60% of the prochlorperazine/diphenhydramine arm vs 31 % of thehydromorphone arm (Friedman 2017b Level ll, n=127, JS 5).
Opioid use for migraine was associated with more severe headache-related disability,
symptomology, comorbidities (depression, anxiety and cardiovascular disease and events), and5th Edition | Acute Pain Management: Scientific Evidence 549

greater healthcare utilisation than no use (Buse 2012 Level III-2, n=5,796). Among current opioid
users for migraine, 16.6% met criteria for probable dependence. Opioids induce migraine
progression with a dose-dependent effect beyond approximately 8 d exposure/mth (Tepper 2012
NR; Bigal 2009 NR).
Despite these disadvantages and recommendations, opioids continue to be used in morethan half of all patients attending EDs in the USA for migraine (Friedman 2014a Level IV). However,when other migraine treatments are contraindicated, use of opioids may have to be considered
as a last resort (Dodson 2018 NR; Finocchi 2013 NR). Among patients requiring readmission forprimary headache, those given opioids initially (22.8%) had significantly longer ED LOS (median
5.0 h vs. 3.9 h) and higher rates of return ED visits within 7 d (7.6% vs. 3.0%) vs those receiving
non-opioids in a univariate analysis (McCarthy 2015 Level III-3, n=574); the association with longer
length of stay remained significant in multivariable regression.
Overall, the most commonly trialled opioids in migraine (pethidine, tramadol andnalbuphine) are more effective in reducing migraine pain than placebo (Kelley 2012 Level I, 23 RCTs,
n unspecified). Morphine without an antiemetic was no more effective than placebo (Nicolodi 1996
Level III-1). Butorphanol was effective when given by the IN or IM route ( Hoffert 1995 Level II,
n=157, JS 3; Elenbaas 1991 Level III-1). There is inadequate evidence to recommend parenteraltramadol in the treatment of acute migraine (Marmura 2015 GL).
Pethidine in particular is not recommended for the treatment of migraine, due to lack ofevidence of efficacy, neurotoxicity of its metabolite norpethidine (epileptogenic) and the highrisk of developing dependency. Pethidine is less effective than dihydroergotamine or antiemetics
for the treatment of migraine; however, its efficacy is similar to ketorolac (Friedman 2008 Level I,
11 RCTs, n=625).
Ketamine
SC ketamine 0.08 mg/kg vs placebo was more effective in treating acute migraine pain (Nicolodi
1995 Level II, n=17, JS 3). In contrast, IV ketamine 0.2 mg/kg was not superior to placebo in acutemigraine (Etchison 2018 Level II, n=34, JS 5). IV ketamine 0.3 mg/kg/IV ondansetron 4 mg vs IV
prochlorperazine 10 mg/IV diphenhydramine 25 mg achieved inferior pain relief at 45 and 60
min (MD 20/100; 95%CI 2.8 to 37.2) and lower patient satisfaction at 24 h in primary headache(Zitek 2018 Level II, n=54, JS 5). Similarly, IN ketamine was not superior to standard treatment(metoclopramide/diphenhydramine) in the treatment of primary headache ( Benish 2019 Level II,
n=53, JS 4).
Other drug treatments
Parenteral dexamethasone reduces the rate of moderate or severe headache recurrence after
24 to 72 h (RR 0.71; 95%CI 0.59 to 0.86) (Orr 2016 Level I, 68 RCTs, n unspecified; Huang 2013 Level I,
8 RCTs, n=905) (1 RCT overlap). There are no differences in efficacy between oral and parenteralsteroids. IM methylprednisolone acetate, a long-acting steroid, was not superior to IM
dexamethasone in this setting (Latev 2019 Level II, n=220, JS 4).
The efficacy of lidocaine in the treatment of migraine is unclear. Analgesia provided by IV
lidocaine was similar to dihydroergotamine but not as effective as chlorpromazine ( Bell 1990
Level II, n=76, JS 2) and, in another trial, no better than placebo (Reutens 1991 Level II, n=25, JS 3). IN
lidocaine was more effective than placebo (Maizels 1996 Level II, n=91, JS 4). IN lidocaine 10 to 20
mg repeated at variable intervals (4 RCTs using Barre method) vs placebo in primary headache(mainly acute migraine) shows some benefit only in poor quality RCTs ( 4 RCTs), but not in fairquality RCTs (2 RCTs); overall there is no effect on recurrence or repeat ED visits, but more
adverse events and lower patient satisfaction (Dagenais 2018 Level I [PRISMA], 6 RCTs, n=685).
No firm conclusions can be drawn on the effect of IV magnesium in acute migraine due to theheterogeneity of the studies included in a systematic review; however, there may be some550

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effects on pain after >1 h, aura duration and need for rescue analgesia (Miller 2019 Level I [PRISMA],
7 RCTs, n=545).
IV sodium valproate is ineffective in treating acute migraine (Frazee 2008 Level IV SR, 3 RCTs &4 studies, n=243). This was contradicted by a subsequent case series ( Shahien 2011 Level IV, n=36),
but confirmed in an RCT, which found sodium valproate inferior to ketorolac andmetoclopramide (Friedman 2014b Level II, n=330, JS 5).
Propofol in 30–40 mg IV bolus doses was more effective than sumatriptan 6 mg SC at 30 min
with less need for antiemetics and lower rate of recurrence (Moshtaghion 2015 Level II, n=91, JS 5).
Propofol in 10 mg IV bolus doses (max 80 mg) was also superior to dexamethasone IV 0.15 mg/kg(max 16 mg) (Soleimanpour 2012a Level II, n=90, JS 5). The efficacy was also confirmed in a numberof case series (Ward 2013 Level IV, n=15; Mosier 2013 Level IV, n=4; Soleimanpour 2012b Level IV, n=8),
including one in paediatric patients (Sheridan 2012 Level IV). A susbequent paediatric RCT
demonstrated similar pain reduction (51% vs 59) with low dose bolus IV propofol 0.25 mg/kg(1–5 doses) with IV fluid bolus vs standard IV combination therapy with less rebound headache
at 24 h (7% vs 25) (Sheridan 2018 Level II, n=74, JS 2). Notably, guidelines give a weakrecommendation against the use of propofol (Orr 2015 GL).
There is no evidence for use of caffeine alone in treatment of tension type headache ormigraine. However, combinations of caffeine with simple analgesics improve their analgesic
efficacy and tolerability in a number of painful conditions including primary headache andmigraine (Derry 2014a Level I [Cochrane], 20 RCTs, n=7,238) (2 RCTs overlap with Stephens 2016).
However, discontinuation of regular caffeine intake improves subsequent acute migraine
management over the next 35 d (Lee 2016b Level III-2, n=108).
Pramipexole has been linked with a significant reduction in migraine, particularly the morning
headaches in patients with concomitant restless legs syndrome ( Suzuki 2013 Level IV).
SC Octreotide 100 mcg vs placebo had no analgesic effect in acute migraine ( Levy 2005
Level II, n=51, JS 5).
Sublingual ginger (Zingiber officinale)/feverfew (Tanacetum parthenium) extract was more
effective than placebo in aborting acute migraine when used in early mild headache (Cady 2011
Level II, n=60, JS 5).
Hyperbaric oxygen therapy
Hyperbaric oxygen therapy was effective in relieving migraine headaches vs sham therapy(RR 6.2; 95%CI 2.4 to 16) (3 RCTs, n=58), but there was no effect on nausea and vomiting, rescue
analgesic requirements or migraine prevention (Bennett 2015 Level I [Cochrane], 11 RCTs, n=209).
Intravenous fluids
IV fluid hydration is a common component of emergency department migraine therapy ( Jones
2017 Level IV, n=1,251). However, in a post hoc analysis of data collected from 4 ED-based migraine
RCTs, IV fluids/metoclopramide vs IV metoclopramide alone did not improve acute migraine
outcomes (Balbin 2016 Level III-2, n=570) similar to the findings of a subsequent RCT (Jones 2019aLevel II, n=49, JS 5).
TENSTENS use in migraine reduces monthly affected days (SMD: -0.48; 95%CI -0.73 to - 0.23) andpharmacological treatment intake (SMD -0.78; 95%CI -1.14 to - 0.42) (Tao 2018 Level I [PRISMA],
4 RCTs, n=161). Similarly, TENS applied to the supraorbital nerve over 12 wk reduced days with
migraine and days using rescue medications among patients with refractory migraine and not
responding to topiramate (Vikelis 2017 Level IV, n=35).

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One 60-min session of TENS treatment reduced pain intensity of acute migraine attacks at
one and 24 h after treatment by 50%, and two thirds of the patients did not require rescue pain
medication at 24 h (Chou 2017 Level IV, n=30).
See also Section 7.2.
Acupuncture
Similarly, acupuncture reduces migraine frequency at 3 mth vs no treatment or routine care
(4 RCTs, n=2,199), but only minor improvements were seen vs sham treatments (14 RCTs,
n=1,825) (Linde 2016 Level I [Cochrane], 22 RCTs, n=4,985 ). Acupuncture reported fewer adverse(5 RCTs, n=931) vs pharmacological prophylaxis and acupuncture was slightly superior at 3 mth
but not 6 mth (3 RCTs, n=739). A subsequent RCT also found a prophylactic effect ofelectroacupuncture (5 sessions per wk for 12 wk) on migraine ( Li 2017a Level II, n=61, JS 3).
See also Section 7.3.
8.6.5.3 | Menstruation-related migraine
Management of acute migraine during menstruation does not differ from treatment at otherphases of the menstrual cycle. Prophylaxis is based on modifying hormone fluctuations, usually
by intake of oestrodiol-containing oral contraceptive preparations (MacGregor 2010 NR).
Sumatriptan, zolmitriptan, rizatriptan and mefenamic acid are more effective than placebo
for acute treatment (Pringsheim 2008 Level I, 10 RCTs [acute abortive treatment], n=3,255). Eletriptan
is as effective to achieve 2 h pain relief in females in and outside of the menstrual phase but withhigher rate of recurrence and less sustained suppression of nausea during menstruation (Bhambri
2014 Level I, 5 RCTs, n=3,217).
8.8.5.4 | Migraine in pregnancy and breastfeeding
Migraine can occur for the first time during pregnancy and pre‐existing migraine may worsen,
particularly during the first trimester or may improve in later pregnancy with the patient
becoming headache‐free (MacGregor 2014 NR). Approximately 60–70% of migraineurs improve
during pregnancy (frequency, duration) with a sharp rise in the incidence after delivery (Kvisvik
2011 Level IV, n=2,126). Breastfeeding is protective (David 2014 NR).
Migraine in pregnancy is a risk factor for gestational hypertension and preeclampsia (OR 2.3;
95%CI 2.1 to 2.5) and is also associated with ischaemic stroke (OR 30.7; 95%CI 11.1 to 22.5),
myocardial infarction (OR 4.9; 95%CI 1.7 to 14.2), deep vein thrombosis (OR 2.4; 95%CI 1.3 to4.2) and thrombophilia (OR 3.6; 95%CI 2.1 to 6.1) (Bushnell 2009 Level III-2, n=33,956).
The major concerns in the management of migraine in pregnancy are the effects ofmedication and the disease itself on the fetus. Medication use should ideally be limited.
Paracetamol, metoclopramide, caffeine, codeine (or perhaps other opioids) can be used during
pregnancy, while aspirin, NSAIDs or coxibs should not be used during the third trimester (David
2014 NR).
There is contradictory information on the safety of triptan therapy during pregnancy. While
there are human data suggesting potential teratogenicity ( David 2014 NR), a large Scandinavian
population study has shown no significant risk of congenital malformation but a small risk ofuterine atony and haemorrhage with use during the second and third trimesters ( NezvalováHenriksen 2013 Level III-2, n=181,124).
Ergot alkaloids during pregnancy may disrupt fetoplacental blood supply and cause uterine
contractions, which can result in low birth weight and preterm birth (Banhidy 2007 Level IV,
n=33,851). Birth defects and stillbirths due to vascular spasm have been reported and it isrecommended that ergotamines be avoided in pregnancy (Acs 2006 NR). However,552

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dihydroergotamine has significantly fewer vasoconstrictor and uterotonic effects vs otherergotamines: dihydroergotamine use in pregnancy did not increase risk for major malformations
but increased the risk of prematurity and resulted in a risk of spontaneous abortion similar tothat of triptan and NSAID use (Berard 2012 Level III-2, n=59,707).
Low-dose acetylsalicylic acid, ibuprofen, sumatriptan, paracetamol, caffeine andmetoclopramide are considered safe for the treatment of acute migraine in breastfeeding
mothers (Davanzo 2014 Level IV SR; David 2014 NR; Hutchinson 2013 NR). Acute migraine medications
that should be avoided include high-dose acetylicsalicylic acid, dihydroergotamine, ergotamineand opioids.
See also Section 9.1 and Tables 9.1 and 9.2.
8.6.5.5 | Cluster headache and other trigeminal autonomic cephalalgias
Cluster headache is a rare primary headache disorder, presenting almost exclusively in maleswith recurrent, acute episodes of brief, severe, unilateral, periorbital pain associatedwith autonomic phenomena such as conjunctival injection and tearing.
Guidelines for the treatment of cluster headache attacks propose as first-line treatments SC
sumatriptan 6 mg, IN zolmitriptan 5 mg and 10 mg, and 100% oxygen 6–12 L/min (Francis 2010 GL).
OxygenHigh-flow oxygen is recommended as a first‐line treatment (Francis 2010 GL); this is supported bya meta-analysis with limited quality of evidence, which suggests that more than 75% of cluster
headaches were likely to respond to non-hyperbaric oxygen therapy (3 RCTs), but possibly notsuperior to ergotamine (Bennett 2015 Level I [Cochrane], 11 RCTs, n=209). One RCT not included inthis meta-analysis found high-flow oxygen (12 L/min) superior vs high-flow air in cluster
headache with regard to the outcome pain free at 15 min (78%; 95%CI 71 to 85 [150 attacks] vs20%; 95%CI 14 to 26 [148 attacks]) (Cohen 2009 Level II, n=109, JS 5). High-flow oxygen treatment
had a superior effect to high-flow room air in all types of headaches in an ED setting (Ozkurt 2012
Level II, n=204, JS 5). In a survey of patients with cluster headache, oxygen was rated highly
effective with few complications (Pearson 2019 Level IV, n=2,193). The presence ofnausea/vomiting and “restlessness” was predictive of a poor response to oxygen (Schurks 2007
Level IV, n=256).
Hyperbaric oxygen is no more effective than sham hyperbaric treatment in reducing thefrequency or duration of cluster headaches (1 RCT) (Bennett 2015 Level I [Cochrane], 11 RCTs, n=209).
Triptans
Triptans are effective to treat cluster headaches; SC sumatriptan 6 mg is superior to IN
zolmitriptan 5 mg or 10 mg for rapid response at 15 min, while oral routes of administration are
not appropriate for this condition (Law 2013 Level I [Cochrane], 6 RCTs, n=1,180).
Calcitonin Gene-Related Peptide Inhibitors
Humanised monoclonal antibodies that selectively bind to calcitonin gene‐related peptide(CGRP) are effective in rapidly reducing the frequency and intensity of acute headaches inindividuals with episodic cluster headache and are awaiting registration (Ashina 2017 NR).
Local anaesthetic blocks
Sphenopalatine ganglion local anaesthetic block has moderate evidence support for thetreatment of acute cluster headaches (1 RCT, 6 studies, 2 CR) (Ho 2017 Level IV SR, 88 studies,n unspecified).

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Occipital nerve blocks have been shown to be effective in multiple case series and two RCTs
but the mechanism is uncertain and the role of additional steroids unclear ( Leroux 2013a Level IV
SR, 12 studies, n≈334).
Neuromodulation
Sphenopalatine ganglion stimulation (1 RCT, 2 studies) and radiofrequency ablation (9 studies) as
well as bilateral occipital nerve stimulation has been used successfully as a prophylaxis(Ho 2017 Level IV SR, 88 studies, n unspecified; Blumenfeld 2013 GL; Pedersen 2013 NR).
Non-invasive vagus nerve stimulation is a well-tolerated and effective acute treatment for
episodic cluster headache (1 RCT, n=112), but less effective for chronic cluster headache (1 RCT,
n=113) (de Coo 2019 Level l, 2 RCTs, n=225).
Other treatments
The efficacy of cannabis in cluster headaches is limited and should not be recommended ( Leroux
2013b Level IV, n=139).
In attacks of high frequency, short courses of high-dose oral corticosteroids,
dihydroergotamine and occipital nerve blocks with local anaesthetic and steroids arerecommended with limited evidence (Becker 2013 NR).
8.6.5.6 | Paroxysmal hemicrania and SUNCT
Paroxysmal hemicrania and SUNCT are rarer forms of trigeminal autonomic cephalalgia.
Paroxysmal hemicrania is similar to cluster headache except that it is more common in females,
episodes are shorter, but more frequent, and diagnosis requires the complete abolition ofsymptoms with indomethacin, which is the suggested treatment of choice (Headache Classification
Committee 2018 GL; May 2006 GL).
There is no high‐level evidence to guide the treatment of SUNCT (Arca 2018 NR). Howeverconsensus guidelines and limited data suggest that IV lidocaine for acute treatment andlamotrigine, topiramate and gabapentin may be useful prophylactics (May 2006 GL; Weng 2018
NR). Occipital nerve stimulation (Lambru 2014 Level IV, n=9; Young 2012 Level IV) and non-invasive
vagal stimulation may be a potential effective treatment for SUNCT and hemicrania continua (Tso2017 Level IV, n=15).
8.6.5.7 | Postdural puncture headache
Postdural puncture headache (PDPH), usually following spinal anaesthesia, inadvertent dural
puncture with an epidural needle, diagnostic or therapeutic lumbar puncture or neurosurgery,occurs with an incidence of approximately 0.7 to 50% (Bezov 2010a NR; Bezov 2010b NR). Up to
85% of cases improve spontaneously within 6 wk.
Risk factors are younger age, female gender, low BMI, history of prior PDPH and history ofchronic headache. Children who undergo lumbar puncture may present a special group (Janssens
2003 NR) (see Section 10.6.3.5).
Spinal needle size, type and lumbar puncture technique
Data in the anaesthesiology and neurology literature indicate that needle calibre, bevel
type and lumbar puncture technique affects the incidence of PDPH. The incidenceof
DPH following spinal anaesthesia is reduced by using a smaller gauge (-g) needle (26-g or less:
NNT 3) or a needle with a noncutting bevel (eg pencil point: NNT 27) (Halpern 1994 Level I, 16
RCTs, n=3,593).

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Subsequent studies support these findings for noncutting bevel needles (Schmittner 2011
Level II, n=363, JS 3) but could not find a difference between 23- and 25-g needles in patients>60 y (Kim 2011b Level II, n=53, JS 5) or between cutting 22- and 25-g needles in children aged 4 to
15 y (Crock 2014 Level II, n=93 [341 punctures], JS 5).
The incidence of PDPH is also reduced by orientating the cutting bevel parallel to the spinal
sagittal plane (dural fibres) (Richman 2006 Level I, 5 RCTs, n=521) or by replacing the stylette prior
to withdrawing a noncutting needle (Strupp 1998 Level II, n=600, JS 3); these techniques
presumably reduce CSF loss. However, a subsequent study could not confirm the benefit ofreplacing the stylette in a 25-g Quincke needle (Sinikoglu 2013 Level II, n=630, JS 4).
Similarly for diagnostic lumbar punctures, noncutting (pencil point) needles significantly
reduced the incidence of PDPH vs cutting (Quincke) needles (Lavi 2006 Level II, n=58, JS 4; Strupp
2001 Level II, n=306, JS 5), leading to a recommendation to use noncutting needles routinely inneurology practice (Arendt 2009 NR).
During epidural catheter insertion in labour, the incidence of accidental dural puncture was
not reduced when using an 18‐g epidural Sprotte (pencil point) needle vs a 17‐g epidural
Tuohy needle (Morley-Forster 2006 Level II, n=1,077, JS 5). However, the incidence of PDPH wassignificantly lower with the epidural Sprotte needle.
Epidural blood patch
The use of an epidural blood patch (EBP) for the treatment of PDPH has been recommended as
first‐line therapy (Bezov 2010a NR), especially in obstetric patients (Thew 2008 NR) and following
inadvertent dural puncture with an epidural needle ( Gaiser 2006 NR). However, the risks of theintervention must be carefully weighed with the benefits (Suescun 2016 NR).
EBP is more effective than conservative treatment (OR 0.18; 95%CI 0.04 to 0.76) ( 1 RCT) anda sham procedure (OR 0.04; 95%CI 0.00 to 0.39) (1 RCT) (Boonmak 2010 Level I [Cochrane], 9 RCTs,
n=379).
The most effective blood volume for EBP administration is not known. Data varysignificantly from 7.5 to 30 mL. There was no difference in the severity of PDPH at 3 d inpatients who received either a 7.5 or 15 mL EBP, except for a lower incidence of nerve-root
irritation during injection with the lower volume (Chen 2007 Level II, n=33, JS 3). EBP volumes in
the range of 10 to 20 mL were effective in relieving PDPH in 98% of patients following
spinal or epidural anaesthesia (Wu 1994 Level IV, n=159). There was no difference in thefrequency of PDPH resolution (approximately 91%) with either 10 or 15 mL blood volumes
randomised according to patient height (Taivainen 1993 Level III-1, n=81). Significant relief of
PDPH was obtained in 93% of patients, who received a mean EBP volume of 23 ( 5) mL(Safa-Tisseront 2001 Level IV, n=504). With use of volumes of 15, 20 and 30 mL, permanent or
partial relief of headache was achieved in 61%, 73%, and 67% respectively and complete reliefin 10%, 32%, and 26% without a difference in backache (Paech 2011 Level II, n=121, JS 5); theauthors recommended 20 mL as the “optimal” target volume.
EBP is sometimes performed prophylactically to prevent PDPH after an inadvertentdural puncture (eg by an epidural needle) (Bezov 2010a NR). However, there is conflicting
evidence of benefit with prophylactic EBP administration; there is improvement vs no treatment(OR 0.11; 95%CI 0.02 to 0.64) (1 RCT), conservative treatment (OR 0.06; 95%CI 0.03 to 0.14)(2 RCTs) and epidural saline patch (OR 0.16; 95%CI 0.04 to 0.55) (1 RCT), but not vs a shamprocedure (1 RCT) (Boonmak 2010 Level I [Cochrane], 9 RCTs, n=379). The authors of this Cochrane
Review do not recommend prophylactic EBP due to concerns about inconclusive findings in small
studies. However, a subsequent RCT showed benefit with reduction of incidence of PDPH from79.6 to 18.3% by a prophylactic blood patch (Stein 2014 Level II, n=60, JS 3).
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The use of autologous blood patch may be contraindicated in patients withcancer,leukaemia, coagulopathy or infection, including HIV, although there is debate for some of thesein the literature (Tom 1992 Level IV, n=252).
Bed rest and hydration
There is no evidence of benefit with bed rest or fluid supplementation in the treatment or
prevention of PDPH (Arevalo-Rodriguez 2013 Level I [Cochrane], 23 RCTs, n=2,477). However,patients with PDPH may have difficulty in mobilising and the headache subsides with bed rest.
Other treatments
PDPH is successfully prevented with morphine, cosyntropin and aminophylline, especially inpatients with high risk of PDPH, while dexamethasone increased PDPH and there wereinconclusive data for fentanyl, caffeine and indomethacin ( Basurto Ona 2013b Level I [Cochrane],
10 RCTs, n=1,611). These findings are based on studies of limited quality with small sample size.
PDPH responds to caffeine (reducing persistence and further treatment requirements) andgabapentin, hydrocortisone and theophylline (reducing pain severity), while there is insufficientevidence for sumatriptan, adrenocorticotropic hormone, pregabalin and cosyntropin (BasurtoOna 2015 Level I [Cochrane], 13 RCTs, n=479). These findings are based on studies of limited quality
with small sample size and limited generalisability.
A number of other studies and treatments were not considered in the above Cochranereviews:• Gabapentin (Vahabi 2014 Level II, n=120, JS 3) reduced the intensity and duration of PDPH;
preoperative administration before spinal anaesthesia for elective Caesarean section did
not reduce PDPH incidence, but did reduce severity (Nofal 2014 Level II, n=88, JS 5);• IT administration of 5 mL normal saline reduced the overall incidence of PDPH from 24 to
2% (Faridi Tazeh-Kand 2014 Level II, n=100, JS 4);• Topical sphenopalatine ganglion block has been used successfully in PDPH (Kent 2016 Level
IV, n=3) and was superior to EBP with no complications (Cohen 2018 Level III-3, n=81; Dubey
2018 Level IV, n=11).
Low CSF pressure headache may result from disruption of the dural integrity, often in cervicalor thoracic levels with persisting headaches of identical character to PDPH. Management
requires careful evaluation of the potential site of CSF leak. Extradural spinal fluid may beapparent on careful MRI and a clue to the site of leak may come from the clinical history.
Management is similar to that of PDPH (Mokri 2013 NR; Mokri 2003 NR).
8.6.5.8 | Other headaches
There is little evidence to guide the treatment of acute cervicogenic headache, post-traumaticheadache (Minen 2019 Level I, 7 RCTs, n=1,108; Larsen 2019 Level IV SR, 7 studies, n=121 [adults]& 618 [children]) or acute headache attributed to substance use or its withdrawal, althoughgeneral principles of evaluation of headache and management of acute pain must apply(Silberstein 2000 GL).
Giant cell arteritis
The treatment of giant cell arteritis is with high‐dose steroids but there are no evidence‐based
guidelines and the steroid dose and route of administration are empirical. Because of thepotential devastating effect on vision in this common vasculitic disorder, high-dose steroid isrecommended: IV methylprednisolone 15 mg/kg/d showed more rapid and sustained remission
vs oral prednisone 40 mg/d (Mazlumzadeh 2006 Level II, n=27, JS 5).

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Tocilizumab, a humanized anti-interleukin-6 receptor (IL-6R) monoclonal antibody has shown
efficacy in the induction and maintenance of remission of giant cell arteritis (Schirmer 2018
Level I, 2 RCTs, n=281).
Headache attributed to substance withdrawal (severe analgesic “rebound” headache)
Patients may present with severe acute‐on‐chronic headache due to the overuse and/or
withdrawal of antimigrainal (triptans or ergot alkaloids) or other analgesics. Inpatient treatment
is often required to manage this chronic pain condition and may include cessation of analgesics,
IV hydration, steroids, NSAIDs, antiemetics and benzodiazepines (Kristoffersen 2014 NR).
Medication withdrawal is usually recommended as a first step in treatment with use of
preventive medications, but current evidence does not provide definite guidance ( Chiang 2016
Level VI SR, 68 studies, n unspecified). Limiting acute headache treatment to no more than 10 or 15
d/mth (depending on medication type) is commonly recommended to prevent headachefrequency progression; analgesics including opioids may carry a higher risk of medication
overuse headache than triptans and ergotamines (Thorlund 2016 Level IV SR, 29 studies, n=3,092).

KEY MESSAGES
Tension‐type headache
1. Acupuncture may be effective in the treatment of tension‐type headache (S) (Level I[Cochrane Review]).
2. Simple analgesics such as paracetamol or NSAIDs, either alone or combined, areeffective in the treatment of episodic tension‐type headache (S) (Level I [PRISMA]).
3. Metoclopramide, metamizole and chlorpromazine as parenteral treatments of tensiontype headache have high efficacy (U) (Level I [PRISMA]).
4. The combination of caffeine/aspirin/paracetamol is superior to paracetamol in thetreatment of episodic tension‐type headache (U) (Level I).
Migraine
5. Paracetamol is effective in the treatment of migraine, however less than otheranalgesics; the efficacy is increased when combined with metoclopramide (U) (Level I[Cochrane Review]).
6. Aspirin, ibuprofen, diclofenac and dipyrone are effective in the treatment of migraine;soluble preparations of ibuprofen provide a faster onset (U) (Level I [Cochrane
Review]).
7. For sumatriptan, subcutaneous administration achieves the fastest onset of effect andhighest efficacy (U) (Level I [Cochrane Review]).
8. The combination naproxen/sumatriptan has increased efficacy and better tolerability
than sumatriptan on its own (N) (Level I [Cochrane Review]).
9. The addition of caffeine to simple analgesics improves their analgesic efficacy andtolerability in acute migraine (N) (Level I [Cochrane Review]).
10. Hyperbaric oxygen therapy is effective in controlling pain in migraine, but no othersymptoms and outcomes (U) (Level I [Cochrane Review]).

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11. A significant placebo effect occurs in migraine treatment (N) (Level I [QUOROM]),
leading to an underestimation of treatment effects of analgesic medications (N)(Level II).
12. Parenteral antiemetics, metoclopramide (S) (Level I [PRISMA]) and droperidol (U)(Level I) are effective in the treatment of migraine.
13. Phenothiazines and butyrophenones (at the expense of more adverse effects) are
effective in the treatment of migraine, in particular in the emergency department (S)(Level I).
14. All triptans are more effective than placebo in the treatment of severe migraine (S)(Level I), however 30 to 40% of patients may not respond (N) (Level I).
15. Triptans and mefenamic acid are effective in treatment of menstruation-related
migraine (U) (Level I).
16. Some opioids are more effective than placebo in the treatment of acute migraine (U)(Level I), but their use in this setting is associated with significant adverse effects andpoor outcomes (S) (Level III-2).
17. Pethidine is less effective than most other migraine treatments and should not be used(U) (Level I).
18. Intravenous magnesium may have some analgesic effect compared to placebo in
migraine (Q) (Level I [PRISMA]).
19. A “stratified care strategy” is effective in treating migraine (U) (Level II).
20. Ergotamine derivatives, but not triptans, increase the rate of severe myocardialischaemic events (U) (Level III-2 SR).
21. Migraine in pregnancy is a risk factor for gestational hypertension, preeclampsia andcardiovascular complications (U) (Level III-2).
Cluster headache
22. Parenteral triptans (sumatriptan or zolmitriptan) or high-flow oxygen therapy are
effective treatments for cluster headache attacks (S) (Level I [Cochrane Review]).
23. Sphenopalatine ganglion local anaesthetic block has moderate evidence support for
the treatment of acute cluster headaches (N) (Level IV SR).
Postdural puncture headache
24. There is no evidence that bed rest or fluid supplementation are beneficial in thetreatment and prevention of postdural puncture headache (S) (Level I [Cochrane
Review]).
25. Epidural blood patch administration is more effective than conservative treatment or asham procedure in the treatment of postdural puncture headache (S) (Level I[Cochrane Review]).
26. Risk of postdural puncture headache is reduced with preventive use of morphine,
cosyntropin or aminophylline, especially in patients at high risk; preventive
dexamethasone use increases risk of postdural puncture headache (N) (Level I[Cochrane Review]).

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27. Caffeine, gabapentin, hydrocortisone or theophylline are effective treatments for
postdural puncture headache (S) (Level I [Cochrane Review]).
28. The incidence of postdural puncture headache is reduced by using smaller‐gauge spinal or non‐cutting bevel needles or by orientating the cutting bevel parallelto the spinal sagittal plane (U) (Level I).
Medication overuse headache
29. Frequent use (>8–10 days/month) of paracetamol, NSAIDs and opioids for recurrent
acute headache (more so than triptans and ergot derivatives) may lead to
medication overuse headache; weaning and use of preventive medication arerecommended management approaches (S) (Level IV SR).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Opioids should be used with extreme caution in the treatment of headache;pethidine should not be used at all (S).

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8.6.6 | Acute pain associated with neurological disorders
Pain associated with neurological disorders is usually neuropathic in nature, although
nociceptive pain due to problems such as muscle spasms may also occur. Neuropathic pain may
be acute or chronic and is due to a lesion or disease of the somatosensory system, either
in the periphery or centrally (Jensen 2011 NR).
Treatment of acute neuropathic pain is based largely on evidence from trials for thetreatment of a variety of chronic neuropathic pain disorders (see also Section 8.1.4 above).
Effective treatments for neuropathic pain include TCAs, anticonvulsants, membrane stabilisers,
NMDA‐receptor antagonists, opioids or tramadol (see Sections 4.3, 4.4 and 4.7 to 4.9).
Associated psychosocial problems and physical disabilities must also be managed
within a multidisciplinary framework.
8.6.6.1 | Multiple sclerosis
Chronic pain is experienced by 26 to 86% of patients with multiple sclerosis (Truini 2013 NR). These
data are confirmed by a systematic review, which finds a prevalence of 63% (95%CI 55 to 70)(Foley 2013 Level IV SR, 17 studies, n=5,319).
A mechanism-based classification distinguishes the following types of pain related to multiple
sclerosis (Truini 2013 NR):• trigeminal neuralgia and Lhermitte’s phenomenon (paroxysmal neuropathic pain directly
related to the MS disease processes due to ectopic impulse generation along primaryafferents) (Solaro 2013 NR);• ongoing extremity pain (deafferentation pain secondary to lesion in the
spinothalamocortical pathways);• spasticity is the most common cause of pain in MS patients with 90% of patients withhypotonia experiencing pain: painful tonic spasms and spasticity pain (mixed pains
secondary to lesions in the central motor pathways but mediated by muscle nociceptors);• pain associated with optic neuritis (nerve trunk pain originating from Nervi nervorum);• musculoskeletal pains (nociceptive pain arising from postural abnormalities secondary to
motor disorders);• migraine (nociceptive pain favoured by predisposing factors or secondary to midbrain
lesions);• treatment-induced pains.
The prevalence of headache (43%; 95%CI 33 to 52%), neuropathic extremity pain (26%; 95%CI
7 to 53%), back pain (20%; 95%CI 13 to 28%), painful spasms (15%; 95%CI 8.5 to 23%), Lhermitte’s
sign (16%; 95%CI 10 to 25%) and trigeminal neuralgia (3.8%; 95%CI 2 to 6%) is reported (Foley
2013 Level IV SR, 17 studies, n=5,319). Treatment approaches need to be targeted to the wide
variety of different pain types occurring in multiple sclerosis balanced with adverse-effectprofiles.
A systematic review of pharmacological management of pain in multiple sclerosis identified
only two treatment approaches amenable to meta-analysis (anticonvulsants and cannabinoids)(Jawahar 2013 Level I [PRISMA], 15 RCTS, n unspecified). Various anticonvulsants have a pooled effectsize (Cohen’s d) of -1.88 (95%CI -3.13 to -0.64) on reducing pain intensity (Jawahar 2013 Level I[PRISMA], 4 RCTs [anticonvulsants], n=78). The pooled effect size (Cohen’s d) for cannabinoids
demonstrates no effect on pain intensity (0.08; 95%CI -0.74 to 0.89) (3 RCTs [cannabinoids],
n=565). In contrast, a subsequent systematic review found moderate- to high-grade evidence
supporting use of nabiximols to achieve modest reductions in pain as adjunctive therapy in MS-

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related pain (Stockings 2018 Level IV SR [PRISMA], 3 RCTs and 13 studies [multiple sclerosis],
n=9,958) (all 3 RCTs overlap). Adverse events occurred in 81.2% of cannabinoid-treated patientsvs 66.2% of placebo treated patients (OR 2.33; 95%CI 1.88 to 2.89) (NNH 6; 95%CI 5 to 8)(10 RCTs, n=1,959); severe adverse events resulting in study withdrawal occurred in 15.8% vs4.6% (OR 3.47; 95%CI 2.64 to 4.56) (NNH 40; 95%CI 35 to 49) (19 RCTs, n=3,265).
In spasticity due to multiple sclerosis, the treatment difference vs placebo is -0.32/10 (95%CI-0.61 to -0.04) for nabiximols (Sativex®; containing THC:cannabidiol = 1:1), with high numbers ofsubjects experiencing at least one adverse effect (Wade 2010 Level I, 3 RCTs, n=666). Overall,cannabinoids may be effective for pain and spasticity control in MS, but the effects may berelatively modest with issues of statistical significance versus clinical relevance and the lack ofreporting of negative results in sponsored trials (Nielsen 2018 Level III-3 SR, 11 SRs of 10 RCTs and
22 studies, unspecified) (see also Section 4.11).
In MS patients, duloxetine (30 to 120 mg/d) vs placebo improved pain at wk 6 (-1.83/10 vs. 1.07/10) (Vollmer 2014 Level II, n=239, JS 5). Similarly, duloxetine (30 mg, then 60 mg) reduced
average daily pain at 6 wk by 39% ( 29) vs placebo 10% ( 18.8) (Brown 2015 Level II, n=38, JS 4).
Microvascular decompression in MS related trigeminal neuralgia has shown limited
effectiveness in comparison to non-MS trigeminal neuralgia; the relapse rate is up to 51% at 2
years and is complicated by sensory dysaesthesia in 11% of patients ( Ferraro 2020 Level III-2,
n=298).
Gamma knife radiosurgery may be effective compared with other interventions ( Helis 2019
Level IV, n=74). The duration of pain relief has not been fully evaluated, although a 12 y follow-up
indicated a clinically useful pain modification lasting up to 5 y with benefit from repeat Gamma
knife treatment.
Overall, there is insufficient evidence to support medical or surgical therapy for MS related
trigeminal neuralgia (Zakrzewska 2018 Level IV SR, 10 studies [medical management], 26 studies[surgical management], n unspecified). No study included long-term follow-up and all studies
evaluated were of low quality.
Transcutaneous spinal direct current stimulation (ts-DCS) reduced MS-related central
neuropathic pain in a pilot trial (Berra 2019 Level II, n=33, JS 3). Other techniques ofneuromodulation may have a role in the management of MS-related pain (Abboud 2017 NR).
Exercise vs passive controls improves pain in patients with MS, however, the evidence isbased on poor quality RCTs with high risk of bias (Demaneuf 2019 Level I, 10 RCTs, n=389). There is
low level evidence from studies with no large-scale trials of yoga and other postural treatments
in reducing acute MS pain (Aboud 2019 NR).
Mindfulness reduces fatigue, but not pain in multiple sclerosis (Simpson 2019b Level I, 10 RCTs,
n=678).
8.6.6.2 | Parkinson’s disease
Pain is a common distressing symptom in Parkinson’s disease; between 30 and 50% of patientswith Parkinson’s disease have pain (Beiske 2009 Level IV, n=176; Fil 2013 NR). Pain may occur
independently of Parkinson's disease, related to underlying musculoskeletal disorders (89%),
radicular and peripheral neuropathic pain (31.5%) and dystonic pain (15.1%); however,
Parkinsonian central pain resulting from disordered nociceptive processing has the lowest
prevalence (4.1%), but highest severity, is poorly characterized and is difficult to describe not
only by patients but also by neurologists (Chaudhuri 2015 Level III-2, n=261; Ozturk 2016 Level IV,
n=113).
Optimization of dopaminergic therapies should always be the first step in the managementof Parkinson's disease pain (Jost 2019 NR; Skogar 2016 NR). Medications used to treat pain include
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specific Parkinson-related agents, mainly dopaminergic, as well as opioid and non-opioid
analgesics, anticonvulsants, antidepressants particularly duloxetine, cannabinoids andbotulinum toxin injections for dystonia related pain ( Rukavina 2019 NR; Sophie 2012 NR; Ford 2010NR). Currently, therapy is prescribed without necessarily considering special requirements ofParkinson patients and drug interactions. In many cases, pain is resistant to standard therapies:
physiotherapy is essential in the management of Parkinson’s disease related pain.
Tapentadol improved pain related to Parkinson’s disease, but also anxiety, depression andquality of life (Freo 2018 Level lV, n=21).
Subthalamic Nucleus deep brain stimulation (DBS) is often used to improve motor functionin advanced Parkinson’s disease, but improvement in pain with this treatment has been
observed, too. Severity of pain (from mean pain score 6.2/10 (SD 2.5) to 3.5/10 (SD 2.2) andnumber of body parts affected by pain (from 21 to 8) decreased over an 8 y follow-up after
surgery; however, new pain developed in 75% of patients ( Jung 2015 Level IV, n=24). In a
comparison of Subthalamic Nucleus vs Globus Pallidus Internus DBS, both techniques provided
similar analgesia (from 4.4/10 [ 1.67] before surgery to 1.1/10 [ 1.39] 4 mth after surgery)(Gong 2020 Level III-3, n=64).
8.6.6.3 | Central post-stroke pain
Central pain develops in 8 to 35% of stroke patients (Kumar 2009 NR). It is not only aconsequence of thalamic stroke but also lateral medullar and parietal cortical stroke or ischaemic
events affecting the spinothalamic or trigeminothalamic pathways (Flaster 2013 NR; Akyuz 2016
NR). The majority of the cases are intractable and unresponsive to analgesic treatment.
Electrical stimulation such as deep brain stimulation and repetitive transcranial magnetic
stimulation seems to be effective in certain cases: anticonvulsants, antidepressant, an opioid
antagonist, acupuncture and transcutaneous magnetic stimulation all have minimal effect on
pain (Mulla 2015 Level I [PRISMA], 8 RCTs, n=459).
IV lidocaine (Attal 2000 Level II, n=6 [poststroke], JS 5) and IV propofol in subhypnotic doses(Canavero 2004 Level II, n=44, JS 5) may provide short‐term relief in central poststroke pain.
Amitriptyline was more effective than placebo and carbamazepine (which were equivalent)(Leijon 1989 Level II, n=15, JS 4). Lamotrigine was moderately effective and well tolerated in central
poststroke pain (Vestergaard 2001 Level II, n=30, JS 5). Pregabalin in poststroke pain did not resultin significant pain relief at the endpoint of the trial but there was a profound placebo response
and pain relief at other time points and secondary outcomes were in favour of pregabalin ( Kim
2011a Level II, n=219, JS 5). The SSRI fluvoxamine showed benefit in poststroke pain ( Shimodozono
2002 Level IV, n=31).
Non-invasive brain stimulation by two approaches (direct current stimulation [DCS] andrepetitive transcranial magnetic stimulation) reduces intensity of post-stroke pain and also
experimental pain sensitivity, however, based on low-quality evidence (Ramger 2019 Level III-3 SR,
1 RCT & 5 studies, n=111). Motor cortex stimulation specifically reduces refractory post-stroke pain
by 35.2% (Mo 2019 Level IV SR, 12 studies, n=198).
Acupuncture may reduce post-stroke pain (MD −1.59; 95%CI −1.86 to −1.32]) (25 RCTs),
however with low certainty due to poor study quality ( Liu 2019b Level I, 38 RCTs, n=3,184).
On the basis of the limited data available, a practical guideline recommends trials ofamitriptyline, lamotrigine, gabapentin or pregabalin or a combination of these to treat central
poststroke pain with consideration of non-invasive brain stimulation for refractory patients (Kim
2014b GL). However, the available evidence suggests limited beneficial effect of any of thetherapies that have been evaluated in RCTs and clinical practice guidelines are mainly empirical.

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8.6.6.4 | Trigeminal neuralgia
Exacerbations of trigeminal neuralgia can present as acute neuropathic pain.
For acute exacerbations of trigeminal neuralgia, local anaesthetic (mainly lidocaine[administered ophthalmic, nasal or oral mucosal, trigger point injection, IV infusion, nerve block),anticonvulsants (phenytoin or IV fosphenytoin) and SC or IN sumatriptan reduce pain by 50%
within 24 h (Moore 2019 Level IV SR, 4 RCTs & 14 studies, n unspecified); there is very limited evidence
supporting IV magnesium sulphate and botulinum toxin by trigger point injection.
Sumatriptan, IN and IV lidocaine and botulinum toxin provide better analgesia vs placebo andophthalmic proparacaine based on pooled estimates in a Bayesian mixed treatment comparison
network meta-analysis (Sridharan 2017 Level I [NMA], 11 RCTs, n unspecified); the evidence is very
low quality except for botulinum toxin. Pulsed and combined continuous and pulsed
radiofrequency thermocoagulation may be the most effective invasive therapies.
Topiramate is as effective as carbamazepine at 1 mth after treatment commencement andslightly more effective at the 2 mth endpoint in trigeminal neuralgia (RR 1.20; 95%CI 1.04 to 1.39)(Wang 2011 Level I, 6 RCTs, n=354). All included RCTs were of poor methodological quality; this isalso an issue for carbamazepine trials, which show probable effectiveness over placebo ( Wiffen
2014 Level I [Cochrane], 10 RCTs, n=480). There is insufficient evidence to support or refute the useof gabapentin for trigeminal neuropathic pain (Ta 2019 Level I [PRISMA}, 2 RCTs, n=95). There isinsufficient evidence to support the use of any nonantiepileptic medications (tizanidine,pimozide, tocainide) in trigeminal neuralgia (Zhang 2013c Level I [Cochrane] 3 RCTs [systemic
medications], n=92). However, IV infusion of magnesium/lignocaine once/wk for 3 wk resulted in
reduction of pain in patients with trigeminal neuralgia not responding to previous treatments(Arai 2013a Level IV, n=9). Duloxetine has been shown to have an effect in trigeminal neuralgia(Anand 2011 Level IV, n=15).
Topical ophthalmic anaesthesia has been studied with varying results. Proparacainehydrochloride 0.5% was not superior to placebo (Zhang 2013c Level I [Cochrane] 1 RCT [proparacainehydrochloride], n=47). Amethocaine 1% eye drops reduced paroxysms of pain in trigeminal
neuralgia (Brill 2010 Level IV, n=40). Intraoral lignocaine 8% was also effective (Niki 2014 Level II,
n=24, JS 4).
Motor cortex stimulation (MCS) has a positive effect on refractory pain and the total
percentage improvement was 46.5% in trigeminal neuropathic pain (Mo 2019 Level IV SR,
12 studies, n=198).
Published guidelines mainly focus on chronic pain medications but do not identify sufficientevidence for the effectiveness of any IV medication in the acute setting (Cruccu 2008 GL). The
same guidelines rate carbamazepine as effective and oxcarbazepine as probably effective andsuggest that baclofen, oxcarbazepine, gabapentin, lamotrigine, tizanidine and pimozide may beconsidered, if the first-line medications are ineffective. An updated review of the evidence
supports carbamazepine and oxcarbazepine with insufficient data to support baclofen,
lamotrigine and gabapentin (Zakrzewska 2014 NR).

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KEY MESSAGES
1. Various anticonvulsants (U) (Level I [PRISMA]) and duloxetine (N) (Level II) havebeneficial effects in the treatment of neuropathic pain associated with multiple sclerosis
2. Cannabinoids have a clinically small effect on spasticity caused by multiple sclerosis (U)(Level I); the effect on neuropathic pain associated with multiple sclerosis is unclear andmay depend on the preparation used (W) (Level I [PRISMA]).
3. With cannabinoid use in multiple sclerosis, there is a high rate of minor adverse effects andserious adverse psychopathological effects occur in nearly 1% of patients (U) (Level I).
4. Acupuncture (N) (Level I), non-invasive brain stimulation (N) (Level III-3 SR) and motor
cortex stimulation (N) (Level IV SR) may reduce post-stroke pain.
5. Local anaesthetics (mainly lidocaine) by local and systemic administration,
anticonvulsants (phenytoin or IV fosphenytoin) and sumatriptan reduce pain in acuteexacerbations of trigeminal neuralgia (N) (Level IV SR).
6. Motor cortex stimulation may reduce acute pain in trigeminal neuralgia (N) (Level IV SR)
7. Deep brain stimulation may improve pain relief in Parkinson’s disease (N) (Level IV).
The following tick box represents conclusions based on clinical experience and expert
opinion: Treatment of acute pain associated with neurological disorders is based largely on
evidence from trials for the treatment of a variety of chronic neuropathic pain states (S).

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8.6.7 | Acute orofacial pain
Acute orofacial pain may be caused by infective, traumatic, neuropathic, vascular, neoplastic andother pathologies (Khawaja 2015 NR; Zakrzewska 2013 NR; Hegarty 2011 NR). Most commonly, acuteorofacial pain is due to either dental or sinus disease. It may also be associated with flare-ups ofmore chronic orofacial pain syndromes eg temporomandibular disorders (TMDs; see Section
8.6.7.4 below), trigeminal neuralgia (see Section 8.6.6.4 above), migraine and other primaryheadaches (see Section 8.6.5 above). Pain may also be referred from adjacent structures such as
the cervical spine, ear and throat.
Post-traumatic neuropathic orofacial pain (including post-traumatic trigeminal neuropathy)
may be caused by nerve injury secondary to common dental surgical procedures eg extractionof teeth, root canal therapy, local anaesthetic injections or placement of dental implants. Suchorofacial pain conditions may be exacerbated by repeated procedures, incorrect treatment andcomorbid psychological factors.
A thorough medical/dental history and clinical examination (particularly of the mouth, jaw
and cranial nerves) are essential components of the assessment of acute orofacial pain
(Zakrzewska 2013 NR; Hegarty 2011 NR).
Recurrent or persistent orofacial pain may require additional biopsychosocial assessment
and appropriate multidisciplinary management (de Leeuw 2018 NR; Vickers 2000 NR).
8.6.7.1 | Acute dental pain
In general, patients suffering acute oral and dental pain should be referred to a dentist for
appropriate diagnosis and management. NSAIDs and emergency pulpectomy reduces pain inpatients with acute apical periodontitis (Sutherland 2003 Level I, 8 RCTs, n=531), but there isinsufficient evidence to determine if the addition of antibiotics reduces pain due to irreversible
pulpitis (Agnihotry 2019 Level I [Cochrane], 1 RCT, n=40) or apical periodontitis or abscess (Cope 2018
Level I [Cochrane], 2 RCTs, n=62). Unless it has been established that infection is the cause, it isinappropriate for antibiotics to be prescribed, even though they may provide some symptomatic
relief (Abbott 2007 NR). Pulpitis due to extension of caries into the pulp or pulp exposure may leadto pulp necrosis and acute apical periodontitis.
The use of local anaesthetics to permit dental treatment is not presented here as it is deemedbeyond the scope of this document.
8.6.7.2 | Acute postoperative dental pain
Common dental surgical procedures, particularly tooth extractions and endodontic treatments,
are frequently associated with acute postoperative pain, requiring pharmacologicalmanagement.
Paracetamol and NSAIDs
Acute pain after third molar extraction is the most extensively studied model for testing
postoperative analgesics in single-dose investigations. Nonselective NSAIDs or coxibs arerecommended as “first-line” analgesics following third molar extraction (Derry 2011 Level I,
155 RCTs, n=16,104), however paracetamol is also safe and effective with a dose of 1,000 mg
providing better pain relief than lower doses (Weil 2007 Level I [Cochrane], 21 RCTs, n=1,968). The
best available evidence suggests the use of NSAIDs either with or without paracetamol iseffective and well-tolerated (Moore 2018 Level I, 5 SRs, n unspecified).
Nonselective NSAIDs are more effective than paracetamol or codeine (either alone or in
combination) (Ahmad 1997 Level I, 33 RCTs, n=5,171). Ibuprofen (200–512 mg) specifically is
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superior to paracetamol (600–1,000 mg) in this setting and combining these two drugs improves
analgesia further (Bailey 2014 Level I [Cochrane], 7 RCTs, n=2,241).
Based on a meta-analysis of limited quality, pre-emptive use of NSAIDs does not appear tobe effective in reducing postoperative pain in this setting (OR 2.30; 95%CI 0.60 to 8.73) (4 RCTs,
n=298) (Costa 2015 Level I, 6 RCTs, n=420).
For acute pain of endodontic origin, NSAIDs are the analgesic of choice (Aminoshariae 2016
Level I [PRISMA], 27 RCTs, n=400). When NSAIDs are not effective on their own, there is support for
combining these with paracetamol, tramadol or an opioid; moderate evidence supports the useof steroids in symptomatic irreversible pulpitis.
In patients with preoperative pain, ibuprofen 600 mg and ibuprofen 600 mg/paracetamol
1,000 mg are similarly effective and provide superior analgesia after endodontic treatment vsplacebo (Smith 2017a Level I [PRISMA], 15 RCTs, n=1,107). Ketoprofen 50 mg and naproxen 500 mg
may be effective alternatives.
A number of RCTs not included in the above meta-analyses support their overall conclusions.
The combination of paracetamol 1,000 mg with ketoprofen 100 mg was more effective thaneither drug given alone (Akural 2009 Level II, n=76, JS 5). IM/IV ketorolac 30 mg provided better
analgesia with fewer adverse effects than IM pethidine 100 mg (Fricke 1992 Level II, n=145, JS 5) orIV tramadol 50 mg (Ong 2004 Level II, n=64, JS 3). IV meloxicam 60 mg showed faster onset of thenlonger-lasting analgesic effect than PO ibuprofen 400 mg ( Christensen 2018 Level II, n=230, JS 5).
PO meloxicam 15 mg provided superior analgesia to PO diclofenac 100 mg in a small RCT (OrozcoSolis 2016 Level II, n=36, JS 4).
In a direct comparison, PO diclofenac 50 mg provided superior analgesia to PO ibuprofen
400 mg and PO paracetamol 1,000 mg (Gazal 2017 Level II, n=120, JS 5).
Coxibs are of similar efficacy to nsNSAIDs in acute postoperative dental pain. Single-dose
celecoxib 200 mg is less effective than ibuprofen 400 mg (Chen 2004 Level I, 18 RCTs, n=2,783); whilecelecoxib 400 mg provided similar analgesia to ibuprofen 400 mg with increased time to rescue
analgesia following dental surgery (Cheung 2007 Level II, n=171, JS 5). In a comparison of
PO celecoxib (400 mg, then 200 mg every 12 h), ibuprofen (400 mg every 8 h) and tramadol (100mg PO every 8 h), celecoxib was the most effective analgesic (Akinbade 2018 Level II, n=135, JS 4).
Single daily doses of etoricoxib 90 mg and 120 mg were similar in analgesic efficacy to ibuprofen
600 mg every 6 h but longer lasting, as well as superior to a paracetamol 600mg/codeine 60 mg
combination (Brown 2013 Level II, n=588, JS 5).
A combination of oxycodone/ibuprofen (5/400 mg) was more effective than othercombinations of paracetamol, ibuprofen, oxycodone or hydrocodone or placebo for analgesia
following dental surgery (Litkowski 2005 Level II, n=249, JS 5).
A systematic review to investigate the influence of pain models revealed that the placebo
response for analgesia was significantly lower post third molar extraction pain than in otheracute pain models (Barden 2004a Level I, 160 RCTs, n=14,410).
TramadolTramadol 100 mg had a similar efficacy to aspirin/weak opioid or paracetamol/weak opioid
combinations in treating acute dental pain (Moore 1997 Level I, 18 RCTs, n=3,453). A
tramadol/paracetamol combination is superior to tramadol alone with fewer adverse effects due
to a reduced tramadol dose (Edwards 2002a Level I, 7 RCTs, n=1,376; Fricke 2004 Level II, n=456, JS 5)
and was comparable to a codeine/acetaminophen/ibuprofen combination preparation ( Jung
2004 Level II, n=128, JS 5).
However, tramadol provides inferior analgesia with an increased rate of adverse events vs
NSAIDs in the treatment of acute dental pain (Isiordia-Espinoza 2014 Level I, 5 RCTs, n=200). This isconfirmed by RCTs not included in this meta-analysis. PO Tramadol 100 mg was significantly less566

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effective than PO naproxen 500 mg (Mehrvarzfar 2012 Level II, n=100, JS 5). In comparison of PO
tramadol (100 mg every 8 h), PO celecoxib (400 mg, then 200 mg every 12 h) and PO ibuprofen(400 mg every 8 h), tramadol was the least effective analgesic (Akinbade 2018 Level II, n=135, JS 4).
Steroids
Perioperative steroid administration reduced swelling and trismus, but not pain following third
molar extraction (Markiewicz 2008 Level I, 12 RCTs, n=287). However, two subsequent studies
suggested there might be an analgesic benefit from dexamethasone (Klongnoi 2012 Level II, n=20,
JS 2), with dexamethasone 4 mg being similarly effective to 120 mg etoricoxib ( Sotto-Maior 2011
Level II, n=50, JS 3).
A submucosal injection of dexamethasone 4 and 8 mg immediately before surgery similarly
reduced postoperative facial swelling, but not pain or trismus, vs placebo at 48 h (Grossi 2007
Level II, n=72, JS 5). A single 40 mg injection of methylprednisolone into the masseter muscle
following third molar extraction reduced pain, swelling and trismus ( Vegas-Bustamante 2008
Level II, n=35, JS 5).
Following root canal treatment, there is an analgesic effect from steroid use, however, withmarked heterogeneity of the included RCTs (Iranmanesh 2017 Level I, 18 RCTs, n unspecified)Painful irreversible pulpitis may be alleviated for up to 24 h by administering dexamethasone(4 mg PO or by intraligamentary or root canal injection) (Nogueira 2018 Level I [PRISMA], 5 RCTs,
n=292).
Ketamine (topical or infiltrated)
After mandibular molar extraction, topical administration (to the extraction sockets on
resorbable gelatine sponges) of ketamine 0.5 mg/kg vs tramadol 1 mg/kg vs saline achieved thelowest pain scores and rescue analgesic use for the first 24 h after surgery (Gonul 2015 Level II,
n=90, JS 2). In a similar setting, the addition of 0.3 mg/kg ketamine to lidocaine 2% for the local
anaesthesia (inferior alveolar, lingual and buccal nerve blocks) reduced pain at 1 and 4 h andfacial swelling at 1 d, while improving mouth opening up to 7 d ( Kumar 2015 Level II, n=60, JS 1).
Pregabalin
Postoperative administration of PO pregabalin 75 mg provided better analgesic effects thanadministration before third molar extraction surgery (Cheung 2012 Level II, n=34, JS 5).
Nonpharmacological treatment
After 3rd molar extraction, cryotherapy is effective at reducing oedema ( Fernandes 2019 Level IV
SR, 11 studies, n=721). Results were mixed for an effect on pain where 5 of 11 studies foundbeneficial effect, but no meta-analysis was performed due to non-standardised evaluation
methods. Facial compression reduced pain for up to 3 d, with no additional benefit from ice packs(Forouzanfar 2008 Level II, n=95, JS 5).
Acupuncture may have a beneficial effect on acute dental pain but the quality of evidence islimited (Ernst 1998 Level III-1 SR, 16 studies, n=941).
Low-level laser energy irradiation fails to reduce either pain or swelling after removal of
third molar teeth, but reduces trismus slightly ( Brignardello-Petersen 2012 Level I, 10 RCTs,
n=581 ). This is contradicted by a subsequent meta-analysis which reports low-level laser
therapy as effective for the treatment of pain, swelling and trismus ( He 2015b Level I [PRISMA],
6 RCTs, n=193) (2 RCTs overlap ). A subsequent RCT supports the effects on pain and swelling
described in the latter meta-analysis (Eshghpour 2016 Level II, n=44, JS 3 ).

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8.6.7.3 | Acute post-tonsillectomy pain
For paediatric patients, see Section 10.4 and 10.6.6
Systemic analgesics
In adults, paracetamol (2 of 2 RCTs), NSAIDs (2 of 9 RCTs: ibuprofen, ketoprofen, rofecoxib,lornoicam, celecoxib, parecoxib vs placebo or active comparator aspirin, diclofenac or ketorolac),dexamethasone (5 of 10 RCTs), gabapentinoids (3 of 3 RCTs), and dextromethorphan (2 RCTs)
provide some limited analgesia on POD 1 after tonsillectomy (Tolska 2019 Level I [PRISMA], 29 RCTs,
n=1,816). The limited efficacy of single medications suggests that multimodal analgesic strategies
are required.
The risks of bleeding with the use of NSAIDs are discussed in detail in Section 4.2.1.2 in adult andin Section 10.4.2.3 in paediatric patients.
Alpha-delta-2 ligands
Preoperative gabapentin (6 RCTs) and pregabalin (3 RCTs) similarly reduce pain in the first 8 h,analgesic requirements in the first 24 h and PONV without increasing adverse effects after
tonsillectomy (Hwang 2016a Level I [PRISMA], 8 RCTs [3 adult, 2 mixed, 3 paediatric], n=608; Tolska 2019
Level I [PRISMA], 4 RCTs [alpha-2-delta ligands], n=255) (2 RCTs overlap).
Steroids
Dexamethasone in doses >10 mg over 24 h given to adults undergoing tonsillectomy reduces
pain by 23% at 4 h (MD -1.4/10; 95% CI -1.6 to -1.2) (Tolska 2019 Level I [PRISMA], 10 RCTs
[dexamethasone], n=590). In tonsillectomy in adults and children, all steroids reduce pain severity
at all time points up to POD 7 with a peak benefit on POD 1 (SMD -0.99/10; 95%CI -1.32 to -0.67)(41 RCTs, n=3,477) (Titirungruang 2019 Level I [PRISMA], 64 RCTs [22 adult], n=6,327) (8 RCTs overlap).
These effects are similar for systemic vs local steroid administration. Furthermore, steroids
reduce PONV (OR 0.31; 95%CI 0.24 to 0.40) (46 RCTs, n=4,784), while not increasing the risk ofprimary (OR 0.96; 95%CI 0.55 to 1.67) (15 RCTs, n=1,736) or secondary haemorrhage (OR 1.05;
95%CI 0.74 to 1.51) (23 RCTs, n=2,440).
Antibiotics
Perioperative antibiotics show no benefit in decreasing post-tonsillectomy pain (3 RCTs positive,
4 RCTs no difference, 1 RCT negative) and secondary haemorrhage rates (12 RCTs, n=1,397); adverse
effects were more common with their use (Abdelhamid 2019 Level I, 12 RCTs, n=1,397). The
conclusions reflected those of an earlier Cochrane review which found no difference in pain
(6 RCTs), need for analgesia (6 RCTs) or secondary haemorrhage (7 RCTs) (Dhiwakar 2012 Level I[Cochrane], 10 RCTs, n=1,035) (5 RCT overlap).
Peritonsillar infiltration with local anaesthesia and analgesics
Peritonsillar injection or topical application of local anaesthetics produce equally modest
reductions in post-tonsillectomy pain for up to 24 h ( Grainger 2008 Level I, 13 RCTs, n=777).
Ropivacaine 1.0% with adrenaline resulted in better pain relief up to 4 d after tonsillectomy thaneither bupivacaine 0.25% with adrenaline or placebo (Arikan 2008 Level II, n=58, JS 5). Peritonsillar
infiltration with bupivacaine provided pain relief comparable to rectal paracetamol ( DahiTaleghani 2011 Level II, n=110, JS 2).
Dexamethasone added to local anaesthetics reduces pain intensity, analgesic requirements
and PONV (3 RCTs, n=361) (Vlok 2017 Level I, 11 RCTs, n=854). Magnesium added to local
anaesthetics reduces pain intensity, analgesic requirements and incidence of laryngospasm,
but not PONV (4 RCTs, n=240). There is only limited support for the addition of pethidine ( 1 RCT,n=80) or tramadol (1 RCT, n=60), and addition of clonidine shows no effect ( 2 RCTs, n=123).

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Infiltration of the tonsillar bed with tramadol (Atef 2008 Level II, n=40, JS 5) as well as anequivalent IM tramadol dose reduced pain and analgesic requirements in the first few hours
after tonsillectomy vs placebo (Ugur 2008 Level II, n=45, JS 5). Peritonsillar infiltration withtramadol resulted in better early pain control with preoperative infiltration (up to 2 h postop),
but better late (beyond 8 h) pain control with postoperative infiltration ( Maryam 2017 Level II,
n=80, JS 3). See also Section 10.4.4.12.
Topical administration
There is poor and inconsistent evidence on the analgesic effects of oral rinses, mouthwashes andsprays after tonsillectomy, although lidocaine spray is more effective than saline spray (1 RCT)
(Fedorowicz 2011 Level I [Cochrane], 6 RCTs, n=528 [131 adults]). While in a subsequent RCT, topicalropivacaine (swabs soaked in 1% ropivacaine packed into the tonsillar beds for 5 min) vs placebo
had no effect on pain after tonsillectomy (Tolska 2017 Level II, n=160, JS 5).
Non-pharmacological treatment
Intraoperative cryotherapy (with a cryotherapy probe [-56°C]) (1 RCT) and ice-water cooling (4°C
to 10°C) (2 RCTS) reduces post-tonsillectomy pain scores consistently by 21 to 32% (0.9/10 to
1.8/10) (Raggio 2018 Level I [PRISMA], 3 RCTs, n=153).
Acupuncture vs control or sham may reduce pain intensity, analgesic requirements and PONV
for up to 48 h after tonsillectomy with high levels of heterogeneity ( Cho 2016 Level I, 12 RCTs,
n=1,025).
Honey in children vs placebo reduces pain and analgesic use for up to 5 to 10 d posttonsillectomy; regimens of honey administered varied substantially in volume (4 to 15 mL),
frequency (daily to hourly) and duration (1 to 10 d) ( Hwang 2016b Level I [PRISMA], 4 RCTs n=264;
Lal 2017 Level I [QUOROM], 8 RCTs n=545) (4 RCTs overlap). The analgesic medication regimens usedin the included studies were not clear.
8.6.7.4 | Acute pain associated with temporomandibular disorders
Temporomandibular disorders (TMDs) are a group of musculoskeletal pains affecting themasticatory muscles and/or temporomandibular joints (TMJs) and are the most common cause oforofacial pain apart from the teeth (Zakrzewska 2013 NR; Hegarty 2011 NR). The common TMDs
include masticatory myalgia, myofascial pain, TMJ disc interference disorders and TMJ
degenerative joint disease. The primary TMD symptoms include painful limitation of mouth
opening and/or deviation of the mandible on opening, TMJ tenderness, TMJ crepitus and/or
clicking noise and masticatory muscle pain or tenderness. Headaches are often an associatedfeature. Management approaches to TMD pain include medication, physiotherapy, occlusal splints,
self-management strategies, and interventions based on cognitive behavioural approaches.
There is limited evidence for the successful pharmacological management of TMD pain
(Mujakperuo 2010 Level I [Cochrane], 11 RCTs, n=496). A subsequent systematic review and network
meta-analysis identified NSAIDs as well as corticosteroid and hyaluronate injections as successfultreatments for TMD joint pain (15 RCTs, n=790), while the muscle relaxant cyclobenzaprine iseffective in TMD muscle pain (9 RCTs, n=375) (Haggman-Henrikson 2017 Level I [NMA], 41 RCTs,
n=2,033). Based on transferable evidence from similar conditions, topical NSAIDs are a treatment
option also as in adult patients with acute pain resulting from strains, sprains or sports injuries,
topical diclofenac, ibuprofen, ketoprofen, piroxicam and indomethacin are effective vs placebo,
whereas benzydamine is not (Derry 2015 Level I [Cochrane] 61 RCTs, n=8,386).
The evidence for IA morphine, tramadol, buprenorphine, fentanyl and NSAIDs wasinconclusive due to a small number of low-quality studies for temporomandibular joint
arthrocentesis (Gopalakrishnan 2018 Level I [PRISMA], 3 RCTs, n=91 [& 3 other studies]).
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Low-level laser therapy in the treatment of TMD has no analgesic benefit vs placebo (WMD 19.4; 95%CI -40.8 to 2.0), but improves functional outcomes (Chen 2015 Level I, 14 RCTs, n=454).
8.6.7.5 | Acute pain associated with pharyngitis
Systemic analgesics
Paracetamol, nsNSAIDs, coxibs and opioids, administered as monotherapy or in combination,
were effective in the treatment of pain associated with acute pharyngitis ( Thomas 2000 Level I,
17 RCTs, n=3,259).
Corticosteroids
Corticosteroids provide relief of pain, in particular in patients with severe or exudative sorethroat (Hayward 2012b Level I [Cochrane], 8 RCTs, n=743). Here, corticosteroids in combination with
analgesics and antibiotics increase the likelihood of complete resolution of pain at 24 h (RR 3.2;
95%CI 2.0 to 5.1) and the time to onset of pain relief by 6.3 h (6 RCTs, n=609). In acute pharyngitis
potentially caused by group A beta-haemolytic Streptococcus, corticosteroids reduce the time
to clinically meaningful pain relief; however provide only a small reduction in pain scores at 24 h(Wing 2010 Level I, 10 RCTs, n=1,096) (8 RCTs overlap). Corticosteroids administered in a single dose(most commonly 10 mg dexamethasone orally) provide pain relief for sore throat including
pharyngitis more effectively and faster than placebo (Sadeghirad 2017 Level I, 10 RCTs [7 RCTs in
adults], n=1,426) (9 RCTs overlap). On the basis of these findings, clinical practice guidelines makea weak recommendation to treat acute sore throat with a single dose of oral corticosteroid(Aertgeerts 2017 GL).
Dexamethasone decreases incidence and severity of sore throat after extubation whenadministered IV at induction (Kuriyama 2019 Level I [PRISMA], 15 RCTs, n=1,849).
Following drainage and antibiotics for peritonsillar abscess, a single dose of IV corticosteroid
reduces fever and with less certainty pain, trismus and hospital LOS (Hur 2018 Level I [PRISMA],
3 RCTs, n=153).
Antibiotics
Antibiotics for sore throat reduce pain, headache and fever by 50% on d 3; this effect was more
pronounced if throat swabs were positive for Streptococcus (Spinks 2013 Level I [Cochrane], 27 RCTs,
n=12,835). Antibiotics reduce throat soreness at 3 d vs controls (RR 0.68; 95%CI 0.59 to 0.72).
Antibiotics also shortened the duration of symptoms by 16 h, although the absolute benefits aremodest.
Topical analgesics
Topical analgesics such as lozenges containing amylmetacresol/2,4-dichlorobenzylalcohol(AMC/DCBA) (Weckmann 2017 Level I [PRISMA], 3 RCTs, n=661), flurbiprofen (Watson 2000 Level II,
n=301, JS 5), ibuprofen (Bouroubi 2017 Level II, n=385, JS 5) and benzocaine (Chrubasik 2012 Level II,
n=50, JS 3) as well as benzydamine spray (Thomas 2000 Level I, 17 RCTs, n=3,259) or
benzydamine/chlorhexidine spray (Cingi 2010 Level II, n=164, JS 5) provide analgesia superior toplacebo in acute sore throat with minimal adverse effects.
Ketamine gargle vs placebo or no treatment reduces the incidence of postoperative sorethroat for up to 24 h (RR 0.42 to 0.52 over time points 0 to 24 h) based on high-quality evidence(Mayhood 2015 Level I [PRISMA] 5 RCTs, n=291); systemic absorption is an unknown factor.
Ambroxol, a mucolytic substance with local anaesthetic properties, reduces pain ofpharyngitis slightly (with questionable clinical relevance) vs placebo (mint lozenges) (Chenot 2014
Level I, 3 RCTs, n=1,772).

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Nonpharmacological treatment
A single-point acupuncture treatment at large intestine meridian for pain of acute pharyngitis
and tonsillitis was not more effective than sham laser acupuncture (Fleckenstein 2009 Level II, n=60,
JS 5).
8.6.7.6 | Acute pain associated with sinusitis and otitis media
Treatment of sinusitis and otitis media is primarily symptomatic using analgesics andantipyretics; it may be appropriate to use nsNSAIDs, coxibs, paracetamol, weak opioids ortramadol, based on evidence for treatment of dental pain. Evidence based clinical practiceguidelines for the diagnosis and treatment of acute sinusitis ( Chandran 2013 GL; Meltzer 2011 GL)
and acute otitis media are published (Rosenfeld 2014 GL). Evidence for individual interventions arepresented here.
Antihistamines and/or decongestants
Antihistamines and/or decongestants have no clinically relevant benefit in acute otitis media(Coleman 2008 Level I [Cochrane], 15 RCTs, n=2,695).
Antibiotics
Antibiotic treatment of acute otitis media vs placebo or control has no effect on acute pain after
24 h and leads to some pain reduction at 2–3 d, but with an NNT50% of 20 (Venekamp 2015 Level I[Cochrane], 13 RCTs, n=3,401). Individual patient data meta-analysis from 959 children show no
better analgesia at d 3 to 7 and from 247 children at d 7 to 14. As the effects on pain arequestionable and adverse effects (such as vomiting, diarrhoea or rash) are increased (RR 1.38;
95%CI 1.19 to 1.59; NNH 14), for most children with mild disease antibiotic use might not bejustified.
Steroids
Oral corticosteroids as a monotherapy are not effective and in combination with antibiotics may
be modestly beneficial for symptoms of acute sinusitis ( Venekamp 2014 Level I [Cochrane] 5 RCTs,
n=1,193).
Topical treatment
For sinusitis, IN corticosteroids have consistently significant benefits for facial pain (Hayward
2012a Level I, 6 RCTs, n=2,495). Improvement or resolution of symptoms are more likely with IN
corticosteroids than placebo or control, with higher doses being more effective (Zalmanovici
Trestioreanu 2013 Level I [Cochrane], 4 RCTs, n=1,943) (4 RCTs overlap).
A phytotherapeutic nasal spray containing Cyclamen europaeum provided better facial pain
relief than placebo in sinusitis (Pfaar 2012 Level II, n=99, JS 3).
Topical local anaesthetic drops (benzocaine/ antipyrine or lidocaine) used in acute otitis
media in children, in addition to PO analgesia, are effective vs saline at 10 min (RR 2.13; 95%CI
1.19 to 3.80) and 30 min after instillation (RR 1.43; 95% CI 1.12 to 1.81) (2 RCTs, n=117) (Foxlee
2011 Level I [Cochrane], 5 RCTs, n=391). Superiority of local anaesthetic (amethocaine/ antipyrine)vs naturopathic drops (3–4 herbal extracts in olive oil) is not established in three RCTs (in addition
to paracetamol in one RCT and amoxicillin in one RCT) (3 RCTs, n=274 [analysed]).
8.6.7.7 | Acute pain associated with oral ulceration/stomatitis
Acute oral ulceration/stomatitis due to trauma (physical, chemical, thermal), infection (eg herpes
simplex), drugs, radiation or chemotherapy (mucositis) may be extremely painful anddebilitating. Mucositis is a common adverse effect of high-dose chemo- and radiotherapy for
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malignancies affecting the head and neck, for conditioning prior to bone marrow transplants andtreatment of leukaemia. For details of chemotherapy-induced mucositis, see Section 8.9.8.2.
For recurrent aphthous stomatitis, laser treatment (Nd:YAG laser ablation, CO2 laser applied
through a transparent gel [non-ablative] and diode laser in a low-level laser treatment [LLLT]mode) vs placebo, no therapy or topical corticosteroids leads to improved immediate anddelayed pain control and reduced duration of healing ( Suter 2017 Level III-1 SR, 10 RCTs & 1 study,n≈512).
In children with acute infectious mouth ulcers in the ED, viscous lidocaine solution applied
did not enable increased oral intake (Hopper 2014 Level II, n=100, JS 5). However, 2% lignocaine gel
was effective in children with mouth ulcers with a reduction of mucosal pain by 20/100 (+/- 18)(Coudert 2014 Level II, n=64, JS 5).

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Acute dental pain
1. NSAIDs and emergency pulpectomy reduce pain in patients with acute apicalperiodontitis (U) (Level I) with insufficient evidence to support analgesic benefit fromadding antibiotics (S) (Level I [Cochrane Review]).
Dental extraction
2. Paracetamol, nonselective NSAIDs and coxibs provide safe and effective analgesia withminimal adverse effects after dental extraction (S) (Level I [Cochrane Review]).
3. Combinations of paracetamol with ibuprofen (U) (Level I [Cochrane Review]) and othernonselective NSAIDs (U) (Level I) provide superior analgesia to either drug alone after
dental extraction.
4. Tramadol provides equal analgesia to paracetamol/weak opioid and aspirin/weakopioid combinations (U) (Level I [Cochrane Review]) and tramadol/paracetamol
combinations provide superior analgesia to tramadol alone after dental extraction (U)(Level I).
5. Nonselective NSAIDs and coxibs provide similar analgesia, which is superior toparacetamol, codeine, combinations of paracetamol/codeine (U) (Level I), tramadol (S)(Level I) and pethidine (U) (Level II) after dental extraction.
6. Perioperative corticosteroid administration reduces swelling, but not pain (U) (Level I),
and reduces postoperative nausea (U) (Level II) after third molar extraction.
Tonsillectomy
7. Nonselective NSAIDs (U) (Level I), in particular aspirin and ketorolac (U) (Level II),
increase the risk of reoperation for bleeding after tonsillectomy in adults, but not inchildren (U) (Level I [Cochrane Review]).
8. Intraoperative dexamethasone administration reduces postoperative pain, nausea andvomiting and time to resumption of oral intake after tonsillectomy (S) (Level I[Cochrane Review]), with no increase in adverse effects (U) (Level I [Cochrane
Review]).
9. Paracetamol, NSAIDs (S) (Level I [PRISMA]), dexamethasone, preoperative alpha-2delta ligands (S) and dextromethorphan are effective analgesics after tonsillectomy (N)(Level I [PRISMA]).
10. Intraoperative cryothgerapy may reduce post-tonsillectomy pain (N) (Level I [PRISMA]).
11. Oral administration of honey versus control reduces postoperative pain and analgesic
use after tonsillectomy (N) (Level I [PRISMA]).
12. Peritonsillar infiltration or topical application of local anaesthetics are equally effective
in producing a modest reduction in acute post-tonsillectomy pain (U) (Level I).
13. Dexamethasone, magnesium (and with limited support pethidine and tramadol)
combined with local anaesthetics for peritonsillar infiltration improve analgesia andother outcomes after tonsillectomy (N) (Level I).
14. Perioperative antibiotics show no benefit in post-tonsillectomy pain, but increase
adverse effects (S) (Level I).
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15. Acupuncture may reduce post-tonsillectomy pain compared to control group or shamacupuncture (N) (Level I)
16. Peritonsillar infiltration with tramadol or ketamine may reduce post-tonsillectomy pain
and analgesia requirements but was no more effective than equivalent doses
administered parenterally (U) (Level II).
Pharyngitis
17. Corticosteroids (S) (Level I [Cochrane Review]) and antibiotics (U) (Level I [Cochrane
Review]) improve analgesia and reduce duration of pain in pharyngitis.
18. Amylmetacresol/2,4-dichlorobenzylalcohol (AMC/DCBA) lozenges (N) (Level I[PRISMA]), ketamine gargle (N) (Level I [PRISMA]), benzydamine spray (U) (Level I) andother topical analgesics (U) (Level II) provide analgesia superior to placebo in acutesore throat with minimal adverse effects.
19. Corticosteroids reduce acute pain associated with peritonsillar abscess (following
drainage and antibiotics) (S) (Level I [PRISMA]).
20. Paracetamol, NSAIDs (nonselective NSAIDs or coxibs) and opioids, administered as
monotherapy or in combination, are effective analgesics in acute pharyngitis (U) (Level I).
Sinusitis and Otitis media
21. Oral corticosteroids have no analgesic effect in sinusitis (U) (Level I [Cochrane
Review]), but intranasal corticosteroids reduce facial pain and improve recovery (S)(Level I [Cochrane Review]).
22. Antibiotic treatment of acute otitis media vs placebo or control has no effect on acutepain, only limited effect on later pain, but increases the risk of adverse effects (N)(Level I [Cochrane Review]).
23. In acute otitis media, topical local anaesthetic drops are effective in children comparedto placebo and equivalent to naturopathic drops (S) (Level I [Cochrane Review]).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Codeine should not be used in children, especially after adenoidectomy ortonsillectomy, due to an increased risk of opioid-induced ventilatory impairment anddeath (U).
 Recurrent or persistent orofacial pain requires biopsychosocial assessment andappropriate multidisciplinary approaches (U).
 Neuropathic orofacial pain, which is often post-traumatic (iatrogenic), may be
exacerbated by repeated dental procedures, incorrect drug therapy or psychosocial
factors (U).

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8.6.8 | Acute pain in patients with HIV infection
Pain is common in people infected with HIV (Ebirim 2013 Level IV, n=157; Namisango 2012 Level IV,
n=302; Simmonds 2005 Level IV, n=100; Frich 2000 Level IV, n=95; Vogl 1999 Level IV, n=504; Larue 1997
Level IV; Breitbart 1996 NR) and may have diverse aetiologies, including HIV itself (which is aneurotropic virus), opportunistic infections and malignancies, and unrelated comorbidities(Hewitt 1997 Level IV, n=274; Glare 2001 NR; O'Neill 1993 NR). In untreated HIV infection, pain
becomes more common as disease progresses and is almost universal among those withadvanced acquired immunodeficiency syndrome (AIDS) (Kimball 1996 Level IV, n=157; O'Neill 1993
NR). Even among relatively well individuals, pain is prevalent and associated with depression andimpaired function (Vogl 1999 Level IV, n=504; Singer 1993 Level IV).
Adults diagnosed with HIV today can have a near normal life expectancy with access toantiretroviral therapy, both in well-resourced and resource-limited settings (Gueler 2017 Level III-2,
n=16,532 [HIV-positive patients]; Mills 2011 Level IV, n=22,315; van Sighem 2010 Level IV, n=4,612). This
improvement in HIV prognosis has however been associated with an ageing HIV-infected
population with increasing numbers of comorbidities and an ongoing high prevalence of pain
(Balderson 2013 Level IV, n=452). The ongoing high prevalence of chronic pain among people livingwith HIV today has prompted the Infectious Diseases Society of America to publish specificmanagement guidelines (Bruce 2017 GL).
Pain continues to be associated with poorer quality of life and impaired function amongpeople living with HIV (Merlin 2013 Level IV, n=1,903; Ebirim 2013 Level IV, n=157; Namisango 2012
Level IV, n=302; Simmonds 2005 Level IV, n=100). Several studies have found that pain isundertreated in those with HIV infection, with both physician and patient barriers suggested(Ebirim 2013 Level IV, n-157; Frich 2000 Level IV, n=95; Breitbart 1998 Level IV, n=199; Larue 1997
Level IV, n=174; Breitbart 1999 NR; Breitbart 1996 NR). An unmet need for analgesia is one of thecommonest reasons for people with HIV to use complementary therapies ( Peltzer 2008 Level IV,
n=618; Tsao 2005 Level IV, n=2,466). HIV/AIDS patients with diagnosed mood/anxiety or substanceuse disorders report much higher levels of pain than HIV/AIDS patients without thesecomorbidities or the general population (Tsao 2009 Level III-2). Further, preliminary data support
an association between perceived HIV stigma and pain in this population ( Wadley 2019 Level IV,n=50).
8.6.8.1 | Treatment of pain in people infected with HIV
The optimal management of pain in an individual with HIV will depend on the cause of the pain.
The general principles of treating the underlying cause where possible and providing adequate
analgesia are the same as for any other individual with the same injury or illness. Some special
considerations (particularly drug interactions) may be important and are set out below.
HIV and its treatment are frequently complicated by a distal, small-fibre, sensory neuropathy
that is typically painful (painful HIV-associated sensory neuropathy) (Cherry 2012 NR). Prevalence
rates >50% are described in cohorts exposed to stavudine (a potentially neurotoxic antiretroviral
agent) (Wadley 2011 Level IV, n=395). Although stavudine use has been phased out, many patientsliving with HIV have previously been exposed to this drug. Further, a large, USA-based
prospective survey found that 15% of adults with HIV who had never used stavudine are affectedby painful sensory neuropathy, with older patients at higher risk ( Ellis 2010 Level IV, n=1,539).
Further follow-up of the same cohort has demonstrated new onset of distal neuropathic pain in
27% of patients after a median of 24 mth observation, associated with factors including older
age, female gender, and failure to suppress HIV replication (Malvar 2015 Level IV, n=493).

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Neuropathic pain is particularly difficult to treat in HIV. Despite anecdotal reports ofindividual patients responding well to each of the pain-modifying agents typically used in othersmall-fibre neuropathies, only smoking of cannabis, topical capsaicin and recombinant humannerve growth factor are more effective than placebo for HIV neuropathy pain (Phillips 2010 Level I[PRISMA], 14 RCTs, n=1,764). Smoking cannabis has only short term effects in studies with potential
bias due to difficulties in patient blinding; in one trial 92% guessed treatment allocation correctly.
Furthermore, no associations were found between marijuana use and either pain intensity or
opioid use (Merlin 2019 Level IV, n=433). A meta-analysis of data on high-dose capsaicin 8% foundlimited efficacy with NNT50% of 11 (Derry 2013c) Level I [Cochrane], 2 RCTs, n=801). Those with lower
baseline pain scores and females may be most likely to respond (Katz 2015b Level I, 6 RCTs,
n=1,014).
In a pilot study of hypnosis for managing HIV-neuropathy pain, 26 of 36 patients were
responders with a mean 44% reduction in pain scores at 7 wk after the intervention (Dorfman
2013 Level IV, n=36). These data together with the larger placebo responses seen in HIVneuropathy analgesia trials compared with studies of neuropathic pain from other causessuggest that nonpharmacological interventions may be useful in this difficult pain syndrome andwarrant further study (Cepeda 2012 Level I, 94 RCTs, n=5,317).
The chronic nature of HIV disease as well as the many possible causes of pain in those infected
mandate a holistic approach to managing HIV-associated pain. Ideally, disease-specific therapy,
psychosocial interventions and physical modalities should accompany standard analgesic
treatment (Glare 2001 NR)
8.6.8.2 | Special considerations in treating pain in patients with HIV infection
Drug interactions
Antiretroviral agents (notably non-nucleoside reverse transcriptase inhibitors, proteaseinhibitors, and the “boosting” agents ritonavir and cobicistat) may cause important druginteractions by inducing and inhibiting various enzymes in the cytochrome P450 family. In
addition, both cobicistat and ritonavir inhibit p-glycoprotein and can therefore increase
absorption of susceptible drugs from the gastrointestinal tract. Several antiretroviral agents arealso hepatically metabolised with potential for drug interactions. Predicting clinically relevantinteractions is made extremely complex, both by the fact that antiretroviral drugs are used in
combinations and because most interactions have not been formally studied. Updated
information on likely interactions between individual antiretroviral agents (and cobicistat) andmedications used to treat common comorbidities are provided by The University of Liverpool
HIV Pharmacology Group at: https://www.hiv-druginteractions.org/checker (including a chart
specific for interactions with a large number of analgesic medicines at https://liverpool-hivhep.s3.amazonaws.com/prescribing_resources/pdfs/000/000/002/original/TS_Analgesic_2019_Feb.pdf?1550073234.
The importance of routinely considering interactions with antiretroviral drugs when prescribing
for individuals with HIV is highlighted by the variable interactions seen with opioids. For example,
ritonavir (an HIV protease inhibitor) is a potent inhibitor of cytochrome P450 3A4. This results inclinically relevant inhibition of fentanyl metabolism (Olkkola 1999 Level II, n=12, JS 3), but no clinicallymeaningful interaction with methadone or buprenorphine (McCance-Katz 2003 Level III-2).
Conversely, both lopinavir (another protease inhibitor) (McCance-Katz 2003 Level III-2) and nevirapine(a non-nucleoside reverse transcriptase inhibitor) (Arroyo 2007 Level III-3, n=10) significantly induce
methadone metabolism and may lead to withdrawal in patients on maintenance doses. Reference
to current resources such as the Liverpool site, together with involvement of a pharmacist576

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experienced in this area whenever possible, is strongly recommended when prescribing additional
medications to patients on antiretroviral therapy.
Some medications used to treat opportunistic infections in HIV patients may also interact
with analgesics. For example, both rifampicin and rifabutin may increase opioid metabolism(particularly methadone) (Finch 2002 NR) and fluconazole (and other azoles) may potentiate
adverse effects of methadone (Tarumi 2002 CR). A useful online tool for checking interactions
with antifungal agents and other medications, including analgesics, can be found at
http://www.fungalpharmacology.org, which also offers a free app for smartphones.
HIV patients with a history of substance abuse
Pain may be more common in those with HIV and a history of injecting drugs (Martin 1999
Level III-2, n=211; Vogl 1999 Level IV, n=504) and is more likely to be inadequately treated in thisgroup (Breitbart 1997 Level IV; Breitbart 1996 Level IV). Two cohort studies showed that that eventhough HIV-positive patients with a history of problematic illicit drug use/substance abuse reporthigher ongoing use of prescription analgesics specifically for pain, these patients continue toexperience persistently higher levels of pain, relative to nonproblematic users ( Tsao 2007
Level III-2, n=2,267; Passik 2006 Level III-2, n=73 [AIDS patients]). Importantly, opioid analgesia wassimilarly effective for treating severe pain in those with AIDS who had previously injected drugs
as in those who were opioid naïve, although higher doses were required ( Kaplan 2000 Level III-2,n=44). Similarly, patients in a methadone-maintenance program, who also suffered from
HIV/AIDS-related pain, gained improved analgesia without adverse effects with use of additional
methadone (Blinderman 2009 Level IV, n=53).
The principles of pain management in patients with a history of substance abuse are outlined
in Sections 9.7 and 9.8.

KEY MESSAGES
1. High-concentration capsaicin patches have some efficacy in treating neuropathic painin patients with HIV/AIDS (S) (Level I [Cochrane Review]).
2. Smoking cannabis has short-term efficacy in treating neuropathic pain in patients with
HIV/AIDS, although potential study bias means that this is not recommended as routine
treatment (Q) (Level I [PRISMA]).
3. HIV/AIDS patients with a history of problematic drug use report higher opioid analgesic
use but also more intense pain (U) (Level III-2).
4. Pain, and notably neuropathic pain, is common in patients with HIV (U) (Level IV).
The following tick boxes represent conclusions based on clinical experience and expert opinion:
 HIV/AIDS has become a chronic, manageable condition; in view of limited specificevidence, the treatment of pain in patients with HIV/AIDS should be based on similar
principles to those for the management of acute, cancer and chronic pain in thegeneral population (S).
 Interactions between antiretroviral medications, antibiotics and analgesics should beconsidered in this population and reference to a current guide of likely druginteractions is strongly recommended (S).

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8.7 | Acute back pain
Acute back pain in the cervical, thoracic or, in particular, lumbar and sacral regions, is a common
problem affecting most adults at some stage of their lives. The causes are rarely from serious
pathology (Hartvigsen 2018 NR). Acute back pain is most often nonspecific and the pain is usually
self-limiting; however, recurrence is common and for a small percentage of people, acute backpain becomes persistent and disabling. Overuse of imaging, opioids, and surgery in back pain
management remains a widespread problem (Maher 2017 NR).
Appropriate investigations are indicated in patients who have signs or symptoms that might
indicate the presence of a more serious condition (‘red flags’). Such ‘red flags’ include symptoms
and signs of infection (eg fever), risk factors for infection (eg underlying disease processes,
immunosuppression, penetrating wounds), history of trauma or minor trauma, history ofosteoporosis or taking corticosteroids, past history of malignancy, age >50 y, failure to improvewith treatment, unexplained weight loss, pain at multiple sites or pain at rest, and the absenceof aggravating features (Oliveira 2018 GL SR, 10 GL [acute low back pain]). In assessment of new acuteback pain, ‘red flags’ to predict potential cancer as a cause have been proposed, yet the only
evidence-based predictor of spinal malignancy is “previous history of cancer” (Henschke 2013 SRof diagnostic studies; Downie 2013 SR of diagnostic studies). A full neurological examination is
warranted in the presence of lower limb pain and other neurological symptoms.
Psychosocial and occupational factors (‘yellow flags’) appear to be associated with anincreased risk of progression from acute to chronic pain. Such factors should be assessed earlyin order to facilitate appropriate interventions (Oliveira 2018 GL SR, 10 GL [acute low back pain]).
NHMRC guidelines for the evidence-based management of acute musculoskeletal pain
include chapters on acute neck, thoracic spinal and low-back pain (Australian Acute Musculoskeletal
Pain Guidelines Group 2003 GL). In view of the high quality and extensiveness of these guidelines,
and the subsequent publication of more recent international guidelines, no independent
assessment of these topics has been undertaken for this document even though the Australianguidelines have been rescinded by the NHMRC because of their age.
However, reviews of best practice for management of low back pain (Strudwick 2018e GL) andneck pain (Strudwick 2018f GL) in the emergency department have been published by an Australiangroup.
Other international guidelines include those produced by:• the Orthopedic Section of the American Physical Therapy Association (APTA) — these also
cover acute and chronic back pain (Delitto 2012 GL);
• the Toward Optimized Practice (TOP) Program of Canada (Canada TOP 2015 GL);
• the NSW Agency for Clinical Innovation (NSW Agency for Clinical Innovation 2016 GL);
• the American College of Physicians (ACP) – presenting a clinical practice guideline on
noninvasive treatments for acute, but also subacute (and chronic) low back pain (Qaseem2017 GL);• the Institute for Clinical Systems Improvement (ICSI 2018 GL);
• the National Institute for Clinical Excellence (NICE 2018 GL).
Overviews of these guidelines have been published (Koes 2010 GL; Verhagen 2016 GL) including
a particularly useful overview of all recent guidelines (Oliveira 2018 GL SR, 10 GL [acute low backpain]). The reader is referred to these references for the diagnosis and management of acuteback pain. All these high quality guidelines for acute back pain recommend the first-line use of
non-pharmacological approaches, including education that supports self-management andresumption of normal physical activity (Foster 2018 NR).

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8.8 | Acute musculoskeletal pain
A summary of findings relating to acute musculoskeletal pain can be found in Evidence-based
Management of Acute Musculoskeletal Pain, published by the Australian Acute Musculoskeletal
Pain Guidelines Group and endorsed by the NHMRC (Australian Acute Musculoskeletal Pain
Guidelines Group 2003 GL). In view of the high quality and extensiveness of these guidelines, nofurther assessment of these topics has been undertaken for this document, even though theseguidelines have been rescinded by the NHMRC in view of a lack of an update.
However, reviews of best practice for management of specific musculoskeletal pain
conditions in the emergency department have been published by an Australian group:• ankle and foot injuries (Strudwick 2018b GL);• closed hand and wrist (Strudwick 2018a GL);• common knee injuries (Strudwick 2018c GL);• common shoulder injuries and conditions (Strudwick 2018d GL).
The same group has also published quality outcome indicators (Strudwick 2020 GL) and process
quality indicators (Strudwick 2019 GL) for musculoskeletal injuries in the emergency department.
An updated clinical practice guideline for acute musculoskeletal pain has been published by theMusculoskeletal Pain Task Force of the Orthopaedic Trauma Association in the USA (Hsu 2019 GL).
Guidelines for specific conditions such as acute shoulder pain by the American College ofRadiology (Wise 2011 GL) or even more specific for acute and chronic subacromial pain by the
Dutch Orthopaedic Association (Diercks 2014 GL) have been published.
A systematic review of clinical practice guidelines has been published, which condenses theseto eleven key recommensations (Lin 2020 SR of GLs, 11 GLs).
Furthermore, the National Institute for Clinical Excellence (NICE) offers access to a multitudeof guidelines via a website providing pathways for musculoskeletal conditions:
https://pathways.nice.org.uk/pathways/musculoskeletal-conditions

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8.9 | Acute cancer pain
Acute pain in the cancer patient may signify an acute oncological event including pathologicalfracture or microfracture, spinal cord or nerve compression, visceral obstruction or cutaneous
ulceration due to tumour. Cancer pain may become acute in the presence of infection, andduring diagnostic or therapeutic interventions. Anticancer therapies, including surgery,chemotherapy, hormonal therapy and radiotherapy, may be associated with both acute andchronic pain of a nociceptive or neuropathic nature. In progressive cancer, there is increasing
potential for acute clinical change.
Pain is commonly associated with cancer and is one of the most feared symptoms ( Swarm2019 GL). The prevalence of cancer pain in an adult population is 39.3% after curative treatment,
55.0% during anticancer treatment and 66.4% in people with advanced, metastatic or terminal
disease, with 38.0% of all patients reporting moderate to severe (NRS  5/10) pain (van den
Beuken-van Everdingen 2016 Level III-3 SR, 117 studies, n=63,533 [pain prevalence], 52 studies, n=32,261[pain severity]). It is recommended that all patients with cancer are screened for pain during theinitial evaluation and at each subsequent contact, and whenever new therapy is initiated, using
self-reported NRS (Swarm 2019 GL; AACPMGWP 2019 GL).
An overarching systematic review of interventions to treat acute cancer-related pain rates
epidural analgesia and local anaesthetic infusions as recommended for clinical practice andgabapentin, intraspinal analgesia, music and music therapy, hypnosis and hypnotherapy as likely
to be effective (Sundaramurthi 2017 Level IV SR, 114 studies, n unspecified).

8.9.1 | Assessment of acute cancer pain
Acute pain requires urgent assessment to exclude cancer recurrence or an oncologicalemergency requiring rapid treatment in addition to acute pain management ( Swarm 2019 GL).
Where malignancy is advanced, there is urgency in differentiating an acute pain crisis, whichis readily reversible, from an intractable painful condition ( Moryl 2008 NR). Standardised
assessment tools for the comprehensive assessment of cancer pain are advantageous, andrequired for quality research trials (Caraceni 2019 NR). There is no consensus on the ideal
multidimensional pain-assessment tool for cancer pain, with electronic tools and a standard
prognostic classification system for cancer pain being considered (Arthur 2017 Level IV, n=386;
Burton 2014 NR). Palliative-care physicians identified the most important dimension to assess was
pain intensity with unidimensional tools (eg NRS, VRS) followed by documentation of temporal
pattern, treatments, exacerbating or relieving factors, location, pain interference, pain quality,
pain affect, duration, pain beliefs and previous pain history ( Holen 2006 NR). The revised
Edmonton Staging System, the MPQ and the Brief Pain Inventory are well validated in manysettings (Arthur 2017 Level IV, n=386; Gauthier 2014 Level IV; Nekolaichuk 2013 Level IV; Wu 2010
Level IV; Bennett 2009 Level IV; Fainsinger 2005 Level IV; Ngamkham 2012 NR).

8.9.2 | Principles of management of acute cancer pain
Comprehensive consensus best-practice guidelines relating to cancer pain management havebeen developed by several agencies worldwide (with online access provided to most)(AACPMGWP 2019 GL; Swarm 2019 GL; Fallon 2018 GL; Jara 2018 GL; WHO 2018 GL; Scarborough 2018
NR). A person-centred, multidisplinary team approach involving allied care health professionals
and primary care health professionals is a recommended approach to pain management.

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5th Edition | Acute Pain Management: Scientific Evidence8.0 | SPECIFIC CLINICAL SITUATIONSThe WHO Analgesic Ladder (WHO 1996 GL) underpins these guidelines but was determined toprovide inadequate pain relief in 12% of patients ( Zech 1995 Level IV, n=2,118). Hence the WHO
ladder has undergone considerable scrutiny over the last decade with proposals to abolish thesecond step of the WHO analgesic ladder in favour of the early use of morphine at low doses
gaining more favour (Fallon 2018 GL). Where pain is moderate to severe, a jump from Step I(simple analgesics) directly to Step III (strong opioids) reduces the time to pain control relative
to staged progression through Step II (weak opioids) (Maltoni 2005 Level II, n=54 [prematurely
terminated], JS 2). In adult patients with moderate cancer pain, low-dose morphine hadsignificantly higher response rate and early onset of response vs weak opioids (Step II), with asimilarly good tolerability and comparable opioid-related adverse effects (Bandieri 2016, Level II,
n=240, JS 3).
Simple analgesics, adjuvants and specific targeted therapies, such as anticonvulsant
medicines for neuropathic pain and radiotherapy and bone-modifying agents for metastaticbone pain, should be considered at every step of the ladder. Despite availability of numerous
consensus guidelines, a survey of Australian palliative care physicians identified barriers to bestpractice, notably access to nonpharmacological interventions, patient-educational resources,and optimal care coordination (Lovell 2013 Level IV).
Patient education about cancer pain is a key factor in optimising pain management ( Marie2013 Level I, 15 RCTs, n=1,710; Martinez 2014 Level III-2 SR 16 RCTs & 3 studies, n=2,192; Lee 2014
Level III-3 SR, 12 RCTs, n=2,380 & 5 studies, n=475; Lovell 2014 NR). Despite this, a patient-centred
approach is often overlooked in guidelines (Luckett 2013 Level IV SR, 70 studies, n unspecified). For

all patients with pain, education should be provided about cancer-related pain and its
management with verbal and written information. It is also recommended to include theperson’s family, carers and significant others in education process (AACPMGWP 2019 GL).
There is similar urgency in managing an acute pain crisis in the patient with cancer as there
is when managing any other medical crisis. Acute pain, particularly in patients with terminal
cancer, causes immense distress in the patient, the family and the care team ( Moryl 2008 NR). In
such a crisis, hospital admission should be considered to evaluate the patient, assess and manage
the aetiology of pain and achieve patient-specific pain goals (Swarm 2019 GL). Treatment of theunderlying cause of pain may be urgent.
For data specific to pain management in children with cancer see Section 10.8.

8.9.3 | Medicines for acute cancer pain
8.9.3.1 | Paracetamol and NSAIDs
Any addition of NSAIDs or paracetamol to strong opioids should be justified on the basis ofindividual improved analgesia or reduction of opioid-related adverse effects, recognising the
NSAID-associated risks of gastrointestinal bleeding and relative contraindications in patientswith renal, hepatic and cardiac failure.
There is no convincing evidence that addition of paracetamol to established treatment withstrong opioids provides any analgesic or quality of life benefit for cancer pain in adults (Wiffen
2017b, Level I [Cochrane], 3 RCTs, n=122).
The efficacy of oral NSAIDs for moderate or severe cancer pain alone or combined with
opioids in adults is not supported by high-quality evidence (Derry 2017b Level I [Cochrane], 11 RCTs,
n=949). There is very low-quality evidence that NSAIDs reduce pain after 1 to 2 wk of treatment(4 RCTs). Side-effects were inconsistently reported and discontinuation occurred commonly due
to lack of efficacy (24%) or adverse events (5%). This is supported by a subsequent systematic
review, which found no additional high-quality evidence and was unable to draw conclusions
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due to heterogeneity in outcome measures and short duration of follow-ups (Magee 2019 Level I,
30 RCTs, n=2,329).
Use of parecoxib by continuous SC infusion for 7 days in cancer patients in a hospice setting
resulted in a reduction in pain scores and the number of rescue opioid doses required without
an opioid-sparing effect (Armstrong 2018, Level III-3, n=80).
Metamizole (dipyrone), another non-opioid analgesic, is effective in reducing cancer pain
intensity vs placebo, even at low doses (1.5 to 2 g/d), with higher doses (3 x 2 g/d) being more
effective than low doses (3 x 1 g/d) (Gaertner 2017 Level III-2 SR, 4 studies, n=252)
8.9.3.2 | Conventional and atypical opioids
Opioid analgesics play an important role in pain management for patients with cancer (NICE 2016a
GL; Caraceni 2012 GL; Ripamonti 2011 GL; WHO 1996 GL). Nineteen out of 20 people with moderateor severe pain who were given and tolerated opioids have a reduction in pain intensity to mild
or no pain within 14 d, although quantity and quality of evidence for this is low ( Wiffen 2016
Level I [Cochrane], 9 SRs [152 RCTs], n= 13,524).
If the patient persistently requires doses of “as-needed” opioids, or if the “around-the-clock”
opioid regimen fails to relieve pain at peak effect or at end of dose, it is recommended toconsider increasing the dose of slow-release opioids (Swarm 2019 GL).
There is increased likelihood of patients using higher than 200 mg of oral morphine
equivalent at home being undertreated with prn opioids in emergency departments (Patel 2017
Level III-2, n=216).
See also Section 4.3.1.
Routes of administration
Rapid analgesic control of acute pain or persistent pain exacerbations may be achieved with aregular dose schedule of a parenteral opioid with frequent reassessment and dose adjustment,
or by use of PCA techniques. A single RCT demonstrated more rapid pain control with IV thanoral morphine for severe cancer pain (Harris 2003 Level II, n=62, JS 2). IV and SC bolus dosing andinfusions have similar tolerability and efficacy but IV route provides faster relief ( Radbruch 2011
Level III-2 SR, 18 studies, n=674; Elsner 2005 Level II, n=39, JS 2; Anderson 2004 NR). The use of IV or SC
PCA in patients with cancer pain is a safe and convenient method of delivering opioid analgesia(Nijland 2019 Level IV SR, 6 RCTs & 44 studies, n unspecified).
Consensus clinical practical guidelines and systematic reviews are available to guide theadministration of short-acting opioids including IV, SC and rectal morphine in exacerbations ofpain (Swarm 2019 GL; WHO 2018 GL; Caraceni 2012 GL; Klepstad 2011 GL).
Controlled release formulations
Once acute pain control is achieved, analgesia should be maintained with CR preparations of
opioids. There is a lack of good evidence in the patient with cancer pain for differences in efficacy
or safety between various CR opioids (Mesgarpour 2014 Level III-2 SR, 5 RCTs & 4 studies, n=2,626).
Combination opioid therapy
Combination opioid therapy for poorly controlled cancer pain has little evidence to support thepractice despite encouraging preclinical scientific studies, and well-designed studies are needed(Fallon 2011 Level III-2 SR, 2 studies, n=36).
Opioid rotation/switching
Opioid rotation, due to preference, uncontrolled pain or intolerable adverse effects, may
improve opioid response and reduce adverse effects ( Mercadante 2011 Level III-2 SR, 31 studies,
n=1,885). Opioid conversion should be carefully individualised, as conversion ratios may be582

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influenced by multiple factors including relative potency, prior doses, tolerance and reason forswitch (Webster 2012 NR). Conversion ratios are less predictable at higher opioid doses andconversion tools of which there are many should be used with caution as opioid rotations
undertaken based on such tables alone without consideration of clinical factors carry a significant
risk of toxicity and even fatality.
When health care professionals (physicians, pharmacists, and nurse practitioners/physician
assistants) were surveyed, there was a large variation in mean opioid conversions ( Rennick 2016
Level IV, n=319). A detailed analysis of equianalgesic doses and suggestions for opioid rotations
based on these calculations has been published (Treillet 2018 Level IV SR, 20 studies, n=949).
FPMANZCA provides an opioid calculator including references and background material on a
website (FPMANZCA 2019 GL), which is also available as an app (“Opioid Calculator”) for
smartphones.
Scientific evidence for opioid rotation remains poor because of a lack of controlled studies(Jara 2018 NR), although a parallel systemic review concluded that opioid rotation can improveanalgesia and patient satisfaction (Schuster 2018 Level IV SR [PRISMA], 3 SRs, 4 RCTs & 5 studies,
n=3,021).
Opioids in patients with renal dysfunction
Fentanyl, alfentanil and sufentanil are recommended in patients with renal impairment basedon pharmacokinetics and clinical experience although there is very little clinical evidence for this(Sande 2017 Level IV SR, 18 studies, n=2,422). Morphine, hydrocodone and pethidine are notrecommended in patients receiving dialysis treatment. Hydromorphone and fentanyl are
advocated as safe opioids in patients receiving dialysis due to their favourable pharmacokinetic
profile. Based on inconclusive evidence, morphine and oxycodone should be used with caution
in patients with renal failure.
See also Section 9.6.
Side effects
As opioid-naïve patients are more vulnerable to opioid adverse effects, pre-emptive plans for
aggressive management of adverse effects need to be clearly documented, including forprophylaxis against constipation from the onset of opioid therapy (for more details see also
Section 4.3.1.4).
There is no evidence that opioids used for pain control in terminal cancer have any adverse
impact on patient survival (Lopez-Saca 2013 Level III-3 SR, 10 studies, n=2,964). Optimising patient
comfort, function and safety should be the goal of care. All management options should be fully
discussed with the treating and palliative care teams, to meet the physical, psychosocial andexistential needs of the patient and family, with consideration of an end-of-life care pathway
when cancer is advanced.
Opioids have immunoregulatory actions that vary with mode and timing of administration.
Concern regarding the potential impact of opioids on immune tumour surveillance is increasing.
Overall, there is currently inadequate evidence to guide opioid selection in cancer patients,
based on immune function, as no studies have measured any clinical endpoints or outcomes,
including cancer progression or disease-free survival (Boland 2014 Level III-3 SR, 5 studies, n=106).
Conventional Opioids
Morphine
Oral morphine remains an effective analgesic for cancer pain (Wiffen 2016 Level I [Cochrane], 62
RCTs, n=4,241). Pain relief did not differ between CR and IR formulations. CR preparations ofmorphine were effective for 12- or 24-hrly dosing depending on the formulation. Adverse eventswere common and predictable; approximately 6% of participants discontinued treatment with
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morphine because of intolerable adverse events. Morphine’s efficacy and toxicity are related tomorphine and morphine-metabolite concentrations (Gretton 2013 Level III-2, n=212). Higher
morphine and metabolite concentrations are associated with severe central adverse effects,
including drowsiness, confusion or hallucinations, particularly with higher metabolite:morphineratios in plasma. Myoclonus occurs unpredictably at morphine doses >400 mg/d, with higher
morphine and metabolite concentrations in adults with moderate to severe cancer pain.
CodeineDespite shortcomings in the evidence available (small study size, other risk of bias, clinical andmethodological heterogeneity), available evidence indicates that codeine is more effective incancer pain treatment than placebo (Straube 2014 Level I [Cochrane], 15 RCTs, n=721).
Fentanyl
The TD route of administration is inappropriate for unstable acute pain due to its slow
titratability. In cancer patients, TD fentanyl shows similar effectiveness for pain control as TD
buprenorphine (Ahn 2019 Level III-2 SR [NMA], 15 studies & 2 SRs, n= 6,368) and oral morphine (RR
1.00; 95%CI 0.97 to 1.03) (29 RCTs, n=2,769), but lower rates of constipation (35 RCTs), nausea andvomiting (31 RCTs), drowsiness (28 RCTs), and urinary retention (24 RCTs) (Wang 2018a Level I[PRISMA], 35 RCTs, n=3,406). Studies of TD fentanyl for chemoradiation-induced mucositis
indicated only gradual reduction in pain intensity over several days ( Xing 2014 Level III-3, n=46).
Hydromorphone
Hydromorphone provides similar pain relief as oxycodone or morphine with a consistentanalgesic effect, although overall quality of the evidence was very low (Bao 2016 Level I [Cochrane]
4 RCTs, n=604). Hydromorphone effectively reduced pain that was inadequately controlled byother analgesics, although pain relief was not associated with improved quality of life ( Han 2014
Level III-3, n=432). Once-daily hydromorphone CR vs oxycodone CR BD (Yu 2014 Level II, n=137,
JS 5) and hydromorphone IR QID vs oxycodone IR QID (Inoue 2018 Level II, n=183, JS 5) were noninferior for relieving moderate to severe cancer pain.
Methadone
Appropriately titrated methadone, although more difficult to manage than morphine, has similar
efficacy and tolerability and has a role in treating cancer pain ( Nicholson 2017 Level I [Cochrane], 6
RCTs, n=388). Methadone requires considerable care in dose estimation, titration and monitoring,
due to complex pharmacokinetics/pharmacodynamics and marked variability in response ( Good2014 Level I, 4 RCTs, n=272). Guidelines outline starting doses and recommended monitoring for
drug accumulation and adverse effects, particularly over the first 4 to 7 days, with the cautionthat a steady state may not be reached for several days to 2 wk (McPherson 2019 GL; Swarm 2019GL). Low-dose methadone may improve pain control when used as a co-analgesic in patients withcancer-related pain that were receiving another regularly scheduled opioid analgesic(Courtemanche 2016 Level III-3, n=146)
Oxycodone
Oxycodone provides similar analgesia and has a similar adverse effect profile to morphine; theseagents can be interchangeable as first-line oral opioids for treatment of cancer-related pain
(Schmidt-Hansen 2017 Level I [Cochrane], 23 RCTs, n=2,648); oxycodone CR provides similar analgesia
to oxycodone IR with no significant differences in adverse events. Oxycodone/naloxone CR
preparations are an effective treatment for moderate to severe cancer-related pain and provide
relief from opioid-induced constipation (Morlion 2018 Level III-3 SR, 7 studies, n=981).

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Buprenorphine
There is insufficient evidence to recommend buprenorphine as a first-line choice for cancerrelated pain vs standard opioids like morphine, oxycodone and fentanyl ( Schmidt-Hansen 2015
Level I [Cochrane], 19 RCTs, n=1,421). However, its various routes of administration, in particular TD(Ahn 2019 Level III-2 SR [NMA], 15 studies & 2 SRs [10 TD buprenorphine], n= 6,368) and SL, make it apractical option in some patients and in some clinical settings.
Tapentadol
There are limited data to support tapentadol use in cancer pain with insufficient numbers to pool
RCTs; efficacy and safety were comparable to morphine and oxycodone (Wiffen 2015 Level I[Cochrane], 4 RCTs, n=1,029; Mercadante 2017 Level IV SR, 2 RCTs & 6 studies, n=791) (2 RCTs overlap). It
may be a suitable alternative in patients who suffer considerable nausea, vomiting or constipation
with use of conventional opioids (Mercadante 2017 Level IV SR, 2 RCTs & 6 studies, n=791; Kress 2019
NR). Opioid-tolerant cancer patients taking the equivalent of at least 60 mg oral morphine daily
could be rotated to tapentadol (oral conversion ratio morphine:tapentadol 1:3.3) with significant
improvement in pain control within the first week and few withdrawals due to uncontrolled pain
(5/30), adverse effects (2/30) or other reasons (3/30) (Mercadante 2014 Level III-3, n=30). An analgesic
benefit of controlled-release tapentadol for moderate to severe bone pain in opioid-naïve
myeloma patients was found (Coluzzi 2015 Level III-3, n=25). Patients with haematologicalmalignancies treated with slowly titrated doses of tapentadol (to a final dose of 244 mg ±106) for
1 mth showed reduction in neuropathic pain from 54% to 14%, and improvement in sleep quality
to “good” or “refreshing” from 20% to 95% of patients (Brunetti 2016 Level III-3, n=36).
TramadolTramadol (with or without paracetamol) has only limited, very low-quality evidence supporting
its use for treatment of cancer pain; tramadol is not as effective as morphine in this setting ( 1
RCT, n=227) (Wiffen 2017a Level I [Cochrane], 10 RCTs, n=958). As a non-controlled substance, it plays
an important role in the treatment of cancer pain in countries where it may be the only opioid
treatment option eg in parts of South-East Asia (Vijayan 2018 NR).
8.9.3.3 | NMDA receptor antagonists
Ketamine
Despite extensive evidence to support the use of ketamine for acute perioperative pain andprocedural analgesia, very limited evidence guides its use in cancer-related pain (Bell 2017 Level I[Cochrane] 3 RCTs, n=215; Bredlau 2013 Level IV SR, 5 RCTs & 6 studies, n=483). The largest multicentre
RCT included in these systematic reviews concluded that ketamine had no therapeutic benefit
with an adverse safety profile in cancer patients (Hardy 2012 Level II, n=187, JS 5). Despite relating
to chronic moderate to severe pain in a palliative setting and a broad patient population, thistrial has negatively influenced the use of ketamine for all cancer-related pain, including acuteexacerbations, with resultant debate and calls for further controlled studies targeting more
specific cancer pain populations (Hardy 2014 Level IV, n=123 [clinicians]; MacKintosh 2012 Level IV;
Jackson 2013 NR; Leppert 2013 NR). Certain types of cancer pain, including mucositis, bone andneuropathic pain, may be “good responders” to ketamine and merit more focussed, higher
quality, controlled studies (Jackson 2005 NR).
Larger case series and individual reports have highlighted the wide range of clinical situations,routes of administration and dose schedules for ketamine in the cancer setting. Ketamine has
been used successfully for morphine-resistant pain (Mercadante 2000 Level II, n=10 [cross over], JS 3),
acute incident pain (Mercadante 2009 Level IV, n=2) and for cancer patients in the perioperative
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period, where ketamine can be morphine-sparing, lower pain scores and promote earlier returnof function (Nesher 2009 Level II, n=44, JS 3; Kollender 2008 Level II, n=60, JS 5). Oral and topical use of
ketamine resulting in effective analgesia has been described in case series (Okamoto 2013 Level IV,
n=46; Uzaraga 2012 Level IV, n=16; Soto 2012 NR & CR; Amin 2014 CR). Analgesia was successfully
maintained when continuous ketamine infusion was converted to oral ketamine (Benitez-Rosario
2011 Level III-2, n=29). Topical ketamine-amitriptyline did not reduce chemotherapy-induced
peripheral neuropathic pain (Gewandter 2014 Level II, n=462, JS 5).
Magnesium
Elemental magnesium (65 mg BD) added to morphine in patients with cancer did not improveanalgesia, functional performance or quality of life nor reduce side effects ( Baaklini 2017 Level II,
n=43, JS 4).
8.9.3.4 | Glucocorticoids
Common indications for glucocorticoids in cancer include spinal cord compression, superior vena
cava compression, raised intracranial pressure, bowel obstruction, anorexia and pain related toinflammation, bone tumour or neuropathy. Despite good evidence for many of these clinicalscenarios, only weak evidence supports glucocorticoids for cancer pain ( Paulsen 2013 Level I[PRISMA], 4 RCTs, n=667; Leppert 2012 NR). Methylprednisolone provided no significant analgesic
benefit but improved fatigue, appetite and patient satisfaction (Paulsen 2014 Level II, n=50, JS 5). A
meta-analysis of studies comparing corticosteroids, notably dexamethasone, to standard
therapy did suggest a statistically significant, but clinically limited, reduction in cancer pain at
1 wk (MD -0.84/10; 95%CI -1.38 to -0.30); however, data were flawed by attrition, potential bias,
small sample size and infrequent indication of adverse effect rates ( Haywood 2015 Level III-2 SR[Cochrane], 15 studies, n=1,926). Once-daily dexamethasone (average dose of 13 mg [SD 10])
recommended by a specialty palliative care team in patients with cancer pain receiving opioids
resulted in an opioid-sparing (-23% MEDD) and analgesic effect (-19% pain scores); in 61% thepain was primarily acute cancer pain (Barghi 2018 Level III-3, n=59).
Consequently, no recommendation can be made regarding selection of glucocorticoid, dose,route or duration of administration, and adverse-effect profile. Dexamethasone is often
preferred due to high potency, long duration of action and minimal mineralocorticoid effect.
Immediate adverse effects include immunosuppression, hyperglycaemia and psychiatricdisorders, whereas longer-term use increases risk of proximal myopathy, peptic ulceration,
osteoporosis and Cushing’s syndrome (Leppert 2012 NR). Steroid/nsNSAID combination therapy
in a large population of general hospitalised patients resulted in a 15-fold increase ingastrointestinal bleeding, reinforcing the need for gastroprotective therapy (Piper 1991 Level III-2,
n=7,478). If glucocorticoids are used in the acute setting for >3 wk, a schedule of dose reduction
must precede cessation.
8.9.3.5 | Anticonvulsants and antidepressantsCombining opioid analgesia with alpha-2-delta ligands does not improve pain relief in patientswith cancer pain vs opioid monotherapy, although benefit in patients with neuropathic cancer
pain could not be excluded due to heterogeneity of patient samples (Kane 2018 Level I SR [PRISMA],
7 RCTs, n=605); data on amitriptyline, fluvoxamine, and phenytoin were inconclusive. However,
RCTs not included in the systemic review above support use of gabapentin with opioids in severe
cancer pain (VAS7) (Chen 2016 Level II, n=60, JS 5) and pregabalin with opioids in cancer patientswith severe neuropathic pain (Dou 2017 Level II, n=40, JS 4). Pregabalin was more effective inrelieving neuropathic cancer-related pain vs TD fentanyl (Raptis 2014 Level II, n=120, JS 3).

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8.9.3.6 | Cannabinoids
In cancer pain, very low-quality evidence shows no benefit of nabiximols or THC (the only
cannabinoids in the included RCTs) on any outcome including pain, sleep problems and opioid
consumption, with increased adverse events (GI and nervous system) ( Hauser 2019 Level I[PRISMA], 5 RCTs, n=1,534). There is no convincing, unbiased, high quality evidence for an effect of
cannabinoids on anorexia or cachexia in a palliative care setting ( Mucke 2018 Level I [PRISMA],
9 RCTs, n=1,561).

8.9.4 | Breakthrough pain
The term “breakthrough pain” typically refers to a transitory acute flare-up of pain in the settingof chronic cancer pain managed with a fixed opioid drug schedule. On the basis of two Delphi
surveys, breakthrough pain has been defined as “a transient pain exacerbation that can occur inpatients with stable and adequately controlled background pain not necessarily treated with
opioids” (Lohre 2016 GL). There are specific tools that have been recommended to assess theprevalence and severity of breakthrough pain in patients with cancer (Webber 2014 GL). Despite
stable therapy, breakthrough pain is common, heterogeneous, frequently severe or excruciating,often paroxysmal, and may occur several times daily for seconds to hours in duration (Deandrea
2014 Level IV SR, 33 studies, n unspecified; Portenoy 1990 Level IV, n=63). Some episodes ofbreakthrough pain may be an end-of-dose failure of maintenance opioids. In contrast, incident
pain is predictably precipitated by some movement or action. Assessment should elucidate theseverity, duration, pattern and cause of breakthrough pain.
Conventional management guidelines dictated that the opioid breakthrough dose should be
a proportion (one-sixth to one-tenth) of the daily dose; for example, an oral breakthrough doseof morphine would be equivalent to a 4-hourly dose, or one-sixth the oral morphine equivalent
daily dose. However, there is little evidence to support the standard practice of utilising the same
opioid for breakthrough pain as for maintenance analgesia, and most recent studies indicate apoor relationship between rescue and maintenance doses ( Zeppetella 2011). Rescue medication
used for breakthrough pain should ideally have a pharmacokinetic profile that mirrors the timecourse of that pain and ideally have high potency, rapid onset and fast offset. Meta-analyses of
emerging evidence support the rapid efficacy and safety of several transmucosal immediaterelease fentanyl (TIRF) preparations for breakthrough pain (Zeppetella 2013 Level I [Cochrane] 15
RCTs, n=1,699; Rogriguez 2015 Level I, 11 RCTs, n unspecified; Jandhyala 2013 Level I, 5 RCTs, n=415; Brant
2017 NR) (significant overlap between all 3 SRs) (see also Section 5.5.3.1). These TIRF are superior toplacebo at 15 min and require individual titration to effect. The titrated rescue dose is largely
independent of background opioid dosing (Portenoy 1999 Level IV). The slower onset of oral
morphine (45 min) limits its suitability to more gradual-onset pain or for pre-emptive anticipationof incident pain (1 RCT, n=89) (Zeppetella 2014 Level I [NMA], 10 RCTs [various transbuccal fentanyl
formulations], n=892). Notably, not all breakthrough pain may be opioid responsive. A large
observational study identified 23% of patients who found nothing to relieve their breakthroughpain, indicating further investigations are required in this area (Davies 2013 Level IV, n=1,000).

8.9.5 | Acute neuropathic cancer pain
8.9.5.1 | Incidence and diagnosis of neuropathic cancer pain
Neuropathic pain or mixed nociceptive-neuropathic pain has an estimated frequency of 31 to
40% in patients with cancer (Roberto 2016 Level IV SR, 40 studies (29 general cancer & 17 palliative
settings), n=18,136; Bennett 2012 Level IV SR, 22 studies, n=13,683). Diagnosis was largely based on
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clinical judgement rather than objective criteria, and most studies predated the updated IASP
definition of neuropathic pain as pain due to a disease or lesion in the somatosensory system.
Peripheral or central neuropathic pain may result from disease progression, cancer treatment, acomorbid condition or be multifactorial. No clear standardised approach or taxonomy has beenused to assess neuropathic pain in cancer or to guide treatment. Improvements in theclassification, assessment and diagnosis of neuropathic cancer-pain conditions are required toaddress gaps in understanding of this diverse condition (Lema 2010 NR). The neuropathic grading
scale of the Neuropathic Pain Special Interest Group of the IASP is recommended for use incancer patients to facilitate recognition, management and study of neuropathic cancer pain
(Mulvey 2014 GL). Screening tools recommended for neuropathic pain such as Leeds Assessmentof Neuropathic Symptoms and Signs (LANSS), Douleur Neuropathique en 4 (DN4) or painDETECT(PDQ) show concordance with clinicians’ diagnosis of neuropathic pain in cancer patients (Mulvey
2017 Level IV SR, 6 studies, n=2,301).
8.9.5.2 | Treatment of neuropathic cancer pain
Adjuvant medications may be needed for acute or persistent neuropathic cancer pain that ispoorly responsive to opioids, or where opioid intolerance limits further dose escalation. Acuteneuropathic cancer pain may also be associated with inflammation and require specific targeted
therapy. A systematic review of European clinical practice guidelines for management of cancerassociated neuropathic pain highlighted a lack of evidence (Piano 2014 SR, 9 GLs). Extrapolation ofdata from individuals without cancer to a population with neuropathic cancer pain may notprovide optimal care. Only 11% of references supporting European clinical practice guidelines
came from patients with cancer.
All of the guidelines include recommendations for TCAs as first -line treatment, despite
the lack of high-level evidence. Imipramine (to 75 mg; 1 RCT ) and amitriptyline (to 50 mg;
1 RCT ) in small RCTs in patients with advanced cancer or chemotherapy -induced painful
neuropathy has resulted in only a small analgesic benefit, with increased adverse effects
including sedation, confusion and dry mouth ( Bennett 2011b Level I, 2 RCTs [TCAs], n=85 ). A
further systematic review included two additional amitriptyline RCTs (to 100 mg), one
venlafaxine and one trazodone RCT and calculated the weighted mean absolute risk benefit
for antidepressants overall as 0.55 (95%CI 0.40 to 0.69) ( Jongen 2013 Level III-2 SR, 6 RCTs
[antidepressants], n=189 [analysed] ); this is comparable to the effect of anticonvulsants here.
Anticonvulsant medications added to opioids for control of neuropathic pain caused bycancer have also only a small effect (Bennett 2011b Level III-2 SR, 3 RCTs and 3 studies[anticonvulsants], n=380). Anticonvulsants (gabapentin 2 RCTs and 2 studies; sodium valproate 1 study;
phenytoin 1 RCT) provide limited improved analgesia within 4 to 8 d, after which benefits do notfurther increase. The addition of an adjuvant to a stable opioid dose results in only modest pain
reduction at the expense of increased adverse effects, whereas when opioid dose is lowered
after the introduction of the adjuvant, pain intensity is maintained or reduced, and adverse
effects decreased. A further systematic review calculated a mean absolute relative benefit of
0.57 (95%CI 0.43 to 0.70) for anticonvulsants (Jongen 2013 Level III-2 SR, 14 RCTs & 16 studies,
n=2,267) (2 RCTs & 3 studies overlap); gabapentin was the most studied anticonvulsant. A
systematic review of pregabalin for neuropathic pain in cancer was unable to make any clear
recommendations due to limitations in the study methodology and data ( Bennett 2013 Level IV SR,
1 RCT, 3 studies & 1 CR, n= 761). A single RCT (included in both systematic reviews) compared theefficacy of amitriptyline, pregabalin and gabapentin for severe neuropathic cancer pain andreported efficacy of all treatments but superiority of pregabalin (Mishra 2012 Level II, n=120, JS 4).

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Beneficial effects of antidepressants and anticonvulsants are found overall to outweighharms in neuropathic cancer pain (Jongen 2013 Level III-2 SR, 14 RCTs & 16 studies, n=2,267). Benefits
did not differ for neuropathic and mixed nociceptive-neuropathic pain states. Use of
anticonvulsants or antidepressants in combination pharmacotherapy vs controls reduces global
pain (MD -0.41/10; 95%CI -0.70 to -0.12) (Guan 2016 Level I, 8 RCTs, n=1,359).
Lack of data precluded conclusions regarding opioids alone, however oral methadone vs TD
fentanyl in treating neuropathic pain in patients with head-and-neck cancer resulted in better
analgesia at 1 and 3 wk (Haumann 2016 Level II, n=52, JS 3). In cancer pain in general, combining
opioids with gabapentin or pregabalin does not improve pain relief and data on amitriptyline,
fluvoxamine and phenytoin are inconclusive (Kane 2018 Level I [PRISMA], 7 RCTS, n=605). See also
Section 8.1.4.
8.9.5.3 | Painful chemotherapy-induced peripheral neuropathy
Chemotherapy-induced peripheral neuropathy (CIPN) is resistant to treatment and remains
poorly understood although multiple risk factors have been identified including cumulative
chemotherapy dose, genetics, age, history of diabetes, history of neuropathy and low levels ofphysical activity (Kim 2017b NR). Approximately 68% of patients developed CIPN within 30 d ofany chemotherapy and by 6 mth 30% of patients are still affected by CIPN (Seretny 2014
Level III-3 SR [PRISMA], 31 studies, n=4,179).
Acute severe CIPN may adversely limit cancer treatment and hence survival, while chronic
CIPN is a major cause of pain and poor QoL in survivors. Chemotherapies causing painful CIPN
include vinca alkaloids (vincristine), platins (cisplatin, oxaliplatin), taxanes (paclitaxel, docetaxel),
the proteasome inhibitor bortezomib and immunomodulatory agent thalidomide. Each class ofagent has a distinct neuropathology, site of toxicity in the peripheral nerves and risk profile ( Park2013 NR). CIPN is dependent on dose and duration of treatment. CIPN is a predominantly sensory
neuropathy, with many agents at higher doses also causing myalgia and myopathy (taxanes),
muscle cramps (oxaliplatin, vincristine, thalidomide) and autonomic neuropathy (vincristine,
bortezomib). Paclitaxel and oxaliplatin have distinct acute and chronic CIPN syndromes.
Significant acute neurotoxicity complicates oxaliplatin infusion in 90% of patients for up to 1 wk
and is exacerbated by exposure to cold. Acute pain (1 wk) is caused by oxaliplatin in 55.6% andchronic peripheral neuropathic pain in 49.2% of patients (Brozou 2018 Level IV SR [PRISMA],
96 studies, n unspecified).
Paclitaxel-induced acute pain syndrome with painful paraesthesias and numbness, poor
motor skills, myalgias and arthralgias may persist up for up to 4 d. Bortezomib-induced CIPN is acommon small-fibre neuropathy characterised by severe, sharp, burning pain in the feet that
resolves by 3 mth in most affected patients. The severity of acute neuropathy and pain
(paclitaxel, oxaliplatin) and the use of combination chemotherapies promoting neurotoxicity
may be predictors of chronic CIPN.
There is a lack of evidence to support any agent for prevention of CIPN. Current protective
strategies include dose modification or cessation of the causative chemotherapy. Risk
stratification should include identification of individuals with pre-existing conditions
predisposing to peripheral neuropathy. Multiple natural products and complementary therapies
have been evaluated as possible preventive measures with some evidence that vitamin E andglutamine may prevent development of CIPN (Brami 2016 Level I, 13 RCTs, n=1,341).
There is limited specific evidence to guide treatment of established CIPN. Duloxetine (30 mg
titrated to 60 mg/d over 5 wk) resulted in a modest reduction in pain severity vs placebo (MD-1.06/10; 95%CI 0.72 to 1.40); additional benefits included improved QoL and reduced numbness

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and tingling of the feet (Smith 2013 Level II, n=231, JS 5). The analgesic benefit of duloxetine wasgreater in patients with oxaliplatin-induced CIPN.
Venlafaxine may be effective in acute oxaliplatin-induced CIPN but additional supportive
evidence is recommended prior to any routine use in clinical practice ( Hershman 2014 GL). Trialsof amitriptyline (to 50 mg/d) and nortriptyline (to 100 mg/d), and gabapentin (2,700 mg/d) wereinconclusive, while lamotrigine (300 mg/d) provided no benefit for CIPN. Tapentadol use inpatients with moderate-to-severe neuropathic pain from CIPN that was unresponsive tomaximum doses of antidepressants and anticonvulsants resulted in a reduction of overall andneuropathic pain scores in 86% of patients (Galie 2017 Level III-3, n=31). Nerve conduction values
were unchanged from baseline to 3 mth suggesting that tapentadol relieved neuropathic pain
without affecting or reversing peripheral nerve damage. There is insufficient evidence to support
acupuncture for the treatment of CIPN (Li 2019b Level I [PRISMA], 3 RCTs, n=203) (1 RCT overlap with
Brami 2016).
Taxane acute pain syndrome (TAPS) is characterised by acute onset of muscle and joint pain
within a couple of days of receiving taxane chemotherapy. The pain is self-limiting and resolves
within one week. Much like CIPN, TAPS can greatly affect patients' quality of life and can lead todose decreases and chemotherapy discontinuation (Chiu 2017 NR). Multiple pharmacologic
agents have been evaluated in the treatment of TAPS, including corticosteroids, gabapentin,
glutamine and glutathione, with no studies showing benefit (Fernandes 2016 Level III-3 SR, 5 studies,
n=311).
Guidelines for the management of CIPN concede that “there are no agents recommended forthe prevention of CIPN” and support only duloxetine with the recommendation to try tricyclic
antidepressants, gabapentin, and a compounded topical gel containing baclofen, amitriptyline
HCL and ketamine despite lack of evidence (Hershman 2014 GL). These statements are supported
by an overarching systematic review, which could only support use of duloxetine in the settingof CIPN (Hou 2018 Level III-3 SR [PRISMA], 13 RCTs & 22 studies, n=2,401).

8.9.6 | Procedural pain in cancer patients
Both adults and children with cancer may undergo multiple painful diagnostic and therapeutic
procedures. Few trials have evaluated procedural pain in adults with cancer. Attention toadequate analgesia and anxiolysis is imperative to reduce anticipatory stress with repeat
interventions. Simple techniques include premedication, administration of prophylactic
breakthrough analgesia, application of topical local anaesthetic, inhalational analgesia including
methoxyflurane via the Penthrox® inhaler and N2O-oxygen as Entonox® (see Section 4.5), andsedation (midazolam, ketamine, propofol) by appropriately trained personnel (see respective
sections of Chapter 4).
For pleurodesis in patients with malignant pleural effusion, NSAIDs provided comparable
analgesia to opioids except for higher rescue analgesia requirements ( Rahman 2015b Level II,
n=206, JS 5); rates of pleurodesis efficacy at 3 mth were not inferior. Placement of 12 Fr vs 24 Fr
chest tubes resulted in a modest pain reduction (MD −6.0/100; 95%CI −11.7 to −0.2), but was
associated with higher pleurodesis failure (30% vs 24%).
Few interventions decrease acute pain during mammography, including provision of priorinformation about the procedure, some degree of self-control over the extent of breast
compression and the use of breast cushions; in contrast, pre-emptive paracetamol was of nobenefit (Miller 2008 Level I, 7 RCTs, n=1,671).
For paediatric information, see Sections 10.7.2 and 10.8.2.

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8.9.7 | Acute pain due to bone cancer
Refractory severe pain with acute incident pain is commonly caused by primary and metastaticbone cancers, notably prostate, breast, lung, bladder, renal and thyroid cancers, and multiple
myeloma. Bone pain may also be precipitated during some cancer treatments eg granulocytecolony stimulating factor (G-CSF) for febrile neutropenia prophylaxis. Malignant bone pain often
has mixed nociceptive, inflammatory and neuropathic components. Preclinical studies havehighlighted the pathophysiology of malignant bone pain ( Mantyh 2014b BS; Mantyh 2014a BS; Falk2014 BS; Currie 2013 BS).
8.9.7.1 | Diagnosis of bone cancer pain
In the setting of known or potential bone primary or metastatic cancer, any new onset constantaching, gnawing pain over bone, or acute incident pain precipitated by movement or weightbearing, requires prompt evaluation to pre-empt or exclude critical bone-related events, withassessment for pathological fracture, neurological deficit or hypercalcaemia. Many studies andreviews have informed guidelines to predict, expedite diagnosis and appropriately treat bonemetastases. A systematic approach to assessment of spinal metastases is imperative. For
detection of bone metastases, MRI and fludeoxyglucose F 18 PET offer advantages of sensitivity
and/or specificity over bone scintigraphy and computed tomography (CT), although tumour typemay influence diagnostic performance (Yang 2011 SR of diagnostic studies; Liu 2011 SR of diagnostic
studies; Cheng 2011 SR of diagnostic studies). In assessment of new, acute back pain, ‘red flags’ topredict potential cancer have been proposed, yet the only evidence-based predictor of spinal
malignancy is “previous history of cancer” (Henschke 2013 SR of diagnostic studies; Downie 2013 SRof diagnostic studies). “History of cancer” increased the probability of malignancy to between 7%(95%CI 3 to 16) and 33% (95%CI 22 to 46); “older age”, “unexplained weight loss”, and “failure
to improve after 1 mth” increased probability by <3% (Downie 2013 SR of diagnostic studies).
Diagnostic imaging pathways that advocate larger lists of red flags and promote imaging for asingle red flag may lead to “substantial and arguably unwarranted” referrals for imaging.
However, there is no data on the diagnostic accuracy of combinations of proposed red flags.
8.9.7.2 | Spinal cord compression
Risk of spinal cord compression is between 5 and 20% of patients with spinal bone metastases,
yet diagnosis and treatment are often delayed until neurological dysfunction is irreversible. Early
suspicion and referral improve outcome. Spinal cord compression risk relates to many factors
including the type and characteristics of malignancy, extent of vertebral invasion, thoracic
metastases, the number and duration of spinal metastases ( Sutcliffe 2013 Level III-3 SR, 33 studies,
n=5,782). Localised back pain is the most common presenting feature and neurological deficit isa late presentation; MRI is the investigation of choice (Cheng 2011 SR of diagnostic studies; Samphao
2010 SR of diagnostic studies).
Early referral for surgical assessment is required within 24 h of MRI. In addition to analgesic
medications and adjuvants for pain, treatment options include corticosteroids, radiotherapy anddecompressive surgery (Loblaw 2012 GL; Ivanishvili 2014 NR; Samphao 2010 NR). The Neurologic,
Oncologic, Mechanical and Systemic (NOMS) framework is a recognised decision tree to optimise
local tumour control, pain relief, neurological preservation and functional restoration ( Laufer2013 NR). A Canadian scoring system (LMNOP) also incorporates a spinal instability neoplastic
score into a similar decision framework (Ivanishvili 2014 NR).

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8.9.7.3 | Treatment strategies for bone cancer pain including spinal cord compression
Treatment strategies for bone cancer pain, including pain of spinal cord compression, should
focus on analgesia, preservation of function and prevention of complications ( WHO 2018 GL; Kane
2015 NR). Rapid analgesia should be provided and advice given regarding nonpharmacologicalstrategies such as rest, avoidance of strenuous activity of painful areas and use of generalmobility aids. For acute bone pain, an accepted approach includes omission of Step II of the WHO
ladder when simple analgesics are inadequate, with progression directly to strong opioids(Maltoni 2005 Level II, n=54 [prematurely terminated], JS 2). For predictable incident pain, preemptive treatment with rapid-onset opioids should be prescribed. Preclinical data indicates arole for NSAIDs for bone pain but there is a lack of clinical evidence to support this. In asystematic review of NSAIDs (7 studies) and paracetamol (5 studies) added to strong opioids forcancer pain, no subgroup analysis of the combination for bone cancer pain was undertaken(Nabal 2012 Level III-2 SR, 12 studies, n=396). Using two NSAIDs (diclofenac 100 mg BD and celecoxib
400 mg/d) along with an opioid resulted in reduced pain scores, lower incidence of breakthroughpain as well as decreased opioid requirements vs using each NSAID in the same dose alone (Liu
2017b Level II, n=342, JS 3). Guidelines recommend topical diclofenac, including as gel or patch, toprovide relief for pain due to bone metastases with minimal systemic adverse effects (Swarm2019 GL)Management of bone pain, in addition to complications of bone cancers, also includes
targeted strategies that may be local (external beam radiotherapy, surgery) or systemic(chemotherapy, bisphosphonates, denosumab, hormonal therapy) ( Kane 2015 NR; Poon 2013 NR;
Samphao 2010 NR).
Tanezumab is a monoclonal antibody against neurotrophin nerve growth factor (NGF). In an
RCT of painful bone metastases assessing tanezumab vs placebo, the primary endpoint of adifference in change from baseline in daily average pain was not achieved (Sopata 2015 Level II,
n=59, JS 5). However, the data suggest improved analgesia and a Phase-3 trial is currently ongoing(Jara 2018 NR).
Electrochemotherapy, the combination of chemotherapy and local delivery of electricpulses to the tumour nodule (through electrodes surgically drilled into healthy bones
surrounding metastases), was shown to be safe and feasible with improved pain scores >50%
in 84% of patients and reduced opioid consumption (Bianchi 2016 Level III-3, n=24)
Generalised bone pain secondary to G-CSF treatment (eg pegfilgrastim) can result from anumber of proposed mechanisms including bone marrow expansion, neuromodulation andalterations in bone metabolism (Lambertini 2014 NR). The most commonly utilised pain relief
method for refractory severe pegfilgrastim-induced bone pain was use of the antihistamine
loratadine (Pawloski 2016 Level IV, n=69).
8.9.7.4 | Surgery
In the case of imminent or actual pathological fracture of long bones and pelvis, surgicalintervention with stabilisation may be of considerable benefit to reduce acute pain but has
attendant risks. The incidences following surgical management of metastases in the humerus,
femur and pelvis/acetabulum are 89 to 94% for pain relief, 91 to 93% for maintained or improved
function, 17% for morbidity and 4% mortality (Wood 2014 Level IV SR, 47 studies, n=807). Placementof catheters for regional nerve or plexus block may eliminate acute incident pain leading up toorthopaedic surgery and during the perioperative period. The high infection rates (10%) after
limb salvage surgery for primary bone cancer should be considered when evaluating andmanaging acute pain in the postoperative period (Racano 2013 Level IV SR, 48 studies, n=4,838). A592

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systematic review of treatment for metastatic spinal cord compression (1970 to 2007) thatcompared surgical stabilisation with or without radiotherapy and radiotherapy alone, concluded
that tumour excision and instrumented stabilisation may improve clinical outcomes, with regard
to both pain and neurological function (Kim 2012 Level IV SR, 33 studies, n=2,495). Periacetabular
metastatic lesions treated by curettage and cemented reconstruction resulted in improved pain
relief and functional status postoperatively, despite high rates of major complications (23%) andlarge mean surgical blood loss (3,150 mL) (Charles 2017 Level IV, n=35).
Radical surgical treatments should be considered where spinal metastases have a favourable
prognosis, such as thyroid metastases (Zhang 2013a Level IV, n=22). Surgery to correct
craniocervical instability also may alleviate acute pain, improve QoL and reduce hospitalisations(Kirchner 2014 Level IV SR, 9 studies, n=48). Prognosis should be re-evaluated, to ascertain the
primary goals of treatment and to undertake risk-benefit assessment of potential treatment(Sutcliffe 2013 Level III-3 SR, 33 studies, n=5,782).
Out of 24 patients with cervical spine metastases who underwent palliative surgicaltreatment, 21 patients experienced complete or almost complete pain relief, and 7 patients
experienced complete neurological recovery (Vazifehdan 2017 Level IV, n=24).
Resection of intradural extramedullary spine tumours appears to significantly improve
patient QoL by decreasing patient disability and pain with improvement in each of the EQ-5D
domains (Viereck 2016 Level IV, n=44).
8.9.7.5 | Radiation therapy
Radiotherapy effectively reduces malignant bone pain and may reduce complications of bone
cancer. It is recommended as the first-line treatment for the majority of patients with spinal
metastases causing spinal cord compression as it provides back pain relief in 50% to 58% of cases(Fallon 2018 GL; WHO 2018 GL).
At 1 mth after radiation therapy, around 25% patients experience complete pain relief (NNT4.2; 95%CI 3.7 to 4.9) and 41% experience 50% pain relief (McQuay 2000 Level I [Cochrane] 43 RCTs,
n=1,933). A later meta-analysis of palliative radiotherapy treatment for uncomplicated bonemetastases indicates similar response rates following single-fraction (60%) and multiple-fraction(61%) radiation, including 23% and 24% complete response rates respectively (Chow 2012 Level I,
25 RCTs, n=5,263). Single fraction conventional radiation therapy for painful uncomplicated bonemetastases shows similar results - improvements in pain in 60% to 81% of patients with complete
responses (no pain and no increase in analgesic requirements) in up to 37% (with use of 10 Gy)(Chow 2017 Level III-3 SR, 27 studies, n=4,071) (7 RCTs overlap).
Radiotherapy for painful bone metastases provides equivalent pain relief with different
regimens, including 3 Gy in 10 fractions, 4 Gy in 6 fractions, 4 Gy in 5 fractions and 8 Gy single
dose (Lutz 2017 GL based on 4 meta-analyses/pooled analyses, 20 RCTs & 32 studies, n=7,163; Rich 2018
Level I [PRISMA] 26 RCTs, n=3,059 [single fraction], n=3,040 [multiple fractions]; Chow 2014 Level I, 25
RCTs, n=5,617) (significant overlap of RCTs between all 3 SRs). However, after single-fraction

treatment, retreatment rates are higher and there is a trend for higher rates of pathologicalfracture and spinal cord compression. Multiple-fraction radiotherapy is favoured for borderline
complicated metastases, without any high-quality supportive evidence.
Shorter hypofractionated radiotherapy (HFRT) schedules of 4 Gy in 5 fractions were aseffective as more prolonged schedules for metastatic epidural spinal cord compression (Rades
2016 Level-II, n=203, JS 3)
For bone metastases with a neuropathic pain component, there was little evidence formultiple fraction vs single treatment in providing longer term benefit (Roos 2005 Level II, n=272,
JS 3).
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Retreatment
Reirradiation of bone metastases improves pain in about 58% patients, with complete response
in 16–28%, time to response from 3 to 5 wk, with duration of 5 to 22 wk (Huisman 2012 Level IV
SR, 7 studies, n=2,694). Retreatment of recurrent bone pain with 8 Gy single dose confirmed its
efficacy and showed no disadvantage vs 20 to 26 Gy in 5 fractions (Chow 2014 Level II, n=425, JS 3);
therefore, European Society for Medical Oncology Clinical Practice Guidelines recommend 8 Gy
single dose to be considered the schedule of choice for re-irradiation (Fallon 2018 GL)
Radiopharmaceuticals
For patients with pain due to widespread bone metastases, radiopharmaceuticals may provide
complete reduction in pain over 1 to 6 mth with no increase in analgesic use, but with common
severe adverse effects of leukopenia and thrombocytopenia ( Roque 2011 Level I [Cochrane], 15
RCTs, n=1,146). There are limited data comparing the various isotopes used (Strontium-89 [89Sr],
Samarium-153 [153Sm], Rhenium-186 [186Re] and Phosphorus-32 [32P]) showing no significant
differences (Fallon 2018 GL). In selected patients with multiple osteoblastic bone metastases,
radioisotope therapy can be highly effective in achieving pain relief in multiple sites.
Radium-223 (an alpha emitter releasing short-range radiation with little bone marrow
toxicity) in patients with castrate-resistant prostate cancer demonstrated improvements inskeletal-related events (SREs), pain, QoL and survival vs placebo (Sartor 2014 Level II, n=921, JS 5).
8.9.7.6 | Percutaneous vertebroplasty
Where other measures fail, percutaneous vertebroplasty is a procedure that aims to stabilise
vertebral compression fractures, restore function and achieve rapid pain relief by the injectionof bone cement (polymethylmethacrylate). A systematic review of vertebroplasty for bonemetastases and myeloma highlighted low-level evidence from heterogeneous studies andidentifies pain reduction rates of 47 to 87%, with no correlation between cement volume andpain relief (Chew 2011 Level IV SR, 30 studies, n=987). Serious complications may result from thetechnique and from cement injection or extravasation, including to the epidural space.
Complications were reported in 2 to 11.5% of patients and may correlate with cement volume.
These included haematoma, neuropathic pain, haemothorax and pulmonary embolism of
cement, with five related deaths. No good evidence currently supports superiority of
kyphoplasty over vertebroplasty. In multiple myeloma, vertebroplasty or kyphoplasty are
equally effective resulting in prompt and sustained reduction in pain and reduced analgesicuse (Khan 2014 Level IV SR, 23 studies, n=923). Vertebroplasty and kyphoplasty have similarcomplication rates in these patients, with the most frequent complication being new vertebral
fracture at untreated levels. Technical difficulties of percutaneous vertebroplasty for a patient
receiving denosumab, believed related to a sclerotic bone response, highlights the need forfurther investigation of this issue ( Mattei 2014 CR).
Cementoplasty, with percutaneous fluoroscopic-guided injection of bone cement into pelvic
bone malignancies involving acetabulum, superior and inferior pubic rami, ischium and sacrum,is also a therapeutic option for acute intractable pain from primary or metastatic bone disease(Kim 2013b Level IV, n=18 [32 sites]; Kelekis 2005 Level IV, n=14 [23 sites]; Marcy 2000 Level IV, n=18;
Jakanani 2010 CR; Harris 2007 CR). A combined technique of embolisation, radiofrequency ablationand cementoplasty for painful pelvic bone metastasis of renal cell cancer resulted in profoundand sustained pain relief and reduction of opioid requirements for up to 6 mth ( Pellerin 2014
Level III-2, n=52).

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8.9.7.7 | Bone-modifying agentsThe evidence to support an analgesic role for bisphosphonates and denosumab is weak ( PortaSales 2017 Level I [PRISMA], 28 RCTs, n=8,595 [bisphosphonates] & 15 RCTs, n=7,590 [denosumab] ).
Bisphosphonates and denosumab appear to be beneficial in preventing pain by delaying theonset of bone pain rather than by producing an analgesic effect per se. Therefore, these agentsshould not be used as a primary therapy for treatment of bone pain ( Swarm 2019 GL).
Bisphosphonates
Bisphosphonates are chemically stable derivatives of inorganic pyrophosphate with affinity forthe hydroxyapatite matrix of bone, where they inhibit osteoclast-mediated bone resorption (seealso Section 4.10.2). By this action, bisphosphonates reduce bone pain (see below), in addition
to the primary role to decrease the risk of, and time to, skeletal-related events consequent tobone cancer, including fracture, spinal cord compression and hypercalcaemia. Hypercalcaemia
is less frequent since bone-modifying agent use has increased but can still complicate
widespread bone cancer and heighten the pain experience (Poon 2013 Level I, 11 RCTs
[6 zoledronate & 4 pamidronate], n=7,834). Later generation bisphosphonates are now most widelyused, have considerably greater inhibition of bone resorption, maximal effect by 3 mth, andprolong residence and duration of action in bone, for up to years for zoledronate ( Kennel 2009NR). Potential serious but uncommon problems include renal impairment and osteonecrosis of
the jaw (ONJ); other effects include gastrointestinal symptoms, acute phase reaction with
pyrexia, myalgia and arthralgia, hypocalcaemia, and idiosyncratic musculoskeletal pain or ocularinflammation. ONJ in cancer patients after bisphosphonates occurred in 6.7% of patients; theincidence is increased with time of exposure, a history of dental procedures, and zoledronate(Bamias 2005 Level IV, n=252). Clodronate or pamidronate use instead of zoledronate may reducerisk of ONJ but dental extractions remain the main risk factor for ONJ (RR 14.04; 99%CI 10.36 to
19.03) (Kyrgidis 2013 Level III-2 SR, 12 studies, n unspecified). Dental preventive measures decrease
ONJ incidence (77.3%; 95%CI 47.4–90.2%) (Karna 2018 Level III-2 SR, 6 studies, n=2,332).
The efficacy of various bisphosphonates has been shown in a number of meta-analyses. In
multiple myeloma, bisphosphonates ameliorate pain (RR 0.75; 95%CI 0.60 to 0.95) (Mhaskar 2012
Level I [Cochrane], 20 RCTs, n=6,692). Bisphosphonates improve pain control in patients withmetastatic bone disease from lung cancer (Lopez-Olivo 2012 Level I, 12 RCTs, n=1,767). Zoledronate
specifically reduces the likelihood of experiencing a bone-pain event in metastatic bone diseasevs placebo (RR 0.83; 95%CI 0.76 to 0.89) (Zhu 2013 Level I, 12 RCTs, n=4,450). Analgesic effect is notshown in advanced prostate cancer (OR 1.54; 95%CI 0.97 to 2.44) ( Yuen 2006 Level I [Cochrane],
10 RCTs, n=1,955). An IV infusion of 4 mg ibandronate gave equivalent overall pain relief to singledose radiation therapy in prostate cancer (Hoskin 2015 Level-II, n=470, JS 3).
Denosumab
Activation of osteoclasts is driven by the receptor activator of nuclear factor kappa-B ligand/osteoprotegerin (RANKL/OPG) gradient. Denosumab is a human monoclonal antibody to RANKLthat blocks osteoclast development and hence bone resorption. In patients with metastatic andprimary bone cancer, denosumab reduces bone pain and slows time to worsening of pain
(Prommer 2015 NR; Rolfo 2014 NR; Iranikhah 2014 NR).
In bone metastases from breast cancer (1 RCT, n=2,046), prostate cancer (1 RCT, n=1,901) orother solid tumours (1 RCT, n=1,597), denosumab vs zoledronate delays onset of moderate/severe
pain by 1.8 mth (median 6.5 vs 4.7 mth) (HR 0.83; 95 %CI 0.76 to 0.92) and clinically meaningfulincreases in overall pain interference by 2.6 mth (median 10.3 vs 7.7 mth) (HR 0.83; 95%CI 0.75
to 0.92) (von Moos 2013 Level I, 3 RCTs, n=5,544). Denosumab also reduces strong opioid use andworsening of health-related QoL. Compared to zoledronate, denosumab delays time to
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worsening of pain in patients with skeletal metastases (RR 0.84; 95%CI 0.77 to 0.91) ( Peddi 2013
Level I, 6 RCTs, n=6,142).
Denosumab can also lead to ONJ (Diz 2012 NR). Use of denosumab instead of zoledronate
does not reduce the risk of ONJ (RR 0.71; 99%CI 0.41 to 1.24) (Kyrgidis 2013 Level III-2 SR, 12 studies,n unspecified), occurring in 1.6% of patients overall (1.3% with zoledronate and 1.8% withdenosumab) (Saad 2012 Level I, 3 RCTs, n=5,723).
Calcitonin
Although calcitonin has been used to reduce metastatic bone pain and skeletal events, thelimited evidence available does not support the effectiveness of salmon calcitonin in thetreatment of acute and persistent metastatic bone pain (Martinez-Zapata 2006 Level I [Cochrane],
2 RCTs, n=90). See also Section 4.10.1.
8.9.7.8 | Treatment of acute malignant extradural spinal cord compression
Comprehensive clinical practice guidelines exist to optimise care and pain control of patientswith malignant spinal cord compression (Loblaw 2012 GL). Corticosteroids are indicated forneurological deficit, particularly if there is to be radiotherapy eg dexamethasone (bolus 8 to
10 mg; maintenance 16 mg/d; higher doses for dense paraparesis). Early surgical consultation isrequired, with due consideration of the associated morbidity. Patients unsuitable for surgery
should receive radiotherapy. Selected groups suitable for stereotactic radiosurgery, with spinal
cord sparing, remain to be clarified. Pain is acute and may be exacerbated during earlyradiotherapy, with incident pain associated with movement and positioning for treatments. See
also Sections 8.9.7.3 and 8.9.7.5 above.

8.9.8 | Other acute cancer pain syndromes
8.9.8.1 | Malignant bowel obstruction
Malignant bowel obstruction frequently complicates advanced abdominal cancers, develops
over days to months, and presents as generalised abdominal pain or visceral colicky pain. Verylittle, and heterogeneous, trial data exists to inform guidelines and choice of best medical care,surgery or endoscopic interventions, which may vary according to acuity, degree ofobstruction, disease prognosis and objectives of care. Treatment should be individualised.
Pharmacological management is based on glucocorticoid, analgesic, antiemetic andantisecretory agents, with attention to adequate hydration ( Mittal 2014 Level IV, n=48 [physicians
surveyed]; Ripamonti 2008 NR). Acute severe pain can be managed with parenteral opioids,
which also reduces colicky pain by reducing bowel motility. Oral opioids should not be used
due to unpredictable absorption. For exacerbations of colic, the antispasmodic hyoscine
butylbromide is of benefit and less sedating than hyoscine hydrobromide. Decompression andreduction in secretions may also assist with pain in patients with inoperable bowel obstruction.
Hyoscine butylbromide and the somatostatin analogues octreotide reduce gastrointestinal
secretions, slow motility and decrease both continuous and colicky pain intensity ( Ripamonti
2000 Level III-1, n=17). There is little evidence for dexamethasone (6 to 16 mg IV) to improvebowel obstruction (Feuer 2000 Level I [Cochrane], 3 RCTs, n=89 ).
For inoperable bowel obstruction with peritoneal carcinomatosis, a staged protocol with
analgesic, antiemetic, anticholinergic and corticosteroid as initial therapy (Stage 1), followed bya somatostatin analogue for persistent vomiting (Stage 2) and then venting gastrostomy (Stage3) was highly effective in relieving symptoms and avoiding permanent nasogastric tube ( Laval2006 Level IV, n=80). Fluoroscopic-guided, percutaneous venting gastrostomy tube placement can

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be technically difficult, with 72 and 77% primary and secondary technical success, and 10%
incidence of major complications; prior intraperitoneal catheter to manage ascites may reduce
the technical difficulty (Shaw 2013 Level IV, n=89). Endoscopic stenting may offer effective and safe
palliation or act as a bridging step before surgery (34 studies, n=14,356) (Frago 2014 Level IV SR,
59 studies, n=20,762). Complications include perforation (3.76%), stent migration (11.81%) andreobstruction (7.34%) (Sebastian 2004 Level IV SR, 54 studies, n=1,198). Reports of no or mild nausea
increased from 10% at baseline to 100% after treatment with olanzapine in patients withinoperable and incomplete bowel obstruction (Kaneishi 2012 Level IV, n=20).
8.9.8.2 | Mucositis
Mucositis is a common adverse effect of high-dose chemo- and radiotherapy for malignancies
affecting the head and neck, acute leukaemias and for conditioning prior to bone marrowtransplants. It may be complicated by opportunistic infections including herpes simplex andcandidiasis. Quality of life and nutrition can be greatly impaired by the pain of cancer-related
acute mucositis. In this indication, there is no significant difference in analgesia between PCA
and continuous opioid infusion, except that PCA is associated with reduced opioid requirements
and pain duration (Clarkson 2010 Level I [Cochrane] 33 RCTs, n=1,505). IV ketamine “burst therapy”
may be effective in mucositis pain that is refractory to opioid analgesia ( Jackson 2005 NR).
Retrospective studies suggest some benefit from PO gabapentin (Milazzo-Kiedaisch 2016 NR) with
one small RCT suggesting lack of benefit (Kataoka 2016 Level II, n=22, JS 3).
Several topical measures have been postulated to treat the pain of oral mucositis. Topical
doxepin, amitriptyline, diclofenac and benzydamine (another nsNSAID) vs placebo provide pain
relief due to mucositis (Christoforou 2019 Level I [PRISMA], 6 RCTs, n=441). One RCT not included
showed that benzydamine reduced mucositis scores, but not pain, when used as an oral rinse
for the prevention and treatment of mucositis (Chitapanarux 2018 Level II, n=60, JS 4). Mucosal
analgesia may be achieved by topical application of EMLA® cream and 5% lignocaine (Vickers 1992
Level II, n=60, JS 5).
Povidone-iodine mouthwash significantly reduces the severity of oral mucositis vs sterilewater, however chlorhexidine was ineffective (Potting 2006 Level I, 7 RCTs, n=863). The lack ofeffect of chlorhexidine has been confirmed by a subsequent specific meta-analysis (Cardona 2017
Level I [PRISMA], 12 RCTs, n=876).
Two different formulations of 200 mcg dose transmucosal fentanyl citrate were equal in
efficacy, tolerability and adverse-effect profile, but no better than placebo for analgesia inradiation-induced mucositis (Leenstra 2014 Level II, n=155, JS 5; Shaiova 2004 Level II, n=14, JS 5).
Topical morphine (Vayne-Bossert 2010 Level II, n=11, JS 5; Cerchietti 2002 Level II, n=26, JS 3;
Cerchietti 2003 Level III-1), and ketamine (Slatkin 2003 CR) may also provide analgesia. Topicalmorphine mouthwash (2%) for patients with severe mucositis (associated with treatment forhead and neck cancer) was more effective than mouthwash containing viscous lignocaine,
magnesium aluminium hydroxide and diphenhydramine, both administered in 10 mL aliquots
3-hourly (Sarvizadeh 2015 Level II, n=30, JS 5). Morphine mouthwash recipients had lowered WHO
grading scores for mucositis after 6 d of treatment and reported increased satisfaction with theirtreatment.
Preventive strategies for mucositis such as palifermin (Bensinger 2008 GL) or oral cryotherapy(Batlle 2014 Level III-2; Tayyem 2014 NR) may be effective in specific circumstances. Polymyxin E,
tobramycin and amphotericin B (PTA), GM-CSF, oral cooling and amifostine have a preventive
effect by significantly reducing the incidence and severity of oral mucositis ( Stokman 2006 Level I,
45 RCTs, n=4,145). Oral cryotherapy by having the patient suck on ice chips or hold ice water in
his/her mouth before, during, and/or after rapid infusions of systemic therapies that are
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associated with mucositis has been shown to be an effective preventive treatment (NNT 4) ( Riley
2015 Level I [Cochrane], 14 RCTs, n=1,280). Situations studied include patients receiving fluorouracil(5-FU) for solid cancers, and, to a lesser extent, patients receiving high-dose mephalan before
haematopoietic stem cell transplantation, melphalan for multiple myeloma and 5-FU for solid
tumours. A subsequent RCT showed similar findings ( Idayu Mat Nawi 2018 Level II, n=88, JS 2). Thisapproach is also recommended in guidelines (Swarm 2019 GL).
Low-level laser therapy (LLLT) may be effective in reducing pain intensity, severity andduration of mucositis based on moderate evidence (Anschau 2019 Level I [PRISMA], 5 RCTs, n=315).
This is in line with findings of two small low-quality studies not included in the meta-analysis(Abramoff 2008 Level II, n=11, JS 2; Arora 2008 Level II, n=28, JS 2). LLLT used prophylactically reduces
the risk of severe mucositis and pain in patients with cancer or undergoing hematopoietic stem
cell transplantation (Oberoi 2014 Level I [PRISMA], 18 RCTs, n=1,144). This approach is recommended
in a specific clinical practice guideline (Zadik 2019 GL).
Honey shows benefit over placebo and other treatments for moderate to severe
chemotherapy induced mucositis in adults, but not in teenagers (Yang 2019 Level I [PRISMA] [NMA],
17 RCTs, n=1,265).
Evidence-based clinical practice guidelines for the prevention and treatment of mucositis incancer patients have been published (Zadik 2019 GL; Alvarino-Martin 2014 GL; Lalla 2014 GL)
For paediatric information, see Section 10.8.3.1.

8.9.9 | Interventional therapies for acute cancer pain
Although pain is adequately controlled in the majority of patients with advanced cancer, patientswith severe acute exacerbations of pain may benefit from interventions.
Where pain is prolonged, but opioid-resistant, intractable, and associated with frequent
acute exacerbations of pain, including incident pain or paroxysmal neuropathic pain, and adverse
effects limit other pharmacological strategies, patients with advanced disease may benefit fromlonger-term local anaesthetic infusions, including neuraxial infusions, or more destructive
neurolytic and other ablative procedures to manage pain.
8.9.9.1 | Peripheral nerve blocks
Local anaesthetic nerve or plexus blocks including continuous peripheral nerve block (CPNBs)
may be used to control pain prior to surgery eg acute or imminent fracture, during painful
diagnostic or therapeutic procedures, or while awaiting a response from other therapy such asradiation therapy (Klepstad 2015 Level IV SR, 16 studies, n=79; Chambers 2008 NR) (see also Section
5.8). Unilateral continuous erector spinae plane block (ESPB) may provide sufficient analgesia inpatients with end-stage pulmonary malignancy suffering from severe unilateral thoracic pain
(Aydin 2018 Level IV, n=2).
8.9.9.2 | Neuraxial techniques
Currently, epidural or IT infusions of several classes of agents by a variety of medication delivery
systems may provide effective analgesia to cancer patients with previously refractory pain, poor
tolerance of oral or systemic analgesia and poor performance status (see also Sections 5.6 and5.7). There is only limited evidence supporting neuraxial treatment of cancer pain summarisedin 2 systematic reviews. There is low quality evidence supporting these techniques resulting in a
weak recommendation for their use based on better pain control found for all interventions;described comparisons include neuraxial combinations of opioid and adjuvant analgesic vs opioid
alone (4 RCTs), neuraxial bolus vs continuous infusion (2 RCTs), neuraxial drug vs neuraxial placebo598

5th Edition | Acute Pain Management: Scientific Evidence8.0 | SPECIFIC CLINICAL SITUATIONS(1 RCT) and neuraxial opioid vs other comprehensive medical management ( 2 RCTs) (Kurita 2015
Level I, 9 RCTs, n=686). Specifically, for IT administration, the 2 RCTs show benefits of IT morphineand IT ziconotide administration (Bruel 2016 Level IV SR, 2 RCTs & 8 studies, n=807) (2 RCTs overlap).
A retrospective chart review of neuraxial analgesia for cancer pain showed good analgesic effectin 50% of 16 epidural and in 70% of 44 IT treatments ( Kiehela 2017 Level IV, n=60). High dose
systemic opioids (in the range of 700 to 900 mg oral MED) could be discontinued or significantly
reduced in 83% of patients who received neuraxial infusions of morphine, commonly combinedwith low-dose bupivacaine and adjuvants including clonidine and ketamine. However, catheter
dislocations occurred in 27% of cases.
Consensus guidelines for the use of neuraxial analgesia in cancer pain are based largely on
this weak evidence, despite broad experience in the use of IT opioids, local anaesthetics,
clonidine, baclofen and other neuraxial medications ( Kurita 2011 Level IV SR, 44 studies, n=2,116[cancer; 7 RCT overlap with Kurita 2015]; Clarke 2017 GL; Deer 2011 GL). These consensus guidelines
and other systematic or practical reviews provide a framework to optimise safety andeffectiveness of these techniques that may be used in various and potentially remote palliative
settings (Myers 2010 SR of 3 SRs, 3 consensus conferences & 12 RCTs; Gulati 2014 NR; Upadhyay 2012
NR; Mercadante 2012 NR).
Breakthrough analgesia with either SL ketamine or an IT local anaesthetic bolus was usedsuccessfully in palliative patients with ongoing IT analgesia (Mercadante 2005 Level IV). Although
infrequently used, morphine by the intracerebroventricular (ICV) route may offer advantages forpatients with head, neck or upper limb malignancy causing intractable pain ( Ballantyne 2005
Level IV SR [Cochrane], 13 studies [ICV], n=337). This review noted few treatment failures andexcellent analgesia reported in 73% after ICV opioids with more reports of respiratory
depression, sedation and confusion, but lower incidence of nausea, urinary retention, pruritus
and constipation with ICV therapy than with IT and epidural routes.
Patient-controlled IT analgesia with a number of agents (morphine, hydromorphone,fentanyl, bupivacaine, clonidine, baclofen, and ziconotide) in the management of refractory
cancer-related pain resulted in improved pain control and faster onset of effect vs conventional
treatment for breakthrough pain (Brogan 2015 Level III-3, n=58).
Patient-controlled epidural analgesia vs intravenous analgesia in patients diagnosed withadvanced cancer showed that epidural analgesia is associated with improved respiratory
parameters, lower pain scores, higher satisfaction scores, and less opioid related GIT side effects(He 2015a Level II, n=50, JS 1).
8.9.9.3 | Spinal cord stimulation
Evidence is insufficient to establish any role for spinal cord stimulation for cancer pain in adults;four case series provide the only evidence base in cancer pain and nil further in an updated
Cochrane review (Peng 2015 Level III-3 SR [Cochrane], 4 studies, n=92).
8.9.9.4 | Destructive procedures
Coeliac plexus block
For pain due to pancreatic cancer, neurolytic coeliac plexus block has been widely used (Nagels
2013 NR) with improved pain scores at 4 wk (-0.42/10; 95%CI -0.70 to -0.13) and at 8 wk (-0.44/10;
95%CI -0.89 to -0.01) and reduced opioid requirements (Arcidiacono 2011 Level I [Cochrane], 6 RCTs,
n=358). Similar findings were reported by a systematic review including additional case series(Nagels 2013 Level IV SR, 5 RCTs, n=295 & 61 studies, n≈4,719) (3 RCTs overlap), while a subsequentmeta-analysis confirmed reduced analgesic requirements with improved pain control only at
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4 and not 8 wk (Zhong 2014 Level I, 7 RCTs, n=403) (4 RCTs overlap with Nagels 2013; 6 RCTs overlap with
Arcidiacono 2011).
Percutaneous coeliac plexus ablation for treating severe cancer pain in upper abdomen
improved not only pain and performance status scores in the treatment group, but also had
health economic benefits by reducing medicine-specific and total health care costs vs controls(Cao 2017 Level III-2, n=81). There were no differences seen between the two groups in
hospitalisation, examinations, or treatment costs. Better performance status and low daily
opioid use before neurolytic coeliac plexus block were independent predictors of good analgesia
after the procedure in patients with unresectable pancreatic cancer (Yoon 2018 Level III-2, n=112).
Bilateral vs unilateral endoscopic ultrasound-guided celiac plexus neurolysis for abdominal
pain management for pancreatic malignancy reduced analgesic requirements, although pain
relief and response to treatment were the same (Lu 2018 Level III-2 SR, 6 studies, n=437).
Splanchnic nerves
There was no difference in pain outcomes or complications when comparing alcohol versus
phenol based techniques in splanchnic nerve neurolysis for pain related to upper abdominal
malignancies (Koyyalagunta 2016 Level III-3, n=93). The treatment reduced pain scores but not
opioid consumption. Furthermore, the procedure resulted in improvements in anxiety,depression, thinking clearly and feeling of well-being.
Radiofrequency ablation vs chemical neurolysis of bilateral thoracic splanchnic nerves in the
management of refractory cancer pain due to upper abdominal cancers provided quicker onset
and longer duration of analgesia with a higher success rate, along with a better safety profile(Amr 2018 Level II, n=60, JS 2).
Bilateral thoracoscopic splanchnicectomy was effective for intractable pain secondary topancreatic cancer with only 28% of patients continuing to experience abdominal pain ( Bhutiani N
2017 Level III-3, n=48). Daily opioid dose decreased in 74% of the patients and 67% discontinued
analgesics completely.
Cordotomies
Cordotomies have also been performed successfully to treat cancer pain in highly selected cases(Raslan 2011 NR). In pain due to mesothelioma, percutaneous cervical cordotomy may be safe andeffective (France 2014 Level IV SR, 9 studies, n=160). In pain mainly due to malignancies, CT-guided
percutaneous cervical cordotomy provided pain relief in 98.13% of cases (Kanpolat 2013 Level IV,
n=210). In another case series, 32 of 45 patients experienced significant pain relief without relevant
adverse effects (Bain 2013 Level IV, n=45).
Other destructive procedures
Early vs later neurolytic sympathectomy for pain from abdominal or pelvic cancer resulted in
reduced oral analgesic use and improved pain control and QoL (Amr 2014 Level II, n=109, JS 4).
Pulsed radiofrequency was used to treat pain from infiltration of the brachial plexus by atumour (Arai 2013b Level IV, n=4; Magistroni 2014 CR; Rana 2013 CR).
In selected cases, IT neurolytic blocks can be a pain-relieving intervention (Candido 2003 NR).
8.9.9.5 | Other Therapies
High Intensity Focused UltrasoundA meta-analysis concluded high intensity focused ultrasound (HIFU: a non-invasive thermal
ablation technique) appears to be effective for pain reduction in advanced pancreatic cancer,
although the heterogeneity of the data and the lack of RCTs prevents a strong recommendation(Dababou 2017 Level IV SR [PRISMA], 23 studies, n=865).

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Acupuncture
Acupuncture for palliative care of cancer shows conflicting evidence regarding treatment ofcancer-related pain, but some evidence for its use in management of cancer-related fatigue,
chemotherapy-induced nausea and vomiting and leukopenia in patients with cancer ( Wu 2015
Level IV SR, 23 SRs of 248 primary studies, n=17,392).
Music Intervention
Music interventions may be effective in reducing pain scores (SMD -0.91; 95%CI −1.46 to −0.36)(7 studies, n=528) as well as having some beneficial effects on physiological variables (heart rate,
respiratory rate and blood pressure), anxiety, pain, fatigue and QoL in people with cancer (Bradt
2016 Level III-1 SR [Cochrane, 52 studies, n=3,731). Most trials were at high risk of bias and, therefore,
these results need to be interpreted with caution.

KEY MESSAGES
1. Intranasal, sublingual and buccal fentanyl preparations are effective treatments forbreakthrough pain in cancer patients (U) (Level I [Cochrane Review]) with similar
efficacy to intravenous administration (U) (Level I [PRISMA]) and superior to oral
morphine (U) (Level I).
2. Radiotherapy is an effective treatment of acute cancer pain due to bone metastases(U) (Level I [Cochrane Review]), while bone-targeting agents (bisphosphonates,
denosumab) are beneficial in delaying the onset of bone pain rather than providing
analgesia (W) (Level I [PRISMA]).
3. Neurolytic coeliac plexus block in pancreatic cancer lowers pain intensity and opioid
analgesic requirements for at least 8 weeks (U) (Level I [Cochrane Review]).
4. Opioids, via PCA or a continuous infusion, provide effective analgesia in mucositis; PCA
is associated with reduced opioid requirements and pain duration (U) (Level I[Cochrane Review]).
5. Oral cryotherapy (sucking on ice chips or holding ice water in the mouth before, during,
and/or after rapid infusions of systemic therapies that result in mucositis) effectively
prevents mucositis (N) (Level I [Cochrane Review]).
6. Music interventions may be effective in reducing pain intensity in patients with cancer(N) (Level I [Cochrane Review]).
7. Topical treatment with doxepin (S), amitriptyline (N), diclofenac (N), benzydamine (N)(Level I [PRISMA]), povidone-iodine (U) (Level I) and morphine (S) (Level II) comparedto placebo improve pain relief due to mucositis.
8. Low-level laser therapy reduces and when used prophylactically prevents pain andseverity of mucositis (S) (Level I [PRISMA]).
9. Patient education about cancer pain is a key factor in optimising pain management (U)(Level I).
10. Opioid doses for individual patients with cancer pain should be titrated to achieve
maximum analgesic benefit with minimal adverse effects (U) (Level II).

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11. Analgesic medications prescribed for cancer pain should be adjusted to alterations ofpain intensity (U) (Level III-2).
12. Neuropathic pain or mixed nociceptive-neuropathic pain has an estimated frequency of
30-40% in patients with cancer (S) (Level IV SR).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Acute pain in patients with cancer often signals disease progression; sudden severe
pain in patients with cancer should be recognised as a medical emergency and
immediately assessed and treated (U).
 Prompt assessment and fast coordinated management of spinal metastases withsuspected spinal cord compression is required to mitigate against neurological deficit (U).
 Cancer patients receiving controlled-release opioids need access to immediate-release
opioids for titration of breakthrough pain; selection of breakthrough medication should
consider the time course and aetiology of the pain flare (U).
 If nausea and vomiting accompany acute cancer pain, parenteral opioids are needed (U).
 Transdermal opioids are inappropriate to control acute unstable pain (U).
 High interindividual variability in opioid conversion rates dictates that all opioid
rotations should be individualised and monitored, particularly where higher opioid
doses are in use (U).

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8.10 | Acute pain management in intensive careAcute pain is a common occurrence in critically ill patients. As many as 80% of intensive care unit
(ICU) patients experience moderate to severe pain at some point in their ICU admission andattribute it to a source of long term psychological morbidity (Rotondi 2002 Level III-2, n=150; Puntillo
2001 Level III-2, n=6,201), while approximately 50% of both medical and surgical patients
experience pain at rest (Chanques 2006 Level III-1, n=230). However, barriers to effective pain
report exist including the presence of an endotracheal tube, sedative infusions, restraints andneurological sequelae of critical illness (eg delirium, traumatic brain injury). Despite thelimitations on pain assessment and the altered physiology of critical illness, a balanced,
multimodal analgesic approach targeted at the sociopsychobiomedical aetiology of acute pain iswarranted.

8.10.1 | Aetiology of pain in the intensive care unit (ICU)
The aetiology of acute pain in critically ill patients is complex and synergistic (see Table 8.2).
Whilst not all of these are modifiable, targeted treatment of each of the potential aetiologies
may result in a profound decrease in patient suffering both in the ICU and thereafter.
Table 8.2 | Aetiology of acute pain in the ICU
Biological

Underlying Illness (eg surgery, sepsis, trauma, burns)
Iatrogenic interventions (eg ETT, repositioning, drains, dressingchanges, vascular access, invasive monitoring)Complications (eg nosocomial infections)
Prolonged immobility
Inappropriate pain management (lack of multimodal analgesia, OIH)
Pharmacotherapy (Sedation type)Pre-existing chronic pain

Psychological

Fear
Hallucinations
Post-Traumatic Stress Disorder
Sleep deprivation
Delirium
Anxiety
Depression

SocialIsolation and Rejection
Circumstances of the injury
Facing own mortality

Sources: Adapted from Sigakis 2015

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8.10.2 | Barriers to pain management in the ICU
There exist multiple barriers to the provision of effective, multimodal analgesia to critically illpatients (see Table 8.3). Both patient-related and provider-related barriers should be addressedin analgesic management strategies. Simple strategies such as communication boards, patient
education about their likely analgesic requirements, and health provider education can result ina marked improvement to overcoming the barriers to effective analgesia. Healthcare systemrelated barriers require policy development (including quality improvement or QI), education,
workflow analysis and change methodology when implementing unit-wide analgesic guidelines.
Table 8.3 | Barriers to effective pain management in the ICU
Patient

Inability to report pain
Differential reporting to doctors and nurses
Fear of the consequences of reporting pain
Fear of the side effects of analgesic medications
Feelings that pain should be tolerated as part of the disease process(fatalistic beliefs)
Altered cognitive status giving the impression of having effective
analgesia (eg hypoactive delirium)

ProviderKnowledge deficits of aetiology, assessment and management
strategies (eg sedation as an analgesic, multimodal analgesia)
Pain management assigned a low priority (seen as “ICU
Housekeeping”)
Failure to assess for the existence of pain
Failure to evaluate effect of analgesic treatment
Inconsistent practices, particularly around periprocedural analgesia
Inappropriate attitudes regarding the use of opioids
Overconcern about the side-effects of analgesics (eg opioid
tolerance, NSAIDs)
Lack of knowledge of the types and appropriate doses of analgesics
Communication difficulties between the patient and the healthcare
team
Personal and cultural biases

Healthcare system

Lack of accountability for unsatisfactory outcomes related toinadequate analgesic management
Inadequate local guidelines to guide pain management
Lack of alternative non-pharmacological therapies (eg hot or cold
compresses, mobilisation therapy whilst intubated)
Inadequate quality improvement processes for pain management
Logistic barriers to timely analgesic administration (eg high nursing
burden)Implementation of change to pre-existing methods of analgesia andsedation

Sources: Adapted from Sigakis 2015604

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8.10.3| Pain assessment in the ICU
Assessment of pain in the critically ill patient is difficult, owing to the barriers previously
mentioned and outlined in Table 8.3. A patient’s subjective index of pain is often not possible orreliable because of altered cognitive status or co-administered sedative agents. In addition, a
health provider’s own biases may prevent recognition of pain. In a study of patient recollections,the presence of the endotracheal tube was rated on average as being 6/10 (5/10 at best and8/10 at worst) (Rotondi 2002 Level III-2, n=150). For this reason, a patient post-laparotomy may be
more likely to be assessed for pain compared with a patient receiving mechanical ventilation due
to severe pneumonia. Hence, it is important to have a structured, consistent approach toanalgesic assessment, regardless of the admission diagnosis.
The Society of Critical Care Medicine’s (SCCM) Pain, Agitation, Delirium, Immobility and Sleep(PADIS) Guidelines (Devlin 2018 GL) advocate for self-reporting scales to be used as first line forpain assessment, followed by behavioural pain scores in those unable to self-report.
In responsive patients, the numerical rating scale (NRS) is the reference standard for pain
assessment. The presence of an endotracheal tube should not prevent self-reporting, and theuse of communication adjuncts (communication board, pen and paper, visual aid) should be
encouraged. In unresponsive patients, the NRS is not applicable. Instead, the observation of
behavioural and physiological responses may be the only information available to modify pain
management (Puntillo 2002 Level IV; Puntillo 1997 Level IV; Chong 2003 NR). The use of such
behavioural scales is recommended but only validated, reliable and feasible scales should be
used (Gelinas 2013b NR).
The critical care pain observation tool (CPOT) has been developed and validated in sedated,mechanically-ventilated critically ill patients (Gelinas 2011 Level III-2; Gelinas 2006 Level III-2),
including the cohorts with a brain injury (Joffe 2016 Level III-2), post-operative elective
neurosurgical patients (Echegaray-Benites 2014 Level III-2) and delirium (Kanji 2016 Level III-2). The
behavioural pain score (BPS) has also been described and validated for the evaluation of pain insedated, mechanically ventilated, unresponsive patients (Aissaoui 2005 Level III-1; Payen 2001
Level III-1; Gelinas 2013b NR). The use of BPS vs CPOT resulted in a higher specificity (91.7% vs
70.8%), but a lower sensitivity (62.7% vs 76.5%) (Severgnini 2016 Level III-2).

8.10.4 | Analgesic management strategies in the ICU
The management of acute pain in intensive care requires an individualised, multimodal analgesic
approach targeted at the sociopsychobiomedical aetiology of acute pain. Although there is a
paucity of evidence to guide specific analgesic practices, the SCCM PADIS guidelines provide aframework for this challenging group (Devlin 2018 GL).
The use of protocolised analgesia management consisting of regular assessment of pain,
analgosedation protocols, sedation assessment and management, delirium screening andmanagement, and targeted analgesia was associated with improved analgesia, decreased
duration of mechanical ventilation, ICU LOS, duration and dose of opioid and sedative infusions
and decreased mortality (Georgiou 2015 Level IV SR [PRISMA], 10 studies, n=3,547; Mansouri 2013
Level II, n=216, JS 3; Chanques 2006 Level III-1; Barnes-Daly 2017 Level III-2, n=6,064; Payen 2009
Level III-2; De Jonghe 2005 Level III-3).

A summary of the principal recommendations of evidence-based pain guidelines includes(Devlin 2018 GL):
• An analgosedation-based protocol for assessment and management should be used (ieassess and treat pain first, followed by agitation/sedation assessment and management,

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•
•
•
•
•
•
•

followed by delirium screening and management and withdrawal assessment/
management during weaning);
Pain should be routinely monitored in ICU, using the BPS and the CPOT for patients who
are unable to self-report;
Vital signs alone should not be used for pain assessment;
Opioids are recommended as first-line analgesics for non-neuropathic pain, administeredat the lowest possible dose to achieve adequate analgesia;
Paracetamol should be used as an adjuvant to opioids in pain management;
Conditional recommendations for NSAIDs as an adjunct to opioids in pain management;
Ketamine should be used to reduce opioid consumption in postsurgical ICU patients;
Neuropathic pain medications should be used with an opioid for neuropathic pain.

Current practice still falls well short of these recommendations. In an Australian and New
Zealand point-prevalence study, fewer than half of patients in the participating ICUs had theirpain assessed within the 4 h period audited and 22% of those assessed were considered to havemoderate or severe pain (Elliott 2013 Level IV, n=41 [ICUs]).

8.10.5 | Nonpharmacological analgesic management
As there may be a large psychosocial influence in development of acute pain in the critically illpatient, non-pharmacological interventions have the potential to act as powerful analgesic
adjuvants. Attention to detail with positioning, pressure care, comfortable fixation of invasive
devices, care in the management of secretions and excretions, minimisation of noise fromspurious alarms and unnecessary equipment (such as the uncritical application of high-flow mask
oxygen) can substantially lessen the burden of discomfort for the patient (Puntillo 2004 Level III-3;
Chong 2003 Level IV; Aaron 1996 Level IV). Maintenance of a day-night routine (lighting and activity)
is thought to aid sleep quality, which may reduce pain perception (Horsburgh 1995 NR).
Specific to analgesic management, cognitive behavioural techniques such as distraction
therapy and music therapy, simple massage and facilitation of family presence were agreed bypatients and nursing staff as the most effective non-pharmacological analgesic adjuvants (Gelinas
2013a Level IV). Massage may have beneficial effects in reducing pain and anxiety in ICU patients(Jagan 2019 Level I [PRISMA], 12 RCTs, n=779).

8.10.6 | Pharmacological analgesic management
Management of acute pain may be difficult in the presence of co-administered sedation. It is
important, however, to attempt to monitor both processes with sedation scoring (via theRichmond Agitation-Sedation Scale: RASS) and an observational pain assessment tool. This may
allow titration of both sedative and analgesic medications separately and decrease the risk of
inappropriate therapies (eg increased sedation for agitation due to acute pain).
The mainstay of treatment of acute pain in mechanically ventilated ICU patients is parenteral
opioid analgesia (Devlin 2018 GL). Despite this, multimodal analgesia should be the goal; the useof non-opioids as adjuvants to opioids in the ICU setting has beneficial effects ( Zhao 2019 Level I[PRISMA], 12 RCTs, n=910). In particular in ICU patients with Guillain-Barre-Syndrome and after
surgery, non-opioids reduce pain intensity, opioid requirements and nausea and vomiting. In
addition to multimodal analgesia, sedative type may play a role in analgesic management. In
healthy volunteers, moderate sedation with midazolam increased the pain perception oftemperature and electrical pain, whilst propofol reduced ischaemic pain and dexmedetomidine
reduced both ischaemic and cold pain (Frolich 2013 Level II EH, n=86, JS 2). This raises the possibility
that midazolam may lower pain thresholds.

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8.10.6.1 | Paracetamol
Paracetamol is a safe non-opioid analgesic in the critically ill cohort. IV paracetamol 1 g every
6 h in ICU patients with fever or suspected infection did not increase the incidence of hepatic
dysfunction vs placebo (Young 2015 Level II, n=700, JS 5). In elective, post-operative surgical ICU
patients, the addition of paracetamol improved analgesia, reduced opioid consumption and time
to extubation (Memis 2010 Level II, n=40, JS 5).
However, IV paracetamol can result in hypotension ( Chiam 2015 NR). The use of IV
propacetamol and IV paracetamol and associated hypotension has been reported (with variable
definitions: systolic vs MAP change in absolute value or 15-20% decrease) in mostly critically ill(often cardiac) patients (14/19 studies) (Maxwell 2019 Level IV SR, 19 studies [5 RCTs, 6 open-label trials& 8 retrospective reviews], n=3,470). Hypotension appears to be more prevalent with IV vsnasogastric paracetamol in an RCT included in the systematic review ( Kelly 2016 Level II, n=50,
JS 3).
8.10.6.2 | NSAIDs
Non-steroidal anti-inflammatory drugs (NSAIDs) are effective analgesics. Their use, however, isrestricted in the critically ill cohort due to the perceived increased risk of acute kidney injury,
gastrointestinal bleeding, platelet inhibition and acute myocardial infarction.
When ketoprofen was added for 24 h to an opioid infusion in post-operative major abdominal
surgery patients, the result was a reduction in pain scores, opioid consumption (byapproximately 20%) and nausea and vomiting (Oberhofer 2005 Level II, n=44, JS 4). There were noreported bleeding events or episodes of acute kidney injury. The use of ketorolac in patients withrib fractures decreased the incidence of pneumonia and ventilation times, with no apparent
increase in the risk of bleeding or renal failure (Yang 2014 Level III-2, n=619).
In a study comparing ibuprofen 10 mg/kg (max. 800 mg) four times daily to placebo in septic
ICU patients, there was no increase in the incidence of acute kidney injury, renal replacement
therapy, bleeding, or gastrointestinal bleeding (Bernard 1997 Level II, n=455, JS 4). Interestingly, theexclusion criteria for renal dysfunction was a creatinine >354 micmol/L. Despite this, there was
no increase in renal adverse events in the ibuprofen group vs placebo. Hence, the incidence ofside effects in the critically ill may be overestimated.
8.10.6.3 | Opioids
Type of opioid
Currently, there are no head-to-head studies comparing the main opioids used in ICU. Morphineand fentanyl are the predominant parenteral opioids administered in the ICU. Analysis of the
opioid infusions in the SPICE 3 trial revealed that 80.0% of patients received fentanyl compared
to 30% receiving morphine (some patients received more than 1 opioid) (Shehabi 2019 Level II,
n=4,000, JS 5). Morphine was traditionally the first-line agent in patients without renal
impairment, whereby accumulation of the active metabolite, morphine-6-glucuronide could
potentiate the opioid effects (Casamento 2019 NR). Fentanyl has a short duration of action after
a single dose due to redistribution, but its long elimination half-life leads to accumulation when
given in high doses for long periods (Mather 1983 NR PK). The replacement of a fentanyl infusion
with enteral methadone in mechanically ventilated patients was associated with a shorter
weaning time (Wanzuita 2012 Level II, n=68, JS 4). Hydromorphone also lacks an active metabolite,
but the inactive metabolite, hydromorphone 3-glucuronide may accumulate in renal failure andresult in neuroexcitation (manifesting as delirium, altered mental status) ( Murray 2005 NR).
Parenteral oxycodone is being used more in the critical care setting, but there is a lack of
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evidence to guide its use, particularly in the setting of end-organ dysfunction. Remifentanil, due
to its pharmacokinetics, has the potential to lead to improved outcomes in ICU. However,remifentanil vs either another opioid or hypnotic agent has no benefits in mortality, durationof mechanical ventilation, ICU LOS or risk of agitation (Tan 2009 Level I, 11 RCTs, n=1,067). The
use of remifentanil is only associated with a reduction in the time to extubation after cessationof sedation (2.04 h; 95%CI 0.39 to 3.69). A subsequent study confirmed this by failing to identify
superiority of remifentanil over fentanyl in terms of analgesia, duration of ventilation or
morbidity (Spies 2011 Level II, n=60, JS 5). There are ongoing concerns about remifentanil withregard to the development of OIH and acute opioid tolerance in the perioperative setting, which
may also have implications in the ICU ( Kim 2014d Level IV SR & EH, number of studies unspecified,n unspecified).
Opioid delivery: intermittent bolus vs continuous infusion
The use of intermittent boluses of opioids has the potential benefit of decreasing the durationof mechanical ventilation, opioid-related side-effects such as gastric stasis and nausea andvomiting and development of opioid tolerance. Patients initiated on a continuous infusion offentanyl experienced more delirium than intermittent boluses of fentanyl ( Wolf 2017 Level III-2,n=60). The duration of mechanical ventilation, ICU and hospital LOS and self-extubation weresimilar between the two groups. Unfortunately, pain scores and opioid consumption were notrecorded. In another study, intermittent boluses of fentanyl were compared to parenteralparacetamol, with no difference in pain scores for 48 h in mechanically ventilated ICU patients(Kouchek 2013 Level II, n=40, JS 2).
Prolonged infusion and tolerance
In ICU patients receiving mechanical ventilation for a prolonged period, there is potential for
opioid tolerance to occur (Martyn 2019 NR). This may manifest upon cessation of the opioid witha withdrawal syndrome and delirium. In a study looking at ICU patients receiving >7 d ofcontinuous opioid and sedative infusions, abrupt cessation resulted in an acute withdrawal
syndrome in 32.1% of patients (Cammarano 1998 Level III-2, n=28). Acute withdrawal was
associated with a higher daily opioid dose. In another study of general ICU patients, the incidenceof withdrawal was 16.7%; higher median cumulative opioid dose and duration of opioid infusion>6 d were associated with withdrawal syndrome, although this study was underpowered (Wang2017b Level III-2, n=54). Hence, cautious opioid weaning should be considered in patients thathave received a high cumulative dose of opioid or have been exposed to prolonged duration of
infusion (>6 d).
See also Section 9.7 and for paediatric opioid tolerance Section 10.4.6.
8.10.6.4 | Alpha-2 agonists
The alpha-2 agonists have analgesic effects and may aid in analgesia both through the
management of psychological contributors for acute pain (eg delirium, agitation and anxiety) andthrough the avoidance of potentially antalgesic sedatives ( Frolich 2013 Level II EH, n=86, JS 2).
However with use of dexmedetomidine, there was no difference in 90-day mortality, deliriumfree or ventilator-free days, with an increased risk of adverse events, namely hypotension,bradycardia and an increased mortality in patients <65 y old (Shehabi 2019 Level II, n=4,000, JS 5).
However in one RCT, dexmedetomidine was associated with lower morphine requirements thanpropofol-based sedation after cardiac surgery (Herr 2003 Level II, n=295, JS 2). It is also of note herethat dexmedetomidine facilitated patient interaction such as the ability to use a VAS for pain
assessment vs midazolam and propofol (Ahmed 2013 Level II, n=500, JS 5).

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8.10.6.5 | Ketamine
Unlike other analgesics and sedatives in ICU, ketamine acts as a potent analgesic, sedative agent andbronchodilator that has positive effects on haemodynamics (Patanwala 2017 Level IV SR [PRISMA], 6 RCTs,
n=223 & 6 studies, n=39). Its use as an adjunct to opioid therapy reduced cumulative morphine
consumption by 27.5% in awake postsurgical ICU patients (Guillou 2003 Level II, n=101, JS 2). In
mechanically ventilated patients in a surgical ICU, administration of low-dose ketamine infusion
resulted in a decrease in morphine consumption by 20%, with a decrease in sedative requirements
and vasopressor use (Buchheit 2019a Level III-3, n=40). There was, however, an increase in the numberof patients with a Richmond Agitation-Sedation Scale (RASS) >0 (10 point scale -5 to +4). This may be
due to the psychomimetic effects of ketamine or the reduced dose of propofol sedation. Additionally,
opioid infusions were ceased within 24 h in 50% of patients receiving a ketamine infusion.
8.10.6.6 | Regional analgesia
Regional analgesic modalities are covered elsewhere (see Sections 5.6 to 5.8). The ICU patients
who may derive benefit are those that receive thoracic epidural analgesia for abdominal aortic
aneurysm surgery (Nishimori 2006 Level I [Cochrane], 13 RCTs, n=1,224 patients), traumatic rib
fractures (Carrier 2009 Level I, 8 RCTs, n=232; Stundner 2012 NR) or thoracoabdominal procedures(Popping 2014 Level I [PRISMA], 125 RCTs, n=9,044).
Furthermore, there is an increasing utilisation of peripheral nerve blocks as techniques ofregional analgesia. See also Sections 5.8 and 8.2.2.
8.10.6.7 | Guillain-Barré Syndrome
Gabapentin and carbamazepine, but not methylprednisolone, have analgesic efficacy in GuillainBarré syndrome but the evidence is limited and of low quality (Liu 2013 Level I [Cochrane], 3 RCTs, n=277).
IV lidocaine may be useful in the treatment of acute neuropathic pain in Guillain-Barré syndrome
based on evidence of benefit in other neuropathic pain disorders (Kalso 1998 Level I, 17 RCTs, n=450).
Plasma exchange in acute Guillain-Barré syndrome was associated with a shortened durationof disease and improved outcomes, including pain (Raphael 2012 Level I [Cochrane], 6 RCTs, n=649).
However, corticosteroids do not offer any benefits in this indication and may even delay
recovery, while causing adverse effects (Hughes 2012 Level I [Cochrane], 6 RCTS, n=587).
8.10.6.8 | Periprocedural analgesia
There is often an assumption that patients who are intubated and sedated in an ICU will notrecall or perceive pain during procedures. Lines and catheters are sometimes inserted without
supplementary anaesthesia. A survey suggests that specific treatment of procedure-related pain
occurs less than 25% of the time (Payen 2007 Level IV, n=1,381). Of patients who have memories
of ICU, 54% recall discomfort and 12% overt pain.
Endotracheal tube suctioning and other medical interventions are consistently reported as
being uncomfortable or painful (Jeitziner 2012 Level III-2, n=21). Therefore, adequate local and/or
parenteral anaesthesia should be provided during any noxious procedure (Casey 2010 Level II,
n=60, JS 5; Puntillo 2004 Level IV). Use of dexmedetomidine as the sole agent for painful procedures
does not reliably prevent recall or acute stress disorder (MacLaren 2015 Level II, n=23, JS 5).
Bolus remifentanil at a dose of 1 or 0.5 mcg/kg prior to removal of chest drains after cardiac
surgery was superior to placebo with the higher dose causing more respiratory depression ( Casey
2010 Level II, n=60, JS 5). In a dose-response study, the 90% effective dose (ED90) of sufentanil was
0.15 mcg/kg for turning patients during the first 5 d of sedation (Chaveron 2012 Level II, n=25, JS 5).
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KEY MESSAGES
1. Plasma exchange in acute Guillain-Barre syndrome improves outcome including
analgesia (U) (Level I [Cochrane Review]).
2. Carbamazepine and gabapentin may reduce the pain associated with Guillain-Barre
syndrome, based on limited and low-quality evidence (U) (Level I [Cochrane Review]).
3. Non-opioids including NSAIDs and paracetamol improve analgesia in selected intensive
care unit patients (S) (Level I [PRISMA]).
4. Remifentanil provides no advantages over other opioids in ventilated intensive care unit
patients (U) (Level I).
5. Ketamine decreases cumulative opioid doses in mechanically ventilated patients, withpositive effects on haemodynamics and reduced requirements for sedation, but with anincreased risk of psychomimetic adverse effects (N) (Level II).
6. The formal assessment and management of pain and agitation in ventilated intensive
care unit patients decreases the incidence of pain, the duration of ventilation, the lengthof ICU stay and mortality (U) (Level III-1).
7. Prolonged opioid infusions for >6 days and higher cumulative opioid dose increase therisk of acute withdrawal if the opioid infusion is abruptly ceased (N) (Level III-2).
8. Procedures such as endotracheal tube suctioning are consistently reported as
uncomfortable and painful (U) (Level III-2).
The following tick boxes represent conclusions based on clinical experience and expert
opinion.
 The aetiology of acute pain in critically ill patients is complex and encompasses all
domains of the sociopsychobiomedical model of pain (N).
 Observation of behavioural and physiological responses permits assessment of pain in
unconscious patients (U).
 Routine monitoring for pain in sedated intensive care patients should be performed,
using the Behavioural Pain Scale or the Critical-Care Pain Observation Tool (U).
 Analgesia management should be targeted to the potential aetiologies of acute pain (N).
 Opioids are the recommended first-line analgesic agents in ventilated intensive carepatients (U).
 The risk of NSAIDs in critically ill patients may be overestimated; NSAIDs may provide
effective analgesia as a part of multimodal analgesia (N).
 Regional analgesia techniques should be considered in patients undergoing large intraabdominal surgical procedures and trauma (N).
 Intensive care unit patients should be provided with appropriate analgesia prior to andduring potentially painful procedures, in particular as recall of discomfort, pain andprocedures can be a source of post-traumatic stress (S).

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8.11 | Acute pain management in emergency departments
Pain is the most common reason for presentation to the emergency department (ED) and many
patients will self-medicate for pain before attending (Kelly 2008 NR). Analgesia should be simple
to administer, safe, patient- and condition-specific and, where appropriate, based on localregional rather than systemic techniques. Systems should be adopted to ensure adequate pain
assessment, timely, adequate and appropriate analgesia, frequent monitoring and reassessmentof pain and additional analgesia as required.
As in many other areas of health care, patients in EDs around the world can receive
suboptimal pain management (Gueant 2011 Level IV, n=11,670), although this has been challenged(Cinar 2012 Level III-3, n=15,387; Green 2012 NR). A substantial proportion of patients in pain refuse
pain medications (Kant 2019 Level IV, n=651). Although 70% of patients presenting to an ED rated
their analgesia as “good” or “very good”, patient satisfaction with analgesia did not correlatewith pain scores at presentation or discharge or change in pain scores ( Kelly 2000 Level IV, n=54).
This indicates that other factors are involved ( Shill 2012 Level III-2, n=476) including a strong
association with staff compassion ( Brown 2018 Level IV, n=115).
Strategies to improve analgesic administration in the ED include nurse-initiated processes(Shaban 2012 Level III-3, n=52 [Australian hospital EDs]), however, nurse-initiated analgesia was not
associated with high satisfaction (Shill 2012 Level III-2, n=476). Other strategies include theintroduction of a protocol-based opioid titration regimen (Curtis 2007 Level III-3), whilst
mandatory pain scoring at triage was also associated with a faster time to analgesia (Vazirani 2012
Level III-1, n=35,628). A review of ED interventions to encourage measurement of pain, remove
barriers which delay analgesia, improve staff attitudes to pain relief, employ multi-facetedinterventions, or investigate specific departmental diagnostic analysis of problems in pain
management did not recommend wide-spread adoption of any interventions (Sampson 2014
Level III-3 SR, 42 studies, n≈76,856).
Often, procedural sedation is required as part of the analgesic management in the emergency
department. In Australian EDs, reductions of fracture/dislocated shoulders (26.7%),
wrist/forearm fractures (15.5%) and tibia/fibula fractures (13.1%) were the most common
procedures requiring additional procedural sedation ( Bell 2011 Level IV, n=2,623 (in 11 Australian
EDs). As analgesics preprocedural morphine (34.1%) and fentanyl (12.3%), either on their own or
combind with other sedative medications. Sedatives used alone were propofol (38.5%),
midazolam (10%) and ketamine (7.4%).

8.11.1 | Systemic analgesics
8.11.1.1 | Paracetamol and NSAIDs
Both paracetamol and NSAIDs are useful for treating mild to moderate trauma pain,
musculoskeletal pain, renal and biliary colic and some acute headaches, as discussed elsewhere(see Sections 4.1 and 4.2). Paracetamol and NSAIDs have comparable analgesic efficacy in adultpatients in ED with minor musculoskeletal injuries, with no significant benefit if given together(Ridderikhof 2019 Level I [PRISMA], 7 RCTs, n=2,100). However, the combination of oral paracetamol
and NSAIDs is generally more effective than the use of either agent alone in postoperative pain
(Ong 2010 Level I, 21 RCTS, n=1,909) or dental pain (Bailey 2013 Level I [Cochrane], 7 RCTs, n=2,241). In
acute musculoskeletal injuries in ED, addition of ibuprofen and codeine did not improve theanalgesic effect of paracetamol but significantly more adverse events were recorded in the
combination group (Gong 2019 Level II, n=119, JS 5). Addition of codeine or oxycodone to
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paracetamol and ibuprofen did not result in improved analgesia in patients with extremity pain
(Chang 2017 Level II, n=416, JS 5), and more adverse events occurred in the group receiving
oxycodone (Graudins 2016 Level II, n=182, JS 4).
IV paracetamol (mostly 1 g) is supported by limited evidence as a primary analgesic for acutepain in the ED based on RCTs with various methodological issues; 3 of 14 RCTs showed superior
pain relief over comparators (IV morphine 2 RCTs, IM piroxicam 1 RCT) and 8 of 14 RCTs showing
no differences in pain scores between IV paracetamol and comparators (opioids, NSAIDs, buccal
paracetamol) (Sin 2016 Level I [PRISMA], 14 RCTs, n=1,472). Two subsequent RCTs showed IVmorphine 0.1 mg/kg was superior to IV paracetamol for sciatica, with both superior to placebo(Serinken 2016 Level II, n=300, JS 2) and IV hydromorphone (1 mg) was superior to IV paracetamolin acute severe pain, again with both causing meaningful analgesia ( Barnaby 2019 Level II, n=220,
JS 5). The addition of IV paracetamol 1 g to IV hydromorphone 0.5 mg did not improve analgesia
in acute severe pain (Chang 2019 Level II, n=162, JS 3). IV paracetamol was comparable to IV
dexketoprofen in acute musculoskeletal pain (Demirozogul 2019 Level II, n=200, JS 5; Yilmaz 2019
Level II, n=200, JS 5). In a comparison of PO to IV paracetamol as analgesia following an initial doseof IV opioid, both groups had modest and comparable improvements in pain scores at 30 min,with high proportions of participants in each group requiring rescue medications ( Furyk 2018
Level II, n=142, JS 5). Consideration should be given to IV paracetamol when other analgesics arecontraindicated.
Dose comparison studies showed similar efficacy for IV ketorolac (10 mg vs 15 mg vs 30 mg)
across doses for acute moderate to severe pain in the ED ( Motov 2017b Level II, n=240, JS 4), andfor PO ibuprofen 400 mg vs 600 mg vs 800 mg (Motov 2019 Level II, n=225, JS 4). This suggests ananalgesic ceiling for NSAIDs in this setting.
For severe pain, IV parecoxib 40 mg reduced pain scores similarly vs IV morphine 0.1 mg/kg
with less adverse effects (Baharuddin 2014 Level II, n=32, JS 4). Similar results were found comparing
morphine to IV dexketoprofen (Eken 2014 Level II, n=137, JS 5), IV ibuprofen (Pan 2016 Level II, n=293,
JS 2) or PO hydrocodone/paracetamol (Pan 2018 Level II, n=206, JS 2). For soft tissue injuries, PO
naproxen 250 mg and PO oxycodone 5 mg had comparable analgesic effects, but oxycodone
required more rescue analgesic medication with higher rates of adverse effects ( Fathi 2015
Level II, n=150, JS 5).
8.11.1.2 | Conventional and atypical opioids
In the ED, opioids are frequently prescribed for the treatment of severe pain and should
preferably be titrated via the IV route, given the wide interindividual variability in dose response
and the delayed absorption via the IM or SC routes (Motov 2018 GL). There is no clear consensus
on what constitutes the most effective IV opioid and dosing regimen for analgesia in the ED. A
comparison of IV opioids to treat severe pain in the ED shows no clinically significant differencesin efficacy or adverse effects between all opioids studied (Patanwala 2010 Level I, 10 RCTs, n=2,095).
Single IV doses below 0.1 mg/kg of morphine, 0.015 mg/kg of hydromorphone or 1 mcg/kg offentanyl may be inadequate for severe acute pain without su bsequent titration. Nurse-initiatedor patient-driven protocols can provide better and faster analgesia but opioid titration is often
poorly done, leading to suboptimal dosing and analgesia (Bijur 2012 Level IV, n=281).
Higher initial opioid doses may be associated with more rapid onset of analgesia but studies
comparing high- vs low-dose titration regimens for IV morphine (Bounes 2008 Level II, n=106, JS 3)
and hydromorphone (Chang 2013a Level II, n=334, JS 3) show similar pain relief by 30 min and atrend towards fewer adverse effects in the lower dose range. Patients require close o bservation
for sedation, respiratory depression and occasionally hypotension (Coman 1999 Level IV, n=401).

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Although studies have heterogenous results, PCA in the ED is at least comparable in analgesic
effect to usual care with titrated opioid analgesia, but consistently improves patient satisfaction(Bijur 2017 Level II, n=636, JS 3; Smith 2015 Level II, n=200, JS 3; Birnbaum 2012 Level II, n=211, JS 3;
Rahman 2012 Level II, n=96, JS 3).
In patients with difficult IV access, intraosseous morphine ( Von Hoff 2008 Level II, n=22, JS 3),
IN fentanyl (Hansen 2013 Level I [PRISMA], 3 RCTs, n=301), IN hydromorphone (Wermeling 2010
Level III-1) and nebulised morphine (Grissa 2015 Level II, n=300, JS 5; Farahmand 2014 Level II, n=90,
JS 5) have similar pharmacokinetic and clinical profiles. Buprenorphine SL demonstrates effective
analgesic effects for acute pain in the ED (Vlok 2019 Level I, 9 RCTs, n=826) as did IN sufentanil inseveral RCTs (Blancher 2019 Level II, n=157, JS 5; Sin 2019 Level II, n=60, JS 5; Lemoel 2019 Level II, n=144,
JS 5). IN fentanyl 2 mcg/kg was more efficacious than IV morphine 0.1 mg/kg in adults withabdominal pain (Deaton 2015 Level II, n=40, JS 5). Oral opioids in situations with delayed or difficult
IV access are another option (Miner 2008 Level II, n=320, JS 3); oral oxycodone 0.125 mg⁄kg in asuspension vs IV morphine 0.1 mg⁄kg resulted in delayed onset of analgesia and lower patientsatisfaction but similar efficacy at 30 min. Fentanyl 200 mcg buccal tablets had similar analgesic
efficacy to PO oxycodone 10 mg/paracetamol 650 mg (Arthur 2015 Level II, n=50, JS 3).
In children requiring analgesia in the ED, fentanyl IN ( Borland 2007 Level II, n=67, JS 5), inhaled(nebulised) (Furyk 2009 Level II, n=73, JS 5) or oral transmucosal (Mahar 2007 Level II, n=87, JS 3)
provided effective analgesia (see Sections 5.5 and 10.9.1 for details). The use of IN fentanyl
improves the time to analgesia in younger children without adverse effects ( Holdgate 2010aLevel III-2, n=118).
With regard to atypical opioids, IV tramadol had similar analgesic efficacy to IV morphinein equianalgesic doses (100 to 200 mg tramadol vs 5 to 20 mg morphine) (Vergnion 2001 Level II,
n=105, JS 5). In patients with right lower quadrant pain, presumed to be due to appendicitis,IV tramadol reduced pain and did not affect the clinical examination ( Mahadevan 2000 Level II,
n=68, JS 5). For renal colic, tramadol was less effective than pethidine ( Eray 2002 Level II, n=47,
JS 1). For acute musculoskeletal pain, IM tramadol was similar to ketorolac in efficacy andadverse effects, also when both were combined with oral paracetamol ( Lee 2008 Level II, n=78,
JS 3). They were also equally effective administered SL in children with suspected fractures or
dislocations (Neri 2013b Level II, n=131, JS 5). However, for musculoskeletal pain in the ED, oraltramadol 100 mg provided inferior analgesia to hydrocodone 5mg/paracetamol 500 mg(Turturro 1998 Level II, n=68, JS 5).
Opioid-tolerant patients pose a special challenge in the ED and their management is
discussed in Section 9.7.
8.11.1.3 | Inhalational analgesics
In patients with moderate to severe traumatic pain in the ED, self-administered nitrous oxide(N2O) 65% in oxygen inhaled by face mask was effective in acute pain management vs 100%
oxygen placebo, with a low frequency of minor adverse events ( Gao 2019 Level II, n=60, JS 5).
Inhaled N2O in oxygen is more effective than oxygen as an analgesic adjunct to IV fentanyl
50 mcg for relieving pain in patients with renal colic in the ED ( Ahmadi 2018 Level II, n=120, JS 5).
The difference was evident particularly 10 min from the start of the intervention but thedifference between groups disappeared after a further dose of fentanyl.
Inhaled N2O in oxygen (see Section 4.5.1) provided effective analgesia and anxiolysis forminor procedures in both adults and children (Gerhardt 2001 Level II, n=11, JS 5; Burton 1998 Level II,
n=30, JS 5; Gregory 1996 Level II, n=28, JS 3; Gamis 1989 Level II, n=30, JS 5) and may be useful as atemporising measure while definitive analgesia is instituted (eg insertion of a digital nerve blockfor finger injury) (see also Section 10.7.4).
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Methoxyflurane (see Section 4.5.2) is used most commonly in pr ehospital emergency care.
In ED patients aged ≥12 y, methoxyflurane was significantly more efficacious than placebo,with only mild transient adverse effects such as dizziness ( Coffey 2014 Level II, n=300, JS 4). Onsetof analgesia was rapid at 4 min; peak analgesia was at 18.5 min. Safety was assessed over
14 d following administration and no significant adverse effects, including renal toxicity, were
found. Since no RCTs comparing methoxyflurane and N 2O directly have been performed, an
indirect comparison showed no significant differences between the two agents ( Porter 2018
Level I [NMA], 2 RCTs, n=263 ). As part of a multimodal analgesic protocol, methoxyflurane withparacetamol and oxycodone de creased pain in the first 5 to 10 min of care, with further
decrease in pain intensity over 1 h (Viglino 2019 Level IV, n=200).
8.11.1.4 | Ketamine
Low dose IV ketamine 0.1 to 0.3 mg/kg was considered a safe and efficacious analgesic in the
ED either as single therapy or in combination with IV morphine 0.1 mg/kg ( Karlow 2018 Level I[PRISMA], 3 RCTs, n=261; Ghate 2018 Level IV SR [PRISMA], 6 RCTs, n=544 & 2 studies, n=65 ) (2 RCTs
overlap). There are comparable improvements in pain intensity and need for rescue analgesia
when comparing IV morphine 0.1 mg/kg with low dose IV ketamine 0.1 to 0.3 mg/kg (Lee 2016aLevel I, 6 studies, n=438 ) (2 & 4 RCTs overlap). There is a higher rate of neurological andpsychological adverse events with ketamine, but more major cardiopulmonary adverse eventsin the opioid group. Administering ketamine as a 15 min infusion de creased the proportion ofpatients with adverse events (particularly feeling of u nreality and sedation) vs an IV bolus dose,with no differences in analgesic efficacy ( Clattenburg 2018 Level II, n=62, JS 5; Motov 2017a Level
II, n=48, JS 5).
As an adjunct to IV morphine, IV ketamine improves pain relief in the first 15 to 30 min andmay have a lower rate of additional analgesic requirement in the ED (Sin 2019 Level II, n=60, JS 5;
Abbasi 2014 Level II, n=220, JS 4).
IN Ketamine (0.5 to 1 mg/kg) was an effective analgesic in the ED (Shrestha 2016 Level IV, n=34;
Andolfatto 2013 Level IV, n=40; Yeaman 2013 Level IV, n=28) and had comparable effects to IV
morphine 0.1 mg/kg, but faster onset of analgesia than IM morphine 0.15 mg/kg ( Shimonovich
2016 Level II, n=90, JS 3) (see also Section 4.6.1.1).
Ketamine/midazolam was more effective and had fewer adverse effects thanfentanyl/midazolam or fentanyl/propofol for fracture reduction in children in the ED ( Migita 2006
Level I, 8 RCTs, n=1,086).
8.11.1.5 | Centrally acting muscle relaxants
Adding cyclobenzaprine (or oxycodone/paracetamol) to naproxen did not improve pain orfunctional outcome at 1 wk in patients with acute low back pain ( Friedman 2015 Level II, n=323,
JS 5). Similar results were found with with adding other centrally acting muscle relaxants toibuprofen or naproxen including orphenadrine, methocarbamol (Friedman 2018 Level II, n=240, JS5), diazepam (Friedman 2017a Level II, n=114, JS 5), or baclofen, metaxolone or tizanidine (Friedman
2019 Level II, n=300, JS 5). IM benztropine for acute non-traumatic neck pain (wry-neck) was noteffective for analgesia or to improve movement, and anti-cholinergic side effects were common(Asha 2015 Level II, n=30, JS 3)
8.11.1.6 | Lidocaine
IV lidocaine has mixed results in treatment of painful conditions presenting to ED ( Silva 2018 Level
IV SR, 6 RCTs and 2 studies, n=536; Masic 2018 Level IV SR, 4 RCTs & 9 studies, n= 512) (4 RCTs overlap).

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5th Edition | Acute Pain Management: Scientific Evidence8.0 | SPECIFIC CLINICAL SITUATIONSThere is limited evidence for effectiveness in critical limb ischaemia and renal colic when vsIV morphine, but inferior to standard treatments for migraine and no better than NSAIDs forradicular low back pain. IV lidocaine 1.5 mg/kg was as effective as IV morphine 0.1 mg/kg for
decreasing pain scores in patients with extremity fractures experiencing moderate or severe pain
(Farahmand 2018 Level II, n=50, JS 5; Forouzan 2017 Level II, n=280, JS 2). IV lidocaine was as effective
as IV morphine in patients with undifferentiated severe pain in the ED, and could provide an
opioid-sparing effect (Clattenburg 2019 Level II, n=32, JS 3), but was less effective thanIV hydromorphone (Chinn 2019 Level II, n=154, JS 5). Safety data is limited with 20 adverse events(rate 8.9%; 95%CI 5.5% to 13.4%) (6 studies, n=225) reported with use of IV lidocaine in the ED(19 nonserious and 1 classified as serious) (Silva 2018 Level IV SR, 6 RCTs and 2 studies, n=536).
IN lidocaine did not improve analgesia when used as an adjunct to metoclopramide for thetreatment of migraine (Avcu 2017 Level II, n=162, JS 5).
8.11.1.7 | Corticosteroids
In low back pain, corticosteroid administration for analgesia has mixed results. For patients withlow back pain with radiculopathy, in addition to routine care, a single dose of IV dexamethasone
8 mg was better than placebo in reduction of 24 h pain scores and decreased ED LOS but had noeffect on functional scores (Balakrishnamoorthy 2015 Level II, n=58, JS 5). However, a 5 d course oforal prednisone 50 mg for patients discharged from ED with acute low back pain showed nobenefit (Eskin 2014 Level II, n=79, JS 5).
For the treatment of acute gout in ED, prednisolone (30 mg/d) was as efficacious asindomethacin (initially 50 mg three times per d) in the first 2 h after commencement oftreatment in ED, and for the subsequent 2 wk (Rainer 2016 Level II, n=416, JS 5). Paracetamol wasused in both groups. Prednisolone was associated with a lower incidence of adverse events,
particularly gastrointestinal symptoms. These findings were confirmed in a systematic review,
where only two of the RCTs recruited patients in the ED (Billy 2018 Level I, 6 RCTs, n=817). There isinsufficient evidence for the use of IA corticosteroids for the treatment of gout ( Wechalekar 2013
Level I, 0 RCTs, n=0). Low dose colchicine is also recommended as treatment for acute gout, but
no studies have compared corticosteroids and colchicine (van Echteld 2014 Level I [Cochrane],
2 RCTs, n=124).

8.11.2 | Analgesia in specific conditions
8.11.2.1 | Abdominal pain
Patients and physicians differ in their assessment of the intensity of acute abdominal pain in theED, with physician estimates of severity of abdominal pain being significantly lower than patientreports (Marinsek 2007 Level IV, n=185). Administration of analgesia correlated with the physician’s
assessment of a pain score greater than 60/100. A patient’s satisfaction with analgesia correlatedwith a reduction in pain of at least 20/100 and titration of analgesia to the patient’s pain reports.
Nevertheless, 60% of patients presenting to the ED with abdominal pain were satisfied with theiranalgesia on discharge. It is therefore reassuring that in patients presenting with abdominal pain
to an ED (over a 10 y period) analgesia administration increased and time to administration
decreased (Cinar 2013 Level IV, n=2,646).
Early pain relief (usually in the form of opioids) does not interfere with the diagnostic process
in acute abdominal pain in adults (Manterola 2011 Level I, 8 RCTs, n=922; Kang 2015 Level II, n=213, JS5) or in children (Green 2005 Level II, n=108, JS 5; Kim 2002 Level II, n=60, JS 5) and does not lead toincreased errors in clinical management (Ranji 2006 Level I, 12 RCTs, n=1,389).
See also Section 8.6.1.
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8.11.2.2 | Renal colic
NSAIDs are effective in the treatment of renal colic vs placebo or antispasmodics (Afshar 2015
Level I [Cochrane], 50 studies, n=5,734). For renal colic in patients with adequate renal function,
treatment with NSAIDs provides effective and the most sustained pain relief, with fewer side
effects, vs IV opioids or IV paracetamol (Pathan 2018 Level I, 36 RCTs, n=4,887; Al 2018 Level II, n=300,
JS 4; Cenker 2018 Level II, n=200, JS 4).
For renal colic, the onset of action of NSAIDs is faster when given IV vs IM, PO or PR
administration (Tramer 1998 Level I, 26 RCTs, n=2,225).
See Section 8.6.1.2
8.11.2.3 | Biliary colic
NSAIDs significantly reduce biliary pain and complications (eg acute cholecystitis, acutepancreatitis, jaundice, cholangitis) vs placebo or spasmolytic drugs (Fraquelli 2016 Level I[Cochrane], 12 RCTs, n=828).
See Section 8.6.1.3.
8.11.2.4 | Acute cardiac chest pain
See Section 8.6.3.
8.11.2.5 | Acute pain and sickle cell disease
See Section 8.6.4.1 and in children see Section 10.9.5.1.
8.11.2.6 | Headache
While a number of different classes of medicines are effective in the treatment of acute migraine,other more serious causes of headache, particularly subarachnoid haemorrhage and CNS
infection, should always be considered during clinical assessment ( American College of Emergency
Physicians Clinical Policies Subcommittee on Acute Headache 2019 GL). Clinical improvement withmedication directed at migraine relief is not specific and does not rule out alternative causes ofheadache (Pfadenhauer 2006 Level IV).
Simple treatment with oral NSAIDs, especially aspirin, is effective in ED patients with migraine
who are not vomiting (Kirthi 2010 Level I [Cochrane], 13 RCTs, n=4,222). In patients unable to tolerateoral therapy, phenothiazines such as chlorpromazine and prochlorperazine (Kelly 2009 Level I,
13 RCTs, n=917), selective serotonin agonists especially sumatriptan ( Derry 2012 Level I [Cochrane],
35 RCTs, n=9,365) and butyrophenones (however with significant adverse effects) ( Leong 2011
Level I, 6 RCTs, n=574) provide effective analgesia in up to 80% of patients in the ED. A systematic
review of treatment of migraine pain in ED settings supports these results with strong evidence
in favour of prochlorperazine and moderate evidence for chlorpromazine, metoclopramide,sumatriptan and IV lysine acetylic acid (Orr 2015 Level I [PRISMA], 44 RCTs, n unspecified). A
subsequent systematic review confirmed these results with neuroleptics providing the greatest
pain reduction in the first h, with metoclopramide and NSAIDs also providing significant relief,
but combinations of medications were not superior to single agents (Westafer 2018 Level I,
40 studies, n=3,489) (significant overlap between all SRs).
Dexamethasone is recommended to prevent headache recurrence vs placebo (OR 0.60;
95%CI 0.38 to 0.93) (3 RCTs, n=358) (Orr 2016 Level I, 68 RCTs, n unspecified). Recurrence following
discharge from ED was comparable between IM dexamethasone 10 mg or IM

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methylprednisolone acetate 160 mg given in ED with IV metoclopramide ( Latev 2019 Level II,
n=220, JS 5).
IV Paracetamol 1 g was comparable to IV dexketoprofen 50 mg for acute migraine ( Turkcuer
2014 Level II, n=200, JS 5). The addition of IV paracetamol to prochlorperazine anddiphenhydramine for the treatment of headache resulted in an improvement of pain score andless need for rescue analgesia (Meyering 2017 Level II, n=90, JS 5) although there has been no directcomparison of adjunctive PO versus IV paracetamol.
Opioids are not recommended in the treatment of migraine or acute primary headache as
the recommended medicines provide superior analgesia in comparisons with fewer adverse
effects (American College of Emergency Physicians Clinical Policies Subcommittee on Acute Headache
2019 GL; Orr 2015 GL; Worthington 2013 GL) The following medications demonstrated worse or no
better analgesia than standard treatment: IV ketamine (Etchison 2018 Level II, n=34, JS 5; Zitek 2018
Level II, n=54, JS 5), IN ketamine (Benish 2019 Level II, n=53, JS 5), caffeine (Derry 2014a Level I[Cochrane], 20 RCTs, n=7,238; Baratloo 2016 Level II, n=110, JS 5), IV valproate (Friedman 2014b Level II,
n=330, JS 5), magnesium (Miller 2019 Level I [PRISMA], 7 RCTs, n=545), and propofol (Moshtaghion2015 Level II, n=91, JS 5). The addition of IV fluids to standard therapy had no effect on analgesia(Jones 2019a Level II, n=49, JS 5; Balbin 2016 Level III-2, n=570).
Evidence-based recommendations for the treatment of migraine in ED settings are published(Orr 2015 GL).
See Section 8.6.5 for a more detailed review of the treatment of migraine and other acuteheadache syndromes and Section 10.9.3 for migraine treatment in children.
8.11.2.7 | Hip fracture
Regional blockade reduces pain after hip fracture, and is associated with a de creased risk ofpneumonia, reduced time to mobilisation, and reduced cost of analgesia ( Guay 2017 Level I[Cochrane], 31 RCTs, n=1,760). Regional nerve blockade in the ED is at least as effective and possiblysuperior to standard analgesia (opioids or NSAIDs) after a hip or femoral neck fracture anddecreases overall opioid consumption (Ritcey 2016 Level I, 9 RCTS, n=447). FICB (Steenberg 2018
Level I, 11 RCTs, n=1,062), FNB (Riddell 2016 Level I, 7 RCTs, n=224) or 3-in-1 blocks (4 RCTs, n=199)(Ritcey 2016 Level I [PRISMA], 9 RCTs, n=547) are superior to systemic opioids in reducing pain on
movement, decrease preoperative opioid requirements and lengthen time to rescue analgesia.
These findings are consistent even in patients with dementia (Unneby 2017 Level II, n=266, JS 2).
Although opioids alone are not particularly effective in providing analgesia and have thepotential for significant adverse effects such as respiratory depression and delirium in the older
patient cohort, regional nerve blocks are underutilised in EDs in Australia (Holdgate 2010b Level IV,
n=646) and the United Kingdom (Rashid 2014 Level IV, n=147 [responding EDs]).
Guidelines to direct care of hip fracture patients are published ( ANZFHR Steering Group 2014
GL); integrated orthogeriatric care, utilisation of care bundles and adherence to clinical carestandards improves outcomes in hip fracture patients (ACSQHC 2016 GL).
For more details, see also section 8.4.
8.11.2.8 | Shoulder dislocation
The majority of shoulder dislocations requiring reduction in an ED occur with procedural sedation
and analgesia. Entonox® (inhaled N2O:Oxygen) as a single agent is not as effective as procedural
sedation using fentanyl and midazolam with regard to analgesia and patient satisfaction(Mahshidfar 2011 Level II, n=120, JS 3).
IA lidocaine (injected via landmark technique) for anterior shoulder dislocations provides
analgesia comparable to systemic analgesics with fewer adverse effects (Wakai 2011 Level I
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[Cochrane], 5 RCTs, n=211; Jiang 2014 Level I, 9 RCTs, n=438) (5 RCTs overlap). US guided suprascapularnerve block (Tezel 2014 Level II, n=41, JS 2) and ultrasound guided interscalene block (Blaivas 2011
Level II, n=42, JS 2) showed similar benefits.

8.11.2.9 | Wounds
Local anaesthesia is frequently required for the treatment of wounds in the ED. Agents mostcommonly used for local infiltration are lignocaine or the longer acting bupivacaine, ropivacaine
or levobupivacaine, depending on the duration of anaesthesia required and whether analgesia
following the procedure is desirable.
It is less painful to infiltrate local anaesthesia by injection through the wound rather than in
the tissues surrounding it (Bartfield 1998 Level II, n=63, JS 4). Buffering of lignocaine withbicarbonate reduces the pain of infiltration, particularly when using lignocaine with adrenaline(Cepeda 2010 Level I [Cochrane], 23 RCTs, n=1,067).
Digital nerve block with 0.75% ropivacaine significantly prolonged analgesia and reduced
rescue analgesia requirements to 24 h, without a clinically significant increase in time to block
onset vs 2% lignocaine (Keramidas 2007 Level II, n=70, JS 2).
Topical application of local anaesthetics has advantages over local injection although there islittle evidence to choose one preparation over another for use on simple lacerations ( Tayeb 2017
Level I [Cochrane], 25 RCTs, n=3,278). Topical tetracaine, liposome-encapsulated tetracaine, andliposome-encapsulated lignocaine are as effective as EMLA® cream for dermal instrumentation(eg cannulation) analgesia in the ED (Eidelman 2005 Level I, 25 RCTS, n=2,096). For simple lacerations
in children, topical anaesthetic preparations such as ALA (adrenaline, lignocaine, amethocaine)are effective alternatives to infiltration with local anaesthesia without the pain of local injection(Ferguson 2005 Level I, 7 RCTs, n=1,260). Topical lignocaine and adrenaline applied to a wound insequential layers significantly reduced reports of pain during initial application vs a 2% lignocaine
injection, but with no difference in pain scores during suturing (Gaufberg 2007 Level II, n=100, JS 3).
A topical gel dressing containing morphine was no more effective than other gel dressings in
reducing burns injury pain in the ED (Welling 2007 Level II, n= 49, JS 3).

8.11.3 | Nonpharmacological management of pain
Although analgesic agents may be required to treat pain in the ED setting, the importance ofnonpharmacological treatments should not be forgotten. These include ice, elevation andsplinting for injuries and explanation of the cause of pain and its likely outcome to allay anxiety.
Psychological techniques such as distraction, imagery or hypnosis may also be of value (seeSections 7.1 and 10.7.5).
In young children, interventions such as distraction, positioning, sucrose and cold application
may be helpful to manage pain in the ED (Wente 2013 Level IV SR, 14 studies, n=1,459).
In general, acupuncture is comparable to standard analgesic care, and provides superior
analgesia when used as an adjunct to standard care in the ED ( Jan 2017 Level I [PRISMA], 14 RCTs,
n=1,210). This included studies of renal colic and back pain. Ear acupuncture shows significant
improvements in pain score vs sham acupuncture or standard analgesic care and when used as
an adjunct to standard care (Jan 2017 Level IV SR [PRISMA], 4 RCTs, n=286 & 8 studies, n=458).
Acupuncture had lower pain scores at 60 min vs morphine 0.1 mg/kg in the treatment of patientswith renal colic in the ED (Beltaief 2018 Level II, n=115, JS 5). Acupuncture and/or standard
pharmacotherapy provided comparable reductions in pain within 1 h of administration for backpain, ankle sprain or migraine (Cohen 2017 Level II, n=528, JS 3). For more details see Section
7.3.2.1.

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Spinal manipulation or exercise therapy for patients presenting to ED with nonradicular low
back pain of less than 12 wk duration is no more effective than analgesic pharmacotherapy alone(Rothberg 2017 Level I, 2 RCTs, n=344 [spinal manipulation]; 4 RCTs, n=930 [exercise therapy] ).
Physical interventions (physical therapy, mobilisation, mechanical support, manipulation),
direct interventions (acupuncture, TENS, ultrasound), and indirect interventions (music therapy,
aromatherapy, hypnosis, guided imagery) initiated in the ED, all significantly reduce pain vscontrols in the short term (immediately in ED) and up to 12 wk later ( Sakamoto 2018 Level I[PRISMA], 7 RCTs, n=593 [physical interventions]; 9 RCTs, n=975 [direct interventions]; 4 RCTs, n=375[indirect interventions]). However, most of the included studies had high risk of bias, variable

outcome measures, and heterogeneity across interventions.

KEY MESSAGES
1. Paracetamol, in particular if administered IV, and NSAIDs are effective primary
analgesics for use in the emergency department (N) (Level I [PRISMA]).
2. Sublingual buprenorphine (N) (Level I [PRISMA]) or intranasal fentanyl (N) (Level I) are
effective alternatives to parenteral opioids in the emergency department.
3. Low dose ketamine is a safe and effective analgesic alone or when combined with
opioids in the emergency department, but increases neuro-psychological adverse
events (N) (Level I [PRISMA]).
4. Appropriate doses of intravenous opioids are effective in treating acute severe pain in
the emergency department and ideally should be titrated according to nurse-initiatedand patient-driven protocols; there is no preference for a specific opioid (U) (Level I).
Abdominal pain
5. Provision of analgesia does not interfere with the diagnostic process in acuteabdominal pain and does not increase the risk of errors in clinical management (U)(Level I [Cochrane Review]).
Migraine
6. NSAIDs, triptans (S) (Level I [Cochrane]), phenothiazines (prochlorperazine,
chlorpromazine), butyrophenones and metoclopramide are effective to treat migraine
in the emergency department (U) (Level I).
Fractured neck of femur
7. Lower limb nerve blocks with local anaesthetics reduce pain, analgesia requirements
and lengthen time to rescue analgesia in hip fracture patients compared to systemic
analgesia; there is no advantage of a specific nerve block, insertion technique orcontinuous versus single injection administration (S) (Level I [Cochrane Review]).
Shoulder Dislocation
8. Intra-articular local anaesthetics provide comparable analgesia for reduction of glenohumeral dislocation to procedural sedation and analgesia methods with fewer adverse
events (N) (Level I [Cochrane Review]).
Wounds
9. Buffering of lignocaine with bicarbonate reduces the pain of infiltration, particularly
when using lignocaine with adrenaline (U) (Level I [Cochrane Review]).

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10. Topical local anaesthetic agents (including those in liposomal formulations) (S) (Level I[Cochrane Review]) or topical local anaesthetic-adrenaline agents (U) (Level II) provide
effective analgesia for wound care in the emergency department.
Musculoskeletal Pain
11. Centrally acting muscle relaxants do not improve analgesia in the acute treatment oflower back pain (N) (Level II).
Non-pharmacological management of pain
12. Acupuncture may provide effective analgesia as a single agent or adjunct in theemergency department (N) (Level I [PRISMA]).
The following tick box represents conclusions based on clinical experience and expert
opinion: To ensure optimal management of acute pain, emergency departments should adopt
systems to ensure adequate assessment of pain, provision of timely, adequate andappropriate analgesia, frequent monitoring and reassessment of pain (U).

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8.12 | Prehospital analgesia
The previous section considered management of acute pain in patients admitted to EDs.
However, many of these patients will also have required prehospital pain relief while under
the care of paramedic or medical retrieval teams. While the term “prehospital” is also used tocover a greater variety of prehospital locations, it is beyond the scope of this document to lookat pain relief administered in more complex situations such as medical retrievals, interhospitaltransfers, wilderness medicine, medical coverage for large public gatherings and disaster or
war settings.
Although there is a paucity of specific research (particularly RCTs), the literature consistently
suggests that substantial improvement in the provision of prehospital analgesia is needed (Parker
2015 NR), and a possible link between poor quality prehospital analgesia and post-traumaticstress disorder has been raised (Parker 2015 NR; Ellerton 2014 NR).
Pain may require management prior to and during transport, and the nature of theprehospital environment presents many challenges in addition to most of the issues seen in thehospital. These issues are often related to the relative paucity of resources, fewer treatment
options (including medications and equipment), and a working environment where light, soundand issues of hygiene will impact on how pain can and should be managed. Furthermore, thepatient is often in the acute or evolving stage of their condition, which may change rapidly.
Guidelines for prehospital analgesia have been published (Gausche-Hill 2014 GL) as well as thosefor treatment of pain in remote environments (Russell 2014 GL) and a systematic review ofguidelines (Yousefifard 2019 GL SR).

8.12.1 | Incidence and undertreatment of acute pain in prehospital settings
Pain in the prehospital setting is common, with pain severity rated as moderate to severe in up
to 64% of ambulance patients (Galinski 2010 Level IV, n=2,279). In these patients, the factors
associated with severe pain were cardiac pain and trauma, yet the proportion of patients given
analgesics (opioid or inhalational) prior to transfer to an ED varies significantly. Subsequent
surveys of ambulance services report an incidence of 28% of moderate to severe pain during
ambulance transport (Friesgaard 2018 Level IV, n=41,241) and an incidence of 17% of severe andintolerable pain in ambulance attendances for trauma (Hebsgaard 2016 Level IV, n=985).
Factors associated with under-treatment of pain in a setting of physician-managed
prehospital care were severe pain at initiation of treatment (OR 8.8; 95%CI 5.1 to 15.2),
treatment by a female physician (OR 2.0; 95%CI 1.0 to 4.0), and relative inexperience of thephysician measured in years of postgraduate experience (4 to 5 y [OR 1.3]; 3 to 4 y [OR 1.6]; 2 to
3 y [OR 2.6]; < 2.0 y [OR 16.7]) (Albrecht 2013 Level IV, n=1,202 [patients] & n=77 [emergency
physicians]). In a subsequent study, male patients were more likely to receive opioids thanfemales (OR 1.5; 95%CI 1.29–1.79), while sex of the paramedic did not influence opioid use (Lord2014 Level III-3, n=42,051). Other factors reported to be associated with under-treatment of pain
include children <15 y and non-white ethnicity in the USA (Hewes 2018 Level IV, n= 276,925[ambulance attendances]) Another single municipality study from the USA showed that analgesia
after falls was provided to 8.2% of patients with factors influencing this rate being ethnicity (lessoften to black vs white patients (OR 0.19; 95%CI 0.08 to 0.44)), an initial higher pain score (9.1/10[95%CI 8.7 to 9.5] vs 5.8/10 [95%CI 5.5 to 6.2]) and injury location (extremity and hip injury vshead and neck injury) (Infinger 2014 Level IV, n=1,200).

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Pain in children is less often assessed and treated than in adults ( Browne 2016 Level IV,
n=1,368 [paediatric ambulance attendances]; Rahman 2015a Level IV, n=202 [paramedics] ) In
paediatric patients <15 y, 55% with severe pain (8/10) did not receive any analgesia ( Lord2016 Level IV, n=38,167 [ambulance records ]). In paramedic led services, barriers to providing
pain relief to paediatric patients were concerns about pain and fear caused by IV cannulation(59.5%), parental influences (51.6%), difficulty assessing pain in children (47.2%), and concerns
about allergic reactions (45.6%) ( Whitley 2017 Level IV, n=127 [paramedics]). Other factors wereperceived negative attitudes from receiving EDs (30.4%) and negative scrutiny fromsupervisors (11.8%). Similarly to adults, non-white ethnicity was associated with less painscore documentation (OR 0.52; 95%CI 0.44 to 0.62) and provision of analgesics (OR 0.64; 95%CI
0.50 to 0.82) (Johnson 2014 Level IV, n=5,057). In children and adolescents (0 to 15 y) admitted
to a burns centre within 24 h of injury, pre-burn-centre analgesic administration (paracetamol,
NSAID and/or opioid) increased over time (68 to 79%: from 2002-2004 to 2007-2008); flame
burns and more extensive burns were predictors of receiving pre-burn-centre analgesics,
whilst transfer/referral by ambulance services or general practitioners were predictors of notreceiving pre-burn-centre analgesics (Baartmans 2016 Level III-3, n=622). For paediatricinformation, see Section 10.9.1.1.
In a survey of a number of emergency services in the Netherlands, nonpharmacological pain
control was used in less than 50% of trauma cases, pharmacological treatment deviated fromguidelines in 73 to 99% and time of administration of medication was not documented in 73 to
100% of cases (Scholten 2015 Level IV, n=1,066). Similarly in Germany, patients with a hip fracturereported an average pain score of 6.8/10 ( 2.7) with 22% rating their pain as 10/10; however
only 28% received analgesia despite its effectiveness (mean pain score reduced from 7/10 [ 2.6]
to 2.8 [ 1.4] at hospital arrival) (Oberkircher 2016 Level III-2, n=156) (See also Section 8.4). In thesetting of a Swiss helicopter rescue service, patients who received pain management had higher
initial pain scores (7.4/10  2.0) vs those who did not (2.8/10  1.8) (Eidenbenz 2016 Level IV,
n=1,156). Beside high pain scores, diagnosis of a fracture was associated with increased analgesic
use. Fentanyl (84%) was preferred over ketamine (14%), but ketamine was preferred by moreexperienced doctors and those with an anaesthesia background.
The presence of cognitive impairment in patients managed by ambulance staff isassociated with markedly less analgesic administration despite having significant injuries(McDermott 2014 Level IV, n=224). “Unnecessary pain” was the second most common type of
injury in 56 of 272 claims against ambulance trusts in the UK between 1995 and 2005 ( Dobbie
2008 Level IV).
A survey of adult patients with suspected extremity fractures showed that just 18 (1.7%) were
given any analgesia and only 2 received morphine (White 2000 Level IV, n=1,073). A later survey
showed that only 12.5% of patients with isolated extremity injuries received any prehospitalparenteral pain relief (Abbuhl 2003 Level IV, n=706). This trend continues with older patients andthose with hip fractures being less likely to be given analgesia prior to arrival in the ED (McEachin2002 Level IV, n=124). In contrast, another group reported that 51% of elderly patients with afractured neck of femur were given prehospital analgesia; methoxyflurane in 47% of cases, N2O
in 10% and morphine in 6% (Vassiliadis 2002 Level IV, n=176).
A large (NSW Ambulance service) audit of ambulance patients who received analgesia foundthat 87% of all patients received single analgesic therapy (Bendall 2011b Level IV, n=97,705).
Overall, inhaled methoxyflurane was the most commonly used analgesic (given to 60% of
patients), followed by morphine IV (26%) and fentanyl IN (19%).

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8.12.2 | Opioid use in the prehospital setting
Despite concerns about opioids in the community, prehospital use of these medications may be
increasing. In a 2005 survey, 29% of patients with isolated extremity injuries were given
morphine (Michael 2007 Level IV, n=953) and 13% of females and 17% of males in pain were given
morphine (Lord 2009 Level IV, n=3,357). Adequate use of morphine during the early treatment of
acute pain after military trauma may significantly reduce the risk of developing post-traumaticstress disorder (OR 0.47; 95%CI 0.34 to 0.66) (Holbrook 2010 Level III-2, n=696). With use of
systemic opioids, 60 to 70% of prehospital care patients have pain scores above 30/100 at
10 min, falling to 30% at 30 to 40 min (Park 2010 Level I, 21 RCTs, n=6,212). Only two patientsrequired naloxone and none needed ventilatory support.
The trend towards increasing opioid use is not universal in adults, and certainly does notseem to flow through to the paediatric patients seen in the prehospital environment. One
study of children with fractures or soft tissue injuries reported that 37% received prehospital
analgesic medicines (Rogovik 2007 Level IV, n=310). Another, which included patients with adiagnosis of limb fracture or burns, reported that analgesia was given to 51% of children
between the ages of 5 and 15 y, but not to any child aged <5 y; a greater proportion of thisyounger group (70 vs 54%) were given opioid analgesia once in the ED ( Watkins 2006 Level IV,n=45). Undertreatment in children under 5 y of age is a repeated finding of many prehospital
investigations. A large study of adult and paediatric ambulance patients found that when asingle agent was used, females were less likely to receive opioid analgesia than males (RR 0.83;
95%CI 0.82 to 0.84) ( Bendall 2011b Level III-2, n=97,705). In contrast to the earlier series above,
opioid use increased with increasing age; those aged >60 y were the most likely to receive
opioids. While, children were less likely to receive opioids vs methoxyflurane (RR 0.65; 95%CI
0.63 to 0.67) and when given, IN fentanyl was the most common opioid. Prehospitaladministration of opioids to children (and assessment of pain intensity) occurred infrequently
despite implementation of several best practice recommendations in a USA ambulanceservice; factors associated with opioid use were presence of vascular access (OR 11.89; 95%CI
7.33 to 19.29), longer patient transport time (OR 1.07; 95%CI 1.04 to 1.11), age (OR 0.93; 95%CI
0.88 to 0.98) and pain score documentation (OR 2.23; 95%CI 1.40 to 3.55) ( Browne 2016 Level
IV, n= 1,368 [paediatric ambulance attendances] ).

8.12.3 | Principles of management of acute pain in the prehospital setting
Although pain relief has been acknowledged as a key area for investigation, evidence regarding
management of acute pain in patients in the prehospital setting remains limited. Many analgesic
techniques that work in hospital environments have been transcribed to the prehospitalenvironment, but these do not always comply with the ideal of simplicity, safety and effectivenesswhen used in the field. Attitudes toward analgesia by the prehospital caregivers may be anotherfactor in the apparent underuse of prehospital analgesia. In a small survey of experienced
paramedics, the following themes arose as reasons why analgesia was withheld: reluctance toadminister opioid unless there were significant signs (for example an obvious fracture), concerns
regarding malingering behaviour, uncertainty regarding the endpoint (“pain free” or “take the edgeoff”), concern regarding analgesia masking diagnostic symptoms and a reluctance to use larger
initial opioid doses (>5 mg morphine) (Walsh 2013 Level IV, n=15 [paramedics]).
System wide interventions in an emergency medical service including education andimplementation of a pain management protocol resulted in increased frequency of opioid
administration, but only a limited and not sustained increase in pain score documentation ( Haley
2016 Level III-3, n=15,228; Brown 2014 Level III-3, n=3,491). Telemedically delegated analgesic
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administration by paramedics in ambulances following an algorithm vs physician-administeredanalgesia was safe and similarly effective (Brokmann 2016 Level III-3, n=160).
Table 8.4 | Factors that influence the provision of prehospital analgesia and the direction ofthis influence
Factors

Negatively affected by:

Variably affected by:

Patient

Paediatric patients
Female sex
Physiological instability
Comorbidities

Reported pain score
CultureSeverity of injury

Clinician

Perceived negative response from receiving
hospital
Concerns regarding IV cannulation inchildrenLack of training
Lack of confidence
Fear of adverse events

Other

Guardian/parental refusal in paediatrics
Presence/lack of IV accessResource limitations
Limitation of therapeutic options
Urgency of transport(compiled from Hewes 2018; Whitley 2017; Samuel 2015; Rahman 2015a; Albrecht 2013)

8.12.4 | Assessment of pain in the prehospital environment
As in other settings, pain intensity is best assessed using patient self-report measures such as
VAS (Galinski 2005 Level II, n=54, JS 4; Kober 2002 Level II, n=60, JS 5), VNRS (Bounes 2008 Level II, n=106,
JS 5; Rickard 2007 Level II, n=258, JS 3; McLean 2004 Level IV, n=1,227; Woollard 2004 Level II, n=175, JS 3),
VDS (Vergnion 2001 Level II, n=105, JS 5; McLean 2004 Level IV, n=1,227) or faces pain scale (Rogovik
2007 Level IV, n=301). In a comparison between VAS and VNRS in the prehospital setting, both
performed comparably (r 0.87 to 0.93) with a preference by patients and paramedics for VNRS(Ismail 2015 Level III-2, n=133). A ruler incorporating both visual analogue and faces pain scales has
also been used to measure pain in patients prior to arrival at hospital (Lord 2003 Level IV). A cohort
study of ambulance patients having had acute trauma showed that patients had poor recall of
initial pain scores at 1–2 d after injury (Easton 2012 Level III-3, n=88). In some instances, it may not
be possible to obtain reliable self-reports of pain (eg patients with impaired consciousness or
cognitive impairment, young children [see Section 10.3], elderly patients [see Section 9.2.2], or
where there are failures of communication due to language difficulties, inability to understandthe measures, unwillingness to cooperate or severe anxiety). In these circumstances othermethods of pain assessment based on observation of patient behaviours should be used. For
further details on assessment tools, see Chapter 2.
In a survey of a number of emergency services in the Netherlands, standardised tools toassess pain in trauma patients were used in 0 to 52% (depending on the service); reassessmentof pain following treatment was only performed in 50% of patients under the care of a helicopterbased service, and not performed by any other services (Scholten 2015 Level IV, n=1,066).

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8.12.5 | Systemic analgesics
The ideal prehospital analgesic agent should be simple to use, safe (both in terms of side effects
and adverse effects on the patient’s condition), effective, not lead to delays in transport andhave a rapid onset and short duration of action, so that it can be repeated as often as necessary
and titrated to effect for each patient (Alonso-Serra 2003 NR). Consideration should be given toboth choice of analgesic medicine and route of administration.
In a systematic review, PO and IV paracetamol and IV opioids (morphine and fentanyl) are
identified as effective analgesics in the prehospital trauma setting, while results for NSAIDs are
mixed (Dijkstra 2014 Level IV SR, 10 RCTs & 15 studies [12 prehospital], n=5,339).
8.12.5.1 | Paracetamol and NSAIDs
The use of parenterally administered paracetamol and NSAIDs has been suggested forprehospital analgesia (McManus 2005 NR; Alonso-Serra 2003 NR) and their use seems to be
increasing. However, their slower onset of effect as well as the risk of adverse effects (egbleeding, renal impairment; see Section 4.2), especially in patients who have lost blood and may
be hypovolaemic, means they are often overlooked ( Scholten 2015 Level IV, n=1,066). Similarly,
injectable paracetamol is not commonly used. Oral paracetamol or other analgesics may have alimited role in the prehospital management of moderate to severe pain.
8.12.5.2 | Conventional and atypical opioids
The administration of systemic opioids as an effective prehospital analgesic is widespread in
ambulance services staffed by paramedics. Their application is influenced by the knowledge andjudgment required to use them and the differing legislation for the drugs of dependence
between countries. In this setting, use of IV or IN routes will enable a more rapid and predictable
onset of action than other routes of administration. Opioids should not be administered IM/SC
in the prehospital environment, because of unpredictable pharmacokinetics in the poorly
perfused patient. Following resuscitation, morphine may undergo reabsorption from earlier IM
administration, which may lead to a potential risk of delayed adverse effects.
Both morphine and fentanyl are commonly used for prehospital analgesia. Morphine(Friesgaard 2016 Level IV, n=2,348; Fullerton-Gleason 2002 Level IV; Bruns 1992 Level IV, n=69), fentanyl(Kanowitz 2006 Level IV, n=2,129) and tramadol (Ward 1997 Level IV, n=142) have been shown toprovide effective and safe pain relief in patients being transported by road. Fentanyl was also
safe and effective when given to patients during helicopter transportation ( Krauss 2011 Level IV,
n=1,055; Thomas 2005 Level IV, n=213 [doses in 177 patients]). Morphine was the most used opioidby the NSW ambulance service, followed by fentanyl, then ketamine (with no difference in therate of vomiting between all three) (Zhang 2018 Level III-3, n=196). IV fentanyl in a dose of 1 to
3 mcg/kg is an effective analgesic in the prehospital care of children ( Samuel 2015 Level IV SR, 19
studies [13 paediatric, 6 mixed adult/paediatric], n>67,287).
IV morphine doses of 0.1 mg/kg followed by 0.05 mg/kg every 5 min as needed provided
more rapid pain relief and patient satisfaction than doses that were 50% lower ( Bounes 2008
Level II, n=106, JS 5). Similarly, a liberal treatment protocol (3 mcg/kg) vs a standard treatment
protocol (2 mcg/kg) of fentanyl administration resulted in use of higher doses (117.7 mcg[95% CI 116.7 to 118.6] vs 111.5 mcg [95%CI 110.7 to 112.4]) with a higher proportion of patientsachieving sufficient pain control (44.0% [95%CI 41.8 to 46.1] vs 37.4% [95%CI 35.2 to 39.6];
aOR 1.47 [95%CI 1.17 to 1.84]) (Friesgaard 2019 Level II, n=5,737, JS 3).
Comparisons of IV fentanyl and morphine bolus for prehospital analgesia demonstrated nodifference in analgesic efficacy or incidence of adverse effects (Galinski 2005 Level II, n=54, JS 4).
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This was also confirmed in ischaemic chest pain (Weldon 2016 Level II, n=207, JS 5). Similarly, there
was no difference in pain relief or adverse effects reported in a comparison of IV tramadol andmorphine (Vergnion 2001 Level II, n=105, JS 5).
A comparison of IV nalbuphine 5 mg and 10 mg given and repeated at 3 min intervals to a
total of 20 mg showed that use of the larger dose led to better pain relief but higher patientreported drowsiness; over half the patients in both groups still had significant pain on arrival at
the hospital (Woollard 2004 Level II, n=175, JS 3).
In rural and suburban settings with ambulance services relying on basic life support
emergency technicians instead of paramedics, SC fentanyl (maximum first dose 1.5 mcg/kg) has
been used successfully to treat pain with only 1.6% of patients experiencing minor adverse
effects not requiring intervention (Lebon 2016 Level IV, n=288).
IN fentanyl is often used in the prehospital setting for treating acute pain in both children
and adults (19% of patients) ( Bendall 2011a Level III-2, n=3,312; Murphy 2017a Level IV, n=94). Thisroute requires a small volume (high-concentration preparation of fentanyl 300 mcg/mL and 50
mcg/mL have been used) and ideally atomisation eg with a metered aerosol device MAD®
attached to a syringe. In Australia, this route is sanctioned under an exemption from the TGA.
Fentanyl has a relatively high lipid-solubility that enables rapid absorption from the nasal
mucosa. Compared with IV fentanyl, the IN route shows similar pharmacokinetics ( Foster 2008
PK). Bioavailability is 89% with an interpatient variability of 30%. Absorption and onset ofanalgesia are slightly delayed vs IV fentanyl (Tmax 13 vs 6 min) (see Section 5.5.2). The analgesic
efficacy of IN fentanyl vs alternatives (IV morphine, methoxyflurane) for the treatment of pain in
the prehospital setting is unclear but appears to be favourable ( Murphy 2017a Level IV, n=940).
There is only low-quality evidence to support the use of IN fentanyl prehospital (Hansen 2013
Level III-3 SR, 4 studies, n=47,407). The one included prehopsital RCT found no difference in painscore reduction between IN fentanyl and IV morphine ( Hansen 2013 Level III-3 SR, 1 RCT: Rickard2007 Level II, n=258, JS 3). The study was likely underpowered and the findings complicated by useof IV morphine as the rescue analgesic in the IN fentanyl group. Oral transmucosal fentanyl(Actiq®) in battlefield casualties showed suitable effectiveness and safety with ease ofadministration (Wedmore 2012 Level IV, n=286).
For paediatric information, see also Section 10.9.1.1.
8.12.5.3 | Inhalational agents
Nitrous Oxide
Inhalational analgesics can provide early pain relief in the prehospital environment. However,variations in the availability of different agents have a marked impact on regional practices. In
one series, patients with extremity fractures were more likely to receive N 2O than morphine(White 2000 Level IV, n=1,073), whereas in another series N2O was not used at all (Rogovik 2007
Level IV, n=310).
N2O is included in prehospital management protocols for manipulation, splinting and transferof patients with lower limb fracture (Lee 2005b NR) and as a second-line in burns patients if
opioids are not available (Allison 2004b GL). Although N2O has been reported to provide pain reliefin >80% of patients requiring prehospital analgesia (Thomas 2008 NR), this practice was not basedon RCTs (Faddy 2005 NR) and there are few studies comparing efficacy with other agents. In one
paediatric series, a higher proportion of children receiving N 2O rather than opioids had pain on
arrival in the ED but interruption of delivery during transfer from the ambulance may havecontributed (Watkins 2006 Level IV, n=45). Based on data from hospital studies, N 2O has beensuggested as a safe analgesic in prehospital settings, although specific contraindications (such as
pneumothorax and decreased consciousness) may be particularly relevant in this patient group626

5th Edition | Acute Pain Management: Scientific Evidence8.0 | SPECIFIC CLINICAL SITUATIONS(Faddy 2005 NR) (see Section 4.5.1 for further details). Administration of 50% N2O vs medical air
to trauma patients in the prehospital setting showed effective analgesia; 67% of the N2O group
had pain score ≤3/10 at 15 min compared with only 27% in the air group ( Ducasse 2013 Level II,
n=60, JS 4).
Provision of N2O in ambulances is hampered by difficulties providing scavenger systems thatminimise occupational exposure and the bulk/logistical issues associated with managing
cylinders of oxygen and N2O (Entonox® cylinders are a mixture of 50% N2O and 50% oxygen) that
separate at low temperatures. The demand valves are costly and require maintenance, and theinability to activate the valve and effectively use Entonox® equipment has been rated as a major
factor limiting use in children <5 y (Watkins 2006 NR).
Methoxyflurane (Penthrane®)
Methoxyflurane is not available in most countries, but in Australia and New Zealand it has largely
replaced N2O in prehospital settings with reviews on its characteristics available in the literature(Blair 2016 NR). Methoxyflurane is delivered by a Penthrox® inhaler which contains 3 mL of
methoxyflurane and lasts for 25–30 min (Medical Developments International 2001). It is now
licensed in the UK, but not in the European Union nor the USA. It is more costly per dose than
opioid analgesics (>$20/dose). Methoxyflurane is contraindicated in patients with renal
impairment, which is difficult to reliably assess in the acute prehospital environment. Caution
against its use has been expressed by one UK medical college until further studies have been
undertaken (Fairhurst 2011 GL).
Methoxyflurane use reduced pain scores (mean 2.47/10 ± 0.24) in adults, the majority ofwhom had musculoskeletal pain (Buntine 2007 Level IV, n=83); the incidence of nausea was 8%,
and 11% had increased drowsiness. Results on the efficacy of methoxyflurane when compared
to Fentanyl (IV or IN) or IV morphine are mixed. Methoxyflurane produced greater initial
reduction in pain scores than IN fentanyl (2.0 vs 1.6/10) but IN fentanyl produced greater pain
reduction by the time of arrival at hospital (3.2 vs 2.5/10) ( Johnston 2011 Level III-3, n=1,024).
Methoxyflurane reduced NRS pain score by ≥30% for 78% of children (aged 5 to 15 y), whileamong those who received IV morphine and IN fentanyl this was achieved for 88 and 90%
respectively (Bendall 2011a Level III-2, n=3,312). In a smaller series, methoxyflurane also reduced
pain scores in children and adverse effects were reported (Babl 2006 Level IV, n=105); the overall
incidence of drowsiness was 27% but the risk of deep sedation was significantly higher in younger
children (see also Section 10.9.1.1). Yet a further review reported IN Fentanyl or IV morphine to
be of superior analgesic efficacy with moderate to severe pain (Blair 2016 NR).
There have been no reports of toxicity with analgesic use of methoxyflurane if doses arelimited to 3 mL repeated once per event with a maximum of 15 mL per wk or a maximum of 0.5%
for 1 h (Grindlay 2009 NR) (see also Section 4.5.2). A large population database study found nolong term (up to 14 y) adverse effects in patients who had been given methoxyflurane by an
ambulance service (Jacobs 2010 Level IV, n=17,629).
8.12.5.4 | Ketamine
Ketamine has been administered for prehospital procedural analgesia and sedation in both
adults (Bredmose 2009b Level IV, n=1,030; Porter 2004 NR) and children (Bredmose 2009a Level IV,
n=164) for many years (Henderson 2016 NR). A preference for ketamine has been reported in adultcases with severe pain but less so in paediatric patients. A case-series of patients treated byparamedics trained in the use of ketamine/midazolam found it was highly efficacious (reductionof mean pain score from 8/10 to 3/10) and safe (adverse effects 2.8%, no change in vital signs)(Haske 2014 Level IV, n=528). IV ketamine provided similar analgesia to IM morphine for trauma
patients in rural areas (Tran 2014 Level II, n=308, JS 2). The ketamine group had a higher rate of
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agitation and hallucinations (11 vs 1.5%) but a lower rate of vomiting (5 vs 19%). After trauma,
patients who responded poorly to a first dose of IV morphine 5 mg had better analgesia withsubsequent IV ketamine than morphine bolus doses but with more minor adverse effects(Jennings 2012 Level II, n=135, JS 3). In a low-resource rural trauma service in Iraq, provision of
prehospital analgesia with IV ketamine vs IV pentazocine resulted in better physiologic severity
scores vs no analgesic recipients (respiration and blood pressure); IV ketamine achieved positivechange for blood pressure in more severely injured patients (Losvik 2015 Level III-2, n=1,876).

8.12.6 | Anxiolytics
Anxiolytics, for example low doses of midazolam, are sometimes used to alleviate some of theacute anxiety or agitation that may complicate effective control of pain in stressful prehospitalconditions (McManus 2005 NR). However, there are no studies looking at efficacy and safety, andmidazolam does not enhance the analgesic effect of morphine in a prehospital setting ( Auffret2014 Level II, n=91, JS 5). It should be remembered that the combination with opioids will increase
the risk of respiratory depression and that anxiety and agitation may be indicators of other more
serious underlying conditions such as a head injury or hypoxia ( McManus 2005 NR). Low-dose IV
midazolam (1 mg typically) in combination with ketamine administered by ambulance officers
did not produce any drug-related adverse effects (Haske 2014 Level IV, n=528).

8.12.7 | Regional analgesia
Use of regional analgesia in the prehospital setting (excluding war or disaster situations) is
uncommon but increasing. Initiation of a fascia iliaca compartment block (FICB) for analgesia inpatients with isolated femoral shaft fractures reduces pain intensity across all studies; successrate is 90% with only one adverse event (Hards 2018 Level IV SR, 1 RCT, 5 studies & 1 CR, n=254[blocks]). In the included studies, these blocks were administered by physicians (3 studies),
paramedics (1 RCT: McRae 2015 Level II, n=24, JS 3), anaesthetists (1 study & 1 CR) and emergency
medical service nurses (1 study: Dochez 2014 Level IV, n=108 [blocks])
The approach was supported by paramedics in a survey (Evans 2019 Level IV, n=11 [paramedics]).
Prehospital treatment of dislocated extremity fractures with US-guided PNBs (FNB, sciatic
nerve block, brachial plexus block) vs analgosedation (midazolam/ketamine or
midazolam/fentanyl) by anaesthetists resulted in lower pain intensity during the reduction(median 0/10 [IQR 0 to 0] vs 6/10 [IQR 0 to 8]) and on the first POD (1/10 [IQR 0 to 5] vs 5/10
[IQR 5 to 7]), as well as higher rate of successful reduction and patient satisfaction ( Buttner 2018
Level II, n=30, JS 2).

8.12.8 | Nonpharmacological management of pain
Although analgesic agents are often used to treat pain in the prehospital setting, the importanceof nonpharmacological treatments should not be forgotten. The role of psychologicalintervention with reassurance and distraction in the management of acute pain in an anxious
patient is often undervalued.
Physical interventions specific for traumatic injuries include ice, elevation and splinting andthese can be effectively delivered in the prehospital environment. Local active warming resulted
in analgesia for females in pelvic pain during prehospital transport (Bertalanffy 2006 Level II, n=100,
JS 3).
TENS used in the prehospital setting reduced pain intensity vs pain before TENS use (MD38/100; 95%CI 28 to 44) and vs sham TENS (MD 33/100; 95%CI 21 to 44), as well as acute anxiety

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secondary to pain (Simpson 2014 Level I [PRISMA], 4 RCTs, n=261). The logistical and practical
implications of implementing TENS into widespread prehospital practice is unclear.
Acupressure performed by paramedics using “true points” led to better pain relief and lessanxiety than acupressure using “sham points” (Lang 2007 Level II, n=32, JS 5) or sham or no
acupressure (Kober 2002 Level II, n=60, JS 5).

8.12.9 | Analgesia in specific conditions
8.12.9.1 | Acute cardiac pain
The mainstay of analgesia in acute coronary syndrome is the restoration of adequate
myocardial oxygenation, including the use of supplemental oxygen (Pollack 2008 GL; Cannon
2008 GL) and glyceryl trinitrate ( Henrikson 2003 Level IV, n=459). Whether supplemental oxygen isbeneficial or harmful (especially if used in a nontargeted way) when used in acute coronary
syndrome remains unclear (Cabello 2013 Level I [Cochrane], 4 studies, n=430 ). Current guidelines
by the Australian and New Zealand Cardiology Society ( Chew 2016 GL) and NICE (NICE 2016b GL)
state that the use of supplemental oxygen is not recommended unless hypoxia (oxygen
saturation [SpO2] <94%) is present because of these concerns.
When used to treat acute cardiac chest pain during prehospital transfer, IV alfentanil
provided more rapid relief than IV morphine (Rickard 2007 Level II, n=258, JS 3; Silfvast 2001 Level II,
n=40, JS 4). In two cohort studies, prehospital use of morphine vs non-use was not associatedwith worse in-hospital complications and 1 y survival (HR 0.69; 95%CI 0.35 to 1.37) (Puymirat 2016
Level III-3, n=2,438 [1,726 survival analysis]).
See also Section 8.6.3 above.
8.12.9.2 | Abdominal pain
As noted in Section 8.6.1 above, administration of opioids does not interfere with the diagnostic
process in acute abdominal pain.
8.12.9.3 | Patients with head injury
Caution is often expressed about the use of opioids for pain relief in patients with a head injury(Thomas 2008 NR). This is largely because of the potential adverse effects of opioids and theirability to interfere with recovery and neurological assessment, as well as the concern that OIVI
will lead to hypercarbia and increased intracranial pressure ( Nemergut 2007 NR). While there islittle specific information regarding the use of opioids in patients with a head injury in theprehospital setting, opioids have been safely used in patients after craniotomy (seeSection 8.1.8 above).
The use of opioids in patients with a head injury in the prehospital environment will need to
be based on an individual risk-benefit assessment for each patient.

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KEY MESSAGES
1. Transcutaneous electrical nerve stimulation TENS provides pain relief in the prehospitalsetting (N) (Level I [PRISMA]).
2. Intravenous morphine, fentanyl and tramadol are equally effective in the prehospitalsetting (S) (Level II).
3. Nitrous oxide is an effective analgesic agent in prehospital situations (U) (Level II).
4. Methoxyflurane, in low concentrations, is an effective analgesic with rapid onset in theprehospital and hospital setting with good safety data (U) (Level II).
5. Ketamine is a safe and effective analgesic in the prehospital setting (U) (Level II).
6. Moderate to severe pain is common in both adult and paediatric patients in theprehospital setting (S) (Level IV) and is often poorly managed (N) (Level III-2).
7. Fascia iliaca compartment block is an effective analgesic technique for patients withisolated femoral shaft fractures in the prehospital setting (N) (Level IV SR).
8. The prehospital setting presents challenges beyond those encountered in hospital to theassessment, documentation, treatment and reassessment of pain in both adult andpaediatric patients (N) (Level IV).
The following tick box represents conclusions based on clinical experience and expert
opinion: Nonpharmacological measures are effective in providing pain relief and should always
be considered and used if practical (U).

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8.13 | Discharge opioid medication for acute pain management
The number of patients discharged from hospital with opioid medication is rising (Macintyre 2014NR), partially because the range of patients and procedures considered suitable for short-stay or
early discharge are increasing (see Section 8.1.7).
Ideally, multimodal analgesia approaches should be the cornerstone of the discharge
analgesic regimen (Desai 2018 Level III-2, n=42,000). A multimodal bundle of standardised use of
preoperative paracetamol, postoperative comfort education, simethicone, postoperative gum
chewing and abdominal binders reduced opioid requirements in hospital and with more women
receiving <20 tablets of oxycodone at discharge (96.7% vs 26.3%) (Burgess 2019 Level III-1, n=9,313).
In a multimodal regimen for discharge, oral immediate release opioid is prescribed if
required, to be used on an ‘as needed’ (prn) basis, ideally for a defined period. Not all, but many
patients will require opioid medications at discharge to manage moderate to severe
postoperative pain and optimise recovery and rehabilitation (Association of Anaesthetists of Great
2011 GL; Steyaert 2013 NR).
Before prescribing discharge opioids, consideration needs to be given to possible opioid
adverse effects including the potential risks of long term opioid use, drug diversion, misuse orabuse, and death from accidental overdose (Roughead 2019 Level III-3, n=24,854; Desai 2018 Level
III-2, n=42,000; Macintyre 2014 NR). See further discussion below in 8.13.2.
Anaesthetists are ideally placed to enforce opioid stewardship ( Macintyre 2014 NR); they andsurgeons need to take responsibility for discharge opioid prescribing as they are in a good
position to influence behaviour (Dunn 2017b NR). Furthermore, emergency departments play acentral role in community opioid supply with need for better coordination between communityand hospital specialities (Allen 2014 NR).
For discharge medication after ambulatory surgery, see also Section 8.1.7.4.
For discharge opioid prescribing in children, see also Section 10.4.5.

8.13.1 | Adverse effects of opioids
8.13.1.1 | Opioid-related deaths
Opioid overdose in 2016 resulted in death for 1,045 Australians aged 15 to 64 y (Roxburgh 2018
Level IV). The majority of these deaths (76%) were attributable to prescription opioids. There has
been a significant increase over the last 10 y in opioid-related deaths, from 3.8 to 6.6 deaths per
100,000 Australians per year. Similarly, but on a lower scale, the rate of opioid-related deaths in
New Zealand has increased by 33% from 2001 to 2012, with more than half (n=179) being
unintentional opioid overdoses (Shipton 2017 Level IV, n=325). In the USA, over a similar period,
over 183,000 deaths have been attributed to prescription opioids with numbers increasing eachyear (Morrison 2017 NR). There is evidence that illicit fentanyl is significantly contributing to thegrowth in opioid deaths in the USA and Canada, but not in Australia or New Zealand ( Roxburgh
2018 Level IV, n=1,045).
Non-fatal overdose events are 7 to 11 times more common than fatal events and lead tosignificant morbidity. Most of the non-fatal overdose events occur in patients who have used
opioids for <90 d (ie acute, not chronic opioid users) (Brat 2018 Level III-2, n=1,015,116).
As the average daily dose (in oral morphine equivalent doses [MED]) increased, so did theopioid overdose death rate (Zedler 2018 Level III-2, n=18,365,497; Mudumbai 2016 Level III-3,
n=64,391; Garg 2017 Level IV, n=150,821). The daily opioid dose correlated with risk of fatal
overdose in patients prescribed opioids (Garg 2017 Level IV, n=150,821). Compared to patients
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taking between 1 and 19 mg/d, the adjusted HRs (aHR) were 2.3 (95%CI 1.4 to 4.1) for 50 to
89 mg/d, 4.0 (95%CI 2.2 to 7.3) for 90 to 119 mg/d, 3.8 (95%CI 2.1 to 6.9) for 120 to 199 mg/d
and 4.9 (95%CI 2.9 to 8.1) for 200 mg/d
In the same study, compared to use of opioids only, using opioids in combination withsedatives and hypnotics increased the risk of overdose death (aHR 6.4; 95%CI 5.0 to 8.4), evenwith lower opioid doses between 1 and 19 mg/d (aHR 5.6; 95%CI; 1.6 to 19.3). The highest risk
was recorded with opioids combined with oral benzodiazepines and centrally acting skeletal
muscle relaxants (aHR 12.6; 95%CI 8.9 to 17.9).
Co-prescription of pregabalin and opioids is associated with increased mortality in a dose
dependent fashion: higher doses of pregabalin were associated with a higher risk of opioidrelated death and low doses associated with a lower, but still statistically significant, increased
risk (Gomes 2018 Level III-2, n=6,514). The mechanism of the association is unclear, but alpha-2delta-ligands can augment the ventilatory impairment associated with opioids (Morrison 2017 NR)
and have reversed opioid tolerance in rodent studies (Nicolodi 1995 BS). Data from many countries(USA, UK, Germany, Finland, India, South Africa and France) show that over 75% of deaths
attributable to alpha-2-delta-ligands also involve opioids (Smith 2016b Level IV SR, 34 studies[including 23 CR], n=49,570).
See also section 4.8.
Contribution of discharge opioids to overdoses and overdose mortality
Although relatively rare, there is a small increased risk of opioid overdose in the month after
discharge from hospital following surgery (Mudumbai 2019 Level III-3, n=64,391; Ladha 2018
Level III-3, n=1,305,715). Immediately after discharge (0-30 d) the risk of overdose is much higher
than later (31 to 365 d) (RR 10.80; 95%CI 8.37 to 13.92) (n=476) and this risk may increase
stepwise as intensity of discharge opioid increases: from no opioids; tramadol only; short-acting
opioid only; long-acting only; to short- and long-acting combined (Mudumbai 2019 Level III-3,
n=64,391). Patients on short- and long-acting opioids combined had the highest risk of overdose(HR 4.84; 95%CI 3.28 to 7.14). Preoperative use of high doses of opioids was another risk factor(Ladha 2018 Level III-3, n=1,305,715).
An analysis of deaths related to opioid toxicity in Canada found that the source of opioid in
6.6% of cases was an acute pain prescription (Madadi 2013 Level III-3, n=2,330 [drug-related deaths]).
While in the USA in people who died of prescription drug overdose, 5% of prescriptions camefrom emergency or urgent care specialists and anaesthetists provided only 1.7% of the total
prescriptions involved (Lev 2016 Level III-3, n=4,336 [prescriptions]).
8.13.1.2 | Opioid-induced Ventilatory Impairment (OIVI)For inpatients, OIVI is estimated to occur in less than 0.5% of acute pain patients using opioids
post-operatively (Dahan 2010 NR). The time periods of greatest risk of OIVI occurrence being the
day of and the night following surgery has implication for discharge of short-stay surgery patients(Lee 2013a Level IV, n=341); in children following tonsillectomy with or without adenoidectomy
most clinically significant OIVI cases occurred within 2 d of the procedure ( FDA 2013 GL). Positive
predictors identified for inpatient OIVI include: age over 70 y, male sex, major organ failure(including cardiac, respiratory and renal disease) and opioid naïvety (Khanna 2018 Level IV,
n=1,650). Other risk factors have included: sleep disordered breathing ( Lee 2013a Level IV, n=341;
Macintyre 2011 NR); increasing daily opioid doses (Zedler 2018 Level III-2, n=18,365,497; Garg 2017
Level IV, n=150,821); and, for chronic opioid users, a history of alcohol dependence ( Gomes 2011
Level III-2, n=1,463 opioid-associated deaths [498 age matched controls]). These have presumed but
unproven significance in patients discharged home postoperatively with opioids.

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For outpatients, risk factors for OIVI have included:• The combination of long-acting plus short-acting opioids (Garg 2017 Level IV, n=150,821);• Additional non-prescribed opioids; alcohol and other nonopioid sedating medications
such as benzodiazepines (Garg 2017 Level IV, n=150,821), antidepressants (Gomes 2011 Level
III-2, n=2,122 deaths [498 opioid-associated]; Rintoul 2011 Level IV, n=320; Webster 2011 NR) andpregabalin (Gomes 2011 Level III-2, n=2,122 deaths [498 opioid-associated]);• Magnitude of prescribed daily opioid dose (a significant positive correlation starts at MED
20 mg/d, with the highest risk in those prescribed MED >100 mg/d) ( Garg 2017 Level IV,
n=150,821)• Duration of opioid use (users with 31 to 89 d cumulative duration 4 times more likely tohave an opioid related death than those using opioids for <30 d) (Garg 2017 Level IV,
n=150,821);• History of opioid dependence; hospitalisation during the 6 mth prior to the event; liverdisease; co-prescription of sedatives including benzodiazepines, skeletal muscle relaxants
and pregabalin; and the use of long-acting opioids (Zedler 2018 Level III-2, n=18,365,497).
For outpatients at perceived increased risk of OIVI due to opioid overdose, WHO is
recommending the provision of take-home naloxone (WHO 2014 GL). In Australia, an IM and an
IN naloxone preparation suitable for take home use are commercially available and guidelines
for their use have been proposed (Lintzeris 2020 GL).
On the basis of these identified risk factors, risk prediction tools for OIVI have been proposed
for both inpatients and outpatients prescribed opioids ( Zedler 2018 Level III-2, n=18,365,497).
Although these factors have been identified to increase the risk of significant OIVI, no patient
can be said to be risk free. As total opioid dose increases, the risk of respiratory depression
increases but some patients experience respiratory depression with very small opioid doses.
Older patients may be at greater risk of OIVI, but young patients with no identified
comorbidities have died of OIVI post-operatively (Lee 2013a Level IV, n=341). Thus, it has been
recommended that health care professionals involved in prescribing, administering or dispensing
opioids should adopt a cautious and standardised approach, consider every patient at risk ofadverse events and titrating dose to effect and side-effects (NPS Medicinewise 2019 GL; Macintyre
2014 NR).
8.13.1.3 | Patient falls
Patients treated with opioids for any reason may be at increased risk of falling.
Those using opioids chronically for noncancer pain may be at greater risk of falling andrequiring hospital admission than those not on opioid medication; the overall risk is greatest in
week 1 following initial prescription and decreases over time ( Rolita 2013 Level III-2, n=13,354).
Patients newly treated with opioids may similarly be at increased risk of falling. There is anincreased risk of presentation to hospital with a falls related injury in the 2 to 4 weeks following
the filling of an opioid prescription (Daoust 2018 Level III-2, n=67 929; Soderberg 2013 Level III-2,
n=167,257). In an analysis of fall-injured patients 4.5% had a first opioid prescription less than
28 d prior to their fall (Soderberg 2013 Level III-2, n=167,257). Fall risk was greatest in younger
patients (18 to 29 y) and decreased with increasing time from initial prescription. In a similar
study, 4.9% of fall-injured patients had filled an opioid prescription in the 2 wk prior to the injury
and were more likely to have a fall related injury than through another mechanism (aOR 2.42;
95%CI 1.94 to 3.02) (Daoust 2018 Level III-2, n=67,929).
Despite the correlation of opioid prescription and increased fall risk, there is no evidence of
causation. The mechanism by which prescribed opioids may trigger injurious falls is unclear; it
may be directly due to adverse opioid effects (sedation, dizziness or cognitive impairment),
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underlying patient risk factors or comorbidities that make the prescription of opioids more likely,
or increase of risky activities which the opioid analgesic effect allows ( Soderberg 2013 Level III-2,
n=167,257).
8.13.1.4 | Impaired driving
Prescription opioid use is associated with a significantly increased risk of fatal crash involvement;
5.0% of US drivers involved in fatal crashes tested positive for prescription opioids vs 3.7% ofdrivers overall (OR 1.72; 95%CI 1.37 to 2.17) (Li 2019a Level III-2, n=19,206). Of drivers involved in
fatal crashes, 56% tested positive for alcohol only vs 7% of roadside tested drivers (aOR 17.9;
95%CI 16.19 to 19.84); 2.2% tested positive for both prescription opioids and alcohol vs 0.2% ofroadside tested drivers (aOR 21.89; 95%CI 14.38 to 33.32). The interaction with alcohol is in linewith previous data (EMCDDA 2012 Level III-2; Brady 2014 Level IV, n=23,591). Pooled data forprescription opioids only showed increased risk for accidents (OR 2.29; 95%CI 1.51 to 3.48) andfor culpability (OR 1.47; 95%CI 1.01 to 2.13) (Chihuri 2017 Level III-3 SR, 15 studies, n=926 to 72,685).
Self-reported driving under the influence of prescription opioids was also asscoiated with anincreased risk of collision (aOR 1.97; 95%CI 1.08 to 3.60) (Wickens 2018 Level IV, n=7,857).
Opioids are known to cause sedation, to diminish reaction times, reflexes and coordinationand to decrease the ability to concentrate (Wilhelmi 2012 Level IV SR, 58 studies, n>80,940); they
reduce attention specifically in cognitive tests and this effect increases when used together withantidepressants or anticonvulsants (Allegri 2019 Level III-2 SR [PRISMA], 9 studies, n=683). They may
thus interfere with the ability to perform a complicated task such as driving. These effects areboth subjectively and objectively evident when opioid naïve patients take medicinal opioids incommonly prescribed amounts, although some studies have found less significant objective thansubjective impairment (Wilhelmi 2012 Level IV SR, 58 studies, n unspecified). Attention and visualfunction are most sensitive in experimental studies, where doses up to 5 mg morphine IV (leading
to plasma concentrations of 50 nmol/L [≈14.3 ng/mL]) had very few effects on traffic-relevant
performance tasks (Strand 2017 Level I EH, 15 RCTs, n=324 [tests performed]). The overall degree ofdriving impairment by prescription opioids was similar to that of a blood alcohol reading of 0.05
to 0.08 g/dL (EMCDDA 2012 Level III-2); no attempt was made in this analysis to distinguishbetween acute and chronic opioid use.
In chronic pain patients, it has been traditionally considered that as tolerance develops thedriving performance of patients on long term stable opioids may not be negatively affected bytheir medication and may not have an increased crash risk (Wilhelmi 2012 Level IV SR, 58 studies, nunspecified; Dassanayake 2011 Level III-2 SR, 21 studies [13 case control n>26,603 drivers in accidents vsn>60,508 controls]). In this setting, no significant impact of regular therapeutic opioid agonists on
people's driving-related psychomotor skills has been found ( Ferreira 2018 Level III-3 SR [PRISMA],
3 studies, n=426). However, driving risk may be increased in the first few weeks following theinitiation of a prescription opioid (Dassanayake 2011 Level III-2 SR, 21 studies [5 opioid n unspecified])and may be dose dependent (EMCDDA 2012 Level III-2). Similarly, when patients on long term
opioids have their dose increased, their psychomotor impairment returns ( Wilhelmi 2012 Level VI
SR, 58 studies, n unspecified). These findings may have implications for the discharge managementof acute postoperative pain.
8.13.1.5 | Risk of inducing long term opioid use
Between 2 and 10% of patients continue to use opioid medication for months or even years
following its postoperative initiation (Roughead 2019 Level III-2, n=24,854; Brat 2018 Level III-2,
n=1,015,116; Stark 2017 Level III-2, n=1,013). Any post-discharge prescription of opioids at all seems634

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to be a risk factor for ongoing use, but risk increases with every further repeat prescription orrefill in all dose ranges (Brat 2018 Level III-2, n=1,015,116).
In Australia, 15.7% of patients admitted to mainly private hospitals under the veteran caresystem for a surgical admission were discharged on opioids, of which 3.9% became chronic usersof opioids (Roughead 2019 Level III-2, n=24,854). Similarly, in Canada, 3.1% of opioid naïve patients
having major elective surgery showed prolonged opioid use after being discharged on opioids(Clarke 2014 Level III-2, n=39,140).
Even after day-stay surgery, patients receiving an opioid prescription within the 7 d following
surgery were more likely to use opioids within the next year in comparison to those without aprescription (OR 1.44; 95%CI 1.39 to 1.50) (Alam 2012 Level III-2, n=391,139). Discharge NSAID
prescriptions were also more likely to be associated with persistent NSAID use (OR 3.74; 95%CI
3.27 to 4.28).
Risk factors for prolonged opioid use have included the type of surgical procedure with higher
rates in orthopaedic and spinal surgery (Stark 2017 Level III-2, n=1,013); after surgical procedures
odds ratios ranging from 1.28 (95%CI 1.12 to 1.46) for Caesarean section to 5.10 (95% CI 4.67 to5.58) for TKA have been reported (Sun 2016 Level IV, n=641,941 [surgical patients]). Risk factors havealso included medical comorbidities such as diabetes, heart failure and chronic lung disease,behavioural and social factors such as lower household income (Clarke 2014 Level III-2, n=39,140;
Namba 2016 Level III-3, n=12,859), mental health comorbidities including depression, anxiety andpsychosis (Brummett 2017 Level III-2, n=36,177; Lalic 2018 Level III-3, n=431,963; Namba 2016 Level III3, n=12,895), preoperative pain disorders (Brummett 2017 Level III-2, n=36,177) and preoperativeuse of certain medications, specifically benzodiazepines, SSRIs and ACE inhibitors ( Carroll 2012
Level III-2, n=109; Sun 2016 Level IV, n=641,941 [surgical patients]). Preoperative prescription opioiduse, alcohol and substance use disorders and depressive or anxiety symptoms have, in somestudies, more accurately predicted prolonged opioid use than the duration or severity of
postoperative pain (Stark 2017 Level III-2, n=1,013; Carroll 2012 Level III-2, n=109).
Characteristics of the initial opioid prescribing pattern have been linked to long term opioid
use. In a database analysis of the records of opioid naïve patients who received a newprescription for opioids in the US, with each additional day’s supply of opioids in the initialprescription, the probability of chronic opioid use increased (Shah 2017 Level IV, n=1,294,247). The
sharpest increases in chronic opioid use occurred after the fifth and thirty-first day of continual
use, after the second prescription and after a cumulative opioid dose of 700 MME. In this study
there was no distinction made between perioperative patients, acute non-operative patients andchronic pain patients.
However, the greatest risk for prolonged opioid use after surgery may be preoperative opioiduse (Mohamadi 2018 Level IV SR [PRISMA], 37 studies, n=1,969,953; Dunn 2018b Level III-3, n=1,477[patient records reviewed]; Bedard 2018 Level III-3, n= 35,894). Of over 6,000 USA veterans undergoing
TKA that did not subsequently require revision, 60% had used an opioid in the year prior tosurgery (Hadlandsmyth 2018 Level IV, n=6,653). In patients on long term opioids at the time ofsurgery, 69% received opioids for at least 6 mth and 57% for at least 12 mth after TKA. In patients
not on long term opioids at the time of TKA, only 4% received opioids for at least 6 mth and 2%
for at least 12 mth after TKA. Similarly, with patients having lower limb arthroplasty who used
opioids at least 80% of the time for >4 mth preoperatively, over 70% became persistent users(Kim 2017c Level IV, n=57,545).
Australian pharmaceutical benefit (PBS) scheme data show persistent opioid use is more
likely if initiated with transdermal preparations, higher doses, in older patients, with comorbid
depression (Sullivan 2018 NR) or psychotic illness, and prior dispensing of pregabalin or
benzodiazepines (Lalic 2019 Level IV, n=769,334).
For paediatric information, see Section 10.4.5.4.
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8.13.1.6 | Risk of diversion, misuse and abuse
There is a growing awareness of prescription opioid abuse in the general population and among
injecting drug users (Degenhardt 2013 Level IV; Fischer 2010 NR). This has been described by someas a major public health problem and is associated with prescription opioid-related overdoses
and deaths (Cicero 2017 Level IV SR [PRISMA], 17 studies, n=816).
Overprescribed and subsequently unused opioids prescribed for postoperative pain arepotentially a large reservoir for opioid abuse, misuse and diversion. Following urological surgery,
67% of those who filled their prescriptions for opioids had leftovers, which 91% planned to keep
(Bates 2011 Level IV). After dermatological surgery, 35% of those prescribed an opioid did not use
it at all and 55% of these planned to keep the leftover tablets ( Harris 2013 Level IV). Following
upper limb surgery, 31% of 245 patients used fewer than half of the opioid tablets prescribedwith over 4,000 tablets in total unused (Rodgers 2012 Level IV). In opioid naïve patients discharged
to home after major gastrointestinal or colorectal surgery, 85% of patients were prescribed an
opioid and only 38% of prescribed tablets were taken ( Hill 2018a Level IV, n=333). For paediatricinformation, see Section 10.4.5.6.
These opioids are not just a danger to the patient for whom they are prescribed. Patients
who retain unused tablets are usually willing to share them. It has been estimated that 71% ofchronic opioid users receive their medications through diversion (Hill 2018a Level IV, n=333). After
receiving opioid prescriptions for an acute episode, 64% of patients kept unused opioids and 34%
shared them with others (Lewis 2014 Level IV, n=191). In the USA, one third of college students
prescribed an analgesic for acute pain report having diverted opioids to others (Arria 2011
Level IV, n=192).
Sharing opioid medication may expose the user to an increased risk of adverse reaction or
drug interaction as there is often no assessment made of the underlying cause of the opioid
requirement and no advice given by a doctor or pharmacist ( Ward 2011 Level IV, n=641; Ellis 2009
NR).
Hoarded medication may also be a source of opioids for nonmedical use ( Macintyre 2014 NR).
The most common source of prescription opioids for nonmedical use in both the USA ( Lipari 2013
Level IV, n10,700,000) and Australia (Belcher 2014 Level IV, n=952) is a friend or relative, with nocharge incurred.
The total duration of opioid use post-operatively may be the strongest predictor ofsubsequent opioid misuse (Brat 2018 Level III-2, n=1,015,116). Prescribing patterns and theirassociation with subsequent misuse events were considered in a study of surgical claims from alinked medical and pharmacy administrative database in the USA. Each additional week of opioid
use was associated with a 34% increase in the rate of misuse. For example, one refill in addition
to the opioid prescription on discharge doubled the rate of misuse, and each additionalprescription increased the rate by 70%. In this study, the dosage prescribed was a far weaker
predictor of misuse. Even high doses (>MED 150mg/d) were associated with only small increases
in misuse risk when the duration of prescription was short. For prescriptions <2 weeks, misuse
rates for MED 40-50 mg/d were similar to rates for MED 100 to 150 mg/d.
Other risk factors associated with opioid misuse events have included benzodiazepine use,bariatric surgery, tobacco use disorder, other chronic pain and major depressive disorder ( Brat2018 Level III-2, n=1,015,116).
For paediatric information, see Section 10.4.5.5.

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8.13.1.7 | Discharge opioid prescribing regimens“Over-prescription” of opioids is common on discharge and may be explained by difficulties in
estimating the postoperative opioid analgesic requirements of patients following day surgery or
short inpatient stay. For post-operative patients, post-discharge opioid requirement may best be
predicted by opioid use the day prior to discharge (Hill 2018a Level IV, n=333); the number of opioid
tablets used at home was associated with the number of tablets taken the day before discharge
and the patient age, but not the type of surgery. The following regimen satisfied home opioid
requirements of 85% of the patients discharged: if a patient took no opioids the day prior todischarge, no prescription was required; if 1-3 tablets were taken the day prior to discharge, thena prescription for 15 pills was appropriate; and if 4 or more pills were used then 30 pills were
given. Such an individualised approach to opioid prescribing is supported after Caesarean section(predicted based on each patient’s inpatient opioid use), where individualised vs standard
prescription (30 PO oxycodone 5 mg tablets) resulted in 50% reduced unused tablets and, mostinterestingly, 50% reduced opioid use (8 vs 15 tablets) with no difference in pain scores(Osmundson 2018 Level II, n=190, JS 3).
Although this approach may seem intuitive, it is not commonly done. Even when opioid
requirements have been established, excessive prescription commonly occurs; 19% of
postoperative patients prescribed oxycodone for discharge from a large Australian teaching
hospital had not needed any opioid in the 24 h prior to discharge ( Platis 2011 Level IV) and of the
36% of an American surgical cohort who received no opioids in the 24 h prior to discharge, 46%
were prescribed opioids to take home (Chen 2018 Level IV, n=18,343).
Opioid prescribing limits for acute pain are a prominent component of the USA response to
the opioid epidemic, often limiting prescription to “7 days” (Chua 2019 NR). Due to theheterogeneity of patient requirements, such prescribing limits may be either excessive for somepatients, contributing needlessly to the community’s “opioid pool”, or inadequate for others,
resulting in inadequate pain control and an increased risk of pseudoaddiction, chronic pain andpotentially overdose (Brat 2018 Level III-2, n=1,015,116).
Many patients discharged from EDs with opioid medication do not safely store and disposeof these medicines (Hill 2018a Level IV, n=333). Other studies have shown that less than 10% of
patients take unused opioid tablets back to the pharmacy or to a safe box drop ( Bicket 2017
Level III-3 SR [PRISMA], 6 studies, n=810), some flush them down the toilet, some simply discardthem and others keep them at home (Hill 2018a Level IV, n=333).
Patients should be advised of these risks and also of the safe way to dispose of unused opioid
medicines; in Australia this is to return them to a pharmacy (Macintyre 2014 NR). In the USA when
patients were provided with a written brochure describing how to dispose of unused opioids,
disposal rates increased from 11% to 22% (Hasak 2018 Level III-3, n=334). A clear plan for analgesia
reduction after discharge and robust systems for communication with usual treating
practitioners in the community is essential and will assist in avoiding unintended dose escalation(Hanna 2019 NR; Katz 2015a NR). In ED, the introduction of education sessions, a staff information
email, posters within the ED, and a patient information brochure resulted in a 22% (95%CI 13 to31%) relative reduction of oxycodone on discharge (Kline 2019 Level III-3, n=43,814). Pain specialists
and clinics have a role in assisting with transition of these patients to the community
postoperatively and future developments may include transitional pain services for thosedischarged home with high dose opioids (Katz 2015 NR, De Pinto 2012 NR). Pharmacist led “opioid
exit plans” can also assist with care on discharge (Genord 2017 NR).
For paediatric information, see Section 10.4.5.7.

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8.13.2 | Selection of opioid for discharge medication
A position paper by ANZCA and FPMANZCA advises that slow-release (SR) conventional opioids(including transdermal opioid patches and methadone) are not recommended for routine use in
the management of opioid naïve patients with acute pain (ANZCA 2018 GL). This position is basedon the following facts:• The inappropriate use of slow-release opioids for acute pain has been associated withsedation and respiratory depression resulting in severe adverse reactions and deaths;• There is significant variation in opioid responsiveness between individuals which makes
accurate dose prediction of slow release opioids difficult;• Initial opioid dose should be titrated to effect and side effects, with the initial dose of
immediate release opioid age-based;• Acute pain intensity normally reduces rapidly over a few days, and so should opioid doses
and controlled-release preparations do not allow for this rapid tapering;• The use of controlled-release opioids in the initial treatment of pain is associated with anincreased risk of long term opioid use and subsequent prescribed opioid dependence(Shah 2017 Level IV, n=1,294,247).
These recommendations are equally applicable to inpatient and discharge opioid medication.
There is no strong evidence that any one immediate release oral opioid is best for the
management of pain on discharge following surgery ( Macintyre 2014 NR). Hydromorphone or
oxycodone, when used as the initial discharge opioid, have both been associated with a higher
rate of long term misuse than other opioids (hydrocodone, codeine and tramadol) in opioid naïve
patients undergoing surgery in the USA (Brat 2018 Level III-2, n=1,015,116). In Australia, the mostcommonly abused prescription opioids are oxycodone, tramadol and morphine ( AIHW 2018a
Level IV).

8.13.3 | Identification of patients at risk of opioid misuse
Many screening tools have been proposed to predict the risk of opioid misuse before opioidprescription in chronic pain patients (Chou 2009 Level IV SR, 16 studies, n=2,570; Passik 2008 NR) andare often recommended and utilised in the chronic pain setting (Webster 2011a NR). Their validity
has, however, been questioned (Clark 2018 Level IV, n=225; Dowell 2016 GL). No risk prediction tool
has been validated for use in acute pain patients although many have been proposed (Calcaterra
2018 Level IV, n=12,933) and an informal ‘risk assessment’ is often advocated using the risk factors
discussed above.

8.13.4 | Practical opioid prescribing on discharge
It has been recommended that prescribing physicians use a “universal precautions” approach toopioid prescribing. Universal precautions have been described as a “systematic set of procedures
and tools that aid the physician in gathering relevant information, help the physician interpretthe information collected and provide a pathway for responsible decisions” ( Webster 2010 NR).
Strategies include:• Risk assessment for chronic opioid use and misuse (the type of surgical procedure,
behavioural and social factors, medical comorbidities and preoperative pain disorders,the use of benzodiazepines, alpha-2-delta ligands, antidepressants (SSRIs), antipsychotics
and ACE inhibitors, prescription opioid use, alcohol and substance use disorders anddepression or anxiety (Carroll 2012 Level III-2, n=109; Sun 2016 Level IV, n=641,941 [surgicalpatients]);

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are not contraindicated (Dowell 2016 GL);
• Appropriate opioid dose when applicable is best predicted by usage the day before
discharge home (Chen 2018 Level IV, n=18,343; Hill 2018a Level IV, n=333);• Limited prescribing and duration of therapy (which should be communicated clearly tothe patient) (Dowell 2016 GL). Patients should be instructed (verbal and written) on the
expected duration of needing opioids, and recommendations should be individualised
based on patient factors and anticipated pain trajectory after discharge;• Appropriate patient education about the risk of opioids, including OIVI and addiction,and the safe disposal of opioids (Dowell 2016 GL) eg by the provision of educational
material such as (NPS Medicinewise 2019 GL);
• Monitoring of effect and compliance (close follow-up of at-risk patients after discharge)
and having a plan should opioid abuse, misuse or diversion be suspected ( Thorson D 2014
GL; Webster 2010 NR; Passik 2009 NR).
A consensus statement for the prescription of discharge medications after surgery has been
published in Canada (Clarke 2020 GL).
Pre-operative opioid users may be included in this strategy. However, patients who are taking
high doses of opioids, long-acting opioids, or have a pain management contracts preoperatively
fall outside of these recommendations and a postoperative pain management plan should be
developed before surgery in coordination with their primary prescriber (Dowell 2016 GL). In using
a multimodal discharge analgesic regimen, oral immediate release opioid should be prescribed
only if required (based on prior in hospital use), to be used on an ‘as needed’ basis, for a defined
period. Discharge planning should include a discussion of the plan for reduction anddiscontinuation of opioids as the acute pain resolves (Chou 2016 GL). If further opioid analgesia isrequired, the patient should first be reviewed by a medical officer ( AMWG 2017 GL).

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KEY MESSAGES
1. Short-term opioid therapy may lead to long term opioid use and misuse (S) (Level III-2);
risk factors for prolonged postoperative use include preoperative opioid use, type of
surgery, slow-release opioids, psychological and social factors and pre-existing alcohol orsubstance use disorder (N) (Level III-2).
2. Recent introduction of opioid therapy may increase the risk of falls (S) (Level III-2).
3. Recent introduction of opioid therapy or recent dose escalation may impair driving (S)(Level III-2), thereby leading to increased driving accidents (N) (Level III-3 SR); this risk isfurther increased by combined use of opioids and alcohol (N) (Level III-2).
4. Many patients who retain unused opioid tablets are willing to share them with others (S)(Level III-2); this contributes to increased risks of abuse and adverse effects in therecipients (N) (Level IV).
5. The most common source of prescription opioids for nonmedical use is a friend or
relative (N) (Level III-3).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Unused opioids prescribed for postoperative pain are potentially a large reservoir for
opioid abuse, misuse and diversion (S).
 A “universal precautions” approach for opioid prescribing should be used in the settingof prescribing discharge medications (S).
 Prescribing discharge medications should be done in consideration of opioid
requirements on the day before discharge, avoiding slow-release opioids and for alimited duration (N).
 Patient education about risks of opioids and safe disposal of unused medication by
return to a pharmacy and follow-up by GP or pain medicine services in case of ongoingissues improve safety of discharge medications (N).

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Open 2(4): 213-16.

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9Other specific patient groups
Section Editors:
Dr Richard Halliwell, Prof Stephan A Schug708

9.1.1 | Management of acute pain during pregnancy
9.1.2 | Pain syndromes in pregnancy
Contributor: Dr Karin Jones

9.1.3 | Management of acute pain during labour and birth
9.1.4 | Pain management during lactation
9.1.5 | Pain in the puerperium
Contributor: Dr Maggie Wong

9.2 | The older patientContributors: Prof Stephen Gibson, A/Prof Benny Katz

9.3 | Culturally responsive care for Culturally and Linguistically Diverse patientsContributor: Ms Monita Mascitti-Meuter

9.3.1 | Aboriginal and Torres Strait Islander peoples
Contributors: Dr Luke Arthur, Prof Alex Brown

9.3.2 | Māori peoples and pain
Contributor: Prof Edward A Shipton

9.4 | The patient with sleep-disordered breathing including
obstructive sleep apnoea
Contributor: Dr Christina Denman

9.5 | The obese patientContributor: Dr Sonya Ting

9.6 | The patient with concurrent renal or hepatic disease
Contributor: Dr Andrew Stewart

9.7 | The opioid-tolerant patient
9.8 | The patient with a substance use disorder
Contributor: Dr Lindy Roberts709

9.1 | The pregnant patient
9.1.1 | Management of acute pain during pregnancy
Pregnant women with pain that is severe enough to need pharmacological treatment (over thecounter or by prescription) represent a challenging group as medications given to them almost
always cross the placenta. While most medications are safe, there are particular times ofconcern, notably the period of organogenesis (wk 4 to 10) and just before birth. Where possible,
nonpharmacological treatment options should be considered before analgesic medications areused. Most of the data reported in this setting are from episodes of prolonged use (eg for chronic
conditions) and there is a lack of data on the risk of short-term exposure such as in the treatmentof acute pain during pregnancy. Ongoing analgesic use requires close liaison between the
pregnant woman, the health professional managing the pregnancy, and the health professional
managing the pain.
9.1.1.1 | Medications used in pregnancy
Studies of analgesic use during pregnancy are often confounded by the indication (the condition
the analgesic was being taken for may alter birth and childhood outcomes), recall bias and thelack of an active comparator. This is evident in various cohort studies discussed below that have
explored the associations of analgesic medication use and different pregnancy or birth outcomes
and childhood issues and results should be interpreted with caution.
Medication use during pregnancy is common and the data on which to make clear statements
about fetal risk is limited (Daw 2011 Level IV SR, 17 studies, n unspecified; Lupattelli 2014 Level IV,
n=9,459; Black 2019 NR; Price 2017 NR). Medications that may be prescribed during pregnancy havebeen categorised according to fetal risk by the TGA (TGA 2011 GL) in Australia, and the same
categories are used in New Zealand (Medsafe 2013 GL). The categories used are listed in Table 9.1.
It is important to note that the system is not hierarchical and that medications in Category B are
not necessarily safer than those in Category C. The classification of some of the medications thatmight be used in pain management is summarised in Table 9.2. A list of these medications,
including regular updates, is maintained by the TGA (TGA 2020 GL) .
The United States has moved away from a ‘letter based’ categorisation of medication safety
in pregnancy to providing a description of risk about individual agents that providers can thenuse to discuss risk with their patients (FDA 2014 GL).
Paracetamol
Paracetamol is classed a Category A medication by the TGA and is regarded as the analgesic ofchoice during pregnancy (Bisson 2019 GL) as no increased prevalence of congenital anomalies has
been reported with its use (Rebordosa 2008 Level III-3; Scialli 2010 NR).
There was also no association of paracetamol with an increased risk of spontaneous abortion(OR 1.2; 95%CI 0.8 to 1.8) (Li 2003 Level III-2). However, it has been suggested that its potential
influence on prostaglandin synthesis may have adverse effects in women at high risk of preeclampsia (Sahlman 2019 Level III-2, n=2,508; Zelop 2008 NR). A yet to be replicated Danish cohort
study suggested an increased risk of preterm birth following paracetamol exposure in earlypregnancy in mothers with pre-eclampsia (OR 1.55; 95%CI 1.16 to 2.07), but not in women
without pre-eclampsia (OR 1.08; 95%CI 0.97 to 1.20) (Rebordosa 2009 Level III-3, n=98,140).

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5th Edition | Acute Pain Management: Scientific Evidence9.0 | OTHER SPECIFIC PATIENT GROUPSChildhood asthma
Paracetamol exposure has also been examined as a potential contributor to the increasing
prevalence of childhood asthma, although there are likely multiple confounders. Plausibility isrelated to the potential for paracetamol to cause depletion of glutathione, an airway antioxidant.
In observational cohort studies any paracetamol use during the first trimester was associatedwith an increased risk of childhood asthma (pooled OR 1.39; 95%CI 1.01 to 1.91) (5 studies) (Cheelo
2015 Level III-2 SR, 11 studies, n=3,663,454). However, there was marked between-study
heterogeneity (I2=63%) and only one of the studies adjusted for maternal respiratory tract
infections. The association was weakened when adjustments for a range of factors, including
respiratory infections was made.
Cryptorchidism
Association between paracetamol exposure in utero and cryptorchidism has been of interest due
to the potential for paracetamol to act as an endocrine disrupter. A systematic review finds little
evidence for an association between ‘ever’ use of analgesia and risk of cryptorchidism (pooled
crude OR 1.11; 95%CI 1.00 to 1.23), including when separated into subgroups of case-control
studies (OR 1.23; 95%CI 0.85 to 1.78) or cohort studies (OR 1.09; 95%CI 0.97 to 1.22) (Gurney 2017
Level III-2 SR [PRISMA], 10 Studies, n=501,456). There was a high degree of heterogeneity amongstudies.
Other childhood issues
Cohort studies have identified weak associations between intrauterine exposure to paracetamoland other childhood issues including neurodevelopmental conditions such as ADHD and ASD (fordetails see section 10.4.1).
There is also a potential association between premature closure of ductus arteriosus andmaternal paracetamol use in pregnancy (Allegaert 2019 Level IV SR, 12 studies, n=25). Given
paracetamol has been shown to be as effective as ibuprofen for closure of a patent ductus
arteriosus in preterm neonates (Ohlsson 2018 Level I [Cochrane], 8 RCTs, n=916), it seems reasonable
to recommend that (as with all medications) use should be limited to the minimum dose andduration that is clinically necessary.
Overall there is insufficient evidence to warrant changing guidelines on early life paracetamol
exposure at this time.
Nonsteroidal anti-inflammatory drugs
Nonselective NSAIDs and coxibs are Category C medications, except celecoxib which is Category B3.
Spontaneous abortion
Exposure to an nsNSAID or coxib was not identified as an independent risk factor for
spontaneous abortion ( Daniel 2014 Level III-2, n=65,457 [n=4,495 exposed to NSAIDs] ). There wasan increased risk with indomethacin found (aHR 2.8; 95%CI 1.70 to 4.69), but the authors
warn that this is possibly due to reverse causation bias, as indomethacin is a tocolytic
medication used in preterm labour. This is supported by the finding that the association withindomethacin use disappeared when omitting all indomethacin use during the last four dbefore the spontaneous abortion. The same authors found in a further analysis of the same
database associations of spontaneous abortion with use of nsNSAIDs in general, andspecifically for diclofenac and indomethacin, which disappear again when exposuresoccurring on the day before the spontaneous abortion for nsNSAIDs and when exposures in
the last week for indomethacin are excluded (Daniel 2015 Level III-2, n=65,457 [n=4,495 exposed
to NSAIDs]). The authors regard these results as confirmation of an indication bias of thesefindings.

5th Edition | Acute Pain Management: Scientific Evidence711

Congenital malformations

Intrauterine exposure to nsNSAIDs was not associated with increased risk for major congenital
malformations (Daniel 2012 Level III-2, n=110,783 [n=5,267 exposed to NSAIDs]). This was also
confirmed in another smaller study ( Van Marter 2013 Level III-3, n=1,213) and four older cohort
studies (Bloor 2013 NR). Major congenital malformations, structural heart defects and infantsurvival did not differ in offspring of women who took one of four different nsNSAIDs(ibuprofen, diclofenac, naproxen and piroxicam) during early pregnancy vs controls ( NezvalováHenriksen 2013 Level III-2, n= 90,417 [n=6,511 exposed to NSAIDs] ). The use in the second trimesterof ibuprofen (aOR 1.7; 95%CI 1.3 to 2.3) or diclofenac (aOR 3.1; 95%CI 1.1 to 9.0) was
associated with low birth weight, possibly related to maternal inflammatory conditions.
A cohort study of 174 women who took coxibs in the first trimester of pregnancy did not finda significantly increased risk of birth defects in their offspring (2.9% vs. 2.7%) (Dathe 2018 Level III2, n=174).

While relatively safe to use in early and mid-pregnancy, NSAIDs can precipitate fetal cardiac
and renal complications in late pregnancy, as well as interfere with fetal brain development andthe production of amniotic fluid and thus should be discontinued from gestational wk 32 (Bloor
2013 NR).
Other neonatal and childhood issues
Fetal exposure to NSAIDs has been associated with persistent pulmonary hypertension in the
newborn in one study (Alano 2001 Level III-2, n=40 [cases] vs n=61 [controls]), but not another (VanMarter 2013 Level III-2, n=377 [cases] vs n=836 [controls]). In the third trimester, associations between
NSAID use and renal injury, oligohydramnios, necrotising enterocolitis and intracranial
hemorrhage have also been reported (Bloor 2013 NR); the incidence may be increased with
exposure occurring closer to delivery.
There is also an increased risk of premature closure of the ductus arteriosus (OR 15.04; 95%CI
3.29 to 68.68) (Koren 2006 Level I [Cochrane], 8 RCTs, n=438).
Ibuprofen use in the second (aOR 1.5; 95%CI 1.2 to 1.9) and third trimesters (aOR 1.5; 95%CI
1.1 to 2.1) was also associated with asthma in 18 mth old children (Nezvalová-Henriksen 2013 Level
III-2, n= 90,417 [n=6,511 exposed to NSAIDs]).
One observational study showed an increased association between maternal aspirin use
during pregnancy and the development of psychotic symptoms during adolescence ( Gunawardana
2011 Level III-3, n=6,437]). However, this association may be related to the presence of maternal
indications, for which the aspirin is taken, rather than the aspirin itself being causative itself(Khandaker 2013 Level III-2 SR, 21 studies, n unspecified).
Conventional Opioids
Large increases in the use of prescription opioids in Western countries has been reflected inwomen of child bearing age and is a major public health concern affecting pregnant women andtheir infants (Lind 2017 Level III-2 SR, 68 studies, n unspecified; Yazdy 2015 NR). Rates of opioid use inAustralia and New Zealand are possibly less than those seen in North America. One Australianstudy estimated that 1% of pregnant women took prescription opioids in a two-week period(Miller 2019 Level III-2, n=192,617 [pregnant patients] vs n=5,448,771 [controls]). In comparison, aCanadian cohort (studied between 2001 and 2013) where opioid use was 6.7 % before
pregnancy, reducing to 4.2%, 3.0% and 2.4% in first, second and third trimesters respectively(Falk 2017 Level III-2, n=174,848).

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Congenital malformations
The risk of congenital malformation related to opioid exposure in early pregnancy is difficult toclarify due to these being rare events and bias due to inaccurate self-reporting about opioid use(Yazdy 2015 NR).
Data from the long running US National Birth Defects Prevention Study (1997-2011) was used
to calculate an adjusted odds ratios for risk of a range of birth defects in offspring exposed in the
periconceptual period to paracetamol, NSAID or opioid (Interrante 2017 Level III-2, n=29,078 [treatedpatients] vs n=10,962 [controls]). In utero opioid exposure (n=196 [treated patients] vs n=110 [controls])
was associated with tetralogy of Fallot, perimembranous ventricular septal defect and atrioventricular septal defect (aOR range 1.8 to 2.3), whereas the use of both opioids and NSAIDs(n=191 and n=86) was associated with gastroschisis, cleft palate, spina bifida, hypoplastic left heart
syndrome, and pulmonary valve stenosis (aOR range 2.0 to 2.9). It was not possible to tellwhether the effects were due to the drug or confounding due to the condition for which the drug
was taken.
The impact of periconceptual opioid exposure for all indications on the risk of neural tube
defects was studied in a well-designed case control study. This found an overall increased risk vs
non-malformed controls (aOR 2.2; 95%CI 1.2 to 4.2) and malformed controls (aOR 1.9; 95%CI 1.0
to 3.4) (Yazdy 2013 Level III-2, n=305 [cases] vs 7,125 [non-malformed controls] vs 13,405 [malformed
controls]). When opioids were used for pain control, the most common indication reported, there
was no significant increase in neural tube defects.
A systematic review of the risk of teratogenic effects with opioid exposure in utero analysed
30 studies where statistical analysis was presented (Lind 2017 Level III-2 SR, 68 studies, nunspecified). Seventeen of these 30 studies (10 of 12 case control studies and 7 of 18 cohort studies)found positive associations for a range of congenital malformations, with the most common
being for orofacial clefts, ventricular or atrial septal defects and, for the cohort studies, club foot.
The authors noted few of these studies were of high quality, and many had been performed
before 1999, and could not differentiate between groups taking opioids for substance use
disorder vs chronic pain.
Neonatal abstinence syndrome
Neonates exposed to regular opioid in utero, particularly in the last three mth of pregnancy, areat risk of neonatal abstinence syndrome (NAS) and should be monitored for it after delivery. A
population based USA cohort study reported the risk of NAS in infants born to women prescribed
opioids during pregnancy (Desai 2015 Level III-2, n=290,605 [1,705 cases of NAS]). The absolute risk
was low (0.59%; 95%CI 0.56 to 0.62). Both the duration (cumulative dose) and timing (later use;in the 90 d prior to birth) increased the risk. Maternal history of opioid misuse or dependence,
alcohol, psychoactive medication use or smoking were also associated with increased risk of NAS.
Long-term known opioid misuse had higher absolute risk 22% (95%CI 20 to 24%) vs short-term
known misuse (19%; 95%CI 18 to 21%).
The longer term impact of NAS is of concern but clouded by the complexity of the effects ofmedication, small sample sizes and lack of control for confounding variables such as poverty andmaternal psychopathology (Conradt 2018 NR).
Other issues are the lack of appropriate tools for its assessment and the lack of earlyrecognition of NAS symptoms resulting in possible underreporting and, as a consequence,
inappropriate and too early neonatal discharge from hospital (Wolff 2014 NR). Guidelines for the
management of NAS have been published (Wiles 2014 GL).

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Other neonatal issues
Preterm infants, prenatally exposed to opioids, had increased rates of intermittent hypoxaemia(defined as episodes with SpO2<80% on continuous pulse oximetry), which persisted beyond theimmediate postnatal period (Abu Jawdeh 2017 Level III-2, n=14 [exposed] vs n=68 [unexposed]).
A small study suggested that neonatal outcome was better in mothers receiving opioids forchronic pain rather than addiction, although differences in dose and other environmental factors
may contribute (Sharpe 2004 Level III-2, n=43), but minimising the use of opioid therapy for chronic
pain during pregnancy has been recommended (Chou 2009 GL).
Neurodevelopmental outcomes
Neurodevelopmental abnormalities resulting from opioid exposure are mechanistically plausible
due to multiple effects of opioids on maternal and fetal physiology, as well as direct receptor
mechanisms; potential confounders such as psychosocial issues leading to childhood deprivationmust also be considered. A pilot study suggested that on MRI scans brain volumes of opioidexposed babies may be smaller than controls, in particular in specific regions such as basal
ganglia (Yuan 2014 Level IV, n=16). Cognitive outcomes of children exposed to opioids in utero havebeen described, showing marked developmental functional impairments vs non-exposedchildren (Farid 2008 NR; Winklbaur 2008 NR).
However, a systematic review found no significant impairments for cognitive, psychomotor
or observed behavioural outcomes after chronic intrauterine opioid exposure in infants (4 studies,n=423) and preschool children (3 studies, n=455) vs non-exposed controls (Baldacchino 2014 Level
III-2 SR [PRISMA], 5 studies, n unspecified). There were significant limitations of this systematic
review (small number of studies analysed, heterogeneous populations, small numbers within theindividual studies).
The school age academic performance (NAPLAN testing) of Australian grade 3, 5 and 7
children (assessed from year 2000 to 2006) who had suffered neonatal abstinence syndrome(NAS) (n=2,234) vs a matched control cohort (n=4,330) and population results (n=598,265) foundsignificantly poorer outcomes in NAPLAN testing (Oei 2017 Level III-2). The risk of not meeting
minimum NAPLAN test result standards was independently associated with a history of NAS (aOR
2.5; 95%CI 2.2 to 2.7).
Beside impairment of general cognitive abilities, children exposed to heroin prenatally show
problems in several behavioural areas, in particular with regard to attention, when assessed byparents and teachers at 4.5 and 8.5 y of age, but these are not specific and not more severe thanthe effect on cognitive function (Nygaard 2016 Level III-2, n=72 [exposed] vs 58 [not exposed]).
For the management of acute pain in pregnant patients with an addiction see Section 9.8.9
below.
Atypical Opioids
Among women identified from the Swedish Medical Birth Register 1997 to 2013, 1,751 mothers(n=1,776 infants) had used tramadol and 96 of the infants had a congenital malformation (Kallen
2015 Level III-2, n=1,682,846 [mothers]; n=1,797,678 [infants]). Tramadol was associated withincreased odds ratios for cardiovascular defects (OR 1.56; 95%CI 1.04 to 2.29) and for pes
equinovarus (club foot) (OR 3.63; 95%CI 1.61 to 6.89).
Alpha-2-delta ligands
Evidence regarding the effects of exposure to alpha-2-delta ligands in utero remains scant. Whileregistries of antiepileptic drug and pregnancy outcomes were established in different countries≈15 y ago, gabapentin and pregabalin have been used relatively rarely vs other antileptic agentsand no relevant outcomes could be reported for the two medications (Veroniki 2017 Level III-2 SR,
29 studies, n=5,100).

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Data on gabapentin use in pregnancy suggest its safety currently, although the number of
documented exposures is small (Guttuso 2014 Level IV SR, 6 studies & 2 case reports, n=294[gabapentin exposures in first trimester]). The rate of congenital malformations (1.7%) was notdifferent from the rate in comparable general populations (1.6 to 2.2%). There were also
equivalent rates of premature birth (including maternal hypertension/eclampsia prematurebirth) and similar birth weight after correction for gestational age at delivery with gabapentin
use vs the general population (n=261). Based on similarly small numbers in another study,
gabapentin exposure was not associated with increased rates of small for gestational age infants(aOR] 2.03; 95%CI 0.68 to 6.01), low birth weight (aOR 1.86; 95%CI 0.56 to 6.15) or preterm
delivery (aOR 1.214; 95%CI 0.501 to 2.946) (Wade 2015 Level III-2, n=53 [gabapentin exposures]). In
contrast, another cohort study revealed no increased rate of malformations, but a higher rate ofpreterm births and birth weight <2,500 g in the gabapentin group ( Fujii 2013 Level III-2, n=223[gabapentin exposures] vs n=223 [unexposed controls]).
Of 477 infants exposed to pregabalin during the first trimester, 5.9% had congenital
malformations vs 3.3% in non-exposed infants (RR 1.80; 95%CI 1.26 to 2.58). However,propensity score adjustment suggested no teratogenic effect of pregabalin (aOR 1.16; 95%CI
0.81 to 1.67), confirmed by analysis of a second database (n=174 [exposed to pregabalin]) (aRR 1.03;
95%CI 0.56 to 1.90) (Patorno 2017 Level III-2, n=1,323,432 [pregnancies followed]).
Data from the Medical Birth Registry of Norway showed no increase of congenital
malformations with gabapentin (n=39) and pregabalin (n=30), however, based on very low
numbers of exposures (Veiby 2014 Level III-2, n=2,600 [exposed to any anticonvulsant] vs n=774,012[unexposed controls]). Similarly, a systematic review examining neurodevelopmental effects fromintrauterine exposure to anticonvulsants could not provide information on gabapentin or
pregabalin due to too few exposures (Bromley 2014 Level III-2 SR [Cochrane], 28 studies [22prospective cohort, 6 registry-based studies], n unspecified).
Withdrawal syndromes can occur in neonates exposed during pregnancy to gabapentin(combined with other substances), with re-introduction of gabapentin being a suggested
treatment for this syndrome (Carrasco 2015 CR).
Table 9.1 | TGA medicine categorisation according to fetal risk
A

Medicines which have been taken by a large number of pregnant women andwomen of childbearing age without any proven increase in the frequency ofmalformations or other direct or indirect harmful effects on the fetus having been
observed.

B1

Medicines which have been taken by only a limited number of pregnant women andwomen of childbearing age, without an increase in the frequency of malformation orother direct or indirect harmful effects on the human fetus having been observed.
Studies in animals have not shown evidence of an increased occurrence of fetal
damage.

B2

Medicines which have been taken by only a limited number of pregnant women andwomen of childbearing age, without an increase in the frequency of malformationor other direct or indirect harmful effects on the human fetus having been
observed.
Studies in animals are inadequate or may be lacking, but available data show noevidence of an increased occurrence of fetal damage.

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B3

Medicines which have been taken by only a limited number of pregnant women andwomen of childbearing age, without an increase in the frequency of malformation orother direct or indirect harmful effects on the human fetus having been observed.
Studies in animals have shown evidence of an increased occurrence of fetal damage,the significance of which is considered uncertain in humans.

C

Medicines which, owing to their pharmacological effects, have caused or may besuspected of causing, harmful effects on the human fetus or neonate withoutcausing malformations. These effects may be reversible. Accompanying texts should
be consulted for further details.

D

Medicines which have caused, are suspected to have caused or may be expected tocause, an increased incidence of human fetal malformations or irreversible damage.
These medicines may also have adverse pharmacological effects. Accompanying
texts should be consulted for further details.

X

Medicines which have such a high risk of causing permanent damage to the fetus
that they should not be used in pregnancy or when there is a possibility ofpregnancy.

Notes:For medicines in the B1, B2 and B3 categories, human data are lacking or inadequate andsubcategorisation is therefore based on available animal data. The allocation of a B category does NOT
imply greater safety than the C category. Medicines in category D are not absolutely contraindicated in
pregnancy (eg anticonvulsants). Moreover, in some cases the ‘D’ category has been assigned on the basisof “suspicion”.
Due to legal considerations in Australia, sponsoring companies have, in some cases, applied a more
restrictive category than can be justified on the basis of the available data.
In some cases there may be discrepancies between the published product information and theinformation in this table due to the process of ongoing document revision.

Source:(TGA 2011) © Commonwealth of Australia. Reproduced with permission.

Table 9.2 | Categorisation of medicines used in pain management
Medicine

Cat

Comments

C

Opioid analgesics may cause respiratory
depression in the newborn. Withdrawal
symptoms in newborns have been reportedwith prolonged use of this class of medicines
including tramadol

codeine, dihydrocodeineA

Prolonged high-dose use of codeine prior tobirth may produce codeine withdrawal
symptoms in the newborn

Paracetamol

A

AspirinC

Opioids
alfentanil, buprenorphine,
dextromoramide,
dextropropoxyphene, fentanyl,hydromorphone, methadone,
morphine, oxycodone,
papaveretum, pentazocine,
pethidine, phenoperidine,
remifentanil, tramadol

716

Aspirin inhibits prostaglandin synthesis. When
given late in pregnancy, it may cause

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Medicine

Cat

Commentspremature closure of the fetal ductus
arteriosus, delay labour and birth. Aspirinincreases the bleeding time both in the
newborn and in the mother because of its
antiplatelet effects. Products containing aspirinshould be avoided in the last trimester. Lowdose aspirin (100 mg/d) does not affectbleeding time.

Other nsNSAIDs
diclofenac, diflunisal, ibuprofen,
indomethacin, ketoprofen,
ketorolac, mefenamic acid,nabumetone, naproxen,
phenylbutazone, piroxicam,
sodium salicylate, sulindac,
tenoxicam, tiaprofenic acid

Coxibscelecoxib
parecoxib
Local anaesthetics
bupivacaine, cinchocaine,
lignocaine (lidocaine),
mepivacaine, prilocaine
etidocaine, ropivacaine
procaine hydrochloride
levobupivacaine
Antidepressants
SSRIs:
citalopram, fluoxetine,
fluvoxamine, sertraline,
paroxetine
Tricyclic antidepressants:
amitriptyline, clomipramine,
desipramine, dothiepin(dosulepin), doxepin, imipramine,
nortriptyline, protriptyline,
trimipramin

C

These agents inhibit prostaglandin synthesis
and, when given during the latter part ofpregnancy, may cause closure of the fetal
ductus arteriosus, fetal renal impairment,
inhibition of platelet aggregation and delayed
labour and birth. Continuous treatment with
NSAIDs during the last trimester of pregnancy
should only be given on sound indications.
During the last few days before expected birth,
agents with an inhibitory effect on
prostaglandin synthesis should be avoided.

B3
C
A
B1
B2
B3

C

SSRIs have had limited use in pregnancy
without a reported increase in birth defects.
The use of SSRIs in the third trimester may
result in a withdrawal state in the newborn.

D

Category changed Sept 2005

C

Withdrawal symptoms in newborn infants
have been reported with prolonged maternal
use of this class of medicines.

Other antidepressants:
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718

MedicineCat

mirtazapine, moclobemide,
nefazodone, duloxetine
venlafaxine, desvenlafaxine

B3
B2

Comments

AnticonvulsantscarbamazepineD

Spina bifida occurs in about 1% of pregnancies
in which carbamazepine is used as
monotherapy. Carbamazepine taken during
pregnancy also has been associated with minor
craniofacial defects, fingernail hypoplasia anddevelopmental disability. Carbamazepine also
can cause coagulation defects with consequentrisk of haemorrhage in the fetus and thenewborn, which may be preventable by theprophylactic administration of vitamin K to themother prior to the birth.

phenytoin sodium

D

This medicine taken during pregnancy has
been associated with craniofacial defects,
fingernail hypoplasia, developmental disability,
growth retardation and, less frequently, oral
clefts and cardiac anomalies. This clinicalpattern is sometimes called the “fetal
hydantoin syndrome”. Phenytoin can also
cause coagulation defects with consequent riskof haemorrhage in the fetus and the newborn,which may be preventable by the prophylactic
administration of vitamin K to the mother prior
to the birth.

sodium valproate

D

Sodium valproate is contraindicated in
pregnancy. A broad range of congenital
malformations can occur in babies born towomen who take sodium valproate during
pregnancy, and the risk of malformations
increases with increasing dose of valproate. If
taken in the first trimester of pregnancy,
sodium valproate (valproic acid) is associatedwith a one to two percent risk of neural tube
defects (especially spina bifida) in the exposed
fetus. Sodium valproate should not be usedduring pregnancy and in women of childbearing potential unless alternative treatments
are ineffective or not tolerated because of thehigh risk of malformation and risk ofdevelopmental disorders in infants exposed tovalproate before birth. Avoid use of valproate
in women of child-bearing age for all non-

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Medicine

Cat

Comments
seizure indications. For seizure indications,consider alternatives if they exist. Always use
the lowest effective dose. Patients andprescribers should reconsider benefit and risk
at regular treatment reviews, at puberty andurgently when a woman of child-bearing
potential treated with valproate plans apregnancy or becomes pregnant. Folic acidsupplementation (5 mg) should be commenced
four weeks prior to and continue for twelve
weeks after conception; specialist prenatal
diagnosis including detailed mid-trimester
ultrasound should be offered.

lamotrigine

D

Category changed June 2006

clonazepam

C

Clonazepam is a benzodiazepine. These
medicines may cause hypotonia, respiratory
depression and hypothermia in the newborn if
used in high doses during labour. Withdrawal
symptoms in newborns have been reportedwith this class of medicines.

gabapentin,

B1

Used for neuropathic pain

tiagabine, topiramate, pregabalin

B3

Lamotrigine
Levetiracetam

D
B3

Anticonvulsants for partial complex seizures,
possibly mood stabilising and antineuropathic

C

When given in high doses during latepregnancy, phenothiazines have caused
prolonged neurological disturbances in theinfant.

Antiemetics, antinauseants
Phenothiazines:
prochlorperazine, promethazine,
thiethylperazine

Others:dimenhydrinate,
diphenhydramine,
metoclopramideAdolasetron, granisetron,
ondansetron

B1

domperidone, hyoscine, hyoscinehydrobromide

B2

tropisetron

B3

Source:TGA 2020 © Commonwealth of Australia. Reproduced with permission.

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KEY MESSAGES
1. Short-term use of NSAIDs in late pregnancy is associated with an increase in the risk ofpremature closure of the ductus arteriosus (U) (Level I [Cochrane Review]).
2. The chronic use of opioids during pregnancy may be associated with some teratogenic
effects, childhood neurocognitive delay and/or negative neurobehavioural outcomes;
however, it is difficult to separate the influence of multiple confounders in this patientgroup (Q) (Level III-2 SR).
3. Retrospective epidemiological studies linking paracetamol use in pregnancy to later
development of childhood asthma are inherently confounded (U); when adjusted forrespiratory tract infections in the child the association is lost (Q) (Level III-2 SR).
4. The use of common nsNSAIDS during pregnancy is not associated with increased risk ofmajor congenital malformations, structural heart defects or difference in infant survival(N) (Level III-2).
5. Exposure to an nsNSAID or coxib is not an independent risk factor for spontaneousabortion (Q) (Level III-2)
6. The safety of alpha-2-delta ligand use in pregnancy remains unclear; limited data has
not raised safety concerns (N) (Level III-2).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: For pain management in pregnancy, nonpharmacological treatment options should beconsidered where possible before analgesic medications are used (U).
 Use of medications for pain in pregnancy should be guided by publishedrecommendations; ongoing analgesic use requires close liaison between the patient,
the health professional managing the pregnancy and the health professional managing
the pain (U).
 Most of the data reported in this setting are from episodes of prolonged use (eg forchronic conditions) and there is a lack of data on the risk of short-term exposure suchas in the treatment of acute pain (N).
 Studies of analgesic use during pregnancy may be confounded by the indication, recall
bias and often the lack of an active comparator; this is exemplified by reported
associations between NSAID use in pregnancy and low birth weight and asthma
confounded by the maternal indications for their use (ie inflammatory diseases) (N).
 Nonselective NSAIDs and Coxibs should be used with caution in the last trimester ofpregnancy and should be avoided after the 32nd week (U).
 Emerging evidence suggests that maternal paracetamol use may influence premature
closure of the fetal ductus arteriosus (N).
 Neonates exposed to regular opioid in utero, particularly in the last three months ofpregnancy, are at risk of neonatal abstinence syndrome and should be monitored for itafter delivery (N).

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9.1.2 | Pain syndromes in pregnancy
9.1.2.1 | Musculoskeletal pain syndromes
Low back pain (LBP) or pelvic girdle pain (PGP) alone or in combination are common during
pregnancy (Casagrande 2015 NR). Low back pain in pregnancy refers to pain in the lumbar spine
without radicular component or pain reproduced with repeated range of motion activity. Pelvic
girdle pain is experienced between the posterior iliac crest and the gluteal fold, particularly inthe vicinity of the sacroiliac joint, may radiate to the posterior thigh or be perceived in the pubic
symphysis (Vleeming 2008 GL). The endurance capacity for standing, walking and sitting is
diminished. The pattern may change during the course of pregnancy and following delivery with
76% of women reporting some form of back or pelvic pain during singleton pregnancy (Weis 2018
Level IV, n=287). Point and period prevalence were respectively 15.7%/17.8% for LBP,
15.3%/33.4% for PGP and 27.9%/30.7% for the combination.
Risk factors for pelvic pain during pregnancy include previous LBP and pelvic trauma (Elden
2016 Level IV, n=371). The group with pre-existing pain may present a more complex picture that
may be more resistant to interventions, although studies do not always examine this groupseparately. Recommendations to improve the consistency of reporting in research using a Core
Outcome Set for PGP have been proposed (Wuytack 2018 GL).
ExerciseA Cochrane review of interventions to prevent or reduce pain severity, functional disability or
absenteeism (in addition to usual prenatal care) examined 15 RCTs in LBP, 6 RCTs in PGP and 13
RCTs in LBP/PGP combination (Liddle 2015 Level I [Cochrane], 34 RCTs, n=5,121). For women withpregnancy related LBP, comparing land-based exercise with usual care provides low quality
evidence for exercise leading to reduced LBP and disability (SMD -0.64; 95%CI -1.03 to -0.25)(7 RCTs, n=645). For PGP alone, low quality evidence shows no significant difference in the numberof women reporting pain when comparing exercise with information about pain management
and usual prenatal care (RR 0.97; 95%CI 0.77 to 1.23) (2 RCTs, n=374). For combined LBP and PGP,
there was moderate quality evidence for reduced pain and related sick leave after participation
in a 12 wk program of land-based exercise in various formats (RR 0.76; 95%CI 0.62 to 0.94)(4 RCTs, n=1,062).
Two further systematic reviews investigated the preventive beneficial effect of exercise. The
first assessed prenatal exercise impact on LBP, PGP and lumbopelvic pain ( Davenport 2019 Level
III-3 SR, 23 RCTs & 9 studies, n=52,297) (13 RCTs overlap with Liddle 2015). Prenatal exercise does not
reduce the incidence of these conditions (13 RCTs), either in pregnancy or the postpartum period,
but exercise in pregnancy is associated with lower pain severity during pregnancy and the early
postpartum period vs non-exercisers (SMD -1.03; 95%CI -1.58 to -0.48) (15 RCTs). Exercise inpregnancy reduces the risk of LBP in pregnancy by 9% (RR 0.91; 95%CI 0.83 to 0.99) (7 RCTs,
n=1,175), whereas it has no protective effect on PGP (RR 0.99; 95%CI 0.81 to 1.21) (4 RCTs, n=565)
or lumbopelvic pain (RR 0.96; 95%CI 0.90 to 1.02) (8 RCTs, n=1,737) (Shiri 2018 Level I [PRISMA],
11 RCTs, n=2,347) (7 RCTs overlap with Liddle 2015 and 9 RCTs overlap with Davenport 2019). However,
exercise prevented new episodes of sick leave due to lumbopelvic pain (RR 0.79; 95%CI 0.64 to0.99) (3 RCTs, n=1,168).
In a cohort prevention intervention study, not included in the above systematic reviews,
women who undertook high impact exercise 3 to 5 times per wk had a lower risk of developing
PGP in pregnancy vs non-exercisers (RR 0.86; 95%CI 0.77 to 0.96) (Owe 2016 Level III-2, n=39,184).

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Manual therapies
Manual therapy interventions (including craniosacral therapy, osteopathic manipulative
treatment, chiropractic interventions, massage and partner-delivered massage) reduce theintensity of pregnancy-related back and pelvic pain vs usual care and relaxation, but not to shaminterventions (Hall 2016 Level I [PRISMA], 10 RCTs, n=1,198).
Pelvic belts
Use of a soft vs rigid pelvic belt was examined in two small non-blinded RCTs, with no nontreatment arm. There was no difference in function but pain was reduced vs the previous 24 h
(Flack 2015 Level II, n=20, JS 2). Combining data from both groups, function and pain were improvedat three wks (MD -2.3/10; 95%CI -1.2 to -3.5). In de novo PGP, two different pelvic support belts
were well tolerated and reduced pain intensity by 20/100 (Bertuit 2018 Level II, n=46, JS 2).
Magnesium
Oral magnesium therapy did not reduce the frequency or severity of painful leg cramps during
pregnancy (Nygaard 2008 Level II, n=45, JS 2).
9.1.2.2 | Meralgia paraesthetica and other compressive neuropathies
These variable conditions comprise some or all of the sensations of pain, tingling and numbness
in the lateral thigh affects pregnant women more than a nonpregnant population (OR 12.0;
95%CI 1.2 to 118.0) (van Slobbe 2004 Level III-2). Multiple therapies have been reported but havenot been fully evaluated or compared, including ice packs, local infiltration with steroid and local
anaesthetic, topical lignocaine or capsaicin, TENS, pharmacological therapy (TCAs, antiepileptics)
and surgical intervention (Harney 2007 NR; Van Diver 1995 NR). Other compressive neuropathies,
such as carpal tunnel syndrome and Bell's palsy, also occur more commonly during pregnancy(Sax 2006 NR).
9.1.2.3 | Diastasis symphysis pubis
Diastasis of the symphysis pubis is defined as the separation of the pubic bones. It may occur
during pregnancy, and following either operative or non-operative delivery. This occasionallydisabling disorder (sometimes also called osteitis pubis or diastasis pubis) has a quoted incidenceof 1:600 (Taylor 1986 Level IV) and can produce persistent pain; but there are limited data to
inform management (Aslan 2007 NR).
Severe traumatic separation is rare and is heralded by a sensation of the separation
occurring, associated with severe pain and swelling at the pubic symphysis. Evidence regarding
management is from case series (Urraca-Gesto 2015 Level IV SR, 4 studies & 14 case reports, n=47
[diastasis symphysis pubis]; Chawla 2017 Level IV, n=2). Recommended management often initially
includes lateral decubitus bed rest with a pelvic girdle and analgesia followed by mobilisationand physiotherapy to reinstate mobility. Rarely surgery is required for cases that do not resolvewith spontaneous treatment (Buitendyk 2018 CR).

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1. Exercise reduces low back and pelvic girdle pain during pregnancy (S) (Level I [Cochrane
Review]).
2. Manual therapy interventions reduce intensity of pregnancy-related back and pelvic pain
versus usual care and relaxation, but not to sham interventions (N) (Level I [PRISMA])
The following tick box represents conclusions based on clinical experience and expert
opinion: The use of a pelvic support belt may reduce pelvic girdle pain during pregnancy (N).

9.1.3 | Management of acute pain during labour and after birthPain during labour and birth represents a complex interaction of multiple physiological andpsychological factors involved in parturition. Women’s desires for and expectations of pain relief
during labour and delivery vary widely. High-quality pain relief does not necessarily equate witha high level of satisfaction. Non-analgesic interventions (eg support person during labour or
education) can provide a significant improvement in satisfaction with the experience of labourand childbirth (Taheri 2018 Level I [PRISMA], 20 RCTs, n=22,800).
Severe pain during labour is one of several factors associated with post-traumatic stresssymptoms following birth (Slade 2006 NR). Personality traits, anxiety and analgesic expectations
partially predict labour pain, epidural analgesic consumption and satisfaction (Carvalho 2014 Level
IV, n=39).
9.1.3.1 | Systemic analgesia in labour pain
Nonopioids
A variety of nonopioids (NSAIDs, paracetamol, antispasmodics, sedatives and antihistamines)
have been investigated with regard to their effect in labour pain ( Othman 2012 Level I [Cochrane],
19 RCTs, n=2,863). Most of these studies are very old (>30 y) and show very limited efficacy vsplacebo and inferior efficacy vs opioids. Sedatives may have a limited benefit vs placebo withregard to analgesia and satisfaction. There is insufficient evidence for the effectiveness of
nonopioids to manage pain during labour.
However, a few studies subsequent to this review show some efficacy of nonopioids in labour
pain. IV paracetamol 1 g and IM tramadol 1 mg/kg provide similar analgesia in labour, buttramadol recipients had a longer first stage of labour and more sedation and nausea ( Kaur Makkar
2015 Level II, n=60, JS 1). IV paracetamol 1 g reduced labour pain slightly at 2, 3 and 4 h after
injection (Zutshi 2016 Level II, n=200, JS 4), but was inferior to IV morphine (Ankumah 2017 Level II,
n=40, JS 3). As an adjunct to patient-controlled epidural analgesia (PCEA), IV paracetamol 1 g
decreased mean epidural infusion rate (7.03 ml/h [ 0.83] vs 8.12 ml/h [ 1.34]) and demandbolus requirements (1.0 [0.93] vs 1.43 [SD 0.90]) (Gupta 2016 Level II, n=80, JS 5).
Opioids
Systemic opioids are used in labour, although practice varies, and their use in Australia isdeclining (21.8% at 2011) (Li 2011 Level IV).

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The following conclusions are for healthy women with an uncomplicated pregnancy giving
birth at or near term when parenteral opioids were compared to no treatment, placebo, anotheropioid or TENS (Smith 2018b Level I [Cochrane], 61 RCTs, n>8,000):• Parenteral opioids provide moderate pain relief in labour;• Maternal satisfaction is variable where reported;• Opioids cause sedation, nausea and vomiting;• For most outcomes there was no good quality evidence of differences between
treatment groups.
There was insufficient evidence to assess the safety of opioids in labour. The quality of theevidence for pain and pain relief outcomes was predominantly poor or very poor.
Opioid analgesia vs epidural analgesia provides inferior pain relief overall (5 RCTs, n=1,133),with less maternal satisfaction (17 RCTs, n=1,911) (Anim-Somuah 2018 Level I [Cochrane], 40 RCTs,
n=12,389).

IN or SC fentanyl was preferred by parturients to IM pethidine, when surveyed six wk after
birth (Fleet 2017 Level II, n=116, JS 2)
Remifentanil intravenous PCA
In comparison to other systemic opioids, remifentanil offers an advantage due to its rapid
metabolism. In some countries, remifentanil IV PCA is used for labour analgesia as an alternative
to both epidural analgesia and other systemic opioids (Devabhakthuni 2013 NR). In the UK, 49% ofobstetric wards use IV PCA with remifentanil as the most common agent followed by morphineand fentanyl. In Belgium, 36% of obstetric wards use IV PCA, with remifentanil being the mostcommonly used opioid (77%).
Remifentanil IV PCA in women with low-risk pregnancies (higher risk groups were excluded)
was compared with other forms of parenteral analgesia in labour ( Weibel 2017 Level I [Cochrane],
19 RCTs, n=3,569):
Satisfaction• Women receiving remifentanil IV PCA are more satisfied with pain relief than women
having other forms of opioids (IV/IM) (SMD 2.11; 95%CI 0.72 to 3.49) (4 RCTs, n=216), butsatisfaction is less than for women in the epidural group (SMD 0.22; 95%CI 0.04 to 0.40);
Note: reversal of conclusion
This reverses the Level I key message in the previous edition of this document; preceding
RCTs had described remifentanil IV PCA as providing superior satisfaction vs epidural
techniques.
Pain relief• Remifentanil IV PCA vs other opioids administered IV/IM provides better pain relief at
1 h (SMD -1.58/10; 95%CI -2.69 to -0.48);• Remifentanil IV PCA vs epidural analgesia shows higher pain scores at 1 h (SMD 0.57;
95%CI 0.31 to 0.84) (6 RCTs, n unspecified);
Additional analgesia• Remifentanil IV PCA lowers the risk of needing additional analgesia vs other opioids(IV/IM) (RR 0.57; 95%CI 0.4 to 0.81), while there is no evidence that remifentanil IV PCA
reduces the requirement for additional analgesia vs other opioids via PCA;
• Remifentanil IV PCA is associated with a higher risk of needing rescue analgesia vsepidural analgesia (RR 9.27; 95%CI 3.73 to 28.03) (6 RCTs, n=1,037);

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Adverse events• Data on adverse events is limited. Low quality evidence demonstrates women receiving
remifentanil IV PCA experience more maternal respiratory depression vs epidural
analgesia (SMD 0.91; 95%CI 0.51 to 1.62) (3 RCTs, n=687);• Newborns of mothers receiving remifentanil IV PCA vs epidural analgesia, do not havean increased risk of Apgar scores < 7 at 5 min (5 RCTs, n=1,322).
There is mostly low-quality evidence to inform practice; further work is needed on maternal
and fetal safety outcomes (maternal respiratory depression, Apgar score) and on optimal modeand regimen of remifentanil administration (Weibel 2017 Level I [Cochrane], 19 RCTs, n=3,569). A
concurrent SR, comparing remifentanil IV PCA to epidural analgesia, finds higher pain scores at
1 h (WMD 1.33/10; 95%CI 0.30 to 2.36) and increased rates of hypoxaemia (OR 7.48; 95%CI 3.42
to 16.36); there were no differences at 2 and 3 h for analgesia, satisfaction or adverse effects
except for overall reduced rates of pruritus (OR 0.54; 95%CI 0.32 to 0.89) ( Lee 2017 Level I[PRISMA], 8 RCTs, n=2,351) (7 RCTs overlap).
Parturients having remifentanil IV PCA vs IM pethidine prn had lower pain scores (MD
13.9/100; 95%CI 21.4 to 6.4), lower conversion to epidural analgesia (19 vs 41%) but with agreater frequency of needing supplemental oxygen (41 vs 1%) ( Wilson 2018 Level II, n= 401, JS 3).
Remifentanil IV PCA achieved better median pain relief scores vs inhaled nitrous oxide (N2O)(2.5/10 vs 0.5) (Volmanen 2005 Level II, n=15, JS 3).
As a potent opioid, remifentanil carries the risk of severe maternal respiratory depression(Van De Velde 2016 NR; Muchatuta 2013 NR). Oxygen desaturation (<90%) is frequent (70% of
women studied) even when continuous supplemental oxygen is administered ( Messmer 2016
Level IV, n=61). A number of respiratory (Bonner 2012 CR; Pruefer 2012 CR) and evencardiorespiratory arrests (Marr 2013 CR) have been reported with its use. Therefore, use of
remifentanil IV PCA is only recommended if there is one-on-one continuous presence of a
midwife, with both continuous oxygen saturation and cardiotocograph (CTG) monitoring (as anindirect method of detecting global hypoxaemia) (Goudra 2013 NR; Muchatuta 2013 NR). In view ofthese risks and the monitoring required, remifentanil IV PCA should not be regarded as analternative to epidural analgesia based purely on economic considerations or convenience(Kranke 2013 NR). Remifentanil IV PCA has been recommended when neuraxial techniques arecontraindicated.
9.1.3.2 | Inhalational analgesia
A meta-analysis of inhaled analgesia for pain management in labour compared various volatile
agents (flurane derivatives) and N2O to each other, placebo or no analgesia (Klomp 2012 Level I[Cochrane], 26 RCTs, n=2,959). Flurane derivatives (multiple volatiles studied, most recently
sevoflurane) provide better pain relief than inhaled N2O in first stage of labour; they result in
lower pain intensity (MD 14.4/100; 95%CI 4.4 to 24.4) (3 RCTs, n=70) and higher pain relief scores(MD -16.3/100; 95%CI -26.9 to -5.8) (2 RCTs, n=70) but cause more drowsiness. Inhaled N2O causes
more nausea vs flurane derivatives (RR 6.60; 95%CI 1.85 to 23.52) (2 RCTs, n=98). However, trial
design was often poor including lack of blinding for volatile agents.
Subgroup analysis of inhaled N2O shows minimal difference in analgesic effect vs placebo (RR
0.06; 95%CI 0.01 to 0.34) (MD -3.5/100; 95%CI -3.75 to -3.25) (Klomp 2012 Level I [Cochrane], 3 RCTs
[N2O], n=819). A subsequent systematic review confirms some analgesic efficacy in labour, but
only two studies were of good quality (Likis 2014, Level IV SR, 58 studies, n=20,266) (1 RCT overlap).
Inhaled N2O provides less pain relief than epidural analgesia, but more than pethidine, bathing,showering or acupuncture. Maternal satisfaction with analgesia during their birth experience isheterogeneous and difficult to assess. A majority of women using inhaled N2O report a positive
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experience (57%), but also report less satisfaction with analgesia (54%) vs epidural analgesia(94%) (Likis 2014, Level IV SR, 58 studies, n=20,266). The maternal adverse effects of inhaled N2O arenausea (RR 43.1; 95%CI 2.6 to 707) (1 RCT, n=509), vomiting (RR 9.1; 95%CI 1.2 to 69) (2 RCTs,
n=619), dizziness (RR 114; 95%CI 7.1 to 1,834) (1 RCT, n=509) and drowsiness (RR 77.6; 95%CI 4.8
to 1,255) (1 RCT, n=509) (Klomp 2012 Level I [Cochrane], 3 RCTs [N2O], n=819); the wide confidence
interval in the latter two outcomes suggests significant uncertainty in the estimate. Apgar scores
are not different for inhaled N2O vs no analgesia.
9.1.3.3 | Neuraxial analgesia in labour pain
Ultrasound guidance for epidural and intrathecal needle insertion
The use of ultrasound as an aid to improve successful placement of an epidural catheter or
intrathecal needle is helpful. It can reduce the risk of failed (RR 0.21; 95%CI 0.10 to 0.43) ortraumatic intrathecal needle and epidural catheter positioning (RR 0.27; 95%CI 0.11 to 0.6) andthe number of needle insertions and redirections (Shaikh 2013 Level I [PRISMA],
14 RCTS, n=1,334)
Epidural analgesia
Epidural analgesia vs systemic opioid analgesia
Epidural analgesia vs opioid analgesia (Anim-Somuah 2018 Level I [Cochrane], 40 RCTs, n=12,389 [34
RCTs vs opioids, n=10,440]):• Provides better pain relief overall (SMD -2.64; 95%CI -4.56 to -0.73) (5 RCTs, n=1,133),with a higher proportion rating their pain relief as ‘excellent’ or ‘very good’ (RR 1.47;
95%CI 1.03 to 2.08) (17 RCTs, n=1,911);
Note: reversal of conclusion
This reverses the Level I key message in the previous edition of this document; a precedingmeta-analysis had described no difference in maternal satisfaction with epidural
analgesia vs systemic opioid analgesia.
•
•
•
•
•
•

•

•

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Achieves substantial decreased need for additional analgesia vs opioid analgesia (RR
0.10; 95%CI 0.04 to 0.25) (16 RCTs, n=5,099);
Achieves lower rate of respiratory depression needing supplemental oxygen
administration (RR 0.23; 95%CI 0.05 to 0.97) (5 RCTs, n=2,031);
Achieves less nausea and/or vomiting (RR 0.62; 95%CI 0.45 to 0.87) (15 RCTs, n=4,440);
Increases duration of first stage (MD 32.28 min; 95%CI 18.34 to 46.22) ( 9 RCTs, n=2,259)
and second stage of labour (MD 15.4 min; 95%CI 9.0 to 21.8) (16 RCTs, n=4,979);
May increase oxytocin augmentation (RR 1.12; 95%CI 1.00 to 1.26) (19 RCTs, n=8,351);
Increases the rate of assisted vaginal delivery (RR 1.44; 95%CI 1.29 to 1.60) ( 30 RCTs,
n= 9,948). However, a post-hoc analysis (assessing only trials after 2005, which used
lower concentrations of local anaesthetic) found no increase in assisted vaginal birth (RR
1.19; 95%CI 0.97 to 1.46);
Does not increase the rate of Caesarean section overall (RR 1.07, 95%CI 0.96 to 1.18)(33 RCTs, n=10,350) or the rate of Caesarean section for fetal distress (RR 1.32, 95%CI
0.97 to 1.79) (12 RCTs, n=5,753);
Reduces the risk of fetal acidosis (cord pH<7.2) (RR 0.81; 95%CI 0.69 to 0.94) ( 8 RCTs,
n=4,783) and need for naloxone administration to newborns (RR 0.15; 95%CI 0.10 to0.23) (10 RCTs, n=2,645); with no increase in admission to a special care/neonatal

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intensive care unit (8 RCTs, n=4,488) and no increase in the rate of Apgar score < 7 at 5
min (1 RCT, n=60);
Does not increase long-term backache (2 RCTs, n=814), headache (4 RCTs, n=1,938),
postnatal depression (1 RCTs, n=313) or itching (8 RCTs, n=2,900).

The most common complications caused by epidural analgesia are maternal hypotension(RR 11.34; 95%CI 1.87 to 67.95) (10 RCTs, n=4,212), motor block (RR 31.67; 95%CI 4.16 to 245)
(3 RCTs, n=322), urinary retention (RR 14.18; 95%CI 4.52 to 44.45) (4 RCTs, n=343) and maternal
fever (RR 2.51; 95%CI 1.67 to 3.77) (9 RCTs, n=4,276) (Anim-Somuah 2018 Level I [Cochrane], 40 RCTs,
n=12,389).
These Cochrane review results are influenced by substantial heterogeneity for pain relief,maternal satisfaction, need for additional means of pain relief, length of second stage of labourand oxytocin augmentation. This heterogeneity did not seem to relate to subgroup or sensitivity
confounders, where data could be analysed. None of these studies reported on the rare, serious
adverse effects of epidural analgesia (see Sections 5.6.5.1 to 5.6.5.3). However, despite evidence
for safety, in a case series of women before childbirth, 39% expressed concerns about neuraxial
analgesia and 46% of 129 women deciding against epidural analgesia did so because of concerns
about the technique (Toledo 2013 Level IV, n=509). Safety data from the above Cochrane review
could help inform pregnant women about these concerns.
Epidural vs no analgesic pharmacological treatment
Epidural analgesia vs no analgesic pharmacological treatment (Anim-Somuah 2018 Level I[Cochrane], 40 RCTs, n=12,389 [7 RCTS vs no pharmacological treatment, n=897]):

•
•
•
•

•

Epidural analgesia results in less pain (SMD -9.55; 95%CI -12.91 to -6.19) (2 RCTs, n=120);
Epidural analgesia achieves a higher proportion rating their satisfaction with pain relief
as excellent or very good (RR 1.32, 95%CI 1.05 to 1.65) (1 RCT, n=70);
Epidural analgesia is associated with a lower Caesarean section rate vs placebo or notreatment (RR 0.46, 95%CI 0.23 to 0.90) (5 RCTs, n=578);
There are no differences between groups for the following outcomes: nausea andvomiting (2 RCTs), pruritus (1 RCT), fever (1 RCT), shivering (1 RCT), drowsiness (1 RCT), andurinary retention (2 RCTs);
Other maternal adverse events and fetal outcomes were not reported.

Epidural vs acupuncture
Epidural analgesia vs electrical acupoint stimulation results in lower pain scores (SMD -53/100;
95%CI -58 to -48) (1 RCT, n=60) (Anim-Somuah 2018 Level I [Cochrane], 40 RCTs, n=12,389).
Epidural versus continuous midwifery support (one-to-one, with non-epidural analgesia):
All 493 women receiving epidural analgesia, and 494 out of 499 women receiving continuous
midwifery support rated their pain relief as 'excellent or very good' (RR 1.01, 95% CI 1.00 to 1.02);
however, pain intensity was not reported (1 RCT, n=992) (Anim-Somuah 2018 Level I [Cochrane], 40
RCTs, n=12,389). No woman receiving epidural analgesia requested additional means of pain relief
vs 262 out of 499 receiving continuous midwifery support (1 RCT, n=992).
Timing of epidural
A meta-analysis assessed outcomes of early vs late initiation of epidural analgesia for labour,
showing no clinically significant differences dependent on timing of epidural analgesia ( Sng 2014
Level I [Cochrane], 9 RCTs, n=15,752). Specifically, there are no differences in rate of instrumental
birth (RR 0.93; 95%CI 0.86 to 1.01) (8 RCTs, n=15,379), duration of second stage of labour (MD 3.22 min; 95%CI -6.71 to 0.27) (8 RCTs, n=14,982) or adverse fetal outcomes.

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The use of labour epidural analgesia given to every parturient at the onset of labour (routineuse), when compared to maternal request for epidural analgesia, found no significant increasein Caesarean deliveries (34.8% vs 26.7%; 95%CI -0.1 to 16.3) (Wassen 2015 Level II, n= 493, JS 3).
There was more hypotension (difference 9.5%; 95%CI 4.2 to 14.9) and motor blockade(difference 6.8%; 95%CI 1.1 to 12.5) in the routine use group.
Local anaesthetic concentrations
Epidural analgesia with low concentrations of bupivacaine (≤0.1%) or ropivacaine (≤0.17%) vsnon-epidural methods of analgesia shows no differences in the duration of the first or second
stage of labour, or the rate of instrumental birth or Caesarean section (Wang 2017 Level I [PRISMA],
10 RCTs, n=1,809).
A prior meta-analysis favours lower concentrations of bupivacaine (≤0.1%) (8 RCTs, n=852) orropivacaine (≤0.17%) (3 RCTs, n=293) over higher concentrations for epidural analgesia in labour(Sultan 2013 Level I, 11 RCTs, n=1,145). Low concentrations are associated with fewer assisted
vaginal births (OR 0.70; 95%CI 0.56 to 0.86), a shorter second stage of labour (WMD -14.03 min;
95%CI -27.52 to -0.55), less motor block (OR 3.9; 95%CI 1.59 to 9.55), greater ability to ambulate(OR 2.8; 95%CI 1.1 to 7.14), and less urinary retention (OR 0.42; 95%CI 0.23 to 0.73) but nodifference in Caesarean section rate (OR 1.05; 95%CI 0.82 to 1.33).
However, lower vs higher concentrations may be associated with increased pruritus (OR 3.36;
95%CI 1.00 to 11.31) and are associated with a higher rate of Apgar scores <7 at 1 min (OR 1.53;
95%CI 1.07 to 2.21), but not persisting at 5 min. No differences are apparent for pain, nausea
and vomiting, hypotension, fetal heart rate abnormalities or need for neonatal resuscitation.
Comparison of ropivacaine vs bupivacaine (alone or with fentanyl)
Use of bupivacaine vs ropivacaine as the sole agent for epidural analgesia shows no differencewith regard to mode of birth, maternal satisfaction or neonatal outcomes ( Halpern 2003 Level I,
23 RCTs, n=2,074).
The combination of fentanyl, with either ropivacaine or bupivacaine, exhibits comparable
efficacy and safety (Li 2015 Level I, 9 RCTs, n=556). However, ropivacaine with fentanyl resulted ina significantly lower frequency of motor block (OR 0.31; 95%CI 0.18 to 0.51) despite a longer
second stage than bupivacaine/fentanyl (MD 6.87; 95%CI 10.98 to 2.77). The concentrations
used varied widely (by a factor of 30), and equipotent concentrations were not compared.
Adjuvant dexamethasone
The analgesic effect of dexamethasone when added to epidural local anaesthetic improves
analgesia, but this may be due to a systemic effect. The addition of dexamethasone 8 mg to
epidural analgesia in labour (levobupivacaine with fentanyl via PCEA) resulted in a reduced
requirement for the PCEA solution (7.0 ml ± 1.2 vs 8.4 ml ± 2.6) ( Dhal 2018 Level II, n=60, JS 5). The
addition of dexamethasone 4 mg to single dose epidural levobupivacaine extended the durationof analgesia (81.6 min ± 14.4 vs 63.8 min ± 12.8) (Wahdan 2019 Level II, n=60, JS 4), this may be duea systemic effect (see also Section 4.12.2).
Adjuvant alpha-2 agonists
Epidural alpha-2 agonists (clonidine and neostigmine) as adjuvants to local anaesthetics in labour
prolong analgesia (MD 37.79; 95% CI 9.37 to 66.21) and reduce hourly local anesthetics andopioid administration (MD -5.49; 95% CI -6.78 to -4.21) (Zhang 2015 Level III-2 SR, 4 studies, n=280).
There is no effect on total duration of labour, mode of delivery and Apgar scores.
The addition of dexmedetomidine to epidural local anaesthetic improved labour analgesia asbolus 0.5mcg/kg (Zhao 2017 Level II, n=80, JS 3) or infusion 0.5mcg/mL (Zhang 2018 Level III-2 EH,n=60). An RCT has compared 0.25, 0.5, 0.75 and 1 mcg/mL (with no local anaesthetic only arm)and the optimum dose is uncertain (Wangping 2017 Level II, n=100, JS 3) (see also Section 4.9.2.1).

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Adjuvant neostigmine
Adding neostigmine (in widely varying doses) to local anaesthetics (bupivacaine or ropivacaine)± opioid for neuraxial administration in labour analgesia and postoperative analgesia after
Caesarean section permits reduction of local anaesthetic doses (MD -4.08 mg/h; 95% CI -6.7 to 1.5) (Cossu 2015 Level I, 16 RCTs, n= 1,186). Only IT neostigmine (5 RCTs, n=275), but not epidural
neostigmine (11 RCTs, n=911), increases risk of nausea (OR 9; 95%CI 4.7 to 17.1). Neuraxial
neostigmine reduces risk of pruritus (OR 0.4; 95%CI 0.2 to 0.7) (6 RCTs), but does not increase
hypotension, sedation or affect fetal outcome (see also Section 4.13.2).
Technique of epidural administration
Patient-controlled epidural analgesia (PCEA) for labour pain
PCEA can provide effective analgesia but the optimal settings are not clear ( Leo 2008 Level IV;
Loubert 2011 NR). A meta-analysis of PCEA in labour concluded that dilute concentrations ofbupivacaine (0.125%) or ropivacaine (≤ 0.16%), with and without background infusion provide
acceptable analgesia (6 RCTs, n=789) and that use of large bolus doses (6 RCTs, n=588) andbackground infusions (7 RCTs, n=573) with PCEA may improve analgesia and result in reduction ofunscheduled clinician interventions vs other interventions (Halpern 2009 Level I, 30 RCTs, n=4,033[bupivacaine vs ropivacaine 11 RCTs, n=2,083]).
A meta-analysis comparing PCEA with and without a background infusion shows that
continuous background infusion was associated with increased instrumental vaginal birth (RR
1.66, 95%CI 1.08 to 2.56), prolonged second stage of labour (WMD 12.3 min, 95%CI 5.1 to 19.5),
reduced requirement for physician-administered boluses (RR 0.35, 95%CI 0.25 to 0.47), with nodifference in Caesarean section rate (RR 0.83, 95%CI 0.61 to 1.13) (Heesen 2015 Level I [PRISMA], 7
RCTs, n=891).
Programmed intermittent epidural boluses (PIEB)
PIEB for analgesia in labour reduces breakthrough pain incidence vs continuous epidural infusion(20 vs 33%) (RR 0.60; 95%CI 0.39 to 0.92) (Sng 2018 Level I, 10 RCTs, n=797). There are nodifferences for Caesarean section and assisted vaginal delivery rates, duration of labour or Apgar
scores. Hourly local anaesthetic dose in the PIEB group is reduced, but the clinical significance ofthe difference is unclear (MD −1.1 mg/h; 95%CI −1.8 to −0.4) (12 RCTS, n=1,121). Maternalsatisfaction is higher in the PIEB group (5 of 7 RCTs, n=570; data unable to be pooled for effect size).
See also Section 5.6.1.5.
Combined spinal-epidural (CSE) and dural puncture epidural analgesia for labour pain
CSE analgesia provides slightly more rapid onset of pain relief than epidural techniques alone(Simmons 2012 Level I [Cochrane], 37 RCTs, n=3,274). In comparison to traditional epidural
techniques (local anaesthetic concentration ≥0.25% bupivacaine), the time to onset is shorter(MD -2.9 min; 95%CI -5.1 to -0.7) (2 RCTs, n=129), with reduced need for rescue analgesia (RR
0.31; 95%CI 0.14 to 0.70) (1 RCT, n=42), lower rates of urinary retention (RR 0.86; 95%CI 0.79 to0.95) (1 RCT, n=704) and instrumental birth (RR 0.81; 95%CI 0.67 to 0.97) (6 RCTs, n=1,015).
However, a comparison of CSE with low-dose epidurals (local anaesthetic concentrationequivalent to bupivacaine <0.25%; reflecting current practice) shows a faster onset of effect (MD-5.4 min; 95%CI -7.3 to -3.6) (5 RCTs, n=461), but no difference in maternal satisfaction (RR 1.01;
95%CI 0.98 to 1.05) (7 RCTs, n=520) and an increased rate of mild pruritus (RR 1.80; 95%CI 1.22 to2.65) (11 RCTs, n=959).
The risk of unilateral block is reduced after CSE vs epidural analgesia (RR 0.48, 95%CI 0.24 to0.97) (Heesen 2014 Level I [PRISMA], 10 RCTs, n=1,722).
Non-reassuring fetal heart rate tracings may be more common with CSE than epidural
analgesia alone (RR 1.31, 95%CI 1.02 to 1.67) (Hattler 2016 Level I [PRISMA], 17 RCTS, n=3,947). The
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mechanism of this effect may be from an abrupt transient reduction in circulatingcatecholamines (Segal 2008 BS).
CSE techniques may be associated with a lower failure rate (6.6%) than standard epidural
analgesia (1.6%) (Booth 2016 Level III-3, n=2,395).
Dural puncture epidural analgesia is a technique similar to CSE, where dural puncture is
performed but no medication is injected intrathecally. There appears to be no certain benefit forthis technique vs standard epidural analgesia (Heesen 2019 Level I [PRISMA], 5 RCTs, n=581).
Intrathecal analgesia for labour pain
Single-injection intrathecal opioids
Single-injection IT opioids are as effective as epidural local anaesthetics for the management ofpain in early labour and they do not affect the rate of nausea or mode of delivery ( Bucklin 2002
Level I, 7 RCTs, n=332). IT opioids increase the risk of fetal bradycardia (NNH 28) and maternal
pruritus (NNH 1.7) in comparison with non-IT opioid analgesia (Mardirosoff 2002 Level I, 24 RCTs,
n=3,513). Adding IT morphine ≤250 mcg to single bolus IT labour analgesia withbupivacaine/fentanyl or bupivacaine/sufentanil prolongs duration of analgesia (60.6 min, range
3 to 155) with no effect on SMD of pain intensity (Al-Kazwini 2016 Level I [PRISMA], 5 RCTs, n=286).
Respiratory depression related to epidural or IT opioids during labour is rare ( Carvalho
2008 NR); see Section 5.7.1.3 for more details.
Intrathecal catheters for labour analgesia
IT microcatheters (24- to 28-gauge) are used infrequently for labour analgesia but may be useful
in some specific cases, such as those patients who are morbidly obese, have significant cardiac
disease or previous spinal surgery (Palmer 2010 NR). Continuous IT medication infusion improved
early analgesia, with no differences in neonatal or obstetric outcomes but more technicaldifficulties vs epidural administration (Arkoosh 2008 Level II, n=429, JS 3); this trial used 28-gauge
catheters and there were no safety concerns. Subsequent case series have used larger catheters:
two have used 23-g successfully (Tao 2015 Level IV, n=113; Tao 2011 Level IV, n=7) with the larger
study reporting a low PDPH rate (2.6%) and a failure rate of 11%, while a further study describeda higher failure rate (20%) with 22-g and 24-g catheters (n=92) and a higher incidence of PDPH
(29%), requiring a blood patch in 18% of these patients (Alonso 2009 Level IV). The authors of thisstudy concluded the risks outweigh the benefits of IT microcatheters as a primary method forlabour analgesia.
Placement of an epidural catheter (20- to 22-g) in women who have experienced anunintentional dural puncture is widely practised. A study comparing IT placement with epiduralplacement of an epidural catheter after unintentional dural puncture ( n=97) reported a similar
PDPH incidence (72 vs 62%) but easier establishment of neuraxial analgesia with the IT method(Russell 2012 Level III-1). Another study found a lower rate of PDPH (42% for IT placement vs 62%
for epidural placement) (OR 2.3; 95%CI 1.04 to 4.86) (Verstraete 2014 Level III-2, n=128).
Comparison of intrathecal ropivacaine with bupivacaine
Single dose IT ropivacaine 0.15%/sufentanil 0.2mcg/mL vs IT bupivacaine 0.125%/sufentanil
0.2mcg/mL for labour pain resulted in lower pain scores (over the time period from 10 min until
full cervical dilatation), and higher satisfaction (94.7% vs 84%) (Li 2018 Level II, n=300, JS 2).
9.1.3.4 | Regional analgesia in labour pain
Paracervical block and pudendal nerve block are the most commonly performed local
anaesthetic PNBs, with a long history of use for pain management in labour.
Local anaesthetic nerve blocks (11 RCTs paracervical; 1 RCT pudendal), using various agents, areeffective (8 RCTs), and superior to placebo (1 RCT, n=200), opioid (2 RCTs, n=129) and nonopioid730

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analgesia (1 RCT, n=100) (Novikova 2012 Level I [Cochrane], 12 RCTs, n=1,549); however it is noted thatthese findings are based on RCTs of unclear quality and limited numbers. Adverse effects are
more common in comparison with placebo (1 RCT, n=200). There is no difference in quality ofanalgesia and satisfaction with analgesia between different local anaesthetics ( 4 RCTs, n=789).
Specifically in comparison to placebo, paracervical blocks with lignocaine 2% are associated withhigher patient satisfaction (RR 32.3; 95%CI 11 to 99) but more adverse effects (RR 29.0; 95%CI
1.8 to 480) (Novikova 2012 Level II [Cochrane], 1 RCT [vs placebo], n=200). In comparison with opioids(IM pethidine or fentanyl IV PCA), nerve blocks provide better pain relief (RR 2.52; 95%CI 1.65 to3.83), without an increase in the rate of assisted vaginal birth (RR 1.02; 95%CI 0.56 to 1.87) or of
Caesarean section (RR 0.23; 95%CI 0.03 to 1.87) (Novikova 2012 Level I [Cochrane], 2 RCTs [vs opioids],
n=129).
Paracervical block was equally efficacious but required supplementation more frequently
than epidural analgesia (Manninen 2000 Level II, n=44, JS 3) and was less effective than singleinjection IT analgesia (Junttila 2009 Level III-2). Serious fetal complications may occur (Shnider 1970
NR), so this technique should be limited to hospitals without other obstetric anaesthesia services(Levy 1999 Level III-2) or for patients with contraindications to neuraxial techniques (Junttila 2009
Level III-2).
9.1.3.5 | Complementary and other methods of pain relief in labour
Continuous or one-to-one support by a midwife or trained layperson during labour reduces
analgesic use, rate of instrumental and operative birth and dissatisfaction, especially if the
support person is not a member of the hospital staff, was present from early labour, or if an
epidural analgesia service was not available (Hodnett 2013 Level I [Cochrane], 22 RCTs, n=15,288).
The effect of continuous midwifery support, with and without epidural analgesia is describedabove (see Section 9.1.3.3).
A qualitative systematic review has assessed women's experiences of pharmacological andnon-pharmacological pain relief for labour (Thomson 2019 Level IV SR, 24 studies, n unspecified).
Overall, experiences were mixed with pharmacological methods assessed as effective, but withadverse effects, while non-pharmacological were described as not as effective, but facilitating
bonding.
For some nonpharmacological or complementary therapies there is weak evidence ofeffectiveness vs standard care:• Water immersion during labour has limited benefit. There is no difference in mode ofdelivery (spontaneous, instrumental or Caesarean), perineal trauma or blood loss.
There is a small reduction in the requirement for regional analgesia (epidural,
intrathecal, paracervical) vs no immersion (39% vs 43%) (RR 0.91; 95%CI 0.83 to 0.99)(5 RCTs; n=2,439) (Cluett 2018 Level I [Cochrane] 15 RCTs, n=3,663). Other maternal outcomes
were not reported. There is insufficient evidence to determine the impact on neonatal
intensive care unit admissions (2 RCTs, n=1,511) or neonatal infection rates(5 RCTs, n=1,295).
•

Acupuncture/Acupressure in labour (Smith 2020 Level I [Cochrane], 28 RCTs, n=3,960) (seealso Section 7.3.2.3):◦ Acupuncture vs sham does not reduce pain scores (2 RCTs, n=325), but does increasesatisfaction with pain relief (RR 2.38; 95%CI 1.78 to 3.19) (1 RCT, n=150) anddecreases use of pharmacological analgesia (RR 0.75; 95%CI 0.63 to 0.89);

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◦

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◦
◦
◦
◦

◦
◦

•

•

•

Acupuncture vs usual care reduces pain scores (4 RCTs, n=495) and use ofpharmacological analgesia (6 RCTs, n=1,059) but does not improve satisfaction(2 RCTs, n=343);
Acupuncture vs no treatment reduces pain scores (1 RCT, n=163);
Acupuncture vs water injection does not reduce use of pharmacological analgesia(1 RCT, n=128);
Acupressure vs sham lowers pain scores (MD -1.93/10; 95%CI -3.31 to -0.55) but has
no effect on use of pharmacological analgesia (6 RCTs, n=472);
Acupressure vs usual care reduces pain scores (SMD -1.07; 95%CI -1.45 to -0.69)(8 RCTs, n=620) and improves satisfaction (1 RCT, n=105);
Acupressure vs both placebo and usual care reduces pain scores (SMD -0.42; 95%CI-0.65 to -0.18) (2 RCTs, n=322) and marginally increases satisfaction with analgesia(1 RCT, n=212);
There was no effect on Caesarean section rate;
Overall, evidence was of low quality with no study at a low risk of bias on all domains.
There is a need for high-quality research that includes sham controls andcomparisons to usual care.

Massage vs standard care reduces pain during first stage of labour (SMD −0.81, 95%CI−1.06 to −0.56) (6 RCTs, n=362), but not second (SMD −0.98/10; 95%CI −2.23 to 0.26)(2 RCTs, n=124) or third stages (SMD −1.03/10; 95%CI −2.17 to 0.11) (2 RCTs, n=122) (Smith
2018a Level I [Cochrane], 10 RCTs, n=1,055). Massage also lessens anxiety during the firststage of labour (MD -16.27; 95%CI −27.03 to −5.51) (1 RCT, n=60), increases sense ofcontrol (MD 14.05; 95% CI 3.77 to 24.33) (1 RCT, n=124) and satisfaction (unable toquantify due to methodology) (see also Section 7.5.2).
The use of birth ball (Swiss ball) exercises for labour pain relief improves pain vs nonuse (SMD -0.9/10; 95% CI -1.3 to -0.6) (Makvandi 2015 Level I, 3 RCTs, n=205). The qualityof the studies was mixed, with most providing little information on the exact methods
they used;
Hypnosis (eight antenatal and one intrapartum intervention) for labour pain reduces
analgesic use (RR 0.73; 95%CI 0.57 to 0.94) (8 RCTs, n=2,916), but has no effect on rate of
spontaneous vaginal birth (6 RCTs, n=2,361), sense of coping with labour (1 RCT, n=420) or
satisfaction with pain relief when combined with either pethidine ( 1 RCT, n=72) or
epidural analgesia (1 RCT, n=127) (Madden 2016 Level I [Cochrane], 9 RCTs, n=2,954);

Note: reversal of conclusion
This reverses the Level I key message in the previous edition of this document; a precedingmeta-analysis had described no effect of hypnosis in the management of labour pain.
•

Relaxation techniques (including yoga, music or audio) has limited and low to very low
quality evidence for reduction in labour pain or improved satisfaction ( Smith 2018a Level
III-1 SR [Cochrane], 15 studies, n=1,731).
For the following interventions, the evidence is not supportive.
• Biofeedback does not affect the use of pharmacological pain relief or the rates ofassisted vaginal birth or Caesarean section (Barragan Loayza 2011 Level I [Cochrane],
4 RCTs, n=186);• Sterile water injections, intra- or subcutaneously, vs saline injection do not reducelabour pain during the first stage of labour, or affect mode of birth or other maternal or
fetal outcomes (Derry 2012 Level I [Cochrane], 7 RCTs, n=766);

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Aromatherapy has no effect on any primary or secondary outcomes in labour ( Smith
2011 Level I [Cochrane], 2 RCTs, n=535);
In labour, TENS has no effect on pain, interventions or outcomes vs sham TENS (10 RCTs)or routine care (7 RCTs), when applied to the back (13 RCTs, n=1,150) or cranium (2 RCTs,
n=140), with the exception of a reduction of reports of severe pain when applied toacupuncture points (2 RCTs, n=190) (Dowswell 2009 Level I [Cochrane], 17 RCTs, n=1,466). The
findings of no analgesic effect were confirmed by two subsequent meta-analyses(Bedwell 2011 Level I, 14 RCTs, n=1,456) (14 RCTs overlap) (Mello 2011 Level I, 9 RCTs, n=1,076)(3 RCTs overlap) (see also Section 7.2).

9.1.3.6 | Analgesia for forceps delivery
Rates of assisted vaginal birth vary throughout the world (10 to 15% in high-resource settings).
Neuraxial analgesia is commonly used for forceps delivery in these settings but local infiltrationand pudendal nerve block are also used, while the rate of general anaesthesia is very low(Osterman 2011 Level IV). Studies in this setting are limited and old (Nikpoor 2013 Level I [Cochrane],
4 RCTs, n=388). Three of these RCTs compared diazepam to other agents for provision of generalanaesthesia, without finding clinically relevant differences. In one RCT, IT analgesia vs pudendal
nerve block resulted in more women regarding their analgesia as adequate (RR 3.36; 95%CI 2.46
to 4.60), with fewer reporting severe pain (RR 0.02; 95%CI 0.00 to 0.27) ( Nikpoor 2013 Level I[Cochrane], 1 RCT [IT]: Hutchins 1980 Level II, n=183, JS 1). The authors conclude that there is a lackof evidence to guide practice.
9.1.3.7 | Pain after Caesarean section
Pain after Caesarean section has been treated by multiple analgesic techniques and multimodal
analgesia is recommended (Sutton 2017 NR); a multimodal bundle of standardised use of
preoperative paracetamol, postoperative comfort education, simethicone PO, postoperative
gum chewing and use of abdominal binders reduced morphine requirements by 61% (Burgess
2019 Level III-1, n=9,313). This approach led to more women receiving less than 20 tablets of
oxycodone (5 mg or 10 mg) at discharge (96.7% vs 26.3).
Pain on POD 1 may be higher than that from many other types of major surgery (Gerbershagen2013 Level III-2, n=456 [Caesarean sections] of total n=70,764).
When asked to rate their pain after Caesarean section, patients using pain scores had
increased pain reporting and a worse experience during the postoperative period than the
comfort score reporting group (Chooi 2013 Level II, n=300, JS 4).
Important considerations in this patient group include transfer of medications via breast
feeding, and facilitating postoperative mobility of the mother for care of the neonate.
Systemic analgesia
Oral analgesia
A meta-analysis of oral analgesia (opioids, tramadol, paracetamol, NSAIDs, coxibs, gabapentin)
for pain after Caesarean section identified mainly small RCTs with contradictory results, notpermitting definitive conclusions regarding the most effective or safest approach ( Mkontwana
2015 Level I [Cochrane], 8 RCTS, n=962). Opioids and nonopioids showed little effect in comparison
to placebo and each other with significant heterogeneity except for ketoprofen 100 mg (RR 0.55;
95%CI 0.39 to 0.79) (1 RCT, n=72). This Cochrane review states based on a single RCT thatgabapentin reduces the need for additional analgesia vs placebo (Short 2012 Level II, n=132, JS 5).
However, the results were incorrectly calculated and the conclusion replaced by a subsequentsystematic review (including this trial) which finds: gabapentin 600 mg improves pain scores on
5th Edition | Acute Pain Management: Scientific Evidence733

movement at 24 h only (MD -11.58/100 VAS; 95%CI -23.04 to -0.12) and increases satisfaction
scores after Caesarean section, with no difference in opioid use, nausea, vomiting, pruritus or
sedation (Felder 2019 Level I [PRISMA], 6 RCTs, n=656). Oral oxycodone was as effective as IV PCA
piritramide (opioid) in this setting, but there was no placebo comparator ( Dieterich 2012 Level II,
n=239, JS 3). Oral naproxen or tramadol were similarly effective, with fewer adverse effects withnaproxen (Sammour 2011 Level II, n=120, JS 3). A study comparing oral oxycodone with IT morphineon top of background oral nonopioid analgesia found comparable analgesia and less pruritus,
but lower maternal satisfaction (McDonnell 2010 Level II, n=111, JS 5).
Parenteral analgesia
IV paracetamol, given before the commencement of Caesarean section, vs placebo reduces
postoperative pain (measured immediately after surgery or during the recovery period) (SMD
−0.72/10; 95%CI −1.31 to −0.13) and reduces postoperative opioid consumption (SMD −0.46;
95%CI -0.828 to -0.092) (Ng 2019 Level I [PRISMA], 5 RCTs, n=409). In women having either
Caesarean section or hysterectomy, IV paracetamol vs oral paracetamol reduced LOS (-11%), useof opioids (-1.6 mg daily morphine equivalent) and opioid-related adverse effects (Urman 2018
Level III-3, n=29,124).
Parenteral (but not oral or rectal) NSAIDs vs placebo after Caesarean section reduce painscores at 12 and 24 h, opioid requirements, drowsiness and sedation, but not PONV (Zeng 2016
Level I, 22 RCTs, n=1,313). In combination with IV PCA morphine, parecoxib and ketorolac had
similar efficacy, but without a placebo control (Wong 2010 Level II, n=66, JS 2).
As mentioned above, IV PCA piritramide (opioid) was as effective as oral oxycodone, but withno placebo comparator (Dieterich 2012 Level II, n=239, JS 3). A continuous IV infusion of tramadolvs IV PCA tramadol resulted in higher tramadol consumption and lower patient satisfaction(Demirel 2014 Level II, n=40, JS 1).
Dexmedetomidine (by IV or neuraxial routes) vs placebo for Caesarean section improves
sensory block and duration of postoperative analgesia (4 RCTs [IT local anaesthetic], n=352) andreduces PONV and shivering (RR 0.26; 95%CI 0.11 to 0.60), with no harmful effects on umbilical
blood gases and Apgar scores at 1 and 5 min (Zhang 2017 Level I [PRISMA], 6 RCTs, n=458). Review
of further systemic dexmedetomidine studies reveal beneficial effects on PONV and shivering(Bao 2017 Level I, 12 RCTs, n=986) (2 RCT overlap); however, IT dexmedetomidine reduces only
shivering, without an effect on PONV (Miao 2018 Level I [PRISMA], 6 RCTs, n=360) (2 & 3 RCTs overlap).
Dexmedetomidine had an opioid-sparing effect when combined with sufentanil PCA (Nie 2014
Level II, n=120, JS 5); this was more pronounced when dexmedetomidine was continued in the
PCA after an initial bolus than if an initial bolus only was administered.
IV dexamethasone 10 mg reduced nausea and vomiting following Caesarean section underbupivacaine/morphine spinal anaesthesia, with fewer complaints of pain at rest and on
movement in the first 24 h vs saline control (Cardoso 2013 Level II, n=70, JS 5). However, IV
dexamethasone 8 mg vs placebo had no effect on opioid consumption after Caesarean section(Ituk 2018 Level II, n=52, JS 5).
Low-dose ketamine bolus and subsequent low-dose infusion for 12 h resulted in an opioidsparing effect for 24 h without any further benefits or improved long-term outcome (Suppa 2012
Level II, n=56, JS 4). However, three different intraoperative IV bolus doses of ketamine (0.25, 0.5,
and 1 mg/kg) had no effect on postoperative pain, opioid requirements or long-term outcomes
after Caesarean section (Bilgen 2012 Level II, n=140, JS 4). Similarly, there were no obvious benefits
when IV ketamine 10 mg was added to IT morphine and IV ketorolac (Bauchat 2011 Level II, n=188,
JS 5). In contrast, IV ketamine 0.15 mg/kg given in addition to a bupivacaine spinal anaesthetic
resulted in a longer duration and better quality of early postoperative analgesia (Menkiti 2012
Level II, n=60, JS 4). There are conflicting RCTs examining the effect of low dose ketamine on734

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reduction of pain after Caesarean section and no conclusion about efficacy can be made in thispatient group (Rahmanian 2015 Level II, n=160, JS 2; Behdad 2013 Level II, n=60, JS 4; Han 2013 Level II,
n=40, JS 2).
Neuraxial analgesia
Neuraxial alpha-2 agonists
Neuraxial clonidine 50 to 150 mcg (epidural and IT) modestly enhances postoperative analgesia
in women having Caesarean section under neuraxial anaesthesia (Allen 2018 Level I [PRISMA],
12 RCTs [IT administration] [9 RCT overlap with Crespo 2017] & 6 RCTs [epidural administration: 2 RCTs
bolus followed by infusion, 2 RCTs repeated bolus, 2 RCTs single bolus], n=1,169) . Neuraxial clonidine

reduces morphine consumption (MD -8.7 mg; 95% CI -15.3 to -2.0); this effect is less with IT
administration (MD -4.3 mg; 95%CI -7.0 to -1.5) than with epidural administration (MD -18.9 mg;
95%CI -34.8 to -3.0). It also increases the time to first analgesic request (MD 150 min; 95%CI
110 to 190) vs placebo, but does not improve pain scores on movement at 0 to 6 h. Neuraxial
clonidine increases the risk of intraoperative hypotension (49%) vs placebo (33%) and of
intraoperative sedation. Risks for bradycardia, nausea/vomiting and pruritus are inconclusive.
There was no case of respiratory depression and neonatal outcome was not different in control
and study group.
Epidural local anaesthetics
A comparison of four different concentrations of ropivacaine (0.2, 0.1, 0.05, or 0.025%) withfentanyl 3 mcg/mL and adrenaline 0.5 mcg/mL, showed that the very low concentration 0.025%
is effective for PCEA after Caesarean section (Cohen 2015 Level II, n=48, JS 5).
All patients receiving this concentration could ambulate, and none had urinary retention.
PCEA with 0.2% ropivacaine vs epidural morphine 2 mg every 12 h, provided equivalentanalgesia (Chen 2011 Level II, n=120, JS 5); although it resulted in more motor weakness, this did
not impair ambulation. Other adverse effects (pruritus, nausea, vomiting and urinary retention)
occurred more often after epidural morphine, resulting in improved satisfaction scores with
PCEA ropivacaine. Intrathecal morphine may be more cost-effective than PCEA after Caesarean
section (Vercauteren 2002 Level II, n=53, JS 2). No differences were found between PCEA with 0.1%
levobupivacaine vs 0.06% combined with fentanyl 2 mcg/mL (Chen 2014 Level II, n=80, JS 4).
Epidural opioids
After Caesarean section, single-dose epidural morphine (1 to 8 mg) increases the time until
rescue analgesic is required and decreases pain and postoperative morphine requirements for
24 h vs systemic opioid analgesia (Bonnet 2010 Level I [QUOROM], 10 RCTs, n=431); however, there
is an increased incidence of pruritus (RR 2.7; 95%CI 2.1 to 3.6) and nausea (RR 2.0; 95%CI 1.2 to
3.3). The requirement for rescue IV opioid reduces as the morphine dose increases from 1.25 to3.75 mg, with no apparent additional benefit from 5 mg (Palmer 2000 Level II, n=60, JS 5). Epiduralmorphine 1.5 mg was noninferior to 3 mg and caused fewer adverse effects ( Singh 2013b Level II,
n=90, JS 5). Extended-release epidural morphine 10 mg decreased supplemental opioid use andimproved functional ability scores for 48 h vs 5 mg of conventional epidural morphine (Carvalho
2005 Level II, n=79, JS 3).
Epidural magnesium
Bupivacaine/morphine/magnesium for epidural administration was superior tobupivacaine/morphine or bupivacaine/magnesium with regard to pain relief, time to rescue
analgesia and patient satisfaction (Sun 2012 Level II, n=200, JS 5), but the neurotoxicity of neuraxial
magnesium has not been adequately investigated ( Albrecht 2013b Level I [PRISMA], 25 RCTs [IVmagnesium], n=1,461).
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Intrathecal analgesia
Intrathecal opioids
IT morphine and other opioids effectively reduce pain and analgesic requirements post
Caesarean section (Dahl 1999 Level I, 15 RCTs, n=535).
Lower-dose (50 to 100mcg) vs higher-dose intrathecal morphine (>100 to 250mcg) has
shorter time to first request for analgesia (MD 4.5 h; 95%CI 1.9 to 7.1) but with less nausea andvomiting (OR 0.44; 95%CI 0.27 to 0.73]) and pruritus (OR 0.34; 95%CI 0.20 to 0.59) (Sultan 2016
Level I, 11 RCTs, n=480). Acknowledging the combined sample size is small, there is no differencein pain score at 12 h nor in morphine consumption at 24 h after surgery. Thus, the higher dose
provides some additional analgesic benefit at the expense of greater adverse effects.
A retrospective study of IT morphine 200 mcg vs 100 mcg had similar findings with sparing ofadditional opioids, but more nausea requiring treatment and more pruritus (Wong 2013 Level III-2,
n=241).
IT morphine 100 mcg added to IT fentanyl vs IT fentanyl alone was superior with regard toanalgesia and its duration as well as patient satisfaction, despite increased adverse effects(pruritus, nausea and vomiting) (Sawi 2013 Level II, n=60, JS 4).
IT hydromorphone 40 mcg produced similar outcomes to IT morphine 100 mcg () (Beatty 2013
Level III-2, n=114) and IT diamorphine 250 mcg similar outcomes to IT morphine 100 mcg (Barkshire
2001 Level II, n=60, JS 4).
IT tramadol 10 mg vs IT fentanyl 10 mcg added to spinal anaesthesia with bupivacaine
increased the duration of analgesia and reduced postoperative shivering ( Subedi 2013 Level II,
n=80, JS 5).
Intrathecal alpha-2 agonists
IT clonidine 30 to 150 mcg as an adjuvant to neuraxial anaesthesia during Caesarean section
prolongs the duration of sensory block (MD 128 min; 95%CI 82 to 175) and motor block (MD45 min; 95%CI 9 to 81) (Crespo 2017 Level I [PRISMA], 12 RCTs, n=1,280). IT clonidine increases
sedation (RR 3.92; 95%CI 1.17 to 13.14), but does not increase the risk of hypotension, affectpruritus or PONV.
In obstetrics patients, the time to achieve highest sensory and complete motor block was lessand duration of analgesia was longer when clonidine and hyperbaric bupivacaine wereadministered sequentially, compared to the mixing of the two medicines in a single syringe(Sachan 2014 Level II, n=60, JS 4).
There is no human or animal evidence of neurotoxicity when preservative-free clonidine isadministered IT (Hodgson 1999 NR). Epidural clonidine is approved by the FDA for relief of chronic
cancer pain. For details see Section 4.9.2.1.
Intrathecal midazolam
IT midazolam gave short duration postoperative analgesia ( Prakash 2006 Level II, n=60, JS 3).
The safety of midazolam with respect to neurotoxicity is not established.
Safety of neuraxial opioids after Caesarean section
The prevalence of OIVI (author-reported, individual study definition) with use of neuraxial
diamorphine and morphine after Caesarean section is 61/10,000 (95%CI 51 to 74) ( Sharawi 2018
Level IV SR, 78 studies [54 RCTs, 21 studies & 3 case reports], n=18,455). However, when classified asclinically significant OIVI, highest prevalence with all doses of neuraxial opioids was 8.67/10,000(95%CI 4.20 to 15.16) and lowest was 5.96/10,000 (95%CI 2.23 to 11.28). These rates dropped
even further with the use of lower but clinically relevant doses of neuraxial morphine: IT dose≤150 mcg 1.63/10,000 (95%CI 0.62 to 8.77) (31 RCTs [IT]) or epidural dose ≤3 mg 1.08/10,000736

5th Edition | Acute Pain Management: Scientific Evidence9.0 | OTHER SPECIFIC PATIENT GROUPS(95%CI 0.24 to 7.22) (32 RCTs [epidural]). No cases were reported for IT diamorphine ≤400 mcg or
epidural diamorphine ≤5 mg.
Other regional techniques
Peripheral regional blocks are useful analgesic techniques after Caesarean section ( Mitchell 2019
NR; Patel 2019 NR). Local anaesthetic techniques in general (wound infiltration, bupivacainesoaked gelatin sponge placement or catheter infusions, ilioinguinal/ iliohypogastric block, TAP
block) reduce opioid consumption following Caesarean section performed under general orregional anaesthesia vs placebo (Bamigboye 2009 Level I [Cochrane], 20 RCTs, n=1,150). The reduction
in opioid consumption is most beneficial where abdominal nerve blocks are used to supplement
regional anaesthesia (MD -25.8 mg; 95%CI -50.4 to -5.4) (4 RCTs, n=175).
Wound infiltration or infusion
After Caesarean section, either continuous wound infusion or single-dose infiltration with local
anaesthetics vs placebo reduces parenteral morphine consumption at 24 h (MD -9.69 mg; 95%CI-14.85 to -4.52) and pain at 24 h at rest (MD -0.36/10; 95%CI -0.58 to -0.14) and with movement(MD -0.61/10; 95%CI -1.19 to -0.03) with no difference between the techniques ( Adesope 2016
Level I [PRISMA], 21 RCTs, n=1,435). These effects are not shown in patients receiving IT morphineand only with catheter placement below the fascia. PONV and pruritus are not reduced. RCTs
not included in this systematic review confirm these results. Continuous wound infiltration withropivacaine was superior to epidural morphine with regard to pain relief, adverse effects, needfor nursing care and hospital LOS (O'Neill 2012 Level II, n=58, JS 3). Combining a pre- with apostincisional wound infiltration with lignocaine 1% had superior efficacy to a pre- or
postincisional infiltration alone (Fouladi 2013 Level II, n=281, JS 4).
There is benefit from adding diclofenac (Lavand'homme 2007 Level II, n=92, JS 3) or low-dose
ketorolac, but not hydromorphone, to a 48 h continuous bupivacaine wound infusion ( Carvalho
2013 Level II, n=60, JS 5). Ketorolac reduced pain scores and need for analgesia and also
inflammatory cytokines (IL-6 and IL-10) in the wound exudate. Adding tramadol (1.5 mg/kg) tolevobupivacaine wound infiltration reduced pain scores early in the postoperative period but
there was no systemic control group (Demiraran 2013 Level II, n=90, JS 4). SC pethidine or tramadol
improved analgesia and were opioid sparing vs infiltration of bupivacaine 0.25% or placebo(Jabalameli 2016 Level II, n=120, JS 3). Placing a multi-orifice catheter for wound infiltration withropivacaine/ketoprofen below the superficial abdominal fascia resulted in improved analgesic
efficacy vs placement above (Rackelboom 2010 Level II, n=56, JS 5).
The number of factors influencing efficacy of local anaesthetic wound infiltration in post
Caesarean section analgesia - catheter placement (superficial versus deep to transversalis fascia),
local anaesthetic dose (high /low volume and concentration) and methods of administration(intermittent boluses versus continuous infusion) - need to be evaluated with further studies.
Ilioinguinal-iliohypogastric block (II-IH block)
Bilateral II-IH block (local anaesthetic vs saline placebo) used in addition to IT morphine improved
analgesia, lowered analgesic requirements and increased satisfaction (Wolfson 2012 Level II, n=34,
JS 5). However in another study, US-guided II-IH blocks with bupivacaine, combined with IT
morphine (variable dosing), conferred no further benefit ( Vallejo 2012 Level II, n=50, JS 4). USguided II-IH blocks vs TAPB provided similar early analgesia with similar adverse event rates;
however at later time points (24 h and 48 h), analgesia was superior with US-guided II-IH block(Jin 2019 Level III-1, n=242).
Transversus abdominis plane block (TAPB)
After Caesarean section, TAPB vs placebo (9 RCTs) or no block (3 RCTs) reduces pain at rest at 6 h(-3.6/10; 95%CI -6.3 to -0.9), to a lesser extent at 24 h (-1.1/10; 95%CI -2.1 to -0.01) and morphine
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737requirements at 2 to 24 h (Champaneria 2016 Level I SR [PRISMA], 18 RCTs, n=1,353). TAPB/IT
morphine vs IT morphine only reduces pain at rest (-0.5/10; 95%CI -1.0 to -0.1) and withmovement (-1.0/10; 95%CI -1.7 to -0.4).
In a preceding SR, TAPB has varying outcomes depending on the comparator, and if added tomultimodal analgesia (IT morphine, or placebo, in combination with paracetamol and NSAID
and/or PCA opioids) (Fusco 2015 Level I [PRISMA], 11 RCTs, n=727) (9 RCTs overlap with Champaneria2016). TAPB in addition to multimodal analgesia may not confer additional analgesic benefit. This
uncertainty is affected by the heterogeneity of analgesic treatment in RCTs. Opioid related side
effects may be reduced. In this systematic review the outcomes were not suitable forquantitative assessment; TAPB reduces opioid consumption vs IT opioid (3 of 4 RCTs), time to firstanalgesic request (5 of 7 RCTs), PONV (10 of 10 RCTs) and pruritus (4 of 7 RCTs). TAPB alone and withIT opioid does not improve postoperative analgesia vs IT opioid (3 RCTs each), but TAPB/IT opioidvs placebo reduces pain intensity (4 RCTs).
Following Caesarean section, local anaesthetic TAPB reduces postoperative opioid
requirements for 24 h and pain scores for 12 h but only when IT morphine is not used ( Mishriky2012 Level I [PRISMA], 9 RCTs, n=524) [7 RCT overlap with Fusco 2015]; Abdallah 2012 Level I [PRISMA], 5
RCTs, n=312 (all 5 RCTs overlap)); IT morphine provides better analgesia than TAP blocks but withan increased rate of adverse effects.
RCTs with small patient numbers of TAPB used in combination with IT morphine have shownno (McKeen 2014 Level II, n=83, JS 5) vs early 0–24 h analgesic benefit (Lee 2013a Level II, n=51, JS 5;
Onishi 2013 Level III-2; Singh 2013a Level II, n=60, JS 5). The latter study compared high-dose (3mg/kg) with low-dose ropivacaine (1.5 mg/kg) and found only high-dose ropivacaine produced
benefits for up to 12 h.
Single-dose US-guided TAPB and continuous wound infusions were compared in women
having Caesarean section under spinal anaesthesia without morphine (Chandon 2014 Level II, n=65,
JS 3). The trial was abandoned after a generalised seizure in the TAPB group; however, there were
no differences between the groups with regard to analgesia and pain at
1 mth. In a similar study, there was also no difference in morphine use or pain when TAPB andSC wound infiltration with bupivacaine 0.25% and adrenaline were compared ( Telnes 2015 Level
II, n=60, JS 5).

With regard to TAPB technique and duration of effect, the posterior approach ( 4 RCTs)
reduced opioid consumption and rest and dynamic pain scores over 48 h vs controls; longer thanthat from a lateral approach where rest pain scores only were lower than controls at 12 h (8 RCTs)(Abdallah 2013 Level I [PRISMA], 12 RCTs [8 Caesarean sections], n=641). Subanalysis of the varying
agents and dose equivalents administered was not performed.
TAPB are associated with high peak plasma concentrations of local anaesthetic after 30 min(Torup 2012 PK) and mild toxicity is reported after total doses of ropivacaine of ≥2.5 mg/kg(Griffiths 2013 Level IV) and convulsions after 150 mg of levobupivacaine (Weiss 2014 CR).
Quadratus lumborum (QL) block
Quadratus lumborum block after Caesarean section in comparison to TAPB provided effective
and prolonged analgesia with a mean time to first analgesic request of 68.8 h (SD 1.74) vs 13.3 h(SD 1.21) (Verma 2019 Level II, n=60, JS 3)
Risk of chronic pain following Caesarean section
Persistent postsurgical pain has been reported in 1 to 18% of women following Caesarean section(Landau 2013 NR). In two studies with detailed follow-up, the incidence of persistent pain was
14.6% at 2 mth, reducing to 4.2% at 12 mth (n=426) (Liu 2013 Level IV) and 11% at 8 wk, reducing
to 0.6% at 12 mth (n=381) (Ortner 2014 Level III-2). For repeat Caesarean section, preoperative scar
hyperalgesia (seen in 41% of patients) is a risk factor for postoperative pain ( Ortner 2013 Level III-738

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2). Patients with chronic postsurgical pain had higher rates of general vs spinal anaesthesia (37%general vs 17% in the no-pain group; p=0.02); in this study the incidence of significant pain at 10
mth postoperatively was 5.9 % (Nikolajsen 2004 Level III-2). A variety of regional analgesia
techniques reduces CPSP at 3 to 8 mth following Caesarean section (NNT 19) (OR 0.46; 95%CI
0.28 to 0.78) (4 RCTs, n=551) (Weinstein 2018 Level I (Cochrane), 63 RCTs, n=3,027).
Prior Caesarean section is also a risk factor for chronic pelvic pain (Latthe 2006 Level III-3 SR,
63 studies, n=64,286). See also Section 1.4.

KEY MESSAGESNeuraxial and regional analgesia for pain in labour
1. Epidural and combined spinal‐epidural analgesia provides superior pain relief for labourand delivery compared with all other analgesic techniques (S) along with improved
maternal satisfaction (R) (Level I [Cochrane Review]).
2. Epidural analgesia compared to systemic opioid reduces maternal nausea and/or
vomiting (N) and need for maternal oxygen supplementation (N), but increases theduration of the first and second stage of labour slightly (Q) (Level I [Cochrane Review]).
3. Epidural analgesia compared to systemic opioid does not increase the rate of
Caesarean section (S), long‐term backache (S), headache (N), pruritus (N) or postnatal
depression (N) (Level I [Cochrane Review]).
4. Epidural analgesia compared to systemic opioids reduces the risk of fetal acidosis (S)and the need for neonatal naloxone administration with no increase in special
care/neonatal intensive care unit admissions (N) (Level I [Cochrane Review]).
5. Epidural analgesia may increase the rate of assisted vaginal delivery (U), but not with
contemporary techniques of epidural analgesia (use of low-concentrations of local
anaesthetics) (Q) (Level I [Cochrane Review]).
6. Lower concentrations of local anaesthetics for epidural analgesia in labour result in ashorter duration of second stage of labour, fewer assisted vaginal deliveries, greater
ambulation and less urinary retention than higher concentrations (S) (Level I [Cochrane
Review]).
7. Early versus late initiation of epidural analgesia leads to no clinically significant
differences in outcome (S) (Level I [Cochrane Review]).
8. In comparison with epidural analgesia, combined spinal‐epidural analgesia reducestime to effective analgesia (U), does not increase maternal satisfaction (U), increases
the incidence of mild pruritus (compared to low-dose epidurals) (U) (Level I [Cochrane
Review]) and reduces the risk of unilateral block (N) (Level I [PRISMA]).
9. Local anaesthetic nerve blocks (in particular paracervical blocks) provide better
analgesia than placebo, nonopioids and opioids for labour pain, but at an increased
rate of adverse effects (U) (Level I [Cochrane Review]).
10. Non-reassuring fetal heart rate tracings can be more common with combined spinal‐
epidural analgesia than epidural analgesia in labour (N) (Level I [PRISMA]).

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11. Ultrasound guidance improves the success of epidural catheter insertion andintrathecal needle placement and reduces traumatic insertions (N) (Level I [PRISMA]).
12. Patient-controlled epidural analgesia provides effective analgesia for labour (U) but
optimal settings (U) (Level I) and the need for a background infusion remain unclear(U) (Level I [PRISMA]).
13. Programmed intermittent epidural bolus versus continuous epidural infusion reduces theincidence of breakthrough pain without increasing adverse outcome (S) (Level I [PRISMA]).
14. Dural puncture epidural analgesia does not appear to offer benefit over standard
epidural analgesia (N) (Level I [PRISMA]).
15. There is no difference between the use of bupivacaine and ropivacaine for epidural
analgesia in labour for any outcome (U), except ropivacaine may reduce the incidenceof motor block (Q) (Level I).
16. Single-injection intrathecal opioids provide comparable early labour analgesia to
epidural local anaesthetics, with increased pruritus but no difference in nausea (U)(Level I). Adding single injection intrathecal morphine (≤250 mcg) to local anaesthetic
combined with shorter acting opioids increases time to first analgesic request, but isassociated with increased adverse effects (N) (Level I).
Systemic analgesia for pain in labour
17. Analgesic concentrations of inhaled volatile anaesthetics provide superior analgesia inlabour but more drowsiness, compared to inhaled nitrous oxide (U) (Level I [Cochrane
Review]).
18. Inhaled nitrous oxide has some analgesic efficacy in labour pain (U), increases maternal
adverse effects (nausea, vomiting, dizziness) (U) but has no adverse effects on the
newborn (U) (Level I [Cochrane Review]); pain relief is comparable to pethidine but
inferior to epidural analgesia (U) (Level IV SR).
19. Use of nonopioid analgesics alone for labour analgesia is not supported by current
evidence (U) (Level I [Cochrane Review]).
20. Parenteral opioids other than remifentanil intravenous PCA provide moderate
analgesic effects in labour pain (S), are inferior to epidural analgesia (S) and cause
increased adverse maternal effects (sedation, nausea, vomiting) (S) and adverse
effects on the newborn remain unclear (Q) (Level I [Cochrane Review]).
21. Remifentanil intravenous PCA is inferior to epidural analgesia (U), but provides better
analgesia in labour compared to other parenteral opioids (S) (Level I [Cochrane]).
Complementary and other methods of pain relief in labour
22. Continuous or one‐to‐one support by a midwife or trained layperson during labour
reduces analgesic use, rate of assisted and operative birth and dissatisfaction (S)(Level I [Cochrane Review]).
23. Immersion in water during labour may reduce the requirements for regional and neuraxial
analgesia, with no difference in other maternal outcomes and insufficient evidence forneonatal outcomes compared to no immersion (W) (Level I [Cochrane Review]).
24. Relaxation by use of yoga, music or audio has limited benefit for pain relief orsatisfaction in labour (Q) (Level I [Cochrane Review]).

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25. Acupuncture and acupressure for labour pain may reduce pain, use of pharmacological
pain relief and increase satisfaction with pain management vs standard care or placebo(Q) (Level I [Cochrane Review]); Caesarean section rates are unchanged (R) (Level I[Cochrane Review]).
26. Acupressure (vs sham) reduces labour pain, but has no effect on the use ofpharmacological analgesia (Q) (Level I [Cochrane Review]).
27. Massage may decrease pain in the first stage of labour pain compared to standard care(S) (Level I [Cochrane Review]).
28. Transcutaneous electrical nerve stimulation has no effect on pain, interventions or
outcomes in labour (U) (Level I [Cochrane Review]).
29. Biofeedback, sterile water injections intra- or subcutaneously and aromatherapy haveno effect on labour pain or other outcomes (U) (Level I [Cochrane Review]).
30. Use of a birth ball may improve labour pain (N) (Level I).
31. Heat packs may reduce labour pain during the first and second stages (N) (Level I[Cochrane Review]).
32. Hypnosis (mostly antenatal interventions) may reduce analgesic requirements forlabour pain (R) (Level I [Cochrane Review]).
Pain relief after Caesarean section
33. Local anaesthetic wound infiltration, in particular abdominal nerve blocks, reduces
opioid consumption following Caesarean section (U) (Level I [Cochrane Review]).
34. Local anaesthetic transversus abdominis plane blocks reduce postoperative opioid
requirements and pain scores after Caesarean section but only when intrathecal
morphine is not used (S) (Level I [PRISMA]).
35. In relation to controls only and with no direct comparison between the two
approaches, local anaesthetic transversus abdominis plane blocks performed by aposterior approach provide a longer duration of benefit versus the lateral approachafter lower abdominal incision surgery including Caesarean section (U) (Level I[PRISMA]).
36. Intravenous paracetamol given before incision reduces opioid analgesic requirements
after Caesarean section (N) (Level I [PRISMA])
37. Epidural (U) (Level I [QUOROM]) and intrathecal morphine (U) (Level I) and patientcontrolled epidural analgesia (U) (Level II) provide effective analgesia after Caesarean
section, but neuraxial morphine increases the rate of pruritus and nausea comparedwith systemic administration (U) (Level I [QUOROM]).
38. Intrathecal morphine (range of 100 mcg to 250 mcg) increases time to first analgesic
request after Caesarean section, but pain scores and opioid consumption areunchanged, and postoperative nausea, vomiting and pruritus increased (N) (Level I).

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The following tick boxes represent conclusions based on clinical experience and expert
opinion: Remifentanil IV PCA for relief of labour pain carries a risk of maternal respiratory
depression; use is recommended only if there is one-on-one continuous presence of a
midwife, continuous oxygen saturation monitoring and continuous cardiotocographmonitoring (as an indirect method of detecting global hypoxaemia) (U).
 Transversus abdominis plane blocks after Caesarean section may result in high plasma
concentrations of local anaesthetic and potential toxicity; minimum effective doses
should be used (U).

9.1.4 | Pain management during lactation
Several general principles apply when administering analgesic and antiemetic medications forpain management during lactation:• The choice of medications should be based on knowledge of their potential impact onbreastfeeding and on the breastfed infant secondary to transfer in human milk;• The lowest possible effective maternal dose of analgesic for the shortest possible
duration is recommended (Reece-Stremtan 2017 GL);
• Breastfeeding is best avoided at times of peak medication concentration in milk and theinfant should be observed for effects of medication transferred in breast milk.
A useful regularly updated peer reviewed resource is the USA National Library of Medicine’s
Drugs and Lactation Database (LactMed®) (https://www.ncbi.nlm.nih.gov/books/NBK501922/)(LactMed GL); this replaces the previously associated Toxicology Data Network (Toxnet) and
LactMed@NIH smartphone/mobile applications. Alternative websites here are( https://www.infantrisk.com) and an Australia-based website with information for parents, too(https://www.breastfeeding-anaesthesia.info).
Importantly, the use of many analgesic and antiemetic medications during lactation is offlabel and the effects have not been adequately investigated, leaving clinical decisions to be madeon evidence derived from pharmacokinetic or observational studies, case reports and anecdotes.
For most medications, information on infant outcome is inadequate (based on single dose or
short-term administration or on case reports) or absent, so maternal consent is advisable andcaution is warranted.
The principles of the passage of medications in human milk ( LactMed GL; Verstegen 2019 NR;
Ilett 2005 NR) including medications relevant to pain management ( Ito 2018 NR; Bar-Oz 2003 NR;
Spigset 2000 NR) have been reviewed. The maternal plasma concentration, which is influenced by
the dose and the ability of the mother to metabolise the medication, is an important determinantof medication concentrations in breast milk. High lipid solubility, low molecular weight, lowprotein binding and the unionised state favour secretion into breast milk. Most medications havea milk-to-plasma ratio of ≤1 (Ito 2000 NR). Relative infant dose (RID) is a weight-adjusted time
averaged (eg daily) dose of drug in milk ingested by the infant, expressed as a percentage of thetime averaged maternal therapeutic dose on a body weight basis; a RID of 100% is the same asdirectly receiving a therapeutic dose per weight.
Infant exposure is often 0.5 to 4% of the maternal dose but infant medication metabolism
may be impaired and much of the data is from single maternal dose studies rather than chronic
therapy (LactMed GL; Berlin 2005 NR). A safe level of infant exposure to a medication has been
arbitrarily defined as no more than 10% of the therapeutic dose for infants (or the adult dose742

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standardised by weight if the infant dose is not known) (Ito 2000 NR). Until mature milkbreastfeeding is established, only very small volumes of colostrum are secreted, so earlybreastfeeding is unlikely to pose a hazard (as overall dose is low including in the setting oflipophillic medications when concentrated vs plasma)(LactMed GL).
Guidelines include the following general recommendations (Mitchell 2020 GL; Martin 2018 GL;
Reece-Stremtan 2017 GL). These recommendations are limited by the sparse clinical trial data inthis patient population. Guidance is based on the experience of historical use, case series andpharmacokinetics (usually presented as relative infant dose [RID]% in breast milk related to theweight-adjusted maternal dose).
• Intracellular junctions between lactocytes close after 7 to 10 d postpartum. Exposure tomaternal medications may be highest during 3 to 10 d postpartum;• Opioids are the most concerning group of analgesics – dose and duration should be
limited;• Analgesic effectiveness needs to be weighed against adverse effects and safetyconcerns (particularly for opioids) because when maternal pain is well treated,breastfeeding outcomes are improved;• There are differences in risk between different opioids. Codeine should be avoided assome mothers who are ultrarapid metabolisers produce higher concentrations ofmorphine with transfer into breast milk. Warnings against codeine use have been made(TGA 2016 GL) and extended to tramadol by some regulatory bodies (Medsafe 2020 GL;
FDA 2019 GL) (see also Sections 10.4.4.5 and 10.4.4.12);• Long acting opioids, and those with active metabolites (eg pethidine, morphine), havebeen associated with respiratory depression, cyanosis and bradycardia in neonates.
Inconclusive evidence suggests doses of cumulative epidural fentanyl >150mcg may be
associated with less successful breastfeeding;• Mothers of healthy full-term infants can breastfeed as soon as they have recoveredfrom anaesthesia. However, infants at risk of sensitivity (eg low birth weight, premature)should probably not be breastfed/receive maternal breast milk until 6 to 12 h afteranaesthesia;• Breastfed infants of mothers on high dose or long-term opioids need observation fordrowsiness, poor feeding and neonatal abstinence syndrome (NAS);• Neonatal observation and monitoring is warranted if there is evidence of maternal CNS
depression;• Regional anaesthesia should have a lower risk than general anaesthesia for babies ofbreastfed mothers, because systemic absorption is very low, and postoperative regional
analgesia may minimise the requirement for opioid analgesia;• Neuraxial morphine and multimodal analgesia (including regional techniques such astransversus abdominis plane block and wound infiltration with local anaesthetic)
reduces systemic opioid requirements.
Advice about specific agents includes:• Paracetamol is widely used. Transfer into milk is low and appears to be less than the
dosage given to infants;• Aspirin in doses < 81mg/d has undetectable concentrations in human milk. Its use as
chronic anti-platelet therapy is considered safe. Variable transfer into milk reflects
nonlinear metabolism at higher analgesic dosages and these should be avoided (Mitchell2020 GL);• nsNSAIDs and Coxibs have a low transfer into milk (low %RDI) however they should be
avoided in infants with ductal dependent cardiac lesions;
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◦

•

Concentrations in breast milk after oral ketorolac are low, but have not beenmeasured after parenteral administration;◦ For diclofenac, limited studies demonstrate undetectable concentrations after oral
or IM administration;◦ For naproxen, milk transfer is low and safe with short-term use (<1 wk), but there
have been reports of neonatal GI disturbances after prolonged maternal use;
◦ For indomethacin, milk transfer is low and is considered safe in the postpartum
period;The effect of epidural analgesia on breastfeeding is uncertain ( French 2016 SR Level III-2,
23 studies, n=36,128);◦ There is minimal data on effects of inhaled nitrous oxide by mothers on neonates.
A review reported no adverse effect on suckling.

9.1.4.1 | Nonopioids
Paracetamol
The weight-adjusted maternal dose of paracetamol transferred to the newborn was 1.85% of a
1 g dose (Notarianni 1987 Level IV PK). Although glucuronide conjugation may be deficient in the
newborn, the medication is considered safe as there have been no reports of adverse effects andconcentrations in breast milk are a fraction of the recommended neonatal doses.
NSAIDsShort-term maternal NSAID use during lactation appears safe for the healthy term infant; aspirin<150 mg/d maybe indicated for long-term use (Bloor 2013 NR). Despite similar proportionaltransfer to paracetamol, salicylates are eliminated slowly by the newborn, cause platelet
dysfunction and have been associated with Reye’s syndrome; aspirin in analgesic doses cannot
be recommended as safe (Bar-Oz 2003 NR).
NSAIDs must be considered individually but, in general, concentrations in breast milk are low
because they are weak acids and extensively plasma protein bound. In particular, ibuprofen hasvery low transfer (<1% weight-adjusted maternal dose), is short acting, free of active metabolites
and has the best documented safety (Ito 2000 NR). Ibuprofen is therefore considered the ideal
agent in this group (Montgomery 2012 GL).
Diclofenac and ketorolac are minimally transported into breast milk and short-term oroccasional use is compatible with breastfeeding (Rathmell 1997 NR). The safety of naproxen is lessclear but it is also considered compatible. Indomethacin has been associated with central
maternal adverse effects, such as agitation and psychosis, in previously healthy postnatal women(n=32) (Clunie 2003 Level IV).
Following a single 200 mg dose of celecoxib, <0.5% of the weight-adjusted maternal dose waspresent in breast milk, suggesting that breastfeeding during routine dosing poses a minimal risk
(Gardiner 2006 Level IV PK; Hale 2004 Level IV PK). The relative infant dose of parecoxib andvaldecoxib after a single dose of maternal parecoxib is very low (<1%) and neonatal
neurobehavioural scores are within the normal range (Paech 2012 Level IV PK).
9.1.4.2 | Conventional and atypical opioids
With some provisos, the short-term use of opioids (2 to 3 d) is generally considered safe duringlactation as most opioids are secreted into breast milk in low doses ( LactMed GL; Ito 2018 NR;
Hendrickson 2012 NR); the RID of opioids is usually low in the range of 1% to 5%, although
individual variations exist (Ito 2018 NR).

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Conventional opioids
An association between opioid exposure in breast milk and episodes of apnoea and cyanosis ininfants has been described (Naumburg 1988 Level IV), leading some to suggest that opioids should
be avoided if the newborn experiences such events during the first week of life. Cases of infant
toxicity due to human milk exposure are reported (LactMed GL; Madadi 2007 CR), mostly involving
codeine in infants <2 mth of age, therefore infants should be monitored for drowsiness(Hendrickson 2012 NR) (see also Sections 1.7.3 and 4.1.1).
RID (relative infant dose) of morphine is 2 to 3%, however, M6G exposure might be higher(Ito 2018 NR). The oral bioavailability in the infant is low (about 25%), so smaller amounts reachthe infant’s plasma (Feilberg 1989 Level IV PK). In mothers treated with IV PCA morphine for 48 hfollowing Caesarean section, concentrations of morphine and M6G were low in breast milk,suggesting minimal medication would be transferred to the newborn (Baka 2002 Level IV PK).
Compared with IV PCA pethidine (meperidine), there is significantly less neurobehaviouraldepression with IV PCA morphine (Wittels 1990 Level III-2). Overall, short-term morphine use postpartum is compatible with safety in breast feeding (Ito 2018 NR).
Pharmacokinetic studies suggest the more lipophilic opioids, such as fentanyl and alfentanil,
are unlikely to cause problems. Following a single dose of IV fentanyl, the weight-adjusted
maternal dose received by the newborn was 3%, concentrations in colostrum became
undetectable within several hours and the nursing infant appeared unaffected (Steer 1992 Level IV
PK; Nitsun 2006 Level IV PK).
Breastfed infants whose mothers received IV PCA pethidine were less alert and oriented toauditory cues after Caesarean section than infants of mothers receiving morphine (Wittels 1997
Level III-2, n=47). As norpethidine (normeperidine) accumulates in breast milk with repeated use
and has a very slow neonatal elimination, pethidine use during breastfeeding is notrecommended (Ito 2000 NR). The American Academy of Pediatrics (AAP) recommends against useof IV pethidine in breastfeeding mothers (Sachs 2013 GL). Pethidine PCEA results in much lower
plasma concentrations than systemic pethidine, with lower infant exposure to pethidine andnorpethidine (1.8%) (Al-Tamimi 2011 Level IV PK) and may be a low risk method during very earlylactation (Sakalidis 2013 Level III-2).
Caution has been advised regarding the use of codeine during breastfeeding (FDA 2019 GL;
TGA 2016 GL). Codeine has a milk-to-plasma ratio of slightly more than 1 and was previously
suggested to be generally safe with short-term use, but should be used with caution when dosing
is repeated (Meny 1993 PK; Hendrickson 2012 NR). A case‐control study that included a newborn
who died while breastfed by a mother taking codeine, has highlighted that breastfed infants ofmothers who are extensive or ultrarapid metabolisers (20–40% of the population, depending on
ethnicity, with duplications of CYP2D6 gene) are at increased risk of life‐threatening CNS
depression (Madadi 2009 Level III‐2). A number of similar cases have been reported and healthcare
workers and breastfeeding mothers should be aware of this risk ( Madadi 2008 Level IV, n=35). A
relationship between infant CNS symptoms (decreased alertness, lethargy, poor feeding) andmaternal symptoms, codeine dose and, in some cases CYP2D6 phenotype, has been identified(Madadi 2009 Level III-3, n=72 [17 symptomatic]). Pharmacokinetic simulation suggests potentially
toxic morphine concentrations can be reached in the newborn within 4 d of repeated maternal
codeine administration (Willmann 2009 PK).
Oxycodone shows a relative infant dose (RID) of 1.5 to 8.5%; it has high oral bioavailability
and is concentrated in human breast milk, so breastfed infants may receive >10% of a therapeutic
dose, and a USA guideline cautions against its use (Sachs 2013 GL), while others suggest amaximum maternal daily dose of 30 to 40 mg (LactMed GL; Mitchell 2020 GL). Poor CYP2D6
metabolisers may have decreased clearance of oxycodone and ultrarapid metabolisers higher
concentrations of the more potent metabolite oxymorphone, leading to sedation (Samer 2010
5th Edition | Acute Pain Management: Scientific Evidence745Level II PK, n=10 [5-arm crossover], JS 5). The safety with repeated maternal dosing has beenquestioned (Ito 2000 NR; Lam 2012 Level III-2); a case of opioid toxicity in a breastfed newborn ofa mother taking oxycodone has been reported (Timm 2013 CR). Oxycodone use during

breastfeeding resulted in increased rate of CNS depression of the newborn vs paracetamol (20.1
vs 0.5%) (OR 46.16; 95%CI 6 to 344) but no difference to codeine (16.7%) (OR 0.79; 95%CI 0.46
to 1.38) (Lam 2012 Level III-2, n=533). As a component of multimodal analgesia in the first 72 h
after Caesarean section, there may be minimal risk to breastfeeding infants as only a low volumeof milk is ingested during this period. Only 1 of 44 newborns had detectable plasma
concentrations and none were over sedated despite maternal exposure up to 90 mg/d (Seaton
2007 Level III-3).
After IN hydromorphone exposure of the mother, 0.67% of the maternal dose ofhydromorphone (adjusted for body weight) is transferred into breast milk ( Edwards 2003 Level IV
PK).
Hydrocodone is metabolised in small quantities to a more potent metabolite,hydromorphone, and ultrarapid metabolisers exist. The RID is 2.4% (Sauberan 2011 Level IV PK)
and possible infant toxicity has been reported (Hendrickson 2012 NR).
Methadone is considered compatible with breastfeeding; even with high methadone doses,
breast milk concentrations were relatively low at 2.1–3.5% (Bogen 2011 Level IV PK). Plasma
concentrations of methadone were low in infants of breastfeeding mothers on methadonemaintenance programs and no effect on infant neurobehavioural outcomes were found on d 3,
14 and 30 following birth (Jansson 2008 Level III-3). Breastfeeding reduced NAS in newborns ofmothers on methadone substitution and is encouraged ( McQueen 2011 Level III-2).
Atypical opioids
Buprenorphine has very low passage into breast milk and the combined RID of bothbuprenorphine and its active metabolite norbuprenorphine is <1% (Ilett 2012 Level IV PK). Whenused for drug substitution therapy in breastfeeding mothers, buprenorphine did not lead toadverse effects in newborns up to 4 wk postnatally (Gower 2014 Level IV).
Information regarding tapentadol in lactaction is limited to 4 case reports of infant exposure
during breastfeeding, with no adverse reactions reported (LactMed Level IV).
Tramadol (100 mg every 6 h) on d 2–4 after Caesarean section was associated with a milk-toplasma ratio of 2.2, a relative infant dose of 2.9% and no detectable behavioural effects in theinfants (Ilett 2008 Level III-2). However, as with other medications, these data cannot be directly
extrapolated to long-term use at later postpartum stages when the volume of ingested milk ishigher. The use of tramadol during pregnancy and in lactation has been reviewed (LactMed
Database 2019 GL; Bloor 2012 NR); the opinion being that during early lactation short-term use oftramadol appears unlikely to cause harm to healthy term infants. However, the USA’s FDA has
elected to apply the same warning as for codeine to tramadol (FDA 2019 GL); New Zealand has
followed this lead (Medsafe 2017 GL), but not the Australian TGA to date.
9.1.4.3 | Other analgesics and medications related to pain relief
Epidural local anaesthetics
After epidural administration, local anaesthetics showed acceptable milk-to-plasma ratios of 1.1
for lidocaine (lignocaine), 0.34 for bupivacaine (Ortega 1999 PK) and 0.25 for ropivacaine (Matsota
2009 PK). These are considered safe (Rathmell 1997 NR), including for anaesthesia and analgesia
during very early lactation (Hirose 1996 Level II, n=30, JS 2; Matsota 2009 Level IV, n=25). Use of
epidural analgesia (local anaesthetic ± fentanyl) during labour ( Chang 2005 Level III-3) or as PCEA
after Caesarean section (Matsota 2009 Level IV) did not influence neurobehavioural scores inhealthy term infants.

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The possible effect of epidural analgesia on breastfeeding is complex and may not only be
related to medications administered, with selection bias (lack of randomised trials),
nonstandardised breastfeeding evaluations and failure to control for confounding variables
making firm conclusions impossible (Szabo 2013 NR). In a study of 1,054 nulliparous women
randomised to different methods of epidural analgesia in labour and matched with 351
nonepidural controls, there was no association with breastfeeding initiation (Wilson 2010 Level III-2,
n=1,405). However, epidural analgesia in labour was associated with an increased risk ofbreastfeeding cessation at 30 d after adjusting for demographic and intrapartum factors(HR 1.26; 95%CI 1.1 to 1.44) (Dozier 2013 Level III-2, n=772).
Alpha-2 agonists
The effects of clonidine on breastfeeding have not been studied, but a single neuraxial dose isunlikely to have any adverse effect. As a neuraxial adjuvant, it may reduce requirements for
systemic opioids in the postpartum period (Martin 2018 GL).
Dexmedetomidine has been used as an adjuvant infusion during Caesarean section; abreastfeeding infant would receive a negligible dose of 0.04 to 0.098% RID ( Nakanishi 2017
Level IV PK).
Alpha-2 delta ligands
The alpha-2-delta ligands are increasingly popular analgesics for acute pain after operative birth,
especially among women with neuropathic pain, opioid tolerance or where opioid dose
minimisation is recommended. For gabapentin, the milk-to-plasma concentration was 0.86, theRID was 2.4% and no adverse effects were noted in the infant ( Ohman 2005 Level IV PK). Whilesuggestive of safety during lactation, a careful individual risk-benefit analysis was suggested(Kristensen 2006 CR PK). There are also limited human data on pregabalin during breastfeeding.
Pregabalin is a small molecule that undergoes negligible metabolism and is thus expected to be
excreted in breast milk. A breastfed infant of a mother on long-term pregabalin (for epilepsy)
had serum concentrations of about 8% of the maternal concentrations, although no adverse
effects were observed (Ohman 2011 Level IV PK). During a much later stage of lactation, the mean
milk-to-plasma ratio was 0.53 to 0.76; and 0.2% of the maternal daily dose was secreted into
breast milk, representing 7% of the body weight normalised maternal dose (Lockwood 2014 Level
IV PK). The medication was well tolerated and the overall safety of anticonvulsants inbreastfeeding mothers is regarded as high, with continuation of breastfeeding recommended(Reimers 2012 NR). Gabapentin is considered the safer of the two agents given its less likely
transfer in breast milk (Reece-Stremtan 2017 GL).
Ketamine
Ketamine has limited data on transfer to breast milk. Given the uncertainty overneurodevelopmental effects with infant/toddler ketamine anaesthesia exposure, concerns exist
over its use (Yan 2014 Level III-3). There is insufficient evidence to support its long-term safety
when this agent is used as an infusion in breastfeeding mothers (Martin 2018 GL). A single study
found there was no effect on duration of breast feeding ( Suppa 2012 Level II, n=56, JS 4).
Antiemetics
There is very little information about antiemetic use and breastfeeding and, in almost all cases,
the manufacturers (approved product information) do not recommend their use duringlactation; although in practice most antiemetics are used, with the best data for metoclopramide(Pistilli 2013 NR). Metoclopramide is used both for cancer chemotherapy and to increase milk
production, so although it concentrates in human milk the RID is much lower than thetherapeutic dose in paediatrics (Kauppila 1983 Level IV PK) and authors have reported the absenceof adverse effects in newborns whose mothers were exposed (Pistilli 2013 NR). Animal studies
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747suggest possible CNS effects in the newborn but human anecdotal experience is favourable withmedications such as metoclopramide, domperidone and dexamethasone. Ondansetron (andother 5HT-3 blockers), dexamethasone, and metoclopramide are recommended over the more
sedating agents prochlorperazine and promethazine, which are considered safe, but could causematernal sedation (Martin 2018 GL).
Laxatives
Stool softeners and laxatives (docusate, senna and bisacadoyl) are minimally absorbed from thegastrointestinal tract, and are thus considered safe for use during lactation (LactMed GL).
See Table 9.3 for recommendations.
Table 9.3 | The breastfeeding patient and medications used in pain management
Medication

Comments

Paracetamol

Safe to use

Aspirin

Avoid analgesic doses due to theoretical risk ofReye’s syndrome; however, single doses of aspirin
can be taken. Low-dose aspirin (75–150 mg daily)
safe.

Other NSAIDs
Non-selective NSAIDs

Safe to use, ibuprofen is preferred

COX-2 selective inhibitors

Limited data but appear safe

Opioids
Buprenorphine, codeine, fentanyl,hydromorphone, methadone,
morphine, oxycodone, pethidine,tramadol, tapentadol

Safe to use occasional doses but avoid codeine. Use
repeated doses with caution, especially if infant ispreterm or <4 weeks old; monitor infant for
sedation and other adverse effects

SSRIs
Citalopram, escitalopram, fluoxetine,
fluvoxamine, paroxetine, sertraline

Considered safe to use (adverse effects, eg
drowsiness, irritability, occasionally occur inbreastfed babies). Avoid fluoxetine due to long halflife; some think sertraline one of the preferred
antidepressants in breastfeeding as its levels inbreast milk are low

TCAs
Amitriptyline, clomipramine,
dothiepin, doxepin, imipramine,
nortriptyline, trimipramine

Avoid doxepin if possible (neonatal respiratory
depression has been reported)

SNRIs
Duloxetine, desvenlafaxine,
milnacipran, venlafaxine

748

Concentrations in breast milk are low but checkbaby for sedation and adequate weight gain;
consider using alternatives to duloxetine or
milnacipran until more is known about them

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Medication

Comments

AnticonvulsantsCarbamazepine

Safe to use; monitor infant for drowsiness and poor
suckling

Phenytoin

May be used

Valproate

Should be safe to use (1 report of adverse effects);
consider monitoring baby for petechial rash

Clonazepam

Few data; avoid repeated doses if possible, as
lethargy and poor feeding may occur due to drug
accumulation in the baby

Gabapentin, pregabalin, lamotrigine,
topiramate

Pass into breast milk; contact one of the Pregnancy
drug information centres

Antiemetics
Prochlorperazine

Safe to use

Domperidone

Safe to use

Metoclopramide

Safe to use

Granisetron, ondansetron,
tropisetron, palonosetron

No data available, although 1 or 2 doses after
delivery should not be a concern

Droperidol, haloperidol

Avoid if possible; there are few data regarding longterm effects

Local anaesthetics
Bupivacaine, levobupivacaine,
lidocaine, prilocaine, ropivacaine,
tetracaine

Unlikely to cause problems

Other
Ketamine

Limited data

Source: Modified information taken with permission from data published in Australian Medicines Handbook 2020; seealso LactMed and Mitchell 2020.

KEY MESSAGES
1. Local anaesthetics, paracetamol and several NSAIDs, in particular ibuprofen, areconsidered to be safe in the lactating patient (U) (Level IV).
2. Morphine, fentanyl, methadone, and short-term oxycodone immediately after delivery
are considered to be safe in the lactating patient and are preferred over pethidine (U)(Level IV).
3. Repeated dosing of codeine or oxycodone in lactating patients should be avoided if
possible and the infant monitored for central nervous system depression (S) (Level IV).

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The following tick boxes represent conclusions based on clinical experience and expert
opinion: Prescribing medications during lactation requires consideration of possible transfer
into breast milk, uptake by the infant and potential adverse effects for the infant; itshould follow available prescribing guidelines (U).
 Breastfed neonates and infants may become sedated from the transfer of maternal
medications; in this case, observation and monitoring of the infant and seeking medical
advice is warranted. Maternal sedation may be an early warning sign (N).

9.1.5 | Pain in the puerperium
Pain during the puerperium is common and of multiple aetiologies, most often being perineal or
uterine-cramping pain initially, and breast pain from postpartum d 4. In the first 6 mth
postpartum, backache was reported by 44% of women and perineal pain by 21% (Brown 1998
Level IV). Headache has multiple aetiologies, mainly primary causes such as tension, migraine andmusculoskeletal headache and, in a large observational study was reported by 40% of women
one wk after delivery (Goldszmidt 2005 Level IV, n=985). Severe perineal and uterine pain limited
mobility during maternal-infant bonding and perineal trauma and pain was associated withdelayed resumption of sexual intercourse after birth (Williams 2007 Level IV). Breast, especiallynipple, pain may result in abandonment of breastfeeding ( Morland-Schultz 2005 Level III-3 SR).
Chronic postnatal pain is also a risk factor for postnatal depression ( Gaudet 2013 Level IV).
9.1.5.1 | Perineal pain
Perineal pain - prevention and physical treatments
Many obstetric and surgical factors contribute to perineal trauma and episiotomy. After
adjusting for parity, perineal trauma and length of labour, women with instrumented vsunassisted vaginal deliveries reported more perineal pain (Thompson 2002 Level IV; Fahey 2017 NR).
Restrictive use vs routine mediolateral episiotomy reduced the rate of episiotomy from 75 to
28% and reduced the risk of severe perineal trauma and the requirement for suturing but did
not influence the incidence or degree of perineal pain (Carroli 2009 Level I [Cochrane], 8 RCTs,
n=5,541).
In comparison with interrupted suturing methods, continuous suturing reduced pain
incidence for up to 10 d (particularly suturing of all layers) (RR 0.65; 95%CI 0.60 to 0.71) (4 RCTs,
n=2,488) but not for skin only (RR 0.89; 95%CI 0.73 to 1.07) (2 RCTs, n=1,217) and reduced
postpartum analgesic use (RR 0.70; 95% CI 0.58 to 0.84) (for all layers 2 RCTs and skin only 2 RCTs,
n=2,973) (Kettle 2007 Level [Cochrane], 7 RCTs, n=3,822).
There is only limited evidence to support the effectiveness of local cooling treatments (icepacks, cold gel pads, cold/iced baths) for relieving perineal trauma pain vs various alternatives
or no interventions (East 2012 Level I [Cochrane], 10 RCTs, n=1,825). Ice packs provided superior
analgesia vs no treatment for 24–72 h postpartum (RR 0.61; 95%CI 0.41 to 0.91) (1 RCT, n=208).
Although improvement in perineal pain has been reported with US, there is insufficientevidence to fully evaluate efficacy (Hay-Smith 2000 Level I [Cochrane] 4 RCTs, n=659). Ear acupressure
did not relieve perineal trauma pain in the first 48 h after birth (Kwan 2014 Level II, n=266, JS 5)
For women without prior vaginal birth, antenatal perineal massage (from 35 wk gestation)
reduced the incidence of perineal trauma requiring suturing (NNT 15; 95%CI 10 to 36) and the750

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requirement for an episiotomy (NNT 21; 95%CI 12 to 75) (Beckmann 2013 Level I [Cochrane], 4 RCTs,
n=2,497). Effects on acute postpartum pain have not been reported, but a reduction in theincidence of perineal pain at 3 mth postpartum was found in women who used antenatal
perineal massage and had previously given birth vaginally (NNT 13; 95%CI 7 to 60)(1 RCT, n=376).
Perineal pain - pharmacological treatments
More women with perineal pain experience pain relief from paracetamol than from placebo (RR
2.14; 95%CI 1.59 to 2.89) (Chou 2013 Level I [Cochrane] 11 RCTs, n=1,367); fewer women require
additional analgesia (RR 0.34; 95%CI 0.21 to 0.55) (8 RCTs, n=1,132).
A single dose of NSAID vs placebo provided adequate pain relief at 4 h (RR 1.9; 95%CI 1.64 to2.23) (10 RCTs, n=1,573) and 6 h (RR 1.92; 95%CI 1.69 to 2.17) (17 RCTs, n=2,079) after administration(Wuytack 2016 Level I [Cochrane], RCTs 28, n= 4,181). NSAIDs were more effective than paracetamol at
4 h (RR 1.54; 95%CI 1.07 to 2.22) (3 RCTs, n=342), but not at 6 h after administration.
Suppositories of nsNSAIDs reduce perineal pain in the first 48 h postpartum more effectively
than placebo (Hedayati 2003 Level I [Cochrane], 3 RCTs, n=249). Rectal indomethacin was as effective
as rectal diclofenac (Yildizhan 2009 Level II, n=200, JS 3). IV dexketoprofen was as effective as IV
paracetamol (Akil 2014 Level II, n=95, JS 5). Both oral celecoxib and diclofenac reduced perineal
pain, with celecoxib showing a slight advantage with respect to pain scores at rest and theincidence of gastrointestinal symptoms (Lim 2008 Level II, n=329, JS 5).
Topical local anaesthetics (lignocaine, cinchocaine, pramoxine plus hydrocortisone
preparations) or placebo did not improve perineal pain in the 24 h postpartum ( Hedayati 2005
Level I [Cochrane], 8 RCTs, n=976). The use of systemic analgesics was not standardised across thesestudies and maybe a confounding factor. Following mediolateral episiotomy repair underepidural analgesia, a pudendal block with ropivacaine improved pain scores and reduced the
proportion of women requiring additional analgesia (Aissaoui 2008 Level II, n=42, JS 4).
9.1.5.2 | Postpartum breast and nipple pain
Painful breasts are a common reason for ceasing breastfeeding ( Amir 2003 NR). Management isfirstly directed toward remedying the cause, whether this is infant-related (incorrect
attachment, sucking, oral abnormalities), lactation-related (breast engorgement, blocked ducts
or forceful milk ejection), nipple trauma, dermatological or infective problems (candida or
mastitis) or other causes. There is insufficient evidence to recommend glycerine gel dressings,
breast shells with lanolin, lanolin alone or an all-purpose nipple ointment for treatment of nipple
pain (Dennis 2014 Level III-1 SR [Cochrane], 4 studies, n=656). Irrespective of treatment, nipple pain
resolves by 7 to 10 d postpartum for most women. Guidance regarding the usual duration of pain
may help women to continue to breastfeed.
Symptomatic treatments for breast engorgement have been assessed (Mangesi 2016 Level III3 SR, 13 studies, n=919): acupuncture (2 studies), acupressure (1 study), scraping therapy (Gua Sha)
(1 study), cabbage leaves (3 studies), cold gel packs (1 study), electromechanical massage (1 study)
and pharmacological treatments (3 studies) did not result in a faster resolution of symptoms vsno treatment.
Mastitis is defined by at least two breast symptoms (pain, redness or lump) and at least one
of fever or flu-like symptoms. The incidence is 17–33% of breastfeeding women, most episodes
occurring in the first 4 wk postpartum (Amir 2007 Level IV). Infective mastitis is most commonly
due to Staphylococcus aureus and noninfective mastitis is equally common. There is insufficientevidence to confirm the efficacy of antibiotics in relieving symptoms, with only two trials meeting
the inclusion criteria for analysis (Jahanfar 2013 Level I [Cochrane], 2 RCTs, n≈125).

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9.1.5.3 | Postpartum uterine pain
Uterine pain or “after pains” often worsen with increasing parity and are experienced by most
multiparous women. Uterine contraction results from the release of oxytocin from the posterior
pituitary gland, especially in response to breastfeeding. Lower abdominal pain may be mild tosevere, accompanied by back pain and is described as throbbing, cramping and aching. Ergot
alkaloids during the third stage of labour increase the requirement for analgesia for pain after
birth due to persistent uterine contraction (RR 2.53; 95%CI 1.34 to 4.78), but also decreases
mean blood loss and the incidence of postpartum haemorrhage vs no uterotonic medications(Liabsuetrakul 2007 Level I [Cochrane], 6 RCTs, n=3,941).
NSAIDs are superior to placebo (3 RCTs, n=204) and paracetamol (1 RCT, n=48) for the relief of“after pains” following vaginal birth (Deussen 2011 Level I [Cochrane], 18 RCTs, n=1,498). Paracetamol
is no better than placebo (1 RCT, n=48). Data on opioids are contradictory and do not permit anassessment of their efficacy for this indication.
High-intensity TENS was more effective than low-intensity TENS for treating postpartum
uterine pain but also produced more local discomfort (Olsen 2007 Level III-2).

KEY MESSAGES
1. Routine episiotomy does not reduce perineal pain (U) (Level I [Cochrane Review]).
2. Continuous suturing of all layers compared with interrupted suturing for repair ofepisiotomy or second-degree tears reduces perineal pain and analgesic use in the
postpartum period (U) (Level I [Cochrane Review]).
3. Paracetamol and NSAIDs are effective in treating perineal pain after childbirth comparedwith placebo (S) (Level I [Cochrane Review]).
4. NSAIDs, but not paracetamol, are effective in treating pain from uterine cramping aftervaginal birth (U) (Level I [Cochrane Review]).
5. There is limited evidence to support the effectiveness of local cooling treatments intreatment of perineal pain after childbirth (U) (Level I [Cochrane Review]).
6. Topical local anaesthetic preparations are not effective for perineal pain after childbirth(U) (Level I [Cochrane Review]).
7. There is insufficient evidence to recommend any specific treatments for nipple pain andbreast engorgement (U) (Level I [Cochrane Review]).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Pain after childbirth requires appropriate treatment as it coincides with new emotional,
physical and learning demands and may trigger postnatal depression (U).
 Management of breast and nipple pain should target the cause (U).

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9.2 | The older patient
The need to manage acute pain in older patients is becoming more common as the population
ages. Advances in anaesthetic and surgical techniques mean that increasingly older patients,
including patients >100 y old (Konttinen 2006 Level IV), are undergoing major surgery (Kojima 2006
Level IV). Medical conditions are more likely in older people and may lead to acute pain; theseinclude acute exacerbations of arthritis, osteoporotic fractures of the spine, cancer and also painfrom other acute medical conditions including ischaemic heart disease, herpes zoster andperipheral vascular disease. Furthermore, older adults are more likely to undergo potentiallypainful medical procedures, and experience trauma as well as surgery.
Adults of advanced age are a particularly vulnerable group. Factors that can combine to makeeffective control of acute pain in the older person more difficult than in younger patients include:
a higher prevalence of coexistent diseases and concurrent medications, which increases the risk ofdrug-drug and disease-drug interactions; the presence of common geriatric syndromes, including
cognitive impairment and frailty; age-related changes in physiology, pharmacodynamics andpharmacokinetics; altered responses to pain; and difficulties with assessment of pain, including
problems related to cognitive impairment (Gibson 2018 NR).
National guidelines on pain management in the elderly have been developed ( APS 2019 GL).
Specific geriatric perioperative guidelines have been developed for general surgery ( Mohanty
2016 GL) and hip fracture surgery (ACSQHC 2016 GL).
Furthermore, the elderly may fail to report pain because they think it is a normal part ofageing, or they acquiesce to family members/medical staff or have fears about intervention or
the unwanted effects of analgesics, especially opioids (Fine 2012 GL). Sensory impairment andsocial isolation may further impair the effective treatment of pain. Lastly, the relative paucity ofdedicated age-specific research on pain and its management, including the lack of randomised
controlled trials conducted in older populations compounds vulnerability due to the lack ofappropriate evidence to help guide clinical practice (Reid 2015 NR). Information on the safety,
efficacy and pharmacokinetics in the elderly patient (>65 y) is often missing from drug
registration trials and regulatory body documents. A structured cross-sectional review of publicly
available initial drug registration data (FDA) found that limited data on older patients waspresent in the following areas: pharmacokinetics (62%) and safety (42%) and efficacy (45%)(Ruiter 2019 Level IV SR).

9.2.1 | Physiology and perception of pain
Several reviews summarise the age-related changes that occur in the neurophysiology ofnociception and pain perception (Gagliese 2005 Level III-2; Gibson 2018 NR; Farrell 2012 NR; Gibson
2004 NR; Yezierski 2012 NR BS). Compared with a younger person’s nervous system, there areextensive changes in the older person’s structure, neurochemistry and function of both
peripheral and central nervous systems, including neurochemical deterioration of the opioid andserotonergic systems. Therefore, there may be changes in nociceptive processing, including
impairment of pain-inhibitory systems.
9.2.1.1 | Neurophysiological changes
In the peripheral nervous system there is a decrease in the function and density of bothmyelinated and, particularly, unmyelinated peripheral nerve fibres ( Kemp 2014 EH; Heft 2017 NR).
There are also increased number of fibres with damage or degeneration and conduction velocity
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slowing. In rats, reductions in substance P, CGRP and somatostatin levels have been reported(Yezierski 2012 NR BS). Similar structural and neurochemical changes have been noted in the CNS.
In older humans, there are sensory neuron degenerative changes and loss of myelin in the dorsal
horn of the spinal cord as well as reductions in substance P, CGRP and somatostatin levels. Agerelated loss of neurons and dendritic connections is seen in the human brain, particularly in the
cerebral cortex; including those areas involved in nociceptive processing. The synthesis, axonaltransport and receptor binding of neurotransmitters also change. Opioid-receptor density isdecreased in the brain but not in the spinal cord, and there may be decreases in endogenous
opioids. However, the functional consequences of such age-related changes remain a subject of
debate. Functional MRI studies show more age-related similarities than differences in themagnitude of activation in response to acute noxious mechanical stimulation ( Cole 2010 EH; Farrell
2012 NR). A specific difference that has been identified was reduced activation in the middle
insular cortex and primary somatosensory cortex in response to noxious heat ( Tseng 2013 EH).
Variations in pain perception are best determined in controlled situations where the severityof the noxious stimulus is standardised, and psychopathology (such as impaired cognitive
function or mood) is absent (Radinovic 2014 Level IV; Kunz 2009 EH). Assessment of variation can bedone with experimental pain stimuli or, to a lesser extent, with standard medical procedures
such as venipuncture and wound dressings.
Studies of the effects of experimental pain stimuli (brief noxious stimuli without tissue injury)
on pain thresholds are conflicting and results depend on the type of stimulus used.
Psychophysical studies using experimental pain provide limited evidence for a modest increasein pain threshold (ie reduced sensitivity to mild pain) with advancing age, particularly for thermal
pain stimuli (Tseng 2013 EH; Gibson 2004 NR) and radiant more than contact heat (Lautenbacher2017 Level III-2 SR EH [PRISMA], 31 studies [pain threshold], n=2,912; 9 studies (pain tolerance threshold],
n=11,295). The results for electrical, mechanical and ischaemic stimuli are equivocal, with reports
of no change or even decreased pain thresholds in adults of advanced age (El Tumi 2017 Level III-2
SR EH [PRISMA], 12 studies, n unspecified). Of note, there were racial differences similar to thosefound in younger patients and increased decrement in the lower extremities (Riley 2014 Level III-3
EH). The applicability of these experimental observations to pain occurring with tissue injury

remains uncertain. These findings could indicate some deficit in the early warning function ofpain with reduced capacity to identify a painful stimulus and that it might cause tissue injury(Hadjistavropoulos 2014 NR; Gibson 2006 NR). For example, in patients with an acute myocardial
infarction, greater intensity of chest pain was inversely correlated with lower pain threshold(Granot 2007 Level III-3 EH); presentation and treatment of those patients with less pain may
therefore be delayed.
Studies looking at age-related changes in pain tolerance are limited, but in general, using avariety of experimental pain stimuli, there is a reduced ability in older people to endure or
tolerate intense pain (Farrell 2012 NR; Gibson 2003 NR EH;). Lessened ability to tolerate pain could
mean that severe pain may have a greater impact on the more vulnerable older person.
Also, in the elderly, there are significantly smaller increases in pain thresholds following
prolonged noxious stimulation and a prolonged recovery from hyperalgesia ( Zheng 2009 EH;
Gibson 2006 EH; Zheng 2000 EH). Using experimental pain stimuli in the elderly, there is a lower
threshold for temporal summation (Lautenbacher 2012 Level III-2 SR EH, 25 studies, n= 13,580; Naugle
2017 Level III-2 EH, n=189; Gibson 2004 EH); older subjects showed temporal summation with trainsof brief electrical stimuli at all stimulation frequencies, unlike younger subjects where this was
not seen at the lower frequencies. Temporal summation of thermal stimuli was increased inolder subjects vs younger subjects. Summation was more prolonged but otherwise temporalsummation of pressure pain showed no age-related effects. After topical application of capsaicin,
the magnitude and duration of primary hyperalgesia was similar in both older and younger754

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subjects but secondary hyperalgesia (tenderness) resolved more slowly in older people. The
proposed underlying mechanism for these findings is impaired descending inhibitory
mechanisms and reduced capacity to down-regulate after sensitisation thereby leading toprolonged recovery in the older person (Gagliese 2005 NR). Findings from human psychophysicalstudies support the contention of impaired function in endogenous pain inhibitory systems inolder adults (Riley 2017 Level III-2 EH, n=17; Grashorn 2013 Level III-2 EH, n=64), and this is also
consistent with many earlier animal studies (Gagliese 2000b BS).
9.2.1.2 | Clinical implications
Several clinical reports (summarised in Cole 2006 Level III-3 EH; Pickering 2005 NR; Gibson 2003 NR)
suggest that pain symptoms and presentation may change in the older patient; pain becomes aless frequent or a less severe symptom of a variety of acute medical conditions. Examples ofdifferences in reports of acute pain are commonly related to abdominal pain (eg associatedwith infection, peptic ulcer, cholecystitis, or intestinal obstruction) or chest pain (eg myocardialischaemia or infarction or pneumonia) and are in general agreement with the experimental
finding of increased pain thresholds in the older person.
Compared with the younger adult with the same clinical condition, the older adult may reportless pain or atypical pain, report it later or report no pain at all ( Pickering 2005 NR). Examples inolder patients include the absence of right upper quadrant or epigastric pain in 85% withcholecystitis, in 30% of those with peptic ulcer disease and up to 90% with pancreatitis, while inthose with advanced peritonitis, pain may be a symptom in only 55%. Chest pain is absent, or
pain is atypical, in up to 33% of older patients with acute myocardial infarction and 50% withunstable angina. This suggests a contradiction to data on experimental pain (reduced tolerance
to intense pain – see Section 9.2.1.1 above); however, many clinical states are characterized bymoderate to strong pain, but not intense pain (approaching tolerance levels). Age-related
decrease in the efficiency of ascending pathways (noted by an increased pain threshold) and aconcomitant decrease in the efficiency of descending inhibitory pathways (as noted by reduced
pain tolerance) may explain this discrepancy.
Pain intensity after surgery may also be less. Older patients, matched for surgical procedure,
reported less pain in the postoperative period: pain intensity decreased by 10 to 20% each
decade after 60 y of age (Thomas 1998 Level III-2). Older men undergoing radical prostatectomy
reported less pain on a present pain intensity scale and MPQ (but not a VAS) in the immediate
postoperative period and used less PCA opioid than younger men undergoing the sameprocedure (Gagliese 2003 Level III-2). In a study of pain following IV cannula placement (a relatively
standardised pain stimulus), older patients reported significantly less pain than younger patients(WMD -15/100; 95%CI -26 to -4) (Li 2001 Level III-2). An observational study of patients
undergoing painful procedures (wound care, drain and femoral sheath removal, tracheal
suctioning, turning, and central line insertion) found there was no age-related difference in painscores (NRS) between the young and the elderly (>65 y), however the younger patients reported
more pain-related distress (Stotts 2007 Level III-2, n=5,957).

9.2.2 | Assessment of pain
The need for specific methods to assess pain in the elderly is recognised in national guidelines(Schofield 2018 SR GL). These also emphasise the need for education of healthcare staff in the useof patient appropriate pain assessment tools (Sirsch 2020 SR GL).

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9.2.2.1 | Cognitive impairment
Even though cognitively impaired patients are just as likely as cognitively intact patients of thesame age to have painful conditions and illnesses, the number of pain complaints and thereported pain intensity decreases with increasing cognitive impairment ( Radinovic 2014 Level IV;
Hadjistavropoulos 2014 NR; Lukas 2012 NR). Reasons for this could include diminished memory,
impairment of capacity to report, or it could be that less pain is experienced.
Dementia
Studies in patients with dementia suggest that they may not experience less pain ( Monroe 2014
Level III-2; Hadjistavropoulos 2014 NR). Functional MRI responses following mechanical pressure
stimulation showed no evidence of diminished pain-related activity in patients with Alzheimer’s
disease vs age-matched controls, indicating that pain perception and processing were notdiminished in these patients (Cole 2006 Level III-2). Moreover, in those with dementia, facial
expressions are increased in response to controlled levels of noxious stimulation ( Kunz 2009
Level III-2 EH; Kunz 2007 Level III-2 EH) and immediately following a uniform clinical pain stimulus,
such as venipuncture, pain on mobilisation (Hadjistavropoulos 2014 NR) or dental local anaesthetic
injection (Hsu 2007 Level III-2). The increased facial expressions in response to pain could suggest
an increased sensitivity to pain in persons with dementia (Kunz 2007 Level III-2) or that facial
actions represent a different aspect of the pain experience: a reflexive, automatic response
which may be disinhibited in persons with cognitive impairment. In support of this conclusion,
persons with dementia have also been found to display enhanced nociceptive flexion withdrawal
reflexes (RIII) (Kunz 2009 Level III-2 EH; Kunz 2007 Level III-2 EH). In contrast, autonomic responses
typically associated with the onset of acute pain (ie increased heart rate, blood pressure, galvanic
skin resistance, breathing) appear to be blunted in persons with dementia ( Plooij 2011 Level III-2
SR EH, 6 studies, n=395). Much of the typical elevation in autonomic indices occurs in anticipationof an impending painful stimulus, yet this anticipatory response is lacking in those with dementia(2 studies, n=135). Group differences in the poststimulus autonomic response, particularly in heart
rate change, are less obvious (1 study, n=95) or unchanged (2 studies, n=103) including to stronger
intensity pain (1 study, n=40).
Another study assessed the placebo component of analgesic therapies by looking at theeffect of both “overtly applied” and “covertly applied” local anaesthetic on pain after
venipuncture in patients with Alzheimer’s disease (Benedetti 2006 Level III-2). The patients with
reduced Frontal Assessment Battery scores (a measure of frontal executive function) had areduced placebo component to their pain relief and dose increases were required to produce
adequate analgesia.
Undertreatment of acute pain is more likely to occur in cognitively impaired patients ( Forster
2000 Level III-2; Morrison 2000 Level III-2; Feldt 1998 Level III-2), although this may be improving(Paulson 2014 Level III-2).
Delirium
Acute perioperative neurocognitive disorders include delayed neurocognitive recovery (dNCR formerly postoperative cognitive dysfunction) and delirium ( Evered 2018 NR). From a pain
management perspective, delirium is the more significant. Delirium is an acute deterioration incognitive state associated with a fluctuating course, inattention, confusion and altered conscious
state. It is most common in the elderly, especially those with pre-existing cognitive impairment,
and occurs in medical patients and in up to 65% of postoperative patients. Delirium is associatedwith increased postoperative morbidity, impaired rehabilitation and prolonged hospital LOS(O'Regan 2013 NR). It is also prevalent during acute illnesses in the older person. It is estimatedthat delirium can be prevented in up to 40% of hospitalised patients; risk factors including age,756

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infection, emergency surgery, pre-existing cognitive impairment, metabolic disturbance,
polypharmacy and unrelieved pain (Thompson 2018 Level IV, n=668; American Geriatrics Society 2015
GL).
Delirium presents clinically in both hyperactive and hypoactive forms, of which the latter ismore common (Rudolph 2011 NR) and mixed forms can occur. Although restlessness and agitation(hyperactive delirium) may trigger assessment, which identifies a trigger associated with pain,
the more frequent hypoactive delirium may mask pain, especially in the elderly.
Effective pain management contributes to strategies to reduce the incidence of delirium, butsome analgesics, especially opioids, also contribute to delirium either through anticholinergic
activity (eg pethidine) or by causing sedation and confusion (Swart 2017 Level III-2 SR, 6 studies,n22,000; American Geriatrics Society 2015 GL).
9.2.2.2 | Measurement of pain
Patient self-report measures of pain
Unidimensional measures of pain intensity are more commonly used to quantify pain in theacute pain setting than multidimensional measures (see also Section 2.2). Unidimensional
measures used in younger adult populations, and which have been shown to be appropriate foruse in the older patient, include the VNRS, FPS, VDS alone and with calorimetry (Iowa pain
thermometer) and the NRS, with equivocal support for use of the VAS (Hadjistavropoulos 2014 NR;
Paulson 2014 NR). Completion rate is high for VNRS in the older patient but this decreases withincreasing cognitive impairment. Several studies confirm that VDS is often the preferred tool anduse of familiar words such as “none, slight, mild, moderate, severe and extreme” is felt to be themost reliable in the older patient, including those with mild to moderate cognitive impairment.
Trialling of different self-assessment scales may be warranted including in those with severe
impairment and the patients may need more time to understand and respond to questions
regarding pain. Immediate reports of present pain may be reasonably accurate and as valid as
those of cognitively intact patients but recall of past pain is less likely to be as reliable. Further
comparative studies in the elderly include patients with fractured hips ( Leino 2011 Level IV) andafter cardiac surgery (Pesonen 2008 Level IV), where VAS was also the least reliable and the VDS
and Red Wedge Scale were most applicable.
Other measures of pain
Assessment of pain in noncommunicative patients is more difficult. Behaviours such as
restlessness, frowning and grimacing or sounds such as grunting or groaning have been used inattempts to assess pain. In cognitively intact adults, some of these behaviours have been shownto correlate with patient self-report of pain (Bell 1997 NR). However, they may not always be valid
indicators of pain in the nonverbal adult (Farrell 1996 NR) and can be difficult to interpret (Herr2011 NR; Herr 2006 NR).
There is some argument that observations of facial expressions and sounds may be accurate
measures of the presence of pain but not pain intensity in patients with advanced dementia (Herr2006 NR), although this position has been challenged in recent studies (Lukas 2013 Level III-2).
More than 28 different observational pain assessment scales have been developed and usedin patients with varying degrees of dementia (Lichtner 2014 Level IV SR of SRs, 8 SRs; Herr 2011 NR).
Scales with the strongest evidence of utility include: FPSs, Abbey Pain Scale, Pain Assessment inAdvanced Dementia (PAINAD) (a simple, reliable and validated five-item observational tool), Pain
Assessment Checklist for Seniors with Limited Ability to Communicate and MobilizationObservation-Behavior-Intensity-Dementia Pain Scale.

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757For more detailed and critical review of pain-assessment tools for use with nonverbal adultssee (Lichtner 2014 Level IV SR of SRs, 8 SRs; Hadjistavropoulos 2014 NR; Herr 2011 NR; Herr 2006 NR;
Zwakhalen 2006 NR).
See also Section 2.2.

9.2.3 | Pharmacokinetic and pharmacodynamic changes
The changes in physiology and effects on pharmacokinetics and pharmacodynamics in older
people, and consequent alterations that might be required in some drug regimens are
summarised in Table 9.4. The information in this table centres on opioids, given their widespreaduse. These changes have variable prevalence and are generally attributable to ageing alone but
may be compounded by the higher incidence of degenerative and other concurrent diseases inolder people.
Assessment of the pharmacodynamic changes associated with ageing is difficult. When suchstudies have been done with opioids, most have used a surrogate measure of effect other thanclinical pain relief. For example, in studying the effects of fentanyl and alfentanil on the EEG, thepharmacokinetics were shown to be unaffected by age, but the sensitivity of the brain to these
opioids was increased by 50% in the older person ( Scott 1987 EH). It is unclear whether this canbe attributed to changes in the number or function of opioid receptors in the CNS (in older rats
there are fewer mu- and kappa-opioid receptors) (Yezierski 2012 NR BS; Vuyk 2003 NR), or whether
it is due to an increased penetration of opioids into the CNS. Some of the changes that may leadto increased drug sensitivity in the older patient are discussed below; see Section 9.2.2 above.
Table 9.4 | Physiological changes in older people, resulting changes of pharmacokinetic
variables and consequences for pharmacological treatment
Body system orprocess

Parameter andchangesResultingpharmacokinetic/
pharmacodynamicchanges

Changes inpharmacologicaltreatment

Body composition

body fat
 10–50%for lipophilic medicines
 Vd  t1/2

calculate doses oflipophilic medicines on
total body weightmuscle 20%

no relevant effectnonebody water 10%

for hydrophilic
medicines Vdcalculate doses ofhydrophilic medicines
based on lean bodyweightplasma volume
↔

None

none

Liver size
 25–40%

 bioavailability of oral
medicines
 hepatic CL of highextraction medicines (egmorphine)↔ IV bolus dose oral dose of somemedicines

Liver

Hepatic bloodflow
 25–40%758

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Body system orprocess

KidneyParameter andchangesResultingpharmacokinetic/
pharmacodynamicchanges

Changes inpharmacologicaltreatment

Phase 1
metabolism
 25% hepatic CL of somelow extraction medicines(eg ibuprofen maintenance dosesof some medicines(eg morphine)

Kidney size
 30%

 clearance of renally
excreted medicines↔ effect on opioids, but
often clearance of
metabolites(eg morphine [M6G],
tramadol [M1]) maintenance dose ofrenally excreted
medicine (alpha-2-delta
ligands: gabapentin,pregabalin) or
medicines with renally
excreted metabolites(morphine, tramadol,
pethidine)monitor foraccumulation of renally
excreted medicines

Renal bloodflow
 10% / decade
GFR 30–50%
Creatinine
clearance (Cl)
 50–70%
Heart

Cardiac output↔ or  to 20%

 central compartment
volume peak concentration
after IV bolus initial IV bolus doses IV injection speed

CNS

Cerebral blood
flow, volume
and metabolism
 20%

 distribution to the CNS
 apparent volume in
the CNS

Blood brain
barrier transport (medicine
specific effect) apparent volume in
the CNS apparent increase in
CNS sensitivity

minimal clinically
relevant changes formost drugs, but: bolus doses of
medicines during
titration
 maintenance dosesof some medicines

oral andtransmucosal
absorption

no relevant effect ofageinghowever oral
bioavailability of somemedicines due to firstpass effectIM absorption

↔

none

SC absorption

↔

none

transdermal
absorption

 hydrophilic medicines↔ lipophilic medicines

no clinically relevant
effect for TD opioids

Plasma albumin
 20%

 unbound fraction of
medicines

Absorption of
Medicines

Protein binding of
medicines

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759

Body system orprocess

Parameter andchangesResultingpharmacokinetic/
pharmacodynamicchanges

Changes inpharmacologicaltreatment

Alpha-1-acidglycoprotein
 30–50%

 cerebral uptake of
medicines↔ hepatic clearance ofhigh extraction
medicines
 hepatic clearance of
low extraction medicines

possibly changed
clearance and oral
bioavailability
possibly changed
cerebral effects

Source: Modified and adapted from Macintyre 2008 and Coldrey 2011

9.2.4 | Drugs used in the management of acute pain in older people
In general, there is limited evidence about the use of analgesic medications in older patients; asbecause of their age, comorbidities or concurrent medications, they are often specifically
excluded from clinical trials (McLachlan 2011 NR).
The American Society of Geriatrics publishes and regularly updates a list of drugs that can beassociated with increased adverse effects when used in the elderly: American Geriatrics Society
Updated Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults ( American
Geriatrics Society 2019 GL). This list comprises drugs that should be prescribed with caution in theelderly, as well as drug-drug interactions and drugs which have additional risk in specific diseasestates.
Drugs used to treat pain which are on the list include:• Pethidine – may cause delirium• nsNSAIDs – risk of GI bleeding in high risk groups, including > 75 y
• Drugs with anti-cholinergic effects – tricyclic antidepressants (TCA), hyoscine• Falls risk – opioids, antidepressants (TCA, SSRI, SNRI), clonidine (CNS effects, orthostatic
hypotension)• Opioids in combination with gabapentin or pregabalin – this combination increases riskof sedation, OIVI and death.
• Heart failure – caution with nsNSAIDs and Coxibs (avoid if symptomatic heart failure)• Cognitive impairment – drugs with anticholinergic effects eg TCAs
• Chronic kidney disease (GFR < 30 mL/min) – nsNSAIDs, Coxibs• Hyponatraemia or Risk of Syndrome of inappropriate antidiuretic hormone secretion(SIADH) – SNRIs, SSRIs, TCAs, Tramadol
Concern is often expressed about the safety of pharmacological approaches to pain
management in older adults due to the increased risk of adverse drug reactions. Analgesics may
be responsible for >5% of adverse drug reactions and can lead to emergency department visits
in the older population (Oscanoa 2017 Level IV SR, 42 studies, n>7,000,000 [>265,000 admissions];
Shehab 2016 Level IV, n=42,585); only anticoagulants and antidiabetic agents result in more
frequent admissions (Shehab 2016 Level IV, n=42,585). Older patients are particularly vulnerable toadverse drug reactions because of the age-associated changes in pharmacokinetics andpharmacodynamics. In addition, comorbid medical conditions and geriatric syndromes that
commonly occur in older people can increase adverse drug reactions (eg for NSAIDs) ( Bhala 2013760

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Level I, 754 RCTs, n=353,809). For instance, the presence of frailty, defined as “a progressive age-

related decline in physiological systems, which confers extreme vulnerability to stressors andincreases the risk of a range of adverse health-outcomes” (WHO 2015 NR) may raise several
concerns in formulating an appropriate pharmacological treatment of pain (Lohman 2017 Level IV,
n=3,652). Frailty is often characterised by the coexistence of multiple diseases states, resulting in
multiple medications with increasing risk of drug-drug and drug-disease interactions, and an
associated increase in the risk of adverse drug reactions (Onder 2018 GL). The known association
between frailty and inflammation may potentially down-regulate drug metabolism andtransporter pathways, thereby impacting upon the clinical pharmacology of analgesics(McLachlan 2011 NR). Likewise, frailty is often characterized by chronic undernourishment, which
could alter the distribution of some drugs as well as changes in pharmacokinetic parameters(Onder 2018 GL). Therefore, when pain medications are prescribed in older adults it is important
to consider their potential side effects, but also possible interacting drugs or diseases in order toprevent ADRs.
While this and the following section concentrate on the use of analgesic drugs and techniquesin the older patient, physical and psychological strategies should also be employed as with other
patients (APS 2019 GL; Abdulla 2013 GL; Makris 2014 NR).
9.2.4.1 | Paracetamol, nonselective NSAIDs and Coxibs
Paracetamol is recommended as a first-line therapy in older adults for both mild to moderate
pain (Abdulla 2013 GL; O'Neil 2012 GL; American Geriatrics Society 2009 GL; Makris 2014 NR). There isinconsistent evidence on the effect of ageing and frailty on clearance of paracetamol, with earlier
authors recommending no dose adjustment (Bannwarth 2001 PK; Miners 1988 PK; Divoll 1982 PK) but
more recent reviews recommending that dose adjustment is prudent (McLachlan 2011 NR; Mitchell
2011b NR). In a small cohort comparison, spot paracetamol plasma concentrations on d 5 of
3 to 4 g/d therapy were in the therapeutic range in 21 of 23 older and frail older patients andelevated in 2 (but less than twice therapeutic range) ( Mitchell 2011a Level III-3, n=71). Plasma
alanine aminotransferase (ALT) levels after 5 d were not elevated in any of the older and frail
participants. Overdose may lead to severe hepatotoxicity and the wide availability ofparacetamol often marketed under diﬀerent names, presentations and combinations may
increase this risk in older persons living at home (Tittarelli 2017 NR). A detailed review ofparacetamol induced liver injury found no good quality evidence to indicate that older patientsare at increased risk of liver injury when treated with paracetamol at normal doses (Caparrotta
2018 NR)NSAIDs may offer more effective control of inflammatory pain, but older patients are more
likely to suffer gastric and renal adverse effects following administration of nsNSAIDs ( Abdulla
2013 GL) and may also be more likely to develop cognitive dysfunction ( Juhlin 2005 Level II, n=14,
JS 4; Pilotto 2003 Level III-2; Peura 2004 NR) (see also Section 4.2). In elderly (age >65 y) medical
inpatients, use of nsNSAIDs was a significant risk factor for renal function deterioration occurringin 6.1% of patients exposed; other risk factors were loop diuretics, hypernatraemia and low
serum albumin levels (Burkhardt 2005 Level IV, n=343). Use of oral nsNSAIDs often does not alignwith current clinical guidelines in the older population and particularly regarding the prolonged
duration of use and lack of PPI coadministration (Gnjidic 2014 Level III-2).
NSAIDs should be used with care in elderly patients given their cardiovascular,
gastrointestinal and renal adverse effects, and patients should be monitored closely ( O'Neil 2012
GL; Fine 2004 GL; Makris 2014 NR). For this reason, opioids are sometimes used in preference to
NSAIDs. A cohort study of elderly patients with arthritis (mean age 80 y) started on nsNSAIDs,
coxibs or opioids challenge the assumption that opioids are safer in this population ( Solomon 2010
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Level III-2, n=12,840). This study found increased rates of fracture, hospital admission and all-cause

mortality in the opioid cohort and similar or higher rates of cardiovascular, renal andgastrointestinal adverse effects. Overall the nsNSAID cohort appeared to have the lowest risk foradverse effects.
Coxibs have a significantly lower incidence of upper gastrointestinal complications(Jarupongprapa 2013 Level I, 9 RCTs, n=7,616) and have no antiplatelet effects (Munsterhjelm 2006
Level II EH, n=18, JS 4), which might be of some advantage in the older patient. The risk of otheradverse effects, including effects on renal function (Zhang 2006 Level I, 114 RCTs, n=116,094),
hypertension and exacerbation of cardiac failure may be lower too, at least for celecoxib (seeSection 4.2.2.2). Compared with paracetamol and placebo, only transient reduction of creatinine
clearance was seen after 3 d treatment with parecoxib 40 mg/d in elderly patients undergoing
major orthopaedic surgery (Koppert 2006 Level II, n=75, JS 5).
Use of both coxibs and nsNSAIDs (possibly lowest with naproxen and celecoxib) can increase
the risk of cardiovascular and cerebrovascular events (Trelle 2011 Level I, 31 RCTs, n=116,429) andregular use of nsNSAIDs may interfere with the clinical benefits of low-dose aspirin (for details
see Section 4.2). Extra precautions are therefore required in older patients.
Topical nsNSAID agents may be a preferred route of administration (due to lower systemiclevels and less gastrointestinal adverse effects) in older adults where there is appropriate andlocalised pain (Massey 2010 Level I [Cochrane] 47 RCTs, n=3,455; Klinge 2013 Level I, 6 RCTs, n=600;
Zacher 2008 Level I, 19 RCTs, n>3,000; Makris 2014 NR) (significant overlap between all three SRs) (seealso Section 4.2.3.6).
9.2.4.2 | Conventional and atypical opioids
Despite the age-related changes listed in Table 9.4, there may be few differences in the older
patient in fentanyl (Scott 1987 EH), morphine, oxycodone (Villesen 2007 PK) and buprenorphine
pharmacokinetics (Kress 2009 NR).
After oral administration, the bioavailability of some drugs may be increased, leading torelatively higher plasma concentrations (Gupta 2012 NR; Mangoni 2004 NR).
Opioid dose
Older patients require less opioid than younger patients to achieve the same degree of pain relief(Gagliese 2000a Level IV; Woodhouse 1997 Level IV; Macintyre 1996 Level IV; Upton 2006 PK); however,a large interpatient variability still exists and doses must be titrated to effect in all patients. The
decrease is much greater than would be predicted by age-related alterations in physiology andseems to have a significant pharmacodynamic component ( Gupta 2012 NR; Macintyre 2008 NR).
In the clinical setting, there is evidence of an age-related 2 to 4-fold decrease in morphineand fentanyl requirements (Gagliese 2000a Level IV; Woodhouse 1997 Level IV; Macintyre 1996
Level IV). The decrease is in agreement with previous findings that the sensitivity of the brain tofentanyl and alfentanil was increased by 50% in older people ( Scott 1987 EH). It has beensuggested that doses of fentanyl, sufentanil and alfentanil should be reduced by up to 50% in
older patients (Shafer 1997 NR); reductions in the doses of other opioids are also advised(Macintyre 2008 NR). In general, patients aged 80 y should receive 50% of the opioid dose of a 40y-old patient due to pharmacodynamic changes and increased sensitivity ( Gupta 2012 NR).
In patients >75 y, the elimination half-life of tramadol is slightly prolonged (Scott 2000 NR);
lower daily doses have been suggested (Barkin 2005 NR). Awareness and consideration of druginteractions in the elderly is necessary, particularly with the high incidence of polypharmacy andantidepressant use (Makris 2014 NR).

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Opioid metabolites
Reduced renal function in the older patient could lead to a more rapid accumulation of active
opioid metabolites (eg M6G, M3G, H3G, nordextropropoxyphene, norpethidine and M1) (seeSection 4.1).
Adverse effects of opioids
The concern regarding respiratory depression in older people, especially those with respiratory
disease, often leads to inadequate doses of opioid being given for the treatment of their pain.
However, as with other patients, significant respiratory depression can generally be avoided if
appropriate monitoring (in particular, of sedation) is in place (see Section 4.3.1.4).
The incidence of nausea/vomiting and pruritus in the postoperative period lessens withincreasing age (Quinn 1994 Level IV). In older patients, IV PCA fentanyl may cause lesspostoperative cognitive dysfunction than morphine ( Herrick 1996 Level II, n=96, JS 2). There is anincreased risk of delirium in the elderly with use of pethidine ( Swart 2017 Level IV SR, 3 studies[pethidine], n=877) and tramadol (Swart 2017 Level IV SR, 1 study [tramadol]: Brouquet 2010 Level IV,
n=133) and a potential protective effect with fentanyl and hydromorphone; however, theunderlying studies are small and of low quality. However, administration of an appropriate
opioid medication is often associated with higher levels of cognitive function andundertreatment of postoperative pain with lower levels (Morrison 2000 Level III-2, n=541; Lynch
1998 Level IV). Constipation is a common adverse effect of treatment with opioids and is arelevant consideration in older adults, many of whom already exhibit altered gastrointestinal
function. Prophylactic management of constipation should be commenced whenever opioids
are prescribed (Hunold 2013 Level IV; Makris 2014 NR).
See also Section 4.3.1.4
9.2.4.3 | Local anaesthetics
Age-related decreases in clearance of bupivacaine (Veering 1987 Level III-2; Veering 1991 PK) andropivacaine (Simon 2006 PK) have been shown. Older patients may be more sensitive to theeffects of local anaesthetic agents because of a slowing of conduction velocity in peripheral
nerves and a decrease in the number of neurons in the spinal cord ( Sadean 2003 NR). Localised
neuropathic pain may be suitable for treatment with topical lignocaine (lidocaine) patch, inparticular in older patients with increased comorbidities and polypharmacy, as systemic adverse
effects are rare (Finnerup 2015 GL Level I [PRISMA], 229 RCTs, n unspecified; Fine 2012 GL; Makris 2014NR).

9.2.4.4 | Ketamine
There are no good data on the need or otherwise to alter ketamine doses in the older patient. In
aged animals, however, changes in the composition of the NMDA-receptor site and function
have been reported (Clayton 2002 BS; Magnusson 2002 BS; Vuyk 2003 NR). Young and elderly rats,
given the same dose of ketamine on a mg/kg basis showed similar EEG changes but thesechanges were quantitatively greater in the older rats (Fu 2008 BS). These data suggest that, apartfrom any pharmacokinetic changes, the older person may be more sensitive to the effects ofketamine and doses may need to be lower in this patient group.
9.2.4.5 | Tricyclic antidepressantsClearance of TCAs may decrease with increasing patient age and lower initial doses arerecommended in older people (Ahmad 2002 NR).
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Older people may be particularly prone to the adverse effects of TCAs ( Abdulla 2013 GL; Fine
2004 GL; Ahmad 2002 NR) including sedation, confusion, orthostatic hypotension, dry mouth,
constipation, urinary retention, and increased risk of mortality and dementia (Coupland 2019 Level
III-2, n=284,343; Fox 2011 Level III-2). Adverse effects appear to be most common with amitriptyline,
and so nortriptyline may be preferred in this patient group ( Argoff 2005 NR; Ahmad 2002 NR).
Clinical conditions that may require TCAs to be administered with caution are more common inolder people and include prostatic hypertrophy, narrow-angle glaucoma, cardiovascular disease
and impaired liver function; ECG abnormalities may be a contraindication to the use of TCAs in
older people (Ahmad 2002 NR).
Overall in elderly patients, TCAs should generally be avoided, as the use of medications with
anticholinergic activity increases the risk of cognitive impairment and even mortality in thispatient group (Fox 2011 Level III-2).
9.2.4.6 | Serotonin–norepinephrine-reuptake inhibitors
Duloxetine has been shown to be effective and safe for the treatment of painful diabetic
peripheral neuropathy in older patients (mean age 60 y) (Goldstein 2005 Level II, n=547, JS 4).
Duloxetine was effective and well tolerated for the treatment of osteoarthritis pain of the kneein older patients (mean age 62 y) (Chappell 2009 Level II, n=231, JS 4).
9.2.4.7 | AnticonvulsantsAs liver and renal function decline with increasing age, elimination of anticonvulsants such as
carbamazepine and gabapentin may be reduced (Ahmad 2002 GL). As with TCAs, initial doses
should be lower than for younger patients and any increases in dose should be titrated slowly.
The “second generation” drugs such as gabapentinoids and topiramate may be less likely toresult in adverse effects in the older patient (Argoff 2005 NR), although the relatively highfrequency of adverse effects such as somnolence and dizziness with pregabalin may be a problem
in this group of patients (Goodman 2017 NR; Guay 2005 NR). However, pooled data from RCTs withpregabalin in neuropathic pain showed an increase of adverse effects only with increasing doses,
but not related to the age of patients (Semel 2010 Level III-3, n=2,516 [65 to 74 y: n=766] & [≥75 y:n=514]). Efficacy was comparable to that in younger age groups; the lack of drug interactions may
be an advantage in particular in older patients.

9.2.5 | Patient-controlled analgesia
PCA is an effective method of pain relief in older people but its use may be limited by thepresence of cognitive impairment or development of postoperative delirium ( Mann 2000 Level II,
n=70, JS 3; Gagliese 2000a Level III-2; Mann 2003 NR). Compared with younger patients (mean age
39 y), older patients (mean age 67 y) self-administered less opioid than the younger group but
there were no differences in pain relief achieved, satisfaction with pain relief and pain scores orconcerns about pain relief, adverse drug effects, risks of addiction or use of the equipment(Gagliese 2000a Level III-2).
Compared with IM morphine analgesia in older men, PCA resulted in better pain relief, lessconfusion and fewer severe pulmonary complications (Egbert 1990 Level II, n=83, JS 2). In older
patients, PCA also resulted in significantly lower pain scores vs intermittent SC morphine
injections (Keita 2003 Level II, n=40, JS 3).

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9.2.6 | Epidural analgesia
In the general patient population, epidural analgesia can provide the most effective pain reliefof all analgesic therapies used in the postoperative setting (see Section 5.6). Epidural analgesia
significantly reduces many of the complications that occur in the elderly after surgery ( Popping
2014 Level I [PRISMA], 125 RCTs, n=9,044). Older patients given epidural PCA using a mixture ofbupivacaine and sufentanil had lower pain scores at rest and movement, higher satisfaction
scores, improved mental status and more rapid recovery of bowel function vs use of IV PCA (Mann2000 Level II, n=70, JS 3). After hip fracture surgery, epidural analgesia with bupivacaine andmorphine also provided better pain relief both at rest and with movement but this did not leadto improved rehabilitation (Foss 2005 Level II, n=60, JS 5). Epidural analgesia, after colectomy forcancer in patients aged >65 y of age, may be associated with improved long-term survival(Cummings 2012 Level III-2, n=42,151). Patients having colectomy for cancer had better 5-y survivalin the epidural group vs the nonepidural group (61 v 55%; HR 0.91; 95%CI 0.87 to 0.94). In a
retrospective study, epidural analgesia was associated with reduced cancer recurrence inpatients aged >64 y having colectomy (Gottschalk 2010 Level III-2). The postulated mechanism isreduced impairment of immune function in patients having epidural analgesia, although overall
data are contradictory (see also Section 5.6.1.2).
Older patients are more likely to have ischaemic heart disease where coronary blood flow
may be reduced rather than increased in response to sympathetic stimulation. In a study ofpatients (average age 67 y) with multivessel coronary artery disease, high (T2 to T3) thoracic
epidural analgesia using 0.5% bupivacaine instituted before CABG surgery was able to partly
normalise myocardial blood flow in response to sympathetic stimulation ( Nygard 2005 Level III-2).
In a small trial of perioperative analgesic regimens initiated preoperatively for hip fracture
repaired under spinal anaesthesia, older patients who had received epidural
bupivacaine/fentanyl analgesia had significantly better postoperative pain relief than those who
were given IM oxycodone; there was no difference in the number of patients who developed
postoperative continuous ECG-detected ischaemia or hypoxia (Scheinin 2000 Level II, n=77, JS 3).
However, the number of episodes and total duration of ischaemia in each patient was markedly
greater in the oxycodone group.
Epidural morphine requirements decrease as patient age increases (Ready 1987 Level IV).
However, a comparison of PCA epidural fentanyl in patients aged >65 y with those aged 20–64 yshowed no difference in fentanyl requirements or pruritus; although pain relief on coughing at
24 h was better in the older patient group (Ishiyama 2007 Level III-3).
Age is also a determinant of the spread of local anaesthetic in the epidural space and thedegree of motor blockade ( Simon 2004 Level III-2; Simon 2002 Level III-2). Thus, smaller volumes
may be needed to cover the same number of dermatomes than in a younger patient. Whenthe same volume of local anaesthetic was given, the concentration required to produce
effective motor block decreased as patient age increased ( Li 2006 Level III-1). Combinationsof a local anaesthetic and opioid are commonly used for epidural analgesia, so it would seemreasonable to use lower infusion rates in older patients ( Macintyre 2008 NR).
Older patients may be more susceptible to some of the adverse effects of epidural analgesia,
including hypotension (Simon 2002 Level III-2; Crawford 1996 Level IV; Veering 2006 NR).

9.2.7 | Intrathecal opioid analgesia
IT morphine using a variety of doses provided more effective pain relief after major surgery vsother opioid analgesia, although the risk of respiratory depression and pruritus was greater(Meylan 2009 Level I, 27 RCTs, n=645).
5th Edition | Acute Pain Management: Scientific Evidence765With neuraxial opioids, advanced patient age is considered by some to be a risk factor for
respiratory depression and it has been suggested that patients >70 y be monitored in an ICU
setting (Gwirtz 1999 Level IV). However, others report that older patients (average age 69 y) given
up to 200 mcg IT morphine at the time of spinal anaesthesia for peripheral vascular and othersurgery have been safely nursed on general wards by nursing staff who have received additional
education and managed by an APS according to strict guidelines (Lim 2006 Level IV).
The optimal dose of IT morphine for older patients remains unknown. The evidence for the“best” dose is provided by data from small trials and remains inconsistent. IT morphine doses of
200 mcg given in addition to general anaesthesia in older patients (average age 70 y) undergoing
abdominal aortic surgery led to better postoperative analgesia and reduced postoperative
analgesia requirements vs general anaesthesia only (Blay 2006 Level II, n=30, JS 4). No conclusion
could be made about adverse effects, as total patient numbers were small. A comparison of threedoses of IT morphine (50 mcg, 100 mcg and 200 mcg) given to older patients after hip surgery
concluded that the 100 mcg dose provided the best balance between good pain relief andpruritus (Murphy 2003 Level II, n=60, JS 4). There was no difference seen in the incidences of nausea
and vomiting or respiratory depression.
Use of IT morphine 300 mcg in addition to IV PCA morphine in elderly patients led to better
pain relief and PCA morphine requirements vs PCA morphine alone (Beaussier 2006 Level II, n=59,
JS 5). However, sedation was increased and there were no differences in time to ambulation,
hospital LOS or incidence of confusion.

9.2.8 | Other regional analgesia
The advantages of regional block in older patients include improved pain relief and a reductionof the adverse effects of opioids (Halaszynski 2009 NR). After hip fracture fixation, those who
received patient-controlled femoral nerve analgesia, in addition to regular paracetamol andmetamizol, were less likely to develop postoperative delirium, were able to sit at the bedside at
an earlier stage, and required no SC morphine vs those getting paracetamol and metamizol only
(28% required additional morphine analgesia) (Rosario 2008 Level III-3).
The duration of action of sciatic nerve (Hanks 2006 Level III-2) and brachial plexus blocks(Paqueron 2002 Level III-2) is prolonged in the older patient.
In older (>65 y) patients undergoing urological surgery via a flank incision, PVB of the lumbar
plexus using either ropivacaine or bupivacaine has been shown to provide good analgesia withno changes in the patients’ heart rate or blood pressure (Akin 2005 Level II, n=60, JS 1).
Unlike epidural analgesia, age did not influence the spread of bupivacaine in the thoracic
paravertebral space (Cheema 2003 Level III-2).

KEY MESSAGES
1. Topical nsNSAIDs for localised pain provide effective analgesia (U) (Level I [Cochrane
Review] with lower plasma concentrations and fewer gastrointestinal adverse effects
than oral nsNSAIDs (U) (Level I); this may improve safety in the elderly.
2. PCA and epidural analgesia are more effective in older people than conventional opioid
regimens (U) (Level II).
3. Experimental pain thresholds to thermal stimuli are modestly increased in older people(U) (Level III-2 SR).

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4. Reported frequency and intensity of acute pain in clinical situations may be reduced in
the older person (U) (Level III-2).
5. Common unidimensional self-report measures of pain can be used in the older patient in
the acute pain setting, but need to be appropriate for the individual patient; the verbal
descriptor and numerical rating scales are preferred in patients who can self-report (U)(Level III-2), while in the older patient with cognitive impairment, specific pain
assessment tools are more appropriate (N) (Level IV SR).
6. Undertreatment of acute pain is more likely to occur in cognitively impaired patients (U)(Level III-2).
7. The use of nsNSAIDs and coxibs in older people requires caution, although use of opioids
may result in more complications (U) (Level III-2); paracetamol is the preferred
nonopioid analgesic (U) (Level III-2).
8. The under-representation of older patients in clinical drug trials limits information about
efficacy, safety and pharmacokinetics of many types of medications including analgesic
medications (N) (Level IV SR}
9. The older patient is at increased risk from adverse effects of medications including many
analgesics (N) (Level IV).
10. Delirium is common in elderly hospitalised patients, including after surgery; risk factors
include inadequate pain management and excessive use of opioids and other sedating
analgesics (N) (Level IV).
11. There is an age-related decrease in opioid requirements; significant interpatientvariability persists (U) (Level IV).
12. The age-related decrease in opioid requirements is related more to the changes inpharmacodynamics that accompany ageing than to the changes in pharmacokinetics (U)(Level IV).
The following tick box represents conclusions based on clinical experience and expert opinion: The assessment of pain and evaluation of pain relief therapies in the older patient may
present problems, arising from differences in reporting, cognitive impairment anddifficulties in measurement (U).
 Measures of present pain may be more reliable than past pain, especially in patientswith some cognitive impairment (U).
 The physiological changes associated with ageing are progressive; while the rate ofchange can vary markedly between individuals and is related to frailty, these changes
may decrease the dose (maintenance and/or bolus) of drug required for pain relief andmay lead to increased accumulation of active metabolites (U).
 The high prevalence of frailty in the older patient is an independent risk factor forincreased adverse drug effects to analgesic medications (N).
 The use of regional analgesics techniques, as an alternative to systemic analgesics, canconfer benefits of improved pain relief, and minimise adverse effects (cognitive, pulmonary) (N).
 Cognitive impairment in the older patient may limit the appropriate use of PCA (N).
5th Edition | Acute Pain Management: Scientific Evidence7679.3 | Culturally responsive care for Culturally and LinguisticallyDiverse patients
Growth in the cultural, linguistic and religious diversity of the Australian community reflects thediversity of migrant communities from many countries, this being a clear shift from early migrantcommunities predominantly of European background. The 2016 Census states that about 49%
of Australians were born overseas or have at least one parent born overseas and 21 % speak alanguage other than English with slight variations across states (ABS 2017). The Aboriginal andTorres Strait Islander community comprises 2.8% of the total population. The five most common
languages spoken at home (other than English) were Mandarin (2.5%), Italian (1.2%), Vietnamese(1.2%), Arabic (1.4%), Cantonese (1.2%) and Greek (1.0%). The top five non-Christian religions in2016 were Islam (2.6% of the population), Buddhism (2.4%), Hinduism (1.9%), Sikhism (0.5%) andJudaism (0.4%). The New Zealand 2018 census (Stats NZ 2019) shows the following ethnic groups:
European (64.1%), Māori (16.5%), Chinese (4.9%), Indian (4.7%), Samoan (3.9%); with the top
3 foreign countries of birth being England (4.5%); Peoples Republic of China (2.9%) and India(2.5%) and the languages spoken at home (other than English) were te reo Māori (4%), Samoan(2.2%), Northern Chinese (including Mandarin) (2%), and Hindi (1.5%).
Economic globalisation and current world events are compelling many communities to seeka home elsewhere. This facilitates ongoing migration, which has a direct impact on the cultural
diversity of many countries. A major ‘immigration nation’, Australia has been made home byover 7.5 million people since 1945 (Phillips 2017 NR). Recent migration patterns and thehumanitarian program in Australia have resulted in the arrival of a variety of cultural groups, themajority of which came from Iraq, Syria, Afghanistan and Myanmar in 2016-17 (Refugee Councilof Australia 2019).
Culture, language and religious convictions have an impact on the clinical encounter. Thisbackground drives a need to understand different cultures when considering pain assessmentand management. This extends beyond the language spoken, because an individual’s culture,faith and migration history influence their linguistic expression, metaphorical language, beliefs,
attitude, need for social support, framework of meaning, health literacy, expectations,perception, methods of communication, norms of behaviour and pain relief preferences. This
also applies to the culture and attitudes of the health professional ( Xu 2018 Level III-2; Al-Harthy
2016 Level III-2; Holt 2018 Level IV; Park 2017 Level IV; Martin 2017 Level IV; Rahavard 2017 NR; Brady
2017 NR; Brady 2016 NR; Pillay 2015 NR). These principles, and culturally competent practices, aresupported by the ANZCA Statement on Cultural Competence PS 62 ( ANZCA 2017 GL). Similarly,
culturally competent practices are endorsed by The Australian Medical Council, the Medical
Board of Australia, and the Medical Council of New Zealand (Medical Board of Australia 2014 GL).
Consequently, a health professional needs to consider their own cultural assumptions andpreconceived biases as well as address the cross-cultural elements that underpin their patients’
individual responses. A person’s empathy and ability to perceive pain in the other differs acrosscultures (Atkins 2016 Level III-3; Rosa 2018 NR). Some evidence shows variation in assessment andthe severity of pain particularly in the case of African American patients; ethnicity can influence
the health care relationship (Vigil 2016 Level IV; Hirsh 2015 Level IV). Investigation into medication
adherence and patient–physician ethnicity/language concordance supports the need for cultural
responsiveness (Ali 2017 Level IV; Ohana 2015 Level IV). The need for cross-cultural sensitivity isparticularly important when addressing verbal and nonverbal indicators of pain and being aware768

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of stoic and emotive responses to pain as they may have different meaning across cultures ( Ford2015 Level IV). Overall, researchers have found significant cultural differences in self-care whenmanaging pain which affects pain-relief seeking behaviour (Xu 2018 Level III-2). These behaviouraldifferences occur as it relates to ethnicity (Meints 2016 Level III-3 SR, 19 studies, n=6,489; Meints 2018
Level III-2 EH; Meints 2017 Level III-2 EH, n=172). On a broader scale, some cultural attitudes may
limit pain-relief seeking behaviour (Wechkunanukul 2016 Level IV SR, 10 studies, n=1,511,382).
Similarly, a patient may vocalise (Burri 2018 Level III-2; Meints 2015 Level III-2 EH, n=190; Brady 2016NR), or appear stoic in managing pain (Cagle 2017 NR). For example, it may be perceived by somepatients as inappropriate to use a nurse’s time to ask for pain relief as it may be seen as aweakness/shameful, or an unnecessary interruption of their time (Carrion 2015 Level III-3). In somecollectivist cultures, the concept of patient autonomy is foreign and interdependence ispreferred. This behaviour may result in patients waiting for a health professional to offer pain
relief as the latter is seen as the primary medical decision maker (Martin 2017 Level IV; Pillay 2014
NR). Health literacy influences a patient’s ability to understand and act on medical advice ( Xu
2018 Level III-3 SR, 23 studies, n=6,110; Teo 2018 Level III-3; Wilkinson 2014 Level IV). Cross-cultural
perception of pain may be a learned behaviour with links that have been made between culture
and pain-related caregiver behaviours (Kristjansdottir 2018 Level III-3). This may explain why, crossculturally, there is a difference in how a patient might approach their ability to manage their pain(or not). A recent study highlighted that the cross-cultural perception of the causation of pain as
something external, impeded the capacity to express it in biomedical terms: ‘The womenreported that not eating the right food, old age and stress could cause pain, with an overlying
belief that pain was often caused by hard work or tiredness.’ (Holt 2018 Level IV). Spiritual coping
needs to be considered as well; faith informs many patients to respond to pain positively without
seeking pain relief. Hindu culture, for instance, understands pain and suffering within the context
of gaining better karma (Dewar 2015 Level IV). Buddhism emphasises the need for stoicism andfatalism, articulating that pain has the ability to strengthen the body, purify the soul and deepen
the spirit (Cheng 2017 NR; Waikakul 2016 NR). Prayer has also demonstrated a powerful way oftolerating pain in both the African American and Latino community ( Meints 2015 Level III-2 EH,
n=190; Gagnon 2014 NR). Research about the impact of the refugee experience on patients withhealth professionals, advises to provide care with great cultural sensitivity, and that mental
health symptoms and chronic pain are commonly experienced by refugee patients ( Crosby 2013
NR).
Communication problems caused by variable linguistic (and non-verbal) proficiency of either
the patient or the health professional, make it difficult to adequately assist patients withinteractive pain management (eg PCA use, requesting analgesia when needed), to gain consent
for invasive analgesic techniques (eg epidural or regional catheters) and to assess their pain
(Taylor 2017 Level III-2; Ali 2017 Level IV; Ford 2015 Level IV). When language is an obstacle, there
should be caution when using nonprofessional interpreters (eg family, friends), because their
linguistic ability/accuracy in the other language has not been tested and may be variable. In
addition, nonprofessional interpreters may inadvertently omit, edit and impose their own values
when conveying the information to the clinician, and the patient may be reluctant to openly
express themselves in front of people they know.
Direct correlation with longer length of hospital admission, as well as higher readmission
rates, longer delay times, not to mention poorer outcomes in emergency treatment (eg lower
likelihood of receiving analgesia or attending to hospital, lower self-reported quality of life andpoorer end-of-life care) have been made with failure to use an interpreter ( Wechkunanukul 2016
Level III-2 SR, 10 studies, n=1,511,382; Taylor 2017 Level III-2; Asghar 2016 Level III-2; Kilkenny 2018 Level
III-3; Santos 2013 Level III-3; Silva 2016 Level IV SR, 10 studies, n unspecified; van Rosse 2016 Level IV;
Lindholm 2012 Level IV). This is in addition to poorer outcomes due to possible delays in seeking
5th Edition | Acute Pain Management: Scientific Evidence769

help, which can be culturally influenced as well (Wechkunanukul 2016 Level IV SR, 10 studies,
n=1,511,382)
The use of alternative methods of communication through translation apps such as Google
Translate in the clinical setting is either not advised or non-conclusive with the risk to the patient
being considered too great (Silvera-Tawil 2018 Level IV; Panayiotou 2019 NR). The use of health-care
specific language translation apps may therefore only be considered as an alternative option in low
risk situations such as non-clinical communication in the sub-acute setting (eg daily routine
communication) when formal healthcare interpreter services are not available. An accredited
healthcare interpreter should always be engaged to communicate the important points in thecontinuum of patient care. To date only two language translation apps, “Talk to Me” and “CALD
Assist” are regarded safe to use when communicating with culturally and linguistically diverse
patients in the sub-acute setting. Both apps incorporate basic questions around pain and weredeveloped in Australia (in November 2019 only available for Apple IOS 10 [iPad] in the case of
CALD Assist and both [iPad] and [iPhone] in the case of “Talk to Me”), therefore incorporating
languages reflecting the local migrant communities (Panayiotou 2019 NR).
Cultural differences in response to pain in both experimental and clinical settings have beenreported. A person’s expression of pain is something that will not change irrespective of thelength of settlement in a host country (Zborowski 1969 NR). In addition, the pain experience issocialised and therefore one will encounter cultural variances in language of distress whenexperiencing pain. Studies conducted using experimental pain stimuli found that culturaldifferences indeed influenced clinically relevant pain ( Lee 2016 Level III-2), pain tolerance andthreshold (Kim 2017 Level III-2 EH SR, 41 studies, n unspecified; Mahadeva 2015 Level III-3; Aufiero 2017
EH; Morris 2015 EH). In a cohort study on large colorectal and lung cancer, African American
patients reported higher sensitivity to pain than Caucasian patients ( Martinez 2014 Level III-2).
Similarly, African American and Latino/a patients were found to experience a greater ‘ethnicity
effect’ when it came to pain related anxiety, severity and vocalising pain than their Caucasiancounterparts (Gagnon 2014 NR).
Several systematic reviews looked at the perception of pain across cultures and the effect ofpatient ethnicity on pain response, assessment and management across a variety of clinical pain
settings (Lee 2019a Level III-2 SR [PRISMA], 14 studies, n=11,733; Xu 2018 Level III-3 SR, 23 studies,
n=6,110; Rahavard 2017 Level III-3 SR, 42 studies, n unspecified; Kim 2017 Level III-3 EH SR, 41 studies, nunspecified; Krupic 2019 Level IV SR, 10 studies, n unspecified; Hampton 2015 Level IV SR, 5 studies, nunspecified). A review of the cultural impact on the pain management of Chinese cancer patients

highlighted that analgesic use, adherence and pain reporting in Chinese cancer patients is poor,
as it is culturally influenced by feelings of ‘fatalism, desire to be good, low pain control belief,
pain endurance beliefs, and negative effect beliefs.’ (Xu 2018 Level III-3 SR, 23 studies, n=6,110).
Similarly, another study compared opioid consumption after major abdominal surgery between
Hong Kong patients and Caucasian patients in Australia found that the Hong Kong patients
requested less opioid, but that their pain scores were higher (Konstantatos 2012 Level III-2). Further
marked disparities in effective pain treatment were reported; in the United States, African
Americans and Hispanics were less likely to receive opioid analgesics and were more likely tohave their pain undertreated vs Caucasian patients (Groenewald 2018 Level IV; Dickason 2015 Level
IV). This disparity was reported for all types of pain visits, was more pronounced with increasing
pain intensity and was unaffected by adjustment for pain severity. A study which looked at apatient receipt of an opioid prescription after a dental diagnosis, found that indeed ethnicity also
mattered (Janakiram 2018 Level IV).
Interestingly, the research that focused on analgesic prescriptions to children in US EDs,
raises the point that the level of opioids is dependent on whether the patient has an ethnicconcordant health care provider (Groenewald 2018 Level IV). This may explain the differences

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reported in patients of different ethnic groups attending EDs and requiring analgesia ( Lee 2019aLevel III-2 SR [PRISMA], 14 studies, n=11,733), while some studies find little to none (Ly 2019 Level III-2;
Jacob 2017 Level III-2; Shavit 2018 Level IV; Shavit 2016 Level IV).
Prescription of opioids also varied with patient ethnicity independent of health professional
bias. There are innate genetic factors that may explain pain disparity in Indian, Malay and Han
Chinese patients, which demonstrates that opioid requirements are indeed ethnicity dependentand have to be administered as such (Somogyi 2016 Level IV).
To ensure culturally responsive care, it is imperative that health professionals continually
improve their cultural competence by increasing their cross-cultural knowledge, skills and selfawareness through cultural competency training (Jongen 2018 Level IV SR [PRISMA], 64 studies[16 studies specific to health work force], n unspecified). Additionally, it is important to use accredited
healthcare interpreters to improve communication between health professionals and patients who
have difficulty communicating in the main language (Berger 2014 Level IV; Cadoret 2014 NR). Other
strategies used to facilitate cross-cultural pain education and management include bilingual
handouts describing varying methods of pain control and Visual Analog Scale (VAS) with carefully
chosen anchor terms or the use of faces scales (see Chapter 2). With some studies showing apreference for the Faces Pain Scale – Revised, these scales might not be effective on their own(Pathak 2018 Level IV). A comparative study involving the assessment of Verbal Descriptor Scale(VDS), the Visual Analog Scale (VAS), the Faces Pain Scale (FPS), the McGill Pain Questionnaire-ShortForm (MPQ-SF) and the Brief Pain Inventory-Short Form (BPI-SF) found that more than a single tool
may be needed to ensure diagnostic accuracy and consistency in assessing severe pain in patientsof CALD backgrounds (Ham 2015 Level IV). A series of pain scales in a number of different languages
has also been produced by the British Pain Society to assist in the assessment of people whose first
language is not English and these are available on their website (BPS 2014 GL). Limitations with thelatter are that it is not available in Italian (one of the largest cultural groups in Australia) and it
assumes a certain level of literacy of the patient. While there is evidence of differences in pain
reports and analgesic use in different cultures or ethnic groups, this should not be used tostereotype patients or promote assumptions about differences in assessment and management ofpain or response to pain therapies. Rather, it should only be used to inform of possible culturalpreferences. Culturally responsive care in this context is used as an extension of person-centredcare and therefore provision of effective analgesia requires not a culturally specific approach but asensitivity to a patient’s ethnicity, spirituality, cultural practices and beliefs, level of acculturationand their behavioural expression of pain. The large individual differences in pain behaviours andanalgesic requirements that exist in any patient group mean that pain is best assessed andmanaged on an individual basis rather than on the basis of what might be expected in a patientfrom a particular cultural, ethnic or spiritual background (Cadoret 2014 NR).

KEY MESSAGES
1. Disparities in assessment, analgesic requirements and effective treatment of pain exist
across ethnic groups (S) (Level III-2 SR).
2. Ethnic and cultural background of both healthcare professional and patient can
influence the ability to assess and treat acute pain (N) (Level III-2 SR).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Cultural competence of health professionals supported by specific training improves
health outcomes for culturally and linguistically diverse patients (U).
5th Edition | Acute Pain Management: Scientific Evidence771 Pain assessment and management should be done on an individual patient basis.
Differences between ethnic and cultural groups should not be used to stereotype
patients but should only be used to inform of possible cultural preferences (U).
 Multilingual printed information and pain measurement scales are useful in managing
patients from different cultural or ethnic backgrounds (U).
 If language proficiency poses a communication barrier, then an accredited health careinterpreter should be included when conducting a pain assessment, to ensure correct
assessment; the use of friends, family or staff member should be avoided (N).
 The use of health-care specific language translation apps may be only considered as analternative option in non-clinical situations in the sub-acute setting (eg daily routine
communication) when formal healthcare interpreter services are not available (N).

9.3.1 | Aboriginal and Torres Strait Islander Peoples
Evidence from the Australian Institute of Health and Welfare highlights that when compared tonon-Indigenous Australians; “Indigenous Australians, on average, have worse health”,
experience “large disparities in health outcomes” and “report greater difficulty in accessing
affordable health services that are close by” (AIHW 2018 NR). Despite limited and predominantly
weak levels of evidence regarding acute pain and its management in Indigenous Australians; thischapter seeks to identify key themes, barriers, concerns and opportunities for improvement (seealso Table 9.5).
Importantly for clinicians navigating this chapter, findings drawn from patient populations
may not be generalisable beyond the cohort where they were originally documented; however,
exploration of these original papers may provide guidance to practitioners working with these
populations. Additionally, examples selected from the literature for this chapter are not tosuggest a universal approach to pain assessment, but instead highlight heterogeneity in thispopulation, the need to counter racial profiling and ensure delivery of individualised care. Thereis a need for personalised care and variable patient preferences were identified for different
mediums of patient information regarding lower back pain ( Lin 2017 Level III-1); it was suggested
that the need for “communication to be individualised, flexible, and patient centred”.
The ramifications of profiling on pain management have been highlighted within theliterature. One example regards pain experience related to vulvar cancer surgery where“Although pain was noted as an issue by the Indigenous women, one of the health professionals
interviewed did not see it as an issue and indicated that Indigenous peoples have high pain
thresholds.”(McGrath 2015 Level IV). Practitioners should be aware that historical literature whichsuggests high pain tolerance or pain threshold has been broadly criticised by contemporary
authors, who have highlighted a potential risk of harm to patients if these beliefs are followed(McGrath 2015 Level IV; Fenwick 2004 Level IV; Fenwick 2006 NR).
Contemporary studies have instead identified unique, culturally appropriate pain behaviours
among Indigenous patients (Fenwick 2004 Level IV) which may have been misinterpreted by healthpractitioners as “a high pain threshold” (McGrath 2015 Level IV). Examples of culturally
appropriate pain behaviours may include “verbal and nonverbal silence in response to pain” asreported in a study of postoperative pain in Central Australian Indigenous women ( Fenwick 2004
Level IV). Multiple authors highlight study populations where pain may not be vocallycommunicated in a manner “expected” by Western health professionals which suggests that
health professionals may be required to change their methods of assessment in order to identify

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pain expression in this population (McGrath 2006 Level IV; Fenwick 2004 Level IV; Honeyman 1996
Level IV). Other examples of “silent” pain performance may include the feigning of sleep, turninga head away or grimacing, also documented in a Central Australian study ( Fenwick 2001 Level IV).
Authors propose multiple reasons for this style of pain expression; ranging from respect for thehealth professional (Fenwick 2006 NR), an individual’s position within their community ( McGrath2006 Level IV), a belief that the practitioner can “see within” the patient akin to the skills of a
traditional healer (Fenwick 2004 Level IV), fear of the healthcare system (Fenwick 2001 Level IV) or
due to fear of the cause of pain (Fenwick 2004 Level IV). Examples of the latter include cohorts
where “illness and pain are understood in relation to the external world and can be caused bysuch things as, breaking of tradition or violation of taboos, crossing into forbidden land or
speaking to the wrong relative at the wrong time… possibly making the (pain) sufferer too
ashamed to complain” (Fenwick 2004 Level IV). Beliefs regarding the cause of pain must however
be contrasted with the findings in regional and remote Western Australia, where the majority ofparticipants with chronic low-back pain believed their pain resulted from problems in spinal
anatomy or structure (Lin 2013 Level IV). Drawing from this evidence, clinicians need toacknowledge the breadth of pain expression and associated beliefs and how this may influence
the establishment of appropriate pharmacological and non-pharmacological therapeutic
regimes.
Consideration should also be given to the systemic factors which may also play a role in an
individual’s decision to report pain. Examples from the literature include patients being reluctant
to disclose pain due to “a lack of established trust relationships with health care providers”,
perception that they were not listened to by health professionals and that negative stereotypes
were affecting their treatment (Strong 2015 Level IV). Additionally, some patients may become“quiet and withdrawn” when hospitalised and may therefore “not be sufficiently assertive toindicate their need for pain relief” (McGrath 2015 Level IV). The impact of historical factors influencing
an individual’s decision to express pain must also not be overlooked (Fenwick 2006 NR).
9.3.1.1 | Assessment
Problems with the utility of frequently used assessment tools have been identified in a variety ofstudies exploring pain assessment in Aboriginal and Torres Strait Islander patients. In a review of
the impact of an Acute Pain Service on postoperative pain, a higher proportion of patients wereable to complete a verbal rating scale than a numerical pain scale (Sartain 1999 Level III-3). Thiswas expanded by later authors who suggested that in some patient populations, linguistic
nuances may favour the use of verbal rating scales and recommend the use of verbal descriptors
based on the patient’s language (Fenwick 2006 NR).
Not appreciating individual differences in pain expression or an individual’s expectations
regarding the assessment of their pain may lead to inadequate pain management. ( Fenwick 2006
NR) An example from postoperative pain management in Central Australian Aboriginal women,highlighted that non-Aboriginal nurses expected pain to be expressed in a manner familiar totheir own culture (e.g. vocalising pain); whereas the Aboriginal women expected pain to beinterpreted in a manner similar to traditional healers such as “to see within” (Fenwick 2004
Level IV).
One particular challenge which may further exacerbate cultural differences and expectations
across the patient/health care professional’s interaction involves the role of communication. A
prospective study identified that anaesthetists were more likely to be unsure if Aboriginal or
Torres Strait Islander patients understood explanations vs non-Aboriginal patients (Howe 1998
Level III-3); subsequently leading to a higher rate of change to the patient’s proposed treatment
plan. From a patient perspective, patients were noted to experience “difficulty describing their
5th Edition | Acute Pain Management: Scientific Evidence773pain problems to health professionals, in making themselves understood and in understanding
what they were being told” (Strong 2015 Level IV). Adding to this, language barriers and the use ofjargon have been identified as potential impediments to communication (Strong 2015 Level IV; Lin2014 Level IV). Suggestions for health practitioners to address this include personalisingcommunication (as discussed above), avoiding the use of jargon ( Strong 2015 Level IV; Lin 2014
Level IV), consider the use of visual aids ((Strong 2015 Level IV; Lin 2014 Level IV; Cusack 2013 Level
IV), and investing in trust development (Mitchell 2018 Level IV; Strong 2015 Level IV; McGrath 2006
Level IV; Fenwick 2006 NR).
The health professional may be required to modify their methods of history-taking withinsome populations in order to improve communication (Fenwick 2001 Level IV). Resources
developed for pain management in Central Australian Aboriginal people highlight that asking twoquestions in one sentence or asking questions with obvious answers may cause confusion or
result in no answer being forthcoming from the patient respectively. They recommend the healthprofessional ask one question at a time and avoid asking “nonsense” questions where the answer
is clear, such as asking about the presence of pain when the experience of pain is obvious.
Likewise, health professionals should be aware that periods of silence may occur following asking
questions of some Australian Aboriginal people, possibly out of respect for the individual asking
the question (Taylor 2014 NR; Fenwick 2006 NR). Alternate suggestions for health professionals
include using a conversational style of history taking (Lin 2014 Level IV; Lin 2013 Level IV; Taylor 2014
NR; Fenwick 2006 NR), which is noted by some authors to improve patient-practitioner trust(Fenwick 2006 NR).
9.3.1.2 | Treatment
Negative interactions with health care professionals may “deter Indigenous people from seeking
further services” (Strong 2015 Level IV). Conversely, the development of trust between thehealthcare provider and patient is noted to improve information disclosure and “participants
taking an active role in their management” (Lin 2014 Level IV).
Variation in treatment or inconsistent use of pain relief has been identified in the literature.
Examples include a recent publication which identified the inconsistent use of pain reducing
techniques for children receiving repeated penicillin injections during acute rheumatic fever
management (Mitchell 2018 Level IV). In this paper the author notes that only a minority ofpatients were able to “negotiate about the pain of their injection” with the children’s ability tonegotiate being linked to “a trusting relationship with clinicians”. As a result, for repeatedprocedures Mitchell suggests “a decolonising stance would ensure that pain reduction measures
are mandated for every instance” referencing current paediatric procedural pain management
guidelines (RACP 2006 GL). Additionally, one study suggested that Indigenous Australian patients
may be less likely to receive complex analgesia than non-indigenous patients in the
postoperative period (RR 0.45; 95%CI 0.18 to 1.15]) (Howe 1998 Level III-3). Another author
suggests Indigenous Australian patients receiving vulvar cancer treatment were “wereundermedicated for pain” (McGrath 2015 Level IV). These findings have not been explored further,and the implications remain unclear.
Finally, higher levels of medical comorbidities such as renal failure have been identified
within the Indigenous Australian population (Howe 1998 Level III-3; AIHW 2011 Level IV). These
comorbidities may influence analgesic choice as reflected within other chapters.

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Table 9.5 | Barriers to effective Pain Management:
Barrier

Recommendations to address these barriers

Communication difficulties
during patient/health carepractitioner interaction
Pain expression in Aboriginal
and Torres Strait Islander
Peoples may not reflect thatwhich is expected by thehealth professional’s cultural
background (Fenwick 2004
Level IV)

• Health practitioners should understand nuances of pain
expression and beliefs within such populations. Using
frameworks such as cultural safety/cultural competency
may be of assistance (The Wardliparingga Aboriginal

Language difficulties may exist
between the patient andhealth care practitioner (Lin2014 Level IV; Strong 2015 Level
IV)• Seek the assistance of an Aboriginal health worker orinterpreter to assist in the bilateral communication
between patient and health care team (Howe 1998 Level
III-3; Cusack 2013 Level IV; Taylor 2014 NR)• Provide support, give information and improved
explanations to patients (Strong 2015 Level IV; McGrath2006 Level IV)• Avoid jargon (Lin 2014 Level IV; Strong 2015 Level IV)• Consider visual aids, (Strong 2015 Level IV; Lin 2014 Level
IV) however this should be personalised to theindividual. (Lin 2017 Level III-1)

Systemic factors may affectpain disclosure by the patient
to health care practitioner(Fenwick 2006 Level IV; Strong
2015 Level IV)• Develop trust with the patient (Mitchell 2018 Level IV;

Racial Profiling• Acknowledge that previous views about pain tolerance
can be harmful to patient care (McGrath 2015 Level IV;
Fenwick 2004 Level IV; Fenwick 2006 NR)

Assessment
Use of culturally inappropriate
measures (Fenwick 2004 Level
IV)• The verbal pain descriptors may be a better choice of
pain measurement tool than numerical rating scales insome Aboriginal Australian Peoples (Fenwick 2006 NR)

Treatment
Potential variation, undertreatment or disparities• Recognition of the risk of harm due to racial profiling(see above)

Research Unit of the South Australian Health and Medical
Research Institute 2017 GL; Fenwick 2006 NR)• Seek the assistance of caretakers in assessment of pain
(Fenwick 2006 NR)

Strong 2015 Level IV; McGrath 2006 Level IV; Fenwick 2006
NR)

• Consider cross-cultural competency/cultural safety
Frameworks (see above)• Consider input from Aboriginal Health Workers• Consider self-exploration of practitioner’s own culture,and the impact this can have on patients of othercultures (process of becoming culturally sensitive)(Fenwick 2006 NR)

5th Edition | Acute Pain Management: Scientific Evidence775treatment of pain for
Indigenous Australian patients(Lin 2018 Level IV SR, 18 studies
n unspecified; Howe 1998 Level
III-3; McGrath 2015 Level IV)• Taking a “decolonising stance” to address power
imbalance, examples include ensuring “that pain
reduction measures are mandated for every instance”(Mitchell 2018 Level IV) of paediatric procedure related
pain as guided by current guidelines. (RACP 2006 NR)

KEY MESSAGES
1. Verbal descriptor scales may be a better choice of pain measurement tool than verbal
numerical rating scales in some Aboriginal and Torres Strait Islander Peoples (U)(Level III-3).
2. Medical comorbidities such as renal impairment are more common in Aboriginal andTorres Strait Islander Peoples and may influence the choice of analgesic agent (U)(Level IV).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Heterogeneity between differing populations of Aboriginal Peoples may require
tailoring of the service delivered to the population and individual being serviced (U).
 Pain expression in Aboriginal and Torres Strait Islander Peoples may not reflect thatwhich is expected by the health professional’s cultural background. This places theonus on the health professional to understand nuances of pain expression and beliefs
within such populations (U).
 Aboriginal and Torres Strait Islander Peoples are at increased risk of underrecognition
and undertreatment of pain (N).

9.3.2 | Māori peoples
Māori peoples make up 16.5% (775,836 people) of the New Zealand population ( Stats NZ 2019
NR). In 1840 in New Zealand, the Treaty of Waitangi, Māori and the Crown contracted torecognise British sovereignty in exchange for guarantees that indigenous rights to customary
resources would be protected. This treaty has impacted on the health resources for thisindigenous population (Durie 2012 NR). Cultural factors play a role in pain experiences in terms ofa person’s pain expression, threshold and tolerance (McGavock 2012 NR; Davidhizar 2004 NR) andalso influence interaction with health professionals and adherence to advice provided(Magnusson 2011 Level IV, n=15). Māori views on health and healing, and the care of Māori people
who are in pain, are different to the biomedical views prevalent in Western culture ( McGavock2012 NR). Māori perceive pain as a multidimensional experience affecting them physiologically,
psychologically and socially (Magnusson 2011 Level IV, n=15). For example, in the Te Whare Tapa
Whā model, health is seen as the interaction between te taha tinana (physical health), te tahahinengaro (mental health), te taha wairua (spirituality) and te taha whānau (family) (Pitama 2011
NR; Durie 1985 NR). Commonly used and widely accepted descriptors and phrases relating to painand established pain measures in Western medicine are appropriate to use when assessing
Māori patients (Magnusson 2011 Level IV; Pitama 2011 NR).

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Demographic data of patients attending for an initial assessment in 2015 were requested
from all District Health Boards that offered a multidisciplinary chronic pain service (Lewis 2018
Level III-3, n=2002). Māori patients scored significantly worse than patients of European descenton all clinical assessment measures. Māori vs to non- Māori had higher pain, and greater
disability, increased levels of stress, anxiety and depression, lower self-efficacy to manage pain,
greater levels of pain-related fear and more catastrophic thoughts that were related to pain. In
another study, data were collected via a comprehensive questionnaire given to consecutive newpatients seen at a New Zealand multidisciplinary Pain Service over a four-year period (Burri 2018
Level III-3, n=798). Cross-cultural comparison discovered that Māori patients reported highest
pain levels, the largest number of pain sites, the greatest pain interference, as well as highest
levels of stress, anxiety, depression, and psychological distress, when vs all other ethnicities.
There has been limited data published about Māori perspectives on pain (Magnusson 2011
Level IV). Some of the quantitative research of Māori health has covered acute experimental pain
(Azariah 1984 Level III-2 EH), acute postoperative pain (Mahmoud 2006 Level IV), pain associatedwith giving birth (Nelson 2006 Level IV), dental pain in children (Jamieson 2006 Level III-2) andprescription rates for analgesia (Crengle 2005 Level III-2).
Using the ischaemic arm test, Māoris were able to tolerate ischaemic pain for longer
durations vs their European counterparts (Azariah 1984 Level III-2 EH, n=60). After accounting forvarious behavioural and material factors, Māori children were more likely to experiencedental pain (OR 1.35; 95%CI 1.08 to 1.70) in a model considering demographic factors only, andPacific Islander children were less likely to have received a general anaesthetic for dental workthan New Zealand European children (OR 0.44; 95%CI 0.24 to 0.82) (Jamieson 2006 Level III-2,
n=3,275).
Māori women were less likely to receive a range of medical interventions during childbirth,
including Caesarean sections or epidural analgesia, vs non-Māori women (Harris 2007 Level III-2;
Sadler 2002 Level III-2; Nelson 2006 Level IV). Māori and Pacific Islander women had a 15% epidural
analgesia rate vs 25% in other New Zealand women, despite the fact that Māori and Pacificwomen were more likely to have pre-existing health conditions that would dictate a higher needfor epidural analgesia (Nelson 2006 Level IV). A retrospective observational study was conductedin New Zealand Māori and New Zealand Europeans with data collected over 21 mth on patients
who had received intrathecal morphine for postoperative pain management ( Woods 2018 Level
III-3, n=96). New Zealand Māori experienced a significantly higher rate and intensity of pruritus
than New Zealand Europeans which was less likely to be treated.
From accident registry data, high levels of adverse outcomes were observed three mths posttrauma among a Māori cohort (Maclennan 2013 Level IV, n=566). Almost half were experiencing
problems with mobility. A majority were having difficulties performing their usual activities andmost were suffering some or extreme pain or discomfort. Over half were experiencing an
increased level of psychological distress as well. Prevalence of disability due to injury in ahousehold survey was slightly higher among Māori (31.4%) than non-Māori (29.3%) aged ≥15 y(Office for Disability Issues and Statistics New Zealand 2010 Level III-2). Overall, these outcomes
highlight the importance of improved prevention strategies and post-injury care.
New Zealand continues to have some of the highest healthcare inequalities in the world with
Māori having a two to three times higher mortality from non-communicable disease than nonMāori populations (Lilic 2015 Level III-2; Kerr 2014 Level III-2; Di Cesare 2013 Level IV; Hsiang 2013 Level
IV). Māori were slightly less likely to consult general practitioners for back pain or
regional pain disorders than European New Zealanders but were more likely to present with gout
(Taylor 2004 Level III-3). Māori have one of the highest prevalence of gout internationally. A
qualitative general inductive approach guided by Māori community principles (‘Kaupapa’) wasused on 12 Māori (aged 48-79 years) with gout (Te Karu 2013 Level IV). Many put up with the pain
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777and put the needs of others before themselves. NSAIDs, prednisone, and colchicine were mostly
used with allopurinol used late in the disease. This showed that early preventive treatment in a
culturally sensitive health care system was needed. In a prospective observational study, patientswith gout for <10 y were recruited from primary and secondary care settings (Dalbeth 2013 Level
III-2, n = 291 [37 Māori, 35 Pacific Islanders and 219 who were neither Māori nor Pacific Islanders]). Māori
and Pacific Islander participants had 9 y earlier age of onset, higher flare frequency and morefeatures of joint inflammation. Māori and Pacific Islander patients also reported greater pain andactivity limitation and lower health-related quality of life.
Similarly, joint replacement registry data collected between 2005 and 2009 demonstrated
that Māori patients experience higher pain and poorer mobility on self-report questionnaires
one year following total joint arthroplasty than non-Māori patients (Singleton 2013 Level III-2). A
validated Monte Carlo computer simulation model estimated quality-adjusted life years (QALYs)
lost due to knee osteoarthritis in the New Zealand (NZ) adult population (aged 40 to 84 y) overtheir lifetimes until death (Abbott 2017 NR). Data were obtained from the NZ Health Survey, NZ
Burden of Diseases, NZ Census, and from the relevant literature. QALY losses were found to belower for Māori than non-Māori due to lower life expectancy. A prospective cohort study ofrotator cuff repairs (March 2009 to December 2010) from the New Zealand Rotator Cuff Registry
showed that Māori present younger with more pain and with significantly poorer function ( Maher
2017 Level III-2, n=1,383). Māori suffer disproportionately from the pain of ischaemic heart disease
with hospitalisation rates for Māori found to be 1.4 times that of non-Māori (Curtis 2010 Level III2); mortality rates were more than twice that of non-Māori.
Alongside inequalities in access to, and quality of care, Māori also experience greater
discrimination than non-Māori (Harris 2006 Level III-2). Research on acute pain suggests thatexperiences of Māori may differ from those of other New Zealanders in terms of tolerance,
healthcare access or treatment, including receipt of pain-relief medication (McGavock 2012 NR).
Given entrenched health disparities across a wide range of conditions and diseases, Māori carrya disproportionate burden of pain. The development and implementation of culturalcompetence training should provide pathways for health professionals to work more effectively
with Māori patients (Pitama 2011 Level IV).

KEY MESSAGES
1. Experimental ischaemic pain is tolerated for longer in Māori people than in European
New Zealanders (U) (Level III-2).
2. Māori people report higher levels of pain and/or disability with dental pain, gout
and after trauma and joint replacement surgery than European New Zealanders (U)(Level III-2).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: High healthcare inequalities exist regarding access and quality of care (across age
ranges, genders and for various medical conditions) between the Māori and PacificIslander peoples compared with New Zealanders of European origin (S).
 Māori culture embraces the multidimensional aspects of pain experiences (S).

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9.4 | The patient with sleep-disordered breathing including
obstructive sleep apnoea
Sleep-disordered breathing (SDB) is a spectrum of disorders where partial or complete cessationof breathing occurs many times during sleep. Obstructive sleep apnoea (OSA) is the mostcommon form of SDB and is the condition most studied in surgical patients. As the prevalence of
OSA is increasing and numbers of patients having surgery is large, the population at risk is
significant (Memtsoudis 2013 NR). Acute pain management in a patient with OSA presents several
potential problems; identification of patients at significant risk, choice of the most appropriate
form of analgesia, the most suitable location in which to provide care and the level of monitoring
required. These difficulties arise primarily from the risk of exacerbating OSA by theadministration of opioid or other medicines with sedative effects (in particular benzodiazepines,
but also butyrophenone or phenothiazine antiemetics and alpha-2-delta ligands). Importantly,
patients with OSA suffer sleep disturbance on postoperative night one, and an increased
frequency of SDB on postoperative night three (Chung 2014 Level III-2, n=38).
The prevalence of moderate and severe OSA in the general adult population is estimated tobe 6 to 17%, and in older age groups (>60y) 49% or more (Senaratna 2017 Level IV SR, 24 studies,
n=3,807). However, a large proportion of OSA patients remain clinically undiagnosed anduntreated. There is a variable prevalence in the surgical population, with an estimated 60 to 70%
prevalence in patients undergoing bariatric surgery of which one-third have moderate or severe
OSA, and would benefit from CPAP (de Raaff 2017 GL). Therefore, many patients with undiagnosed
OSA will have had treatment for acute pain without significant morbidity. The risk will dependon the severity of OSA, the nature and extent of surgery, the type of anaesthesia and analgesia
and the extent of postoperative monitoring.
Patients with known OSA are at increased risk of postoperative complications vs other
patients (Memtsoudis 2013 NR). However, the main risk may lie more with the body size and buildof the patient, especially those who are morbidly obese, rather than the fact they have a specificdiagnosis of OSA (Loadsman 2009 NR).
The simple to use STOP-Bang screening questionnaire has been validated for theidentification of patients with OSA (Nagappa 2017 Level III-2 SR [PRISMA], 10 studies, n=23,609).
A score 3 has been demonstrated to have high sensitivity for detecting moderate to severe
OSA, whereas patients with a score <3 are considered to be low risk. Patients at high risk of OSA(STOP-BANG ≥3) have been demonstrated to have higher rates of perioperative complications.
Specifically, in 7,877 high risk patients for OSA vs 15,732 low risk patients undergoing different
surgeries, postoperative complications (6.86% vs 4.62: OR 3.93; 95%CI 1.85 to 7.77) and LOS(5.0 d ± 4.2 vs 3.4 ± 2.8: MD 2.01 d; 95%CI 0.77 to 3.24) are increased. Similarly,
preoperative apnoea-hypopnoea index (AHI) and identification of nocturnal hypoxemia byoxygen desaturation index (ODI), cumulative sleep time percentage with SpO2 <90% (CT90),
minimum SpO2, mean SpO2, and longest apnoea duration are associated with postoperativecomplications (Suen 2019 Level IV SR, 21 studies, n unspecified).
A large retrospective database study using the USA Nationwide Inpatient Sample comparedpostoperative respiratory outcomes in surgical patients either with or without OSA based on
ICD-9 coding on discharge and matched by propensity scoring ( Memtsoudis 2011 Level III-2,
n=6,051,703). Coding for OSA was associated with respiratory complications after bothorthopaedic and general surgery: aspiration pneumonia (OR 1.41; 95%CI 1.35 to 1.47 and OR
1.37; 95%CI 1.33 to 1.41 respectively), acute respiratory distress syndrome (OR 2.39; 95%CI 2.28
to 2.51 and OR 1.58; 95%CI 1.54 to 1.62 respectively) and requiring intubation/mechanical
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ventilation (OR 5.20; 95%CI 5.05 to 5.37 and OR 1.95; 95%CI 1.91 to 1.98 respectively). The
relative contribution of each component of perioperative care (eg type of analgesia oranaesthesia) is impossible to ascertain. Several other studies have analysed patient outcomesusing the Nationwide Inpatient Sample database. These studies found:• SDB was independently associated with postoperative cardiopulmonary complications(atrial fibrillation, intubation with mechanical ventilation, noninvasive ventilation) but
not with an increased rate of in-hospital death (Mokhlesi 2013b Level III-2, n=1,058,710);• For the subgroup of bariatric surgery patients, a diagnosis of SDB/OSA was surprisingly
negatively associated with inhospital mortality (OR 0.34; 95%CI 0.23 to 0.50) (Mokhlesi
2013a Level III-2), n=91,028), while being positively associated with increased risk of atrial
fibrillation (OR 1.25; 95%CI 1.11 to 1.41), need for intubation (OR 4.35; 95%CI 3.97 to4.77) and of noninvasive ventilation (OR 14.12; 95%CI 12.09 to 16.51);• For patients having shoulder arthroplasty, there was no association with adverse
outcomes (Griffin 2013 Level III-2, n=22,988);• In patients having revision hip or knee arthroplasty, OSA was associated with increased
inhospital mortality (OR 1.9; 95%CI 1.3 to 2.8), as well as pulmonary embolus (OR 2.02;
95%CI 1.3 to 2.9) and wound complications (D'Apuzzo 2012 Level III-2, n=258,455).
OSA has been associated with a higher risk of postoperative cardiac adverse effects (OR 2.07;
95%CI 1.23 to 3.50) and acute respiratory failure (OR 2.43; 95%CI 1.34 to 4.39) (Kaw 2012 Level
III-2 SR, 13 studies, n=3,942). Desaturation and ICU transfer were also more likely, but these two
findings were hindered by a high degree of heterogeneity in the studies.
Following outpatient surgery, there was no association between preoperative diagnosis of
OSA and an increase in adverse effects or unplanned hospital admission ( Bryson 2012b Level III-2,
n=674; Sabers 2003 Level III‐3, n=234).
A major limitation of these studies is the reliance on existing diagnostic codes to identify
patients with OSA using administrative data which may significantly underestimate the risk of
undiagnosed OSA. This question was subsequently investigated . Patients presenting for generaland vascular surgery were categorised into three groups: no diagnosis or low risk OSA;
documented OSA without therapy or suspicion of OSA (STOP-Bang ≥3); and diagnosis of OSA withtreatment. Untreated OSA, was independently associated with an increase in cardiopulmonary
complications (risk-adjusted rates 6.7% versus 4%; aOR 1.8), especially unplanned reintubation(aOR 2.5) and myocardial infarction (aOR 2.6) (Abdelsattar 2015 Level III-2, n=26,842). Furthermore,
the available evidence was recently reviewed by the Society of Anesthesia and Sleep Medicine
Task Force (USA) which concluded that despite the low level of evidence, the majority of studies
suggest OSA is associated with an increased risk of postoperative complications, including
pulmonary and cardiovascular complications (Opperer 2016 Level III-2 SR [PRISMA], 61 studies,
n=8,969,583). These findings are confirmed by subsequent studies: The rates of a composite
outcome (myocardial injury, cardiac death, heart failure, thromboembolism, atrial fibrillation,and stroke within 30 d of surgery) were 30.1% for patients with severe OSA, 22.1% for patientswith moderate OSA, 19.0% for patients with mild OSA, and 14.2% for patients with no OSA ( Chan
2019c Level III-2, n=1,364). The association between composite outcome and OSA was significant
only for patients with severe OSA (aHR 2.23; 95%CI 1.49 to 3.34). A hospital registry study
assessing a bundle intervention for perioperative screening and management of patients withsuspected OSA (BOSTN) identified associations between high BOSTN score (2) and a number ofoutcomes vs low scores; increased risk of postextubation desaturation (aOR 1.34; 99.3%CI 1.21
to 1.48) and increased LOS (3.7 d vs 4.3: aRR 0.87; 99.3%CI 0.84 to 0.91) but reduced requirement
for postoperative invasive ventilation (aOR 0.89; 95%CI 0.80 to 0.98) (Raub 2020 Level III-2,
n=3,834).

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Despite the evidence presented above, in a Canadian survey, 50% of anaesthetists continue
to rely on their clinical suspicion and only 30% on a screening tool to identify patients with OSA
preoperatively (Cordovani 2016 Level IV, n=992). Furthermore, 47% did not know of or had noaccess to a specific institutional policy for perioperative management of OSA, and 40% would
send a patient with OSA home after ambulatory surgery. An accompanying editorial criticises thissituation on the basis of 12 perioperative deaths in OSA patients the author assessed as an expert
witness (Benumof 2016 Level IV, n=12).
In light of the increased postoperative risks associated with OSA, recent studies have aimed
to determine the effect of treatment on outcome. A prospective cohort study screened patientsfor OSA risk and after surgery instituted extra care and observation (options included continuous
pulse oximetry, oxygen, CPAP/BiPAP and others) for those identified as high risk, but the actual
usage of these interventions was not recorded (Lockhart 2013 Level III-2, n=14,962). There was noincrease in 30 d or 1 y postoperative mortality; however, it is not possible to determine if thiswas due to the use of the targeted interventions.

9.4.1 | Opioids and obstructive sleep apnoea
One of the main concerns in patients with OSA is that administration of opioids for the treatmentof acute pain may lead to an increase in the number and severity of obstructive episodes andoxygen desaturation. OSA is associated with an increased sensitivity to opioid analgesia, possibly
due to upregulation of opioid receptors secondary to recurrent hypoxia, and increased sensitivity
to pain, due to chronic sleep fragmentation, in both adult volunteers (Doufas 2013 Level III-2 EH,n=43) and children (Brown 2009 NR) (see also 10.10.3). Furthermore, CPAP treatment appears to
reduce pain sensitivity in patients with OSA, likely by the restoration of sleep continuity andimproved ventilation (Cozowicz 2018 Level IV SR [PRISMA], 40 studies, n unspecified).
Patients assessed to be at risk of having OSA (by history, BMI and physical examination) vscontrol patients had more obstructive events during the first postoperative night (39±22 vs
14±10 events/h) and spent more time with oxygen saturation levels <90% (Blake 2008 Level III-2,n=63). There was no difference between the groups in the cumulative morphine dose over thattime or frequency of central and mixed apnoeas. Classification of risk for OSA correlated with anincreased number of desaturation events per h in patients monitored for 48 h postoperatively(Gali 2009 Level III‐3, n=693).
Furthermore, while perioperative morphine dose is predictive of central apnoeas regardlessof OSA status, patients at risk of OSA experienced significantly more severe hypoxaemia, largely
due to obstructive respiratory events (Cozowicz 2018 Level III-SR [PRISMA], 40 studies, n=223,368).
OSA was a risk factor for OIVI in surgical patients (OR 1.4; 95%CI 1.2 to 1.7) (Gupta 2018b Level
IV SR [PRISMA], 12 studies, n = 841,424). In patients with OSA, opioids attenuated the arousal
response to hypoxia and prolonged airway obstruction.
Two early studies concluded that opioid administration in the postoperative period led toepisodes of pronounced oxygen desaturation while the patients were asleep, and this was morecommonly the result of obstructive and central apnoea than a decrease in respiratory rate ( Catley1985 Level III-2, n=32; Clyburn 1990 Level III-2, n=10). Those studies, however, involved bolus dosesof opioids in the PACU and subsequent infusion rates of IV morphine that would now be
considered much larger than current practice. A subsequent study using continuous infusion
doses of remifentanil calculated to be analgesic in volunteers with moderate OSA demonstrated
a substantial increase in the number of central events, while the number of obstructive eventswas reduced (possibly secondary to the REM-suppressing effect of opioids); minimum arterial
haemoglobin oxygen saturation during the night was significantly lower in patients receiving
remifentanil (Bernards 2009 Level II, n=19, JS 4). In another study, the central apnea index and5th Edition | Acute Pain Management: Scientific Evidence781

obstructive apnea index on postoperative night 1 were correlated with the first 24-h opioid
requirements (Chung 2014 Level III-2, n=38).
Despite a Cochrane review (Mason 2015 Level I [Cochrane], 14 studies, n=293: including Bernards
2009 Level II), there remains a paucity of information regarding the effects of analgesics, including
opioids, in the acute pain setting in patients with OSA and therefore limited data on which tobase recommendations for their postoperative care (ASA 2014 GL).
The apparent ceiling effect on respiratory depression, but not analgesia in healthy young
patients, has favoured the use of buprenorphine in patients with SDB. Buprenorphine has unique
pharmacological properties - it is a mixed agonist-antagonist, with a higher affinity for the muopioid receptor and consequent long half-life (166 min) (White 2018 Level I [Cochrane], 28 studies,
n=2,210). However, in the setting of acute pain management, buprenorphine was found to haveno difference in pain scores or the incidence of respiratory depression or sedation vs morphinein adults (White 2018 Level I [Cochrane], 28 studies, n=2,210) and children (Murray 2018 Level I[Cochrane], 4 studies, n=195). Buprenorphine’s effect on respiratory drive may have potentially
profound adverse effects in acute pain management, especially in patients with SDB.
A small study in children undergoing adenotonsillectomy for OSA showed a trend to fewer
episodes of postoperative desaturation in children given tramadol vs morphine, but thedifference was only significant for the second h after surgery (Hullett 2006 Level II, n=66, JS 4). In
patients with a BMI ≥28 and with signs or symptoms suggestive of OSA, there was no differencein the numbers of respiratory events (obstructive apnoeas, hypopnoeas or central apnoeas) inpatients receiving IV morphine PCA and those receiving an “opioid‐sparing” analgesic regimen(IV tramadol PCA, parecoxib and “rescue‐only” morphine); however there was a correlation
between >15 respiratory events/h and total morphine dose (Blake 2009, Level II, n=65, JS 4).
Multimodal, opioid-sparing, analgesia has also been examined in adult OSA patients
undergoing elective lower extremity arthroplasty (Cozowicz 2019 Level III-2, n=181,182).
Assessment of this higher perioperative risk population demonstrated a step-wise reduction in
opioid dose prescription and PCA use (26.6% in opioid only vs 19.2%, 13.7%, and 7.7%) withincreasing modes of multimodal analgesia over 10 y. With regards to postoperativecomplications, there were significantly reduced odds for postoperative mechanical ventilation(OR 0.23; 95%CI 0.16 to 0.32) and critical care admission (OR 0.60, CI 0.48; 0.75) with the additionof two or more non-opioid analgesic modes. Of note, the most commonly used components ofmultimodal analgesia included paracetamol, coxibs, nsNSAIDs, gabapentin or pregabalin,regional analgesia, ketamine and corticosteroids.
In a number of case reports, the use of opioid medications by various regimens (intermittent
IM, IV PCA and PCEA) in patients with OSA appeared to be a common factor for complications,
including death (Parikh 2002 Level IV, n=19; Ostermeier 1997 Level IV, n=3; Etches 1994 Level IV, n=8;
Lofsky 2002 NR; Cullen 2001 CR; Reeder 1991 CR; VanDercar 1991 CR). However, caution is required
when interpreting these reports. Most of the cases involved excessive opioid doses (eg excessive
bolus dose or a background infusion with PCA) and/or inadequate monitoring for respiratory
depression (Macintyre 2005 NR). It appeared there was an over-reliance on monitoring respiratory
rate; and sedation levels were not checked and/or increasing sedation was not recognised as an
early indicator of respiratory depression.
Examination of the legal literature provides a similar story. From analysis of the Anesthesia
Closed Claims Project database, OSA or suspected OSA was identified in 24% of patients withpostoperative OIVI (Lee 2015 Level IV, n=357). Furthermore, the majority of critical events (88%)
occurred within 24 h of surgery and nearly half of patients had a continuous opioid infusion at
the time of the event, highlighting the requirement for appropriate postoperative monitoring inhigh risk patients. A retrospective review of the legal literature between 1991 and 2010 found24 cases in which OSA (a known diagnosis in 96%) was directly implicated in the postoperative782

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adverse outcome (death in 45.6% and anoxic brain injury in 45.6%) (Fouladpour 2016 Level IV,n=24). The most common complications were respiratory arrest in an unmonitored environmentand difficulty in airway management. Furthermore, opioid use was thought to play a role in 38%
of cases. Finally, examination of case reports of critical complications (death, near-death, andcritical respiratory events) in surgical patients with OSA reinforced the importance of early
postoperative monitoring, with 80% of events occurring within the first 24 h and 67% on thegeneral hospital ward (Subramani 2017 Level IV, n=60).
An updated ASA task force report (USA) on the perioperative management of patients with
OSA concluded that there remains only limited evidence to evaluate the effects of various
postoperative analgesia techniques in patients with OSA and no good comparisons between
conventional opioids such as morphine, and tramadol or nonopioid analgesics ( ASA 2014 GL).
Expert opinion, however, consistently suggests that nonopioid analgesics and regional
techniques should be considered, either as an alternative to opioids or to help limit the amountof opioid required both for adults (ASA 2014 GL) and children (Patino 2013 NR).

9.4.2 | Obesity as a risk factor
The prevalence of obesity continues to grow, from 5 to 8% in 1980 to 13% in 2015 (WHO 2017),
and is strongly associated with OSA (Young 2004 NR). Using polysomnography, OSA was identified
in 71% of patients presenting for bariatric surgery (Frey 2003 Level IV, n=40) and an estimated one
third of these patients suffer from moderate to severe OSA (de Raaff 2017 Level IV, n=15 [experts
surveyed]). It is still unclear if the use of PCA, with appropriate bolus doses and monitoring, inmorbidly obese patients is less safe than regional analgesia or other systemic opioid analgesic
techniques.
In patients having bariatric surgery, all of whom underwent preoperative polysomnography
and were prescribed CPAP therapy preoperatively if indicated, complications were common(33%) but, while age, open surgery and BMI were associated with those complications, OSA
severity was not (Weingarten 2011a Level III-2, n=797). In morbidly obese children having
tonsillectomy, obesity was similarly associated with adverse outcome, independently of OSA(Gleich 2012 Level III-2, n=100).
For further information see Sections 9.5 and on paediatric patients see Section 10.10.3.

9.4.3 | Approaches to treatment
9.4.3.1 | Oxygen
While oxygen therapy alone may not prevent the disruptions of sleep pattern or symptoms suchas daytime somnolence and altered mental function that may occur in patients with OSA, it can
reduce the likelihood of significant hypoxaemia (Landsberg 2001 Level III-3, n=43; Phillips 1990 Level
III-3, n=8). As patients with OSA are more at risk of hypoxaemia after surgery or when given
opioids, the use of supplemental oxygen would seem appropriate (ASA 2014 GL) despite concerns
about reducing respiratory drive during apnoeic periods and potential life-threatening
respiratory depression (Lofsky 2002 NR) from removing hypoxaemia as a key trigger for respiratory
arousal. However, in patients with newly diagnosed (AHI >5 per h on preoperative
polysomnography) and untreated OSA, postoperative supplemental oxygen 3 L/min via nasal
prongs improved oxygenation, and decreased the AHI, mainly due to a decrease in hypopnea
index and, to a smaller degree, central apnoea index (Liao 2017 Level II, n=123, JS 3). Furthermore,
there was no significant difference in PaCO2 measured by transcutaneous CO2 monitor, however,patients with COPD and obesity hypoventilation syndrome (OHS) (serum HCO3- level >30
mmol/L) were excluded from this study and a significant proportion of patients (11.4%)
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experienced CO2 retention, especially those receiving supplemental oxygen on postoperative
night one.
9.4.3.2 | Continuous positive airway pressure
The perioperative use of CPAP may theoretically help to reduce postoperative risk and isrecommended for patients with OSA (ASA 2014 GL). The effectiveness of CPAP (used appropriately
and in highly supervised environments) for the management of OSA in the postoperative setting
was initially supported by case reports (Rennotte 1995 Level IV, n=16; Mehta 2000 NR; Reeder 1991
CR). However, a number of studies examining perioperative initiation of both fixed andautotitrated CPAP for patients considered or known to be at risk, have demonstrated very poor
adherence by those accepting the therapy (Liao 2013 Level II, n=177, JS 2; Guralnick 2012 Level IV,
n=211), with no obvious outcome benefit (O'Gorman 2013 Level II, n=133, JS 2). Poor patientadherence may be improved by initiation of CPAP prior to surgery with more effective educationand individualisation of therapy.
The effective de-novo use of CPAP in the setting of acute pain management likely requires ahigher level of supervision than that available in the general surgical ward; most reports of thesuccessful use of postoperative CPAP utilise extended periods of high-dependency nursing withstaff educated and experienced in its use (Rennotte 1995 Level IV, n=16; Mehta 2000 NR; Reeder 1991
CR). Established CPAP use may, however, be associated with a lower risk of perioperativecomplications, as cardiovascular complications in particular (cardiac arrest and shock) wereincreased in patients with untreated OSA vs those previously established on CPAP in a study
using a Manitoban health administrative database (OR 2.20; 95%CI 1.16 to 4.17) ( Mutter 2014
Level III-3, n=20,488).
In adult patients with OSA undergoing surgery, there was no significant difference inpostoperative adverse events between CPAP and no-CPAP treatment groups, but postoperative
CPAP reduced the AHI vs preoperative baseline AHI values without CPAP (37 ± 19 events/h vs 12± 16 events/h) (Nagappa 2015 Level IV SR [PRISMA], 6 studies, n=904). In patients in PACU following
bariatric surgery, CPAP treatment decreased AHI, decreased oxygen desaturations, andincreased the mean oxygen saturation by 3% (Zaremba 2016 Level III-1, n=45). Patients with aknown diagnosis of OSA, who are currently using CPAP at home, should therefore have CPAP
continued while in hospital (ASA 2014 GL). As such, the Society of Anaesthesia and Sleep Medicine
guidelines recommend the perioperative usage of CPAP therapy (prescribed setting) to reduce
the risk of postoperative respiratory failure and cardiac events in patients with OSA who areeither adherent, or poorly adherent, to CPAP therapy (Chung 2016 GL).
In paediatric patients with CPAP intolerance and moderate to severe OSA, there are limited
data that high-flow air via nasal cannula (10 to 50 L/min) reduced respiratory events, improved
oxygenation, and reduced heart rate (Hawkins 2017 Level III-2, n=10).
Evidence indicates that the risk of CPAP causing gastric distension and anastomotic leaks after
all types of oesophageal and upper abdominal surgery appears to be unfounded in adults(Weingarten 2011b Level III-2, n=797; Huerta 2002 Level III-2, n=1,067). In patients undergoing bariatricsurgery postoperative CPAP usage was not a risk factor for suture line disruption and leakage (deRaaff 2018 Level III-2, n=2,153).
9.4.3.3 | Monitoring and environment
Advice on the most appropriate environment for the care of OSA patients requiring analgesia,
along with the level of monitoring required, is based on expert opinion only and suggests thatthe severity of SDB, efficacy of any current therapy, relevant comorbidities (eg cardiac) and theanalgesia required all be taken into consideration both for adults (ASA 2014 GL; Joshi 2012 GL) and784

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children (Patino 2013 NR). The ASA recommends continuous pulse oximetry monitoring andsupplemental oxygen use after discharge from the recovery room in patients at increased risk of
respiratory compromise from OSA until baseline oxygen saturation can be maintained on roomair (ASA 2014 GL). Recommendations for postoperative monitoring of OSA patients after bariatricsurgery include a minimum of continuous pulse oximetry in a designated surgical ward or a
medium care unit, independent of CPAP usage (de Raaff 2017 GL).
Continuous pulse oximetry monitoring has the potential disadvantage of delaying thedetection of hypoventilation when supplemental oxygen is administered. However, whencontinuous pulse oximetry was compared with standard monitoring (intermittent nursing spotchecks) in postoperative patients prescribed opioids, the detection of oxygen desaturation was
15 times more common, with a trend toward less ICU transfer in the pulse oximetry group (Lam2017 Level I [PRISMA], 9 RCTs, n unspecified).

See also Section 4.3.1.4.

KEY MESSAGES
1. Continuous pulse oximetry compared to intermittent nursing spot-checks detects more
episodes of hypoxaemia in postoperative patients with obstructive sleep apnoea
prescribed opioids (N) (Level I).
2. The STOP-Bang questionnaire has high sensitivity for the identification of patients at riskof moderate to severe obstructive sleep apnoea (S) (Level III-2 SR).
3. Patients with sleep-disordered breathing, including obstructive sleep apnoea, having
surgery are at increased risk of adverse cardiac and respiratory effects (S) (Level III-2 SR),in particular cardiac arrest/shock, atrial fibrillation, aspiration pneumonia, acuterespiratory distress syndrome and need for intubation, mechanical and noninvasive
ventilation (N) (Level III-2) and increased hospital length of stay (N) (Level III-2 SR).
4. Patients with obstructive sleep apnoea have an increased risk of exacerbation of
obstructive episodes and hypoxaemia during the postoperative period (U) (Level III‐2), in
particular in the first 72 hours with peaks on the first and third postoperative night (N)(Level III-2).
5. Morbidly obese patients may be at increased risk of postoperative hypoxaemia,
independent of a diagnosis of obstructive sleep apnoea (U) (Level III‐2).
6. Continuous positive airway pressure does not increase the risk of anastomotic leak after
upper gastrointestinal surgery (S) (Level III‐2).
7. Increasing severity of obstructive sleep apnoea is associated with increased risk of
postoperative respiratory complications including opioid-induced ventilatory impairment(Q) (Level III‐3).
8. The prevalence of obstructive sleep apnoea in the surgical patient population is high andthe majority (80%) of these patients are undiagnosed (S) (Level IV SR).
9. Higher preoperative apnoea-hypopnoea index and identification of nocturnal hypoxemia
are risk factors associated with postoperative complications in patients with sleepdisordered breathing (N) (Level IV SR).

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10. Patients with obstructive sleep apnoea have increased sensitivity to pain that improves
with use of continuous positive air way pressure (N) (Level IV SR).
11. Opioids in patients with obstructive sleep apnoea attenuate arousal to hypoxia andprolong airway obstruction, and thereby lead to more severe hypoxaemia (S) (Level IV SR).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Preoperative screening for obstructive sleep apnoea combined with treatment (ideallyinstituted preoperatively) and increased postoperative observation may decrease
postoperative morbidity and mortality (S).
 Management strategies that may increase the efficacy and safety of pain relief inpatients with obstructive sleep apnoea include multimodal nonsedating opioid-sparing
analgesia such as regional techniques, continuous positive airway pressure, monitoringand supervision (in a high‐dependency area if necessary) and supplemental oxygen (U).
 Perioperative commencement of continuous positive airway pressure may bebeneficial in patients with obstructive sleep apnoea but requires high levels ofsupervision; significant problems are poor patient acceptance and postoperative
adherence (U).
 In patients with obstructive sleep apnoea, monitoring should be extended beyond 24
hours to capture the high-risk period for late postoperative hypoxaemia (N).

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9.5 | The obese patientOver the past three decades, the prevalence of obesity has increased significantly and is a major
public health concern worldwide (Arroyo-Johnson 2016 NR). Obesity is associated with manycomorbidities, with obstructive sleep apnoea (OSA) and the risk of hypoventilation being ofparticular concern with regards to acute pain management. As more obese patients arepresenting for surgery, the need to manage acute pain safely in these patients becomesincreasingly relevant. Multimodal analgesia and opioid-sparing techniques provide superior pain
relief, improve perioperative outcomes and enhanced recovery in bariatric surgical care.

9.5.1 | Definitions of obesity
Obesity can be defined according to either anthropometric or body composition diagnostic
criteria (Lang 2017 NR). Body mass index (BMI) is commonly used to define obesity, calculated byusing weight in kilograms divided by height in metres squared. Other methods, including waist
circumference, central and peripheral fat mass have also been used ( Engin 2017 NR). The World
Health Organization has established an international adult classification of BMI, whereby a BMI
of 30 kg/m2 or higher is defined as obese (Arroyo-Johnson 2016 NR). Obesity can be further subclassified into class 1 (30 to 34.9 kg/m2); class 2 (35 to 39.9 kg/m2) and class 3 or morbid obesity(greater than 40 kg/m2) (Engin 2017 NR). Currently, there is no consensus on an internationalclassification of obesity for the paediatric population.
See Section 10.10 for paediatric issues.

9.5.2 | Prevalence
In Australia, 67% of adults are currently overweight or obese ( AIHW 2019c Level IV). In New
Zealand, 30.9% of adults are obese with differences by ethnicity (66.5% of Pacific Islanders,
48.2% of Māori, 29.1% of European/Other and 13.8% of Asian) ( NZ MoH 2019 Level IV); the adultobesity rate has increased from 29% in 2011/12. Worldwide, the prevalence rate for being
overweight or obese between 1980 and 2013 increased 27.5% for adults and 47.1% for children,
to a total of 2.1 billion individuals considered overweight or obese ( Ng 2014 NR). It has been
predicted that by 2030, up to 86% of adults in the USA will be overweight or obese ( Wang 2008
NR).

9.5.3 | Morbidity associated with obesity
Obesity has been linked to decreased life expectancy by approximately 3 to 18 y and large
increases in healthcare expenditures (Leung 2015 NR). For every 5 unit increase in BMI above 25
kg/m2, overall mortality increases by 29%, vascular mortality by 41% and diabetes-related
mortality by 210% (Prospective Studies 2009 Level IV SR, 57 studies, n=894,576).
Body mass is an important determinant of respiratory function, which can manifest as
reduced lung volume, derangements in lung and chest wall compliance, increased resistance andmoderate to severe hypoxaemia (Wang 2008 NR). These physiological alterations are moremarked in obese patients with OSA. In surgical patients, the OSA prevalence is 40% in obese
female and 50% in obese males, and OSA incidence increases to approximately 70% in morbid
obesity (Lang 2017 NR).
The incidence of hypertension, dyslipidaemia, type 2 diabetes mellitus and cerebrovasculardisease are directly proportional to BMI (Engin 2017 NR). Obesity is also associated with increased
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risk of several cancer types and certain pro-inflammatory conditions such as osteoarthritis andchronic pain (Belcaid 2019 NR).
Common characteristics in obese persons with pro-inflammatory conditions include fatigue,
lethargy, social withdrawal, irritability as well as anxiety and depression (Seaman 2013 NR; Hoftun
2012 Level IV, n=7,373). Obesity is an independent risk factor for major depressive disorder (OR5.25; 95% CI 1.41 to 19.58) (Kasen 2008 Level IV, n=544). Obese patients with high depression,anxiety and alexithymia levels rated their postoperative pain as more intense and requested
more analgesia vs obese patients with normal psychological indicators (Aceto 2016 Level IV,
n=120).

9.5.4 | Pharmacokinetic impact of obesity
Unfortunately, obese subjects are often excluded from clinical trials during the drug
development process (Hanley 2010 NR). As a result, information regarding the impact of obesityof the pharmacokinetics and pharmacodynamics of the majority of drugs remains limited.
Absorption
Although gastric emptying and gut permeability are affected by obesity ( Teixeira 2012 Level III-2,
n=40; Cardoso-Junior 2007 Level III-2, n=38; Xing 2004 NR), oral bioavailability and absorption does
not appear to be altered in obese individuals, and may increase in morbid obesity ( Cheymol 2000
NR; Blouin 1999 NR).
Distribution
Total blood volume, cardiac output and plasma protein binding are increased in obesity ( Cooney
2016 NR). Volume of distribution (Vd) changes in the obese patient appear to be drug-specificand for the most part, can be attributed to the physiochemical properties of the individual drug
(Hanley 2010 NR). However, it is clear that Vd is influenced by many factors and its obesity relatedchanges are therefore difficult to predict on the basis of drug properties such as lipophilicity
alone (Belcaid 2019 NR; Smit 2018 NR).
Metabolism and Elimination
Obese patients appear to undergo TBW-proportional increases in phase II conjugation ofparacetamol (Abernethy 1982 Level III-2). There is limited evidence of an increase in cytochrome
P450 (CYP) 2E1 activity with obesity, with a reduction in activity noted after weight loss ( Emery2003 Level III-2, n=32; O'Shea 1994 Level III-2, n=24). The clinical relevance of this is unclear andprobably not significant. Although hepatic clearance is usually unchanged or increased in theearly stages of obesity, it could eventually become reduced due to hepatic steatosis, liver
fibrosis and cirrhosis (Leykin 2011 NR; Adams 2000 NR)
The direct effect of obesity on renal clearance is unclear. Studies of creatinine have foundincreased, decreased or similar GFR estimates in obese versus non-obese individuals. Presently,
there is no single, well validated weight descriptor to characterise drug clearance in the obese
population (Belcaid 2019 NR; Hanley 2010 NR).
9.5.4.1 | Indirect measures of body composition
A number of indirect measures to assess body composition have been developed for clinical use,
including BMI, total body weight (TBW), ideal body weight (IBW), lean bodyweight (LBW) andpredicted normal weight (PNWT).
Methods for calculating indirect measures of body composition are as follows ( Duffull 2004
Level III-3 PK):788

5th Edition | Acute Pain Management: Scientific Evidence9.0 | OTHER SPECIFIC PATIENT GROUPS•••IBW (kg) = 45.4 (49.9kg if male) + 0.89 x (height in cm – 152.4)
LBW (kg) = 1.07 (1.1 if male) x TBW – 0.0148 (0.0128 if male) x BMI x TBW.
PNWT (kg) = 1.75 (1.57 if male) x TBW – 0.0242 (0.0183 if male) x BMI x TBW – 12.6
(10.5 if male)

There is a lack of evidence regarding dose adjustments of analgesia in the obese and morbidly
obese patient and no clear consensus on what measures to use (Budiansky 2017 NR). It is advisable
not to use TBW to calculate doses in obese patients to avoid risk of overdosing. Additionally, it
is important to consider that LBW does not increase proportionally with fat mass in obesity.
Normal fat mass is a size descriptor that partitions total body mass into fat and fat-freecomponents. It uses allometric theory to calculate the fraction of fat mass that will make fat
equivalent to fat-free mass. The value of normal fat mass is drug specific and specific to a PK
parameter (eg Vd or CL) (Anderson 2017 NR PK). Calculating normal fat mass for drug dosing has
been proposed as a principle-based approach that explains size and body composition effects on
PKs of all drugs in adults of all sizes.

9.5.5 | Drugs used in the management of acute pain in the obese patient
An overarching systematic review of pain management after laparoscopic gastric bypass surgery
shows that the administration of NSAIDS (1 RCT, n=47), dexmedetomidine (2 RCTS, n=157),
ketamine (1 RCT, n=60) and intraperitoneal (2 RCT, n=188) or subfascial/subcutaneous (1 RCT, n=40)
local anaesthetics or by transversus abdominis plane block (TAP) ( 2 RCTs, n=157) may improveanalgesia vs placebo/controls (Andersen 2014 Level I [PRISMA] 9 RCTs, n=644).
Specifically for laparoscopic sleeve gastrectomy, a systematic review identified paracetamol(2 RCTs, n=161), NSAIDs (1 RCT, n=28) and opioids as rescue analgesics as well as TAP block (5 RCTs,
n=247), but preferably port-site infiltration instead (1 RCT, n=147) as evidence-based analgesic
options (Macfater 2019 Level I [PRISMA], 18 RCTs, n unspecified.; alpha-2-delta ligands (3 RCTs, n=253),
while effective, should be used with caution in this population due to the risk of increasing OIVI
(Belcaid 2019 NR).
RCTs included in the above two systematic reviews are partially mentioned again in thefollowing more detailed paragraphs.
9.5.5.1 | Paracetamol
IV paracetamol improves pain scores (MD -0.66/10; 95%CI -1.03 to -0.28) and reduces opioid
consumption (MD -6.44 mg; 95%CI -9.26 to −3.61) during the first 24 h after laparoscopic
bariatric surgery vs placebo (Lee 2019b Level I [PRISMA], 4 RCT, n=349 patients).
The use of paracetamol in morbidly obese patients undergoing laparoscopic sleeve
gastrectomy reduces opioid consumption, hospital LOS and reduces the number of emergency
representations postoperatively due to abdominal pain ( Cooke 2018 Level II, n=127, JS 5; El Chaar
2016 Level II, n=100, JS 5). The combined use of IV paracetamol with IV ketorolac has been shown
to provide similar analgesic efficacy vs hydromorphone patient-controlled analgesia (PCA) after
gastric bypass surgery (Ziemann-Gimmel 2013 Level III-3, n=181).
Pharmacokinetics in morbidly obese young adults appears to be altered as serum
concentrations are virtually undetectable two h after administration of 1000 mg IV paracetamol(Hakim 2019 Level IV PK, n=11). This suggests that morbidly obese patients may require dose
adjustment, although there is currently no consensus on what dosing regimen to use.

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9.5.5.2 | Non-steroidal anti-inflammatories (NSAIDs)
In the absence of contraindications, the use of non-selective NSAIDs following bariatric surgery
has been shown to reduce opioid consumption and improve pain scores and postoperative
nausea and vomiting (PONV) (Govindarajan 2005 Level II, n=50, JS 2). IV ibuprofen vs IV paracetamol
provided better reduction in pain scores and similar reductions in post-operative opioid
consumption (Erdogan Kayhan 2018 Level II, n=80, JS 5). Intraoperative ketorolac was associatedwith reduced haemoglobin, although there was no difference in transfusion requirements ( Klein
2012 Level III-2, n=162).
9.5.5.3 | Conventional Opioids
The use of conventional opioids for acute pain management in obese patients is a challenge dueto the increased risk of OIVI. An opioid-sparing approach with multimodal techniques andindividualised pain management may mitigate the risks.
Comparisons between opioids offer conflicting evidence and slight differences in outcomes.
Sufentanil vs remifentanil infusions offered better quality of recovery (Aldrete score,
psychomotor recovery) despite slower awakening times in morbidly obese patients undergoinglaparoscopic gastroplasty (Bidgoli 2011 Level II, n=100, JS 5).
Studies comparing remifentanil and fentanyl in patients with class 2 and 3 obesity undergoinglaparoscopic gastric banding surgery provided conflicting results, however remifentanil had
predictably faster recovery of respiratory parameters (Kontrimaviciute 2012 Level II, n=66, JS 3;
Bidgoli 2011 Level II, n=100, JS 5; De Baerdemaeker 2007 Level III-3, n=40).
Pharmacologic dosing models for fentanyl in morbidly obese patients have not yet beendeveloped, but data suggest that fentanyl should be dosed based on LBW or IBW ( Belcaid 2019
NR; Lang 2017 NR). One small trial demonstrated the pharmacokinetic mass versus TBW curve
was essentially linear below 100 kg and approached a plateau above 140 kg ( Shibutani 2004 Level
III-2 PK, n=109). Prolonged infusions of fentanyl in obese patients have been associated withprolonged effects (Porhomayon 2013 NR). Remifentanil infusion dosing is governed by either IBW
or LBW (Egan 1998 Level III-2 PK, n=24). Metabolism of morphine does not appear to be altered inmorbidly obese patients, however, decreased elimination of active metabolites is evident,
prolonging duration of action and exposure to these metabolites (de Hoogd 2017 Level III-2, n=40).
9.5.5.4 | Tramadol
After laparoscopic bariatric surgery, tramadol was superior to morphine in providing
postoperative analgesia, with lower opioid requirements, lower hypopnoea episodes, earlier
ambulation, early PACU discharge and shorter hospital LOS (Bamgbade 2017 Level III-3, n=412).
Drawbacks for routine use include potential interactions with multiple antidepressants, which isparticularly relevant as obesity is associated with a higher risk of developing depressive disorders(Kasen 2008 Level IV, n=544; Apovian 2016 NR).
9.5.5.5 | NMDA receptor antagonists
Intraoperative ketamine vs placebo improved early analgesia and reduced opioid requirementsin patients undergoing laparoscopic gastric bypass surgery when added to remifentanil infusion)(Hasanein 2019 Level II, n=60, JS 3). Addition of low dose ketamine to morphine appears tosignificantly reduce opioid consumption and improve oxygen saturation and lung function vspatients using morphine alone (Kamal 2008 Level II, n=80, JS 4). The use of ketamine combined withclonidine or dexmedetomidine also reduces intra- and post-operative opioid consumption, along790

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with reduction of PONV and earlier time to extubation. This combination may cause significant
drowsiness however (Sollazzi 2009 Level II, n=50, JS 3). A single dose of ketamine (0.4 mg/kg)
resulted in no significant difference in pain intensity, however a clinically significant
improvement in the affective component of pain was observed ( Wang 2019 Level II, n=100, JS 5).
There is limited data available regarding ketamine dosing in obese patients. One study
examining dose adjustments for induction of anaesthesia suggests using LBW or IBW ( Sollazzi
2009 Level II, n=50, JS 3).
Perioperative IV magnesium sulfate vs placebo lowered pain scores and morphine consumption
in patients undergoing sleeve gastrectomy (Kizilcik 2018 Level II, n=80, JS 5).
9.5.5.6 | Alpha-2-delta ligands
A single preoperative administration of pregabalin 150 mg demonstrated reductions in morphine
consumption and pain scores with a low incidence of adverse effects after laparoscopic sleeve
gastrectomy (Cabrera Schulmeyer 2010 Level II, n=80, JS 5). A single dose of preoperative gabapentin
was found to have similar effects after laparoscopic gastric bypass surgery in patients withmorbid obesity (Hassani 2015 Level II, n=60, JS 5). Caution with the routine use of these agents isrequired in the obese population, as they are known to cause sedation and may increase the riskof OIVI (Belcaid 2019 NR).
9.5.5.7 | Alpha-2 agonists
Dexmedetomidine in class 3 obese patients undergoing bariatric surgery results in improved
analgesia, reduced opioid requirements and PONV with the most common infusion dose being
used at 0.2 to 0.4 mcg/kg/hr (Singh 2017 Level I [PRISMA], 6 RCTs, n=362). This is confirmed by asubsequent RCT; intraoperative dexmedetomidine infusion reduced pain scores, morphine
consumption and improve the quality of recovery after laparoscopic sleeve gastrectomy (Sherif 2017
Level II, n=150, JS 5). Clonidine vs dexmedetomidine had comparable effects on pain scores, quantityof analgesic consumption, return to normal function and patient satisfaction after laparoscopic
sleeve gastrectomy (Naja 2014 Level II, n=60, JS 5).
9.5.5.8 | Corticosteroids
In postoperative obese patients undergoing laparoscopic sleeve gastrectomy, the addition of
dexamethasone 8 mg and haloperidol 2 mg to ondansetron 8 mg vs ondansetron 8 mg only
reduced pain intensity, morphine consumption and nausea (Benevides 2013 Level II, n=90, JS 5).
9.5.5.9 | Systemic local anaesthetics
Intraoperative systemic lidocaine infusion in the obese population undergoing laparoscopic
gastric reduction surgery reduced pain scores, opioid consumption and improved quality ofrecovery (Sherif 2017 Level II, n=150, JS 5; De Oliveira 2014a Level II, n=50, JS 5).
9.5.5.10 | Cannabinoids
Self-reported marijuana use is associated with higher perioperative opioid use in the context ofobesity and weight loss surgery (Bauer 2018 Level III-2, n=434).

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9.5.6 | Local and regional anaesthetic techniques used in the management of
acute pain in the obese patient
9.5.6.1 | Wound infiltration including wound catheters
Continuous SC and subfascial infusion of bupivacaine provided similar analgesia to IV PCA
pethidine with reduced opioid requirements following laparoscopic gastric bypass surgery(Cottam 2007 Level II, n=40, JS 2).
Intraperitoneal local anaesthetic infusions for bariatric surgery reduce postoperative pain,
decrease opioid consumption (Andersen 2014 Level I [PRISMA] 2 RCTs [intraperitoneal], n=188); Omar
2019 Level II, n=100, JS 3; Sherwinter 2008 Level II, n=30, JS 5) and are associated with earlier
mobilisation, earlier intake of oral fluids and a shorter hospital LOS (Ruiz-Tovar 2018 Level II, n=110,
JS 5). However, spraying 20 mL of 2.5% (?dosing error in manuscript) bupivacaine vs placebo
onto the diaphragm during a laparoscopic gastric bypass did not reduce pain or opioid
consumption (Schipper 2019 Level II, n=127, JS 4).
Preperitoneal bupivacaine infiltration reduced acute pain intensity, opioid consumption andthe incidence of chronic post-surgical pain after bariatric surgery (Boerboom 2018 Level II, n=100,
JS 4).
9.5.6.2 | Continuous and single-injection peripheral nerve blocks
Obesity was associated with a higher rate of peripheral block failure using landmark techniques(Franco 2006 Level III-3, n=2,020) and lower rates of patient satisfaction (Hanouz 2010 Level III-2,
n=605). The use of US-guided regional blocks in obese patients improved procedural time,
efficacy and patient satisfaction vs nerve stimulation (Lam 2014 Level II, n=24, JS 5). Even with theuse of US guidance, elevated BMI is associated with an increased time required for block
placement and higher pain scores and opioid consumption in PACU ( Schroeder 2012 Level IV,
n=528).

Ambulatory hernia repairs under local anaesthesia appear to be feasible and safe in obese
patients with a BMI up to 45 kg/m2 (Acevedo 2010 Level III-3, n=2,031).
There is conflicting evidence regarding the analgesic benefit of a single injection US-guided
TAP blocks in morbidly obese patients undergoing laparoscopic bariatric surgery ( De Oliveira
2014b Level II, n=19, JS 5; Wassef 2013 Level II, n=35, JS 3). There was a short-term reduction in painscores by US-guided TAP blocks, however other parameters including opioid consumption, time
to ambulation or hospital LOS were similar to placebo (Saber 2019 Level II, n=90, JS 5). Another RCT
found no difference in pain scores or opioid consumption with US-guided TAP blocks (Albrecht
2013a Level II, n=70, JS 5). Continuous local anaesthetic infusions appear to be more successful,with reduced pain scores and opioid consumption, earlier oral intake and ambulation times with
US- guided (Said 2017 Level II, n=90, JS 2) or laparoscopic guided TAP block catheter placement(Ruiz-Tovar 2018 Level II, n=140, JS 4).
Brachial plexus blocks have been shown to provide safe and effective analgesia in patientswith morbid obesity (Melton 2017 Level III-2, n=28; Franco 2006 Level III-3, n=2,020; Schroeder 2012
Level IV, n=528; Schwemmer 2006 Level IV, n=70). However, concern has been raised regarding thesafety of supraclavicular blocks following a case report of severe respiratory distress in amorbidly obese patient who received a US-guided block (Guirguis 2012 CR).
There is currently no evidence-based recommendation for peripheral nerve block local
anaesthetic dosing in patients with morbid obesity. Based on expert opinion, IBW should be used
(Leykin 2011 NR PK; Ingrande 2010 NR PK; Adams 2000 NR).

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9.5.6.3 | Neuraxial techniques
Neuraxial blocks are challenging in obese obstetric patients, with a significant increase in failure
rate at times (Kula 2017 Level IV, n=2,485; Vaananen 2017 Level IV, n=842). US guidance is likely to
improve success rate (Shaylor 2016 Level IV, n=63), and estimated epidural depth visualised on
ultrasound is strongly correlated with actual distance upon successful needle placement ( Balki2009 Level IV, n=46). A handheld ultrasound device provides comparable depth estimates to a
console ultrasound machine (Carvalho 2019 Level III-2, n=47).
Obese parturients report significantly lower efficacy from labour epidurals ( Bonnet 2017a Level
IV, n=9,337). After an accidental dural puncture, the incidence of postdural puncture headaches(PDPH) is less in obese parturients vs non-obese (Peralta 2015 Level III-2, n=518 [dural punctures]).
The effect of obesity on the spread and block height in spinal anaesthesia remains
controversial (Ngaka 2016 Level III-2, n=50; Kim 2015 Level III-2, n=209). More extensive spread ofspinal anaesthesia is noted in females with central obesity vs those with non-central obesity(Chang 2017 Level III-2, n=57).
The addition of IT morphine vs placebo as part of a multimodal analgesic regimen after
laparoscopic bariatric surgery markedly reduced postoperative pain, systemic opioid
consumption and hospital LOS (El Sherif 2016 Level II, n=100, JS 4).
Epidural administration of local anaesthetic in obese patients has been associated withincreased risk of cephalad spread (Carvalho 2017 Level II, n=40, JS 5; Lamon 2017 Level III-2, n=5,015;
Kim 2015 Level III-2, n=209; Vricella 2011 Level III-2, n=250), thus dose reductions are likely to berequired.
Thoracic epidural infusions of morphine at 200 mcg/h have been used safely in patients withclass 3 obesity (Zotou 2014 Level II, n=48, JS 5). A loading dose of epidural morphine appears tooffer no additional benefit in pain control and prolongs delay to normal bowel function andambulation. Post laparotomy, the use of a thoracic epidural offers better measurements on
spirometry function tests and quicker recovery of respiratory function (von Ungern-Sternberg 2005
Level III-2, n=84). Thoracic epidural use in obese patients undergoing off-pump coronary artery
bypass surgery was shown to provide better analgesia, early tracheal extubation and shorter ICU
LOS (Sharma 2010 Level II, n=60, JS 3).
PCA morphine vs epidural analgesia in gastric bypass surgery resulted in similar pain control,
time to ambulation, bowel recovery or hospital LOS (Charghi 2003 Level III-3, n=86). Epidural
analgesia was associated with an increased incidence of wound infections (39% vs 15%).

9.5.7 | Non-pharmacological techniques used in the management of acute painin the obese patient
Various non-pharmacological therapies have been assessed in small trials for their efficacy inimproving postoperative pain, though none are common practice.
Pulmonary recruitment manoeuvres reduced pain intensity and opioid requirements in thefirst 24 h after laparoscopic bariatric surgery (Pasquier 2018 Level II, n=150, JS 5).
A single session of postoperative prefrontal repetitive transcranial magnetic stimulation vssham was associated with a 40% reduction in PCA morphine use in gastric bypass surgery
patients (Borckardt 2008 Level II, n=20, JS 5).
The use of lavender aromatherapy in the post-anaesthesia care unit has been found to reduce
the total analgesic and opioid requirements of patients undergoing laparoscopic gastric banding(Kim 2007 Level II, n=54, JS 3).

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9.5.8 | Multimodal concepts
Introduction of a multimodal protocol for analgesia in laparoscopic sleeve gastrectomy(preoperative etoricoxib, intraoperative and postoperative paracetamol with optional
postoperative tramadol) vs historic control (previous standard care) resulted in reduced opioid
requirements, reduced adverse effects of opioids (8.8% vs 33%) with similar analgesic efficacy(Ng 2017 Level III-3, n=158).

KEY MESSAGES
1. Perioperative dexmedetomidine infusion reduces pain intensity, opioid requirements
and PONV after bariatric surgery (N) (Level I [PRISMA]).
2. Intraoperative peritoneal local anaesthetic administration reduces pain intensity andopioid requirements after bariatric surgery (N) (Level I [PRISMA]).
3. Paracetamol (multi-dosing) r educes opioid requirements, hospital length of stay andrepresentations for pain after bariatric surgery (N) (Level II).
4. Intraoperative systemic lidocaine infusions reduce pain intensity, opioid requirements
and improve the quality of recovery after bariatric surgery (N) (Level II).
5. Epidural administration of local anaesthetics in obese patients has been associated withincreased risk of cephalad spread (N) (Level III-2).
6. Obesity increases the failure rate of neuraxial and peripheral nerve blocks (N) (Level IV);
ultrasound guidance improves the success rate (N) (Level IV).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Obesity has significant detrimental effects on respiratory function and is linked to anincreased rate of obstructive sleep apnoea (N).
 Obesity influences pharmacokinetic and pharmacodynamic parameters of analgesic
medications leading to uncertainty about dosing and caution should be used withweight-based dosing (N).
 Multimodal analgesic techniques including use of regional techniques result in opioidsparing effects and thereby improve safety of acute pain management after bariatricsurgery (N).

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9.6 | The patient with concurrent renal or hepatic disease
The efficacy and effectiveness of most analgesic medicines is altered by impaired renal or hepaticfunction. This change is not only because of altered clearance of the parent medicine, but also
through the accumulation of therapeutically active or toxic metabolites. Some analgesic agentscan aggravate pre-existing renal and hepatic disease, causing direct damage and thus altering
their metabolism.
A brief summary of the effects that renal or hepatic disease may have on some of the
medicines used in pain management, as well as alterations that might be required in analgesic
medicine regimens, is given in Tables 9.6 and 9.7.

9.6.1 | Patients with renal disease
The degree to which analgesic medicine regimens require alteration in patients with renal
impairment depends largely on the extent of renal impairment. Some medicines have active
metabolites that are dependent on the kidney for excretion, and the medicine or its metabolites
may further impair renal function.
A standard definition for chronic kidney disease (CKD) is provided by the US National Kidney
Foundation (kidney.org) Kidney Disease Outcome Quality Initiative Advisory Board; patients withCKD should have either a glomerular filtration rate (GFR) <60 mL/min/1.73 m 2 for ≥3 mth or
structural/functional kidney damage with or without changes in GFR (Levin 2014 GL). Thisdefinition quantifies five stages from Stage 1 (kidney damage with normal or increased GFR) via
Stage 2 (mild reduction in renal function and GFR), Stages 3 and 4 (moderate to severe
impairment of renal function and reduction in GFR) to Stage 5 (end-stage kidney diseaserequiring dialysis or renal replacement therapy).
There is some limited information about the ability of dialysis to clear many medicines and/or
their metabolites. Molecules are more likely to be removed by dialysis if they have a low
molecular weight, greater water solubility and lower volume of distribution; while a higher
degree of protein binding and use of lower-efficiency dialysis techniques will reduce removal(Trainor 2011 NR; Dean 2004 NR).
The available data indicate the following (see Table 9.6 for references):• Analgesics that exhibit the safest pharmacological profile in patients with renal
impairment are alfentanil, buprenorphine, fentanyl, ketamine, paracetamol (except
with compound analgesics) and sufentanil. None of these medicines deliver a highactive metabolite load or have a significantly prolonged clearance.
• Oxycodone can usually be used without any dose adjustment in patients with renal
impairment. Its metabolites do not appear to contribute to any clinical effect in patientswith normal renal function.
• Amitriptyline, bupivacaine, levobupivacaine, lignocaine, ropivacaine, clonidine,
gabapentin, pregabalin, codeine, hydromorphone, methadone, morphine, tramadol
and tapentadol have been used in patients with renal disease but may need dosing
adjustment depending on the degree of impairment. For local anaesthetics andprolonged administration, a reduction in dose may be required. Levobupivacaine,with similar clearance mechanisms, and ropivacaine may be safer than bupivacaine
due to their higher therapeutic ratio. Haemodialysis clears some medicines, and soa supplemental dose may be needed at the end of dialysis (eg gabapentin,pregabalin).

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•
•
•

NSAIDs (both nsNSAIDs and coxibs), dextropropoxyphene and pethidine should not be
used in the presence of significant renal impairment.
Carbamazepine, sodium valproate and lamotrigine require no dose reduction. Caution
is advised for the use of lamotrigine in patients with an eGFR <15 mL/min/1.73m2
Oxcarbazepine and topiramate require dose reduction in renal disease

Detailed reviews of pain management in patients with CKD have been published ( Nagar 2017
Level III-3 SR [PRISMA], 12 studies, n unspecified; Sande 2017 Level IV SR, 18 studies, n unspecified;Davison 2019 NR; Pham 2017 NR; Nayak-Rao 2011 NR), also with an emphasis on the perioperative
period (Tawfic 2015 NR) and on paediatric patients (Reis 2018 NR). Reviews of perioperative
management (Trainor 2011 NR) and of prescribing for the dialysis patient has also been published(Smyth 2016 NR).
Additional information can be found in the Australian Medicines Handbook (AMH 2019 GL).
Table 9.6 | Analgesic medicines in patients with renal impairment
Medicine

Comments

Recommendations*

No active metabolites

No dose adjustment
required unless renal
failure is severe

Opioids
Alfentanil

92% protein bound; increases in free fraction
may result from alterations in protein binding(Sande 2017; Tawfic 2015)
Buprenorphine

Pharmacokinetics unchanged; predominantly
biliary excretion of metabolites

No dose adjustment
required

Pharmacokinetics also unchanged with dialysis(Davison 2019; Pham 2017; Sande 2017)
CodeineAccumulation of active metabolites can occur;
prolonged sedation and respiratory arrest havebeen reported in patients with renal
impairment

Dose adjustment
recommended or use
an alternative opioid

No good data on removal by dialysis(Davison 2019; Pham 2017; Sande 2017)
Dextropropoxyphene

Accumulation of active metabolite(nordextropropoxyphene) can lead to CNS andcardiovascular system toxicity. Contraindicatedif creatinine clearance <40 mL/min.

Use of alternative
agent recommended

Blood concentrations not significantly changed
during dialysis(Davison 2019; Niscola 2010)
Dihydrocodeine

Metabolic pathway probably similar to codeineTime to peak concentration and terminal halflife prolonged(Pham 2017; Craig 2008; Murtagh 2007)

796

5th Edition | Acute Pain Management: Scientific EvidenceInsufficient evidence:
use not
recommended

9.0 | OTHER SPECIFIC PATIENT GROUPS

Medicine

Comments

Recommendations*

Fentanyl

No active metabolites

No dose adjustment
required; may be
used in patients withsevere renal
impairment

Not removed to any significant degree by dialysis(Davison 2019; Sande 2017; Pham 2017; Tawfic
2015)
Hydromorphone

Neurotoxicity from accumulation of H3G
possible
H3G is effectively removed during HD; PD nodata

Dose adjustment
recommended or use
alternative opioid(Davison 2019; Sande 2017; Pham 2017; Tawfic
2015)
Methadone

Methadone and its metabolites are excreted inurine and faeces; in anuric patients it may bemostly in faeces
High protein binding, high volume of
distribution and moderate water solubility
would suggest that it is likely to be poorly
removed by HD

Dose adjustment
may be required insevere renal
impairment(Davison 2019; Pham 2017; Opdal 2015; Nayak-Rao
2011)
Morphine

Major metabolites M3G and M6G excreted via
kidney and accumulate in renal impairment
M6G is an opioid agonist that crosses the
blood-brain barrier slowly; delayed sedationfrom M6G has been reported in renal failure

Dose adjustment
recommended or use
alternative opioid

Neurotoxicity from accumulation of M3G
possible
Oral administration results in proportionallyhigher metabolite load
Morphine and its metabolites are cleared bymost HD procedures but may not besignificantly affected by PD
M6G also removed but slow diffusion from CNS
delays response(Davison 2019; Sande 2017; Pham 2017; Tawfic 2015)

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Recommendations*

Oxycodone

The metabolite oxymorphone is active but
plasma levels are normally negligible andtherefore it has an insignificant clinical effect inpatients with normal renal function

No dose adjustment
required in mostpatients
Monitor and adjust if
necessary

Higher blood concentrations of oxycodone andmetabolites with moderate to severe renal
impairment; half-life significantly increased in
end-stage renal disease
Oxycodone and its metabolites are dialyzable(HD, no data on PD)(Davison 2019; Samolsky Dekel 2017; Pham 2017;
Sande 2017)
Pethidine

Norpethidine is the only active metabolite andis renally excreted; it is dialysable (HD)Use of alternative
agent recommended

Accumulation of norpethidine can lead toneuroexcitation including seizures(Tawfic 2015; Craig 2008; Launay-Vacher 2005)
Sufentanil

Minimally active metabolite(Sande 2017; King 2011; Murphy 2005)

Tramadol

Increased mu-opioid effects from active
metabolite O-desmethyltramadol (M1) asrenally excreted
Tramadol is removed to some extent by HD(Davison 2019; Pham 2017; Tawfic 2015)

Tapentadol

Metabolised by glucuronidation
Major metabolite will accumulate in renal
failure but significance unknown
Likely to be removable by HD

No dose adjustment
required
Dose adjustment
recommended
Use of alternative
agent recommended
in significant renal
impairment
Do not use in severe
renal impairment(Creatinine clearance<30 mL/min)(AMH 2019; Pham 2017; Xu 2010)
Nonopioids
Paracetamol

Terminal elimination half-life may be prolonged
Is dialysable(Nayak-Rao 2011; Kuo 2010; Craig 2008)

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5th Edition | Acute Pain Management: Scientific Evidence

May need to increase
dose interval if renal
impairment is severe
Some evidence thatit may accelerate therate of progression
to chronic renal
failure9.0 | OTHER SPECIFIC PATIENT GROUPS

Medicine

Comments

Recommendations*

NsNSAIDs andcoxibsCan affect renal function

Some evidence thatthey may accelerate
the rate of progression
to chronic renal
failure, in particular indehydration.
Progression of renal
disease more likely with
nsNSAIDs than coxibs

Behaviour during dialysis not clearly elucidated
for most NSAIDs(Nayak-Rao 2011; Kuo 2010; Launay-Vacher
2005)

AnticonvulsantsAlpha-2-delta
ligands

Gabapentin: impaired renal function reduces
clearance in direct proportion to creatinine
clearance; about 35% cleared by dialysis(Davison 2019; Asconape 2014)
Pregabalin: Impaired renal function reduces
clearance in direct proportion to creatinine
clearance; highly cleared by dialysis

Carbamazepine

Dose adjustment
recommended on
basis of creatinine
clearance(Davison 2019; Asconape 2014)

Dose adjustment
recommended on
basis of creatinine
clearance

No dose adjustment necessary
Highly protein bound, poorly dialysed

No dose adjustment
needed(Bansal 2015)
Lamotrigine

Limited data
(Bansal 2015)

Dose reduction if
GFR<15 ml/min

Topiramate

Up to 80% renal excretion unchanged(Bansal 2015)

Dose reduction

Valproic acid

Hepatic elimination(Bansal 2015)

No dose reduction

There may be no significant difference in plasma
concentration of levobupivacaine, bupivacaine orropivacaine in patients with chronic renal failure
unless renal failure is severe, or continuous
infusions are used or repeated doses are used

Risk of toxicity may
be affected byabnormalities in acidbase balance and/or
potassium levels
Doses may need tobe reduced if
prolonged orrepeatedadministration(eg continuous
infusions)

Other medicines
Local
anaesthetics

Increases in free fraction may result fromalterations in protein binding
Higher peak plasma concentrations ofropivacaine in uraemic patients but nodifference in free fraction; uraemic patients
have significantly higher alpha-1-acidglycoprotein plasma concentrations(AMH 2019; De Martin 2006; Jokinen 2005; Crews 2002)

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Recommendations*

Clonidine

Half-life is increased in severe renal failure

Limited data; dose
adjustment has been
recommended

50% metabolised by the liver; remainder
excreted unchanged by the kidney(Khan 1999; Lowenthal 1993)
TCAs

Amitriptyline is metabolised in the liver tonortriptyline, the active agent
Not significantly removed by dialysis(Davison 2019; Raymond 2008; Dargan 2005)

SNRIs

Duloxetine
Venlafaxine(AMH 2019; Raymond 2008)

Ketamine

Dehydronorketamine levels are increased but it
has only 1% of potency of ketamine
Ketamine is not removed well by HD(Davison 2019; Tawfic 2015)

Note: * Doses must still be titrated to effect for each patient.
HD – haemodialysis
PD – peritoneal dialysis

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5th Edition | Acute Pain Management: Scientific Evidence

Limited data;
metabolite
accumulation may
occur and increase
the risk of adverse
effects but little
evidence to indicate
need for dose
reduction
Dose reduction if
creatinine clearance<30 mL/min
Limited data;probable that nodose adjustment isrequired9.0 | OTHER SPECIFIC PATIENT GROUPS

9.6.2 | Patients with hepatic disease
Not all patients with hepatic disease have impaired liver function. In patients with hepatic
impairment, most analgesic medicines have reduced clearance and increased oral bioavailability
but the significance of these changes in the clinical setting has not been studied in depth.
Patients with cirrhotic liver disease may have renal impairment despite a normal serum
creatinine. This can affect clearance of renally excreted medications and dose adjustment may
be required.
The available data indicate the following (see Table 9.7 for references).
• While there are limited data, dose adjustments are usually not required for alfentanil,
buprenorphine, fentanyl, morphine, oxycodone and sufentanil. However, all opioids
carry an increased risk of toxicity and hepatic encephalopathy.
• Tramadol may need to be given at lower doses.
• Methadone should be used with caution in the presence of severe liver disease becauseof the potential for accumulation due to impaired clearance.
• Combination preparations of slow-release oxycodone and naloxone (Targin®) should be
avoided in hepatic impairment as the reduced naloxone clearance leads to increased
systemic levels and potential antagonism of the analgesic action of the oxycodone.
• The clearance of local anaesthetics may be significantly impaired; doses may need to be
decreased if use is prolonged.
• Carbamazepine and valproate should be avoided in patients with severe hepatic
impairment.
• It may be wise to reduce the dose of paracetamol in patients with significant degrees ofhepatic impairment.
Detailed reviews of analgesic use in hepatic disease have been published ( Dwyer 2014 NR;
Imani 2014 NR; Bosilkovska 2012 NR) other detailed but lower quality reviews have also been published(Soleimanpour 2016 NR). Additional information can be found in the Australian Medicines
Handbook (AMH 2019 GL).
Table 9.7 | Analgesic medicines in patients with hepatic impairment
Medicine

Comments

Recommendations*

No significant difference in half-life found inchildren undergoing liver transplant

Limited data: no dose
adjustment requiredin most patients

Opioids
Alfentanil

In alcoholic cirrhosis, plasma clearance andprotein binding decreased and elimination halflife increased after single dose
(Davis 1989; Ferrier 1985)
Buprenorphine

Lower blood concentrations of buprenorphineand norbuprenorphine

Limited data: no dose
adjustment required

Chronic use in patients with HIV or HCV
associated with increased incidence of hepatic
enzyme rise
(Tetrault 2016; Dwyer 2014; Johnson 2005)

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801MedicineComments

Recommendations*

Dextropropoxyphene

Reduced oxidation leading to reduced clearance

Limited data: dose
adjustment may berequired

Fentanyl

Disposition appears to be unaffected(Tegeder 1999)(Dwyer 2014; Chandok 2010)
Methadone

Increased half-life but limited significance(Dwyer 2014; Lugo 2005)

Limited data: no dose
adjustment required
Limited data: no dose
adjustment requiredin stable chronic liverdiseaseMorphine

Hepatic impairment does not appear to have asignificant effect on morphine pharmacokinetics;
even in patients with cirrhosis there is a large
hepatic reserve for glucuronidation
Blood concentrations of morphine but notmorphine metabolites higher after liverresection; blood concentrations also higher inpatients with liver cancer
Increased oral bioavailability of morphine due toits normal high first pass metabolism when given
via this route
Morphine pharmacokinetics altered in
Nonalcoholic Steatohepatitis (NASH)(Pierre 2017; Rudin 2007; Kotb 2005)

In most patients nodose adjustment
requiredHydromorphone

Increased half-life of hydromorphone

Consider dose
reduction

Oxycodone

Decreased oxycodone clearance with mild tomoderate hepatic impairment(AMH 2019; Soleimanpour 2016; Chandok 2010)

Avoid fixed dose combination with naloxone(Targin®) in moderate to severe hepatic
impairment as systemic absorption of naloxone
may be increased

Limited data: no dose
adjustment requiredin most patients(AMH 2019; Riley 2008; Kalso 2005)
Pethidine802

Reduced clearance(Tegeder 1999)

Limited data: dose
adjustment may berequired; use notrecommended

Sufentanil

No difference in clearance or elimination(Tegeder 1999; Chauvin 1989)

No dose adjustment
requiredTramadolReduced clearance(Dwyer 2014; Kotb 2008; Tegeder 1999)

Limited data: dose
adjustment may berequired if
impairment is severe

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Medicine

Comments

Recommendations*

Tapentadol

Elimination by hepatic glucuronidation

Avoid in severe
hepatic impairment(Child-Pugh score 10–
15)
Adjust dose inmoderate hepatic
impairment (ChildPugh score 7–9)

(AMH 2019; Xu 2010)

Nonopioids
Paracetamol

Metabolised in the liver; small proportion
metabolised to the potentially hepatotoxic
metabolite N-acetyl-p-benzoquinone imine. This
is normally inactivated by hepatic glutathione
Clearance is reduced(Hayward 2016; Dwyer 2014; Imani 2014; Graham
2013; Chandok 2010)

nsNSAIDs

Metabolised in liver. Altered metabolism andbioavailability in cirrhosis.
Avoid if renal impairment present or risk ofhepato-renal syndrome(Dwyer 2014; Imani 2014; Chandok 2010)

Commonly suggested
that it should be usedwith caution or in
reduced doses orfrequency with active
liver disease, alcoholrelated liver disease
and glucose-6phosphate
dehydrogenase
deficiency
However, others
report that it can beused safely inpatients with liverdisease and ispreferred to NSAIDs,
and that therapeutic
doses ofparacetamol, at least
for short-term use,are an unlikely causeof hepatotoxicity inpatients who ingest
moderate to large
amounts of alcohol
Dose reduction forchronic use
May be used in mild
chronic liver disease
Avoid in cirrhosis
COX2 selective
agents may be safer

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MedicineComments

Recommendations*

Alpha-2-delta
ligands

Eliminated renally

Safe in liver disease

Carbamazepine

Transient rises in hepatic enzymes occur in 25–
61% of patients treated; has been reported tocause hepatic failure (rare)

Anticonvulsants(Asconape 2014; Dwyer 2014; Chandok 2010)

Primarily metabolised in the liver(Asconape 2014; Ahmed 2006)
Valproate

Transient rises in hepatic enzymes occur in 10–
15% of patients treated; has been reported tocause hepatic failure (rare)
Primarily metabolised in the liver(Asconape 2014; Ahmed 2006)

Dose adjustment
may be required; use
not recommended insevere hepatic
impairment
Dose adjustment
may be required; use
not recommended insevere hepatic
impairment

Other
medicines
Localanaesthetics

Amide-type local anaesthetics undergo hepatic
metabolism and clearance may be reduced inhepatic disease
Increased plasma concentrations of ropivacaine
after continuous infusion but not a single dose

Limited data; dose
adjustment may berequired withprolonged orrepeated use(AMH 2019; Jokinen 2007; Jokinen 2005; Bodenham
1990)
TCAs

Amitriptyline is metabolised in the liver tonortriptyline, the active agent(Dwyer 2014; Chandok 2010)

SNRIs

Duloxetine
Venlafaxine(Dwyer 2014; Chandok 2010)

Ketamine

In acute use, rare incidence of hepatic enzyme rise
Prolonged infusion associated with hepatic
enzyme rise
Chronic use possibly associated with sclerosing
cholangitis(Wong 2014; Noppers 2011)

Note: *Doses must still be titrated to effect for each patient804

5th Edition | Acute Pain Management: Scientific Evidence

Reduce dose if
hepatic impairment issevereDuloxetine should
not be used inhepatic impairment
Venlafaxine dose
reduction in hepatic
impairment
Desvenlafaxine may
be safer
Monitor hepatic
enzymes whencontinuous infusion is
prolonged beyond
about five d9.0 | OTHER SPECIFIC PATIENT GROUPSKEY MESSAGE
The following tick box represents conclusions based on clinical experience and expert
opinion: Consideration should be given to the choice and dose regimen of analgesic agents inpatients with hepatic and particularly renal impairment (S).

5th Edition | Acute Pain Management: Scientific Evidence8059.7 | The opioid-tolerant patientWith increased opioid prescribing for chronic pain, partly due to an ageing population, andincreased use and misuse of prescription opioids, increasing proportions of patients with acutepain are opioid-tolerant. The proportion of opioid-tolerant patients varies widely with country
and context. For example, it is higher in those presenting for orthopaedic and spinal surgery(Hilliard 2018 Level IV, n=34,186).

9.7.1 | Definitions
Misunderstandings in the terminology related to addiction (see also Section 9.8 below),
tolerance, and physical dependence may confuse health professionals and patients, leading to
inappropriate and/or suboptimal acute pain management as well as stigmatisation ( Patel 2017
Level IV, n=216). Terms such as addiction, substance abuse, substance dependence anddependence are often used interchangeably. Relevant terms are defined in Table 9.8.
The definitions of many of these terms were not developed for people suffering with chronic
pain. Consensus statements from the IMMPACT and ACTTION panels address definitions for thepatient with chronic pain (O'Connor 2013 GL; Smith 2013 GL) as follows:• Misuse: opioid use contrary to the directed or prescribed pattern of use, regardless ofthe presence or absence of harm or adverse effects• Abuse: intentional use of the opioid for a nonmedical purpose, such as euphoria or
altering one’s state of consciousness• Addiction: Pattern of continued use with experience of, or demonstrated potential for,
harm.
Table 9.8 | Definitions of relevant terms

806

Aberrant drugrelated behaviours“Behaviours that may be suggestive of the development of abuse,
addiction or misuse” (Moore 2009)

Addiction

A disease that is characterized by aberrant drug-seeking andmaladaptive drug-taking behaviours that may include cravings,
compulsive drug use and loss of control over drug use, despite the riskof physical, social and psychological harm
While psychoactive drugs have an addiction liability, psychological,
social, environmental and genetic factors play an important role in thedevelopment of addiction
Unlike tolerance and physical dependence, addiction is not apredictable effect of a drug
“Primary chronic disease of brain reward, motivation, memory andrelated circuitry. Dysfunction in these circuits leads to characteristic
biological, psychological, social and spiritual manifestations” (AAPM
2001 GL)

Chemical coping“The use of opioids to cope with emotional distress, characterized byinappropriate and/or excessive opioid use” (Kwon 2015 NR)

5th Edition | Acute Pain Management: Scientific Evidence9.0 | OTHER SPECIFIC PATIENT GROUPS

Dependence
syndrome (ICD 10)“A cluster of behavioural, cognitive, and physiological phenomena thatdevelop after repeated substance use and that typically include astrong desire to take the drug, difficulties in controlling its use,
persisting in its use despite harmful consequences, a higher priority
given to drug use than to other activities and obligations, increased
tolerance, and sometimes a physical withdrawal state” (AAPM 2001 GL)

Diversion

Sharing, selling or trading prescribed drugs to someone for whomthey are not prescribed (Arria 2011 Level IV)
Sourcing activities or paths which redirect psychoactive prescription
drugs from legitimate production or medical-use environments into
the hands of nonmedical consumers (Fischer 2010 NR)

Medication
assisted treatment

Use of medications in combination with counselling and behaviouraltherapies for the treatment of substance use disorders ( SAMHSA 2019GL)

Non-medicalprescription opioiduse (NMPOU)

Used by National Survey on Drug Use (SAMHSA 2019 GL)

Opioid Induced
Hyperalgesia (OIH)“State of nociceptive sensitization caused by exposure to opioids”(Ramasubbu 2011 NR)
Declining nociceptive threshold after opioid exposure without overt
withdrawal signs (Mao 2015 NR)

Physicaldependence

A physiological adaptation to a drug whereby abrupt discontinuation
or reversal of that drug, or a sudden reduction in its dose, leads to awithdrawal (abstinence) syndrome
Withdrawal can be terminated by administration of the same orsimilar drug

Pseudoaddiction

Behaviours that may seem inappropriately drug-seeking but are a
result of undertreatment of pain and resolve when pain relief isadequate (Weissman 1989 NR)

Substance use
disorder (SUD)

The essential feature of a substance use disorder is a cluster of cognitive,
behavioural and psychological symptoms indicating that the individual
continues using the substance despite significant substance-related problems(American Psychiatric Association 2013b)

Tolerance(pharmacological)

A predictable physiological decrease in the effect of a drug over timeso that a progressive increase in the amount of that drug is required
to achieve the same effectTolerance develops to desired (eg analgesia) and undesired (egeuphoria, opioid-related sedation, nausea or constipation) effects at
different rates

Tolerance(associative,
psychological)“Can arise for all the central effects of opioids, including euphoria anddysphoria, sedation, analgesia and nausea. This type of tolerance
involves learning, and its development is linked to environmental orcontextual cues” (Ballantyne 2017 NR)

Source: Adapted from (AAPM 2001 GL) and the references in the table.
5th Edition | Acute Pain Management: Scientific Evidence807

9.7.2 | Clinical implications of opioid tolerance and opioid-induced hyperalgesia
Opioid exposure can lead to desensitisation processes commonly described as opioid tolerance
and pronociceptive processes referred to as opioid-induced hyperalgesia (OIH) ( Mao 2015 NR).
OIH may be modulated by amongst others NMDA and GABA receptors and possibly the innate
neuroimmune system (Arout 2015 BS NR) as well as peripheral mu-opioid receptors (Weber 2017
NR).
The relative roles played by tolerance and OIH in the patient who is taking long-term opioids
are unknown and both may contribute to increased pain ( Higgins 2019 Level III-3 EH SR [PRISMA],
26 studies, n=2,706; Weber 2017 NR). It is also possible that different opioids vary in their ability to
induce OIH and tolerance (see Section 4.1.1). Studies of OIH are confounded by factors such as
pain modality tested, route of administration and opioid type ( Weber 2017 NR). Psychologicalfactors such as pain-related distress and catastrophising might also affect pain sensitivity in thosetaking opioids for chronic pain (Edwards 2011 Level III-2; Eyler 2013 NR). Illicit substance use,
affective characteristics, and coping styles may also play a role ( Higgins 2019 Level III-3 EH SR[PRISMA], 26 studies, n=2,706).
There are some features of OIH that may help to distinguish it from pre-existing pain. With
OIH, pain intensity may be increased above the level of the pre-existing pain; the distribution
tends to be beyond that of the pre-existing pain as well as being more diffuse; and QST may showchanges in pain thresholds and tolerability (Higgins 2019 Level III-3 EH SR [PRISMA], 26 studies,
n=2,706; Weber 2017 NR; Lee 2011 NR; Ramasubbu 2011 NR). Additionally, increasing opioid dose will
worsen OIH (Colvin 2019 NR). Practical clinical challenges include lack of consensus on “the”
diagnostic test, and overlap with tolerance, withdrawal and neuropathic pain.
OIH is identified by reduced pain tolerance to noxious thermal (hot and cold), but notelectrical stimuli, in patients with chronic opioid exposure (Higgins 2019 Level III-3 EH SR [PRISMA],
26 studies, n=2,706); pain detection thresholds remain unchanged. However, an attempt toidentify a quantitative sensory testing method to detect hyperalgesia in chronic pain patients on
long-term opioids failed, as none of the measures could be used as a definitive standard ( Katz
2015b Level IV EH SR, 14 studies, n unspecified). The methods investigated include pain due to cold,
heat, pressure, electrical stimulus, ischemia, and injection; only heat pain sensitivity showedsome promise.
In subjects in methadone-maintenance programs, the presence of chronic pain may
differentially increase pain thresholds and there may be a dose-related effect on abnormal pain
processing (Chen 2009 Level III-2 EH; Peles 2011 Level III-3 EH; Hooten 2010 Level IV EH). In chronic pain
patients on opioid treatment, patients with negative affect (ie more distressed) show morefeatures of OIH (Edwards 2016 Level III-2, n=31). There is controversy about the impact of opioid
cessation, with some evidence suggesting resolution of OIH after a few months opioid abstinence(Treister 2012 Level III-3 EH) and others showing that heat and pain perception remain abnormal
even after abstinence for at least 6 mth (Prosser 2008 Level III-2 EH).
After intraoperative use of remifentanil (at ≥0.1 mcg/kg/min), there is evidence of acute opioid
tolerance and OIH of limited clinical relevance (Kim 2014 Level IV SR, number of studies unspecified, nunspecified; Rivosecchi 2014 Level IV SR, 35 studies, n unspecified). Another meta-analysis confirms
clinically small but statistically significant OIH only after high-dose remifentanil (≥0.3 mcg/kg/min)with insufficient data on fentanyl and sufentanil (Fletcher 2014 Level I [PRISMA] 27 RCTs, n=1,494).
Patients had increased postoperative pain scores at 1 h (MD 9.4/100; 95%CI 4.4 to 14.5) up to 24 h
(MD 3/100; 95%CI 0.4 to 5.6) and higher opioid requirements over 24 h (SMD 0.7; 95%CI 0.37 to1.02). Overall, the effect of remifentanil is dose dependent (Angst 2015 NR). Gradual (by 0.6 ng/ml
target concentration every 5 min) vs abrupt withdrawal of a remifentanil infusion (target
concentration 2.5 ng/ml for 30 min) induced no OIH (pain similar to placebo) measured with the808

5th Edition | Acute Pain Management: Scientific Evidence9.0 | OTHER SPECIFIC PATIENT GROUPS

heat pain test, but not the cold pressor test (Comelon 2016 Level II EH, n=19, JS 5). This was confirmed
in a clinical setting of thyroidectomy, where gradual tapering of a high-dose remifentanil infusion(from 0.3 to 0.1 mcg/kg/min over at least 30 min) reduced postoperative pain at 1 and 2 h andrescue analgesia requirements (Han 2015 Level II, n=62, JS 5).
NMDA-receptor antagonists (mainly ketamine [8 RCTs] but also magnesium [5 RCTs] andamantadine [1 RCT]) reduce the development of acute tolerance/OIH associated with remifentaniluse (Wu 2015 Level I [QUOROM], 14 RCTs, n=729). Pregabalin had an attenuating effect (Lee 2013b
Level II, n=93, JS 5; Jo 2011 Level II, n=60, JS 5) as did propofol in a subgroup analysis (6 RCTs, n=341)
of a systematic review (Fletcher 2014 Level I [PRISMA], 27 RCTs, n=1,494) as well as N2O (Wehrfritz
2016 Level II EH, n=21, JS 5; Echevarria 2011 Level II, n=50, JS 4). Low-dose naloxone (0.25 mcg/kg/h
intraoperatively) also reduced postoperative opioid requirements when combined with highdose remifentanil (and improved time to bowel recovery) ( Xiao 2015 Level II, n=75, JS 5).
The challenge faced by the health professional is that if inadequate pain relief is due to OIH,
reducing the opioid dose may help; if it is due to opioid tolerance, increased doses may provide
better pain relief (Colvin 2019 NR; Huxtable 2011 NR; Mao 2008 NR). There are case reports ofpatients with cancer and chronic noncancer pain taking high doses of opioid who developed OIH
and whose pain relief improved following reduction of their opioid dose ( Chang 2007 CR; Angst
2006 CR). There are no data in the acute pain setting.
When a patient who has been taking opioids for a while (either legally prescribed or illicitly
obtained) has new and ongoing tissue injury with resultant acute pain, a reasonable initial
response to inadequate analgesia, after an evaluation of the patient and in the absence ofevidence to the contrary, is a trial of higher opioid doses (Huxtable 2011 NR; Chang 2007 NR). If thepain improves, this would suggest that the inadequate analgesia resulted from tolerance; if pain
worsens, or fails to respond to dose escalation, it could be a result of OIH ( Chang 2007 NR).
Fortunately, some of the strategies that may be tried in an attempt to attenuate opioid-tolerance
in the acute pain setting may also moderate OIH (see below).
Other reasons for increased pain and/or increased opioid requirements should also be
considered. These include acute neuropathic pain, pain due to other causes including
postoperative complications, major psychological distress and aberrant drug-seeking behaviours(see Section 9.8 below) (Edwards 2011 Level III-2; Macintyre 2015 NR; Gourlay 2008 NR).

9.7.3 | Patient groups
Four main groups of opioid-tolerant patients are encountered in acute pain settings.
1. Patients with chronic noncancer pain (CNCP) being treated with opioids, where acutepresentations may be due to a new acutely painful condition (eg surgery, trauma) or toexacerbation of the underlying chronic condition (eg sickle cell crisis, pancreatitis) (Quinlan
2012 NR). Opioids for CNCP are associated with increased risk of acutely painful injuries,
including fractures (Teng 2015 Level III-2 SR, 8 studies, n=500,819), other injury and overdose(Landsman-Blumberg 2017 Level III-2, n=21,203), with increasing risk as opioid dose increases(Bedson 2019 Level III-2, n=98,140; Murphy 2018 Level IV, n=19,480 [SAEs]). In USA veterans,
chronic opioid use is more likely at younger ages, in males, in rural areas, in smokers, inthe presence of back pain, and in those with post-traumatic stress disorder (PTSD) andmajor depression (Hudson 2017 Level III-2). Australian pharmaceutical benefit (PBS) scheme
data show persistent opioid use is more likely if initiated with transdermal preparations,higher doses, in older patients, with comorbid depression ( Sullivan 2018 NR) or psychotic
illness, and if there is prior dispensing of pregabalin or benzodiazepines ( Lalic 2019 Level
IV, n= 769 334). Some of the patients in this group may exhibit features of OUD.

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2. Patients with cancer pain being treated with opioids, who may be at various stages of
their illness including active treatment (eg surgery), palliation and in remission. In thelatter case, survivors of cancer may experience specific issues relating to “survivorship”(Yazdani 2014 NR). Some of these issues will be similar to those in patients with chronic
noncancer pain.
3. Patients with a OUD with current status ranging from using illicit prescription or nonprescription opioids and/or on an opioid-maintenance treatment program, or inremission; many patients with active or past OUD report chronic non-cancer pain (seealso Section 9.8 below).
4. Patients who have developed acute or subacute opioid tolerance (or OIH) due toperioperative opioid administration, particularly opioids of high potency, in high dose andfor “extended” periods (e.g. in an ICU).
Recognition of the presence of opioid tolerance or OIH may not be possible if the patient’s
history is not available or accurate (eg following major trauma with ICU admission or if thepatient is unconscious at presentation). If a patient is requiring much larger than expected opioid
doses and other factors that might be leading to the high requirements have been excluded,
opioid tolerance or OIH should be considered.
See Sections 10.6.3.1 and 10.7 for paediatric issues.
9.7.3.1 | Overlap between chronic pain (cancer- or non-cancer related) treatment and opioid
use disorder
Chronic non-cancer related pain (CNCP)
The past twenty years have seen a multi-fold rise in opioid prescription for CNCP, primarily indeveloped countries (Karanges 2016 Level IV; Dowell 2016 GL) including Australia, which
experienced a a 15-fold increase in opioids dispensed over the 20 years to 2015 (Donovan 2020
Level IV SR, 24 studies, n unspecified). This is despite evidence of only small and probably clinicallyinsufficient improvements in pain, physical function and social functioning, and no improvement
in emotional functioning vs placebo, and no evidence of better outcomes than most non-opioid
alternatives (Busse 2018 Level I [PRISMA], 96 RCTs, n=26,169). There is insufficient evidence of longterm benefit (Chou 2015 Level IV SR, 39 studies, n unspecified; Dowell 2016 GL).
Concurrently, there has been a rising incidence of opioid-related harms, including opioid use
disorder (OUD), opioid diversion, traumatic injury such as road trauma, myocardial infarction,
overdose (intentional and unintentional) and mortality (Els 2017 Level I [Cochrane] 14 SRs of 61 RCTs,
n=18,679; Tucker 2019 Level I [PRISMA], 14 RCTs, n=3,071; Ray 2016 Level III-2, n=22,912 [prescription
episodes]; Chou 2015 Level IV SR, 39 studies, n unspecified; Dowell 2016 GL). Adverse events are more
likely at higher doses, typically greater than 100 mg oral MED/d (Chou 2015 Level IV SR, 39 studies,n unspecified; Dowell 2016 GL; Ballantyne 2017 NR) and with greater dose variability (Glanz 2019 Level
III-2, n=14,898).

The relationship between CNCP and addiction exists on a continuum with a “complicatedreciprocity” between the two conditions (Manhapra 2018 NR). Ballantyne defines “complex
persistent dependence” in CNCP by the inability to taper opioids, accompanied by OUD-likebehaviours on attempted cessation (Ballantyne 2012 NR). CNCP and addiction have overlapping
mechanisms with disruption of reward in both, noting that acute pain in the context of CNCP
may have “positive reinforcing qualities” (Elman 2016 NR).
Observed rates of OUD in CNCP depend on the definitions used. The varying criteria in DSMIV, DSM-V, ICD-9, -10 and -11 classifications lead to different estimates (Kaye 2017b NR), notingthat these definitions were not developed for those with concurrent pain (Campbell 2016 Level IV,
n=1,134).

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•

•

•

In those with CNCP, “misuse” prevalence was 21 to 29% (95%CI 13 to 38%), and“addiction” 8 to 9% (95%CI 3 to 17%) (Vowles 2015 Level IV SR [PRISMA], 38 studies,
n=1,026,427).
Using IMMPACT and ACTTION consensus statements in mixed studies of chronic noncancer and cancer pain, the pooled incidence of “dependence/abuse” was 4.7% (95%CI
2.1 to 10.4%) (Higgins 2018 Level IV SR [PRISMA], 12 studies, n=310,408).
The Australian POINT Study found 18% of community members with CNCP prescribed
opioids met DSM-V ‘opioid use disorder’ criteria, 19% ICD-11 ‘dependence’ criteria, and
24% the ‘addiction’ definition used in pain medicine, with substantial concordance(Campbell 2016 Level IV, n=1,134).

In USA veterans, chronic opioid use is more likely if younger, male, white, married, living inin a rural area, PTSD (OR 1.22; 95%CI 1.2 to 1.25), major depression (OR 1.14; 95%CI 1.12 to1.17), tobacco use disorder (OR 1.18; 95%CI 1.15 to 1.2), back pain (OR 2.50; 95%CI 2.45 to 2.55),
and with increasing pain severity (Hudson 2017 Level IV, n=1,397,946). American patients on higher
opioid doses for musculoskeletal pain are less likely to be working, with greater depression, more
fear-avoidance, decreased pain self-efficacy and greater primary care and pain clinic visits(Morasco 2017 Level III-3, n=517). Depressed patients are twice as likely to transition to long-term
opioid use for CNCP; depression increases risk of abuse or non-medical prescription opioid use(although dose and duration contribute to this risk, duration is more important) ( Sullivan 2018
NR).
These factors are similar to the factors that are associated with SUD. In patients presenting
for surgery, a higher Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R)
score is associated with increased likelihood of preoperative prescribed and illicit opioid use andincreased postoperative surgical site pain (Hah 2015 Level IV, n=107). OUD is more likely in thepresence of psychosocial factors, particular if the person has a genetic predisposition ( Kaye 2017bNR). Past-year “dependence” is increased in younger people and if there is a history of
benzodiazepine dependence (Campbell 2015 Level IV, n=1,424). There is a strong association withpsychiatric illness including mood disorders, antisocial personality disorder and PTSD, and ahistory of SUD (Kaye 2017b NR). In one USA series, of those prescribed opioids long-term, 73.1%
had a comorbid psychiatric diagnosis (Glanz 2019 Level III-2, n=14,898).
In those with chronic pain and history of SUD, pain catastrophising is associated with greater
likelihood of prescription opioid misuse (Morasco 2017 Level III-3, n=517). High-dose opioidprescription also increases the likelihood of self-reported heroin use (adjusted HR 2.54; 95%CI
1.26 to 5.10) in USA veterans, although long-term opioid prescription did not increase this risk
(Banerjee 2019 Level III-2, n=3,570). In Canada, prescription of opioids is a common pathway to OUD
requiring addiction treatment, more commonly in women; those taking this route are older andmore educated with chronic pain a significant association (Sanger 2018 Level III-2, n=976).
Addiction treatment outcomes may be worse in those with pain volatility ( Worley 2015 Level IV,
n=149). There is growing evidence that buprenorphine maintenance therapy may be preferred inthose with combined CNCP and addiction (Berna 2015 NR) (see Section 9.8 below).
Screening for risk of OUD is addressed in Section 9.8.5 below.
Cancer pain
Those with cancer pain exist on a continuum in terms of disease stages, conforming roughly tothree main groups – those undergoing active treatment with curative intent, those undergoing
palliative care/treatment with reduced life expectancy and those in remission.
In a palliative care setting, physician-assessed “chemical coping”, defined as “usingprescribed opioids to control non-nociceptive symptoms”, was found in 18% (95%CI 14 to 21%)and (on multivariate analysis) more likely in patients who were younger, CAGE (“cut-annoyed5th Edition | Acute Pain Management: Scientific Evidence

811

guilty-eye” screening questionnaire for problematic alcohol use) positive, with better function,higher pain and lower wellbeing scores (Kwon 2015 Level IV). There was high prevalence of
positive SOAPP-SF and CAGE in a palliative care clinic, noting approximately one quarter had noevidence of ongoing disease and one quarter had CNCP; there were also positive urine drug
screens in those with cancer and active treatment (56% of the subsample) (Childers 2015 Level IV,
n=323)
With improved oncological treatment, there is a growing population of cancer “survivors”,
defined by the American Cancer Society as survival at least 5 y following a cancer diagnosis. In
this group, CNCP is common and multifactorial due to surgery, radiotherapy, chemotherapy
and incidental causes (Carmona-Bayonas 2017 NR). An integrative review estimated that at least
one in five cancer patients may be at risk of OUD (Carmichael 2016 NR). Cancer survivors are
more likely than the general population to be prescribed long-term benzodiazepines andopioids, with such prescriptions often not conforming to professional guidelines ( Fredheim 2019
Level IV, n=21,426). Particular issues arise in those with co-morbid psychiatric disorders
including an addiction history ( Carmona-Bayonas 2017 NR). Surveys of USA palliative careproviders and hospice social workers found limited systems in place to screen for and manage
OUD in this context (Merlin 2019 Level IV, n=157 [health care professionals]; Sacco 2017 Level IV,
n=107 [US Medicare certified hospices] ).
The American Society of Clinical Oncology practice guidelines recommend a universal
precautions approach to chronic pain in survivors of adult cancers, with regular screening for
pain, multidisciplinary care for complex situations, preference for non-opioids, opioid trials in
selected patients with clear goals and regular risk assessment (Paice 2016 GL [based on SR of
63 studies]).

9.7.4 | Chronic opioid use and perioperative outcomes
9.7.4.1 | Effects on perioperative outcomesA growing body of evidence, primarily in patients undergoing elective orthopaedic and spinal
surgery and primarily retrospectively collected, shows an association between chronic
preoperative opioid use and worse postoperative outcomes. This includes increased likelihoodof 90-d complications (Sing 2016 Level III-2, n=174), revision arthroplasty following primaryarthroplasty (Bedard 2018a Level III-2, n=17,695; Bedard 2018b Level III-2, n=35,894; Weick 2018 Level
III-2, n=324,154; Ben-Ari 2017 Level III-2, n=32,636) and periprosthetic joint infection (Bell 2018 Level
III-2, n=23,754).
In primary knee arthroplasty, preoperative opioid use was associated with poorer outcomes– longer hospital LOS, more additional surgeries for stiffness or pain, more referrals to pain
specialists and worse knee society scores (Zywiel 2011 Level III-2, n=98). In spinal surgery, opioids
increase the risk of 90 d wound complications, readmission and revision spinal fusion ( Jain 2018a
Level III-2, n=29,101; Jain 2018b Level III-2, n=24,610). Likewise, opioid abuse and dependence(defined by ICD-9 codes) are associated with increased aggregate morbidity (OR 2.3; 95%CI 2.2
to 2.4), surgical site infection (OR 2.5; 95%CI 2.0 to 3.0), pneumonia (OR 2.1; 95%CI 1.8 to 3.2)
and prolonged LOS (OR 2.5; 95%CI 2.4 to 2.5) following joint arthroplasty and spinal fusion(Menendez 2015 Level III-2, n=9,307,348). Greater preoperative opioid use is associated with worse
general health, quality of life and disability at 3 and 12 mth following spinal surgery ( Lee 2014
Level III-2, n=583). However, evidence is conflicting, with multivariate analysis of spinal surgery
showing preoperative opioid use not being associated with complications (identified on
retrospective chart review), but only with increased LOS (Armaghani 2016 Level III-2, n=583). On
multivariate analysis, preoperative opioid use is associated with longer LOS, more complications,812

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more readmissions and increased (covariate-adjusted) costs following abdominal and othersurgeries (Gupta 2018a Level III-2, n=16,016,842; Cron 2017 Level III-2, n=2,413; Waljee 2017 Level III-2,
n=200,005).
Chronic opioids may also suppress the hypothalamic-pituitary-adrenal axis. As many as one
in five patients on chronic opioids may have low cortisol levels, although is not clear which
patients should be screened (Demarest 2015 NR). This led the US Food and Drug Administration(FDA) in 2013 to issue a warning to be added to all opioid labelling ( FDA 2013 GL). Addisoniancrises have been described in some postoperative patients ( Fountas 2018 NR). Although theprevalence is unknown, the implications for perioperative care include investigation should
patients present with symptoms and signs suggesting adrenal insufficiency.
9.7.4.2 | Strategies for outcome improvement
Preoperative opioid use may be a modifiable risk factor for perioperative outcomes. There islimited low quality evidence that ceasing opioids preoperatively may ameliorate perioperativerisk (Jain 2018a III-2, n=29,101; Nguyen 2016 Level III-2, n=177).
Opioid tapering should be considered prior to elective surgery, although there is limited
evidence as to the best strategy in terms of efficacy and safety ( Eccleston 2017 Level I [Cochrane],
5 RCTs, n=278; Berna 2015 GL). Whatever strategy is used, it should consider patient-centred
barriers (fear of withdrawal and that nonopioids might be ineffective) and facilitators (social
support and a trusted practitioner) along with reassurance about long-term benefits (including
improved pain and quality of life) (Goesling 2019 Level IV, n=49; Frank 2016 Level IV, n=24).
Expert advice is for shared decision making, reduction by 5 to 20% every 4 wk (Pergolizzi 2018GL), and support for self-efficacy, resilience and alternative pain management strategies(McAnally 2017 GL). The USA Department of Veterans Affairs has developed an opioid tapering
tool (U.S. Department of Veterans Affairs 2016 GL). Alpha-2 agonists such as clonidine are effective
for withdrawal symptoms, although have side effects including hypotension ( Gowing 2014 Level I[Cochrane], 25 RCTs, n=1,668).
In opioid-tolerant patients, improved compliance with enhanced recovery after surgery(ERAS) protocols may mitigate the impact of opioid tolerance on postoperative complications(Owodunni 2019 Level III-2, n=646). ERAS may provide a framework to reduce the risk of ongoing
opioid use; it is multidisciplinary, patient-centred, includes multimodal analgesia (which
decreases opioid reliance), includes site-specific regional analgesia, promotes morecomprehensive preoperative assessment, and has formalised pathways for community
transition; it is a logical extension for ERAS to guide use of post discharge opioids including
tapering and follow-up (Stone 2017 NR).

9.7.5 | Chronic opioid use and sleep-disordered breathing
Opioids can affect ventilatory function via decreases in central respiratory drive, level ofconsciousness and upper airway tone causing opioid-induced ventilatory impairment (OIVI)(Macintyre 2011 NR).
Long-term opioid use is a risk factor for sleep-disordered breathing (SDB) (prevalence in thispopulation 24%) (Correa 2015 Level III-3 SR, 8 studies, n=560); SDB (in particular central sleep
apnoea) is strongly associated with morphine equivalent daily dose (high risk >200 mg MED/d)with body mass index inversely related to the severity of SDB. A study not included in thissystematic review has similar findings (Rose 2014 Level IV, n=24); severe SDB (again mainly central
sleep apnoea) was found in 46 % of patients on opioids in a dose-dependent fashion and of these
45% had daytime hypercapnia, indicating chronic respiratory failure.
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In patients undergoing methadone-maintenance treatment, SDB was common (35.2% OSA
and 14.1% central sleep apnoea), but not related to methadone dose and subjective sleep
complaints (Sharkey 2010 Level IV, n=71). Patients on methadone-maintenance programs weremore likely to have sleep abnormalities, especially central sleep apnoea, than were matched
controls, although the effect was confounded by greater use of benzodiazepines in themethadone group (Teichtahl 2001 Level III-2, n=19).
Particular care should be taken when the total opioid dose is rapidly escalated above theusual dose and when other sedative agents are coadministered ( Macintyre 2011 NR).
See also Section 9.4 above.

9.7.6 | Assessment and management of acute pain
A number of articles, chapters and a book (Bryson 2012a NR) have been published outlining
suggested strategies for the assessment and management of acute pain in the patient taking
long-term opioids for chronic pain or because they have a SUD, perhaps treated in a drug
treatment program. These focus on postoperative (Coluzzi 2017 NR; Simpson 2017 NR; Buckley 2014
NR; Tumber 2014 NR; Eyler 2013 NR; De Pinto 2012 NR; Geary 2012 NR; Quinlan 2012 NR; Schug 2012 NR;
Huxtable 2011 NR) and post-traumatic pain (Karamchandani 2019 NR).

Evidence for the most appropriate assessment and management in these patients is very
limited and the advice given in these papers remains based primarily on case series, case reports,
expert opinion and personal experience. Opioid-tolerant patients are heterogeneous and thus
difficult to study, and thus are often excluded from studies of acute pain management. The past
few years have seen a growing number of RCTs in opioid-tolerant patients or inclusion of thesepatients in broader studies, often after spinal or orthopaedic surgery. However, details of the
opioid tolerance and pre-existing pain are sometimes not well described. In general, assessmentand management of these patients should focus on:• Coordinated care that includes an interdisciplinary approach and liaison with othertreating health professionals and specialist teams, as required,• Effective analgesia;• Use of strategies that may attenuate tolerance or OIH;
• Prevention of withdrawal;• Appropriate discharge planning to ensure continuity of long-term care.
9.7.6.1 | Models of care and clinical pathways
Given that opioid-tolerant patients may present complex assessment and management
challenges, there is an international trend towards improved perioperative coordination of carewith interdisciplinary input. This aims to provide patient-centred care, robust preoperative risk
stratification, planning, optimisation and consent, reduced practice variability and care
continuity, including bidirectionally in transition from hospital to the community. These models
promote safe opioid management that conforms to professional guidelines, by identifying thoseat risk, offering tapering strategies, ensuring ongoing follow-up, and promoting coordination andcommunication with other providers.
One such integrated model of care is the Perioperative Surgical Home, which has been
extensively discussed in the literature (Kaye 2017a NR) and might be of particular value in thesetting of high risk patients including the opioid-tolerant patient (Pozek 2017 NR). Other models
have been described which involve pain medicine physicians (and others) early in the
preoperative and then the postoperative phase; these are either described as a Transitional Pain
Service (Huang 2015 NR; Katz 2015a NR) or an Acute Pain Outpatient Service (Tiippana 2016 Level IV,
n=200). There are limited data supporting successful opioid reduction by such services ( Huang814

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2016 Level IV, n=51; Tiippana 2016 Level IV, n=200). There is the suggestion that such services could
become an integrated part of the Perioperative Surgical Home (Vetter 2017 NR).

“Ambulatory pain physicians” based in ambulatory surgical centres could be anotherapproach (Vadivelu 2016a NR), in particular as the management of opioid-tolerant patients in thissetting is often even more complex (Vadivelu 2017 NR).
Interdisciplinary management of patients with aberrant opioid-related behaviour has beensuccessfully implemented in the palliative care setting (Arthur 2018 Level IV, n=30). Peer-reviewed
clinical pathways including standardised postoperative analgesia orders for opioid-tolerant
patients developed with multidisciplinary input improved pain management and PACU discharge
readiness (Naqib 2018 Level III-3, n=169). A Safer Opioid Prescribing Protocol (SOPP) introduced inan electronic medical record at a level 1 trauma centre improved prescribing of non-opioids andreduced high-dose opioid prescribing (Baird 2019 Level III-3, n=507).
9.7.6.2 | Assessment
Assessment using unidimensional measures is frequently inadequate, in particular in thesecomplex patients (Radnovich 2014 NR; Gandhi 2011 NR). The need for multidimensional assessment
is recognised in the ACTTION-APS-AAPM pain taxonomy which uses five dimensions (corecriteria, common features, modulating factors, impact/functional consequences, putative
pathophysiologic pain mechanisms) to better describe pain complexity ( Kent 2017 GL). The USA
is abandoning pain scores and pain as “the fifth vital sign”, as an unintended consequence has
been excess opioid administration to chase pain scores (viewed as a contributor to the opioid
epidemic). This has been exacerbated by the direct link between pain self-report andreimbursement; the Hospital Consumer Assessment of Healthcare Providers and Systems(HCAHPS) survey uses pain scores as a surrogate measure of care quality. Treating
unidimensional scores may lead to increased adverse events like oversedation and should be
avoided (Levy 2019 NR). This is in particular true in the setting of opioid-tolerance and chronic
pain (Allen 2014 NR).
Other considerations in acute pain assessment in opioid-tolerant patients include:• Psychological and social, as well as biological, triggers for pain deterioration in thosewith chronic pain should be identified (Quinlan 2012 NR);
• Specific factors that should be sought in all opioid-tolerant patients, those with chronic
pain and those with SUD (see Table 9.9) (Huxtable 2011 NR);
• Practitioners determining the need for elective procedures (eg surgeons, physicians,
radiologists) or for labour analgesia planning (obstetricians, general practitioners)
should refer patients early for pain management planning and optimisation (Tumber
2014 NR);• Previous records should be reviewed and information about prior experiences of acutepain management should be sought to avoid or optimise strategies that were ineffective
and to replicate those that were effective (Tumber 2014 NR);• Meaningful engagement of the patient and their family or other caregivers (Geary2012 NR), is key to assessment, management and adherence to the proposed plan (Haber2009 NR) through expectation management, addressing concerns and education;• Communication should involve engagement, empathising, educating, enlisting and end
by summarising, reviewing and indicating next steps (Jamison 2011 NR).

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Table 9.9 | Pain-related assessment in opioid-tolerant patient
Information from all
opioid-tolerant patients

Additional information inpatients with CNCP or cancer
pain

Additional information inpatients with a substanceuse disorder

Current treatment
providersPain diagnosis

Opioid substitution
therapies and doses(methadone,
buprenorphine)

Opioid and nonopioid
medications

Usual pain scores

Other prescribed ordiverted prescription
medicine or illicit substanceuse (polyabuse is common)

Dose verification of all
relevant medications

Functional status

Routes of administration

Nonprescribed drugs (egover-the-counter and illicit
drugs, alcohol, nicotine)

Prognosis (cancer pain)

Where relevant, registeredprescriber and dispensing
pharmacy

Drug allergies andreactions

Psychospiritual issues(including end-of-life issues,
anxiety, depression, coping
style and strategies)

Medical and psychiatriccomorbidities (eg bloodborne viruses, hepaticdisease, other infections,chronic pain, personality
disorder)Experiences andexpectations of acute pain
management including
goals of care

Where relevant, the authorizedprescriber of any opioids

Concerns about opioids(especially for those inremission)

Support systems after
discharge

Presence of invasive pain
treatment (eg IT pump, spinal
cord stimulator)
Medication misuse, evidence ofaberrant drug-related
behaviour or SUD
Expectations about theiradmission (eg expectation thatchronic back pain will be
improved after spinal surgery;palliative vs curative surgery inpatients with cancer)

Source: From Huxtable 2011; reproduced with permission and modified.

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9.7.6.3 | Effective analgesia
Even more than in other patients, the basis for successful pain management in opioid-tolerant
patients must be the utilisation of multimodal and interdisciplinary analgesia strategies ( Schug2012 NR; Huxtable 2011 NR). However, opioids will often be needed and then require additional
considerations.
Opioids
It is known that opioid use is usually significantly higher in opioid-tolerant vs opioid-naïve
patients and that the interpatient variation in the doses needed is even greater. After a variety
of surgical procedures, opioid-tolerant patients using PCA (Rapp 1995 Level III-2, n=3,508) or
epidural analgesia (de Leon-Casasola 1993 Level III-2, n=116) require approximately three times thedose (on average with large standard deviations) vs their opioid-naïve counterparts. The
increased acute opioid dosing required to address tolerance continues to be under-recognised.
Opioid-tolerant patients with cancer (78% with metastatic disease) presenting acutely to an
emergency department were frequently under-dosed, due primarily to “standard dose”
administration failing to account for their opioid tolerance (Patel 2017 Level IV, n=216). Uptake ofexpert opinion about managing opioid-tolerant patients for ambulatory surgery is poor, with
only 37% taking their usual long-acting opioid on day of surgery and many not receiving
recommended non-opioids and adjuvants (Wilson 2015 Level IV, n=148).
Opioid-tolerant patients reported higher pain scores (both resting and dynamic) andremained under the care of an APS longer than other patients (Rapp 1995 Level III-2, n=3,508).
Compared with opioid-tolerant patients with cancer pain, opioid-tolerant patients with
noncancer pain had higher rest and dynamic pain scores and required longer APS input but there
was no difference in opioid requirements (Rapp 1995 Level III-2, n=3,508). In addition, staff reliedmore on functional measures of pain than on pain scores to assess pain intensity in these patients(Rapp 1994 Level IV, n=482 [health care professionals] ). Their postoperative pain is initially more
intense and needs therefore more time to resolve than that in opioid-naïve patients (Chapman2009 Level III-2, n=138).
The incidence of opioid-induced nausea and vomiting may be lower in opioid-tolerant
patients, although the risk of excessive sedation/OIVI may be higher ( Rapp 1995 Level III-2,
n=3,508) and may be particularly likely if opioid doses are rapidly escalated above the baseline
level (Huxtable 2011 NR).
Where possible, oral or sublingual opioids should be used in preference to parenteral opioids(Donroe 2016 NR). IV PCA is a useful modality for pain relief in a subset of opioid-tolerant patients,
including those with a SUD, provided that pain intensity and opioid consumption are carefully
monitored and background requirements are provided if the patient cannot take their usual
opioid; larger bolus doses will often be needed (Macintyre 2015 NR; Huxtable 2011 NR; Mitra 2004
NR). The size of an appropriate dose (on an individual patient basis) has been calculated by one
group of investigators by using a preoperative fentanyl infusion until the patient’s respiratory
rate was <5/min; pharmacokinetic simulations were then used to predict the size of the PCA
bolus dose and the rate of a background infusion that would be required for postoperative
analgesia (Davis 2005 Level IV PK). It may also be based on the dose of opioid the patient is alreadytaking (Macintyre 2015 NR; Hadi 2006 NR). Regardless of the initial dose prescribed, subsequent
doses will need to be titrated to effect for each patient, bearing in mind realistic expectations
about pain control and optimisation of non-opioid and non-pharmacological strategies. Caution
should also be exercised as high opioid use may result in OIH (see section above).
Neuraxial opioids have been used effectively in opioid-tolerant patients, although higher
doses may be required without increasing adverse effects (de Leon-Casasola 1993 Level III-2).
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Effective analgesia using IT or epidural opioids will not necessarily prevent opioid withdrawal(Huxtable 2011 NR; Carroll 2004 NR).
Nonpharmacological strategies
Behavioural and cognitive techniques may minimise anxiety and reduce catastrophising, andphysical techniques should also be considered (Tumber 2014 NR); however, there is limited
evidence for their effectiveness in opioid-tolerant patients in acute pain settings
9.7.6.4 | Attenuation of tolerance and opioid-induced hyperalgesia
A number of strategies may attenuate opioid tolerance and OIH. These include:• NMDA-receptor antagonists• opioid-receptor antagonists;• opioid rotation;• other adjuvant medicines.
NMDA-receptor antagonists
As noted in Section 4.6, the NMDA receptor is involved in tolerance and OIH development ( Chang2007 NR). In rodents, the NMDA-receptor antagonist ketamine attenuates both the developmentof tolerance (Laulin 2002 BS; Shimoyama 1996 BS) and OIH (Van Elstraete 2011 BS; Minville 2010 BS;
Haugan 2008 BS; Laulin 2002 BS).
NMDA-receptor antagonists (mainly ketamine [8 RCTs], but also magnesium [5 RCTs] andamantadine [1 RCT]) reduce the development of acute tolerance/OIH associated withremifentanil use (Wu 2015 Level I [QUOROM], 14 RCTs, n=729). This statement is based on reduced
postoperative pain scores and opioid requirements and increased time to first analgesic request
and satisfaction scores in the NMDA-receptor antagonist vs placebo groups.
After spinal surgery in opioid-tolerant patients, perioperative ketamine resulted insignificantly less pain but did not reduce PCA opioid use (Urban 2008 Level II, n=26, JS 3) andreduced opioid requirements and pain scores in the early postoperative period and at 6 wks(Loftus 2010 Level II, n=101, JS 4). For multilevel spinal fusion, ketamine decreased PCA
hydromorphone use in opioid-tolerant but not opioid-naïve patients, with the effect primarily
from 16 h postoperatively (Boenigk 2019 Level II, n=129, JS 5). Intraoperative S-ketamine in opioidtolerant patients undergoing spinal surgery resulted in reduced PCA morphine use at 24 h (MD 42 mg; 95%CI -59 to -25) with reduced sedation and without increasing other adverse effects.
Furthermore, at 6 mth there was improved back pain, longer walking distance and less disability(Nielsen 2017a Level II, n=150, JS 5). This beneficial effect was maintained at 1 y with lower opioiduse, lower dynamic pain scores, greater likelihood of working and lower disability scores (Nielsen
2019 Level II, n=147, JS 5).
After noncancer general surgery in a similar patient group, a postoperative ketamine infusion
at 0.2 mg/kg/h decreased average pain scores (13.5% decrease vs 15.5% increase) but not opioiduse (Barreveld 2013 Level II, n=64, JS 4).
Consensus guidelines for the use of ketamine infusions in acute pain support its use for
opioid-dependent or opioid-tolerant patients undergoing surgery to limit opioid use (Schwenk
2018 GL).

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Opioid receptor antagonists (low dose)
In rodents, ultra-low dose naloxone has been shown to attenuate opioid tolerance ( Wang 2005
BS; Crain 2000 BS; Crain 1995 BS) and remifentanil-induced OIH (Aguado 2013 BS).
In the experimental pain setting in healthy volunteers, the coadministration of ultra-low
doses of naloxone (La Vincente 2008 EH) or naltrexone (Hay 2011 Level II EH, n=10, JS 5) tobuprenorphine significantly increased tolerance to cold-pressor pain.
Clinical studies have concentrated on the concurrent use of naloxone and an opioid given
acutely, with conflicting results; improved postoperative pain and reduced opioid use as well as
no differences in either have been reported (Angst 2006 NR; Sloan 2006 NR). The use of low-dose
naloxone added to postoperative opioid analgesia (most commonly by PCA) decreases the riskof pruritus (OR 0.40; 95%CI 0.21 to 0.79) and nausea (OR 0.62; 95%CI 0.43 to 0.89), but not
vomiting, pain intensity or opioid use (Murphy 2011 Level I, 8 RCTs, n=800). Use over 3 mth of a
combination of oxycodone/ultra-low-dose naltrexone in patients with chronic pain vs oxycodone
alone, showed that those given the combination had similar pain relief but with 12% lower daily
oxycodone use, as well as less constipation, sedation, pruritus and physical dependence asassessed by a withdrawal scale (Webster 2006 Level II, n=719, JS 4). Low-dose naloxone(0.25 mcg/kg/h intraoperatively) also reduced postoperative opioid use when combined withhigh dose remifentanil (and improved time to bowel recovery) ( Xiao 2015 Level II, n=75, JS 5).
Opioid rotation
Opioid rotation (also called “switching”) is commonly used in the treatment of chronic noncancer
and cancer pain when a change to another opioid can improve analgesia and reduce adverse
effects (Mercadante 2012 Level IV; Nalamachu 2012 NR). Opioid rotation (eg using an opioid that isdifferent from the preadmission opioid) may also be useful in the acute pain setting ( Huxtable2011 NR; Hadi 2006 NR). The underlying rationale is that different opioids do not act to the same
degree on various opioid receptor subtypes, are metabolised differently, that cross-tolerance islikely to be incomplete (Huxtable 2011 NR; Mitra 2008 NR; Jage 2005 NR) and that the degree of OIH
and tolerance appears to vary between opioids (see Section 4.3.1).
Adjuvants
Adjuvants are primarily used for their antitolerance, antiallodynic and antihyperalgesic effects(Huxtable 2011 NR).
In rats, intraoperative use of paracetamol, metamizol, ketoprofen and parecoxib abolishedacute tolerance caused by remifentanil infusion (Benito 2010 BS). In an experimental pain setting
using intradermal electrical pain stimuli, parecoxib given before but not during a remifentanil
infusion modulated the hyperalgesia after withdrawal of remifentanil ( Troster 2006 Level II EH,
n=15, JS 5).
Gabapentin has also been shown to attenuate opioid tolerance (Aguado 2012 BS; Lin 2005 BS)
and OIH (Wei 2012 BS) in rats and this effect was synergistic to ketamine ( Van Elstraete 2011 BS).
Pregabalin shows similar effects in animal models (Lyndon 2017 BS; Hasanein 2014 BS). In
methadone-maintained patients, gabapentin increased cold-pressor pain threshold and pain
tolerance (Compton 2010, Level II EH, n=26, JS 2). In the setting of OIH associated with remifentanil,
150–300 mg pregabalin preoperatively attenuated this effect after hysterectomy (Jo 2011 Level II,
n=60, JS 5) and laparoscopic urological surgery (Lee 2013b Level II, n=93, JS 5).
Other adjuvants that may influence tolerance and OIH but for which there is limited evidence
include alpha-2 agonists (clonidine and dexmedetomidine), buprenorphine ( Lee 2011 NR;
Ramasubbu 2011 NR; Patch III 2017 CR) and systemic lidocaine (Eipe 2016 NR). OIH /tolerance after
remifentanil use was also reduced by propofol ( 6 RCTs, n=341) (Fletcher 2014 Level I [PRISMA],
27 RCTs, n=1,494) and N2O (Wehrfritz 2016 Level II EH, n=21, JS 5; Echevarria 2011 Level II, n=50, JS 4).

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Use of regional analgesia techniques to manage the early postoperative pain of total knee
joint replacement did not reduce longer-term opioid use (1 y postop) in the overall population
nor after stratification into opioid naïve patients, intermittent opioid users and chronic opioid
users (Sun 2017 Level IV, n=120,080).
9.7.6.5 | Prevention of withdrawal
Withdrawal from opioids is characterised by excitatory and autonomic symptoms including
abdominal cramping, muscle aches and pain, insomnia, dysphoria, anxiety, restlessness, nausea
and vomiting, diarrhoea, rhinorrhoea and sneezing, trembling, yawning, watery eyes (epiphora)and piloerection (or “gooseflesh”) (Rehni 2013 NR; Tetrault 2008 NR). Withdrawal-associated injury
site pain (WISP), a temporary reactivation of pain at an old injury site that was pain-free prior to
opioid initiation, has also been described (Rieb 2016 Level IV, n=47). The time of onset ofwithdrawal symptoms after cessation of the drug will depend on the duration of action of the
opioid. To assess withdrawal, the use of validated withdrawal tools (Clinical Opioid Withdrawal
Scale, Subjective Opioid Withdrawal Scale, Objective Opioid Withdrawal Scale) is recommended(Donroe 2016 NR) (See also Section 10.4.6.2 in children).
Withdrawal should be prevented by maintenance of normal preadmission opioid regimens(including on the day of surgery) or appropriate substitutions with another opioid or the same
opioid via another route (Macintyre 2015 NR; Schug 2012 NR; Huxtable 2011 NR). It may be of benefit
to check preadmission opioid doses with the patient’s doctor or pharmacist; the use ofunauthorised additional opioids (licit or illicit) or of lower doses than prescribed may affect bothpain relief and the risk of adverse effects.
While multimodal analgesic regimens (eg NSAIDs, paracetamol, ketamine, tramadol, regional
analgesia) are of analgesic benefit (Rajpal 2010 Level III-3), opioid-tolerant patients are at risk of
opioid withdrawal if a purely nonopioid analgesic regimen or atypical opioids with low mureceptor effects such as tramadol or tapentadol are used (Macintyre 2015 NR; Huxtable 2011 NR).
For this reason, opioid antagonists (naloxone, naltrexone) should be avoided as their use canprecipitate acute withdrawal reactions (Schug 2012 NR; Alford 2006 NR).
Alpha-2 agonists such as clonidine and lofexidine are more effective than placebo in the
management of opioid-withdrawal symptoms (Gowing 2014 Level I [Cochrane], 25 RCTs, n=1,668).
During a 10-d buprenorphine detoxification procedure, gabapentin reduced opioid use vsplacebo (Sanders 2013 Level II, n=30, JS 5) and in a dose of 1,600 mg/d reduced withdrawal symptoms
in patients during methadone-assisted detoxification (Salehi 2011 Level III-1). Pregabalin attenuatednaloxone-induced withdrawal symptoms in opioid-tolerant rats (Hasanein 2014 BS) and has also
been used successfully to attenuate withdrawal symptoms from a number of drugs including
alcohol and benzodiazepines, although data on opioid withdrawal are limited (Freynhagen 2016 NR).
Pregabalin added to methadone in maintenance program patients reduced methadone
requirements and withdrawal symptoms vs placebo (Moghadam 2013 Level II, n=60, JS 5).
9.7.6.6 | Discharge planning and transition to community care
Discharge planning for opioid-tolerant patients is optimally commenced prior to admission andmust consider any regulatory requirements (eg the authority to prescribe an opioid may have tobe delegated to a particular physician only), the duration of use of any additional opioids
prescribed for short-term acute pain management and the weaning of those drugs and, in somepatients, the potential for prescribed opioids to be abused, misused or diverted. Without robust
discharge systems, there is a significant risk of unintended opioid dose escalation with attendantrisks (Quinlan 2012 NR; Schug 2012 NR; Huxtable 2011 NR).

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Preoperative opioid use, especially at higher dose, is a significant risk factor for ongoing
postoperative opioid prescription, even in circumstances where long-term prescription is notindicated (Dunn 2018 Level III-2, n=1,477; Goesling 2016 Level III-2, n=574). This was confirmed in an
Australian population after total hip replacement, where longer preoperative opioid use
increased the risk of persistent chronic use (opioid use for 157 to 224 d vs 94 to 157 d [OR=3.75;
95%CI 2.28 to 6.18] and >225 d [OR 5.18; 95%CI 2.92 to 9.19]) ( Inacio 2016 Level IV, n=8,925).
Similar findings are reported after spinal surgery, where preoperative opioid use increased therisk of prolonged postoperative requirements (OR 4.71; 95%CI 3.11-7.13) (Reid 2019 Level III-3,
n=552). Opioid use in the year prior to elective colorectal surgery was the only risk factor for postdischarge opioid use within 1 y (Scow 2019 Level IV, n=367). After minor upper limb surgery (carpal
tunnel release, trigger finger release, cubital tunnel release, and thumb carpometacarpal
arthroplasty) 59% of patients filled an opioid prescription; patients preoperatively on opioids vsnot on opioids filled more postoperative opioid prescriptions (66 % vs 59 %), were given longerlasting prescriptions (24 d vs 5 d), received more refills (24 % vs 5 %) and 19 % vs 6% had at least
one indicator of potentially inappropriate prescribing (Waljee 2016 Level IV, n= 296,452).
A “reverse analgesic ladder” approach is recommended, with the aim being stepwise returnof the patient to their usual opioid regimen (Huxtable 2011 NR). Considerations include the likely
duration of acute pain (and thus the amount of opioid that should be prescribed), the choice of
opioid and its “abuse liability”, and the use of nonopioid agents. In this context it is of note that
postoperative pain resolved more slowly in opioid-tolerant than that in opioid-naïve patients(Chapman 2009 Level III-2).Appropriate use of nonopioid analgesics where possible, use of abusedeterrent formulations, provision of small quantities and staged pharmacy supply,
communication with the primary physician and other treating health care professionals(including a plan for cessation), and patient education and support must all be considered.
An ethical dilemma arises where the preadmission opioid regimen is not consistent withwidely accepted professional guidelines for opioid prescription in chronic pain or SUD (Dowell2016 GL; FPMANZCA 2015 GL). In these cases, and/or when there is a high risk of opioid misuse,referral to a pain specialist and/or an addiction service should be considered (Huxtable 2011 NR).
The USA CDC guidelines, although criticised, offer some good principles for opioidprescribing, which might be useful in the setting of discharging opioid-tolerant patients after anacute pain episode (Dowell 2016 GL):
• Preference for non-drug and non-opioid therapy;• Defined goals including when opioids would be discontinued;• Risks discussed at baseline and periodically;• Immediate-release instead of slow-release opioids;• Lowest effective dose – reassess at 50mg OME, avoid greater than 90 mg OME;• For acute pain, lowest effective dose of IR for shortest duration;• Reassess benefits and harms early and frequently;• Evaluate risk of opioid-related harms before and episodically;• Avoid concurrent benzodiazepines;• If OUD, offer evidence-based treatment for this (see Section 9.8 below).
The Australian NPS MedicineWise program (NPS MedicineWise 2019 GL) recommends referral
to an addiction or pain medicine specialist if the patient:• is taking two or more psychoactive drugs in combination;• is taking opioids and benzodiazepines;• has serious psychiatric illness;• mixes pharmaceutical and illicit drug intake;• has been discharged from a general practitioner for problematic behaviour;
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•
•

was recently discharged from a correctional service;shows evidence of high-risk behaviours.

For more details on opioid use and discharge medication see Sections 9.8., 8.13. and 10.4.5.

KEY MESSAGES
1. Alpha-2 agonists (clonidine and lofexidine) reduce opioid-withdrawal symptoms (U)(Level I [Cochrane Review]).
2. Remifentanil use leads to opioid-induced hyperalgesia (U), which is attenuated bypropofol (U) (Level I [PRISMA]), NMDA-receptor antagonists (U) (Level I [QUOROM]),
pregabalin (U) (Level II), nitrous oxide (N) (Level II) and gradual tapering of remifentanil
dose (N) (Level II).
3. Gabapentin and pregabalin attenuate opioid-induced hyperalgesia/tolerance and reduce
opioid-withdrawal symptoms (U) (Level II).
4. In opioid-tolerant patients, ketamine improves pain relief after surgery and reduces
opioid requirements (S) (Level II).
5. Long-term opioid use is a dose-dependent risk factor for sleep-disordered breathing,which requires appropriate perioperative assessment, monitoring and management (S)(Level III-2 SR).
6. Long-term opioid use is associated with dose-dependent increased risks of injuries (N)(Level III-2) including fractures (N) (Level III-2 SR) and overdose (N) (Level III-2).
7. Preoperative opioid use is associated with worse outcomes after a variety of operations(N) (Level III-2).
8. Preoperative opioid tapering may ameliorate the risk of postoperative complications andmorbidity (N) (Level III-2)
9. Preoperative opioid use is a risk factor for prolonged postoperative opioid use (N)(Level III-2).
10. Opioid-tolerant patients report higher pain scores, have slower pain resolution leading tolonger hospital stay and increased readmissions but have a lower incidence of opioidinduced nausea and vomiting (U) (Level III-2).
11. Opioid-tolerant patients may have significantly higher opioid requirements andinterpatient variation in the doses needed than opioid-naïve patients (U) (Level III-2).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Usual preadmission opioid regimens should be maintained where possible orappropriate substitutions made (S).
 Liaison with all health care professionals involved in the treatment of the opioidtolerant patient is important (S).
 Opioid-tolerant patients are at risk of opioid withdrawal if nonopioid analgesic
regimens, tramadol or tapentadol alone are used (U).

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5th Edition | Acute Pain Management: Scientific Evidence9.0 | OTHER SPECIFIC PATIENT GROUPS PCA settings may need to include a background infusion or other background opioid toreplace the usual opioid dose and a higher bolus dose (U).
 Neuraxial opioids can be used effectively in opioid-tolerant patients, although higher
doses may be required and these doses may be inadequate to prevent withdrawal (U).
 Adjuvants are used for their antitolerance, antihyperalgesic, and antiallodynic effects
and there is some evidence upon which to base the choice of agent (S).
 In patients with escalating opioid requirements, management considerations are thedevelopment of tolerance or opioid-induced hyperalgesia (S).
 Following short-term opioid dose escalation for acute pain, a “reverse analgesic
ladder” approach, using stepwise reduction to the patient’s usual opioid regimen isrecommended (S).
 For assessment of withdrawal reactions, the use of a validated withdrawal tool in
opioid-tolerant patients is recommended; management strategies vary and include
weaning, rotation and adjuvant use (N).

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9.8 | The patient with a substance use disorder
The information in this chapter overlaps with that in section 9.7 above and readers are referredto that section for information on definitions, implications of tolerance and opioid-induced
hyperalgesia (OIH), overlap between chronic pain (non-cancer and cancer-related) andsubstance use disorders, impact of opioids on perioperative outcomes, and assessment andmanagement of acute pain including models of care, clinical pathways and discharge planning.
Terminology
Whilst “addiction” was recommended in the consensus statement from the American Academyof Pain Medicine, the American Pain Society and the American Society of Addiction Medicine(AAPM 2001 GL; Ballantyne 2007 NR), more recently the use of the term “substance use disorder”(SUD) has been recommended by DSM-5 (American Psychiatric Association 2013a GL) and by ICD-11(WHO 2018 GL).
For patients taking drugs that induce tolerance and physical dependence long-term, it isimportant to separate out these expected physiological phenomena (albeit potentially withpsychological components in the case of “dependence”). This reduces the potential forstigmatisation of those who have physical dependence and tolerance (Ballantyne 2007 NR).
Problematic use in the setting of chronic pain is defined by the IMMPACT ACTTION consensus
panels in terms of misuse, abuse and addiction (see Section 9.7.1 above)
A SUD exists when the extent and pattern of substance use interferes with the psychologicaland sociocultural integrity of the person (see Table 9.7). For example, there may be recurring
problems with social and personal interactions or with the legal system, recurrent failures tofulfil work or family obligations, and these patients may put themselves or others at risk of harm(Haber 2009 NR).
The artificial divide between “good and bad drugs” is being eroded as there has been increasing
misuse and abuse of legally prescribed drugs (notably prescription opioids) and drugs that wereformally illegal have been legalised for therapeutic use (notably cannabinoids) (Nielsen 2017b NR).
Although cannabis, cocaine and amphetamines are more widely abused, opioids contribute to 82%
of fatal overdoses worldwide (UNODC 2016 Level IV)
Centres in many countries regularly monitor the use of illicit drugs, including prescription
opioids and permit identification of current trends in drugs abused/misused. These include:• internationally, the World Health Organization through the International Narcotics
Control Board (https://www.incb.org) (INCB 2019);• in
Australia,
the
National
DrugandAlcohol
Research
Centre(https://ndarc.med.unsw.edu.au) (Roxburgh 2018 Level IV), the annual overdose reportfrom the Pennington Institute based on Australian Bureau of Statistics data ( Penington
Institute 2019 Level IV) and the annual pharmacotherapy statistics from the AustralianInstitute of Health and Welfare (https://www.aihw.gov.au) (AIHW 2019a Level IV);• in New Zealand, the Centre for Social and Health Outcomes Research and Evaluation(https://shoreandwhariki.ac.nz/shore/) (SHORE 2014 Level IV);• in the UK, the surveillance systems set up by the National Health Service under NHS
Digital (https://digital.nhs.uk) which includes regular reports on drug misuse statistics;• in the USA, the Substance Abuse and Mental Health Services of the US Department of
Health and Human Services (https://www.samhsa.gov) (SAMHSA 2019), National
Institute on Drug Abuse, and other schemes specifically tracking prescription opioid
abuse, such as Researched Abuse, Diversion and Addiction-Related Surveillance(RADARS) (https://www.radars.org) (Murphy 2018 Level IV);824

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in Canada, the Canadian Institute for Health Information (CIHI) (https://www.cihi.ca/en)
includes reporting on opioid prescription and related harms, and other substance use.

Pain management goals
Effective management of acute pain in patients with a SUD may be complex due to:• psychological, social and behavioural characteristics associated with the disorder;
noting that SUD is more common in those with comorbid psychiatric illness ( Vietri 2014
Level IV, n=1,242; Webster 2017 NR);• presence of the drug (or drugs) of abuse including intoxication or acute withdrawal
syndromes;• medications used to assist with drug withdrawal, relapse prevention and rehabilitation;• complications of drug abuse including organ impairment, infectious diseases andincreased risk of traumatic injury and other drug-related presentations; and• the presence of tolerance and physical dependence which are expected physiologicalresponses to chronic use of some substances.
Impact on outcomes
SUD can impact perioperative outcomes, implying that some patients will require deferral for
optimisation prior to elective procedures (eg referral for substance use and chronic pain
management). In elective spinal fusion, opioid dependence (ICD-9) prolonged LOS (adj OR 2.11;
95%CI 1.78 to 2.49), increased costs, resulted in higher infection rates, higher anaemia, andhigher pulmonary insufficiency and this has implications for pain management and consent ( Tank
2018 Level III-2, n=1,826,868).
Trauma outcomes are impacted by the types of substances abused, with increased mortality inthose concurrently using benzodiazepines and opioids (Cheng 2016 Level III-2, n=10,166).
Unaddressed opioid use disorder (OUD) and subsequent undertreatment of pain leads topremature discharge, worse medical outcomes, readmission, relapse and overdose (Ward 2018 NR).
For impact of chronic opioid use on outcomes see Section 9.7.4 above.

9.8.1 | CNS-depressant drugs
Although not inevitable, abuse of CNS-depressant drugs (eg opioids, alcohol, benzodiazepines)
is often associated with physical dependence and tolerance (see Section 9.7 above). Withdrawal
from CNS-depressant drugs produces symptoms of CNS and autonomic hyperexcitability, theopposite of the effects of the drugs themselves (Quinlan 2017 NR).
9.8.1.1 | Opioids including prescription opioids
Acute pain in those with an opioid use disorder (OUD) should be treated using the strategies
outlined in Section 9.7 above and in the remainder of this section.
United States of America
In the USA, the Centre for Disease Control (CDC) has labelled the current trends in opioid use an“opioid epidemic”, as reflected in rising prescription and other opioid use, and related harms.
The CDC Opioids Portal (https://www.cdc.gov/opioids/strategy.html) describes three “waves” inthis epidemic from the 1990s a rise in use of prescription opioids, from 2010 of heroin and from2013 of synthetic opioids, especially illicitly-manufactured fentanyl.
From 2002 to 2010, there were large increases in overall opioid prescriptions, followed by aslight decrease from 2011 to 2013; diversion and abuse showed large increases from 2002 to
2010, then a plateau or decline; and there have been similar patterns for opioid-related deaths
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(Dart 2015 Level IV). The 2015 US National Survey on Drug Use and Health found that, in thegeneral community, 37.8% had ever used prescription opioids, 4.7% had misused and 0.8% had
an OUD; the most common reason for misuse was for physical pain relief (63.4%); misuse anduse disorders were more common in the presence of unemployment, low income andbehavioural health problems; 59.9% had used prescription opioids without a script and 40.8%
had obtained them from friends or relatives (Han 2017 Level IV, n=52,200). Past-year rates ofprescription opioid misuse amongst American adolescents and young adults have also risen(Jordan 2017 Level IV SR [PRISMA], 19 studies, n=503,845).
Patterns of heroin use in the USA have changed with recent users more likely to be
introduced via prescription opioids, with reasons for the transition being that heroin is easier toaccess and cheaper, along with changing demographics of use (greater geographical spread andnot now predominantly involving minorities) (Cicero 2014 Level III-3, n=2,851). From 2013 to 2014
in the USA, there was a rapid increase in age-adjusted death rates involving fentanyl whichcoincided with increased availability of illicitly manufactured fentanyl, according to law
enforcement reports; this underpins the need for public health, coroners and law enforcement
to work together on this public health problem (Rudd 2016 Level IV).
Emergency departments (ED) are an important source of opioids for misuse and diversion
with ED physicians amongst the top prescribers of opioids; 10% of diverted opioids originate
from ED prescription, 10% of prescriptions have indicators of “inappropriate prescribing”(Lyapustina 2017 NR), noting that some providers prescribe opioids to expedite ED discharge(Pomerleau 2017 Level IV, n=443 [health care professionals]).
Systematic approaches to these issues in the USA have included support for prescribing
decisions, reducing inappropriate access (eg Prescription Drug Monitoring Programs [PDMPs]
and Opioid Analgesic Risk Evaluation and Mitigation Strategy [REMS]) (Bucher Bartelson 2017 Level
IV), increasing access to overdose treatment and providing substance use treatment ( Collins 2018
NR; Volkow 2014 NR).
Concerns have been raised about the inadvertent impact of such strategies on pain
management and that some approaches are not evidence-based, leading to a call for pain
specialists to advocate for patients to ensure adequate treatment especially for vulnerable
populations (Pergolizzi 2019 NR) and to oppose forced opioid tapering (Darnall 2019 NR).
Other countries
Some authors have viewed the opioid epidemic as primarily a North American problem, with themain issues being opioid prescribing for inappropriate indications and in doses that are too high(Hauser 2016 NR). Although the worldwide literature shows that the highest growth in prevalenceof prescription opioid use is in USA government-insured populations (Roland 2016 Level IV SR[PRISMA], 16 studies, n unspecified), there is ample evidence that other countries have a similar,
albeit possibly less severe, issue. Prescription opioid use is also rising in the European Union,
Canada and Australia (Quinlan 2017 NR; Hauser 2017 NR). Prediction estimates show opioid“dependence” is a global issue with high prevalence in Australia, New Zealand, Western Europe
and North America; with lower estimates in Africa and Asia (Degenhardt 2014 Level IV SR [PRISMA],
31 studies, n unspecified). A comparison of five countries (USA, UK, France, Germany and Australia)
via the Global Drug Survey 2015 (online anonymous) found country of residence accounted for<3% of the variance in opioid misuse or abuse (Morley 2017 Level IV, n=5,670). German data showthat first opioid prescriptions increased by 37% from 2000 to 2010, noting professional guidelines
are not always followed (Just 2016 NR).
In Australia in 2016, 11% of those aged  14 y had ever used a prescription opioid for nonmedical purposes (3.7% in the past year); commonly multiple substances were used (alcohol inover 35%, smoking in approximately 25%, cannabis in nearly 20%); pharmaceutical opioids were826

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responsible for more deaths and poisonings than heroin; there was a mortality peak in 1999,
followed by decline and then 62% increase in death rate from 2007 to 2016 ( AIHW 2018 Level IV).
Opioids contributed to two-thirds of drug-induced deaths in Australia; in 2016, 1,045 opioidinduced deaths occurred in Australia (6.6/100,000 people vs 3.8/100,000 people in 2007)(Roxburgh 2018 Level IV) and 75% of these were prescription opioids. In 2015, a cluster of fentanyllaced heroin deaths was reported in Melbourne, Australia, the first report of this nature outside
North America (Rodda 2017 Level IV, n=9 [fentanyl related deaths out of 4,000 deaths investigated]).
Comorbid disorders
In those who use prescription opioids non-medically, the prevalence of chronic non-cancer painis 48 to 60% (Voon 2017 Level IV SR [PRISMA], 18 SRs, n unspecified). For those treated withbuprenorphine for OUD, relapse is more likely with increased chronic pain severity (adj OR 1.15;
95%CI 1.06 to 1.24) (Griffin 2016 Level II, n=148, JS 2). Long term opioid prescription receipt is more
likely in those with a prior diagnosis of ADHD (HR 1.53; 95%CI 1.48 to 1.58), nonopioid SUD (HR3.15; 95%CI 3.06 to 3.24) and prior OUD (HR 8.70; 95%CI 8.20 to 9.24) (Quinn 2018 Level IV, n=1,224,520).
Abuse deterrent formulations
More recently, focus has turned to the use of “abuse deterrent” or “tamper-resistant”
formulations (Schaeffer 2012 NR); strategies that are being assessed include the use oftechnologies that prevent the release of active opioid when tablets are crushed or attempts are
made to extract the drugs by other means, combinations of the opioid with an opioid antagonist
such as naloxone or with a second substance with aversive effects ( Passik 2014 NR; Webster
2011 NR). It is important to note that such formulations are not preventing abuse in principle but
are making it more difficult to abuse these opioids by routes other than the oral one (ie injecting,snorting).
Studies of opioid abuse potential can be limited by methodological issues and best practiceprinciples have been described (Setnik 2017 NR). Post-marketing surveillance is significantly
challenging and future studies may need to compare one abuse deterrent formulation withanother, as other formulations decline in use over time.
Slow-release oxycodone, reformulated to be abuse deterrent, was introduced to the USA in2010 and was associated with reduced intentional abuse, diversion and overdose (Larochelle 2015
Level III-3; Dart 2015 Level IV); however, this coincided with an increase in heroin overdoses. From2012 to 2014, 25 to 30% of those with an OUD reported past-month abuse of this reformulated
product, reflecting transition to oral abuse (43%), successful defeat of the formulation withongoing inhaled or injecting use (34%), or exclusive use of the oral route (23%) (Cicero 2015 Level
IV, n=10,784).
In Australia, reformulated slow-release oxycodone was introduced in 2014. The National
Opioid Medications Abuse Deterrent (NOMAD) cohort reported cheaper street prices and lower
use via tampering (injection), but no change in harms ( Larance 2018 Level III-3; Degenhardt 2015aLevel III-3). Whilst some tampering continued, the agent was reported as less attractive formisuse (Peacock 2015 Level III-3, n=522).
9.8.1.2 | Alcohol and benzodiazepines
Excessive alcohol use predisposes to particular types of acute pain eg due to trauma (77% of
screened Australian trauma patients had a probable alcohol-related injury or were engaging inrisky drinking regularly [Browne 2013 Level IV, n=729]) and pancreatic disease (RR 1.37; 95%CI 1.19
to 1.58) (Alsamarrai 2014 Level IV SR, 51 studies, n3,000,000). It may also lead to hepatic
dysfunction, which may affect the metabolism of other drugs, including analgesics.
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Alcohol and/or benzodiazepine use disorders are relatively common, particularly in certain
subgroups of the population. The Australian POINT study of patients with CNCP prescribed
opioids found a 33% lifetime prevalence of alcohol use disorder, and 16% of those who drank in
the prior 12 mth did so for pain control (Larance 2016 Level IV, n=1,514). Heroin users also takebenzodiazepines to potentiate the effects of the opioid (Bluth 2016 NR); concurrent use of opioids
and benzodiazepines increases the risk of opioid-related overdose (Dowell 2016 GL).
In terms of screening for benzodiazepine use, short-acting (eg midazolam) appear in urine
drug screens for 12 h and long-acting (eg diazepam) for over 7 d (Quinlan 2017 NR).
There is no cross-tolerance between opioids and alcohol or benzodiazepines in animal studies(Bell 1998 BS). The effective concentrations of remifentanil were not different between alcoholicand non-alcoholic patients (Liang 2011 Level II, n=60, JS 5). There is therefore no pharmacologicalreason to use higher than “standard” initial opioid doses in patients with an alcohol or
benzodiazepine dependence.
Prevention of withdrawal should be a clinical priority in all patients. Benzodiazepines are
effective for alcohol withdrawal symptoms, especially prevention of seizures (Amato 2010 Level I[Cochrane], 64 RCTs, n=4,309). If benzodiazepines are administered for the treatment of withdrawal
symptoms and signs, patient sedation levels must be monitored, especially if patients arereceiving concurrent opioids or other sedating drugs ( Macintyre 2011 NR). Excessive sedation will
limit the amount of opioid that can be given safely.
There are inconclusive results on the effect of pregabalin on alcohol withdrawal ( Guglielmo
2012 Level IV SR, 3 studies [withdrawal], n=271).
Naltrexone is used for treatment of alcohol use disorder and this complicates acute pain
management (see Section 9.8.3.3).
9.8.1.3 | Cannabinoids
Recreational use“Recreational” cannabis users had approximately 50% greater rescue pethidine requirements,
as well as higher pain intensity and dissatisfaction scores, than nonusers over the first 6 h after
orthopaedic surgery (Jefferson 2013, Level III-2).
Synthetic cannabinoids may contain a large number of components and are more potent than
the naturally occurring drug, resulting in agitation, hypertension, hypokalaemia, vomiting andseizures (Tait 2016 Level IV SR, 106 studies, n>4,000 [26 deaths]).
Use for chronic pain
Despite Level I evidence that cannabinoids have limited efficacy and potential for harm in CNCP
(Stockings 2018 Level IV SR [PRISMA], 47 RCTs and 57 studies, n=9,958), the Australian POINT study
found that, over a 4 y period, one quarter of those prescribed opioids for CNCP had also usedcannabis, usually for pain management, with 12% meeting criteria for cannabis use disorder (ICD10 criteria) (Degenhardt 2015c Level IV, n=1,514). Those using cannabis were younger, with greater
pain severity and interference, lower pain self-efficacy, greater concurrent benzodiazepine
prescription and greater non-adherence to the prescribed opioid regimen (Campbell 2018 Level
IV, n=1,514). Presence of (chronic) pain may make reducing cannabis use more difficult (Sznitman
2018 Level IV, n=18) (see also Section 4.11).
Withdrawal syndromes
Withdrawal is usually only seen in high-dose cannabis smokers in whom tolerance develops
quickly (Beaulieu 2017 NR). Both DSM-5 and ICD-11 define cannabis withdrawal as part of use
disorders and dependence (WHO 2018 GL; American Psychiatric Association 2013a GL).

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Withdrawal commences within 24-48 h and can last up to 3 wk; symptoms may include
depressed mood, abdominal pain and headache, all of which can confound acute pain
management (Bonnet 2017b NR).
Screening
In terms of screening for use, after single use, cannabis and its metabolites appear in urine drug
screens for 3-4 d (Quinlan 2017 NR). With heavy or chronic use, they may appear in urine drug
screens for up to 45 d.
For information about the use of cannabinoids for pain management see Section 4.11.
9.8.1.4 | Alpha-2-delta modulators (Gabapentinoids)
Increasingly, these are recognised as drugs of abuse with rising misuse rates ( Crossin 2019 Level
IV, n=1,201 [pregabalin misuse-related ambulance attendances]); Bonnet 2017c Level IV SR [PRISMA], 106
studies, n unspecified). Risk factors for abuse include prior substance abuse and psychiatriccomorbidities. Rates of abuse are higher in opioid abusers than in the general population anduse with opioids increases the risk of opioid-related death (OR 1.99; 95%CI 1.61 to 2.47) (Gomes
2017 Level III-2, n=5,875).
See also Section 4.8.1.1.

9.8.2 | CNS-stimulant drugs
Abuse of CNS-stimulant drugs (eg cocaine, amphetamines, ecstasy, ketamine) is associated withpsychological rather than physical dependence and only a low degree of tolerance; these drugs
do not exhibit any cross-tolerance with opioids (Buckley 2014 NR).
Cocaine and ecstasy (N-Methyl-3,4-methylenedioxyamphetamine or MDMA) are known toenhance the analgesic effects of morphine in animal studies ( Gatch 1999 BS; Kauppila 1992 BS;
Nencini 1988 BS). This effect may be age-dependent as exposure to methamphetamine inadolescent rats enhances morphine antinociception (and tolerance development) with inverse
effects in adult rats (Cyr 2012 BS). In experimental-pain settings, subjects taking ecstasy have beenshown to have a reduced pain tolerance (O'Regan 2004 Level III-2 SR EH); this was also true for
abstinent previous users (lower pressure pain thresholds, increased cold pain ratings, increased
pain ratings during testing of DNIC) (McCann 2011 Level III-2 EH). Those taking cocaine also had
reduced cold pressor pain thresholds (Compton 1994 Level III-2 EH).
There are very few data from the clinical setting of any differences in opioid requirements.
Compared with those with negative urine drug screens, trauma patients in intensive care who
were urine screen positive for cocaine and/or amphetamines required similar opioid doses ( Kram2017 Level III-2, n=150).
Epidemiological data from the USA show rising rates of cocaine- and/or psychostimulant
deaths since 2015; cocaine deaths are partially attributable to lacing with synthetic opioids(Kariisa 2019 Level IV). Analysis of urine drug tests in the USA show rising rates of fentanyl positivity
in those positive for cocaine and methamphetamine, reflecting a growing risk to stimulant usersof opioid-related overdose in that country (LaRue 2019 Level IV, n=1,000,000).
While behavioural and autonomic effects are seen during acute exposure, withdrawal
symptoms are predominantly affective rather than physical ( Quinlan 2017 NR). Stimulants areassociated with particular types of acute pain (eg cocaine use and chest pain including acutecoronary syndromes).

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9.8.2.1 | Nicotine
In volunteer studies, nicotine increases pain threshold ( n=393) and tolerance (n=339) and has
therefore an acute small to medium analgesic effect (Ditre 2016 Level III-2 EH SR [PRISMA], 13
studies, n unspecified). The authors speculate, that this could make smoking more rewarding andharder to give up.
In African-American smokers, smoking abstinence increased self-reported pain, with greater
abstinence-induced pain in those with pre-existing CNCP (Bello 2018 Level III-3, n=214). In patients
attending a Danish pain clinic, smoking rates were higher than those in the general population;compared with non-smokers, smokers and ex-smokers were more likely to use opioids and at
higher doses, although were not more likely to have opioid addiction (Plesner 2016 Level IV, n=98).
Opioid-dependent smokers are more likely to be nicotine-dependent, with greater severity of
nicotine dependence (Parker 2018 Level IV, n= 58,971).
9.8.2.2 | Cocaine
Whilst cocaine use does not induce physical dependence, its regular use is very reinforcing (iepsychological dependence) which can be managed with tricyclic antidepressants (Bluth 2016 NR).
“Withdrawal” is described as having three phases – “crash” within h to d, “acute” for up to 3 wk,
and “extinction” over several mth (Beaulieu 2017 NR). Cocaine is also known to enhance theeffects of morphine in animal studies.
Cocaine use may present with seizures, arrhythmias, coronary vasospasm, myocardialischaemia or stroke (Vadivelu 2018 NR). Dexmedetomidine may be useful to achieve
sympatholysis (Vadivelu 2016b NR).
Cocaine appears in urine drug screens for 48 to 72 h (Quinlan 2017 NR).
9.8.2.3 | Amphetamines and methamphetamine
Methamphetamines are highly addictive with long-term use leading to anxiety, mood
disturbance, insomnia and sometimes psychosis, all of which can impact on acute pain ( Becker
2018 NR). There are no effective pharmacotherapies, although there is low quality evidence formethylphenidate (2 RCTs, n=88) (Chan 2019a Level I [PRISMA], 34 RCTs, n unspecified).
Methamphetamines, used for ADHD, are increasingly drugs of abuse especially by school
students, with non-medical regular users 1.8% of Australians aged 15 to 35 y, commonly
declining by mid-30s (Chan 2019b Level III-3, n=1,755).
Withdrawal from methamphetamines is characterised by increased sedation and appetitethat can last for a few days; the severity of sleepiness correlated with the amount used(calculated by cost per mth) and length of regular use (McGregor 2005 NR).
Amphetamines appear in urine drug screens for 48 h (Quinlan 2017 NR).

9.8.3 | Drugs used in the treatment of addiction disorders
Close liaison with all treating clinicians and drug and alcohol services should occur. In the case of
those receiving opioid substitution therapy (OST), this may include arrangements with the usualprescriber and pharmacist for a “takeaway” dose on the day of elective surgery/procedureadmission, as well as liaison at discharge to ensure continuity of ongoing therapy (Schug 2012 NR;
Huxtable 2011 NR).
Good acute pain management is particularly important for patients on OST as acute pain
exposure was associated with reduced retention in treatment (aOR 0.46; 95%CI 0.23 to 0.93)(Bounes 2013 Level III-2, n=323 [prescribers]). The presence of chronic pain increases the odds of830

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craving in those on OST (aOR 3.10; 95%CI 1.28 to 7.50), which may impact outcomes in thissubgroup of patients (Tsui 2016 Level III-2, n=105).
Continuity of OST is important, as all-cause and overdose-related mortality risk drops sharply
in the first 4 wk of therapy, but rises substantially with cessation (Sordo 2017 Level III-3 SR [PRISMA]
19 studies, n=122,885 [methadone], n= 15,831 [buprenorphine] ). With regard to mortality under OST,
methadone vs buprenorphine use shows higher crude mortality, but also substantially higher
relative risk reduction when time in-treatment is compared to time out-of-treatment (Bahji 2019
Level III-3 SR [PRISMA], 32 studies, n=150,235) (19 studies overlap with Sordo 2017). As in the previous
systematic review, greatest mortality reduction occurred in the first 4 wk. Short-term
detoxification is rarely effective and there is an increased risk of one-year mortality vs OST(Harrison 2018 NR).
A comparison of OST with methadone vs buprenorphine found no difference in self-reported
opioid use or positive urine drug screens, no difference in retention (low quality evidence), buteach was more effective than detoxification or psychological treatment alone (Nielsen 2016 Level
I [Cochrane], 6 RCTs, n=607).
In Australia in 2017, 50,597 clients were receiving OST, of which 65% were male and 10%
identify as Aboriginal and/or Torres Strait Islander (AIHW 2019b Level IV). Overall rates of OST
have been stable since 2010 (20 clients per 10,000 population); there are 3,168 authorizedprescribers (90 in prisons), and 2,852 dosing points (mostly pharmacies); overall there areroughly similar numbers of clients on methadone, buprenorphine (Subutex®) andbuprenorphine/naloxone (Suboxone®).
9.8.3.1 | Methadone
Methadone is a long-acting opioid agonist used in the management of patients with an opioid
addiction (see Section 4.3.1.3). It is commonly prescribed in doses in the range 50–120 mg andonce/d, which is adequate to suppress symptoms of opioid withdrawal.
In the acute pain setting, methadone should be continued, where possible, at the usual dose.
If there is any doubt about the dose (eg there is suspicion that the patient is diverting all or partof the prescribed amount), it is prudent to give part of the reported dose and repeat this overthe day if needed, monitoring the patient for sedation (Huxtable 2011 NR; Peng 2005 NR). If thepatient is unable to take methadone by mouth, substitution with parenteral methadone or
another opioid will be required in the short-term (Huxtable 2011 NR; Mitra 2004 NR). Parenteralmethadone doses were 0.7 times the oral doses ( Gonzalez-Barboteo 2008 Level IV); half to twothirds of the oral maintenance dose can be given in equal divided doses by SC or IM injection 2
to 4 times/d or by continuous infusion (Huxtable 2011 NR; Alford 2006 NR).
The duration of any analgesic effect from the dose is much shorter (Alford 2006 NR); although
this is sometimes not well understood by treating physicians ( Bounes 2014 Level IV). Dividing thedaily dose on a temporary basis (eg giving half the usual daily methadone doses twice a day or
one third of the usual dose every 8 h) may result in a better analgesic effect ( Basu 2007 NR).
Divided doses or continuous infusion have been recommended for palliative care managementof those on methadone OST (Taveros 2017 Level IV SR [PRISMA], 7 studies, n=142).
Care should also be taken with concurrent administration of other drugs that prolong thecorrected QT interval; although this is thought to be an issue only with very high methadone
doses (Andrews 2009 NR).
If patient receiving methadone OST require additional opioids at discharge, consider daily
dispensing; overdose prevention education and nasal naloxone prescription have also been
recommended in this circumstance (Ward 2018 NR).
Methadone appears in urine drug screens for 7 to 8 d after cessation (Quinlan 2017 NR).
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Patients taking methadone may have OIH (see section 9.7 above for more information
including implications for management).
9.8.3.2 | Buprenorphine
Buprenorphine is a partial opioid agonist used effectively in the treatment of opioid addiction(Mattick 2014 Level I [Cochrane], 31 RCTs, n=5,430) and commonly prescribed for OUD in doses of 8
to 32 mg (Roberts 2005 NR). Regulatory controls on prescribers and those providing acute pain
management vary by country and state.
Administered SL, it has a mean terminal half-life of 28 h (Johnson 2005 NR). It is usually given
once every day or every second day, which is adequate to suppress symptoms of opioid
withdrawal; like methadone the duration of any analgesic effect from the dose is much shorter(Alford 2006 NR).
Some preparations combine buprenorphine and naloxone (the latter is poorly absorbed by
the SL route) (Orman 2009 NR); naloxone is added to buprenorphine with the aim of reducing
parenteral abuse of the drug.
Furthermore, long-acting buprenorphine preparations are now becoming available
worldwide (Harrison 2018 NR; Chavoustie 2017 NR). In Australia, two such preparations areregistered for SC injection: a SC gel depot preparation (Buvidal ) previously used in France(Vorspan 2019 NR) for weekly or monthly injection and Sublocade for monthly injection. There
are multiple reasons why such preparations could be advantageous; they reduce need for
frequent attendance at the dispensing facility, reduce inconvenience for patients and staff,
reduce the risk of diversion and injecting and may result in better adherence. Guidelines forthe use of these preparations in Australia are published ( Lintzeris 2019 GL).
In opioid-naïve subjects, administration of buprenorphine resulted in decreased hyperalgesia
following transcutaneous pain stimuli vs placebo, suggesting that unlike morphine andmethadone, buprenorphine may exert an antihyperalgesic effect ( Koppert 2005 Level III-2).
However, both methadone-maintained and buprenorphine-maintained patients were similarly
more sensitive to cold-pressor pain than opioid-naïve controls (Compton 2012 Level III-2).
Whilst there are still conflicting views in the literature regarding perioperative managementof OST with buprenorphine, the evidence supports its continuation. A systematic literaturesearch found limited evidence to support discontinuation ( 4 CR) and more support forcontinuation (1 Level III-1, 4 Level III-3, 3 Level IV) (Quaye 2019 Level IV SR, 8 studies & 4 CR, nunspecified). There is no evidence that the outcomes are worse if it is continued and limited
evidence about relapse rates with discontinuation (Goel 2019 Level IV SR [PRISMA], 6 studies & 12 CR,
n unspecified) (5 of 6 studies overlap). Significant risks of discontinuation include relapse andaccidental overdose (Lembke 2019 NR).
As with methadone, dividing the daily doses on a temporary basis (every 8 or 12 h) may takeadvantage of the analgesic properties of buprenorphine (Alford 2006 NR).
If buprenorphine has been ceased (eg unconscious patient, intraoral surgery or trauma
preventing SL administration), its reintroduction should be managed in consultation with theprescribing health professional who should also be involved in discharge planning to ensure
continuity of long-term care and availability of usual replacement therapy on discharge (Huxtable2011 NR).
With its metabolites, buprenorphine appears in urine drug screens for 8 d (Quinlan 2017 NR)
In-hospital or emergency department initiation
OST with methadone or buprenorphine are both better than clonidine and lofexidine inameliorating withdrawal symptoms (Gowing 2017 Level I [Cochrane], 27 RCTs, n=3,048). This has
implications for commencing OST in hospital or emergency departments.

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Comparison of in-hospital OST initiation of buprenorphine and continued outpatient followup with a 5-day detoxification protocol using buprenorphine showed the former led to morepatients receiving treatment and less illicit opioid use at 6 mth post-discharge (RR 0.60; 95%CI
0.46 to 0.73) (Liebschutz 2014 Level II, n=139, JS 3).
Emergency department initiation of buprenorphine/naloxone for OUD may improveengagement with and retention in treatment (D'Onofrio 2015 Level II, n=329, JS 3).
Management of patients treated for CNCP with transdermal buprenorphine is addressed in 9.7.
9.8.3.3 | Naltrexone
Naltrexone is a pure opioid antagonist used in the management of patients with opioid or alcohol
dependence. In the USA, it is available as tablets or in a long-acting injectable form.
There is good evidence for its effectiveness in alcohol dependence ( Rosner 2010 Level I[Cochrane], 50 RCTs, n=7,793).
There is mixed evidence for its use in opioid use disorder. Neither oral naltrexone (Minozzi
2011 Level I [Cochrane], 13 RCTs, n=1,158) nor long-acting naltrexone implants (Larney 2014 Level I, 5
RCTs, n=576 & Level IV SR, 4 studies, n=8,358) have good evidence of efficacy and safety. On thecontrary, there is a significant excess mortality in patients on oral naltrexone vs methadonemaintenance treatment (RR 3.5; 95%CI 2.2 to 5.8) (Degenhardt 2015b Level III-2). There is a limited
evidence base for extended release naltrexone injections with no change in mortality, except for
those recently released from correctional facilities (Babu 2019 NR). Compared with oral
naltrexone, extended release naltrexone implant (both combined with CBT) for opioid use
disorder results in better treatment retention at 6 mth (Sullivan 2019 Level II, n=60, JS 2).
The usual oral maintenance dose is 50 mg/d; orally administered, naltrexone has an apparent
half-life of about 14 h and binds to opioid receptors for over 24 h following a single dose (Vickers
2006 NR); this can create difficulties in the acute pain setting as opioid agonists will be
antagonised. It has been recommended that, where possible, naltrexone should be stopped forat least 24 h, and preferably 72 h, before surgery ( Kampman et al 2015 GL; Harrison et al 2018 NR;
Vickers 2006 NR; Mitra 2004 NR).
These difficulties are even greater when the patient has an active implant ( Vickers 2006 NR;
O'Brien 2006 NR); the duration of efficacy of the 1.1 g implant is approximately 95 d and that of
the 2.2 and 3.3 g implants approximately 140 d (Ngo 2008 PK). In cases where effective opioid
analgesia is required, removal of the implant might be considered ( Sadleir 2011 Level IV).
In addition, a microsphere-based formulation of naltrexone incorporated intoa biodegradable matrix for IM injection (XR-NTX) is now becoming available, and is approvedby the FDA for alcohol and opioid dependence (Sudakin 2016 NR). For this preparation (380 mg
IM), the peak activity is at 7 d and duration of effect is 28 d (Harrison 2018 NR). Whilst it has
proven difficult to provide analgesia during the first two wk post-injection, effective analgesia
has been described in the last wk of the four. Elective surgery should be scheduled 4 wk after
the last injection; with recommendations including a preoperative consultation with a pain
and addiction specialist, development of a relapse risk management plan including with
community provider input and education ( Ward 2018 NR).
In patients receiving naltrexone therapy, multimodal analgesic regimens (eg NSAIDs, paracetamol,
ketamine, tramadol, tapentadol, regional analgesia, lidocaine, dexmedetomidine, gabapentinoids,
non-pharmacological strategies) should also be employed (Harrison 2018 NR).
There is experimental evidence of mu-opioid receptor upregulation following antagonist
withdrawal (Millan 1988 BS) and abrupt discontinuation of naltrexone may therefore lead to aperiod of increased opioid sensitivity (Vickers 2006 NR). As the effect of naltrexone diminishes

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after it has been ceased, the opioid dose required for analgesia may also need to be decreased
in order to avoid opioid overdose (in particular OIVI).
Planning around cessation and reintroduction of naltrexone should be done in consultation
with the prescribing health professional and an acute pain service/specialist.

9.8.4 | The therapeutic relationship and behavioural management
Pain management in patients with SUD often presents significant challenges for both clinicians
and patients. Patients fear being stigmatised or discriminated against; they are concerned about
inadequate pain relief with their past experiences leading to physician distrust; and they fear
experiencing withdrawal (especially whilst waiting in ED or after admission, before their usual
drugs are prescribed) and relapse precipitated by acute opioid exposure ( Quinlan 2017 NR; Buckley
2014 NR; Eyler 2013 NR; Roberts 2008 NR).
Providers experience mistrust, concerns about drug seeking, fear of overtreatment withadverse events, concerns about diversion, and risk of discharge against medical advice. Many
health professionals (and some patients) have misconceptions about acute pain management inthis setting (Bounes 2014 NR). Evidence for the most appropriate management of acute pain inpatients with an addiction is limited and thus advice is based primarily on case series, casereports, expert opinion and personal experience.
In Canada, 48% of injecting drug users report having ever been denied pain medication as
inpatients and this is positively associated with using illicit drugs whilst in hospital (adj OR 1.46;
95%CI 1.14 to 1.88) (Ti 2015b Level IV, n=1,053). Injecting drug users who discharge against medical
advice experience inadequate pain and withdrawal management, often leading to continued
drug use in hospital settings (McNeil 2016 Level IV, n=30). Risk factors for discharge against medical
advice are recent injecting drug use, “pension day”, Indigenous patients (although this is likely
to be multifactorial), and day of the week (more likely on weekends); rates are lower with inhospital methadone use, community-based hospital in the home, older age and more social
support (Ti 2015a Level IV SR [PRISMA], 17 studies, n unspecified).
A more patient-centred approach has been recommended, with a (perhaps controversial)
shift in focus for these patients from abstinence-based policies to risk reduction (McNeil 2016
Level IV). Integration of OUD treatment into hospital care (eg as occurring in some USA
emergency departments) might reduce conflict between teams and reduce discharge against
medical advice (Fanucchi 2016 NR). A multidisciplinary addiction consultative service (IMPACT‘improving addiction care team’) improved staff experiences as they felt relieved, viewed care as
more humanised, understood addiction as a disease and valued the support provided bydischarge referral pathways (Englander 2018 Level IV).
Inappropriate behaviours can be prevented to a significant extent by the development of arespectful, honest and open approach to communication and, as with all other patients, anexplanation of treatment plans and the fact that complete relief of pain may not be a realistic
goal, as well as involvement of the patient in the choice of plan (within appropriate boundaries)(Jones 2014 NR; Haber 2009 NR; Roberts 2008 NR). One communication framework is the “7 Es”(Becker 2016 Level IV): Express empathy, Elicit functional goals, Educate, Endorse an alternativeplan, Enlist patient buy-in, Enact follow-up plan, and maintain Equanimity (calm, even-tempered,
non-judgemental).
A proactive, rather than reactive, discussion about medications and behaviours is
recommended (Haber 2009 NR) and sometimes limit setting (Huxtable 2011 NR). Episodes of acutepain may negatively impact upon long-term retention in addiction treatment programs andbetter acute pain control may improve such retention (Bounes 2013 Level III-2). Addiction “talking
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being best to have treatment from a specialist (as in any chronic disease), and “[caring] enough”
to set boundaries (Allen 2014 NR).

9.8.5 | Assessment including screening for risk of opioid use disorder andmitigation strategies
The first step in managing patients with a SUD is identifying the problem, although obtaining an
accurate history can sometimes be difficult. Risk factors for OUD include past or current
substance abuse, untreated psychiatric disorders, younger age, social and family factors thatencourage misuse (Webster 2017 NR). Risk factors for opioid overdose include those of middle
age, opioid use disorder and other psychiatric comorbidities. At times, it may be in the setting of
unsuccessful overdose that inpatient contact occurs.
Identification of patients abusing drugs or at risk of drug abuse may be difficult. The ability ofhealth professionals to predict which patients may misuse or abuse opioids is poor (Jung 2007
Level IV SR, 6 studies, n unspecified) and patient self-report of drug use may not correlate withevidence from drug screening (Sehgal 2012 NR).
Screening tools are widely used in chronic settings especially in the USA; and increasingly arerecommended prior to short-term therapy also (Ballantyne 2015 NR). These tools were largely
developed in an outpatient (often pain clinic) setting, and are not validated for acute hospitalsettings including emergency departments, so as yet it is not clear who should be screened andwith what tool (Duber 2018 NR). Opioid Risk Tool (ORT), Screener and Opioid Assessment for
Patients with Pain (SOAPP-R) and Current Opioid Misuse Measure (COMM) are poor at predicting
risk of subsequent aberrant behaviours in patients with CNCP in the emergency department(Chalmers 2019 Level IV). The SOAPP-R applied in emergency department patients, in whom
discharge opioid prescribing was being considered, had sensitivity 54%, specificity 71%, positive
predictive value 26% and negative predictive value 89% for identifying subsequent high-risk
behaviour (Weiner 2016 Level IV, n=82). A further limitation is that self-reported tools can be
manipulated (Kaye 2017b NR).
Polysubstance use is common and many patients use drugs from different groups, the mostcommon being CNS-depressant drugs (such as opioids, alcohol, benzodiazepines andcannabinoids) and CNS-stimulant drugs (including cocaine, amphetamines and amphetaminelike drugs). The group from which the drugs come determines their withdrawal characteristics (ifany) and their interaction with acute pain treatment (Peng 2005 NR; Mitra 2004 NR). Patientsshould be asked about the route of administration used, as some may be injecting prescription
drugs intended for oral, TD or SL use. Verification of opioid doses should be undertaken where
possible or else a divided dose given with monitoring of effect, in case the reported dose isincorrect or the drug is being wholly or partly diverted (Huxtable 2011 NR; Alford 2006 NR).
Recommendations include establishing a supportive non-judgemental environment,
determining what drugs are misused, developing an analgesic plan (which optimise non-opioids,
increases opioids if required with careful monitoring for adverse effects and change to oral
analgesia from parenteral as soon as feasible), a withdrawal management plan (continuing OSTor replacing, and consider withdrawal from other drugs), minimising stress and multidisciplinarydischarge planning (Quinlan 2017 NR).
“Universal precautions” are increasingly recommended for acute pain settings (Webster 2017
NR). In this context, universal precautions encompass use of multimodal analgesia, abusedeterrent formulations, urine drug screening, use of prescription drug monitoring programs(PDMP) and risk management strategies (eg REMS programs in the USA).
An acute admission offers an opportunity to engage with the chronic condition of SUD as wellas to treat the acute issues; failure to engage is a missed opportunity (Donroe 2016 NR). Screening,
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Brief Intervention and Referral to Treatment (SBIRT) is promoted and commonly used in the USA(Kaiser 2016 NR)
Involvement of an addiction medicine specialist or service may be required; suggested referral
criteria are (Nack 2017 NR):
• Abuse of medication;• Excessive alcohol use;
• Unwilling to try other pain treatments;• Concurrent opioid and sedative prescriptions;• Psychiatric disorder;• On ORT with persistent pain.

9.8.6 | Transition to community care
In all cases, close liaison with other treating health professionals and drug and alcohol services
is required. This is especially important if the management plan includes additional opioids forpain relief for a limited period after discharge or if any alteration has been made, after
consultation with the relevant services, to methadone or buprenorphine doses while in hospital.
In many countries, regulatory requirements will dictate that only one physician has theauthority to prescribe for these patients. However, restricted use of additional opioids after
discharge may be possible in some circumstances. For example, it could be arranged for thepatient to pick up a limited and progressively decreasing number of tablets daily or every otherday, along with their usual methadone or buprenorphine (Peng 2005 NR).
For those with concurrent chronic pain, referral to an outpatient pain service may berequired; the patient not currently in SUD treatment may require referral to a drug and alcohol
service (Huxtable 2011 NR).
It is necessary to notify usual prescribers of medications used in hospital as these may appear
in subsequent urine drug screens (Vadivelu 2016a NR).
For discharge medication see also Section 8.13.

9.8.7 | Patients in recovery from substance use disorders
Patients in drug-treatment programs or in drug-free recovery may be concerned about the riskof relapse if they are given opioids for the management of their acute pain (Eyler 2013 NR;
Markowitz 2010 NR). However, there is no evidence that the use of opioids to treat acute painincreases the rate of relapse; a more likely trigger is unrelieved pain, although this is primarily
based on expert opinion (Ward 2018 NR; Buckley 2014 NR; Markowitz 2010 NR; Alford 2006 NR)
IV opioids may present greater risk for relapse due to more rapid and higher peakconcentrations and patients may be very reluctant to receive opioids ( Quinlan 2017 NR). Those atparticular risk of relapse when given opioids include younger patients, males and those using
multiple illicit drugs, especially cocaine (Markowitz 2010 NR). Effective communication andplanning, the use of multimodal analgesic strategies, reassurance that the risk of reversion to an
active addiction is small, and information that ineffective analgesia can paradoxically lead torelapse in recovered patients, are important and help avoid undertreatment ( Huxtable 2011 NR;
Mitra 2004 NR).
The anxiety associated with surgery might trigger conditioned responses resulting in drug
craving (Volkow 2016 NR). Those with prior maintenance opioid addiction treatment but
prolonged abstinence demonstrate increased cold sensitivity, decreased tolerance and cravings(similar to their opioid-maintained counterparts); but they had greater sense of control overthese cravings which may reflect that they have developed skills to cope with pain to avoid

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relapse (Wachholtz 2019 Level III-2, n=120). Expert opinion suggests that both uncontrolled pain
and uncontrolled opioid access can trigger relapse (Ward 2018 NR).

9.8.8 | Acute pain in pregnant patients with an opioid use disorder
Many women with an addiction are of childbearing age (AIHW 2019a Level IV); the prevalence ofprescription-opioid abuse is rising in this population (Klaman 2017 GL). The prevalence of neonatal
abstinence syndrome (NAS) has risen in the USA and Canada (Filteau 2018 Level IV; Ko 2016 Level
IV), although it has stabilised in Australia (Uebel 2016 Level IV, n=1,022,263) and England (Davies
2016 Level IV).
The management of acute pain in pregnant patients with an addiction must consider
treatment of the mother, as well as possible effects on the foetus and newborn.
Identification of these patients during pregnancy allows time for assessment and appropriate
management planning; however, this is not always possible as antenatal care is often suboptimal(Kampman 2015 GL; Jones 2014 NR). Routine screening may increase the rate of addiction detection(Jones 2014 NR) and validated screening tools include the 4Ps and CRAFFT ( ACOG 2012 GL; Jones
2014 NR). Care is complicated in these patients by other factors related to their use of drugs suchas respiratory infections, endocarditis, untreated cellulitis, abscesses, HIV/AIDS, hepatitis andsocial factors such as abuse, interpersonal violence and homelessness (Jones 2014 NR; Ludlow 2007
NR). Stabilisation with OST, as early as possible in pregnancy, is preferred to withdrawal
management or abstinence due to risks to both mother and foetus with addiction relapse andtreatment dropout (Klaman 2017 GL; Kampman 2015 GL).
Reviews of pain management in these patients (Buckley 2014 NR; Jones 2014 NR; Stanhope 2013
NR) as well as guidelines have been published (Klaman 2017 GL; Kampman 2015 GL). Collaborative
team care is essential.
9.8.8.1 | Methadone
Methadone maintenance is regarded as the gold standard for antenatal OST ( ACOG 2012 GL).
Pregnant patients taking methadone as part of a drug-dependence treatment program should
receive whatever dose is needed to prevent heroin use, and the dose may need to be increasedin the third trimester because the physiological changes associated with pregnancy can alter drug
pharmacokinetics (Jones 2012a NR; Ludlow 2007 NR).
9.8.8.2 | Buprenorphine
The largest study of OST in pregnancy, the Maternal Opioid Treatment Human Experimental
Research (MOTHER) study compared methadone and buprenorphine and showed similarmaternal outcomes (Jones 2012b NR, summarising results of 1 RCT: Jones 2012a Level II, n=175).
Buprenorphine resulted in less foetal cardiac and movement suppression, lower rates of pretermlabour, less severe NAS (a treatable condition), but lower maternal satisfaction and lower
treatment retention rates, vs methadone maintenance ( Bandstra 2012 NR, secondary analysis of 1
RCT: Jones 2012a Level II, n=175). When compared with methadone maintenance, buprenorphinemaintenance may lead to better neonatal outcomes, but this might be due to systemic bias instudies (Brogly 2014 Level III-2 SR [PRISMA], 4 RCTs & 8 studies, n=1,380 [includes Jones 2012a]).
9.8.8.3 | Naltrexone
Although not recommended in professional guidelines, there is emerging evidence that neonatal
outcomes may be no worse for those treated with implanted naltrexone when compare with
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837

OST (Kelty 2017 Level III-2, n=775). Issues with naltrexone include that its induction requires an
opioid-free period after detoxification and it is also more challenging for peripartum pain relief(Tran 2017 NR).
In the absence of specific evidence, management of pain in the peripartum period should be
extrapolated from the non-pregnant patient with reliance on non-opioids including regional
blocks.
9.8.8.4 | Peripartum management
Methadone maintenance should be continued without interruption in the peripartum period; if
for some reason the women is unable to take it orally, it can be given subcutaneously. As withany opioid-tolerant patient, additional opioids will be required for pain relief and the newborn
will require high-level neonatal care because of the risk of NAS (Jones 2012a NR; Jones 2008 NR;
Ludlow 2007 NR). Pain scores after Caesarean section are also higher (Meyer 2010 Level III-3).
Buprenorphine maintenance should be continued without interruption as it does notinterfere with pain control after vaginal delivery or Caesarean section (Vilkins 2017 Level III-2,
n=273; Hoyt 2018 Level IV, n=14; Leighton 2017 Level IV, n=4). These women will also have higher
opioid requirements after surgery and the newborn is still at risk (albeit maybe a lower risk) ofNAS (Jones 2012a NR; Jones 2010 NR; Ludlow 2007 NR).
Delivery should occur at a tertiary centre and needs clear criteria for opioid use,neonatologist involvement pre-delivery and consent during pregnancy regarding NAS ( Pritham
2014 NR). Opioid requirements during labour were not significantly increased, althoughmethadone- and buprenorphine-maintained patients had higher pain scores and higher opioid
requirements postpartum than did controls (Meyer 2010 Level III-3). In another study, opioidmaintained patients required epidural analgesia more often than controls (38.1 vs 14.3%) but
had no higher opioid requirements after Caesarean section (Hoflich 2012 Level III-2).
Opioid requirements and the risk of withdrawal, for the patient and the newborn, will behigher in patients still using heroin prior to childbirth (Ludlow 2007 NR). In all patients with opioid
addiction, naloxone is not recommended except in situations of life-threatening overdose(Kampman 2015 GL).
Opioid requirements in those addicted to non-opioid substances should be similar to nonpregnant patients.
For further information on maternal and neonatal outcomes see Section 9.1.

KEY MESSAGE
1. Benzodiazepines are effective for alcohol-withdrawal symptoms, in particular reducing
seizures (U) (Level I [Cochrane Review]).
2. Opioid substitution therapy with methadone or buprenorphine is better than clonidine
and lofexidine in ameliorating withdrawal symptoms (N) (Level I [Cochrane Review]).
3. Methadone and buprenorphine maintenance regimens should be continued
throughout acute pain episodes wherever possible (S) (Level III-2 SR [PRISMA]).
4. Poorly managed acute pain episodes may decrease retention in opioid-maintenanceprograms (U) (Level III-2).
5. To achieve better analgesic efficacy, daily methadone maintenance doses should be
divided and given 8 to 12 hourly (S) (Level IV SR [PRISMA]).

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The following tick boxes represent conclusions based on clinical experience and expert
opinion: Pain management in patients with substance use disorder often presents significant
challenges for both clinicians and patients. Patients fear being stigmatised or
discriminated against, are concerned about inadequate pain relief with their pastexperiences leading to physician distrust; they fear experiencing withdrawal (before
their usual drugs are prescribed) and relapse precipitated by acute opioid exposure.
The challenges for the clinician Include mistrust, concerns about drug seeking, fear ofovertreatment with adverse events, concerns about diversion, and risk of discharge
against medical advice (N).
 A “universal precautions” approach is increasingly recommended for patients with
substance use disorder in acute pain settings; it may include use of multimodal
analgesia, abuse-deterrent formulations, urine drug screening, use of prescription drug
monitoring programs and risk management strategies (N).
 An acute admission offers opportunity to engage with patients with substance use
disorder as well as to treat the acute issues (N).
 There is no cross-tolerance between alcohol or benzodiazepines or central nervous
system stimulants and opioids (U).
 Oral naltrexone should be stopped at least 24 hours, ideally 72 hours, prior to elective
surgery (U); naltrexone implants may need surgical removal in cases of severe acutepain where opioid responsiveness is required (U).
 Patients who have ceased naltrexone therapy should be regarded as opioid naïve; inthe immediate post-treatment phase they may be more opioid sensitive (U).
 To achieve better analgesic efficacy, daily buprenorphine maintenance doses could be
divided and given 8 to 12 hourly (U).
 Nicotine has a small to medium analgesic effect in volunteers and smoking abstinence
increased self-reported pain (N).

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10

Paediatric Volume II
Section Editors:
A/Prof Greta M Palmer
Dr Mark M Alcock882

10.1 | Developmental neurobiology of pain
Contributor: Dr Jonathan De Lima

10.2 | Consequences of early pain and injury
Contributor: Dr Susan Hale

10.3 | Paediatric pain assessment
10.3.1 | Pain assessment in neonates
10.3.2 | Pain assessment in infants and children
Contributors: A/Prof Dianne Crellin, A/Prof Greta Palmer

10.3.3 | Self-report in children and adolescents
10.3.4 | Children with cognitive impairment or intellectual disability
Contributors: Dr David Sommerfield, A/Prof Greta Palmer

10.4 | Analgesic agents
Pharmacokinetics advisor: Prof Brian Anderson

10.4.1 | Paracetamol
Contributors: Dr Dana Weber, A/Prof Greta Palmer

10.4.2 | NsNSAIDs
10.4.3 | Cox-2 inhibitors
Contributor: Dr Derek Rosen

10.4.4 | Opioids and atypical opioids
Contributors: Dr Laura Burgoyne, Dr Nicole Wylie, A/Prof Greta Palmer

10.4.5 | Discharge opioid prescribing for children
Contributors: Dr Kate Drummond, A/Prof Greta Palmer

10.4.6 | Opioid tolerance in children and adolescents
Contributor: A/Prof Greta Palmer

10.4.7 | NMDA antagonists
Contributors: Dr Paul Davies, Dr Mark Alcock

10.4.8 | Alpha-2 agonists
Contributors: Dr Caroline Mann, A/Prof Greta Palmer

10.4.9 | Alpha-2-delta ligands (gabapentinoids)
10.4.10 | Corticosteroids
Contributors: Dr Angela Yeo, Dr Mark Alcock, A/Prof Greta Palmer

10.4.11 | Systemic local anaesthetics
Contributor: A/Prof Greta Palmer

10.5 | Opioid infusions and PCA
Contributor: Dr Jordan Wood883

10.6 | Paediatric regional analgesia
10.6.1 | Peripheral nerve blocks
10.6.2 | Efficacy of Peripheral nerve blocks and catheters
Contributors: Dr Sarah Brew, A/Prof Greta Palmer

10.6.3 | Neuraxial Blocks
10.6.4 | Intrathecal Opioids
Contributors: Dr Sarah Johnson, Dr Stuart Ross, Dr Mark Alcock

10.6.5 | Topical therapies
Contributor: Dr Su May Koh

10.6.6 | Use of Paediatric Regional Analgesia (PRA) in Specific PaediatricSurgical Procedures
Contributors: Dr Sarah Brew, A/Prof Greta Palmer, Dr Sarah Johnson, Dr Stuart Ross, Dr Mark Alcock

10.7 | Management of procedural pain in children
10.7.1 | Procedural pain in the neonate
Contributors: Dr Alex Donaldson, Dr Mark Alcock

10.7.2 | Procedural pain in infants and children
Contributors: Dr Vanessa Rich, Dr Mark Alcock

10.7.3 | Vaccination injection pain in infants and children
Contributors: Dr Kathleen Cooke, Dr Mark Alcock

10.7.4 | Procedural pain management in the emergency department
Contributors: Dr Peter Barnett, Dr Mark Alcock

10.7.5 | Nonpharmacological strategies in children and adolescents
Contributors: Dr Alex Donaldson, Dr Vanessa Rich, Dr Mark Alcock

10.8 | Acute pain in children with cancer
Contributors: Dr Christine Mott, Dr Jacqueline Duc, Dr Mark Alcock

10.9 | Other acute pain conditions in children
10.9.1 | Management of pain due to trauma in children
10.9.2 | Management of Acute Burn Injury
10.9.3 | Paediatric migraine
Contributor: Dr Mark Alcock

10.9.4 | Acute pain Associated with Haematological disorders in children
Contributor: Dr Harith Al-Rawi

10.10 | The overweight or obese child or adolescentContributor: Dr Mark Alcock

10.11 | Complementary and alternative medicines and therapies
Contributor: Dr Mark Alcock884

5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

10.1 | Developmental neurobiology of pain
The majority of information on this topic to date is experimental (mostly rodent) data, which
presents translational challenges to the interpretation of developmental changes in theneurodevelopmental pathways of the human embryo-foetus-infant. The combination of basic
science, fetal surgery and neonatal imaging studies is enhancing our understanding of pain
pathway development and the influence of pacemakers and various receptors. In embryonic
life, nociceptive pathways develop under the influence of (generally non -noxious) afferent
input (Skaper 2018 NR BS; Li 2011a BS) and several trophic signalling pathways eg nerve growth
factor and tropomyosin receptor kinase (NGF-TrK). Growth factor signalling systems are
extremely important in the developing cytoarchitecture of nociceptor pathways and remain
well conserved across species (Wheeler 2014 BS). Interspecies differences appear to stem fromdivergent roles played by (downstream) transcription factors (Guo 2011 BS). The expression of
a number of molecules and channels involved in nociception are developmentally regulated.
During early life, there are changes in the distribution and density of many important receptors
and the levels and effects of several neurotransmitters alter significantly (Verriotis 2016a NR;
Fitzgerald 2005 NR).
Animal studies confirm that activity-dependent maturation is a cornerstone ofdevelopment and, in early gestation, intrinsically active neurons (endogenous pacemakercells) contribute significantly to this (Li 2011b BS). Within lamina I of the spinal cord,
pacemakers are positioned to regulate both the level of activity in developing motor circuits
and the ascending flow of nociceptive information suggesting a role in the maturation of pain
and sensorimotor networks (Li 2015 BS). Postnatal tuning of these pathways requires continued
somatosensory (again non-noxious) input at a spinal level. The development of inhibitory
pathways within nociceptor systems appears somewhat later and involves a developmentally
regulated alteration in the synaptic effects of glycine and GABA (Hathway 2012 BS; Rajalu 2009
BS). Little is known about the trophic factors and essential synaptic inputs that guide thedevelopment of these pathways. Neuropeptides, receptors and ion channels implicated in thedevelopment of (and activity within) these pathways include sodium leak channels(spinoparabrachial tracts: Ford 2018 BS), metabotropic GABA-B receptors (Brewer 2018 BS) andatypical cadherins (Wang 2017 BS). Important signalling systems in early development include
the ephrin-receptor tyrosine kinase system which influences cell movements (Wilkinson 2001
NR) and extracellular signal receptor kinases (O'Brien 2015 BS). Modulation of activity withinthese spinal pathways by tissue injury and inflammation appears to be mediated throughglutaminergic signalling in an age-dependent fashion (Baccei 2010 BS). As a result, corticalcoding of ‘injury-induced pain states’ also appears to be developmentally regulated (Chang
2016 BS).
Rodent studies confirm that C-fibre polymodal nociceptors are mature in their pattern offiring at stages equivalent to term gestation in humans. They are capable of being activated in
the periphery by exogenous stimuli, although their central synaptic connections in the dorsal
horn are initially immature. However, “wind-up” can be produced by relatively low-intensity
A-fibre (rather than C-fibre) stimulation. A-beta fibres initially extend up into the spinal cord’slaminae I and II and only withdraw once C fibres have matured. This overlap means there isless discrimination between noxious and non-noxious stimuli and, as the receptive fields of
dorsal horn neurons are large, peripheral stimuli can excite a greater number of central
neurons in early development. In addition, descending inhibitory pathways and inhibitory
networks in the dorsal horn are not fully mature in early development (Schwaller 2017 BS).
While activity of the rostroventral medial medulla (RVM) can facilitate or inhibit dorsal horn
5th Edition | Acute Pain Management: Scientific Evidence

885neuron inputs in the mature animal, in young animals descending facilitation dominates andis likely generated by spontaneous brainstem activity (Hathway 2012 BS). Only later in postnatal
life does this descending activity become modulated by ascending nociceptive inputs in afunctional spinal-bulbo-spinal loop (Schwaller 2016 BS).
By 7 wk gestation, human primary afferent nerve fibres that innervate skin and projection
neurons from the dorsal horn of the spinal cord reach the thalamus. Ascending pathways arepresent and functional by 25 wk gestation. Central neural projections and synaptic
connections continue to mature and, from 26 wk gestation, peripheral noxious stimuli canelicit responses in the increasingly layered thalamic and cortical neurons (Verriotis 2016a NR).
Anatomical and electrophysiological evidence confirms that biological systems necessary
for nociception are intact and functional from 26 wk gestation (Verriotis 2016a NR). This isclearly confirmed during fetoscopy and medical interventions in utero (Bellieni 2018 NR).
Despite this, inferences regarding fetal pain are limited. Our understanding of the conscious,
cognitive, affective and evaluative experience of pain during fetal and late gestational life
remains conjectural (Derbyshire 2006 NR). In contrast to the protected environment in utero (inwhich the fetus is buffered from environmental stimuli and continuously exposed to theanaesthetic effects of endocrine neuroinhibitors), postnatal life brings intense afferent
stimulation and wakefulness (Lagercrantz 2009 Level IV). With this, comes the possibility ofpsychological processes involving content derived from the environment (objects, people andsymbols) (Derbyshire 2006 NR). Following birth, the neural pathways required for nociception
are functional and cortical responses to noxious stimuli such as skin lancing can bedemonstrated in even the most preterm neonate (Verriotis 2016a NR; Slater 2006 Level IV).
However, as significant functional and structural changes occur in nociceptive pathways during
the postnatal period (Hirschfeld 2012 Level IV), the pattern of activity evoked by tissue trauma
also changes (Fitzgerald 2009 Level IV).
Although the underlying mechanisms may differ from adults, nociceptive pathways can besensitised by painful stimuli in early life, as demonstrated by a reduction in reflex thresholds
in neonates following repeated heel lance (Fitzgerald 1988 Level IV) and infants following
abdominal surgery (Andrews 2002 Level IV). Both animal and human studies suggest that there
is a relative excess of excitatory mechanisms and delayed maturation of inhibitory mechanisms
in early life (Fitzgerald 2005 NR). Hence, neonates once thought to be less sensitive to painfulstimuli in fact, produce more generalised and exaggerated reflex responses to lower intensity
stimuli.
The disposition and clinical effects of drugs administered in early life are subject to manyfactors including changes in body composition, protein binding and membrane permeability
as well as maturation of major organ systems and receptor signalling systems. Each of these
may in turn be affected by disease-related alterations (van den Anker 2011 NR). Factors affecting
the pharmacokinetic (PK) profile of analgesic drugs (body water and fat composition, plasma
protein binding, hepatic metabolism and renal function) change rapidly during the first weeks
of life (Funk 2012 NR). Postnatal changes in the PK profile of a number of analgesic drugs (egmorphine and paracetamol [acetaminophen]) result in significant age-related changes in dose
requirements during infancy and childhood (Allegaert 2014 NR; Palmer 2008 PK; Prins 2008 PK;
Bouwmeester 2004 NR). In addition, changes in nociceptive processing may have significant
effects on the pharmacodynamic response to analgesics in early life (Walker 2008 NR).
Therefore, developmental age and not just weight should be considered when calculating
analgesic dosing (Allegaert 2014 NR) (see also Section 10.4 for PKs of the various analgesic
drugs). Laboratory studies have demonstrated postnatal changes in the mechanism of action,
analgesic efficacy and adverse-effect profile of analgesics that can inform subsequent clinical
trials (Nandi 2005 NR; Walker 2008 NR; Fitzgerald 2009 NR).

886

5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

Prolonged reductions in synaptic activity by general anaesthetics and analgesics can
produce neurotoxic effects, such as accelerated apoptosis, in the developing nervous systemeg in rodent models. The clinical significance of these laboratory findings remains uncertain(Mellon 2007 NR BS). Researchers are now assessing long term outcomes of repeated or
extended exposure but the assessment of the impact of analgesic and general anaesthetic
administration upon the infant’s developing brain and pain pathways will always remain
confounded by the underlying pathology, concomitant surgical intervention and comorbidities
present (Davidson 2018 NR).

KEY MESSAGES
1. Following birth, even the most preterm neonate responds to nociceptive stimuli (U)(Level IV).
2. In early development, more generalised reflex nociceptive responses occur in response
to lower intensity stimuli (U) (Level IV).

5th Edition | Acute Pain Management: Scientific Evidence887

10.2 | Consequences of early pain and injury
10.2.1 | Early neurodevelopmental consequences
Significant reorganisation of synaptic connections occurs in the postnatal period. Activity withinsensory pathways is required for normal development but abnormal or excessive activity related
to pain and injury during the neonatal period may alter normal development and produce
persistent changes in sensitivity that outlast the injury (Walker 2013 NR; Fitzgerald 2009 NR; Walker
2009 Level III-2).
However, the effect of pain in the neonatal period on neurodevelopment and the child or
adult’s later pain experience is difficult to quantify. In researching this, there are many factors that
may confound the determination of the contribution of early pain to altered neurodevelopment
and the extent to which this can be modulated by interventions. The likely patient confounders
include sex, birth weight, gestational age at birth and at the time of insult, intercurrent illness typeand severity (including hypotension), the extent of tissue damage (Brummelte 2012 Level IV), as wellas genetic and epigenetic factors (Provenzi 2018 Level IV SR [PRISMA], 9 studies, n=1,516). While thetreatment confounders that may influence neurodevelopment include type, dose and duration ofanalgesia (including opioids and benzodiazepines), other drugs administered (such as
dexamethasone [for chronic lung disease] and anaesthetic agents (Davidson 2013 NR), as well as theneonatal unit’s practices (which vary) and the quality of neonatal intensive care (see below:
Montirosso 2012 Level IV). An additional confounder is the limited ability to quantify the neonate’s
pain experience in the intensive care setting; some studies have used the number of skin-breaking
procedures (including blood tests, heel lances, vascular access and surgery) received by theneonate as a surrogate measure to then investigate impact on adverse outcomes. Nociceptive
related reflex withdrawal activity and activation of higher cortical areas do not correspond well toobservational pain assessment (or outward phenotype) of the neonate when compared to theadult (Fitzgerald 2015 NR). This means that behavioural pain assessment may not reflect
physiological responses to pain. Importantly, our understanding is expanding regarding theinterplay of stress exposure vs developmentally targeted care (eg in the NICU) and the influence
upon epigenetics and resultant phenotypic trajectory (in terms of brain maturation,neurobehaviour, the child’s current and later capacity to regulate stress, behaviour or emotions
and social functioning) (Provenzi 2018 Level IV SR [PRISMA], 9 studies, n=1,516).
In clinical studies of ex-preterm neonates, neuroimaging studies done at the equivalent ofterm age showed greater pain exposure was associated with structural changes. White matterand subcortical grey matter maturation was reduced in infants born at 24–32 wk (related to thenumber of heel lances and single but not multiple surgical interventions), as assessed by diffusion
tension and magnetic resonance spectroscopy (Brummelte 2012 Level IV). In a group of similarly
premature infants, both neonatal pain and greater early illness severity (measured by the Score
for Acute Neonatal Physiology–II) were associated with delayed microstructural development of
the corticospinal tract (Zwicker 2013 Level IV). In MRI imaging of ex-extreme and very preterm(24─32 wk) neonates at a median of 32 and 40 wk post menstrual age (PMA), early exposure to
repetitive procedural pain was associated with volume loss in the lateral thalamic(somatosensory) region with abnormal thalamocortical pathway development ( Duerden 2018
Level IV, n=155). These changes were more pronounced in the extreme preterm infants.
Neurodevelopmental outcome assessments (Bayley-III scores) showed that increased volumetricthalamic growth predicted higher cognitive and motor scores at 3 y corrected age.
Among extremely preterm infants (born at <30 wk gestation), those exposed to surgery (andanaesthesia) had greater white matter injury and smaller total brain volumes, particularly888

5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

smaller deep nuclear grey matter volume (Filan 2012 Level III-3). In those born at <29 wk gestation,clinical outcomes associated with greater pain exposure were delayed growth with lower bodyweight at 32 wk (Vinall 2012 Level IV) and poorer cognitive and motor function at 8 and 18 mth(Grunau 2009 Level III-2). No difference was seen in mental development scores at 2 y in exextreme preterm patients (<30 wk) who had surgery vs no surgery, following adjustment for
confounders (Filan 2012 Level III-3).
Preterm behavioural epigenetics (PBE) is the study of the role of environmental factors suchas pain-related stress, which may influence epigenetic modifications in the preterm infant andthus development and behavioural phenotype (Provenzi 2018 Level IV SR [PRISMA] 9 studies,
n=1,516). In very preterm neonates exposed to high levels of pain-related stress, serotonintransporter gene SLC6A4 methylation in peripheral blood samples increased from birth to NICU
discharge at CpG sites 5 and 6 vs neonates exposed to low pain-related stress (Provenzi 2015
Level III-2, n=88).

10.2.2 | Longer term consequences of early pain and injury
Longer-term consequences of early pain and injury have been well described, particularly inrodent models and ex-neonatal intensive care unit (NICU) populations. In laboratory studies, thedegree of long term change varies with the type and severity of injury (Fitzgerald 2009 NR).
Inflammation, full thickness skin wounds and skin incision produce prolonged alterations insensitivity and the response to future injury, in the absence of any visible persistent peripheral
injury. By contrast, allodynia following nerve injury is less apparent in early life (Moss 2007 BS;
Howard 2005 BS). These findings are of considerable importance, as pain and injury in neonates
may have effects on nociceptive processing that differ in mechanism and duration from thoseexperienced by older children and adults. There is accumulating evidence in neonatal animalmodels that there are complex interactions between increased excitatory and decreased
inhibitory synaptic signalling within the spinal cord in addition to changes in descending
inhibitory control from the brainstem in response to tissue injury during the neonatal period (see10.1 above and Beggs 2015 NR).
Neonatal pain results in an increased response to future painful stimuli months to years
after the initial insult. Neonatal circumcision without anaesthesia or analgesia is associatedwith an increased behavioural response during immunisation at 4–6 mth when vs
uncircumcised infants (Taddio 1995 Level III-2). Increased perioperative analgesia requirements
and pain scores occurred when subsequent surgery was performed months later in the samedermatome, vs children who had no previous surgery (Peters 2005 Level IV). Early pain-related
stress was associated with greater SLC6A4 methylation and greater behavioural problems asassessed by the Child Behaviour Checklist in ex-extreme to very preterm children at age 7 y vsfull term controls, but only in individuals with the COMT 158 Met/Met genotype (Chau 2014
Level III-2, n=111).
Ex-preterm preschool children show alterations in pain-related behaviour such as increased
somatisation (Grunau 1994 Level IV) and ex-NICU school-aged children had higher levels of painrelated catastrophisation (Hohmeister 2009 Level III-2). In ex-NICU preterm children andadolescents, thermal pain thresholds were reduced at age 9–14 y (Hermann 2006 Level III-2), andat 11 y in ex-extreme preterm children born at <26 wk gestation (along with reduced thermal
and mechanical sensitivity around their neonatal thoracotomy scars) ( Walker 2009 Level III-2).
Increased gain in pain pathway signalling was seen at 11–16 y on functional magnetic resonanceimaging (fMRI) in response to painful heat stimulus (Hohmeister 2010 Level III-2) and responses
were enhanced to noxious stimuli (dolorimetry and number of tender points) vs term peers

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at age 12–18 y, more so in girls (Buskila 2003 Level III-2). The clinical significance of these findings
is uncertain.
A prospective cohort study of children born in 1958 investigated the association of chronic
widespread pain in adulthood with “early trauma” (Jones 2009 Level III-2, n=7,571). It found noassociation between surgery in childhood before the age of 7 y (RR 1.0; 95%CI 0.9 to 1.1) but
positive association for hospitalisation following a road traffic accident (RR 1.5; 95%CI 1.1 to 3.0).
A later survey of this British cohort showed no increased risk of chronic widespread pain at 45 y
in ex-premature adults (RR 1.26; 95%CI 0.95 to 1.67) (Littlejohn 2012 Level III-2, n=8,572).

10.2.3 | Modification by pain management intervention
Importantly, analgesia at the time of the initial painful stimulus may modulate long term adverse
effects. The behavioural response to immunisation of male infants was reduced in those who
had neonatal circumcision with local anaesthetic applied prior to surgery, vs neonates who had
no local anaesthetic (Taddio 1995 Level III-2). Infants undergoing surgery in the neonatal period
who received morphine did not show any increase in response to later immunisation vs infants
without significant previous pain experience (Peters 2003 Level III-2). The quality of pain
management in the NICU setting may also be important. Very preterm infants cared for in NICUs
with high-quality infant pain management (ie use of pharmacological and nonpharmacologicaltreatments for procedural pain, use of pain assessment tools and guidelines for preventing andtreating pain) had better neurobehavioural outcomes vs low-quality scoring NICUs (Montirosso
2012 Level IV).
Further research is required to determine the most developmentally appropriate andeffective analgesia regimens for modulating the effects of early pain and injury. This research
will be challenged in its capacity to identify the impact of a single analgesic intervention as inand out-patient ‘care packages’ have evolved including nonpharmacological intervention to
support preterm and term neonates in intensive care (Provenzi 2018 Level IV SR [PRISMA], 9 studies,
n=1,516; Valeri 2015 Level IV SR [PRISMA,] 13 studies, n unspecified) and procedural interventions ininfants and younger children (see procedural Section 10.7).

KEY MESSAGES
1. Pain and injury in early life cause structural changes in cortical and subcortical pathways
and are associated with alteration in somatosensory thresholds in later life (U) (Level III-2).
2. Analgesia may modulate the long term effects of pain and injury in early life but more
information is required to determine the optimal dosing and type of agents to avoid
negative impact of the pharmacological intervention itself (U) (Level III-2).
3. Improving quality of infant pain management delivery in neonatal intensive care(including pharmacological and nonpharmacological interventions) may result in
improved neurodevelopmental outcomes (U) (Level III-2).
4. Understanding of the epigenetic factors that contribute to the behavioural pain
trajectory is evolving; this may lead to enhanced developmentally targeted care to
reduce stress exposure and long term impacts for infants (N) (Level IV SR [PRISMA]).

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10.3 | Paediatric pain assessment
Pain assessment is a complex social interaction, with multiple factors contributing to the child’s
pain experience, its expression, subsequent interpretation and response (Voepel-Lewis 2012 NR).
Assessment is a prerequisite to optimal pain management; it should involve a clinical interview
with the child and/or their parent/carer, physical assessment and use of an age and contextappropriate pain intensity measurement tool (Howard 2008a NR). However, pain in hospitalised
children remains common and is often under assessed and inadequately managed (WaltherLarsen 2017 Level IV, n=570 [4 hospitals]; Friedrichsdorf 2015a Level IV, n=178). Improvements in pain
management and in patient, parent and staff satisfaction have been associated with regularassessment and measurement of pain (Deindl 2013 Level IV). Uniformity within an institution lends
to staff familiarity. This and ease of use are major factors in the successful implementation of apain management strategy. Adoption of written guidelines or pain management algorithms
improved both assessment and management of pain in neonates and children (Williams 2019
Level IV SR 20 studies, n=6,390; Stevens 2014b Level III-2, n=3,822; Gharavi 2007 Level IV, n=225 neonatal
units; Falanga 2006 Level IV, n=56). Clinical interventions have focussed usually on assessment ofpain intensity (and rescue analgesic use). As in adults, domains of pain other than intensity(eg location, quality), the multidimensional nature of the pain experience (eg concomitantemotional distress, coping style of the child, previous pain experience) and parental expectations
should be incorporated into overall assessment (Pillai Riddell 2013 Level IV, n=458 to 574; Liossi 2007
Level IV, n=45).
Verbal self-report is considered to be the best measure of pain in adults. Child self-report isdesirable but not always possible, as a child’s understanding of pain and their ability to describe
it changes with age; while cognitive impairment alters a child’s capacity to contribute to anassessment of their pain experience. Therefore, the measurement tools employed must be
appropriate to the developmental stage. A range of alternative assessment methods have been
established as surrogates for/or adjuncts to self-report. These include assessment scales
incorporating observable behaviours, physiological markers and brain imaging techniques. Over
65 paediatric pain scales are published (Andersen 2017 Level IV SR of S [PRISMA], 12 SRs [number ofstudies & n unspecified]), examples of which are listed in Tables 10.1 to 10.4. These scales can be
unidimensional (behavioural indicators only) or multidimensional (combining behavioural,
physiological or contextual factors). Assessment should be expanded to evaluate aspects thatare relevant to the patient and their family and the clinician, and include tools measuring global
satisfaction, adverse effects, assessment of the emotional and financial impact, and physicalrecovery following paediatric acute pain (Walco 2018 GL; Berde 2012 NR; McGrath 2008 GL).

10.3.1 | Pain assessment in neonates
Noxious stimuli have deleterious short and long term effects on the developing neonate (Valeri
2015 Level IV SR [PRISMA], 13 studies, n unspecified) making recognition and management of pain
crucial in this age group (see also Sections 10.1 and 10.2).
10.3.1.1 | Uni- and multi-dimensional neonatal pain scales
Over 40 scales have been developed for neonates and infants ( Lee 2014 NR). These scales arecomprised of overlapping combinations of surrogate measures (eg physiological signs such asincreased heart rate) or behavioural responses (eg facial characteristics and cry). Choice of themost appropriate tool depends on contextual factors (the infant’s age, health status), thestimulus (eg procedural or postoperative pain and whether repeated acute episodes ─ also
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termed recurrent or “persistent” pain) and the purpose of the measurement (eg clinical care or
research).
Table 10.1 lists examples of uni- and multi-dimensional scales used in neonates.
10.3.1.2 | Physiological measures used in neonatal pain assessment
Changes in physiological parameters associated with procedural interventions are assumed toindicate the presence of pain, including increases in heart rate (HR), respiratory rate, bloodpressure, intracranial pressure, cerebral blood flow and palmar sweating; and decreases inoxygen saturation, transcutaneous CO2 tension and vagal tone (Cong 2013b NR). As these changes
are reduced by analgesia, they have been considered useful surrogate outcome measures ofpain. Researchers have pursued the use of physiological parameters as objective measures ofpain, particularly for preterm neonates (born at 24 to <36 wk). However, as their sensitivity andspecificity are influenced by concurrent clinical conditions (eg HR increase with sepsis, illness
severity, prematurity) and other factors (eg distress, environment, movement), they are
predominantly experimental, have limited clinical utility and should be used in conjunction withbehavioural measures.
Heart rate variability
Heart rate variability (HRV) analyses the R-R interval as a noninvasive marker of autonomic
sinoatrial node input. It decreased during procedures ( Padhye 2009 Level IV) and withpostoperative pain (Faye 2010 Level IV). This contrasts with changes seen in adults withexperimentally induced pain where HRV generally increases (Koenig 2014 Level IV SR [PRISMA], 20
studies, n=642).
Skin conductanceSkin conductance measures palmar/plantar stress-induced sweating electrically. In a review, skinconductance correlates with 3 unidimensional pain scales (ABC Pain Scale, 1 study; Neonatal
Facial Coding System (NFCS), 1 of 2 studies; Comfortneo, 1 of 2 studies), crying time (1 study)
and with one of two arousal/movement scales (Prechtl Scale: 8 studies). It has low positive
predictive value for moderate pain (NFCS>4/10) and does not correlate with HR (in 6 of 8
studies), O2sat (6 studies), respiratory rate (2 studies), or multidimensional pain scales (8 studies)(Hu 2019 Level IV SR [PRISMA], 28 studies, n=1,061). Study results assessing the impact of gestational(10 studies) and postnatal (9 studies) age are conflicting. Counterintuitively, skin conductancecan be increased following oral (PO) glucose (Solana 2015 Level IV; Munsters 2012 Level IV). Due tothe inconsistent results, skin conductance cannot be recommended for pain assessment inneonates (Hu 2019 Level IV SR [PRISMA], 28 studies, n=1,061).
Near infrared spectroscopy
Near infrared spectroscopy (NIRS) measures changes in haemoglobin oxygenation to calculate
cerebral blood flow as a proxy for neuronal activity. Regional cerebral blood flow increases in thesomatosensory cortex, contralateral to the side receiving a painful stimulus. Two systematic
reviews have assessed NIRS correlations with other pain assessment scales ( Relland 2019 Level IV
SR [PRISMA], 8 studies [NIRS], n=237; Benoit 2017b Level IV SR [PRISMA], 9 studies [NIRS], n=272) (7 study
overlap). NIRS correlated with Premature Infant Pain Profile (PIPP) particularly for the facial
expression component (r 0.53 for the right prefrontal area: Ozawa 2011 Level III-2, n=80) (r 0.57:
Slater 2008 Level IV, n=12 [33 tests]) and Neonatal Facial Coding System (NFCS) scores (r 0.27─0.41:
Roue 2018 Level IV, n=133) but not with Faces Legs Arms Cry Consolability (FLACC) scores (Ranger
2013a Level IV, n=42) or Neonatal Infant Pain Scale (NIPS) (Bembich 2015 Level IV, n=16).
Confounders include gestational age, activation of nearby motor cortex, sleep-wake cycle andprevious pain exposure (Bembich 2016 Level IV, n=16; Ozawa 2011 Level III-2, n=80). Of note, one892

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third of infants showed NIRS responses without facial changes during some procedures (Slater2008 Level IV, n=33 tests). Similarly NIRS and electroencephalography (EEG) changes do notconsistently co-occur in neonates following innocuous cutaneous stimulation ( Verriotis 2016b
Level III-2, n=36). Use of NIRS for pain assessment requires further research.
Neurophysiological monitoring
Using scalp EEG, a pain-specific response that correlates with the spinal withdrawal reflex (1 RCT),and is reproducible, dependent on stimulus intensity and independent of sleep state isdemonstrated in preterm and term neonates and infants ( Relland 2019 Level IV SR [PRISMA],
7 studies [EEG], n=265; Benoit 2017b Level IV SR [PRISMA], 8 EEG, n=298) (4 study overlap). A templateof brain activity that is sensitive to analgesic administration and quantifies procedural pain inneonates has been identified (Hartley 2017 Level IV, n=18). Data has also demonstrated temporal,
topographic and amplitude patterns in EEG potentials evolving with neonate and infant neuralmaturation: from 28 wk gestation nonspecific neural bursts transition to specific somatosensory
tactile and nociceptive potentials at 35–37 wk (Green 2019a Level IV, n=122; Fabrizi 2016 Level IV,
n=18 infants & 21 adults; Fabrizi 2011 Level IV, n=30 term & 30 preterm). The EEG evolution correlateswith development of discriminative facial expression from 33 wk gestational age (Green 2019aLevel IV, n=122). Additionally, sex-related differences in cortical pain responses in females wereconsistent with those of adult females (Verriotis 2018 Level III-2, n=81), with individual differencesin neonates in simultaneously recorded EEG and NIRS data ( Verriotis 2016b Level III-2, n=36).
Researchers reported that PO sucrose reduced PIPP score but did not alter cortical nociceptive
activity to heel lance (Slater 2010 Level II, n=59, JS 5), and controversially concluded that sucrose
may not be an effective analgesic. Scalp EEG measurement has shown promise as a surrogate
measure of neonatal pain.
Functional magnetic resonance imaging
Functional magnetic resonance imaging (fMRI) to study brain responses to pain in neonates has
gained attention (Benoit 2017b Level IV SR [PRISMA], 2 studies [fMRI]: details below). Some similarities
are seen in the unique patterns of activity between the neonatal and adult brain in response topainful stimuli (Goksan 2015 Level IV, n=10 infants & 10 adults), including when sedated with chloral
hydrate (Williams 2015 Level IV, n=19 infants). However, the role that this modality may play in pain
assessment is still unclear.
Stress markers
Markers of stress have been measured in infant pain studies. In critically ill neonates postcardiac
surgery, plasma but not urinary cortisol rose (Franck 2011 Level IV, n=81). In healthy newborns,
salivary chromogranin and amylase did not change peri-heel lance (Shibata 2013 Level IV, n=47), while
salivary cortisol rose after venipuncture and correlated with NFCS scores (r 0.42: Roue 2018
Level IV). In expreterm neonates in NICU, salivary cortisol was measured in patients receiving painfulstimuli (8 studies: 5 heel lance), physical examination and heel lance (2 studies), and standard (2studies nappy change; 1 study prone positioning) vs pleasant handling (3 studies) (Morelius 2016
Level IV SR [PRISMA], 16 studies, n=1,027). Plasma and salivary (but not urinary) cortisol rises withpainful procedures, is modified by intervention (cocaine, prone positioning and music), while
salivary cortisol does not change with non-painful handling eg nappy change. The review suggests
future study designed to address the gaps in our understanding of cortisol regulation in neonates.
Integrated multimodal measurement
An integrated system (NIRS, EEG, electrocardiograph [ECG], electromyelograph [EMG],
combined with physiological and behavioural indices) is likely to provide the most reliable andreproducible measurements of noxious stimulation (Roue 2018 Level IV, n=113; Worley 2012
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Level IV, n=6). This expensive system may feasibly assist bedside tool validation but is unlikely toplay a direct role in pain assessment.
10.3.1.3 | Behavioural measures used in neonatal pain assessment
Noxious stimuli produce a series of behavioural responses in neonates and infants that can beused as surrogate measures of pain including crying, changes in facial activity, torso and limb
movement, consolability and sleep state (Chorney 2014 NR).
CryingCrying is described in terms of presence or absence, duration, amplitude or pitch. Up to 20% of
preterm and some acutely ill infants do not cry or cry inaudibly during heel stick ( Johnston 1999
Level IV). Amplitude or audible cry occurrence did not correlate with nociceptive brain activity
measured with NIRS (Bucher 1995 Level IV) and EEG (Relland 2019 Level IV SR [PRISMA], 1 study [cryresponse]: Maitre 2017 Level IV, n=54).
Facial expression
Facial expression in response to pain is widely studied and forms part of a number of pain scales,for preterm neonates up to school-aged children (Schiavenato 2012 Level IV, n=63) (see Tables 10.1
to 10.3). In neonatal intensive care, facial actions were more reliable than physiological measuresfor evaluating pain responses (Stevens 2007 Level IV) but may be dampened in preterm neonates(Green 2019a Level IV, n=122; Slater 2008 Level IV, n=12 [33 tests]; Holsti 2007 Level IV, n=92) and, like
cry, may be absent (Hartley 2017 Level IV, n=18; Slater 2008 Level IV, n=33 tests), not linked to
nociceptive brain responses (Hartley 2017 Level IV, n=18) or be present only if previous noxious
stimulus has been experienced (Ozawa 2011 Level III-2, n=80). The use of video recordings fortranslation to pain scales’ graphics (Schiavenato 2012 Level IV, n=63) has been superseded by facialrecognition software. The latter has been validated with various neonatal and infant observer
pain scales and provides automated identification of the expression of pain ( Sakulchit 2019
Level IV, n=77; Xu 2018b Level IV, n=143; Zhi 2018 Level IV, n=26 [204 images]; Zamzmi 2018 Level IV, n=8[15 videos]; Heiderich 2015 Level IV, n=30 [360 images]) and may overcome clinician bias whenassessing facial expression (Blais 2019 Level IV, n=20 [adults]).

Contextual influences
Contextual factors include physical, psychological and social elements. A number of contextual
factors influence the specificity and sensitivity of behavioural responses in ex-preterm neonates(Sellam 2011 Level IV SR [PRISMA], 23 studies, n=1,649). Pain can be affected by behavioural state(awake, asleep, activity prior to a stimulus), distress for other reasons (eg hunger and fatigue), age(postmenstrual and postnatal) and neuromuscular developmental status. Previous pain exposureand handling (Ozawa 2011 Level III-2, n=80; Holsti 2006 Level IV, n=43) altered both behavioural andphysiological responses, eg infants experiencing higher numbers of procedures have reduced facial
expression in response to pain, reduced nociceptive brain activity (Ozawa 2011 Level III-2, n=80),
reduced brain maturation (Ranger 2013b Level IV, n=42; Brummelte 2012 Level IV, n=86) and long termalteration of their pain pathway processing on MRI (Hohmeister 2010 Level III-3, n=27). Sex differences
are inconsistent: female vs male neonates, both preterm and term, have more facial actions(Verriotis 2018 Level III-2, n=81; Guinsburg 2000 Level III-2, n=65) but no difference in PIPP scores or
cortical activity (Ozawa 2011 Level III-2, n=80) and, in preterm infants only, no difference in NFCS
scores (Valeri 2014 Level III-2, n=53). In most studies, severity of illness or neurological impairment
was not associated with altered behavioural pain responses. However, data in term infant NICU
patients suggested that stress and illness impacts on cortical activity in the absence of behaviouralchanges (Jones 2017 Level IV, n=56). Surveyed health providers’ knowledge gaps and attitude affectscoring and provision of pain relief (Cong 2013a NR).

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Observational scales
The reliability and validity of behavioural measures is best established for proceduralinterventions such as heel lance but many observational scales have not been rigorously
evaluated (Meesters 2019 Level IV SR, 9 studies, n=645). The PIPP (Stevens 2010 Level IV SR, 62 studies,
n=3,158) and COMFORT scales (Maaskant 2016 Level IV SR [PRISMA], 30 studies, n=2,593) are the best
validated and most widely used (McGrath 2008 GL). The PIPP-revised (PIPP-R) has had validation
initially (Stevens 2014a Level IV, n=137) and after translation into 6 other languages (Bueno 2019
Level IV, n=187; Olsson 2018 Level IV, n=37; Taplak 2019 Level IV, n=200). The FLACC scale, developedfor infants >2 mth old, was used in hospitalised neonates with simultaneous assessment with
PIPP in a skin conductance study (Ahmed 2015 Level IV, n=85 [measurements]).
The following scales are recommended in reviews spanning a decade (Eriksson 2019 NR;
Hatfield 2015 Level IV SR, 10 studies n=742; Lee 2014 NR; Cong 2013b NR; Howard 2008a NR). They aresupported by current data (see Tables 10.1 and 10.2 with relevant references) acknowledging
that the evidence supporting the psychometrics of recommended scales is usually Level III or IV(Andersen 2017 Level I [PRISMA], 12 SRs (number of studies & n unspecified):• Acute procedural pain — PIPP; Neonatal Facial Coding Scale (NFCS); Neonatal Pain,
Agitation and Sedation Scale (N-PASS);• Postoperative pain — PIPP; N-PASS;• Intensive care — COMFORT; COMFORTneo; COMFORT B (for repeated acute pain
exposures termed “persistent” pain in intensive care patients); Faceless Acute Neonatal
Pain Scale (FANS) (when facial expression is concealed eg with nasal continuous positive
airway pressure) (Milesi 2010 Level IV, n=53).

10.3.2 | Pain assessment in infants and children
Observational and behavioural scales
Assessment for infants and young children is largely achieved using observational assessment
scales. Many scales incorporate both physiological and behavioural parameters to determine
an overall pain score and may result in more comprehensive measurement (Lee 2014 NR;
Chorney 2014 NR). Some examples are included in Table 10.2 but a wider range of measures,
their strengths and limitations and issues of testing reliability and validity have been reviewed(von Baeyer 2007 Level IV SR, 129 studies, n unspecified; Chorney 2014 NR; Lee 2014 NR; van Dijk 2012
NR; McGrath 2008 GL; Johnston 2003 NR). In infants and young children, behavioural items thatpredicted analgesic demand in the postoperative period were crying, facial expression, trunkand leg posture and motor restlessness, but physiological variables were unreliable ( Buttner
2000 Level III-2).
There is still no single gold standard for pain assessment as requirements vary with the age
and developmental stage of the child, the type of pain (eg procedural vs postoperative), and thecontext (eg clinical utility vs research reliability). Based on reviews summarising the wide dataon this topic, the following observational/behavioural measurement tools are recommended forpain measurement in infants ≥1 y (McGrath 2008 GL), children and adolescents (Crellin 2015 Level
IV SR [PRISMA], 52 RCTs & 26 psychometric studies, n unspecified; von Baeyer 2007 Level IV SR, 129 studies,n unspecified; Crellin 2018 Level IV, n=100; Chorney 2014 NR) (see Table 10.2):• Acute procedural and postoperative pain — FLACC;• Postoperative pain managed by parents at home — Parents Postoperative Pain Measure(PPPM); and• Intensive care — COMFORT & COMFORT B scales.

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10.3.3 | Self-report in children and adolescents
10.3.3.1 | The change in capacity of children to self-report with age
Self-report of pain is preferred when feasible, and is possible to an extent from 4 y of age,dependent upon the child’s cognitive and emotional maturity. Scales for self-report need toconsider the child’s age, their ability to differentiate intensity levels, and their ability to separate
the emotional from the physical components of pain ( von Baeyer 2014 NR) (see Table 10.3). It is
important that a measurement tool be used regularly and uniformly within each centre as staff
familiarity and ease of use are major factors in the successful implementation of a pain
management strategy. Children aged 3 y cannot provide valid graded self-report of pain
intensity, and the evidence is weak for the capacity of those aged 4 y with published scales ( Birnie
2019 Level IV SR [PRISMA], 80 studies, n unspecified; von Baeyer 2017 Level IV SR [PRISMA], 14 studies
n=766) (8 study overlap). For 4 y olds and some 3 y olds, performance can improve by confirming

pain is present, then providing an explanation of the scale with a reduced number of choices (eg3 choices with the Simplified Faces Pain Scale or Pieces of Hurt: low, medium, high hurt). From 5 y,
the standard 6 choice Faces Pain Scale-revised (FPS-R) (Figure 10.1) can be used and provides
extra data (Emmott 2017 Level II, n=180, JS 3). At around 5 y, children have some capacity toappraise current pain and match it to previous experience, but they are more likely to choose
the extremes of the scale (von Baeyer 2009b NR). In scales anchored with smiling or tearful faces,
pain may be confused with other emotional states such as happiness, sadness or anxiety(Tomlinson 2010 Level IV SR, 127 studies, n=17,372).
Between ages 7–10 y, children develop numerical competency skills with measurement,
classification and seriation (ie placing things in ascending or descending order). The upper endof the scale is less static than in adults changing with the individual child’s ability to objectify,label and remember previous pain experiences (von Baeyer 2014 NR). Literacy is also important
regarding the wording associated with the scales’ upper anchor (such as most pain or worst pain
imaginable vs very much hurt); this is also relevant for between study consistency ( Castarlenas2017 Level IV SR [PRISMA], 15 studies n=2,174; von Baeyer 2009a NR).
It is not until 10–12 y that children can clearly discriminate the sensory intensity and theaffective emotional components of pain and report them independently ( McGrath 1996 Level III2). Verbally competent children aged ≥12 y can understand multidimensional tools designed for
adults such as the McGill Pain questionnaire (MPQ) (see below).
10.3.3.2 | Unidimensional pain intensity paediatric self-report scales
Of sixty self-report scales, only eight have well established reliability and validity for acute pain
assessment in children and adolescents (aged 3–18 y): Pieces of Hurt tool (scored 0–4); Faces
Pain Scale-Revised (FPS-R) (0–10); Oucher pain scale photographic and numeric scales (0–10);
Wong-Baker FACES Pain Rating Scale (WBFPRS) (0–10); Visual Analogue Scale (VAS) (0–100 mm),
Colour Analogue Scale (CAS) (0–10) and Numeric Rating Scale NRS-11 (0–10) (Birnie 2019 Level IV
SR [PRISMA], 80 studies, n unspecified).
Numeric Rating Scale (NRS)-11
The NRS-11 has the greatest number of studies assessing its measurement properties (Birnie 2019
Level IV SR [PRISMA], 24 NRS-11 studies [7 postoperative], n unspecified) including correlation between
PACU scores by children aged 4–16 y with the nurse and parent (Brahmbhatt 2012 Level IV, n=33).
This scale has been validated across a variety of paediatric settings and is available in a numberof formats (verbal/printed/electronic) (Castarlenas 2017 Level IV SR [PRISMA], 15 studies n=2,174) (14study overlap with Birnie 2019). Children <8 y may require screening tasks to assess numericalcompetency to then use the NRS-11 effectively.

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Faces pain scales (FPS)
Of the fourteen FPSs, four have undergone extensive psychometric testing: FPS, FPS-R, Oucher
and WBFPRS (Tomlinson 2010 Level IV SR [PRISMA], 127 studies, n=13,388). When given the choice,children prefer faces scales in general. The WBFPRS is most preferred but its smiling and crying
anchor faces may lead to confounding with affect and it has weak recommendation for use (Birnie
2019 Level IV SR [PRISMA], 16 WBFPRS studies [1 postoperative], n unspecified). While the FPS-R(second to NRS-11 in the number of studies assessing measurement properties) is strongly
recommended for research purposes (Birnie 2019 Level IV SR [PRISMA], 21 FPS-R studies [8postoperative], n unspecified). In the ED setting, FPS-R (Tsze 2013 Level IV, n=620) and WBFPRS (Garra
2013 Level IV, n=197) have been validated. An electronic version FPS-Re has also been validated
and is preferred by children (Birnie 2019 Level IV SR [PRISMA], 4 FPS-Re studies, n unspecified).
Coloured analogue scale (CAS)The CAS has been assessed in the same review as the above 2 scales, mostly in English (and4 other languages) and is strongly recommended for ≥8 y (Birnie 2019 Level IV SR PRISMA, 19 CAS
studies [5 postoperative], n unspecified). It is coloured from small white gradations widening up to
deep red, with a slider form with a 0─10 back measure or a pocket sized scale with variations in
the upper anchor’s wording.
Visual analogue scale (VAS)
The VAS form in children is the same as that used for adults with either a line or rule and 100mm
scale, with numerical values of 0─10 or 0─100 mm. It has been assessed in children mainly inacute pain conditions with a weak recommendation for use ≥ 8 y (Birnie 2019 Level IV SR [PRISMA],
15 VAS studies [4 postoperative], n unspecified).
10.3.3.3 | Recommended scales according to age
Using chronological age as a guide of developmental stage, the below scales are recommended
for acute pain assessment (with weaker recommendations for postoperative and chronic pain
assessment) (Birnie 2019 Level IV SR [PRISMA], 80 studies n unspecified; von Baeyer 2017 Level IV SR[PRISMA], 14 studies, n=766; Tomlinson 2010 Level IV SR [PRISMA], 127 studies, n=13,388; Emmott 2017
Level II, n=180, JS 3):

•
•
•
•

<4 y
4–5 y
Some 5y and ≥6y≥8 y—self-report unreliable—Simplified-FPS or Pieces of Hurt
—NRS-11 (which requires numerical competency) & FPS-R—CAS & VAS

The validity of the gold standard of asking for and documenting pain scores is being
questioned, due to the inherent subjective nature of self-report (von Baeyer 2014 NR; Berde2012 NR). As is occurring in paediatric chronic pain assessment (Varni 2010 Level IV, n=3,048), acutepaediatric pain measurement may warrant inclusion of measures of self and observed functional
impairment (eg post laparotomy the child is remaining in bed vs able to sit out in chair vs attend
ward play room or in-hospital school) combined with rescue analgesic use. This is particularly
relevant when self-reported pain scores are either high or low and conflict with the clinicalcontext and the paediatric clinicians’ observations (von Baeyer 2014 NR).
Paediatric pain scale investigators argue that self-report scales of pain intensity are morevaluable on a population or research level than for effective pain management for an individual
child (Twycross 2015 NR). They suggest pain scores are best considered a primary source of
information rather than a gold standard. Particularly in younger children, assessment should
combine self-report with observations of activity, parental report and consideration given to
psychosocial influences.
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10.3.3.4 | Concordance between pain scales and subdivisions within scales
Debate continues as to concordance between the various scales ( Le May 2018 NR; SanchezRodriguez 2012 NR). NRS-11 correlates with FPS-R, VAS and CAS but this does not reflectagreement or interchangeability.
The minimum clinically significant difference (MCSD) for the NRS-11 is 1/10 (Castarlenas 2017
Level IV SR [PRISMA], 4 studies [MCSD], n=496). In the ED triage setting, for the Verbal V-NRS, MCSD
and Perceived Patient Adequate Analgesia (PPAA) were both 2/10 and for the FPS-R was 2/10
and 4/10 respectively (Tsze 2019a Level IV, n=431 [344 VNRS and 415 FPS-R analysed]); the same groupassessed FPS-R with MCSD of 2/10 vs CAS which was 1/10 (Tsze 2015 Level IV, n=314).
Suggested subdivisions for no, mild, moderate and severe pain are respectively: 0 to 2, 4, 6,
and 8 to 10 for FPS-R vs 0 to 1, 1.25 to 2.75, 3 to 5.75 and 6 to 10 for CAS (Tsze 2018 Level IV,
n=620).
Suggested VAS cut-offs for children and adolescents are 35 mm for mild pain and 60 mm forsevere pain (in contrast to adult cut-offs of 30 mm and 70 mm respectively) (Hirschfeld 2013
Level IV, n=5,258). Pain intensity measurements within 12 mm on the paper VAS may beconsidered the same (Bailey 2012 Level IV, n=151).
Of importance, pain scale subdivisions or cut-offs and pain scores, as a uni-dimensional
assessment, should not be used solely to guide the administration of analgesia.
10.3.3.5 | Facial recognition software applications
Types of facial recognition software applications (relevant to infants, children and adults)
presented in computing conference abstracts over the last decade have been summarised(Subramaniam 2018 NR).
Digital burst photographs taken by iPhone® of young children during venipuncture were
imported into an Emotion Application Programming Interface (Sakulchit 2019 Level IV, n=77). A
subsequent 8 face pain scale was developed which correlated with FLACC scores (positively for‘sadness’ and negatively for neutral expression) and was sensitive to EMLA® use.
Facial videos of older children aged 5─18 y were taken post-laparoscopic appendicectomy atrest (ongoing pain) and with abdominal palpation (transient pain) at three time points(postoperatively, 20 h post and POD 21) to assess pain trajectory (Sikka 2015 Level IV, n=50). These
were analysed with a computer expression recognition toolbox. The facial action units werecompared to blinded self, parental and nursing report using NRS-11. A binary pain (4/10) vs nopain (0/10) and continuous model were developed. The computer version machine learning(CVML) system was accurate for binary classification and correlated with self and parental report(including over time). As nurses under reported pain vs child and parents, the CVML detected
pain more accurately than nurses (particularly for ongoing pain). A similar CVML process was
conducted in primarily Hispanic teenagers also at three time points post-laparoscopic
appendicectomy (within 24 h, subsequent day, and POD 25) (Xu 2018b Level IV, n=143). Withtransfer learning, the ROC curve improved to better detect true positives and was consistent
when tested on a new pain data set.
10.3.3.6 | Observer-rated or composite scales used prehospital and in EDs
The French Evaluation ENfant DOuLeur (EVENDOL) scale (0─15) for children aged 0–7 y wasdeveloped as a single observer-rated scale for pain assessment prehospital (Beltramini 2019
Level IV, n=422 [144 in pain]) and in EDs (Fournier-Charriere 2012 Level IV, n=291). It has beentranslated into English but not reviewed systematically.

898

5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENTThe UK Royal College of Emergency Medicine launched the Composite Pain Scale; thiscombines a modified WBFPRS (4 faces) (observer-rated <8 y and self-reported ≥8 y) with anobserver-rated behaviour scale, injury example prompts and NRS-11 self-report for older
children (James 2017 Level III-2, n=117). Pain scores were then categorised as absent, mild,moderate or severe. Doctors and nurses correlated well including with the older child’s face scale
report, but not with the V-NRS-11 component.
10.3.3.7 | Function scales: observed vs self-report
As in paediatric chronic pain assessment (Varni 2010 Level IV, n=3,048), acute paediatric pain
measurement may warrant inclusion of measures of self and observed functional impairment(eg post laparotomy the child remaining in bed vs able to sit out in chair vs attend ward playroom or in-hospital school) and rescue analgesic use.
An in-hospital Youth Acute Pain Functional Ability Questionnaire has been developed inchildren admitted with sickle cell crises and subsequently validated in children post-surgery(Rabbitts 2017 Level IV, n=564). A 3 item short form with 5 point Likert rating of capacity to dress,
wash and go outside the room was developed (assuming normal baseline capacity). Functional
capacity is particularly relevant when self-reported pain scores are either high or low and conflictwith the clinical context and the paediatric clinicians’ observations ( von Baeyer 2014 NR).
10.3.3.8 | Multidimensional pain intensity self-report scales for adolescents
One tool modelled after the MPQ, the Adolescent Pediatric Pain Tool assesses pain with a body
diagram, word intensity scale and multiple quality descriptors ( Fernandes 2014 Level IV SR, 23
studies, n=1,750 children & adults). It has been validated in multiple settings: acute and chronic
pain, hospital, home, and in English and Spanish (pending further validation in Portuguese andChinese). The extra dimensions are useful to examine effectiveness of pain management but
pen/paper and 3─6 min time is required to complete it, and further validation in interventional
studies and consistency scoring across studies is needed.

10.3.4 | Children with cognitive impairment or intellectual disability
Most children with intellectual disability (ID) or severe cognitive impairment (CI) experience pain
proportional to their degree of neurological impairment (Hauer 2017 NR) and probably in a similar
way to their peers. However, there are some examples of disorder-specific alterations in pain
perception eg the higher pain and temperature threshold seen in patients with Prader-Willi
syndrome (de Knegt 2011 NR). In addition, children with ID/CI or communication difficulties(including neonates at risk of neurological impairment in intensive care) may experience more
pain episodes than other children because of their associated complex medical
disorders/neurological impairment, physical comorbidities and increased need for procedures(Stevens 2003 Level III-2, n=194; Hauer 2017 NR; Breau 2009 NR). Both neonates (who were perceived
in the past as being less responsive to painful stimuli) (Breau 2006 Level III-2, n=99 [clinicians];
Stevens 2007 Level IV, n=149) and older children with CI (Valkenburg 2012 Level III-3, n=45 [15 Downs
syndrome]) have received less analgesia vs peers. Assessment of pain is difficult in ID/CI,
particularly in the severe neurological impairment cohort, and can contribute to inadequate
analgesia (Hauer 2017 NR). Older children with CI received less analgesia during surgery but
comparable amounts and types of analgesics as cognitively intact children postoperatively(Valkenburg 2012 Level III-3, n=45; Long 2009 Level III-3, n=148; Koh 2004 Level III-2, n=290) contrastingwith the findings in an earlier series (Malviya 2001 Level III-3, n=42).

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10.3.4.1 | Pain assessment scales for children with neurodevelopmental disorders and severe
cognitive impairment (CI)
Observer-rated scales
Specific observer-rated behavioural tools have been developed for children withneurodevelopmental disorders and severe CI (Crosta 2014 Level IV SR, 7 studies [4 tools], n≈270;
Valkenburg 2010 NR) (see Table 10.4). Behaviours reported by carers to be associated withpotentially painful stimuli, and that discriminate these from distressful or calm events, havebeen compiled in the revised Non-Communicating Children’s Pain Checklist (NCCPC-R) for
home (Breau 2002a Level IV) and postoperative use (NCCPC-PV) (Crosta 2014 Level IV SR 1 study:
Breau 2002b Level IV, n=24). Cut-off scores for NCCPC-PV were developed against VAS scores,
with good inter-observer reliability between primary carer and the researcher who had not
met the child. It has been translated and validated in French, Swedish and German. NCCPC
does not need to be individualised for the patient, it discriminates distress from pain but was
rated least desirable by clinicians based on complexity and length (2 h observation) vs otherscales (Quinn 2015 NR). The NCCPC scales have formed the basis of validated adult scales –Chronic Pain Scale for Non-verbal Adults with Intellectual Disabilities (CPS-NAID) (24 items for
persistent pain) and Non-Communicating Adult Pain Checklist (NCAPC) (18 items for
acute/procedural pain) ( Breau 2009 NR).
The Paediatric Pain Profile (PPP) rates 20 behaviours to assess pain in children withneurodevelopmental disorders and severe CI (Crosta 2014 Level IV SR, 1 study: Hunt 2004 Level IV,
n=140). It includes the child's pain history, baseline and ongoing pain assessments, interventions
and discussion with clinicians about the child's pain but does not require knowing the individual
behaviours. This scale had demonstrated potential for children with recurrent acute (persistent)
pain at home but was less sensitive perioperatively. Its usability is limited by its teachingrequirements and length (Crosta 2014 Level IV SR). The PPP is validated and used across all Gross
Motor Function Classification System (GMFCS) levels of cerebral palsy (CP) (Kingsnorth 2015
Level IV SR, 240 studies, [54 chronic pain assessment tools screened]). It is more accurate but takes
longer (5 min vs 1) and is less preferred than revised (r)FLACC (see below). Of note (as withneonates), salivary cortisol measurement in children with severe neurological disability was notfound a useful marker for pain assessment (Hunt 2007 Level IV, n=29).
An Individualised Numeric Rating Scale (INRS), where carer proposed pain indicators areranked on a 0–10 NRS scale, has been validated for pain assessment in children with severe CI(Crosta 2014 Level IV SR, 1 study: Solodiuk 2010 Level IV, n=50). The bedside nurse INRS scores
correlated with but were lower than the carer’s assessment, with only modest correlation with
NCCPC-PV. INRS use fosters carer and nurse collaboration. As it is developed with input fromcarers and educators, it may be the best option for school nurses ( Quinn 2015 NR).
The rFLACC scale (0–10), incorporating specific descriptors and parent-identified behaviours
for individual children, has also been developed for children with severe CI (Crosta 2014 Level IV
SR, 1 study: Malviya 2006a Level IV, n=52). It remains the easiest, preferred and most flexible tool to
use in the acute hospital setting (Crosta 2014 Level IV SR, 7 studies, n≈270). Compared to VASobserver (0─10), rFLACC (Danish) was valid and reliable for pain assessment post-orthopaedic
surgery in children with CP GMFCS II─V; 2 nurse observers experienced in nursing children with
CP scored video-recordings and had high intra-rater reliability (Pedersen 2015 Level IV, n=27).
When assessing videotapes without audio of children with CP (all GMFCS grades I to V) having
physiotherapy, the Child Facial Coding System (which codes 13 facial actions; 10 of which indicate
pain not present) correlated with observer-rated NRS-6 (Hadden 2016 Level IV, n=85). Future work
using pain expression facial coding combined with facial recognition software and computer

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learning algorithms may be useful in children who cannot self-report, as is being explored for
adults with dementia (eg PainChek®) (Atee 2018 NR).
Self-report scales in children with neuromuscular disorders and lower degrees of cognitive
impairment
Self-report scales may not be reliable even in those with mild to moderate CI (Quinn 2015 NR). For
physically disabled children aged 8–20 y with various neuromuscular disorders and no CI, selfreport with NRS outperformed the WBFPRS (4 faces) and 6 point Verbal rating scale (Miro 2016
Level IV, n=113). A study assessed self-report NRS-6 (0–5) vs observer-rated NCCPC-PV in children
with CP of varying severity (diplegic 32% to quadriplegic 54 %) having physiotherapy (Hadden 2015
Level III-2, n=63). The children had their hearing, vocabulary and receptive knowledge assessedand 52% were able to self-report. Carer ratings were lower than ratings by researcher,
physiotherapist and the child capable of self-report.
10.3.4.1 | Children with Autism Spectrum Disorder (ASD)
ASD is a developmental disorder affecting communication, socialisation and sensory processing
to varying degrees, which may influence the reliability of the pain assessment scales (Allely 2013
Level IV SR [PRISMA], 10 studies & 5 case reports, n=1,137). Assessment is further complicated by thefrequent comorbidities of altered perception (hypo and hypersensitivity), anxiety, attentional
deficient disorder and ID. Typical pain behaviours (pain expression) may be absent in somepatients, which does not reflect an absence of pain perception and can lead tounderappreciation, even by carers. In fact, individuals with ASD who self-injure may have pain
insensitivity (Allely 2013 Level IV SR [PRISMA] , 10 studies & 5 case reports, n=1,137) or enhanced pain
expressions (Courtemanche 2016 Level III-3, n=51). For children with limited understanding of
graded response, carers should be asked to complete individualised pain behaviours on therFLACC scale. For children with ASD who are verbal and can grade response, a qualitative
perioperative study recommends the following (Ely 2016 Level IV, n=40):• Individualise care by using words familiar to each child;• Describing pain is possible and often preferred to using a numerical scale ─ extremes are
selected when using self-report scales;• Locating pain is a favoured technique to start with ─ most can describe but some find thisanxiety provoking;• Children frequently rely on their parents to confirm or validate their report or to interpretbehaviours/social cues;• Facial expressions and body language often do not match pain scores or descriptors of
pain intensity.
For pain assessment in less acute daily living, NCCPC (French) with some modifications for
ASD behaviours was useful (Dubois 2017 Level IV, n=35).

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KEY MESSAGES
1. Pain measurement tools are available for children of all ages (S) (Level IV SR).
2. Paediatric pain measurement tools must be matched to the age and development of
the child (U) (Level IV SR).
3. Adoption of written guidelines or pain management algorithms improves bothassessment and management of pain in neonates and children (N) (Level IV SR).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Pain assessment and measurement are important components of paediatric pain
management (U).
 Pain scores generated from different pain scales may not be congruent and this should
be considered when used clinically and in research (N).
 Pain scores and pain score subdivisions (cut-offs) should not be used as a sole guide toadministration of analgesia (N).
 Children with neurodevelopmental disorders (with and without cognitive impairment
and varying levels of physical disability) may be more susceptible to pain andcommunicate it in different ways (N).
 Pain measurement tools must be appropriate for the clinical context, be explained andused consistently (U) and be validated when translated into other languages (Q).
 Facial recognition software applications may reduce clinician bias and become useful
bedside tools in neonates and children with and without cognitive impairment (N).

Figure 10.1 | Faces Pain Scale — Revised

Numbers are
not shown to
child

Note:

The full-size version of the FPS-R, together with instructions for administration (available inmany languages), are freely available for non-commercial clinical and research use fromwww.iasp-pain.org/FPSR.

Source: FPS-R; (Hicks 2001); adapted from (Bieri 1990).
Copyright ©2001 IASP. Used with permission.

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Table 10.1 | Acute pain intensity measurement tools — neonates
Scale

Indicators

Score

Utility

Brow bulge
Deep nasolabial foldEyes squeezed shut
Open mouth
Taut tongue
Horizontal mouth stretch
Vertical mouth stretch
Pursing of lips
Chin quiver
Tongue protrusion

Presence or absence ofaction during discrete
time intervals scored

Preterm to
4 mth
Procedural
pain

Postmenstrual age
Behavioural stateHeart rate
Oxygen saturation
Brow bulge
Eye squeeze
Nasolabial furrow

Each scored on 4-point
scale (0,1,2,3)≤6 = minimal pain;>12 = moderate tosevere pain
In the revised form
postmenstrual age andbehavioural state
points are only applied
if other variables
indicate pain.

Proceduralpain inpreterm andtermneonates;
Postoperative
pain in termneonates

Facial expression
Cry
Breathing patterns
Arms
Legs
State of arousal

Each scored on 2 (0,1)
or
3-point (0,1,2) scale;total score: 0–7

Preterm andtermneonates;
Procedural
pain

CryingRequires oxygen for SaO2
>95%
Increased vital signs(heart rate/bloodpressure)
Expression
Sleeplessness

Each scored on 3-point
scale (0,1,2);
total score: 0–15

32–60 wk
Postoperative
pain

Unidimensional
NFCS
Grunau 1987
Johnston 1993

Multidimensional
PIPP
Stevens 1996

PIPP-Revised(PIPP-R)
Stevens 2014aNeonatal Infant
Pain Scale (NIPS)
Lawrence 1993

CRIES
Krechel 1995

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ScaleIndicators

Score

Utility

N-PASS

Crying/irritability
Behavioural state
Facial expression
Extremities tone
Vital signs (heartrate/bloodpressure/SaO2)

Each scored on 5-point
scale (-2,-1,0,1,2);
Total score: -10 to +10
with minus scoresreflecting responses if
sedatedExtra point added forprematurity <30 wk
Score >3 indication fortreatment

23–40 wk
Postoperative
pain;
Procedural
pain;
Persistentpain;
Sedationlevel

Alertness
Calmness/agitation
Respiratory response(ventilated) or crying(spontaneous ventilation)
Body movement
Facial tension
Muscle tone

Each scored on 5-point
scale (1–6);
total score: 6–30
Score >14 indicating
moderate-severe
pain/distress

24–42 wk
Prolonged
pain;
Sedation

Acute discomfort
Limb movements
Vocal expression
Heart rate variation

Each scored differently;
total score: 0–10
Nonintubated but face
not visible

30–35 wk
Procedural
Pain

Hummel 2008

COMFORTneo
Modified from
COMFORT B
van Dijk 2009

FANS
Milesi 2010

Note:

Further details available in Lee 2014; Cong 2013b; Howard 2008a; Bandstra 2008.

Table 10.2 | Composite scales for infants and children
Scale

Indicators

Score

Utility

CHEOPSCry
Facial expression
Verbal expression
Torso position
Touch
Leg position

Each scored as
0, 1, 2 or 3;
total score
4–13

1–7 y
Postoperative pain;
Procedural pain

Face
Legs
Activity
Cry
Consolability

Each scored on
3-point scale(0,1,2);
total score
0–10

Young children
Postoperative pain

Alertness
Calmness/agitation
Respiratory response
Physical movement

Total score
8–40

Newborn toadolescent
Distress in paediatricintensive care unit;

Chorney 2014

FLACC
Merkel 1997
Crellin 2015

COMFORT scale
Ambuel 1992904

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Scale

Indicators

COMFORT B scale(behaviouralelements)

Muscle tone
Facial expression
Mean arterial pressure
Heart rate

van Dijk 2000

Score

Utility
Postoperative pain 0–
3 y (van Dijk 2000);
Downs Syndrome 0–
3y(Valkenburg 2011);
Burns 0– 5 y(de Jong 2010);
Post-cardiac surgery interm infants(Franck 2011)

Further details available in Chorney 2014 and Howard 2008a.

Table 10.3 | Self-report tools for children
Scale

Components

Anchors

Utility

Poker Chip Tool

4 chips=pieces of “hurt”± white “no pain” chip;
1 chip=“a little hurt”;
4 chips=“most hurt you
could ever have”

4–6 yProcedural;
Acute and
Postoperativepain

6 graphically depicted
faces
Simplified version for 4 yelectronic versions
available

Neutral anchors
Verbal anchors: No pain
to Very much pain

>5/ 6 yAcute pain;
Postoperative
pain;
Chronic pain

6 cartoon faces(and 4 cartoon faces)
culturally adapted
versions

Faces graded fromsmiling to tears withverbal anchors from “nohurt” to “as much as
you can imagine”

6y
Acute pain;
Procedural
pain

McGrath 1996

Modification of 10 cm
horizontal VAS; scored 0–
10 in 0.25 increments
ruler or flat
Electronic version

Gradations in colour(white to deep red) andarea (progressively
wider tetragon); verbal
labels “no pain” to“most pain”>6 yAcute pain;
Postoperative
pain

Numeric Verbal
Scale (NRS-11)

Pain intensity from 0─10Electronic version

0=No pain or hurt
10 worst pain or hurt
you canimagine/possible>6 yAcute pain;
Postoperative
pain;
Chronic Pain

Hester 1979

FPS-R
Hicks 2001

WBFPRS
Wong 1988

Coloured
Analogue Scale

Miro 2009

Further details available in Birnie 2019 and von Baeyer 2014.

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Table 10.4 | Sample of observational pain assessment scales for intellectually disabled children
Scale

Components

Score

Utility

NCCPC-PV

FacialVocal
SocialActivity
Body and limbs
Physiological(Eating/sleeping in NCCPCR)

27 items over 6
domains, rated 0–3
based on frequency of
behaviour over a 10 min
observation period;
total score 0–81 score
6–10/81 mild pain
>11/81 mod pain (≥3 on
VAS)(NCCPC-R 30 items
scored over a 2 hperiod: >7/90 indicatespain)

Nonverbal/ID
3–18 yPostoperative
pain
Familiarity
with child notnecessary
Otherlanguages
Requires 2 hobservation

20 typical pain behaviours
selected based oninterview andquestionnaire

20 items scored 0–3
based on frequency of
behaviour; total score
0–60
14/60 moderate pain

1–18 yPain
Takes 5 min

Face
Legs
Activity
Cry
Consolability

5 items each scored on
3-point scale (0,1,2);
total score 0–10
4/10 Moderate Pain
Can individualise

4–19 yID
Postoperative
pain
Takes 1 min

Individual Pain indicators
proposed by carers

0–10 NRS scale withpain indicators
superimposed
Needs to becollaboratively
individualised

6–18 yNonverbal
ID
Postoperative
pain
Needs time
to designBreau 2002b

NCCPC-R for homesetting
Breau 2002a

PPP
Hunt 2004

Revised (r)FLACC
Malviya 2006a

INRS
Solodiuk 2010

Further details available in Chorney 2014, Crosta 2014 and Valkenburg 2010.

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10.4 | Analgesic agentsThe following section describes the evidence supporting the use of various medications as
analgesics in children. Most medications listed (beyond paracetamol, ibuprofen and morphine)
are not licensed for paediatric use. Consequently, they are often used off-label (Kimland 2012
Level IV SR, 18 international hospital & primary care studies) for acute (and also chronic) pain
management, or are used below licensed age cut-offs (such as 6 or 12 mth or 12, 16 and 18 y) or
by non-licensed novel routes, with both being accepted practice. The result is varying locally andregionally accepted regimens. Commonly doses for ‘routine and non-routine off-label’ use (TGA
2013 GL) are extrapolated from adult dosing and this is frequently unsupported by either
paediatric pharmacokinetic (PK) data (in particular) or pharmacodynamic (PD) study.
Considerations pertinent to paediatrics are that countries differ in their licensing for single
agents including nonuniformity of age cut-offs and in the formulation types and strengths
available. Further to this, when a suspension is not available, adult tablets and capsules require
cutting/crushing/dispersing and often disguising (eg in food to improve palatability), which has
implications for compliance and dose administration error.

10.4.1 | Paracetamol (acetaminophen)
Paracetamol is effective for mild to moderate pain in children (Allegaert 2017 NR; Marzuillo 2014
NR). The dose required for analgesia is greater than for antipyretic effect. The proposedmechanism of analgesic action includes inhibition of prostaglandin synthesis and central
cannabinoid/TRPV1 receptor (Allegaert 2017 NR; de Martino 2015 NR; Graham 2013 NR) and indirectserotonergic effects (see also adult Section 4.1.1). The serotonergic mechanism has been
investigated in adults, and subsequently in children undergoing tonsillectomy (Ramirez 2015
Level II, n=69, JS 4). Children received paracetamol, corticosteroid, fixed dose morphine/
nonselective non-steroidal anti-inflammatory drugs (nsNSAIDs) and ondansetron vs droperidol
intraoperatively. More ondansetron vs droperidol recipients required rescue morphine in PACU
(57 vs 21%), suggesting ondansetron suppressed paracetamol’s analgesic effect.
10.4.1.1 | Efficacy
Paracetamol has similar efficacy to nsNSAIDs depending on the surgery type assessed.
Paracetamol is a useful adjunctive treatment as part of multimodal analgesia for more severe
pain. A systematic review of paracetamol has defined the NNT for different doses in adults, withno evidence of dose-dependent effect (see Section 4.1.2 and in Chapter 5 Table 5.1); this has notbeen defined for children. Paracetamol is established as opioid-sparing in adults (see Section
4.1.2). In children, opioid-sparing efficacy is variably demonstrated and dependent upon theroute of administration, the duration of therapy and follow-up, and dose size used. The RCTs andsubsequent systematic reviews are challenged by variable timing of administration and various
outcomes. Interpretation is complicated by study heterogeneity and inclusion of surgicalprocedures with low postoperative analgesic requirements, as well as the lack of data regarding
equipotent dosing between the different comparators ( Marzuillo 2014 NR). In many instances,
paracetamol is considered the standard of care in various RCTs where additional medicationintervention is then assessed. It has been recommended as part of routine multimodal therapy
for post tonsillectomy analgesic protocols by various bodies ( Mitchell 2019 GL). The RCTs whereparacetamol is one of the treatment arms are presented below.

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Paracetamol use in neonates and infants
A review has been performed of use in neonates and infants in heterogeneous painful conditions(Ohlsson 2016 Level I [Cochrane], 9 RCTs, n=728):• Post major thoracic (noncardiac) or abdominal surgery, IV paracetamol 30 mg/kg/d
reduced cumulative morphine dose in the first 48 h postoperatively (MD -157 mcg/kg;
95%CI -27 to -288) but did not reduce pain scores or opioid-related adverse effects(Ohlsson 2016 Level I [Cochrane], 1 RCT: Ceelie 2013 Level II, n=71, JS 5). While in a similar
patient group, PR paracetamol was not morphine-sparing (Wong 2013b Level I [PRISMA], 1
RCT: van der Marel 2007 Level II, n=71 [57 analysed], JS 5);• Following heel lance, PO paracetamol given 60─90 min prior did not reduce pain vsplacebo (water or cherry elixir) or EMLA® cream applied at 60 min (3 RCTs, n=346); PO
glucose-treated infants had lower pain scores 3 min after heel lance vs thoseparacetamol-treated (MD 2.21/21; 95% CI 0.72 to 3.7) (1 RCT, n=38) (Ohlsson 2016 Level I[Cochrane], 9 RCTs, n=728);• For eye examinations, RCT results conflicted for PO paracetamol 15─20 mg/kg 30 to 60
min prior vs water or sucrose 24% 0.2 mL: in two RCTs, no difference was found in painscores taken in the first 45 s, last 45 s and 5 min after the examination, whilst the thirdand largest RCT reported lower pain scores vs water during the examination (Ohlsson 2016
Level I [Cochrane], 3 RCTs [eye], n=213).
For PICC placement in very preterm neonates <32 wk, paracetamol vs PO sucrose 24% 0.5─1mL had similar median pain scores: 8/21 (IQR 6─10.5) for 10 mg/kg, 7 (IQR 6─9) for 15 mg/kg and
8 (IQR 6─10) for both 20 mg/kg paracetamol group and 24% sucrose ( Roofthooft 2017 Level II,
n=80, JS 5).
For pain management in very preterm neonates <32 wk, IV paracetamol 20 mg/kg load thenmultidosing with 7.5 mg/kg 6 hly (mean dose number 17 [SD 11.7]) decreased cumulative
morphine requirements from median 0.37 mg/kg (SD 0.96) (prior to its introduction) to 0.17
mg/kg (SD 0.45) (Harma 2016 Level III-2, n=218). For postoperative pain management in termneonates, IV paracetamol 20 mg/kg initial dose then dosed according to age below or above 30
d of 10 or 15 mg/kg 6 hly was administered first line in preference to IV morphine infusion, with
99% adherence to the protocol (Baarslag 2018 Level IV, n=75).
Perioperative Analgesia
In a systematic review of paediatric use comparing paracetamol (IV, PO and PR routes) to placebo
or nsNSAIDs or in combination, 7 of 13 RCTs are positive with an opioid-sparing effect in cleft
palate repair (1 RCT), inguinal surgery (2 RCTs), ureteroneocystostomy (1 RCT), adenoidectomy
and tonsillectomy (3 RCTs) (Wong 2013b Level I [PRISMA], 31 RCTs, n=2,624). A further systematic
review of multiple opioid-sparing adjuvant medications lists outcomes for the paracetamol trials
individually (Zhu 2017 Level I, 11 RCTs [paracetamol], n=1,011) (3 RCT overlap). While a subsequentsystematic review of systematic reviews does not include these two systematic reviews but
includes the other reviews (including the Cochrane reviews) discussed later in this chapter(Radman 2019 Level I [PRISMA], 17 SRs: 72 RCTs [42 both agents, 17 paracetamol], n unspecified). Thissystematic review assesses paracetamol and ibuprofen in combination or each agent alone
concluding that the evidence is disappointingly limited considering these two medications
listings as WHO essential medicines.
In young children following ureteroneocystostomy, IV paracetamol (15 mg/kg initial bolus andsubsequent infusion with bolus prn) vs placebo added to IV fentanyl (infusion with bolus prn) had
similar pain scores, with reduced fentanyl requirements (POD 1 and 2), reduced vomiting (16% vs56) and sedation (10% vs 47) (Zhu 2017 Level I, 1 RCT: Hong 2010 Level II, n=63, JS 5).

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Following scoliosis surgery, IV paracetamol 90 mg/kg/d for 24 h reduced pain scores vsplacebo, but not opioid use or PONV (Zhu 2017 Level I, 1 RCT: Hiller 2012 Level II, n=36, JS 5).
Post cleft palate repair, paracetamol 12.5 mg/kg IV and 15 mg/kg PO (given every 6 h for 24 h)
reduced postoperative morphine requirements vs placebo (Nour 2014 Level II, n=48, JS 5).
Post paediatric dental restorations, patients who received IV paracetamol 15 mg/kg vs IM
pethidine 1 mg/kg had modestly higher pain scores but with less sedation and 10 min earlier
discharge from PACU (Zhu 2017 Level I, 1 RCT: Alhashemi 2007 Level II, n=40, JS 5). Preemptive
administration of very low dose paracetamol prior to dental treatment under local anaesthesia
did not have benefit over placebo (2 RCTs, n=120) (Ashley 2016 Level I [Cochrane], 3 RCTs
[paracetamol], n=165).
For inguinal herniorrhaphy in young children, both PR and IV paracetamol 15 mg/kg reduced
pain scores (0─2 h) and vomiting postoperatively vs placebo (Khalili 2016 Level II, n=120, JS 3). For
the same procedure, addition of PR paracetamol 30 mg/kg to caudal block had similar time to
first rescue analgesia vs caudal block alone (while PR diclofenac 1 mg/kg with caudal block wassuperior to both) (Nnaji 2017 Level II, n=90, JS 4).
Post paediatric (adeno)tonsillectomy, paracetamol by different routes has had varying
analgesic benefits:• PO vs PR 40 mg/kg reduced opioid requirements (Anderson 1996 Level II, n=100, JS 5);• PR 40 mg/kg vs IV 15 mg/kg resulted in a longer time to first rescue analgesic request(median 10 h vs 7) (Capici 2008 Level II, n=50, JS 5);• PR 15 mg/kg vs IV 10 mg/kg had slightly lower pain scores at 4 and 6 h, with more patientspain free (44% vs 10) and a longer time to analgesic rescue (5 h vs 3.8) (Haddadi 2014
Level III-1, n=96);• PO 15 mg/kg, as a single preoperative dose, resulted in lower early pain scores vsibuprofen 10 mg/kg and placebo (Mahgoobifard 2014 Level II, n=60, JS 5);• PO 12 mg/kg and 6 mg/kg ibuprofen, alone and in combination, were similarly effective
over 48 h, with similar area under the curve for pain scores at rest and on swallowing(Merry 2013 Level II, n=152, JS 5);• IV 15 mg/kg provided similar analgesic effects to IV tramadol 1 mg/kg in the early
postoperative period (Uysal 2011 Level II, n=64, JS 5) and was similarly effective vs IM
pethidine 1 mg/kg with similar pain scores, slightly less sedation and 10 min earlier
discharge from PACU. However, 17 vs 0% of patients required morphine rescue (Alhashemi
2006 Level II, n=80, JS 4); and• There were no differences in pain intensity between patients administered PO
paracetamol (alone or in combination with codeine or hydrocodone) as required vs fixedschedule for 3 d despite the 33 to 68% lower dose/volume of analgesia used in the prngroups (Erskine 2015 Level I [Cochrane], 3 RCTs, n=207).
PO paracetamol 15 mg/kg with PO diclofenac 1 mg/kg provides equivalent analgesia to PO
paracetamol 30 mg/kg (Hannam 2014 Level I PK, pooled data from 3 RCTs, n=466).
A subsequent PK-PD study has determined analgesic plasma concentrations for ibuprofen
and paracetamol (Hannam 2018 PK, n=251 [1,168 paracetamol and ibuprofen samples]). The simulated
time concentration effect profiles for varying doses demonstrate that ibuprofen alone decreased
pain scores further and for longer than paracetamol alone. In combination, the simulated effect
was additive: clinically used doses of paracetamol 15 mg/kg combined with ibuprofen 4.5 mg/kg
decreased the pain score by 65%. Adding tramadol 0.5─1 mg/kg to this combination model
maintained the pain score <6/10 for a further 7 h.

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Paracetamol use in other painful conditions (non-surgical)
For acute otitis media [AOM], monotherapy with either PO paracetamol 15 mg/kg or PO
ibuprofen 10 mg/kg had more children pain free at 48 h (90 and 93%) vs placebo (75%) (1 RCT
n=148) (RR [paracetamol] 0.38, 95%CI 0.17 to 0.85; NNT 7) with no difference at 24 h, 48 to 72 h
or 4─7 d (Sjoukes 2016 Level I [Cochrane], 3 RCTs, n=327 [AOM]).
For musculoskeletal injuries in children presenting to the ED, PO paracetamol 15 mg/kg vscodeine 1 mg/kg were both inferior to ibuprofen 10 mg/kg analgesia 1 h post dose (Clark 2007
Level II, n=300, JS 5), and paracetamol combined with codeine was equivalent to ibuprofen (Friday
2009 Level II, n=68, JS 4) (both RCTs in Le May 2016 Level I [PRISMA], 8 RCTs, n=1,169).
10.4.1.2 | Pharmacokinetics and pharmacodynamics
Paracetamol’s bioavailability is dependent on the route of administration. Oral bioavailability ishigh (hepatic extraction 0.11–0.37) (Anderson 2014a PK) and peak plasma concentrations arereached in 30 min with the liquid and effervescent formulations (longer with tablet and capsule)(Marzuillo 2014 NR; Gibb 2008 NR); the equilibration halftime (t1/2keo) between plasma and effectcompartment is 53 min (Anderson 2001 PK). Rectal administration is associated with slower andless predictable absorption and PR loading doses of 30–40 mg/kg paracetamol may be required
to achieve therapeutic plasma concentrations associated with analgesia (eg 10 mg/L whichcorrelates with VAS reduction of 2.6/10) (Howell 2003 Level II, n=24, JS 2; Anderson 1996 Level II,
n=100, JS 5). Neonates generally have delayed oral absorption, attributed to slower gastric
emptying which reaches adult rates at 6–8 mth of age (Marzuillo 2014 NR; Gibb 2008 NR). An IV
formulation of paracetamol achieves more predictable concentrations, because PK variability
attributable to absorption is avoided, but also has more rapid offset than a PR formulation thathas slow delayed absorption (Capici 2008 Level II, n=50, JS 5) as explored with simulation (Anderson
2014a PK).
Clearance is reduced in neonates and increases with age to reach adult rates during infancy(using allometric scaling expressed as L/h/kg). The volume of distribution (Vd: L/kg) is increased
in neonates and rapidly reduces in the first year of life (Wang 2014 PK; Allegaert 2013 NR;
Mohammed 2012 PK; Allegaert 2011a PK). Dose regimens that target a steady state plasma
concentration of 10–20 mg/L have been determined. There is some evidence for analgesic
efficacy at this concentration in children and neonates ( Allegaert 2013 NR; Anderson 2001
Level III-1 PK). A PK model based on data from 220 subjects (neonatal up to adult) proposes dosing
to achieve a concentration of 9 mg/L, chosen as this concentration is predicted with the clinicallyused schedule of 15 mg/kg every 6 h (for patients weighing 10–50 kg) (Wang 2014 PK). For
paracetamol dosing see Table 10.5 where expert opinion is combined with supportive PK data,
where available.
Table 10.5 | Suggested paracetamol dosing for infants and children
Postmenstrual
age or weight

Oral (PO)/Rectal (PR) dose

IV doseMaximum
daily dose

References

Infants
28–29 wk

Nil data

10 mg/kg
12 hlyproposed

20 mg/kg/d
proposed

Caution against use:
van den Anker 2011

Note: Limited data inextreme premature
Allegaert 2011a PK;
Allegaert 2013 NR;
Veyckemans 2014910

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Postmenstrual
age or weight

Oral (PO)/Rectal (PR) dose

IV doseMaximum
daily dose

Infants
30–31 wk

Nil data

10 mg/kg
8–12 hly

25–30 mg/kg/d(Weight 0.5–
2 kg)

Infants
32–44 wk
(Weight 3–
5 kg)Infants >45 wk

Older children
6 mth–12 yWang 2014 PK

Initial bolus
12 mg/kg;
6–7 mg/kg
6 hly
15 mg/kg
8 hly

15–20 mg/kg
4–6 hly

References

Initial bolus
0–
20 mg/kg;
10 mg/kg
6 hly

IV: 40 mg/kg/d
PO:
45 mg/kg/d

Palmer 2008 Level IV PK;
Allegaert 2011a PK;
Allegaert 2013 NR;
Wang 2014 PK;
Veyckemans 2014.

15 mg/kg
6 hly

IV/PO:
60 mg/kg/d

Veyckemans 2014;
Palmer 2007 Level IV;
Howard 2008b NR;
Wang 2014 PK

15 mg/kg
6 hly

IV: 60 mg/kg/d
PO:
90 mg/kg/d
suitable for
acuteadministrationfor 2–3 dAnderson 2002 PK;Wang 2014 PK

10.4.1.3 | Adverse effects and safety
Overall safety
Paracetamol use at therapeutic doses can generally be considered safe. Dosing
recommendations have been revised and capped at 75─80 mg/kg/day for PO and IV acute use(Ajjan 2016 Level IV, n=72) and 60 mg/kg/day for short term use (eg in the British National
Formulary or Australian Medicines Handbook), but the margin for safety particularly in ill
children and adults weighing less than 50 kg is unclear (Caparrotta 2018 NR). A review assessing a
range of adverse effects (including abdominal, hepatic, skin, respiratory and neurological effects)
suggests paracetamol and ibuprofen have similar safety and tolerability profiles vs placebo ifprescribed and administered at recommended doses in children (Southey 2009 Level IV SR, 24 RCTs,
n=119,166 & 12 studies, n=221,459).
Safety in neonates and preterm infants
Data regarding safety of paracetamol (all routes) in neonates is scant and cautious dosing andmonitoring of hepatic function is recommended (Anderson 2009 NR). There is minimal safety data
in preterm <32 wk (Allegaert 2011a PK). Dosing practices in NICUs vary (with decreasing dose andor frequency) and are not informed by pharmacodynamic data (Allegaert 2017 NR).
Limited data on liver function during repeated IV (Palmer 2008 Level IV, n=50) and PR dosing
for pain or fever (Chen 2018 Level IV, n=25) suggest alteration was contributed to by factors otherthan paracetamol.
5th Edition | Acute Pain Management: Scientific Evidence

911Use of paracetamol for patent ductus arteriosus (PDA) closure also provides some limited
safety data in preterm neonates ≤34 wk (Ohlsson 2018a Level I [Cochrane], 8 RCTs, n=916).
Paracetamol has equivalent efficacy for this indication to NSAIDs, with reduced gastrointestinal
bleeding vs ibuprofen (RR 0.28; 95%CI 0.12 to 0.69) (4 RCTs, n=537), higher platelet counts (2 RCTs
[ibuprofen], n=287; 1 RCT [indomethacin], n=200), lower bilirubin (2 RCTs [ibuprofen], n=290) and lessrenal impact with lower creatinine (4 RCTs [ibuprofen], n=537; 1 RCT [indomethacin], n=200), lessoliguria (3 RCTs [ibuprofen] ,n=337) and greater daily urine output (1 RCT [ibuprofen], n=200; 1 RCT[indomethacin], n=200).
In extreme preterm neonates ≤28 wk, PO paracetamol 15 mg/kg 6 hly for 3 d vs ibuprofen 10
mg/kg d 1, 5 mg/kg d 2 and 3 was as effective for PDA closure 89 vs 84%, with similar side effectprofile in terms of intestinal, liver and renal function (Karabulut 2019 Level III-2, n=87).
Hepatotoxicity
Paracetamol is metabolised in the liver, predominantly via glucuronidation and sulphation.
Increased production of a reactive oxidative product, N-acetyl-p-benzoquinone imine (NAPQI),
occurs if the usual metabolic enzyme systems become saturated (eg acute overdose) or if
glutathione is depleted (eg with prolonged fasting). An increased contribution of sulphation tometabolism and reduced production of oxidative metabolites may reduce the risk of toxicity inneonates, particularly in the presence of unconjugated hyperbilirubinaemia (Palmer 2008 Level IV,n=50) but, as overall clearance is reduced, a lower dose is appropriate. Hepatotoxicity has beenreported in infants aged 3–7 wk having received PO dosing of 60 mg/kg/d for 3 and 6 d and100 mg/kg/d for 2 d (Bucaretchi 2014 Level IV, n=3).
Risk factors for paracetamol hepatotoxicity may include fasting (malnourished state),
vomiting, dehydration, systemic sepsis, pre-existing liver disease and prior paracetamol intake,however the situation remains unclear (Caparrotta 2018 NR; Kaplowitz 2004 NR) (see also 4.2.3).
Hepatic injury results from the NAPQI metabolite. Single overdoses in children of 120 to 150
mg/kg have caused hepatic injury (AAP 2001 NR). Notably, acute liver failure has occurred with3─4 d dosing of 68─82 mg/kg/d in 4 young children in an Australian and New Zealand cohort(Rajanayagam 2015 Level IV, n=14 [paracetamol]). Hepatic failure in this paediatric series (age range
0.7–13 y) was mostly associated with medication error involving higher multiday (median 4 d,range 2 to 24) dosing: 7/14 (50%) received >120 mg/kg/d and the remainder had double doses
or excessive frequency, were coadministered other medications containing paracetamol orreceived regular dosing. Ten survived without requiring transplant, 2 survived post-transplant;
while 2 died (1 without and 1 post-transplant). A Spanish series documents similar reported
acute and chronic dosing with accidental overdose in younger children (n=38) and attemptedsuicide in teenagers (n=43) with 50% receiving acetylcysteine, 4 patients developing acute liver
failure with none requiring transplant or dying (Tong 2017 Level IV, n=90). In adolescent overdose,
early predictors of severity of paracetamol hepatotoxicity included the initial INR elevation,
presence of hyperbilirubinaemia and hypophosphataemia, the number of prehospital vomiting
episodes (≥3) and time to acetylcysteine administration (Hedeland 2014 Level IV, n=25). In contrast
to adults, no relationship was found for the severity of hepatoxicity and the amount ingested(either as overall dose [mean 16.4 g, range 6.5–60 g] or when weight adjusted). All patients
received acetylcysteine and recovered; none required transplant.
Repeated paracetamol ingestion (dose known for 78 patients as >76 mg/kg/d [median 120]for median 3 d [IQR 2─5]) resulted in severe hepatic damage (ALT/AST ≥1000 IU/L) (93%), liver
failure (69%) and death (39%) (Acheampong 2016 Level IV SR, n=199 [78 children ≤6 y]).
The commonest prescribing error in paediatrics is a ten-fold dosing error. This has significant
impact when involving paracetamol, as occurred for an infant where 2 doses of 150 mg/kg were given(detected after the 2nd dose) with hepatotoxicity; successfully treated with NAC (Aslan 2019 CR).

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A review of therapeutic dosing of paracetamol beyond 24 h in children assessed hepatic
adverse effects (Lavonas 2010 Level IV SR, 62 studies, n=32,414). It reports no cases of liver disease,need for antidote or transplantation or death (0.0%; 95%CI 0.000 to 0.009) and only 10 children
experienced major or minor hepatic adverse effects (0.031%; 95%CI 0.015 to 0.057). This review
identified 22 case reports of hepatotoxicity associated with therapeutic doses of paracetamol;
in 9 cases, Naranjo scoring suggested probable causation.
Of note, the guidelines for the management of paracetamol poisoning have been revised(Chiew 2020 GL). Specifically for younger children <6 y who have ingested an excessive dose of
the more rapidly absorbed liquid preparation, an earlier measurement of plasma concentrationfrom at least 2 h is recommended (rather than at ≥4 h for tablet ingestion) and intervention
tailored to whether this is >150 mg/L. The guideline also incorporates response to modified
release paracetamol overdoses, large or massive overdose and repeated supratherapeutic
ingestions. The three infusion NAC dosing schedule has been revised to two (Chiew 2018 Level I[Cochrane], 4 RCTs [NAC route and dose regimens in adults], n=518), with the recommendation to
double the 2nd infusion if the plasma concentration is greater than twice the height of theparacetamol toxicity nomogram line.
Cardiovascular effects of paracetamol
Paracetamol has poorly understood vasoactive effects. It is as effective as ibuprofen for closureof a PDA in preterm neonates (Ohlsson 2018a Level I [Cochrane], 8 RCTs, n=916). There is also a
potential association between constriction and premature ductus arteriosus closure andmaternal paracetamol use in pregnancy (see below: Allegaert 2019 Level IV, n=25).
The overall effect of paracetamol on blood pressure in adults and children remains
unclear (see also adult Section 4.1.3.3). Observational studies show a variable association
between PO paracetamol use and hypertension, but RCTs are inconsistent ( Turtle 2013 Level
III-3 SR, 6 RCTs, n=152 & 4 studies n=155,910 ). While use of IV propacetamol and IV paracetamoland hypotension has been reported (with variable definitions: systolic vs MAP change as
absolute value or 15─20% decrease) in mostly critically ill (often cardiac) patients (14/19
studies) ( Maxwell 2019 Level IV SR, 19 studies (5 RCTs, 6 open label trials & 8 retrospective reviews ),n=3,470 [2 paediatric, n=680] ). Clinically significant hypotension appears to be an issue when
patients have cardiovascular compromise prior to administration; importantly regular fourtimes daily dosing with IV paracetamol where mannitol is the stabilising agent exposes thepatient to 0.23 mg/kg/d mannitol (with its diuretic and secondary hypotensive effect) (Chiam2015 NR). Within the above systematic review, IV paracetamol (with mannitol excipient) vsmannitol vs placebo reduced MAP by only 1.8 mmHg in healthy adult volunteers ( Chiam 2016
Level II, n=24, JS 5 ). Of the two paediatric studies, the first included neonates receiving IV
propacetamol where a minor decrease in MAP (-3 mmHg) occurred 60 min post dose
(Allegaert 2010, Level IV, n=72 ). This may reflect analgesic effect, although the 8 neonates whodeveloped hypotension all had lower baseline MAP prior to administration. Further to this,
5% of young children in a cardiac PICU (mostly postsurgical), whose MAP had started to
decline prior to IV paracetamol administration, progressed to clinically significant
hypotension (≥15% decrease in MAP from baseline) within 30─75 min of IV paracetamol,and 20% experienced a 10─14% decrease ( Achuff 2019 Level IV, n=608 [777 doses] ). This series
excluded patients who had a vasoactive medication within 1 h before or after paracetamol.
Severe hypotension and cardiac arrest is also described in a toddler with febrile neutropenia
occurring 5 min into the infusion ( Yaman 2016 CR).

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Paracetamol hypersensitivity
Hypersensitivity to paracetamol is uncommon (Gabrielli 2018 Level IV SR [PRISMA], 85 studies,
n=1,030). The classification of reaction types and mechanisms of immune reaction in children aresummarised (Kidon 2018 GL) (and discussed further below in nsNSAID hypersensitivity Section
10.4.2.3).
Most reported cases of hypersensitivity to paracetamol involve the skin, including
nonimmediate cutaneous eruptions, fixed drug eruptions, Stevens-Johnson syndrome (SJS)/toxic
epidermal necrolysis (TEN) and urticarial/angioedema/anaphylaxis. Reactions to paracetamol
have been reported usually in association with suspected nsNSAIDs reactions; with its proposed
weak cyclooxygenase (COX) effect, paracetamol was presumably included to explore crosssensitivity with nsNSAIDs. Three such paediatric series have focussed on nsNSAIDs
hypersensitivity, skin and oral drug provocation testing and explored associations eg with atopy(Arikoglu 2017 Level IV, n=106; Topal 2016 Level IV, n=64; Cousin 2016 Level IV, n=107). Paracetamol
was either implicated directly or was coadministered with nsNSAIDs at the time of reaction; aswith nsNSAIDs most reactions were cutaneous or urticarial/angioedema. No anaphylaxis toparacetamol was reported in these series. One confirmed two patients with positive skin testing
to paracetamol and two further (aged 6 and 15 y) skin test positive to a nsNSAID then reacting
to ‘high-dose oral provocation’ with 90─120 mg paracetamol (Topal 2016 Level IV, n=18 confirmed[2 paracetamol] of 64 evaluated). The second explored applicability of the European Network ofDrug Allergy (ENDA) classification to children and association of allergy with urticaria and atopy;
it confirmed 7 reactions to paracetamol with ‘urticaria/angioedema or anaphylaxis’ (defined as‘single agent reaction’ as the patients tested negative with at least one other nsNSAID; whereparacetamol was not implicated in the patient subgroup with cross-intolerant hypersensitivity)(Cousin 2016 Level IV, n=107). While the third also explored the ENDA concepts of selective
responders vs cross intolerant and confirmed patients with nsNSAID allergy (with skin and/or
drug provocation testing) (Arikoglu 2017 Level IV, n=33 confirmed of 106 evaluated [6 paracetamol; 27
nsNSAIDs]). Paracetamol was frequently implicated on history (59%) but oral provocation was
only positive for 6 patients (two of whom tested negative on skin prick testing). The majority ofpatients with confirmed nsNSAID allergy in this series subsequently had oral drug provocation
with paracetamol establishing its use as a safe alternative for the nsNSAID allergic children (seealso Section 10.4.2.3). A subsequent meta-analysis (including the first of these series) establisheda pooled estimate for paracetamol hypersensitivity prevalence in children who reported aprevious reaction to paracetamol and underwent an oral challenge of 10.1% (95% CI 4.5–15.6)(Gabrielli 2018 Level IV SR [PRISMA], 10 studies [meta-analysed] [5 mixed/ 5 paediatric], n=259].
Skin testing has not been developed as a diagnostic tool for paracetamol (and other nsNSAIDs
beyond aspirin).
In 2013, the USA’s Food and Drug Administration (FDA) investigated paracetamol as a rarecause of SJS/TEN syndrome (FDA 2013a Level IV, n=91, 6 [probable]; 85 [possible]). While, a French
pharmacovigilance study reported 112 cases involving 574 suspected drugs (5.1 per case)(Lebrun-Vignes 2018 Level IV, n=23 [children]). In 80 cases, drugs other than paracetamol had ahigher suspicion for causality; in a further 12 paracetamol was unlikely to be involved. In theremaining 20 cases, paracetamol was possibly or probably involved, but in 14 there wasprotopathic confounding bias (where the drug is taken for a symptom or illness).
Anaphylactic reactions to paracetamol have been reported rarely, mostly following PO
administration and one following IV (Sørensen 2014 Level IV, n=12). Six (50%) of these children
notably had negative skin tests with initial or subsequent reactions to low dose, high doseprovocation or therapeutic dosing.

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Pregnancy and early childhood exposure and association with various childhood issues
Paracetamol is a Category A medicine and is regarded as the analgesic of choice during pregnancy
and infancy in Australia and New Zealand (currently unassigned in the USA). There are numbersof observational cohort studies in the literature claiming modest associations between
paracetamol exposure in utero and various early infancy and childhood issues (as presented
below). Caution should be used with interpretation of these retrospective analyses because of
the possible effect of unknown or unmeasured confounding factors; the relevance of thesereports to limited acute use remains unclear.
Childhood asthma
The scientific literature has debated whether paracetamol can precipitate asthma (byincreased de novo myeloperoxidase production) or causes a shorter less severe asthmatic
episode in aspirin-sensitive people with asthma ( Graham 2013 NR). An important potential
confounder of the below epidemiological study is protopathic: where the indication forparacetamol is fever due to viral upper respiratory tract illness (in mother and or the child),
which in itself precipitates asthma.
Two systematic reviews, with no overlap of included studies, report an association between
paracetamol use in pregnancy and subsequent childhood wheezing (OR 1.5; 95%CI 1.1 to 2.1)
(Etminan 2009 Level III-3 SR, 5 studies [wheezing], n unspecified) and asthma (OR 1.28; 95%CI 1.13 to1.39) (Etminan 2009 Level III-3 SR, 4 studies [asthma], n unspecified) (OR 1.21; 95%CI 1.02 to 1.44)(Eyers 2011 Level III-2 SR, 6 studies, n=28,038). A subsequent systematic review of heterogeneousstudies (with 2 study overlap with each of the above SRs) revealed any paracetamol use wasassociated with increased childhood asthma risk: during the ﬁrst trimester (pooled OR 1.39;
95%CI 1.01 to 1.91) (5 studies, n unspecified) and during the second and third trimesters (OR 1.49;
95%CI 1.37 to 1.63) (3 studies, n unspecified) (Cheelo 2015 Level III-2 SR (PRISMA), 11 studies, n=910,054[4 pregnancy studies n=896,313; 2 pregnancy and infant studies n=9,527; 4 infant-toddler studies
n=4,241]). Importantly, only one study adjusted for maternal respiratory tract infections.

The epidemiological literature has also reported an association between childhood asthma
and paracetamol exposure in children in the year prior to diagnosis (pooled OR 1.60; 95%CI 1.48
to 1.74) (3 studies, n unspecified) and in the first year of life (pooled OR 1.47, 95%CI 1.36 to 1.56)(3 studies, n unspecified), with one study reporting an association with high doses (Etminan 2009
Level III-3 SR, 19 studies, n=425,140 [15 paediatric, n=361,018]). However, when adjusted forrespiratory tract infections in the child, increasing frequency of use (defined as doubling of dose)of paracetamol during infancy (up to 6, 12 and 24 mth) was no longer associated with increased
odds of childhood asthma (OR 1.06; 95% CI 0.92 to 1.22) ( Cheelo 2015 Level III-2 SR (PRISMA), 3
studies [infant & toddler use], n=3,327).
A subsequent RCT in children with mild persistent asthma (on glucocorticoid and leukotriene
receptor antagonist inhaler treatment) assessed acute use of paracetamol vs ibuprofen for painor fever and frequency of asthma exacerbations (over a 48 wk period) (Sheehan 2016 Level II,
n=300, JS 5). Participants received a median of 5.5 doses (IQR 1 to 15) with no difference in thenumber of asthma exacerbations (RR 0.94, 95%CI 0.69 to 1.28), asthma-control days (85.8 and86.8%), albuterol rescue inhaler use (2.8 vs 3.0 inhalations per week) or unscheduled health careutilisation for asthma (0.75 and 0.76 episodes per participant).
Childhood atopy
Paracetamol exposure during pregnancy has been implicated in childhood atopy (nutritional,
eczema, wheezing) in early infancy (Allegaert 2017 NR). Certain maternal antioxidant gene
polymorphisms may modify this relationship, as is also relevant to asthma above ( Shaheen 2010
Level IV, n=4,000 [mothers]). At present, the association may be explained by confounders.

5th Edition | Acute Pain Management: Scientific Evidence915Cryptorchidism
Association between paracetamol exposure in utero and cryptorchidism has been of interest due
to paracetamol’s potential to act as an endocrine disrupter. For the association between ‘ever’
use of paracetamol and cryptorchidism in highly heterogeneous studies, the pooled crude OR
was 1.11 (95%CI 1.00 to 1.23), and when separately analysed as study type no association wasshown for case-control studies (OR 1.23; 95%CI 0.85 to 1.78) or cohort studies (OR 1.09; 95%CI
0.97 to 1.22) (Gurney 2017 Level III-2 SR [PRISMA], 10 Studies, n=501,456).
Premature closure of the ductus arteriosus
Maternal paracetamol use in pregnancy has been proposed as causal in premature constriction
or closure of the ductus arteriosus: 4 certain and 11/25 probable (Allegaert 2019 Level IV, n=25).
Childhood neurobehavioural outcomes
The relationship of paracetamol exposure in utero and early childhood to neurobehavioural
outcomes has been explored. Suggested mechanisms for an effect of paracetamol include impact
on cerebral inflammation and metabolite production eg cannabinoids or again this may reflect a
protopathic bias. Three overlapping reviews have included birth cohort studies with follow-up at
various ages (18 mth vs 3, 5, 7 and 11 y) including different assessments for several
neurobehavioural outcomes eg attention deficit hyperactivity disorder (ADHD) (4 studies,
n=75,633), conduct and emotional problems (1 study, n=7,796), attention/executive function (1study, n=1,491), and autistic spectrum disorder (ASD) with hyperkinetic disorder (HR 1.51; 95%CI
1.19 to 1.92) (1 study, n=1,491) (Bauer 2018 Level III-2 SR, 9 studies, n=176,955; Masarwa 2018 Level III-2 SR[PRISMA], 7 studies, n=132,738; Allegaert 2017 Level III-2 SR, 7 studies, n=174,732) (6 to 7 study overlap). Lower
IQ (by 3.4 points; 95%CI 0.3 to 6.6) was reported (1 study, n=1,491); where an earlier study(included in the 1st and 3rd review) had found no effect (Streissguth 1987 Level III-2, n=421). Durationof exposure (<28 vs >28 d) was assessed in 2 studies and was associated with reduced
communication/motor attainment and greater hyperactivity ( Bauer 2018 Level III-2 SR, 1 study:
Brandlistuen 2013 Level III-2, n=48,631 [2,919 same sex sibling matching]); when adjusted forconfounders, delayed motor milestone attainment remained an association (OR 1.35, 95%CI
1.07–1.70), but not communication issues (OR 1.38, 95%CI 0.98 to 1.95) (Bauer 2018 Level III-2 SR,
1 study: Vlenterie 2016 Level III-2, n=51,200). In the largest study (in all 3 reviews), the use ofparacetamol in pregnancy was associated with child hyperkinetic disorder (HR 1.37; 95%CI 1.19
to 1.59), use of ADHD medications (HR 1.29; 95%CI 1.15 to 1.44) and ADHD-like behaviours atage 7 y (RR 1.13; 95%CI 1.01 to 1.27) (Liew 2014 Level III-2, n=64,322). The third review determinedmean duration of use as 4-7 d and range 4 to more than 28 d (Masarwa 2018 Level III-2 SR [PRISMA],
7 studies, n=132,738). It calculated increased risk for ADHD (RR 1.34; 95%CI 1.21 to 1.47) (6 studies,n=118,085), hyperactivity symptoms (RR 1.24; 95%CI 1.04 to 1.43) (5 studies, n=124,264) and ASD(RR 1.19; 95%CI 1.14 to 1.25) (5 studies, n=117,214). A subsequent study analysed the number ofdays of use of paracetamol in pregnancy and after adjustment for family history also revealed
association with childhood ADHD for longer >29 d (HR 2.2; 95%CI 1.5 to 3.2) but not short term
<8 d use (HR 0.9; 95%CI 0.8 to 1.0) (Ystrom 2017 Level III-3, n=112,973 [2,246 ADHD]).
In addition, a birth cohort study subsequently linked to administrative data, paracetamol wasused in 49% of pregnancies and was associated with a modest increase in numbers of cerebral
palsy (CP) affected children (OR 1.3; 95%CI 1.0 to 1.7) and unilateral spastic CP (OR 1.5; 95%CI
1.0 to 2.2), where confounders (use for fever and viral illness) are again likely relevant (Petersen
2018 Level III-2, n=185,617).

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1. Post tonsillectomy in children, paracetamol (alone or combined with opioids) administeredas required compared to fixed schedule achieved similar pain scores over 3 days; with lower
dosing administered in the as required groups (N) (Level I [Cochrane Review]).
2. For pain of acute otitis media in children, paracetamol is similar to ibuprofen and bothare superior to placebo in achieving pain freedom at 48 hours, but not other time
points (N) (Level I [Cochrane Review]).
3. Paracetamol is effective for moderately severe pain and decreases opioid requirements
after major and minor surgery in children (U) (Level I [PRISMA]).
4. Paracetamol has a similar safety and tolerability profile compared with ibuprofen andplacebo if prescribed and administered at recommended doses in children (U) (Level IV SR).
5. Retrospective epidemiological studies linking paracetamol use in pregnancy or infancy
to later development of childhood asthma are inherently confounded (U); when
adjusted for respiratory tract infections in the child the association is lost (Q) (Level III2 SR [PRISMA]).
6. Retrospective epidemiological studies report modest association of paracetamol use inpregnancy with childhood neurodevelopmental disorders such as attention deficit andhyperkinetic disorders; this is strengthened when adjusted for longer term use (>28days) and disappears for short term use (<8 days) (Q) (Level III-2 SR [PRISMA]).
7. Paracetamol has unclear vasoactive effects; in critically ill children, hypotension isreported with both IV formulations (N) (Level IV SR).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Safe dosing of paracetamol requires consideration of the age and body weight of thechild and the duration of therapy (U).
 Paracetamol related hepatotoxicity generally occurs in children who have received
doses greater than 120 mg/kg, as single or repeated daily dosing; with contributions
from rounding up or 10-fold dosing error and formulation substitution or confusion byprescribers and parents (N).
 Paracetamol is recommended routinely following tonsillectomy andpharmacokinetic/pharmacodynamic simulation is exploring the optimal combinationsof multimodal analgesia in this surgical model (N).
 There is insufficient pharmacokinetic/pharmacodynamic and safety data of use ofparacetamol in preterm and term neonates; use for patent ductus arteriosus closure inpreterm neonates provides limited data in this age group of an improved safety profile
compared with nsNSAIDs (N).
 Emerging evidence suggests that maternal paracetamol use may influence premature
closure of the fetal ductus arteriosus (N); use in pregnancy should be limited to theminimum dose and duration that is clinically necessary.
 Intravenous paracetamol in haemodynamically unstable patients has been associatedwith hypotension (N).

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10.4.2 | Nonselective NSAIDs
For mild to moderate pain, nonselective non-steroidal anti-inflammatory drug (nsNSAIDs) are
effective analgesic agents. The product information states that safety in children <2 y isunestablished, while the lower age limit for licensing varies by country and by NSAID agent.
Despite this, nsNSAIDs have been studied and used in all age groups including infants, asreported by surveyed anaesthetists (Eustace 2007 Level IV, n=314) and German anaesthetic
departments (Emons 2016 Level IV, n=342 [hospitals treating children]). Use of nsNSAIDs for analgesia
is generally not approved for infants aged <3 mth; some authors suggest caution under 6 mth ofage due to a paucity of data (Tobias 2014 NR). There is off-label use in neonates postoperatively(Moffett 2006 Level IV; Papacci 2004 Level IV) and in patent ductus arteriosus [PDA] closure andintraventricular haemorrhage prevention providing limited safety data (Aranda 2017 NR). The
choice between ibuprofen, diclofenac, ketorolac, naproxen, ketoprofen and others mainly
depends on available formulations and convenience of administration.
10.4.2.1 | Pharmacokinetics and pharmacodynamics
Data on pharmacokinetics (PKs) for the commonly used NSAIDs are available for children but
pharmacodynamic (PD) studies are few. The clearance (CL) of diclofenac (Litalien 2001 NR),ketorolac (Lynn 2007 PK) and ibuprofen (Anderson 2019 PK; Kyllonen 2005 PK) is immature inneonates and matures within the first year of life. Equilibration half times of drug concentration
with clinical effect (t1/2 keo) are 14 min for diclofenac (Hannam 2014 Level II, n=151, JS 3), 24 min for
ketorolac (Mandema 1996 PK) and 28 min for ibuprofen (vs 53 min for paracetamol) (Li 2012a PK).
Studies of analgesic effects are frequently flawed by failing to account for the variations in time
to onset when assessing outcomes. A paediatric pain consortium has determined acute pain
clinical trial models to improve study design for analgesic trials in children ( Walco 2018 GL).
Rectal bioavailability of diclofenac is high in children (van der Marel 2004 PK). A population PK
study estimated diclofenac CL as 16.5 L/h/70 kg and bioavailability as 35% for dispersible tablet
or suspension and 63% for suppository (Standing 2011 PK). Dosing for children aged 1–12 y waspredicted as IV 0.3 mg/kg, PR 0.5 mg/kg and PO 1 mg/kg. A PK-PD study revealed the maximum
effect of both paracetamol and diclofenac (VAS reduction 4.9/10; 95%CI 4.7 to 5.2) ( Hannam 2014
Level II, n=151, JS 3) as similar to that described for ibuprofen in adults ( Li 2012a PK). Combination
therapy of PO diclofenac 1 mg/kg with PO paracetamol 15 mg/kg is predicted to achieveequivalent analgesia to PO paracetamol 30 mg/kg. Synergistic interaction is complex as the drugs
have different onset and half-lives. Studies must take this into account to determine theoptimum combination-dosing schedule to improve or extend duration of analgesia.
Plasma and cerebrospinal fluid (CSF) concentrations after PO naproxen have been studied inchildren (mean age 5–6 y, range 0.25–12 y), establishing that CL and Vd <5 y of age are similar tovalues for adults and children >5 y (Valitalo 2012 PK). High unbound naproxen concentrations in
CSF suggest an active uptake mechanism. Ketoprofen PKs are summarised in a narrative review(Kokki 2010 NR). PKs in children (aged 0.25–13 y) after PO and IV flurbiprofen have been reported,with increased concentrations in CSF vs plasma (Kumpulainen 2010 PK).
Adult data suggest ketorolac has a half maximal effective concentration (EC50) of 0.37 mg/L
(Mandema 1996 PK). PK modelling demonstrates that current IV dosing regimens of 0.5 mg/kg
every 6 h maintain a trough concentration above this EC 50 in children (aged 0.75–16 y) (McLay
2018 PK). In adolescents, the PKs of IN ketorolac 15–30 mg (via metred aerosol device) has goodbioavailability (81%) and similar time to maximum plasma concentration (Tmax) and clearance toadults. A 30 mg dose reached a predicted effect compartment concentration of 0.37 mg/L at
30 min and remained above this target for 10 h (Drover 2012 PK).

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For ibuprofen, clearance maturation, as studied with use in ductus arteriosus closure inneonates and analgesic use in young infants and older children, was rapid with near adult values
90% at 44 wk PMA and mature 98% at 53 wk PMA (Anderson 2019 PK). Clearance informed
ibuprofen dosing predictions to achieve steady state plasma concentrations >7.2 mg/L (in allages) matching 10 mg/kg dose recommendations three to four times daily in children >3 mth. Of
note, analgesic plasma concentrations of >7.2 mg/L have been suggested post paediatric inguinal
hernia repair (Kokki 2007 NR). Target analgesic concentrations (ideally surgery-specific) for other
NSAIDs, developmental changes in PDs, and the impact of different stereoisomer forms and theinfluences of various covariates (including weight, postmenstrual and postnatal age, renal
function, obesity, enzyme maturation and influence of ethnicity/pharmacogenomics andcomedications) on the differential PK, efficacy and adverse-effect profile require further
evaluation (Admiraal 2014 NR; Anderson 2011 NR).
10.4.2.2 | Efficacy
Clinical studies of nsNSAIDs and paracetamol suggest similar (Shepherd 2009 Level II, n=72, JS 3; Riad
2007 Level II, n=108, JS 3; Hiller 2006 Level II, n=120, JS 5; Tay 2002 Level II, n=63, JS 2) or superior
efficacy of nsNSAIDs (Wong 2013b Level I [PRISMA], 4 RCTs (nsNSAIDs vs paracetamol), n=330). Benefit
is dependent on dose and route (absorption PKs eg via PR vs IV routes), timing(preop/intra/postoperative), intermittent vs regular and duration of administration, and type of
surgery (eg cleft palate, hernia repair vs laparotomy).
Three systematic reviews on use of NSAIDs in paediatrics are published, reporting results
differently. The 2017 review does not perform meta-analysis and references the earliest metaanalysis and 2 further tonsillectomy trials detailed below (Zhu 2017 Level I, 1 meta-analysis [27 RCTs,
n=978] and 2 RCTs, n=443). The earliest meta-analysis includes two RCTs using coxibs and finds
NSAIDs, alone or as a component of multimodal analgesia, decrease opioid consumption in PACU
and at 24 h (Michelet 2012 Level I [QUOROM], 27 RCTs, n=985). NSAIDs also reduce pain intensity in
PACU but not in the first postoperative 24 h. The second meta-analysis overlaps by 24 RCTs,
including 1 coxib RCT, but also incorporates outcomes for paracetamol (13 RCTs) (Wong 2013b
Level I [PRISMA], 31 RCTs, n=2,624). NSAIDs (and/or paracetamol) reduce opioid consumption in 38
of 48 treatment arms (21 of 31 RCTs), with a higher proportion positive in NSAID-only trials andwith this being more apparent in moderate to major surgery. Where systemic opioids wereavailable via patient-controlled or nurse-controlled analgesia (PCA/NCA) (ie after major surgery),mean opioid consumption was reduced by 32% (95%CI 17 to 47) (7 RCTs) when studied for >24 hand not reduced when studied for ≤6 h (24%; 95%CI -1.7 to 50) (3 RCTs). Where systemic opioids
were available by intermittent bolus (21 RCTs, usually short or day-stay surgery), opioid consumption
was decreased by 24% (95%CI 6.3 to 43). Pain scores, reported in various ways, were reduced in
16 of 29 RCTs. The impact on adverse effects is difficult to interpret due to study heterogeneity
and small study size.
In a review of diclofenac studies only, diclofenac reduces the need for postoperative rescue
analgesia vs placebo (5 RCTs) and paracetamol (NNT 3.6; 95%CI 2.5 to 6.3, 2 RCTs) (Standing 2009b
Level I [Cochrane], 7 RCTs [analgesic rescue], n=404) (1 & 2 RCT overlap with above meta-analyses).
In a review of low quality ketorolac only studies with 3 and 4 RCT overlap with the above
2 reviews there was no difference in PACU rescue (4 RCTs) or PACU opioid requirement (3 RCTs),
with a small reduction in postoperative morphine requirement (1.58 mg; 95%CI -2.58 to -0.57
mg, 2 RCTs) in the 4 postoperative h only vs placebo (McNicol 2018 Level I [Cochrane],
13 RCTs, n=920).
Additional trials have found NSAIDs effective with reduced pain scores and rescue morphine
use post inguinal hernia repair (Riad 2007 Level II, n=108, JS 5), reduced need for early rescue
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analgesia post tonsillectomy (Pickering 2002 Level II, n=103, JS 5), reduced pain scores post multiple
dental extractions (Gazal 2007 Level II, n=201, JS 5) and reduced pain scores and need for rescue
opioid 0–48 h post cleft palate repair (more so when combined with paracetamol) ( Mireskandari2011 Level II, n=120, JS 5). A ketorolac infusion was more effective than fentanyl infusion following
ureteric-bladder surgery with less bladder spasm (4% vs 30) and less rescue analgesic
administration over 48 h (21% vs 65) (Jo 2011 Level II, n=52, JS 5). SL ketorolac was equianalgesic
vs SL tramadol for moderate and severe pain post fracture or dislocation (Neri 2013 Level II, n=131,
JS 5). Intraoperative IV ibuprofen resulted in a small reduction in early postoperative fentanyl
rescue administration after adenotonsillectomy surgery vs placebo (Moss 2014 Level II, n=161,
JS 4). A combination of individually titrated intraoperative opioids and regularly administeredperioperative nonopioid analgesics (NSAID and/or paracetamol) is recommended for pain
management following paediatric tonsillectomy (Hamunen 2005 Level I, 36 RCTs, n=2,309). The
combination of paracetamol (48 mg/kg/d) and ibuprofen (24 mg/kg/d) was not superior to either
agent alone following tonsillectomy (Merry 2013 Level II, n=152, JS 5). Ketoprofen has been studied
using IV, PO and PR route (Kokki 2010 NR). It is not currently used in children in Australia and New
Zealand, where it is available as CR and topical forms only.
A Cochrane review of nsNSAIDs (and paracetamol) found ibuprofen use for acute otitis media
reduces the number of patients in pain at 48 h vs placebo (7 vs 25%) (RR 0.28; 95%CI 0.11 to
0.70: NNT=6) (3 RCTs, n=146) with similar efficacy to paracetamol (Sjoukes 2016 Level I [Cochrane],
3 RCTS, n=327).
A Cochrane review of efficacy of NSAIDs in paediatric cancer found no RCTs (Cooper 2017b
Level I [Cochrane], 0 RCTs).
Nonselective NSAIDS and reduction of postoperative nausea and vomiting
Diclofenac use in acute pain is associated with reduced nausea and vomiting (or both) vs placebo,
paracetamol and opioids (OR 0.58; 95%CI 0.47 to 0.73: NNT 7.7; 95%CI 5.3 to 14.3) (Standing
2009b Level I [Cochrane], 13 RCTs, n=775). NSAIDs do not affect vomiting in PACU but reduce
vomiting over 24 h (OR 0.75; 95%CI 0.57 to 0.99) (Michelet 2012 Level I [QUOROM], 17 RCTs, n=1,302[events analysed]). Less vomiting occurs following tonsillectomy when nsNSAIDs are part of theanalgesic regimen (RR 0.72; 95%CI 0.61 to 0.85) (Lewis 2013 Level I [Cochrane], 13 RCTs, n=1,021).
The suggested mechanism is through improved pain relief, rather than reduced opioid rescue
requirement. A fourth meta-analysis, of heterogeneous surgery types, found no association (withconfidence interval overlap) between opioid-sparing effect and PONV reduction; 47% (95%CI 22
to 72) for those reporting PONV reduction vs 26% (95%CI 20 to 31) for those reporting equivalent
PONV rates (Wong 2013b Level I [PRISMA], 31 RCTs, n=2,624).
10.4.2.3 | Adverse effects of nsNSAIDs in children
Overall safety
In large series of children with febrile illnesses (n=55,785), the risk of serious adverse effects
following short term use of ibuprofen was low, and similar to that following the use ofparacetamol (Lesko 1995 Level II, n=84,192, JS 4) including in the subgroup of children aged <2 y(Lesko 1999 Level II, n=27,065, JS 4). Diclofenac use for postoperative pain is also safe, with an
overall serious adverse effect rate (including bleeding) of 8 in 10,000 (95%CI 2 to 24) (Standing
2009b Level IV SR [Cochrane], 18 RCTs and 54 studies [diclofenac], n=3,611). See also Section 4.2.1.2.
Ketorolac has been used as an analgesic in preterm and term neonates with no reported adverse
effects (Gupta 2004 Level III-1, n=70; Moffett 2006 Level IV, n=53; Papacci 2004 Level IV, n=18).
In children (<19 y) admitted to hospital with community acquired pneumonia, pre-hospital
exposure to NSAIDs is associated with empyema in 4 of 5 studies, but use at home may

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reflect illness, pain and fever severity rather than causation ( Voiriot 2019 Level III-3 SR, 5 paediatricstudies, n=1,753).
Nonselective NSAID hypersensitivity
NsNSAID hypersensitivity reactions may be immune or non-immune mediated. Immune
mediated include immediate reactions (IgE mediated, onset <1 h), which may be single ormultiple nsNSAID induced, and delayed reactions (T cell mediated, onset >24 h) ( Kidon 2018 GL;
Blanca-Lopez 2015 NR). Non-immune nsNSAID hypersensitivity includes NSAID-exacerbatedrespiratory disease (NSAID-ERD) (see below), NSAID exacerbated cutaneous disease and NSAID
induced urticaria/angioedema; a mixed phenotype is common in children ( Cousin 2016 Level IV,
n=107). These reactions are COX-1 mediated with consequent excessive release of leukotrienes,
and present within several hours of nsNSAID exposure (Cavkaytar 2019 NR). Also called crossintolerance hypersensitivity, these accounted for most of the reaction types (67-85%) in a groupof drug provocation test positive children (Arikoglu 2017 Level IV, n=106; Cousin 2016 Level IV, n=107).
Cutaneous symptoms of NSAID hypersensitivity reactions vary from urticaria/angioedema to
more rare severe cutaneous reactions (Stevens-Johnson Syndrome [SJS] and toxic epidermal
necrolysis [TEN]). The skin reactions are confounded by the use of the nsNSAID for the possible
underlying viral or bacterial infection (Blanca-Lopez 2015 NR). Chronic urticaria (OR 7.74; 95%CI
3.38 to 18.30), atopic status (OR 2.51; 95%CI 1.50 to 4.36) and allergic rhino-conjunctivitis (1.80;
95%CI 1.14 to 2.84) are risk factors for nsNSAID hypersensitivity (Cousin 2016 Level IV, n=107).
Life-threatening NSAID-exacerbated respiratory disease (ERD) (see section below) andanaphylaxis are rare events. Anaphylaxis rates to nsNSAIDs are very low (0/100,000
hospitalisations; 95%CI 0 to 5.4) (Lesko 1995 Level II, n=84,192, JS 4). Allergic reactions are
infrequently reported with diclofenac: one fatality from study data (Standing 2009b Level IV SR[Cochrane], 18 RCTs and 54 studies [diclofenac], n=3,611) and nine nonfatal from case reports (Standing
2009a Level IV). The frequency of implication of a particular nsNSAID in published series ofchildren with allergic reactions likely reflects local prescribing and parental administration
practices and has included all subclasses of nsNSAIDs (and also paracetamol) (Arikoglu 2017
Level IV, n=106; Topal 2016 Level IV, n=64). These children have been admitted for skin testing
and/or oral provocation tests with either the drug implicated or aspirin. Predictors include:• Onset of the reaction within 1 h of administration - OR 3.0; 95%CI 1.2 to 7.7 (Arikoglu 2017
Level IV, n=33 confirmed of 106 evaluated [6 paracetamol, 27 nsNSAIDs]) and OR 26.4; 95%CI 1.7
to 403 (Topal 2016 Level IV, n=18 confirmed of 64 evaluated [2 paracetamol, 16 nsNSAIDs]);• Reported history of multiple nsNSAID-hypersensitivity (OR 27; 95%CI 1.5 to 482) (Topal
2016 Level IV) and (OR 2.9; 95%CI 1.2 to 7.6) (Arikoglu 2017 Level IV); and• Family history of atopy (OR 4.0; 95%CI 1.50 to 10.82) ( Arikoglu 2017 Level IV).
In these two series, the proven allergic children were subsequently tested to find a safe
alternative. This is a better approach than telling the families to avoid all nsNSAIDs in their childas recommended by a prior paediatric series (Quiralte 2007 Level IV, n=223) referenced in thisbook’s previous edition. Cross sensitivity may be limited to those in the same chemical group eg
arylpropionic agents (ibuprofen and ketoprofen), arylacetic derivatives (diclofenac andaceclofenac) and pyrazolones (propyphenazone and dipyrone) ( Blanca-Lopez 2015 NR).
Aspirin or NSAID-exacerbated respiratory disease (NSAID-ERD)
NSAID-ERD prevalence is reported at 1.8-44%; the variability is influenced by whether the
population is from the community self-reporting sensitivity or a patient cohort with known subclassified severity of their asthma and nasal disease, assessed with spirometry or provocation
tests vs admitted to intensive care units (Kowalski 2019 NR). Age is relevant: younger children arestated to have reduced prevalence vs adults, with case series mostly of older children with
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moderate to severe asthma (usually with coexistent nasal disease/polyps) developing NSAIDERD (Kanabar 2017 NR; Tuttle 2016 Level IV, n=3; Karagol 2015 Level IV, n=10; Cavkaytar 2015 Level IV,
n=161; Palmer 2005 CR). Old series (referenced in the two narrative reviews) report prevalence of
5% in children, but a lower value of 2% (95% CI 0.2 to 7.0) in older asthmatic children reporting
sensitivity (n=100) assessed with spirometry post ibuprofen provocation. In most children withmild asthma, nsNSAIDS are likely to be safe. Single-dose diclofenac had no significant effect on
respiratory function tests (spirometry) in children with asthma ( Short 2000 Level III-3) and shortterm use of ibuprofen (vs paracetamol) reduced the risk of outpatient visits for asthma (RR 0.56;
95%CI 0.34 to 0.95) (Lesko 2002 Level II, n=1,879, JS 4). In toddlers with mild persistent asthma, nodifference in asthma control or the exacerbation frequency was found between as-needed useof paracetamol and ibuprofen over 48 wk (Sheehan 2016 Level II, n=300, JS 4).
Reye’s syndrome
Aspirin should be avoided in children with a febrile illness, as it has been associated with Reye’s
syndrome (encephalopathy and liver dysfunction) (Schror 2007 NR). The Therapeutic Goods
Administration (TGA 2004 GL), Medsafe (Medsafe 2015 GL), the FDA (FDA 2003 GL) and the
Medicines and Healthcare Products Regulatory Agency (MHRA 2003 GL) all recommend against
aspirin under the ages of 12, 12, 12 and 16 y respectively.
Platelet effects and bleeding
The issue of nsNSAIDs and postoperative bleeding risk remains controversial.
Diclofenac use for various surgery types was not associated with increased bleeding risk
requiring reoperation (OR 1.25; 95%CI 0.31 to 5) (Standing 2009b Level I [Cochrane], 7 RCTs, n=463).
In children (median 5 y, IQR 0.7-12) having neurosurgery (mostly major cranial and spinal
interventions), perioperative ketorolac (dose unspecified) was not associated with an increase
in clinically significant bleeding events (OR 0.69; 95% CI 0.15 to 3.1) or radiographic haemorrhage(OR 0.81; 95% CI 0.43 to 1.51) (Richardson 2016 Level III-2, n=1,451 [955 ketorolac]). In three small
trials, ketorolac did not increase the risk of bleeding complications in infants after congenital
cardiac (Gupta 2004 Level III-1, n=70; Moffett 2006 Level IV, n=53) or general surgery (Papacci 2004
Level IV, n=18).
Bleeding after tonsillectomy is of clinical significance but occurs infrequently: 1–5% inchildren depending on how bleeding is defined – any bleeding (which can have rates up to 10%),
postoperative primary or secondary (>24 h) vs those requiring admission/transfusion/surgicalintervention. Past studies have been small with contradictory results. Bleeding risk has been thesubject of several meta-analyses with varying conclusions (6─7 RCT overlap). Ketorolac use isassociated with increased post tonsillectomy bleeding in adults (RR 5.64; 95%CI 2.08 to 15.27)(n=246) but not children (RR 1.39; 95%CI 0.84 to 2.30) (n=1,111) (Chan 2014 Level III-2 SR [PRISMA],
10 studies [7 paediatric], n=1,357). An earlier review of only paediatric tonsillectomy trials (with
7 ketorolac RCT overlap) demonstrates no increased bleeding requiring either nonsurgical or
surgical intervention (Lewis 2013 Level I [Cochrane], 15 RCTS, n=1,101). A larger tonsillectomy review
also found no increased bleeding risk (surgical or nonsurgical) for all NSAIDs in adults andchildren, children only or for specific NSAIDs (Riggin 2013 Level I, 36 RCTs, n=3,193 [1,747 children]).
Importantly, to definitively answer the question of whether NSAIDs increase bleeding post
tonsillectomy, a study size of 2,400 is required (Lewis 2013 Level I [Cochrane], 15 RCTS, n=1,101).
Of note, the majority of studies in these meta-analyses have used a single dose of NSAID vsplacebo. A multicentre RCT in children (median 5 y, range 2 to 18) comparing ibuprofen andparacetamol (with an overall rate of any bleeding of 9.4%) was unable to show non-inferiority
for returns to theatre for bleeding post tonsillectomy (1.2 vs 2.9%: difference of 1.7% where noninferiority margin was set at 3%) (Diercks 2019 Level II, n=741, JS 5). Multiple postoperative dosing
for some days is routine clinical practice and has not been prospectively studied, with regard to922

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the issue of bleeding, and surgical techniques are evolving. In a single institution with low returnto theatre for post-tonsillectomy bleeding (3.3% in 3.5 years), postoperative ibuprofen exposure(n=2,122 of 6,710) did not increase post-tonsillectomy haemorrhage requiring surgicalintervention (OR 0.90; 95%CI 0.68 to 1.19), but of those returning to theatre, ibuprofen users
had a 3-fold greater transfusion rate than non-users (OR 3.2; 95%CI 1.0 to 9.9) (Mudd 2017
Level III-3, n=6710 [222 return to theatre: 15 transfusion requiring]). Predictors for post-tonsillectomy
haemorrhage requiring surgical intervention included age ≥12 y (OR 2.74; 95% CI 1.99 to 3.76)
and preoperative diagnosis of recurrent tonsillitis (OR 1.52; 95% CI 1.12 to 2.06) but not
obstructive indications. Cumulative dose data per patient was not reported.
Gastrointestinal effects
Epigastric discomfort, gastric or duodenal inflammation, oesophageal and peptic ulceration has
occurred in association with nsNSAID use for fever and pain in children (Kanabar 2017 NR; Cardile
2016 Level IV, n=51). Following ibuprofen use for fever management, the incidence of hospital
admission for gastrointestinal bleeding was low at 7.2 per 100,000 (95%CI 2 to 18) and similar to
those treated with paracetamol (Lesko 1995 Level II, n=84,192, JS 4). A prospective series of young
children admitted with gastroduodenal symptoms, haematemesis or melaena after mostly shortterm use had increased upper gastrointestinal complications with ibuprofen (OR 2.9; 95% CI 2.1
to 4.0), PO steroids (OR 2.9; 95% CI 1.7 to 4.8) and paracetamol (OR 2.0; 95% CI 1.5 to 2.6) vsnon-use (Bianciotto 2013 Level III-2, n=486).
Although NSAIDs are used infrequently for analgesia in young infants, limited data on adverse
gastrointestinal effects is available following PO, IV, bolus and infusion for PDA closure.
Ibuprofen is as effective as indomethacin (indometacin) for PDA closure (PO or IV; 32 RCTs,
n=1,862) with reduced risk of necrotising enterocolitis (18 RCTs, n=1,292) (Ohlsson 2018b Level I[Cochrane], 39 RCTs, n=2,843) – of relevance recent trials comparing NSAID with paracetamol forthis indication suggest equivalent efficacy for paracetamol with reduced gastrointestinal
bleeding (4 RCTs, n=537) and lower creatinine (4 RCTs) and bilirubin (2 RCTs) ( Ohlsson 2018b
Level I [Cochrane], 8 RCTs, n=916).
Renal effects
Renal blood flow, glomerular filtration and renal drug clearance are affected by nsNSAIDs(Allegaert 2005a PK). Acute kidney injury and renal failure (due to acute tubular necrosis orinterstitial nephritis) in association with nsNSAID use is a serious but rare complication. It has
occurred in all age groups (Misurac 2013 Level IV; de Martino 2017 NR; Musu 2011 NR with reviewed
case series overlap;) from newborns (after maternal use), neonates (Andreoli 2004 NR), and infants
to older children (Taber 2006 NR). A review has shown the risk in children is lower than in adults
but paediatric fatalities have occurred ( Musu 2011 NR). No renal impairment with ibuprofen
exposure was observed in a large fever trial including the subgroup of patients admitted tohospital (risk 0/100,000; 95%CI 0 to 5.4) (Lesko 1995 Level II, n=84,192 [n=55,785 ibuprofen], JS 4).
NSAID induced acute renal failure is usually reversible with cessation of the drug (Musu 2011 NR).
Children susceptible to dehydration (eg with high fever, vomiting and diarrhoea) may be atincreased risk of nephrotoxicity.
Retrospective analysis of the FDA's spontaneous reporting system suggests increased risk ofacute kidney injury with ibuprofen alone, which is higher when paracetamol was coprescribed(Yue 2014 Level IV). However, no data on illness type, severity, comorbidity or suspected causation(determined by expert panel review) was provided.

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Vascular effects
Neonatal bolus and short term use for PDA closure can alter pulmonary (although no pulmonary
hypertensive events were reported in Ohlsson 2018b Level I [Cochrane], 3 RCTs [pulmonary
hypertension], n=255), cerebral (Naulaers 2005 NR), gastrointestinal and renal blood flow (Aranda
2006 NR; Allegaert 2005b PK) with oliguria (Ohlsson 2018b Level I [Cochrane], 6 RCTs [oliguria], n=576;
Musu 2011 NR). Ibuprofen for PDA closure is associated with reduced risk of transient renal
insufficiency vs indomethacin (Ohlsson 2018b Level I [Cochrane], 6 RCTs [oliguria], n=576 and 11 RCTs
[creatinine levels], n=918). Subsequent to findings in non-RCT data (Musu 2011 NR; Ment 2004
Level III-2, n=431 [65 events]), the relative effects of indomethacin on the risk of intraventricularhaemorrhage (IVH) continue to be debated: of relevance, RCTs do not have a placebo arm, theydiffer in their report of outcomes eg severity grade of the bleed including all IVH grades(83 events/524 [7 RCTs]) vs severe grades (71/798 [10 RCTs]) or the consequence of cystic
periventricular leukomalacia 37/573 [6 RCTs]) and duration of follow-up (Ohlsson 2018b Level I[Cochrane], 39 RCTs, n=2,843).
Bone healing effects
NSAID use following orthopaedic injury and surgery remains controversial. NSAIDs do improveanalgesia, increase mobility and reduce opioid consumption following orthopaedic (including
spinal) surgery, but they are also used to suppress and treat heterotopic bone ossification. The
paediatric data is limited and we still do not have an understanding of the effects on bonehealing and, more specifically, the impact of dosing schedules, timing and duration of exposure
and whether they only delay union or contribute to non-union (Borgeat 2018 Level III-2 SR[PRISMA], 5 studies [paediatric], n=1,602 ) (see also Section 4.2.1.2). In this review, the three small
retrospective reports of paediatric spinal fusion patients did not find adverse effects from
<14 d of ketorolac use (total n=415) (Horn 2010 Level III-3; Sucato 2005 Level III-3; Vitale 2003
Level III-3). Specifically the incidence of pseudoarthrosis and revision surgery was notincreased. Two retrospective series of fracture and osteotomy surgery (with one surgeon)
report no delayed or non-union with perioperative ketorolac (0.5 mg/kg every 6 h) (n=468
ketorolac treated vs n=80 not ) (Kay 2011 Level III-3 in neither above nor below review; Kay 2010
Level III-3 in both reviews). Ibuprofen exposure in children presenting to ED with a fracture (tibia,
femur, humerus, scaphoid, or fifth metatarsal) and followed in orthopaedic clinic did notincrease bone healing complications (OR 0.8; 95% CI 0.4 to 1.8) ( DePeter 2017 Level III-2, n=808).
The cohort were initially managed conservatively or by closed reduction or surgery. Data on
ibuprofen dosing and duration was not reported.
A meta-analysis of 4 of the above studies concludes that NSAID exposure did not increase
delayed or non-union risk (OR 0.58; 95%CI 0.27 to 1.21) (Wheatley 2019 Level III-3 SR [PRISMA], 4
studies [paediatric], n=2,017 [analysed as broken bones]) (4 study overlap with Borgeat).
The balance of low-level evidence suggests that a short-duration NSAID regimen is safe forpost fracture or osteotomy pain control and for postoperative use in spinal fusion surgery.
Local necrosis following intramuscular injection
Serious local necrosis following IM injection of diclofenac is reported in six patients ( Standing
2009a Level IV).

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Table 10.6 | Common nsNSAIDs and dosing recommendations in children
nsNSAID

Suggested
age cut-off

Recommended
Dose

Suggested dosing
frequency

References

Ibuprofen(PO)#>3 mth (>5 kg)Some suggest>6 mth5–10 mg/kg(max 400-800 mg)

6–8 hly(max 30-40
mg/kg/d)Ziesenitz 2017 NR PK

Diclofenac(PO/PR)

1–12 y1-2 mg/kg(max 50 mg)

PO: 6–8 hly
PR: 12 hly

Hannam 2014 PK

Ketorolac*(parenteral)
Australia>16 y0.2–0.25mg/kg(Aust.: max 10 mg)

6 hly

Marzuillo 2018 NR;
McLay 2018 PK

Ketorolac(parenteral)USA>3 mth–2 y
2–16 y>16 y

0.5 mg/kg (USA:<50 kg max 15 mg;≥50 kg max 30 mg)

6 hly# IV formulation of ibuprofen is minimally used clinically to date as it is more costly than ketorolac* These dosing recommendations are based upon study data: ketorolac does not have regulatory approvalin Australia for use under 16 y (and is not available in New Zealand).

KEY MESSAGES
1. Nonselective NSAIDs do not increase the risk of either surgical or nonsurgicalintervention for bleeding after paediatric tonsillectomy (U) (Level I [Cochrane Review]);
however this was not supported by a large non-inferiority RCT where surgicalintervention was increased with ibuprofen versus paracetamol (Q) (Level II).
2. Nonselective NSAID (ibuprofen) use for acute otitis media reduces pain (at 48 hours) vsplacebo, with similar efficacy to paracetamol (N) (Level I [Cochrane Review]).
3. Nonselective NSAIDs are effective for moderately severe pain and decrease opioid
requirements after major paediatric surgery (U) (Level I [PRISMA]) and postoperative
nausea and vomiting (U) (Level I [QUOROM]).
4. Serious adverse effects after nonselective NSAIDs are rare in children over 6 months ofage (U) (Level II).
5. Ibuprofen may increase severity of haemorrhage post tonsillectomy in patients
returning to theatre (N) (Level III-3).
6. Short term use of ketorolac or ibuprofen do not increase bone healing complications inchildren undergoing posterior spinal fusion, osteotomy, or fractures managed
surgically (S) (Level III-3) or conservatively (N) (Level III-3).
The following tick boxes represent conclusions based on clinical experience and expert opinion: Aspirin for acute pain indications should be avoided in children (U).
 Combined population pharmacokinetic-pharmacodynamic modelling is required to
inform targeted dosing recommendations of analgesics in children (U).
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10.4.3 | Coxibs
Paediatric trial data is limited and thus the understanding of the degree of COX-2 selectivity, thepharmacokinetic-pharmacodynamic (PK-PD) relationship and adverse effects of these agents inchildren remains poor and paediatric use is again off-licence.
10.4.3.1 | Pharmacokinetics
The PKs of a celecoxib suspension, capsule sprinkles and the commercial capsule have been
compared (Krishnaswami 2012 PK). The different formulations achieve similar areas under the
curve post ingestion. For pain relief in juvenile idiopathic arthritis (JIA), a suggested dosing
regimen is 2–4 mg/kg bd. Although metabolism and excretion processes are typically fully
functional by age 2 y, absolute oral clearance (L/h) of celecoxib is reduced in younger patients;
by 40% in infants weighing 10 kg and by 24% in children weighing 25 kg vs a 70 kg adult. The
major clearance pathway for celecoxib is via CYP2C9 (Murto 2015 Level II, n=195, JS 5). Other drugs
cleared by this pathway (eg ibuprofen) have increased clearance (L/kg/h) in childhood. It isreported that clearance may be further increased in children with oncological disease (Stempak
2002 PK).
Parecoxib is a prodrug metabolised to the active valdecoxib, which reaches peak serum
concentration at 27 min (Tan 2016 PK). A pooled PK analysis of parecoxib demonstrates no change
in clearance with age for children over 1 y (Tan 2016 PK, n=112). The first year of life is when the
major clearance pathways for parecoxib mature. Parecoxib dose-response relationship modellingsuggest a ceiling analgesic effect at doses of less than 1 mg/kg (Tan 2016 Level II, n=59, JS 5).
Allometric dosing of parecoxib IV (0.9 mg/kg for 2 y, 0.75 mg/kg for 7 y and 0.65 mg/kg 12 y: 40 mgmax) is suggested to maintain the concentration of valdecoxib above the in vitro 50% inhibitory
concentration for cyclooxygenase for >12 h. This achieves dose equivalence of 40 mg in a 70 kg
adult, where 12 h dosing may be appropriate for both adult and paediatric age groups (Tan 2016 PK
incorporated data from Hullett 2012 PK). A dose reduction or increased dosing interval is suggested forchildren aged <2 y. In practice for older children, paediatric centres are using 1 mg/kg (max 40 mg).
10.4.3.2 | Efficacy
Celecoxib (6mg/kg pre-induction then 3 mg/kg 12 h for 3 days) reduced early pain (POD 0-2) andco-analgesic use following adenotonsillectomy (Murto 2015 Level II, n=195, JS 5). Carriers of the
CYP2C9*3 allele are slow celecoxib metabolisers and demonstrate less pain and improved
functional recovery. This suggests dosing may need to be more frequent than 12 h for normal
metabolisers. Celecoxib use has previously been reported in children with chronically painful
medical conditions. Celecoxib (3–6 mg/kg twice/d) was as effective as naproxen (7.5 mg/kg
twice/d) in children with JIA (Foeldvari 2009 Level II, n=242, JS 5). Celecoxib use was reported in aseries of JIA patients (n=68; 68 person-years) vs nsNSAID treatment (mostly naproxen, meloxicam,
and nabumetone) (Sobel 2014 Level III-2, n=268 [person-years]) and in a small series of haemophiliac
patients (Rattray 2006 Level IV).
Parecoxib 0.5–1.5 mg/kg for various surgery types reduces pain scores at 2 h (MD -1.9/10;
95%CI -3.0 to -0.8) and 12 h (MD -2.0; 95CI -2.3 to – 1.8) (Bu 2015 Level I [PRISMA], 6 RCTs [painscores], n=350). Its use reduces PONV (4 RCTs) vs fentanyl and tramadol and postoperative opioid
consumption (2 RCTs) (Bu 2015 Level I [PRISMA], 12 RCTs, n=994). Parecoxib 1mg/kg for post
tonsillectomy pain was modestly effective in the immediate postoperative period ( Li 2016
Level II, n=60, JS 5; Tan 2016 Level II, n=59, JS 5). IV parecoxib 20–40 mg (alone and combined with
topical local anaesthetic) was superior to IV fentanyl 2 mcg/kg for pain after repair of corneal

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perforation, with reduced rescue analgesic requirements and PONV ( Subramaniam 2007 Level II,
n=90, JS 3).
10.4.3.3 | Adverse effects of Coxibs in children
Overall safety
Prospective data from 3–12 mth use in JIA patients had similar incidence of treatment related
adverse events to nsNSAIDs (Sobel 2014 Level III-2; Krishnaswami 2012 PK). None were serious whichis reassuring but sample size was limited (overall n=220) (See Section 4.2.2.2 for discussion ofsafety and adverse effects in adults).
Safety in overdose
Paediatric overdose of celecoxib was reported in children aged 0–5 y (Forrester 2009 Level IV,
n=177). For 92 patients, the dose was known and was large; mean 506 mg (range 10–2,300 mg)
equating to mean ingested amounts of 22–39 mg/kg (for the half with documented weight)
across the age groups. This resulted in no adverse effects in 96%, and minor adverse effects (rash,abdominal pain, vomiting, agitation or drowsiness) in only 4%.
NSAID hypersensitivity including NSAID-exacerbated respiratory disease (ERD)
Based upon adult data (see Section 4.2.2), coxibs are generally considered safe for use inpaediatric patients with asthma and aspirin- or NSAID-exacerbated respiratory disease. In
223 patients (aged 5–78 y) with various levels of allergic reaction to nsNSAIDs or paracetamol(cutaneous/angioedema/urticaria/rash [61%], naso-ocular/cutaneous/asthma [15%], respiratory
alone [9%] and anaphylaxis [16%]) having placebo-controlled multidrug oral challenges (n=697),
celecoxib precipitated no events and meloxicam one event (Quiralte 2007 Level IV). Other smaller
series have reported cross-sensitivity for coxibs in patients with cutaneous or naso-ocular
reactions. In 28 nsNSAID-sensitive patients (aged 10–61 y), use of rofecoxib and valdecoxib
produced urticaria or angioedema in 3 (10%) (Sanchez-Borges 2005b Level IV). Of 58 similarly aged
patients, 5 (9%) had reactions to celecoxib and 3 (5%) had reactions to etoricoxib (Sanchez-Borges
2005a Level IV). As a small percentage of patients have reactions suggesting cross-sensitivity, oral
challenge under medical supervision for 2 h is advisable (see Section 10.4.2.3 regarding detail of
Anaphylaxis and allergy, and of NSAID-ERD with nsNSAIDs in children).
Platelets effects and bleeding
In adolescent haemophiliac patients, etoricoxib and rofecoxib treated patients had similar
numbers of presentations for bleeding vs placebo ( Tsoukas 2006 Level II, n=102, JS 5). Bleeding
following paediatric tonsillectomy has been assessed (Lewis 2013 Level I [Cochrane], 15 RCTS,
n=1,101) (see Section 10.6.5.1). This meta-analysis includes only one small coxib trial, with nodifferences in bleeding rates of rofecoxib vs ibuprofen vs placebo (added to paracetamol)(Pickering 2002 Level II, n=98, JS 5). A subsequent still relatively small trial found no difference inpost tonsillectomy bleeding rates for celecoxib vs placebo (Murto 2015 Level II, n=195, JS 5).
Gastrointestinal effects
In children with JIA treated chronically (where 68–71% were receiving disease-modifying agents,
with the number on corticosteroids unspecified), rates of abdominal pain were similar between
those treated with nsNSAIDs (15/100 patient-years; 95%CI 10 to 19 [n=225 patient-years]) andcelecoxib (18/100 patient-years; 95%CI 8 to 28 [68 patient-years]) and not statistically different
from patients in “off-NSAID” periods (8/100 patient-years, 95%CI 2 to 15 [n=75 patient-years])(Sobel 2014 Level III-2). One patient experienced gastrointestinal ulceration in an off-NSAID
period. Nausea and vomiting rates were similar in the three groups.

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Renal effects
Two unspecified renal disorders (not categorised as serious) occurred in chronically celecoxibtreated children with JIA during 68 patient-years of therapy (Sobel 2014 Level III-2). Celecoxib’s
safety profile for acute kidney injury in adults is specified in Section 4.2.2.2.
Table 10.7 | Coxib dosing recommendations in children
Coxib Drug

Age

Celecoxib(PO)*
Parecoxib
(IV)*

>2 y

Recommended Dose

Dosing frequency

References

3-6 mg/kg(max 200mg)

12 h (2-4 mg/kg repeat
dosing)Murto 2015
Level II

1 mg/kg (max 40 mg)
was studied:Single intraop. dose, >12 h
before next NSAID doseTan 2016 PK
Hullett 2012 PK

to derive allometric dose
scaling see doses in text.

* These dosing recommendations are based upon study data; at the time of writing neither coxib islicensed for acute postoperative pain indication under 18 y.

KEY MESSAGES
1. Parecoxib use in children reduces early postoperative pain scores, PONV (compared totramadol and fentanyl) and postoperative opioid consumption (N) (Level I [PRISMA]).
2. Parecoxib may have a ceiling analgesic effect in children in doses less than 1 mg/kg (N)(Level II).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: The safety profile of coxibs in the setting of allergy or contraindication to nonselective
NSAID in adults and children is encouraging; but safety data specific to short term use
in the perioperative period is limited (Q).
 Celecoxib for 3 days reduces pain and additional analgesic requirement posttonsillectomy in children (N).
 Some paediatric centres retain the 1 mg/kg (40 mg) maximum daily dosing schedule for
Parecoxib for off license use (N).

10.4.4 | Conventional and atypical opioids
There are significant developmental changes in the pharmacokinetic (PK) handling andpharmacodynamic (PD) response to opioids (Allegaert 2014 NR; Anderson 2014b NR; Holford 2012
PK). Doses must therefore be adjusted according to age, body weight, coexistent liver or renal
impairment, and individual response. Routine and regular assessment of pain severity, theanalgesic response, and the incidence of adverse effects (particularly nausea, vomiting, sedationand opioid induced ventilatory impairment [OIVI]) is essential, with titration of opioid treatment
according to individual needs. As with adult patients, appropriate dose regimens, guidelines formonitoring, documentation, management of adverse effects, and education of staff and carers
are required (Ellis 2011 Level IV; Wrona 2007 Level IV) (see Section 4.3.1 and subsection 4.3.1.5).

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The issue of sleep-disordered breathing (SDB) is discussed here under the individual
opioid adverse events subheadings and not as a subsection (See also the adult Section 9.4
on sleep-disordered breathing and subsection 9.4.1 Opioids and obstructive sleep apnoea).
The issue of opioid-related tolerance and withdrawal in children and adolescents is
discussed in Section 10.4.6.
10.4.4.1 | Pharmacogenomics
The evidence for the effect of pharmacogenetics on opioid responses is accumulating.
Examples of relevant polymorphisms include: the liver enzyme cytochrome-P450 CYP2D6(Balyan 2017a PK, n=30; Yee 2013 Level IV; Friedrichsdorf 2013 Level IV; Soderberg Lofdal 2013 NR; Kelly
2012 Level IV); enzymes involved in glucuronidation (UGT1A1) ( Toce 2019 CR); liver celltransporter proteins (OCT1) ( Fukuda 2013 Level IV), ATP-binding cassette (ABC) subfamily
member B1 (or MDR1) (Horvat 2017 Level III-3, n=63; Sadhasivam 2015b NR) and ABCC3(Chidambaran 2017c Level III-3, n=316; Venkatasubramanian 2014 Level III-3); opioid receptor
subtypes (Anderson 2014a NR), including OPRM1 genes involved in pain perception ( Sadhasivam
2015c Level III-3, n=259; Lee 2016 Level III-3, n=88) and COMT, a regulating enzyme involved inpain pathways (Elens 2016 Level III-3, n=34; Sadhasivam 2014 Level IV). Genome wide association
studies have also identified single nucleotide polymorphisms associated with opioid effects inchildren (Cook-Sather 2014 Level IV). Further considerations are the differential risk with genetic
differences and varying prevalence of racial/ethnic phenotypes ( Anderson 2014a NR) andconsequent variability in sensitivity to adverse effects ( Balyan 2017b Level III-3, n=30;
Chidambaran 2017a Level III-3, n=101; Sadhasivam 2015c Level III-3, n=259; Fukuda 2013 Level IV;
Jimenez 2012 Level III-3) (see also Sections 1.7.2 and 1.7.3). Despite a growing understanding of

the genetic factors determining drug effects, the link between genetic polymorphisms and therelevance to the observed clinical outcome is not always clear ( Balyan 2017b PK). For some of
the best understood polymorphisms, genetic screening to support clinical decision making isbeing explored (Gammal 2016 Level IV, n=2,468 [621 sickle cell disease] ).
10.4.4.2 | Medication prescribing errors
Medication errors continue to be problematic, particularly in children. Ten-fold dose errors inprescribing made up a small proportion of hospital prescribing errors (3.8%) but were associatedwith significant morbidity when involving opioids (Doherty 2012 Level IV, n=6,643). In a single
paediatric centre 5 y audit (≈1,320 medication error reports per year), the most frequently
implicated drug class was opioids (8.5%) (Doherty 2012 Level IV) and drug was morphine (3.2%)(Mc Donnell 2011 Level IV). This is concerning due to the frequency of prescription within hospitals
and the community and the adverse effect profile of opioids.

Conventional opioids
10.4.4.3 | Morphine
Morphine has a long history of use in paediatric acute pain management as either the gold
standard comparator or rescue agent in analgesic trials.
Pharmacokinetics and pharmacodynamics
Morphine clearance is influenced by postmenstrual/postnatal age and weight ( Holford 2012 PK;
Krekels 2011 PK). Morphine clearance is reduced and half-life prolonged in neonates and infants,
achieving adult values from age 2 y, related to the maturation of glucuronidation. Within age
groups, individual variability in kinetics results in large interindividual variation in clearance, from5th Edition | Acute Pain Management: Scientific Evidence929

2 to 20 fold (Altamimi 2015 NR), with subsequent variability in observed maximum plasma
concentration, including after PO administration (Dawes 2017 PK, n=34). In neonates, infants andchildren to 3 y, age is the most important factor affecting morphine requirements and plasma
morphine concentrations (Bouwmeester 2003b Level II, n=68, JS 2). Mechanical ventilation reduces
hepatic blood flow (up to 45%) and is associated with reduced clearance, as is renal failure(Anderson 2014b NR). Post cardiac surgery, there was no difference in morphine PKs seen between
patients with Down syndrome vs without (Goot 2018 Level III-2 PK, n=42; Valkenburg 2016 Level III-2
PK, n=38). Pharmacodynamics also change with age eg the change seen in older children for
average patient-controlled morphine requirements (Hansen 1996 Level IV) with contribution, as
outlined above, from genetics with resultant racial differences (Anderson 2014b NR).
The risk of respiratory depression is reduced when infusions are targeted to plasma morphine
concentrations <20 mcg/L. However, no minimum effective concentration for analgesia has been
determined (Anderson 2014b NR). No clear relationship between plasma concentration andanalgesia has been identified due to variability in individual requirements, clinical state of thechild, type of surgery, assessment measure used and small sample size in many studies.
EfficacyMorphine (administered via IV, epidural, IM and IT routes) has analgesic efficacy in comparison
with inactive controls, but with significantly increased vomiting and sedation ( Duedahl 2007
Level I, 36 RCTs, n=1,908). The majority of studies analysed compared single perioperative doses
and only one study evaluated a postoperative infusion of morphine. A further trial in bilateralmyringotomy demonstrated equivalence of IN fentanyl, IV and IM morphine (Hippard 2012 Level II,
n=171, JS 5). In children with SDB post tonsillectomy, more desaturation events per h occurredwith PO morphine vs ibuprofen, leading to early RCT termination (Kelly 2015 Level II, n=91, JS 3).
In children having minor day-stay orthopaedic surgery with low pain scores, multidosing withprn PO morphine 0.5 mg/kg (max 20mg) was not more effective than ibuprofen 10 mg/kg (max
600mg) and, similar to above, was associated with more adverse effects ( Poonai 2017 Level II,
n=154, JS 5). While in a systematic review of single and repeat dosing, IV morphine 50–150 mcg/kg
is inferior to IV buprenorphine 1.5–6mcg/kg in time to rescue analgesia in a range of paediatricsurgeries (MD: 115 min; 95% CI 43 to 186) (Murray 2018 Level I, 4 RCTs, n=137).
10.4.4.4 | Fentanyl
Fentanyl is a highly lipophilic and potent mu-opioid agonist and is used in paediatric acute pain
management.
Pharmacokinetics
Fentanyl’s rapid redistribution contributed to its relatively rapid offset of action following
single IV bolus doses (Tibboel 2005 NR). Fentanyl is metabolised by CYP3A4 to inactive
metabolites and clearance is only 70–80% of adult levels in neonates but rapidly matures
within the first 2 weeks of life, when standardised using allometric scaling. Clearance is greater
per kg than adults in older infants and children 3 mth and 6 mth to 6 y (Ziesenitz 2018 Level IV
SR PK, 24 studies [IV fentanyl], n=777 ).
After transbuccal administration, when children retained the lozenge in the cheek, thebioavailability was 50% vs other studies of lozenge (2 studies) vs solution (1 study), where
swallowing likely contributed to the lower bioavailabilities of 33 to 36% ( Lotsch 2013 NR PK;
Ziesenitz 2018 Level IV SR PK, 3 studies [oral transmucosal fentanyl citrate], n=67) (1 study overlap).
Intranasal (IN) fentanyl PKs have been assessed in adults demonstrating high bioavailability(and rapid onset of effect), but not in children to date. Small volumes are necessary to reducedelivery to the posterior pharynx (where it is swallowed).

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5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENTTD fentanyl has high bioavailability. In children vs adults, the time to reach steady state
serum drug concentrations following TD application is longer, and the elimination half -life
is shorter as clearance is enhanced (Ziesenitz 2018 Level IV SR PK, 1 study [TD fentanyl]: Paut 2000
PK, n=8).
Efficacy
Fentanyl has been administered for perioperative pain management in neonates and children(APAGBI 2012 GL) and also in the intensive care setting (Anand 2013a Level III-2) by multiple routes,
including IV bolus (He 2013 Level I, 3 RCTs, n=283; Elshammaa 2011 Level II, n=60, JS 4), infusion (Jo2011 Level II, n=52, JS 5), patient-controlled analgesia (PCA) (Antila 2006 Level II n=45, JS 4) (seeSection 10.5.2), IT injection (Duman 2010 Level II, n=50, JS 5; Batra 2008 Level II, n=56, JS 5) and as anadditive to peripheral nerve and epidural infusions and patient-controlled epidural analgesia(PCEA) (Saudan 2008 Level III-3) (see Section 10.6.3.3).
Due to its rapid onset and short duration of action, fentanyl can be used alone or in
combination with sedatives to control procedural pain (see Section 10.7.2 and APAGBI 2012 GL;
Tibboel 2005 NR).
Due to its high lipophilicity, fentanyl can also be administered via transmucosal (transbuccal,
IN, nebulised) and TD routes. Transmucosal fentanyl is attractive when IV access is challenging
or unavailable. Transbuccal fentanyl has been used for children having burns dressing changes
and lumbar punctures (see Section 10.7.2).
In the prehospital or ED setting for orthopaedic trauma, 10–15 mcg/kg by transbuccal route(Davis 2011 Level IV SR, 1 RCT [paediatric]: Mahar 2007 Level II, n=87, JS 3) and 1–4 mcg/kg IN havebeen used effectively ( O'Donnell 2013 Level III-3, n=946; Karlsen 2014 Level IV, n=903). It has also
been used to manage pain from abdominal, back and other conditions ( Bendall 2011a Level III-2,
n=3,312). In paediatric EDs, IN fentanyl (INF) 1.5–2 mcg/kg (usual max 100 mcg) was used forpain from injured extremities (Schoolman-Anderson 2018 Level IV, n=132; Setlur 2018 Level IV SR[PRISMA], 4 RCTs, n=281 and 2 studies (fracture) n=1800), burns, the abdomen and other sources(Hansen 2012 Level IV SR, 7 studies [paediatric], n=878 analysed ). A second systematic review
describes efficacy of similar dosing in three ED studies (one of fractures, one mixed pain types
and one in burns [see Section 10.9.1 and 10.9.2]) and four perioperative myringotomy studies(Mudd 2011 Level IV SR, 12 studies, n=1,743) (5 study overlap). Further myringotomy studies havealso been published (Dewhirst 2014 Level II, n=100, JS 5; Karlsen 2014 Level IV, n=903; Hippard 2012
Level II, n=171, JS 5). A Cochrane review did not perform meta-analysis due to the 3 different
active comparator arms studied (Murphy 2014b Level I [Cochrane], 3 RCTs, n=313) (1 & 2 RCT overlap
with above & below ). In a fourth systematic review (1 & 3 study overlap: 2 RCTs and the largest
prehospital study above), INF 1.5–2 mcg/kg in a variety of settings was superior to placebo andIM morphine and similar to IN and IV ketamine and IV morphine in reducing pain scores ( Setlur
2018 Level IV SR [PRISMA], 6 RCTs, n=350; 4 retrospective studies n=5,595). In acute care settings,
use of INF vs IV morphine achieved earlier time to analgesic administration in 2 cohorts by 24
and 29 mins (Borland 2008 Level III-3, n=617); and in a further study by 8.5 min (SchoolmanAnderson 2018 Level III-3, n=132). A subsequent RCT in procedural pain showed INF added tonitrous oxide (N 2O) did not improve analgesia over N 2O alone in children with low
preprocedural pain scores and short procedure duration ( Seiler 2019 Level II, n=402, JS 5). No
serious adverse effects of INF were reported in the above studies with a total of >6,000
patients.
Data on nebulised fentanyl in children is limited showing similar reduction in pain scores vsIV fentanyl and IV morphine (Thompson 2016 Level I [PRISMA], 2 RCTs (paediatric), n=118). There havebeen no randomised trials of efficacy of the TD route.

5th Edition | Acute Pain Management: Scientific Evidence931Adverse effects to morphine and fentanyl in children
Side effects
Mild to moderate but not life threatening opioid-related adverse effects that greatly disturb
children, and their parents, include nausea, vomiting, constipation, dizziness, sedation,
dysphoria, nightmares, itch/skin rash and urinary retention. They occur commonly; no large scalecomparative data is available. See data for other opioids in Table 10.8.
Major adverse events
Respiratory complications, coma and death have occurred with these two opioids. Younger aged
children may have increased risk postoperatively (Tait 2016 Level III-2, n=678; Chidambaran 2014
Level IV, n=38), including post tonsillectomy (Sadhasivam 2015a Level IV, n=275). Comorbidities arelikely to contribute (see below) but the degree of interplay of other factors such as variation in
opioid potency, prescriber error (dosing or with change of opioid) and severity of pathology is
unknown. National outpatient ‘weak and strong opioid’ prescription data has been published for
New Zealand (HQSC 2019 Level IV, n=58,272), Australia (Bell 2019a Level IV, n=78,320) and USA (Chung
2018a Level IV, n=1,362,503), with low level (0 to 3.5%) oral morphine prescription in children.
Certain groups of paediatric patients are at higher risk of opioid induced ventilatory
impairment (OIVI). Children with neurodevelopmental disabilities (eg cerebral palsy, Down’s
syndrome and encephalopathy) experienced more OIVI than children without (1.1 vs 0.6%; OR1.8) with similar median dosing of morphine infusions POD 0-2 (Jay 2017 Level III-3, n=12,904).
Children with SDB receiving postoperative opioids following various surgery types (frequently
tonsillectomy in the SDB group) triggered oxygen desaturation alarms, required escalation of careand treatment with naloxone more than children without SDB (53 vs 27%: OR 2.0; 95%CI 1.6 to2.5) (Tait 2016 Level III-2, n=678). Additionally, children with SDB who have worse night time oxygen
desaturation (<85% nadir) required half the morphine dose to achieve the same analgesic effect(Brown 2006 Level III-2, n=22). Amongst hospital inpatients (n=60,467), 38 (0.06%) opioid-induced
respiratory events requiring naloxone occurred, with higher incidence in those patients who were
under pain service care (0.23%) (Chidambaran 2014 Level IV, n=38). Most patients were
postoperative (71%) and were more likely to have had recent airway surgery, be underweight orobese, age <1 y and ex-premature vs pain service patients who did not receive naloxone. See also
the adult Section 9.4 on sleep-disordered breathing and subsection 9.4.1 Opioids and obstructive
sleep apnoea. Of three patients with renal failure who received morphine, two experienced OIVI
and one died, with likely contribution of metabolite accumulation (Niesters 2013 Level IV, n=27).
Fentanyl-related deaths are described in children unrelated to therapeutic use. Illicitly
manufactured fentanyl has caused death in a teenager and two toddlers (related to parental
administration) (DeRienz 2018 Level IV, n=3). The transdermal patch formulation has resulted inpoisonings in young children (mostly in boys with 48% mortality: Stoecker 2016 Level IV, n=25) andhas been deliberately misused in an adolescent suicide attempt (five 100 mcg/h patches applied)(Lyttle 2012 CR). Partial occlusion of fentanyl patches does not reduce the dose received (Nelson
2009 NR). Thus the practice of applying an occlusive dressing to the skin surface of a transdermal
fentanyl delivery system to limit drug delivery is not supported; some authors haveinappropriately suggested this practice (Mitchell 2010 NR).
10.4.4.5 | Codeine
Codeine has been used for decades in paediatric acute pain. Multiple factors have led toreduced prescription of this opioid prodrug. These include the publications of codeine-related
deaths, increased understanding of the relevant pharmacogenomics (see below),upscheduling (eg in Australia) and removal by the World Health Organisation (WHO) ofcodeine from its tiered analgesic ladder for treatment of (persistent) pain in children ( WHO932

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2012 GL) in response to the blacklabelling by the USA’s Food and Drug Administration (FDA)(2012 statement archived: FDA 2013b GL) and European Medicines Agency (EMA) ( EMA 2013 GL).

National USA data is available for 1996 to 2013 with opioid use in trauma, dental pain,
outpatient procedures, postsurgery and for infections, where codeine comprised 27-40% ofprescriptions (Chung 2018a Level IV, n=547,726 [codeine]; Livingstone 2017 Level IV, n=1.03 million[codeine in 2013]; Groenewald 2016 Level IV, n=917,700 [codeine in 2012] ). Comparison of USA
adenotonsillectomy claim data pre and post FDA investigation assessed children who received
opioid prescriptions ( Chua 2017b Level III-3, n=362,992 [246,459 prescriptions] ). In Jan 2010 vs Dec
2015, codeine decreased from 46.8% to 9.1% of prescriptions (while hydrocodone increased
from 48.4 to 72.7%). In Dec 2015, off label prescription of codeine occurred for 5.1% of allchildren and 3% of children with OSA. While still in 2017, codeine made up the majority ofcommunity opioid prescriptions in Australia for children <17 y (50.5%: AIHW 2019 Level IV) andin New Zealand for <24 y (54.3%: HQSC 2019 Level IV).
Pharmacokinetics
PO codeine has a similar time to peak effect but decreased total absorption vs PR and IM delivery(McEwan 2000 PK). Administration IV should be avoided as severe hypotension may result(Shanahan 1983 Level IV).
Pharmacogenomics and adverse effects
Relevant to codeine as a prodrug, the numerous CYP2D6 enzyme’s polymorphisms result in four
phenotypes, which demonstrate an overlapping spectrum of activity (Chidambaran 2017b NR) (seealso Sections 1.7.3 and 4.3.1.2). The phenotypes are variably represented in populations of different
ethnicities. The most common (>70% of Caucasians to 92% of Asians) “normal” phenotype, termed
extensive metabolisers, has 1─2 x CYP2D6 activity and analgesic effect with codeine. Intermediate
metabolisers have reduced (0.5 x CYP2D6 activity) and poor metabolisers no effect (nil CYP2D6
activity) from codeine: affecting 46% of a group of UK children having tonsillectomy (Williams 2002
Level II PK, n=96, JS 4) and 49% (intermediate 44% and poor 5.3%) of children with sickle-cell disease(Yee 2013 Level IV, n=75); while ultra metabolisers (>2 x activity) attain high peak morphine levels andare at risk of sedation and respiratory depression (Chidambaran 2017b NR; Yee 2013 Level IV, n=75;
Racoosin 2013 Level IV, n=7) (case report overlap). Somnolence, lethargy and respiratory depression
have been reported with antitussive use of codeine (Paul 2018 Level IV, n=98 [38 codeine related]).
Several paediatric deaths associated with codeine administration have been reported, some withconfirmed ultra and extensive metaboliser phenotype. Subgroups at particular risk included
breastfeeding neonates (whose ultra/extensive metaboliser mothers were taking codeine in thepuerperium) (Madadi 2007 CR), toddlers (Racoosin 2013 Level IV, n=7; Kelly 2012 Level IV, n=3 [2 deaths])
and obese older children following adenotonsillectomy (Chidambaran 2017b NR, case report summary
including Friedrichsdorf 2013 Level IV, n=3 [obese]).
The USA’s FDA has subsequent to 2013 contraindicated against codeine use in all children
under 12 y and in adolescents who are obese or having adenotonsillectomy (with arecommendation against use by breastfeeding mothers) (FDA 2017 GL). The EMA has extended
their 2013 contraindication to also exclude use as an antitussive (EMA 2015 GL). Australia’s
Therapeutic Goods Administration (TGA) applied the same warnings as the FDA in 2017 (TGA 2017GL) and further limited access with upscheduling of combination codeine containing products in2018 (TGA 2019 GL). New Zealand applied the same warnings in children and breastfeeding
mothers in mid 2018 (Medsafe 2018 GL) and plans scheduling changes in 2020. Several paediatrichospitals have removed codeine from their drug formularies (Tremlett 2013 NR).

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Efficacy
Codeine efficacy data has been published in a few RCTs prior to 2009. In the majority of studies
with a codeine treatment arm (see below), CYP2D6 activity is not accounted for and is asignificant confounder contributing to conflicting reports of efficacy for postoperative pain. Early
perceived advantages of codeine include less respiratory depression in neonates and reduced
nausea and vomiting vs morphine (at one only of four time points) (Williams 2002 Level II, n=96,
JS 4). These conclusions are probably compromised by low levels of active metabolites andresultant reduced efficacy (Williams 2001 NR). Comparison of codeine and morphine fortonsillectomy has shown either no difference ( Semple 1999 Level II, n=40, JS 4) vs an increased
requirement for rescue analgesia following codeine (Williams 2002 Level II, n=96, JS 4). Codeine wasless effective than ibuprofen for acute musculoskeletal pain in children (Clark 2007 Level II, n=336,
JS 5). Addition of codeine to paracetamol has been reported to improve analgesia (Pappas 2003
Level II, n=120, JS 5) or have no effect (Moir 2000 Level II, n=79, JS 5) and was as effective as ibuprofen
for fracture pain but ibuprofen-treated patients had fewer adverse effects and better functional
outcomes (Drendel 2009 Level II, n=336, JS 5). Use of codeine in paediatric neurosurgical case series
has been published (Bronco 2014 Level IV; Teo 2011 Level IV).
10.4.4.6 | Oxycodone
Oxycodone is increasingly used in paediatric acute pain management. USA prescription data forchildren is available. One tertiary USA centre has documented oxycodone as the most commonlyprescribed opioid (72.5%) by mostly surgical services, with decreased annual codeineprescription over 7 y from 377 to only 3 prescriptions (George 2016 Level IV, n=34,218). The USA’snational community opioid prescription data has not yet reflected this change with only 4.6%
and 15.5% being for oxycodone vs the more commonly prescribed codeine and hydrocodone(Chung 2018a Level IV, n=62,675 [oxycodone]; Groenewald 2016 Level IV, n=314,650 [oxycodone]; see
Table 10.8 for data detail). In the USA’s adenotonsillectomy claim analysis pre and post FDA
investigation, oxycodone prescription increased from 3.8% in 2010 to 17.4% in 2015, outranked
by increased hydrocodone (Chua 2017b Level III-3, n=362,992 [246,459 prescriptions]). Community
prescription of oxycodone for children in 2017 was low in New Zealand at 1.3% of all opioidprescriptions (HQSC 2019 Level IV), while in Australia oxycodone was commonly prescribed
comprising 36.5% of opioid prescriptions for children (AIHW 2019 Level IV).
Pharmacokinetics and pharmacogenomics
In children aged >6 mth, the PK profile of oxycodone is similar to adults and dosing can be basedon weight (El-Tahtawy 2006 PK). Similar absorption is seen following buccal and SL administration(Kokki 2006 PK). PK variability remains large, exacerbated by CYP2D6 polymorphism, as is the casewith other opioids (Soderberg Lofdal 2013 NR). In expreterm to term neonates and infants, thehalf-life is prolonged with an inverse relationship to age (reflecting the lower body weightadjusted clearance and higher apparent Vd) and increased variability in kinetics is seen evenfollowing IV administration (Valitalo 2017 PK, 3 Studies, n=119). The body weight adjusted clearance
is lowest and the apparent Vd is highest in preterm babies, which results in elimination half lives
typically around 8 h in extremely preterm neonates. The parent compound contributes the
majority of drug effect but the impact of polymorphisms and cotherapies that influence CYP2D6
and CYP3A4 enzymes, and thus metabolite (eg oxymorphone, noroxymorphone andnoroxycodone) concentration, has been debated (Kokki 2012a NR) (see Section 1.7.3). In children,a difference in the plasma concentrations of oxycodone metabolites relating to CYP2D6
genotypes was found, but the clinical significance has not yet been explored ( Balyan 2017a PK,n=30). See adult Section 1.7.3.4.

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Efficacy
Oxycodone’s efficacy has been shown in various paediatric settings: PO use of 0.1–0.2 mg/kg in
the ED for children with orthopaedic injuries (Charney 2008 Level II, n=107, JS 5; Koller 2007 Level II,
n=66, JS 5), use of a PO controlled-release (CR) preparation as a step-down following PCA inadolescents after spinal fusion (Czarnecki 2004 Level IV), IV bolus dose administration for
postoperative rescue analgesia (Kokki 2006 Level IV) and IV PCA in adolescents and adults (Silvasti
1999 Level II, n=52, JS 4). Oxycodone CR (OxyContin®) has been approved in the USA for use inchildren >11 y who are ‘opioid-tolerant’ defined as minimum 5 d prior oxycodone therapy of >20
mg/d (Product information: FDA 2018b), but use is off-label elsewhere. There has been no study
reporting paediatric use of the CR oxycodone/naloxone combination (eg Targin®) to date.
Adverse effects
Like for the other commonly used opioids, large scale data on mild to moderate adverse effects
is not available for oxycodone specifically. USA data following outpatient opioid prescription andsubsequent ED presentation with an adverse event likely related to the prescribed opioid issummarised in Table 10.8 below. See also 10.4.5 Issues with discharge opioid prescriptions forchildren.
Literature search reveals no data specific to oxycodone and QT prolongation in children,
however this is different for adults. See adult Section 4.3.1.5 Adverse effects of opioids where
the issue of cardiac effects of opioids and also nausea and vomiting and QT prolongation related
to antiemetics is discussed.
Table 10.8 | Opioid prescription data (USA) for children and adolescents including subtypes of
opioids and adverse events
Author Year

Groenewald
2016

Chua 2017b

George 2016

Chung 2019

Chung 2018a

Data type

National

National

One hospital

One state#

National

Prescriptions, n

2,030,000
in 2012

246,459

34,218529,731prescriptionsfor 201,940
adolescents

1,362,503

Years

1996-20122010-20152007-2014

1999-2011

1999-2014

42.1
39.9
15.5
NS
NS
NS
--

72.7
9.1
17.4
-NS
-0.8

2
7.3
73
3.7
1.1
NS
--

59
27
8.6
NS
NS
5.5
--

42.1
40.2
4.6
NS
NS
2.9
5.2 (meperidine)25(7/1 million)275(5/1 million)437(3/1 million)

Prescribed
opioids* (%)
Hydrocodone
Codeine
Oxycodone
Hydromorphone
Morphine
Tramadol
Other
Adverse events
related to opioids,n (per prescription)

5th Edition | Acute Pain Management: Scientific Evidence935Author Year

Groenewald
2016

Chua 2017b

George 2016

Chung 2019

Chung 2018aNS

1 (0.36%)
10 (3.3%)
71 (25.8%)
83 (30.2%)
57 (20.7%)51 (18.5%)
35 (12.7%)
4 (1.5%)3 (0.7%)12 (2.8%)
97 (22.2%)
83 (30.2%)
134 (30.7%)102 (23.3%)
77 (17.6%)
15 (3.4%)

Adverse event
subtype n (%)
Death
Resp. depression
CNS depression
Neuro-psychiatric
Gastrointestinal
DermatologicalAllergic
Other
Prescriber error

25 total
16 patients with weight entry error:
14 with <10% error; two with >15% error-one under and one over

# Tennessee *(alone or as combined products) CNS = Central nervous systemNS= not specified Resp.=respiratory

Other conventional opioids
A large number of opioid preparations have been used in children (see below), but availability
varies by country and many have not been investigated in controlled trials. For additional detailssee (APAGBI 2012 GL).
10.4.4.7 | Hydromorphone
Hydromorphone has no advantage over other opioids in terms of analgesic efficacy or adverseeffect profile, administered by PO, IV, caudal or epidural route (Quigley 2002 Level I [Cochrane],
4 RCTs [paediatric], n=122). Oral hydromorphone prescriptions were uncommonly dispensed froma single USA paediatric institution over 8 years (George 2016 Level IV, n=1,266 prescriptions). IV
Hydromorphone has been used in the PICU setting usually as second or third line opioid therapy
for analgesia and sedation for malignancy and following trauma with a median dose 10 mcg/kg/h(Reiter 2012 Level IV). IN Hydromorphone was titrated in children presenting to the ED withvarious painful conditions (such as fracture or abdominal pain); 30─60 mcg/kg over 30 min total
achieved ≥3/10 pain reduction (Tsze 2019b Level IV, n=35).
See Section 10.6.3.3 and 10.6.6 for neuraxial use and Section 10.8.1 and 10.8.3 for use inpaediatric cancer.
10.4.4.8 | Hydrocodone
Hydrocodone is not available for analgesic use in Australia or New Zealand. In other countries, it
is generally used in combination with paracetamol (Sutters 2010 Level II, n=123, JS 3; Rees 2019
Level IV, n=1,246). In the USA in 2014, hydrocodone (combination product with paracetamol) wasupscheduled. As documented in Table 10.8, it has been the most commonly prescribed opioid
for children in the USA over a 16 year period, with no evidence base.
Oral clearance is higher in children (weight adjusted) vs adults; weight-based dosing inchildren thus leads to reduced exposure which is overcome if body surface area adjusted dosing
is used for children aged 6─17 y (Liu 2015 PK, n=17). Hydrocodone is metabolised by CYP2D6 to936

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hydromorphone and CYP3A4 to norhydrocodone. Inhibition of these enzymes by coadministeredantibiotics and anticonvulsants resulted in a child’s death where hydrocodone was being used
for antitussive effect (Madadi 2010 CR). Three further fatalities have been reported in children <12 yassociated with antitussive use of hydrocodone combined with antihistamine and a further 57
patients had respiratory depression, somnolence and/or lethargy ( Paul 2018 Level IV, n=98). The
FDA has limited hydrocodone (along with codeine) containing cough and cold products to adults≥18 y (FDA 2018a GL).
10.4.4.9 | Methadone
Methadone is used in children for persistent pain, for opioid weaning (Dervan 2017 Level IV SR[PRISMA], 12 studies, n=459; Johnson 2012 Level IV, n=96) and as part of a multimodal approach tocomplex surgeries. In adolescent posterior spinal fusion patients receiving intraoperative
remifentanil infusion up to 0.3 mcg/kg/min, the addition of IV methadone 0.1 mg/kg reduced
intraoperative hydromorphone administration with resultant lower overall 0─24 h requirementof 0.26 ± 0.10 mg/kg vs magnesium (50 mg/kg bolus then intraoperative infusion 10 mg/kg/h)
0.38 ± 0.10 mg/kg vs remifentanil alone 0.34 ± 0.11 mg/kg, with no difference in pain scores(Martin 2018 Level II, n=60, JS 4). Methadone has also been used for the Nuss procedure ( Singhal
2016 Level III-2, n=125) and as a third line intervention for acute neuropathic pain in children post
limb salvage surgery (Anghelescu 2011a Level IV, n=6/150). The more extensive published use inchildren is in oncology and palliative care (Habashy 2018 NR; Mott 2018 Level IV, n=16) and inneonatal abstinence syndrome.
There is limited PK information in children, but the available data show similar parameters inneonates, infants and children to adults (Ward 2014 PK). The conversion to methadone from otheropioids is complex and dependent on recent opioid exposure. Patients with higher opioid
exposure require relatively lower methadone conversion ratios (Mott 2018 Level IV, n=16).
In children receiving methadone for cancer pain, some QT prolongation was seen in patientstaking a median dose of 0.37 mg/kg/day (most of whom were on other QT prolonging agents),
but there have been no published reports of severe dysrhythmias in children receiving
methadone for pain (Habashy 2018 NR).
See adult sections 4.3.1.2 Methadone and 4.3.1.5 Cardiac effects of opioids for discussion of
QT prolongation.
10.4.4.10 | Sufentanil, Alfentanil and Remifentanil
Sufentanil
Sufentanil PKs have been assessed after IV use, and clearance maturation is the same as for otherdrugs metabolised by CYP3A4 eg fentanyl (Ziesenitz 2018 Level IV SR PK, 8 studies [sufentanil], n=129).
After IN sufentanil 2 mcg/kg, maximum concentration (Cmax) occurred at 15-30 min with syringe
dropper technique (Ziesenitz 2018 Level IV SR PK, 1 study [IN sufentanil]: Haynes 1993 PK, n=15).
IN sufentanil 0.5 mcg/kg combined with IN ketamine via actuating device spray was effectivefor various procedures (n=50) with respective bioavailabilities of 25 and 36% and a Cmax at 13.8
min (Nielsen 2014 Level IV). IV sufentanil infusion was used to manage post-thoracotomy pain in
intubated preterm neonates at 0.1─0.2 mcg/kg/h initially and subsequently reduced to
0.03─0.04 mcg/kg/h, with no difference in time to extubation (Soreze 2017 Level III-3, n=109).
Epidural sufentanil use alone and with local anaesthetic is described in Section 10.6.3.
There is no current data on SL sufentanil use in children.

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937

Alfentanil
Alfentanil PKs have been reviewed (Ziesenitz 2018 Level IV SR PK, 15 studies [alfentanil], n=244). Useof IN alfentanil 10 mcg/kg (in low volume solution 0.2 mL) is described in the ED for analgesic
management of mostly orthopaedic injuries (Brenchley 2006 Level IV, n=36). Only intraoperativeand not postoperative use of alfentanil in children has been described. Caudal epiduraladministration with local anaesthetic is described in Section 10.6.3.
Remifentanil
Remifentanil PKs have been reviewed (Ziesenitz 2018 Level IV SR PK, 7 studies [remifentanil], n=118).
Mostly intraoperative use of remifentanil in children has been described. Extension of use into
PACU has been reported for modification of emergence agitation (and is not presented here).
Use in neonates having non cardiac surgery and while in NICU to facilitate endotracheal tube
tolerance and sedation has been described (Kamata 2016 NR; Allegaert 2016 NR), as well as in PICU
for sedation without documenting pain scores (Hungerford 2019 Level IV, n=38).
See Sections 10.7.2.2 for use in procedural intervention in children with cancer and 10.7.2.9
for use of remifentanil in combination with propofol for procedural intervention in burns.
See Section 10.4.7 and adult Sections 4.6.1.1 and 4.6.1.3 for data on the adjuvant use of
ketamine and magnesium to reduce remifentanil induced tolerance.
10.4.4.11 | Diamorphine (diacetylmorphine, heroin)
This opioid is not available for analgesic use in Australia and New Zealand. In the UK, it is used IN
in paediatric EDs (by 118 of 205 surveyed paediatric EDs) (Hadley 2010 Level IV) for trauma pain
management eg alone post fracture (Kendall 2001 Level II, n=404, JS 3; Kidd 2009 Level III-2; Regan
2013 Level III-3; Kendall 2015 Level IV, n=226) or for fracture reduction with N2O (Kurien 2016 Level IV,
n=100), and for sickle cell crises (Telfer 2009 Level IV) (see Section 8.6.4.1). The bioavailability
following IN drop installation is 33%, with Tmax of 10 min (Kidd 2009 Level III-2).

Atypical opioids: Tramadol, Buprenorphine and Tapentadol
10.4.4.12 | Tramadol
Tramadol, first launched as an opioid, is now recognised as an atypical opioid with its multimodal
antinociceptive and antineuropathic effects. Its two enantiomers act via noradrenaline andserotonin reuptake inhibition and mu-receptor agonistic effect, where for the latter the
metabolite O-desmethyl-tramadol (or M1) has greater efficacy than the parent compound(Anderson 2017b NR). Evidence for tramadol use in paediatric acute pain is still limited by studies
of small sample size and difficulty determining comparative analgesic doses. With the 2012 FDA
black box warning for young children and tonsillectomy, codeine prescription has decreased
post-tonsillectomy (Van Cleve 2017 Level IV, n=230 [477 tonsillectomies]). Meanwhile from 2012 to2015, tramadol use has increased in the USA by 23% from 170 to 209 per 1,000 population (Bigal
2019 Level IV, n=18.8 million [12 to 64 y olds]); but it is not known how many prescriptions are
paediatric or post-tonsillectomy. Interestingly codeine prescription over the same period, after
an initial decrease, has also increased. Subsequent to codeine’s relabeling, the FDA has applied
the same warning against tramadol use in paediatric acute pain (FDA 2017 GL). Frequent off label
use occurs in young children with variable paediatric licensing internationally: over 1─3 y inEurope (country-dependent) (Rodieux 2018 NR) vs ≥12 y previously in Australia (with June 2019revised Consumer medicine information leaflets for the oral capsule stating ‘should not be usedin children’) (NPS Medicinewise 2019a GL) with New Zealand changing its licensing from ≥2 y938

5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT(Medsafe 2017 GL) to follow the USA FDA with contraindication <12 y and <18 y following
tonsillectomy/adenoidectomy (Medsafe 2020 GL).
Pharmacokinetics and pharmacogenomics
Oral bioavailability is 68─75% post single dose in adults (See section 4.3.1.3) and is likely similar
in children. Due to extensive first-pass hepatic metabolism and higher hepatic blood flow inchildren and infants, plasma concentrations are lower (Vandenbossche 2015 PK; Allegaert 2011b PK).
Rectal bioavailability is good with low interindividual variability (Zwaveling 2004 PK, n=12 in Bozkurt2005). Maximum plasma concentrations post IV, PO and PR dosing are achieved between 0.3–
2.4 h (Bozkurt 2005 Level III-3 SR PK, 3 studies, n=164), with peaks post PO at 1─2 h for tramadol and
3 h for M1 (Vandenbossche 2015 PK, 3 studies, n=97). Analgesic efficacy is associated with a plasma
concentration of tramadol of 100 ng/mL in adults and children and M1 of 15 ng/mL ( Garrido 2006
PK).
Tramadol is transported to the liver via the organic cation transporter-1 (OCT1). Reduced
OCT-1 function resulted in lower tramadol requirements in adults ( Stamer 2016 PK, n=205). It ismetabolised primarily to M1 by the hepatic enzyme CYP2D6 ( Anderson 2017b NR) (see also
Sections 1.7.3 and 4.3.1.3). CYP2D6 activity matures with age increasing rapidly from 25 wk
postmenstrual age to 50% of the adult value by 44 wk postmenstrual age and to 90% by 1 y ofage (Allegaert 2011b PK). M1 is primarily inactivated via glucuronidation, most extensively by
UGT2B7 and UGT1A8 (with the glucuronide forms then renally excreted) (Lehtonen 2010 BS). The
relevance of the UGT enzymes is now being explored. In addition to this, M1 is eliminated renally
but preterm neonates, because of their reduced renal function, have relatively higher plasma
M1 concentrations (Allegaert 2008 PK). While, infant size and postmenstrual age constitute thegreater contribution (53%) to inter-individual variability in tramadol and M1 metabolism andclearance, significantly more so than CYP2D6 activity score in the very young (Allegaert 2008 PK).
In older children, tramadol clearance is linked to weight (Bressolle 2009 PK). OCT1 expression andfunction is highly genetically variable and may be a further consideration, alongside CYP2D6
phenotype, in at risk groups (Tzvetkov 2017 NR BS) (see also Section 10.4.4.5).
The poor, normal, extensive or ultra metaboliser CYP2D6 phenotype has been the reason forcodeine’s black box warning, but the clinical significance in terms of tramadol/M1’s analgesic
efficacy and adverse effect profile is still unknown.
Dose and efficacy
Systemic administration
In children IV dosing is the same as in adults (1–2 mg/kg every 6 h), with an initial IV dose 2 mg/kg
recommended, followed by IV infusion rates of 0.25–0.41 mg/kg/h (6–10 mg/kg/24 h) (Allegaert
2011b PK; Bressolle 2009 PK). Lower infusion rates have been reported (Alencar 2012 Level II, n=160,
JS 5; Moyao-Garcia 2009 Level II, n=24, JS 5).
A meta-analysis has graded the existing heterogeneous RCTs as low in quality withmethodological problems (Schnabel 2015 Level I [Cochrane], 20 RCTs, n=1,170). It finds single dosesof IV tramadol 0.5–3 mg/kg for postoperative pain relief in children is superior to placebo
reducing the number of patients in moderate to severe pain (2 RCTs, n=94), need for rescue
analgesia in PACU (RR 0.4; 95%CI 0.2 to 0.8) (5 RCTs, n=189), with similar efficacy in terms of rescueuse (0–24 h) to morphine (3 RCTs, n=127), fentanyl (1 RCT, n=42), pethidine 1 mg/kg (2 RCTs, n=120)
and nalbuphine (2 RCTs , n=110).
For tonsillectomy, PO tramadol 2.5 mg/kg was more effective than low-dose PR paracetamol(Pendeville 2000 Level II, n=50, JS 5), IV 1 mg/kg had similar efficacy to IV paracetamol 15 mg/kg (Uysal
2011 Level II, n=64, JS 5), IV 1–2 mg/kg had similar efficacy to IV morphine 0.1 mg/kg (Engelhardt 2003
Level II, n=60, JS 5) as did PCA IV tramadol bolus of 0.2mg/kg vs 0.02 mg/kg morphine for 24 h
postoperatively (Ozalevli 2005 Level III-1). Conversely IV 1 mg/kg was less effective than IV pethidine
5th Edition | Acute Pain Management: Scientific Evidence939

1 mg/kg (Ozer 2003 Level II, n=50, JS 3), PO dextromethorphan 1 mg/kg (Ali 2008 Level II, n=90, JS 1),
ketoprofen (IV initial bolus 2 mg/kg and 6 h infusion of same dose) (Antila 2006 Level II, n=45, JS 4)
and ropivacaine infiltration, while being similarly effective to placebo (Cocelli 2012 Level II, n=90, JS 3)(all 4 RCTs in Schnabel 2015 Level I [Cochrane]). Multidosing post tonsillectomy in 4─15 y olds for 5─10d of PO tramadol 1.05 mg/kg (max 52.5 mg) alone 6 hly provided comparable analgesia to
combination paracetamol 7.2 mg/kg with codeine 0.72 mg/kg (max 36 mg) (Friedrichsdorf 2015b
Level II, n=84, JS 2). More paracetamol-codeine treated patients were sedated only on POD 1 (21 vs3%), while the tramadol-treated experienced more itch in the 10 d (33 vs 13%).
Post abdominal surgery, IV tramadol 2 mg/kg was similarly effective to IV pethidine 1 mg/kg(Ekemen 2008 Level II, n=110, JS 3). In postoperative ventilated neonates, multidosing of IV
tramadol 2 mg/kg 6 hly vs placebo in addition to IV paracetamol and morphine infusion did notoffer clinical benefit in pain scores, morphine requirements or time to extubation ( Olischar 2014
Level II, n=71, JS 5). In ventilated neonates following major abdominal and minor surgery, IV
tramadol infusion (0.1–0.2 mg/kg/h) was similar to fentanyl infusion (1–2 mcg/kg/h) in terms ofpain scores over 72 h, time to extubation and to full enteral feeding ( Alencar 2012 Level II, n=160,
JS 5). In children having various surgery types, IV tramadol infusion 0.12 mg/kg/h for 72 h wastrialled against nalbuphine infusion (Schnabel 2015 Level I [Cochrane], 1 RCT [nalbuphine]: MoyaoGarcia 2009 Level II, n=24, JS 5).
For further data on IV tramadol administration to children: see Section 10.5.2 for PCA and10.5.3 for NCA.
Sublingual administration
SL tramadol 2 mg/kg use in paediatric fracture pain was effective and comparable to SL ketorolac
0.5 mg/kg at 100 min (Neri 2013 Level II, n=131, JS 5), but PK data to support this route is
not available.
Neuraxial administration
After neuraxial administration, efficacy has generally not been compared to systemic
administration; the safety of this route remains uncertain (Walker 2012c NR; Engelman 2012 Level I[PRISMA], 9 RCTs [tramadol], n=258). Caudal tramadol 1–2 mg/kg added to caudal local anaesthetic
prolongs the time to first rescue analgesic (4.5 h; 95%CI 2.8 to 6.1) at the expense of increased
vomiting (OR 2.5; 95%CI 1.3 to 4.6), with no IV comparator.
For inguinoscrotal surgery, caudal tramadol 2 mg/kg added to bupivacaine andlevobupivacaine was similarly effective (Sezen 2014 Level II, n=68, JS 5). Post abdominal surgery,
epidural tramadol 2 mg/kg added to epidural ropivacaine 0.2% was superior to ropivacaine
alone, with lower pain scores, reduced rescue requirement and longer time to first analgesic
request (14.5 h vs 5) (Inanoglu 2010 Level II, n=44, JS 5). For lower abdominal, urological and lower
extremity surgery in young children, caudal tramadol 1 mg/kg added to caudal bupivacaine
0.25% 1 mL/kg increased time to first analgesia vs local anaesthetic alone (7.8 h vs 4) (Regmi 2017
Level II, n=60, JS 5). As a sole agent for urological surgery (without a systemic arm or epidural local
anaesthetic comparator), epidural tramadol 2 mg/kg vs morphine 0.1 mg/kg had similar painscores and time to first rescue analgesic, but with reduced adverse effects (Demiraran 2005 Level II,
n=80, JS 3) (see also Section 10.6.3.1 and 10.6.3.3).
Infiltration and topical administration
Whether tramadol has clinically useful local anaesthetic effects has been debated. Peritonsillar
infiltration of tramadol 2 mg/kg has been studied in several small RCTs and was effective forcontrol of early (0–8 h) postoperative pain following adenotonsillectomy. Its benefits weresimilar to lidocaine (Heiba 2012 Level II, n=60, JS 4), similar (Ugur 2013 Level II, n=75, JS 5) and superior
to ketamine infiltration (Ayatollahi 2012 Level II, n=126, JS 4), superior to placebo (Atef 2008 Level II,

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n=40, JS 5) and, when combined with IV ketamine, superior to either agent alone and placebo(Honarmand 2013 Level II, n=75, JS 5). Only one small systemic comparator trial is available, whichfound infiltration of tramadol 2 mg/kg to be superior to IM administration and placebo ( Ugur
2008 Level II, n=45, JS 5).

For inguinal herniorrhaphy in young children, preincisional infiltration of tramadol 2 mg/kg
was as effective as bupivacaine 0.25% with regard to pain scores and time to first analgesic use(Numanoglu 2014 Level II, n=52, JS 4). While infiltration post hernia repair of SC tramadol 2 mg/kg
resulted in higher initial pain scores but similar time to first rescue analgesic request vsbupivacaine infiltration, with both having a longer effect than IM tramadol (6.7 h vs 6 vs 4.5)
(Demiraran 2006 Level II, n=75, JS 5).
For awake circumcision, ring block combined with pudendal nerve block with tramadol
5%/adrenaline was effective and superior to prilocaine/adrenaline with reduced rescue
requirements (Kargi 2010 Level II, n=40, JS 4), but was ineffective vs lidocaine/adrenaline (Polat 2013
Level II, n=47, JS 4).
A small tonsillectomy study showed no benefit on POD 0 following single topical applicationof tramadol 5%, but pain scores were reduced on POD 6 (Akbay 2010 Level II, n=40, JS 5). Tonsillar
application of tramadol 40 mg/ketamine 20 mg was superior to placebo, with similar pain scoresand rescue analgesic requirements on POD 0 (Tekelioglu 2013 Level II, n=60, JS 5).
Adverse effects
Tramadol has similar or reduced rates of nausea and vomiting (10–40%), sedation and fatigue tothose found with conventional opioid use, generally with lower rates of constipation and pruritus(Bozkurt 2005 Level III-3 SR, 20 studies, n unspecified). Following a large tramadol overdose withplasma level >1 mg/mL, a seizure and cardiogenic shock have been reported in a child; cardiac
function normalised within 48 h (Perdreau 2015 CR). Anaphylaxis (Mori 2015 CR) and deaths havebeen reported (see below).
Nausea and vomiting
In mixed surgery types, PONV is not reduced in tramadol vs placebo recipients in PACU (RR 0.84;
95%CI 0.28 to 2.52) (3 RCTs, n=215) or to 24 h (RR 0.78; 95%CI 0.54 to 1.12) (4 RCTs, n=150) (Schnabel2015 Level I [Cochrane], 20 RCTs, n=1,170). In accidental and intentional overdose, nausea andvomiting rates were 16 to 25% (Stassinos 2019 Level IV n=1,115; Hassanian-Moghaddam 2015 Level IV,
n=20; Tsutaoka 2015 Level IV, n=3,051 [tramadol exposures in children under 19y]; Marquardt 2005
Level IV, n=190).

Sedation and ventilatory impairment
Lower sedation rates with tramadol vs conventional opioids have been described ( Schnabel 2015
Level I [Cochrane], 7 RCTs, n=526 ); the heterogeneity of the included RCTs documenting sedation
scores did not permit subanalysis. Drowsiness is common post overdose with rates in adults of
27% (Marquardt 2005 Level IV, n=190) and 55─100% in children (mean dose of 13.1 mg/kg) (Stassinos
2019 Level IV, n=1,115 [symptomatic children] of 7,334 exposures; Tanne 2016 Level IV, n=7; HassanianMoghaddam 2015 Level IV, n=20; Marquardt 2005 Level IV, n=8 [<5 y]) and may or may not be

associated with miosis.
In the Cochrane review, no tramadol-treated child had ventilatory impairment, but sample
sizes were small. Subanalysis of tramadol vs placebo (3RCTs, n=165) and multiple opioid
comparator arms (8 RCTs, n=532) revealed non-estimable or minimal effect sizes (Schnabel 2015
Level I [Cochrane], 20 RCTs, n=1,170). In an RCT included in the Cochrane involving tonsillectomy inchildren with OSA, fewer desaturation events were reported with tramadol 2 mg/kg than withmorphine 0.1 mg/kg, significant only between 1─2 h postoperatively (Schnabel 2015 Level I[Cochrane], 1 RCT: Hullett 2006 Level II, n=66, JS 4). Three ex-premature infants given tramadol
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2 mg/kg (with local anaesthetic drops: for outpatient eye examination) experienced prolonged
sedation, returned and were admitted (Bilgili 2012 Level IV, n=20). One experienced frequentapnoea required continuous positive airway pressure (CPAP) and transfusion, one required
supplemental oxygen and one was observed only.
Following mostly supratherapeutic doses or accidental/intentional overdose, ventilatory
impairment is reported in both adults (following a high mean dose of 2,125 mg, range 200-4,600)(Hassanian-Moghaddam 2013 Level IV, n=19 [1 death] in 114 hospital presentations post-tramadol) (seeSection 4.3.1.3) and children (following high doses of ≥7─10 mg/kg) (Stassinos 2019 Level IV, n=37
[36 ventilatory impairment, 1 death]; Moulis 2018 Level IV, n=5 [4 life threatening, 1 death]; Rodieux 2018
Level IV, n=18 [15 ventilatory impairment, 3 deaths] and a further 14 deaths [tramadol implicated but not
as sole agent]; Tanne 2016 Level IV, n=7 [6 ventilatory impairment, 1 death]; Hassanian-Moghaddam 2015
Level IV, n=3 [ventilatory impairment]). The FDA investigation identified nine cases of ventilatory

impairment following tramadol over 1969─2016 (overlapping with the above series; including
three deaths of children under 6 y) (FDA 2017 GL). This is in the context of a single year’s USA
dispensing data for 167,000 prescriptions for children (<18 y) for 2014.
In the event of excess sedation or ventilatory impairment, naloxone has been used as areversal agent (Tanne 2016 Level IV, n=3/7; Hassanian-Moghaddam 2015 Level IV, n=16/19 [apnoeic
patients]; Tsutaoka 2015 Level IV, n=540 [naloxone use age unspecified]; Hassanian-Moghaddam 2013
Level IV, n=3/19 [apnoeic adult patients]; Marquardt 2005, Level IV n=2/51 young children; Grosek 2009CR).

Seizures
Lowering of the seizure threshold and seizures are reported in adults (46.1% of adult
presentations: Tsutaoka 2015 Level IV, n=5,491 [tramadol exposures >19 y]; Hassanian-Moghaddam 2013
Level IV, n=525; see also Section 4.3.1.3) and children with therapeutic and supratherapeutic
dosing (Li 2012b Level IV, n=2) vs overdose >4.8 mg/kg with variable incidences of: nil (HassanianMoghaddam 2015 Level IV, n=20), 2.2% (Stassinos 2019 Level IV, n=24/1,115), 13.7 % (Marquardt 2005
Level IV, n=26/190; but 0/51 under 5y), 20% (Moulis 2018 Level IV, n=1/5 seizures), 71% (Tanne 2016
Level IV, n=7) and case series (Tsutaoka 2015 Level IV, n=3,051 [tramadol exposures <19 y; higher RR vstapentadol]; Mazor 2008 Level IV, n=2), including in association with hypoglycaemia ( Aliyu 2016 CR).
In one report, naloxone administration is suggested to have terminated a recurrent seizure in asingle toddler with tramadol overdose (Tanne 2016 Level IV, n=7).
Agitation and serotonin syndrome
Agitation occurs with therapeutic dosing and in adult and paediatric overdose in 0.7─14% of
patients (Stassinos 2019 Level IV, n=51/7,334; Moulis 2018 Level IV, n=1/7; Marquardt 2005 Level IV,
n=1/8 [children]). Drug-drug interactions are an important consideration. In adults, serotonin
syndrome has been reported; it occurs more frequently with SSRIs sometimes in combination
with tramadol. It has occurred with tramadol in isolation and has been reported in an infant
following 28 mg/kg ingestion, but not older children (Marechal 2011 CR).
Fetal, neonatal and infant exposure with maternal use
Neonatal abstinence syndrome is described after chronic (maternal) exposure ( Hartenstein 2010
CR; Willaschek 2009 CR). Infant exposure through breastmilk has been a literature focus
subsequent to the FDA adding warning against tramadol by breastfeeding mothers (FDA 2017 GL).
Exposure of infants was very low relative to maternal exposure and well below therapeutic
dosing used in this age group (LactMed Database 2019 NR; Palmer 2018 NR).
Formulation issues and adverse outcome
A concentrated drop formulation (100 mg/mL) is available in many countries, licensed for adultpalliative care (eg in Australia) but also in children (eg in France). Dosing error confusing the942

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number of drops with the number of mL is a concern in paediatrics (10 drops=25 mg=0.25 mL).
Two children dosed at home with the concentrated oral tramadol drops post
adenotonsillectomy had adverse outcomes. One aged 5 y with ultrarapid genotype
experienced significant respiratory depression ( Orliaguet 2015 CR). The single urine sample ofM1 reported for this case was not accompanied by plasma concentrations of tramadol or M1.
Thus, the accuracy of the stated single analgesic dose administered cannot be determined anddosing confusion was likely. The second child aged 2 y died due to tramadol toxicity withconcentrated oral drops treatment. The TGA subsequently does not support the use of thisconcentrated oral formulation in children aged <12 y (TGA 2015 GL). New Zealand (NZ)’s
Medicines and Medical Devices Safety Authority (Medsafe) has delisted the concentrated
formulation (for all ages) and compounding pharmacists in NZ make a 10 mg/mL formulation(Medsafe 2017 GL; Pharmac 2016 GL). An Australian centre has described dispersing 50 mg in 5
mL (10 mg/mL) for administration to smaller children (Kluger 2016 Level IV, n=20 [dosepreparations]). In France, following a further death with the concentrated formulation of a 3 y
old boy of normal CYP2D6 metaboliser phenotype, the formulation has been retained with arevised dosing leaflet instruction (Moulis 2018 CR).
Impact of the FDA announcement for tramadol
Particularly following the FDA’s contraindications for use of codeine and tramadol (in children
and warning against use in breastfeeding mothers), further data is required to determine therole, optimum dose and safety of tramadol in children and the monitoring level required.
Inadvertent overdose and formulation issues are likely of greater risk than CYP phenotypes
resulting in variable drug metabolism; evidence for harm from this second mechanism is lacking(Anderson 2017b NR). Restriction of use of an effective analgesic and replacement with full agonist
conventional opioids presents a similar or greater hazard in the at-risk population with SDB/OSA
and post adenotonsillectomy.
10.4.4.13 | Tapentadol
Tapentadol is available in tablet IR and ER forms in Australia, but as of 2020 not in New Zealand.
Both formulations are only indicated for adult use: IR for acute pain and ER for chronic pain.
Evidence for tapentadol use in acute paediatric pain is limited in terms of number of studies andtheir sample size. There is drug company sponsored data for use of an oral solution in children
postoperatively (studied for regulatory application in Europe: see below). See also Section
4.3.1.3 for summary of tapentadol in adults.
Pharmacokinetics and efficacy
Non-obese children received tapentadol 1 mg/kg oral solution postoperatively following dental
or adenotonsillectomy (aged 2–18 y: Muse 2019 Level IV PK, n=66) and mixed surgery types (aged
6–18 y Finkel 2019 Level IV PK, n=44). Plasma concentrations of tapentadol were similar to adult
data (following 50–100 mg) peaking at 1─1.5h (while the non-active metabolite tapentadol-Oglucuronide concentrations were lower or the same) ( Muse 2019 Level IV PK). Pain scores
decreased over 15 to 120 min post-dose in 2–18 y olds using developmentally-appropriate pain
scales (Muse 2019 Level IV). Median times to rescue analgesia intake were 5 h (Finkel 2019 Level IV)
and 6.3 h (Muse 2019 Level IV).
Adverse effects
Adverse events in the above studies included PON, POV, dizziness and headache (without
placebo comparator nor provision of anaesthetic details including antiemetic prophylaxis).
USA toxicity data is available for single agent (mostly accidental) ingestion by children where
61% were aged ≤2 y (Borys 2015 Level IV, n=104). Most had no (59.6%) or minor (32.7%) ill effect;
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5.8% had moderate and 2% major effects. Most common was drowsiness (29%), with otherneurocognitive effects (in 6%) and nausea/vomiting, tachycardia and dizziness (each in 2 to 4%).
The two patients with major effects were an infant who experienced coma with respiratory
depression requiring naloxone (and was discharged) and a toddler with drowsiness anddyspnoea requiring oxygen and critical care monitoring. There were no deaths. No detail offormulation, dose or mg/kg was provided.
A further USA study analysed single agent exposures of tapentadol (n=217) vs tramadol(n=8,566) (Tsutaoka 2015 Level IV). The analysis included 31 tapentadol vs 1,785 tramadol
accidental ingestions by children <6 y vs 9 and 1,266 accidental and intentional ingestions inolder children (6–19 y). The children <6 y had greater risk of severe outcome from tapentadol
exposure vs tramadol (formulation/ dose detail not provided). Neurological sequelae occurredin both groups: the tapentadol vs tramadol exposed more commonly experienced hallucinations,coma (RR 4.2; 95% CI 2.3-7.4), drowsiness, slurred speech, confusion and respiratory depression(RR 5.6; 95% CI 3.5 to 8.8), and use of naloxone (RR 3.8; 95% CI 3.0-4.9). Tramadol exposed morecommonly experienced seizures (RR 7.9; 95% CI 3.0 to 21) and vomiting (RR 2.0; 95% CI 1.1 to
3.6). A cohort study assessing trends in selfpoisoning in children aged 5─19 y reported no adverse
events related to tapentadol (2006─2016: Cairns 2019 Level IV, n=33,501).
See adult Section 4.3.1.3 for post-marketing surveillance ADR data, reports of serotonergic
syndrome and mortality where tapentadol has been implicated (rarely as a single agent).
Potential for abuse
Intentional ingestions have been reported by adolescents (3 abuse, 3 suicide attempts and 2other: Borys 2015 Level IV, n=104 [8 intentional]). There is no further data on abuse potential oftapentadol in adolescents. Reported nonmedical use in USA college students was low incomparison to conventional opioids and has decreased post initial launch (Dart 2014 Level IV);
diversion rates and black market cost are low (Dart 2016 Level IV).
10.4.4.14 | Buprenorphine
Buprenorphine is used off-label in children for the treatment of acute pain including in cancer
pain, palliative care (Vicencio-Rosas 2018 NR; Michel 2011 Level IV SR, 8 studies & 3 RCTs, n=274), opioid
misuse disorders in teenagers (Borodovsky 2018 NR) and neonatal abstinence syndrome (NAS)(Kraft 2018 NR), with low level evidence support.
Pharmacokinetics and pharmacodynamics
With IV bolus 3 mcg/kg and infusion of 0.72 mcg/kg/hr, ex-preterm neonates have reduced
clearance consistent with their immature CYP450 and glucuronidation (UGTB27) pathways anda prolonged half-life of 20–26 h. Following a single IV 3 mcg/kg dose, allometric scaling suggested
clearance is higher in children (Michel 2011 Level IV SR, 8 studies & 3 RCTs, n=274). Combined PKpharmacodynamic study is required to explore a possible paradoxical prolongation of effect.
See adult Sections 4.3.1.3 and 5.4.1.2, 5.5.2.2 and 5.5.3.1 for discussion of buprenorphine’s
PKs and PDs in adults (Butler 2013 NR).
A liquid formulation has been made for SL administration for NAS (Anagnostis 2011).
Efficacy
Buprenorphine via various routes (IV, SL, caudal usually 2.5–5 mcg/kg and transdermal [TD]) has
been used in a few small studies of children having thoracotomy, orthopaedic, abdominal, hernia
and genitourinary surgery (Michel 2011 Level IV SR, 8 studies & 3 RCTs, n=274):
Following inguinal herniorrhaphy or orchidopexy surgery,• Caudal and IV buprenorphine 2.5 mcg/kg was added to and compared with caudal
bupivacaine 0.5% 1 mL/kg alone with no difference in pain outcomes. The RCT ceased944

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recruitment with higher vomiting in both buprenorphine arms (80% caudal vs 50% IV vs
20% caudal bupivacaine alone) (Khan 2002 Level II, n=30, JS 5);• Caudal buprenorphine 4 mcg/kg vs caudal bupivacaine 0.25% 0.5 mL/kg was equieffective
on a 3 point Lickert scale, with longer duration following buprenorphine ( Girotra 1990
Level III-1, n=40);• Caudal buprenorphine 4 mcg/kg vs caudal morphine 50 mcg/kg was equieffective withlonger duration (Girotra 1993b Level II, n=65, JS 5).
In orthopaedic surgery,• IV buprenorphine 3 mcg/kg vs IV morphine 100 mcg/kg was transitioned to ward
treatment with SL buprenorphine 6 mcg/kg vs IM morphine 150 mcg/kg withequianalegsic effect with self-report on a 4 point scale, similar side effect profile (fornausea and vomiting and urinary retention) and longer duration in the buprenorphinegroup (Maunuksela 1988a Level II, n=60, JS 4);• Caudal buprenorphine 4 mcg/kg had a longer time to rescue analgesic request vs IM route(Girotra 1993a Level III-1, n=44).
Following thoracotomy, IV buprenorphine 1.5 or 3 mcg/kg vs IV morphine 50 or 100 mcg/kg was
similarly effective (Sum of Pain Intensity Difference scores) (Maunuksela 1988b Level II, n=57, JS 4).
In a later systematic review of single and repeat IV dosing, IV buprenorphine 1.5–6mcg/kg
was superior to IV morphine 50–150 mcg/kg in time to rescue analgesia (MD: 115 min; 95% CI
43 to 186) (Murray 2018 Level I, 4 RCTs, n=137) (2 RCT overlap with Michel 2011 above).
SL buprenorphine 50 mcg rescue use has been reported for acute pseudo-obstruction pain
crises in children who had chronic abdominal pain managed with TD buprenorphine (Prapaitrakool
2012 Level IV, n=3). A small dose finding study (2.5–10 mcg/kg) suggests 5 mcg/kg SL 12 hly iseffective in children with cancer pain (Massimo 1985 Level IV).
Adverse effects
In the past, it was suggested that buprenorphine had a ceiling effect for ventilatory impairment(Khanna 2015 NR); this is now under debate with increasing overdose presentations and reports
of death (Michel 2011 Level IV SR, 8 studies and 3 RCTs, n=274; Butler 2013 NR). It has not beenreassessed recently in the paediatric population (Vicencio-Rosas 2018 NR). Case series of accidental
paediatric overdose (total n=150) document opioid adverse effects including ventilatory
impairment requiring hospitalisation for young children ( Toce 2017 Level IV, n=88; Vicencio-Rosas
2018 NR). Children <6 y have accounted for the majority of buprenorphine poisoning exposuresin the USA (5,761 of 5,078; 88%) and of these, 51% were admitted to a health care facility ( Allen2017 Level IV, n=188,468 [opioid poisonings]). One series found no relationship between ventilatory
impairment incidence and estimated ingested dose in the range of 0.03–7.62 mg/kg (Toce 2017
Level IV). Naloxone boluses of 0.04–0.2 mg/kg were administered to most paediatric patients inthese series and some received continuous infusion. The resistance to naloxone reported in adultvolunteer studies (Dahan 2010 NR) was not noted in these children.
Plasma vs cord concentrations are low at birth following maternal opioid replacement therapy,
with NAS incidence similar to other opioids of 6/10 (60%) (Bartu 2012 PK Level IV). In infants bornto buprenorphine vs methadone-treated mothers, the NAS incidence was similar between groups
with 27/58 (47%) buprenorphine-exposed infants requiring therapy for NAS (Jones 2012 Level II,
n=175, JS 4). In each of two further studies, 4/7 infants had NAS and 1/7 required therapy; breast
milk penetration after maternal SL administration was assessed and resulted in a relative infant
dose exposure of 0.18 to less than 1% (Ilett 2012 PK; Lindemalm 2009 PK).
See also subsection 9.1.1.1 opioids use as Medications used in pregnancy and subsection
9.8.9.2 of Pain in pregnant patients with an opioid use disorder.
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10.4.4.15 | Nalbuphine
Nalbuphine is a mu antagonist and partial kappa agonist. It has been used in paediatrics andCochrane reviewed (Schnabel 2014 Level I [Cochrane], 10 RCTs, n=658). The trials were old,heterogeneous and determined low quality. Nalbuphine reduces the number of patients insevere pain at 1 and 2 h (1 RCT) and requirement for rescue (1 RCT) vs placebo, was similar tomorphine for patients in severe pain at 2 h (2 RCTs), was similar to tramadol at 2 h (1 RCT) and 12 h
(1 RCT), and pethidine at 2 h and 24 h (1 RCT). PONV rates in PACU were similar vs placebo
and morphine.

KEY MESSAGES
Opioids
1. Young and obese children with history of obstructive sleep apnoea/sleep-disorderedbreathing are at higher risk of developing serious opioid-induced ventilatory impairment
and death (U) (Level IV).
2. Opioid-induced ventilatory impairment and death occur rarely with therapeutic dosing inchildren taking opioids at home (N) (Level IV).
3. Safe dosing of opioids requires consideration of the child’s age, body weight,
comorbidities and ethnicity (U) (Level IV).
Fentanyl
4. Intranasal fentanyl is an effective treatment for paediatric acute pain management, withan acceptable adverse effect profile and ease of delivery (N) (Level I).
Codeine5. The efficacy of oral codeine in children is unpredictable due to genetic differences in theability to generate the active metabolite morphine (U) (Level II), as are adverse effects
and serious toxicity (U) (Level IV).
6. Codeine should not be used in children, especially after adenoidectomy or tonsillectomy,
due to an increased risk of opioid-induced ventilatory impairment and death (S) (Level IV).
Tramadol
7. Tramadol provides superior analgesia to placebo and has similar efficacy to conventional
opioids in children of all ages administered by various routes for multiple surgery types(S) (Level I [Cochrane]).
8. It is unclear if tramadol causes less ventilatory impairment than other opioids in children
due to insufficient trial size (N) (Level I [Cochrane]).
Buprenorphine
9. Buprenorphine administered IV or caudally has similar efficacy to morphine or caudal
local anaesthetic in children for different surgery types (N) (Level II).
Nalbuphine
10. Nalbuphine intravenously is effective for postoperative pain relief in children in several
low quality heterogeneous trials (N) (Level I [Cochrane]).

946

5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENTThe following tick boxes represent conclusions based on clinical experience and expert
opinion: Careful titration of opioids is advised according to the individual child’s response(analgesia and adverse effects) (U).
 Despite the regulatory response with boxed warning and upscheduling of codeine,prescription continues in at risk patients (with obstructive sleep apnoea/sleepdisordered breathing or post adenotonsillectomy) or has been replaced by prescriptionof potent conventional opioids such as oxycodone and hydrocodone which present
similar or greater hazard (N).
 The practice of applying an occlusive dressing to the skin surface of a transdermal
fentanyl delivery system does not limit dose delivery (U).
 Tramadol shares some adverse effects with the conventional opioid class in children,with similar or reduced rates of nausea and vomiting, sedation and fatigue but lessconstipation and pruritus (U). Sedation (not necessarily associated with miosis),seizures, ventilatory impairment and deaths have occurred (N).
 Naloxone has been used to treat tramadol overdose in children with effect (N).
 CYP2D6 phenotype has been the reason for codeine’s black box warning, but theclinical significance in terms of tramadol/M1’s analgesic efficacy and adverse-effectprofile including safety is still unknown (S). Inadvertent overdose and formulation
issues are likely of greater risk than CYP phenotypes resulting in variable drug
metabolism; evidence for harm from this second mechanism is lacking (N).
 Tramadol 100mg/mL concentrated drops formulation use is potentially harmful in children
with possible dosing confusion (drops with millilitres) and resultant overdose (U).
 In paediatric overdose, buprenorphine causes the spectrum of neurocognitive adverse
events as seen with conventional opioids which may be reversible with naloxone (N).
 More studies are required to determine tapentadol’s comparative efficacy in paediatricacute pain and if its adverse effect profile in children is improved versus placebo,
conventional opioids or tramadol (N).
 In paediatric overdose, tapentadol causes the spectrum of neurocognitive adverse
events seen with conventional opioids, which may be reversible with naloxone (N).

10.4.5 | Discharge opioid prescribing for children
USA survey data from 1996─2012 indicates that whilst opioid prescriptions for adults havemore than doubled in this time, it has not increased for children <18 y ( Groenewald 2016 Level
IV, n=144,918 children). Despite this, the public health concerns surrounding discharge andcommunity opioid prescribing have extended to children; there are relevant implications ofcurrent opioid prescribing practices and consumer use patterns in both adults (who are
relatives of children and adolescents who may then have access to these medications) andchildren for postoperative, post-trauma and medical indications. The recent literature focus
on community and discharge prescribing for the paediatric age group is presented below; themajority is North American data, with Australia and New Zealand data provided whereavailable.
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947See also the relevant adult Section 8.13 Discharge opioid medications for acute pain
management.
10.4.5.1 | Prescribers of opioids and types of opioid prescribed
A systematic review identifies the paucity in research on opioid prescription and usage inchildren and adolescents for at home pain management postoperatively or post trauma(Dautremont 2017 Level IV SR [PRISMA], 9 studies [5 adolescent], n unspecified). Post hospital discharge,
prescribers are generally surgeons. Since the FDA investigation of children after(adeno)tonsillectomy, codeine use has reduced in the USA ( Chua 2017b Level III-2, n=362,992).
However, as of December 2015, 1 in 20 children undergoing these procedures were stillprescribed codeine (by ear nose and throat surgeons), with high potency agents such ashydrocodone and oxycodone increasingly prescribed. In two USA audits of paediatric patients(surgical and medical) discharged from hospital, discharge opioids were mostly prescribedpostoperatively by surgical teams, most commonly orthopaedic (Monitto 2017 Level IV, n=343
families; George 2016 Level IV, n=34,218). Long acting preparations were rarely prescribed.
Oxycodone was the most frequently prescribed agent at both centres, with the larger audit
revealing near cessation of codeine prescribing. In the smaller audit, over 80% of patients alsoutilised paracetamol and/or ibuprofen (Monitto 2017 Level IV, n=343). Nearly half (47%) of patientswere discharged with diazepam, having had mostly orthopaedic (70%) or urological surgery(22%). Notably, the Society for Pediatric Anesthesia guidelines recommend that opioids should
not be prescribed in combination with benzodiazepines in outpatient management of paediatricpatients, adding the proviso ‘unless there are specific indications, with parents being warned of
the risk of sedation and respiratory depression’ ( Cravero 2019 GL). These guidelines also state
there is insufficient evidence to guide whether prn or scheduled opioid dosing strategies aremost appropriate for paediatric patients following surgery, with expert consensus tending
toward prn dosing (Cravero 2019 GL).
10.4.5.2 | Opioid-related poisonings and deaths
In Australia between 2003 and 2013, prescription opioids were the commonest cause of
poisoning death (accounting for 24%) in children (of which 59% were adolescents: 12─16 y)(Pilgrim 2017 Level IV, n=90 deaths). New Zealand paediatric poisoning data is not available.
From the USA’s National Poison Data System review 2000─2015, poisoning exposures toprescription opioids (most often hydrocodone, oxycodone, codeine and tramadol) was common
among children <6 y and teenagers (Allen 2017 Level IV, n=188,468; Tadros 2016 Level IV, n=21,928).
Causes of opioid poisoning varied between age groups with unintentional or therapeutic error
most common for children <6 y and intentional overdose most common for teenagers. Over 6%of children poisoned with opioids experienced serious medical outcomes (particularly withfentanyl exposure) with overall fatality of 0.1%. In a third USA series, the mortality rate ofchildren and adolescents with opioid poisonings has increased nearly 3-fold over 18 years, whereprescription opioids were implicated in over 70% of deaths (Gaither 2018 Level IV, n=8,986 deaths).
In this latter series, one quarter of deaths in children <5 y were homicide, while most opioidrelated deaths were adolescents aged 15─19 y (88%); most (80%) were unintentional (in contrast
to the above series). Co-ingestion of one or more prescription or illicit substances was found in
38.5% of adolescent cases; in adolescents, synthetic opioids (eg illicitly manufactured fentanyl)
was an increasing cause of death (Gaither 2018 Level IV, n=8,986 deaths). For a further USA cohortof opioid-naïve adolescents, prescription opioid overdose rate was 1 in 1,600 (0.06%)(Groenewald 2019b Level IV, n=725). In this cohort, a subanalysis revealed the risk for overdose inadolescents increased with increased number of dispensed tablets: ≥30 opioid tablets vs ≤18948

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tablets (HR 1.35; 95%CI 1.05 to 1.7). Tramadol was also associated with increased risk after
controlling for sociodemographic level, pre-existing health conditions, pill quantity and dose (HR2.7; 95%CI 1.9 to 3.8). Receipt of oxycodone, presence of comorbid mental health conditions or
receiving multiple opioid prescriptions did not increase risk. Across the first three series, themajority of opioid-related deaths occurred outside a medical setting. The increase of accidental
opioid overdoses in children and adolescents (Burghardt 2013 Level IV, n=62,416 [opioid-related
overdoses]) and paediatric mortality rates for opioid poisonings follow similar temporal and drug
use patterns to adults and the prescribing patterns for prescription opioids ( Gaither 2018 Level IV,
n=8,986 deaths).
From USA’s outpatient prescription data, the most commonly prescribed opioids includehydrocodone, oxycodone, codeine, hydromorphone, pethidine (meperidine) and tramadol(included by some authors) (see Table 10.8). One of the series reported combined rates for
paediatric opioid-related ED visit, hospitalisation or death of 1 in 2,611 opioid prescriptions forchildren, with three deaths overall (Chung 2018a Level III-3, n=1,362,503 [outpatient prescriptions])
and subsequently published their state’s data with one death ( Chung 2019 Level III-3, n=529,731[opioid prescriptions]). A further USA series specific to opioid-related deaths demonstrated
increase across all age groups between 2001 and 2016: from 0.4 to 1.5% of all-cause mortality(Gomes 2018 Level III-3, n=335,123 [opioid-related deaths]). The rates were 1.4 /1 million for children<15 y and higher at 92.3/1 million in 15─24 y olds, without stating if relating to overdose(intentional or accidental). Simultaneously (between 2004 and 2015), the rate of opioid-related
paediatric hospitalisations (where 43% required intensive care) increased in the USA (Kane 2018
Level IV, n=3,647 [opioid-related] of 4,175,624 admissions [31 hospitals]). The majority wereadolescents 12─17 y, but one-third were children <6 y; events were coded as accidental
poisoning (1,658: 80% related to opioids other than methadone and heroin) and poisonings(1,989: 61% related to opioids other than opium, methadone and heroin). The number specificto therapeutic prescriptions was not stated in this series.
In a legal settled claims post-tonsillectomy series, opioids (most commonly codeine) were
implicated in death (17 of 96 claims), respiratory depression (20 of 137) and hypoxic brain injury(20 of 137) (Subramanyam 2013 Level IV, n=233). The ultrarapid metabolism issue for codeine andpublished cases of serious adverse events (including deaths) led to the 2013 FDA restriction oncodeine administration in this paediatric surgical population (see Section 10.4.4.5).
Subsequently, a paediatric anaesthetist survey revealed 92 cases and closed claim report analysis
a further 19 serious adverse events, including apnoea and subsequent death post tonsillectomy(and adenoidectomy); 57% of patients were determined to be at risk of OSA ( Cote 2014 Level IV,
n=111). Importantly 58% of the postoperative events occurred within 24 h and 48% occurred
after hospital discharge.
10.4.5.3 | Opioid-related adverse events: out of hospital
National USA prescription data revealed opioid-related adverse events were increased inadolescents vs young children (12–17 y vs 2–5 y: incidence rate ratio [IRR] 2.22; 95%CI 1.67 to2.96) and with higher opioid doses (>0.66 mg/kg/d MED vs ≤0.38: IRR 1.86; 95%CI 1.45 to 2.39)(Chung 2018a Level III-3, n=1,362,503 [outpatient prescriptions]). The most frequent prescribed
opioid-related adverse drug events (ADEs) were gastrointestinal (31%), neuropsychiatric (28%),
CNS depression (22%) and dermatological (23%). Respiratory depression was uncommon at
2.8%. Notably most ADEs (72%) were associated with therapeutic use of the prescribed regimen.
The same author group published their state’s data with the same ADEs and similar incidences(Chung 2019 Level III-3, n=529,731 [opioid prescriptions]) (see Table 10.8). In children prescribed
opioids upon discharge from hospital, ADEs were also common: 48% of 218 responding parents
reported that their child had ≥1 ADE; these were also dose-related (MD 0.05 MED mg/kg/d;
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95%CI 0.02 to 0.08) (Voepel-Lewis 2015b Level IV, n=514 parents). Concerningly, only 14 of 38
parents who reported their child as experiencing over sedation changed their child’s analgesic
therapy in response to this ADE. Children who received an opioid prescription post laparoscopic
appendicectomy vs those who did not had increased risk of ED presentation in one audit for
constipation (overall 1%; with increasing RR related to duration of opioid use) but not for pain
(Sonderman 2018 Level III-2, n=9,684) and in a second audit for both constipation and abdominal
pain (OR 3.3; 95%CI 1.3 to 8.2) (Anderson 2018 Level III-2, n=590). Post paediatric tonsillectomy,
less severe adverse effects in patients prescribed codeine after discharge included nausea,
vomiting and light-headedness; pain scores and time (POD 0) predicted sedation, but not
obstructive sleep apnoea or CYP2D6 phenotype (Prows 2014 Level IV, n=249).
Prescribing and dispensing error is a recognised source of harm with paediatric opioidprescription. For young children <3 y, excessive dose prescribing errors (>10%) were made in
2.7% of outpatient opioid prescriptions, with higher frequency in infants (8.9% 0─2 mth and 5.7%
2─5 mth) (Basco 2015 Level IV, n=59,536). While discharge opioid prescriptions for children writtenby trainees at one USA paediatric centre had errors in 82% (re weight, dispensing information ordate) and 2.9% had the potential for serious harm if dispensed and administered as prescribed(Lee 2009 Level IV, n=314 prescriptions). Electronic prescribing, including weight-based dosing logic
with alerts, may reduce the rate of errors in paediatric opioid prescribing (George 2016 Level IV,
n=34,218).
See also Section 8.13.2.4 Impaired driving as relevant to adolescents who drive.
10.4.5.4 | Risk of inducing long term opioid use in adolescents
Unintended prolonged opioid use was identified as a significant concern following acutepostoperative opioid prescribing (Harbaugh 2018b Level III-2, n=88,637 perioperative opioidprescription fills). Following various surgeries, 3–15% (4.8% overall) of previously opioid naïve
adolescents were using opioids at 90–180 d. Factors that increased risk slightly included olderage (OR 1.07; 95%CI 1.05 to 1.08), female sex (OR 1.22; 95%CI 1.14 to 1.31), substance use
disorder (SUD) (OR 1.41; 95%CI 1.12 to 1.77), chronic pain diagnosis (OR 1.48; 95%CI 1.33 to1.66), preoperative opioid use (OR 1.26; 95%CI 1.17 to 1.36) and cholecystectomy or colectomy
surgeries. Following cleft palate related surgery in children >8 y, persistent opioid use was 4.4%
at 90 to 180 d vs 0.1% of non-surgical controls (Bennett 2018 Level III-2, n=4,139). Distractor surgery
increased risk (OR 5.34; 95%CI 2.00 to 14.24) and older age only slightly (OR 1.11; 95%CI 1.04 to1.17). Following traumatic injury (46.2% major trauma), 7% of adolescents reported prescription
opioid use prior and 12.5% of adolescents continued on opioids at 1 y, with increased risk inthose with preinjury mixed substance use and higher baseline pain score, but not older age(Whiteside 2016 Level IV, n=120). Of adolescents treated at one USA major paediatric and one adulttrauma hospital (where 10 % experienced major trauma), after discharge 20% had filled >2 opioidprescriptions at 1 y, while 13% had filled >8 prescriptions at 4 y (Bell 2019b Level IV, n=736).
Concurrent mental health diagnoses were relatively uncommon compared with adults: anxiety
11 %, depression 6% and post-traumatic stress disorder (PTSD) 2.1%.
Following each new opioid prescription filled by adolescents in the USA, the incidence of longterm opioid therapy (>90 days' supply within 6 mth) was estimated as 3 in 1,000 (95%CI 2.8 to3.1) within 3 y (Quinn 2018 Level III-2, n=1,224,520 prescriptions). Adolescents with mental healthconditions were more likely to be prescribed opioids than those without (OR 1.13; 95%CI 1.10 to1.16). While, the risk of long term opioid therapy was increased with ADHD (HR 1.73; 95%CI 1.54
to 1.95), non-opioid SUD (HR 4.02; 95%CI 3.48 to 4.65) and prior opioid use disorder (OUD) (HR8.90; 95%CI 5.85 to 13.54); a greater number of co-existing or pre-existing mental healthconditions increased risk of long term opioid therapy.

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10.4.5.5 | Misuse, abuse, overdose and diversion of prescription opioids in children
North American data
Between 1990 and 2014, the prevalence of past-year prescription opioid misuse in the USA had
increased in young people aged 11–30 y by 0.4% each year (Jordan 2017 Level IV [PRISMA], 19
studies, n=503,845). The pooled prevalence in high-school/college settings was 7.4% (95%CI 5.8 to
8.9). In 2016, of the USA’s 12–17 y olds, 3.6% reported opioid misuse (Groenewald 2019a NR).
However, medical prescription without nonmedical use of prescribed opioids was not associatedwith OUD development reported at age 35 (McCabe 2016 Level IV, n=4,072). In an adolescent
trauma series 5 y post-discharge from two USA centres (one paediatric and one adult), 11%required opioid antagonist injection, 14% had SUD diagnosis and 8% an overdose (Bell 2019b
Level IV, n=736). Older age (>15 y), male sex, African ethnicity, penetrating injury and treatment
at the adult hospital were associated with later overdose and SUD (the latter was also associatedwith positive alcohol/drug screen and non-blunt/non-penetrating injury). Injury severity score
was not an association (where 10% experienced major trauma).
The most common reported motives for adolescents misusing medically prescribed opioids
were to get high (sensation seekers) and to relieve pain (self treaters) ( McCabe 2013b Level III-3,
n=393). Medical opioid users are up to 10 times more likely to report lifetime and past-year
nonmedical opioid use, however use is usually not consistent (Boyd 2006 Level IV, n=1,086). Most
paediatric nonmedical opioid users obtain the medications from family or friends ( SAMHSA 2019
Level IV; McCabe 2013a Level IV, n=8,888 [647 nonmedical use]; Brands 2010 Level IV, n=2,914; Boyd 2006
Level IV, n=1,086).
Opioid use disorder in the past-year is estimated to affect 0.4–0.6 % of adolescents (12─17 y)in the USA in 2015─2018 surveys (SAMHSA 2019 Level IV, n=104,000 [2018 data]). In 2018,
approximately 310,000 adolescents (850 per day) in the USA misused prescription pain relievers
for the first time in the past-year. Nearly all OUD (99%) reported in 2016 by USA adolescents was
related to prescription opioids and OUD was a risk factor for opioid overdose (HR 3.1; 95%CI 2.3
to 3.4) (Groenewald 2019b Level IV, n=1,146,412 new prescriptions). Rates of opioid prescribing forchildren and adolescents with common, noncancer pain conditions (eg dental, postoperative andtrauma indications) are high (Groenewald 2019b NR). Legitimate opioid use prior to high school
graduation in the USA is independently associated with a 33% increase (from 1.7–3% to 3–5%)
of nonmedical use of prescription opioids by age 23 ( Miech 2015 Level IV, n=6,220). Importantly,
these individuals report little to no history of drug use and have a baseline disapproval of druguse. In USA high school seniors with nonmedical use of prescription opioids, their most common
pattern was initial use of medically prescribed opioids followed by subsequent nonmedical use(McCabe 2017 Level III-3, 40 cohorts [Monitoring the Future], n=2,181 to 3,791 per cohort).
In Canada, the nonmedical use of prescription opioids by adolescents (at least one occasion)is common (prevalence: 20%; 95%CI 18.9 to 22.3), but behind alcohol and cannabis (Brands 2010
Level IV, n=2,914). Of prescription drugs, opioids were the most frequently misused by 5.9%
adolescents, particularly females (Currie 2012 Level IV, n=44,344 [Youth Smoking Survey]).
Medical use of prescription opioids without any history of nonmedical use in adolescence is
not associated with SUD symptoms at age 35 (McCabe 2016 Level III-3, n=4,072 surveyed). Adults at
age 35, who as adolescents used opioids with high misuse potential or more than one opioid, coingested them with other substances or used them nonmedically and/or progressed to later
medical use, have increased odds of subsequent SUD symptoms compared with those who usedprescription opioids medically or no opioids during adolescence (McCabe 2019 Level III-2, n=8,373).
Compared to low prevalence of OUD in adolescents, past-year use and misuse of prescription
opioids is common, and was highest for those not engaged in schooling ( Schepis 2018 Level IV,
n=13,585 adolescents & 14,553 young adults).
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National USA data has shown correlation of increased opioids prescriptions with increased
poison centre telephone calls by adolescents who had abused opioids (Sheridan 2016 Level IV,
n=4,186). For each opioid prescription increase per 100 persons per year, the annual rate of calls
increased by 1.8% (95%CI 0.9 to 2.8) or 4–5 calls per 1,000 teens annually.
In one USA state (Ohio), while overall opioid prescriptions for adolescents have decreased (7per capita annually), adult prescriptions remained unchanged (100 per capita annually) over2008─2012 (McKnight 2017 Level IV, n=50,030,820 doses for 12–20 y & 3,811,288,395 doses for adults>20 y). This provides a potential source for nonmedical access by adolescents.
Low parental monitoring and low adolescent perception of parental warmth predicted prosubstance attitudes and social ties, which in turn predicted higher levels of lifetime nonmedicalprescription opioid use (Donaldson 2015 Level III-3, n=17,339).
Harm minimisation interventions for young people who use prescription opioids
nonmedically, such as provision of and education on the use of naloxone, as well as harm
reduction education in schools has been proposed to address the known risks associated with
opioid misuse (Marshall 2016 NR).
New Zealand and Australian data
In New Zealand in 2017, national opioid prescriptions for children and young adults (0─24 y)remained low: most prescriptions per 1,000 population were for the ‘weak opioids’ codeine(24.8) and tramadol (18.7), and infrequently the ‘strong’ opioids: morphine (1.6), oxycodone(0.6) and fentanyl (0) (HQSC 2019 Level IV, n=3,327 [dispensed to ≤24 y]). Morphine prescriptions had
increased from 0.8 per 1,000 in 2011 to 1.6 per 1,000 in 2017 in this age group. A small percent
of morphine (4.1%) and oxycodone (5.9%) were prescribed for more than 6 wk; the division forcancer vs noncancer indications was not specified. The majority of prescriptions in this age groupwere in association with a hospital event (73%). New Zealand data for nonmedical use is notavailable.
In Australia between 2012 and 2017, the number of prescriptions of opioids has increased by
11% (AIHW 2019 Level IV, n=15,419,793 [dispensed in 2016─17] with n=232,588 to ≤24 y). The extent ofpharmaceutical opioid consumption is lower per capita when compared to the USA, however
has specifically risen in the population aged >14 y (Chan 2019b Level IV, n=23,233). The Australian
National Drug Strategy Household Survey 2016 found 3.6% of the population >14 y old usedprescription opioids nonmedically, 33% with other illicit substances. The latter were more likely
to be younger (and possibly started nonmedical prescription opioid use opportunistically and forrecreation). While Australia’s Pharmaceutical Benefit Scheme’s data, which captures community
prescriptions only (and not over the counter, hospital or private purchase), revealed annual
opioid dispensing to children decreased slightly by -2.2% (CI -3.5 to -0.8) between 2013─2017(Bell 2019a Level IV, n=78,320 prescriptions to 50,730 children). In 2017, one in 74 Australian children(0–17 y) overall were dispensed an opioid, highest in the adolescent age group at one in 25. Like
New Zealand, codeine and tramadol comprised most dispensed prescriptions (51 and 10%
respectively); oxycodone was the most frequently dispensed ‘strong’ opioid (37%), with otheropioids dispensed infrequently (4%). Strong opioid dispensing increased in all age groups, withthe 1.5 fold increased oxycodone dispensing; codeine dispensing decreased in all age groups,
except those <1 y. Long acting opioids were dispensed to 7.5% of children (1–12 y) and 9.5% ofadolescents prescribed opioids. Noncancer vs cancer indication information was not provided.
The majority of children (80%) were dispensed one prescription only. General practitioners
prescribed 48%, medical specialists 28% and other prescribers 22%. General practitioners
prescribed mostly codeine and tramadol, while specialists prescribed strong opioids.

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and sleeping pills/tranquilisers (2.7%) by adolescents (14–19 y) in the previous 12 mth (AIHW
2019 Level IV).
10.4.5.6 | Consequences of excess prescribed opioids
Practice varied widely regarding doses and amount of opioid prescribed for children andadolescents <21 y following various surgery types eg arthrodesis, humeral supracondylar fracture
repair and Nuss surgery (Harbaugh 2018b Level III-3, n=88,637) and laparoscopic appendicectomy(Anderson 2018 Level III-2, n=590). As a consequence, many children are prescribed and dispensed
excessive amounts of opioid that remain at large in the community. Several audits havedocumented a mean or median duration of discharge opioid prescription: 4.8 d (± 2.9) prescribedfor 63% post laparoscopic appendicectomy (Anderson 2018 Level III-2, n=590), 4 d (IQR 3–5 d) for 68%
post laparoscopic appendicectomy (Sonderman 2018 Level III-2, n=9,684) and 4 d (IQR 1–8) for 100%post mixed surgery (Monitto 2017 Level IV, n=343). In the latter, 36% of patients were still taking
opioids 7 d post discharge. Of concern, one prescription at times provided opioid for up to 30 and
65 d (Sonderman 2018 Level III-2, n=9,684; Anderson 2018 Level III-2, n=590) and in separate series, thenumber of dispensed opioid doses (median 43, IQR 30–85) (Monitto 2017 Level IV, n=343), liquidvolumes (mean 106 mL  125) and tablets (mean 51  51) (George 2016 Level IV n=34,218) were high.
Another centre reported a low median of 10 doses (IQR 6-15) of discharge opioid prescribed for
22%; this audit included the 7 commonest (mostly day-stay) paediatric surgical procedures(Harbaugh 2019 Level IV, n=404). Postoperative intake of non-opioids with opioids was high (but could
be improved upon): paracetamol 88% and/or ibuprofen 78% were taken for a median of 3 d (IQR
2–5 d), with opioids used for a median of 2 d (IQR 1–3 d) (Harbaugh 2019 Level IV, n=404); and both
agents by 81% of patients at a second centre (Monitto 2017 Level IV, n=343).
Where opioid prescription exceeds use, leftover medications result. Parental surveys havedocumented high proportions (25─90%) of unused/leftover prescription opioid doses following
paediatric surgeries (Groenewald 2019a NR; Hunsberger 2019 Level IV, n=115 interviewed; Monitto 2017
Level IV, n=343), where 14% (Voepel-Lewis 2015a Level IV, n=223) to 31% of parents report using
none of the prescription and 37% less than half (Harbaugh 2019 Level IV, n=404 [78 prescribed
opioid]). Various factors contribute to this such as age of the child (younger patients consumed
fewer doses than patients >15 y), decrease in daily use with recovery (and appropriate cessationas pain is well controlled) or early cessation due to side effects (as reported by 18% of parents
whose children had nausea, vomiting or sedation) (Monitto 2017 Level IV, n=343) versus early
tapering and discontinuation of opioid medications by parents (Voepel-Lewis 2015a Level IV,
n=223). However, for some surgery types such as Nuss and major orthopaedic surgery, themismatch of dispensed vs use was large (Monitto 2017 Level IV, n=343). Leftover opioids represent
a major source of nonmedical use of prescribed opioids in adolescents ( McCabe 2013a Level III-3,
n=647 [nonmedical use]) and leftover prescription opioids have been implicated in accidental
opioid overdoses (Groenewald 2019b NR). The strongest predictor of the number of doses
remaining was the number of doses dispensed (Monitto 2017 Level IV, n=343).
10.4.5.7 | Safe opioid storage and disposal
Opioids were kept in locked storage in the USA by only 28% parents whose children weredischarged with opioids (Harbaugh 2019 Level IV, n=404) and 29% of adults who had past-year useof opioids and were living in households with children and adolescents (McDonald 2017 Level IV,
n=681). The lack of childproof packaging for many commonly prescribed opioids has beenrecognised as an area for concern (Gaither 2018 Level IV, n=8,986 deaths). Young children commonly
gain access to prescribed medications which are stored incorrectly, in plain sight or accessing
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from an adult’s purse or bag (Allen 2017 Level IV, n=188,468). Disposal of leftover opioids is widely
variable: 85% of parents were unaware of how to manage leftover opioids and 33% planned tokeep them for future use (Groenewald 2019a NR), 19% recalled being advised on how to disposeof opioids (Monitto 2017 Level IV, n=343) eg by return to a pharmacy, with only 4% and 11%
appropriately disposing of the leftover opioids (Harbaugh 2019 Level IV, n=404; Monitto 2017 Level IV,
n=343). Dual harm potential with unsafe storage and non-disposal of prescription opioids leads
to a reservoir for nonmedical use by families and adolescents (including diversion) and accidental
ingestion by young children. Parents may also be an important source of prescription opioids
that are intentionally shared for medical (and nonmedical) use by children and adolescents.
10.4.5.8 | Education of prescribers, families and patients: pain trajectories and safe practices
Perceptions of the expected duration of pain following common surgical procedures varysignificantly (Raney 2018 NR), although it is known that postoperative pain is commonly
experienced by children at home, lasting for days to weeks. The adult Education Section 3.1
provides an overview of the impact of education on various clinical staff members, patients andcarers assessed by different outcomes including postoperative pain, analgesic use and quality oflife. The safe and practical prescribing sections in 8.13 Discharge analgesia (sections 8.13.2.5 and8.13.5) have overlap with this paediatric section, which focuses on staff and family education
pertaining to opioid prescription and additional safe practices relevant to children.
Barriers to adequate pain relief include various factors (Walker 2015b GL):
• Parental factors, eg tendency to underdose and not optimise therapy;• Child factors, eg anxiety/distress, difficulty swallowing medication (or formulation) or
refusal;• Medication factors, eg incorrect dosing or lack of palatable paediatric formulation that
permits appropriate dosing; and• System factors, eg knowledge base, training, confidence and seniority of staff prescribing
analgesia and provision of adequate information.
As highlighted above by the variability in practice, it is important to optimise discharge opioidprescription in the paediatric population (Monitto 2017 Level IV, n=343) and create guidelines forsafe and responsible opioid prescribing (Groenewald 2019a NR; Cravero 2019 GL). Educationinterventions at a hospital level should focus on hospital prescribers, particularly surgical services
who write the majority of postsurgical discharge prescriptions (George 2016 Level IV, n=34,218).
This needs to be informed by research with focus on understanding the pain trajectories after
common surgical procedures, to reduce leftover medications and educate the broader opioidprescribing and dispensing community and then carers (Raney 2018 NR). There is growth in webbased delivery of education programs for health professionals focussing on opioid prescribing.
Online educational resources improve knowledge and skills, but not confidence and competence(Liossi 2018 Level IV SR [PRISMA], 32 studies [6 paediatric], n unspecified). Studies were heterogeneous,
including paediatric and adult patients, and acute and chronic pain populations in various clinicalsettings (one specific to primary care and opioids); relevant health outcomes for patients were
not assessed. The interventions were generally 1 h in duration and permitted multiple logins. A
subsequent survey of clinicians who had completed an interactive online opioid prescription
learning module determined that clinician knowledge, likelihood of adherence to prescription
guidelines and perceived competence in opioid prescription improved following participation(Langford 2020 Level III-3, n=167 [clinical staff]). Quality improvement initiatives include review of
postoperative opioid consumption eg post urological surgery where investigators found the
median consumption was 2 (IQR 3–6) of the 10 doses prescribed, with subsequent revision ofprescription to 5 dose maximum (Cardona-Grau 2019 Level IV, n=98). A rapid cycle audit initiative954

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in the paediatric palliative care setting (for consideration for postoperative patients) has
increased use of a risk stratification tool for opioid misuse when seeing children in the clinic, with
implications for ongoing prescribing and managing abuse or opioid diversion ( Thienprayoon 2017
Level IV, n=17 [positive risk ≤18 y]).
It is important to target education of carers to set expectations and simultaneously address
the barriers and concerns highlighted above. Web-based parental education and preoperative
child preparation strategies have been recommended (Walker 2015b GL). A systematic review
evaluating educational websites included only two RCTs with information on acute postoperative
pain (Bender 2011 Level I, 17 RCTs, n=2,503). One was paediatric and assessed preparation ofadolescents prior to tonsillectomy (O'Conner-Von 2008 Level II, n=69, JS 3). Improved satisfaction
and knowledge were seen with internet (commonly viewed >1 time) vs standard face to faceafterhours preparation program vs no treatment, with no difference in pain scores or anxiety(the latter were high normal at 34─37, but below the therapeutic cut off of 39/80). A written
oxycodone information sheet supplement to verbal instruction was provided to parents after
tonsillectomy in children with information regarding dose and timing vs verbal instruction alone(Bailey 2015 Level II, n=60, JS 5). The information sheet recipients had higher parental satisfaction
and knowledge and some improvements in pain scores up to POD 7. Parental recall of instruction
for “around the clock” opioid administration predicted greater opioid use ( Voepel-Lewis 2015aLevel IV, n=166 [prescribed opioids]). This could be positive or negative depending on the responseof parents to subsequent adverse events such as sedation ( Voepel-Lewis 2015b Level IV, n=514
parents). To reduce harm from opioid medications, interventions should also include educationof adolescents, and carers (and adults in the home) on the risk of opioids, the importance ofstorage in a locked medicine cabinet and safe disposal (Cravero 2019 GL; Groenewald 2019a NR;
Binswanger 2015 NR). Initiatives such as the Australian National Prescribing Service Choosing
Wisely program permit dialogue between consumers and clinical staff with written take home
information that addresses at home pain management and safe practices (NPS Medicinewise
2019b GL).
The use of state prescription drug monitoring programs is also recommended ( Groenewald
2019a NR). Some USA states have seen a reduction in problematic opioid behaviours since theutilisation of prescription drug monitoring programs; however it is difficult to directly attribute
this change to the use of these programs versus other social and regulatory changes.

KEY MESSAGES
1. Postoperative opioid therapy in children and adolescents may lead to long term opioid
use and misuse in later life (N) (Level III-2); risk factors include type of surgery,
psychological and social factors and other substance use (N) (Level III-2).
2. Long term opioid use following therapeutic medical prescription is uncommon inchildren and adolescents (N) (Level IV). However, prior diagnosis of chronic pain,
substance use or mental health conditions are risk factors (N) (Level IV).
3. Misuse of prescription opioids is common amongst adolescents and young adults either
as medical use (self-treatment) or nonmedical use (sensation seeking/recreational) (N)(Level IV).
4. Leftover prescribed opioids are a common source of nonmedical opioid use in adolescents,
with most adolescents gaining access through family or friends (N) (Level IV).

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5. Unsafe storage of prescription opioids in the home and non-disposal of leftover opioids
is common (N) (Level IV).
6. Prescription opioids are a large source of opioid-related poisonings: usually accidental inyoung children and related to recreational use or with intentional overdose inadolescents (N) (Level IV).
7. Adverse drug events in children and adolescents sent home with prescription opioids arecommon (N) (Level IV).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: As for adults, a sensible approach should be used in the setting of prescribing discharge
opioid medications for children and to adults with children at home (N).
 As for adults, prescribing discharge medications for children should be done withconsideration of the child’s anticipated opioid requirements. The tablet number andvolume of opioid solution prescribed should be judicious and individualised (N).
 Understanding and education is required to determine procedure specific pain
trajectories in children (N).
 Carer/parental, patient and clinical staff education is necessary about risks of opioids
and how to safely dispose of unused medication by return to a pharmacy (N).
 Carer/parental and patient education in case of ongoing pain and analgesic issues isappropriate with follow-up by general practitioners or pain medicine services as
indicated (N).
 Education and guidelines are desirable for adult and paediatric discharge andcommunity opioid prescribers with focus on information provision for staff delivering
the advice (ideally written and verbal combined) to carers and families (N).

10.4.6 | Opioid tolerance in children and adolescents
10.4.6.1 | Groups of opioid-tolerant children
Opioid tolerance is discussed in the adult section; for the definitions of tolerance anddependence see adult Section 9.7; see Table 9.8. Opioid-tolerant paediatric patients have beenless well studied than opioid-tolerant adults.
Like adults, there are four main groups of opioid-tolerant children and adolescents:
1. Chronic non-cancer pain (CNCP)
The prevalence of moderate to severe CNCP in children is suggested to be 1 in 20 (Brooks
2016 NR). An Australian dataset revealed opioid use by 15.7% of children at referral topaediatric chronic pain clinics (Lord 2019, Level IV, n=1,100) with data also for paediatricsickle cell patients chronically taking opioids (see 10.9.5), but not for other potentially
opioid-tolerant paediatric groups with chronic pain (eg inflammatory bowel disease,inflammatory arthritis or pelvic pain). There is no RCT data available in this patient group(Cooper 2017a Level I [Cochrane], 0 RCTs).

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2. Paediatric cancer patients being treated with opioids
Many government prescription databases provide data that is not linked to a cancer
diagnosis and so the prevalence of chronic opioid use in patients with active disease(undergoing treatment or in the palliative phase), in remission or survivors of childhood
cancer is unknown. Prescription analgesic use was reported by 16.7% of survivors 16.5 y(mean) post cancer diagnosis vs 12.6% of their siblings (Lu 2011 Level IV, n=10,397). Manyadolescents and young adults with cancer have at least one psychosocial risk factor for
misuse and some have documented aberrant opioid-related behaviours (Ehrentraut 2014
Level IV, n=94 [opioid using]); survivors may be at increased risk of opioid use disorder inlater life. This raises the ethical challenge of withholding analgesia on the basis of
addiction risk – thus screening and subsequent monitoring and management of thosefound to have opioid misuse is recommended (Pinkerton 2017 NR). An initiative inpaediatric palliative care increased use of a risk stratification tool for opioid misuse whenseeing children in the clinic, with implications for ongoing prescribing and managing abuseor opioid diversion (Thienprayoon 2017 Level IV, n=17 [positive risk ≤18 y]).
3. Nonmedical prescription opioid use (NMPOU)This group are mostly adolescents. Nonmedical use is either long term prescription opioid
use postoperatively (4.8 % of previously opioid naïve adolescents (13─21 y) continued useof opioids at 90─180 d) (Harbaugh 2018b Level III-2, n=88,637 perioperative opioid prescription
fills) or illicit opioid misuse (non-prescription or prescription): 3.6% of USA adolescents(12─17 y) (Groenewald 2019a NR), 5.9% of Canadian high school students (Currie 2012 Level
IV, n=44,344 [Youth Smoking Survey]) or 7.4% of adolescents/young adults (11─30 y) (Jordan
2017 Level IV SR [PRISMA], 19 studies, n=503,845) had addiction or SUD, including those on
an opioid treatment program (see also Section 10.4.5.4, 10.4.5.5 and adult Section 9.7).
4. Acute or subacute tolerance in childrenChildren and adolescents, like adults, are at risk of opioid-tolerance, dependence andwithdrawal after opioid therapy during inpatient or paediatric intensive care unit (PICU)
stay. Opioid tolerance and/or dependence may occur with 5─10 d of therapy with most
opioids, particularly with synthetic opioids and/or at high cumulative doses (Best 2015
Level IV SR [PRISMA], 33 studies, n unspecified; Anand 2010 NR).
i.

Acute opioid tolerance

Intraoperative remifentanil was associated with an increase in PCA morphine
requirement in the 24 h post scoliosis surgery (Crawford 2006b Level II, n=30, JS 5),
possibly due to acute opioid tolerance or opioid-induced hyperalgesia. In younger
children having surgery of approximately 3h duration, patients who received
intraoperative remifentanil 0.6-0.9 mcg/kg/min had higher postoperative fentanyl
requirements for 24 h vs those who received 0.3 mcg/kg/min or saline ( Kim 2013
Level II, n=60, JS 4). Intraoperative weaning strategies for remifentanil in children havenot been explored (see adult Section 9.7.2).
ii.
Subacute opioid tolerance
During and following fentanyl and morphine infusion, children, whilst in (Ibach 2017
Level IV, n=21/59) and post discharge from PICU and neonatal intensive care units (NICUs)
have exhibited tolerance and experienced withdrawal symptoms (Anand 2013b Level III-2,
n=419 [7 centres]; Anand 2010 NR; Birchley 2009 NR). Fentanyl administered as a prolonged
IV infusion in the NICU and PICU has been associated with more rapid dose escalation andgreater likelihood of doubling the daily dose than when the primary opioid is morphine

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(Anand 2013b Level III-2, n=419 [7 centres]). This was also true for the subgroup admitted
immediately postoperatively.
10.4.6.2 | Perioperative outcomes and management of opioid tolerance in children
There is no data on the influence of opioid-tolerance on paediatric perioperative outcomes.
Recommendations for management have been primarily based upon extrapolation frommultimodal management of opioid naïve patients with severe pain (see paediatric Sections
10.9.1 Management of pain due to trauma in children and 10.9.2 Management of acute burninjury in children) and the adult literature (See Sections 9.7.4.2 and 9.7.6).
Strategies include perioperative use of multimodal analgesia with adjuvant use of (Brooks
2016 NR; Geary 2012 NR):
• Ketamine (see paediatric Section NMDA Antagonists 10.4.7);• Alpha-2 agonists (see paediatric Section 10.4.8);• Alpha-2-delta ligands (see paediatric Section 10.4.9);• Local anaesthesia – peripheral nerve blocks (see Section 10.6.1), regional (10.6.2 and10.6.3) and systemic lidocaine infusion (see Section 10.4.11 and adult Section 4.4.1).
Opioid-related withdrawal syndromes in children and management
Recognition and management of opioid-related withdrawal is important to reduce physiologicaldisturbance. This is particularly relevant for PICU patients receiving opioids for sedation,
endotracheal tube tolerance and acute or postoperative pain (eg post cardiac surgery, majorburns or trauma), where tolerance (particularly to shorter acting opioids eg fentanyl) is
recognised (Anand 2013b Level III-2, n=419 [7 centres]; Gish 2011 Level III-3, n=31) including
polytolerance eg to other sedatives such as benzodiazepines (Best 2015 Level IV SR (PRISMA), 33
studies (9 opioid only, 22 opioid/benzodiazepine, 2 benzodiazepine only), n unspecified). These patients
may frequently experience withdrawal; reported by 63% of burns centres (Singleton 2015 Level IV,
n=41 centres).
There are several paediatric withdrawal assessment scales such as the validated withdrawal
assessment tool (WAT-1) and others (Fenn 2017 Level IV SR, 15 studies, n=567; Best 2015 Level IV SR[PRISMA], 33 studies, n unspecified; Whelan 2015 NR) (8 study overlap). Some paediatric institutions
have weaning and concurrent observation guidelines (SickKids 2018 GL; Starship 2017 GL). Weaning
10–20% of the total opioid dose every 48 h is generally recommended (Galinkin 2014 NR; Anand2013b Level III-2, n=419 [7 centres]). There is little evidence to recommend any particularwithdrawal prevention or treatment regimen eg with methadone ( Dervan 2017 Level IV SR[PRISMA], 12 studies, n=459) (7 and 8 study overlap with above SRs) or alpha-2 adrenergic agonist use
including as ‘bridging therapy’ (Whelan 2015 NR). IV Ketamine infusion at anaesthetic doses has
been used to facilitate opioid rotation for a median of 3 d in patients (median age 2.5 y) who hadreceived opioid infusions for several days with clonidine/midazolam infusion in PICU (Neunhoeffer2017 Level IV, n=32). Upon cessation, fentanyl requirements were reduced and COMFORT-B
scores improved vs prior to commencement (See 10.4.7 ketamine use for opioid-induced
hyperalgesia).

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1. Iatrogenic withdrawal syndrome following prolonged inpatient intravenous opioid
therapy in critically ill children is common (N) (Level IV SR [PRISMA]).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: There are groups of paediatric patients who are opioid-tolerant, as in adults. They
require special consideration for inpatient pain management and perioperative care. In
children with opioid tolerance, inadequate pain relief and withdrawal (if opioids are
acutely ceased) are specific risks. Acute pain service input can assist with preadmission
planning and use of various adjuvants beyond standard multimodal interventions (N).
 For assessment of withdrawal reactions, the use of a validated withdrawal tool in
paediatric opioid-tolerant patients is recommended; management strategies vary andinclude opioid weaning, rotation and adjuvant use (N).

10.4.7 | Systemic NMDA-receptor antagonists
10.4.7.1 | Ketamine
This section covers the use of ketamine for acute pain management in children. Ketamine has
been studied at varying doses, via various routes and regimens, for multiple paediatric surgery
types, generally in small studies rendering interpretation of its effects challenging.
See also Section 10.7 for use in paediatric procedural sedation, Section 10.8 for use inpaediatric cancer pain, and Section 10.6.3 for regional adjuvant use and peritonsillar infiltrationin addition to those summarised in the various systematic reviews below. See also Adult
ketamine Section 4.6.1.1, where neuraxial, adjuvant peripheral nerve use and topicaladministration are discussed in the one section.
Pharmacokinetics and pharmacodynamics of ketamine in children
Ketamine has a large volume of distribution at steady state (mean 3.3 L/kg  1.3) and a clearance
that approximates liver blood flow in children above 1 y of age (Elkomy 2019 PK). Pharmacokinetic(PK) modelling reveals ketamine infusions of 0.2 mg/kg/h for 24 h will achieve a median steadystate plasma concentration of 0.15 mg/L (Herd 2007 PK). Median ketamine concentration is
maintained >0.1 mg/L (assumed minimum analgesic serum concentration) for 0.5 h post
cessation of infusion. The metabolite norketamine is thought to have one third the potency of
ketamine. With this assumption, the combined “effective” concentration of
ketamine/norketamine is >0.1 mg/L for 1.5 h post infusion cessation. After IV ketamine 2 mg/kg,
norketamine plasma concentration peaks within 1 h, and may contribute to analgesia for up to
4 h. In an adult volunteer study an anti-analgesic effect of norketamine has also been proposed(Olofsen 2012 EH).
Ketamine is a racemic mixture. The isomeric formulation S(+) ketamine has twice theanalgesic potency of the racemate, and is shorter acting with slightly less adverse cognitiveeffects in adults (Mion 2013 NR).
For procedural sedation up to 20 min, PK modelling has suggested doses for IV ketamine of
2 mg/kg and for IM ketamine 6-8 mg/kg (Hornik 2018 PK). With IM ketamine, bioavailability wasestimated at 41% and desired effect achieved at 10 min. Children on extracorporeal membrane
5th Edition | Acute Pain Management: Scientific Evidence959oxygenation (ECMO) had higher ketamine clearance, with a dose suggestion of >5 mg/kg IV forprocedural sedation.
Oral ketamine has a high first-pass clearance (See adult Sections 4.6.1.1 Ketamine and 5.5.3.2
regarding sublingual ketamine). This results in high early norketamine concentrations vs IV
administration. The peak ratio of norketamine/ketamine at 1 h is 2.8 after PO administration
allowing an analgesic contribution from the metabolite at this time. This property has proved
useful when racemic ketamine is given 1 h before burns dressings ( Brunette 2011 Level IV). The
PKs following SL and IN route administration have been studied in adults with respective
bioavailabilities of 30 and 45% (Yanagihara 2003 PK). In adults, a ketamine lozenge (25 mg) had
24% bioavailability by both SL and PO routes (with peak plasma levels at 30 min and 120 min
respectively, and high norketamine concentrations) (Chong 2009 PK); a SL wafer presentation (25mg) had similar SL bioavailability of 29% (Rolan 2014 PK). For procedural analgesia, thebioavailability of IN racemic ketamine (0.5 mg/kg combined with sufentanil 0.5 mcg/kg) was
36%, with a Tmax of 8.9 min in awake children (half the value reported in anaesthetised children)(Nielsen 2014 Level IV). The IN spray was acceptable to the majority of patients. IN S-ketamine
2 mg/kg has also been administered to anaesthetised children and its PKs assessed but data
quantifying effect are not available (Weber 2004 PK).
Efficacy of ketamine
Perioperative use of ketamine
Four meta-analyses have assessed perioperative paediatric ketamine use by various routes forvarious surgery types (Michelet 2016 Level I [PRISMA], 11 RCTs, n=508; Cho 2014 Level I [PRISMA], 24
RCTs, n=1,257; Tong 2014a Level I (PRISMA), 10 RCTs, n=522; Dahmani 2011 Level I [QUORUM], 35 RCTs,
n=1,925) (0-10 RCT overlap). Studied systemic dose regimens generally consist of a bolus ranging
from 0.1 mg/kg to 0.5 mg/kg mostly, to as high as 6 mg/kg. Some incorporated intraoperativeand postoperative ketamine infusions which have generally ranged between 0.08 and 0.25
mg/kg/h, with 2 RCTs using 1─1.4 mg/kg/h. Findings for all administration routes are generally
positive, mainly for early analgesic outcomes.
Caudal ketamine for inguinal and urological surgery
Caudal ketamine increases the duration of sensory block (SMD 2.26; 95%CI 1.53 to 2.98) (10 RCTs,
n=686) and reduces analgesic requirement in PACU (OR 0.26; 95%CI 0.10 to 0.66) (10 RCTs, nunspecified), but did not reduce pain intensity in PACU or in the first 6 h postoperatively (Dahmani
2011 Level I [QUORUM], 13 RCTs [caudal], n unspecified).
Systemic ketamine for various surgery types
In patients having adenotonsillectomy (13 RCTs), inguinal hernia repair and circumcisions (2 RCTs),
appendicectomy (1 RCT), scoliosis surgery (1 RCT) and ambulatory surgery (1 RCT) (Dahmani 2011
Level I [QUORUM], 18 RCTs [systemic], n=985), systemic ketamine:• Reduces pain intensity in PACU (SMD -0.45; 95%CI -0.73 to -0.16) (10 RCTs, n=647);• Reduces analgesic requirement in PACU (OR 0.46; 95%CI 0.29 to 0.72) (7 RCTs, nunspecified);• But not intensity or analgesic requirement later in the 6─24 h postoperative period; and• Does not reduce opioid consumption in the first 24 h.
Peritonsillar and topical ketamine for adenotonsillectomy
Peritonsillar (2 RCTs) and topical ketamine (1 RCT):• Reduces pain intensity in PACU (SMD -1.62; 95%CI -2.83 to -0.41) (3 RCTs, n=190) ;• Reduces analgesic requirement in PACU (OR 0.09; 95%CI 0.03 to 0.27) (2 RCTS, n=90)(Dahmani 2011 Level I [QUORUM] 35 RCTs, n=1,925).

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Systemic, peritonsillar and topical ketamine for tonsillectomy
Intraoperative ketamine by all three routes:• Vs opioid, achieves similar pain scores at five time points over 0─24 h (Cho 2014 Level I[PRISMA], 9 RCTs [opioid], n=428);• Vs placebo, reduces early pain intensity
o at 0 h (SMD -1.7; 95%CI -3.17 to -0.24) (Cho 2014 Level I [PRISMA], 6 RCTs [placebo],
n=290);o at 0.5─2 h (Tong 2014a Level I (PRISMA), 10 RCTs, n=522) (10 RCT overlap with Cho);o and 4 h (SMD -0.8; 95%CI -1.2 to -0.4) (Cho 2014 Level I [PRISMA], 14 RCTs [placebo],
n=718), but not later at 6─24 h;• Subgroup analysis reveals similar results for IV and peritonsillar administration with astronger effect size for peritonsillar route, countered by higher heterogeneity of thestudies. There is reduced need for (LogOR -1.2) and amount of analgesia required (SMD 1.3) and longer time to first rescue analgesic (SMD 0.96) (Cho 2014 Level I [PRISMA], 24 RCTs,
n=1,257) (overlapping with the first SR by 8 RCTs [4 IV, 1 topical and 3 peritonsillar infiltration]);• Adminstered as peritonsillar infiltration 2 mg/kg, PR 2 mg/kg or IV 0.5 mg/kg vs IV
tramadol 2 mg/kg reduced pain scores similarly (Yenigun 2015 Level III-1, n=120).
Multidose perioperative ketamine
IN pump-pack administration of ketamine 1.5 mg/kg vs fentanyl 1.5 mcg/kg (at induction andthen three times daily) reduced pain scores over 24 h similarly (Yenigun 2018 Level III-1, n=63). Bothwere superior but with more sedation vs IV paracetamol 10 mg/kg, with no difference in otheradverse effects.
Systemic perioperative ketamine and postoperative opioid-sparing effectFor various surgeries (Michelet 2016 Level I [PRISMA], 11 RCTs, n=508) (with 7, 3 & 0 RCT overlap
respectively with the above SRs), systemic ketamine vs placebo does not reduce:• Opioid consumption in the first 24 h (primary outcome) (6 RCTs, n=278) or in PACU or in
the first 48 h;• Pain intensity (in PACU, or in the first 24 and 48 h);• PONV or psychotomimetic symptoms in the first 24 h.
There was also no difference in subgroup analysis of postoperative ketamine infusions only
(4 RCTs, n=179) and use in scoliosis surgery (3 RCTs, n=128) on opioid consumption to 24 h vsplacebo. Overall, the authors calculated a sample size of 445 patients would adequately power
an RCT to determine if ketamine is opioid-sparing.
• A single additional scoliosis surgery RCT conflicts with those included in the meta-analysis
where IV ketamine (0.5 mg/kg bolus and 0.12 mg/kg/h for 48 h) reduced cumulative
morphine consumption at 24 and 48 h vs placebo (Minoshima 2015 Level II, n=36, JS 5). There
was no difference in pain intensity, sedation score or PONV incidence;• In a further scoliosis RCT, intraoperative IV infusion of ketamine (0.2 mg/kg bolus and 0.15
mg/kg/h)/remifentanil/magnesium (50 mg/kg bolus and 8 mg/kg/h) vs ketamine/
remifentanil/placebo reduced 0-48 h PCA morphine requirements by 29.5% (Jabbour 2014
Level II, n=50, JS 5).
Postoperative combined PCA ketamine/opioid
Adding ketamine to opioid in the PCA pump improves pain at rest at 24 h (WMD -21.1/100 mm;
98%CI 21.8 to 20.4) (9 RCTs, n=595), reduces opioid consumption by 28% (7 RCTs, n=495) and PONV
by 44% (7 RCTs, n=435) (Assouline 2016 Level I [PRISMA], 19 RCTs [2 paediatric], n=1,453). Respiratory
depression (RR 0.31; 98%CI 0.06 to 1.51) (9 RCTs, n=871) and hallucinations (OR 1.16; 98%CI 0.47
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to 2.79) (7 RCTs, n=690) are not increased. Both included paediatric studies involved Nuss surgery.
Intraoperative ketamine bolus 0.3 mg/kg followed by PCA IV ketamine added to fentanyl (ratio
per mL 0.15 mg/kg: 0.5 mcg/kg) vs fentanyl PCA alone resulted in a small but statisticallysignificant decrease in mean pain scores at 6 h (2.5/10 vs 2.9), 24 h (1.4/10 vs 1.9) and 48 h
(1.0/10 vs 1.6) and reduced cumulative fentanyl consumption at 24 and 48 h (Assouline 2016
Level I [PRISMA], 1 RCT: Cha 2012 Level II, n=60, JS 3). Combining ketamine withhydromorphone/ketorolac in a PCA (ratio per mL 0.15mg/kg: 3 mcg/kg: 0.05 mg/kg) reduced
postoperative PCA use (50.8 ± 1.9 mL vs 57.8 mL ± 2.5) with no difference in other outcomes(Assouline 2016 Level I [PRISMA], 1 RCT: Min 2012 Level II, n=44, JS 4).
S(+) ketamine
The efficacy of S(+) ketamine has been investigated in a limited number of paediatric studies.
Following major urological procedures, children treated with intraoperative low-dose IV S(+)
ketamine (bolus 0.2 mg/kg and infusion 0.3 mg/kg/h) vs placebo had a longer time to firstanalgesic request, but similar pain scores and 72 h IV NCA morphine consumption (Becke 2005
Level II, n=30, JS 5).
Adjuvant caudal S(+)ketamine 0.5 mg/kg increases the duration of analgesia vs local
anaesthetic alone (SMD 2.35; 95%CI 1.02 to 3.67) (4 RCTs) (Dahmani 2011 Level I [QUORUM], 35
RCTs, n=1,925). The duration was similar to that for adjuvant caudal racemic ketamine 0.25─0.5
mg/kg (9 RCTs).
Ketamine use by various routes in acute non-surgical pain
Ketamine has been used prehospital and in the ED for analgesia, commonly for severe pain(>6/10) following limb injury/fracture, burns, falls or road traffic accidents. Doses of0.25─1 mg/kg have been used in children via IV, IM and IN routes (Yeaman 2013 Level IV; Bredmose
2009a Level IV; Bredmose 2009b Level IV; Reid 2011 CR), as well as higher doses IM (Svenson 2007
Level IV). IN Ketamine 1─1.5 mg/kg was similarly effective vs IN fentanyl 1.5─2 mcg/kg for children
presenting to the ED with limb injuries, with reduced pain scores at 20─60 min (Frey 2019 Level II,
n=90, JS 5; Reynolds 2017 Level II, n=87, JS 3; Graudins 2015 Level II, n=80, JS 5). (See also adult Sections
5.5.2.3 Ketamine via IN route and 8.6.5.2 for use in acute headaches).
Beneficial use of low-dose 0.1─0.2 mg/kg/h infusion in sickle cell crises is described in children
in addition to (n=4) or to replace (n=1) IV opioid PCA (Zempsky 2010 Level IV). Bolus IV ketamine
1 mg/kg for sickle cell crisis resulted in similar mean maximum percentage change in pain score
during a 2 h period vs bolus IV morphine 0.1 mg/kg (66.4% vs 61.3), but with a higher rateof minor adverse effects (37.5% vs 3.3: mainly nystagmus and dysphoria) (Lubega 2018 Level II,
n=240, JS 5).
Nebulised ketamine 2 mg/kg vs dexmedetomidine 2 mcg/kg vs combination ketamine
1 mg/kg and dexmedetomidine 1 mcg/kg has been trialled for paediatric pre-medication 30 min
prior to dental surgery and may contribute to improved postoperative analgesia (although thedata on acceptance of the nebulised technique by the young children is not specified) ( Zanaty
2015 Level II, n=60, JS 5).
When IV ketamine is used for procedural sedation, there is a steep concentration-response
relationship (almost all or no response) with an EC 50 for arousal of 0.56 mg/L (Herd 2008 Level IV).
A dose finding study of rectal ketamine 4─8 mg/kg with midazolam 0.5 mg/kg achieved effective
sedation and analgesia for burns dressing changes in young children; the higher dose of 8 mg/kg
was associated with prolonged recovery time and adverse events (Grossmann 2019 Level II, n=90,
JS 5). Similar doses were effective for botox injections in children with cerebral palsy (Nilsson 2017
Level IV, n=61 [128 procedures]).

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Ketamine use in opioid-induced hyperalgesia (OIH)
Three RCTs have assessed the opioid-sparing effect of perioperative ketamine in adolescentsreceiving remifentanil based anaesthesia for scoliosis surgery (Perello 2017 Level II, n=48, JS 5;
Pestieau 2014 Level II, n=54, JS 5; Engelhardt 2008 Level II, n=34, JS 4). They each found no differencein pain scores and opioid consumption up to 72 h. The validity of using opioid consumption as asurrogate for OIH has limitations; the 2017 RCT also assessed peri-incisional hyperalgesia at 72 h
(using Von Frey hairs) but found no difference between groups. Additionally, there was nodifference in the measured area of peri-incisional hyperalgesia in patients who had any vs nopain 6 mth later.
The paediatric data differs to the positive findings in adults: see the adult Section 4.6.1.1
Ketamine.
See also Section 10.4.6 for discussion of use of ketamine in opioid-tolerant children and adult
Sections 9.7.2 and 9.7.6.4 for use in opioid-tolerant adults.
Adverse effects of ketamine
Generally, when analgesic (low dose) ketamine has been used perioperatively in children,
increased incidence of adverse effects has not been reported. IV Ketamine (median dose
0.5 mg/kg) is not associated with PONV during the ﬁrst 24 h, or psychomimetic manifestations
such as hallucinations, dysphoria-euphoria and sedation (Dahmani 2011 Level I [QUORUM], 18 RCTs
[systemic], n=985). Similar results were found in a more recent meta-analysis assessing PONV at 2time points (7 RCTs) and psychomimetic effects (6 RCTs) (Michelet 2016 Level I [PRISMA], 11 RCTs,
n=508) (7 RCT overlap). The odds ratios were similar for these outcomes in the topical/peritonsillar(4 RCTs) and caudal (13 RCTs) administration routes (Dahmani 2011 Level I [QUORUM], 35 RCTs,
n=1,925).
After Nuss surgery, ketamine added to fentanyl PCA reduced nausea and vomiting incidence
over 48 h when compared to fentanyl PCA alone (23 vs 53%) (Cha 2012 Level II, n=60, JS 3).
However, when used in the ED, minor adverse effects (mostly dizziness, bad taste in mouthand sleepiness) were more common with IN ketamine vs IN fentanyl: RR 2.5 (95%CI 1.5 to 4.0)
(Frey 2019 Level II, n=90, JS 5); 100 vs 61% (Reynolds 2017 Level II, n=87, JS 3); and 78 vs 41% (Graudins
2015 Level II, n=80, JS 5).
In patients who received ketamine for procedural sedation in the ED, the following adverse
effects were recorded: airway and respiratory events (3.9%), laryngospasm (0.3%), apnoea(0.8%), emesis (8.4%), any recovery agitation (7.6%), and clinically important recovery agitation(1.4%) (n=8,282) (Green 2009b Level IV; Green 2009c Level IV).
Neurotoxicity and ketamine
The possible neurodegenerative effect of ketamine (and other analgesic/anaesthetic agents) on
the developing brain is under discussion (Davidson 2013 NR; Walker 2012c NR). Racemic ketamine(with its preservative benzethonium chloride) and S(+) ketamine have been associated withneuronal apoptosis in developmentally regulated cortical and subcortical areas in rodents andsensorineural consequence in animal models following high dose and/or long term IV and IT
administration (Davidson 2013 NR; Walker 2012c NR; Walker 2010 BS; Green 2009a NR). Conversely,
ketamine has demonstrated neuroprotective effects in the presence of noxious stimuli in animals(Cheung 2019 NR). Proposed mechanisms include inhibition of neuronal excitotoxicity, and antiinflammatory effects. The translatability of these findings to humans is questioned and theimpact of lower subanaesthetic doses (bolus and perioperative infusion) is uncertain.
See adult Section 4.6.2.1 ketamine regional administration and neurotoxicity issues.

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10.4.7.2 | Magnesium
Efficacy
Magnesium (Mg) administered by local infiltration or IV (bolus and/or infusion) has been studiedin children having tonsillectomy (Cho 2018a Level I [PRISMA], 10 RCTs, n=615; Xie 2017a Level I[PRISMA], 10 RCTs, n=665) (9 RCT overlap). In the earlier systematic review, Mg sulphate (IV or local
infiltration) vs control does not reduce pain scores (8 RCTs, n=555), but does reduce the numberof patients receiving rescue analgesia (RR 0.53; 95%CI 0.31 to 0.91) (5 RCTs, n=305), having
emergence agitation (OR 0.18; 95%CI 0.07 to 0.48) (2 RCTs, n=105) and laryngospasm (OR 0.36;
95% CI 0.13 to 0.96) (7 RCTs, n=500) (Xie 2017a Level I [PRISMA], 10 RCTs, n=665). The subsequentsystematic review found overall Mg (IV or local infiltration) does not reduce early pain scores at≤1 h but does reduce late pain scores at 24 h vs control (SMD -0.39; 95%CI -0.71 to -0.07) (6 RCTs,
n=330), with sub-analysis revealing that local infiltration is effective (SMD -0.62; 95%CI -0.89 to 0.36) (4 RCTs, n=230) and IV route is not (2 RCTs, n=100) (Cho 2018a Level I [PRISMA], 10 RCTs, n=615).
Mg vs control increases time to first analgesia (SMD 0.75; 95%CI 0.20 to 1.31) (3 RCTs), reduces
rescue analgesia administration (SMD -0.39; 95%CI -0.71 to -0.07) (5 RCTs), postoperative
agitation at 15 min (SMD -0.31) (3 RCTs) and 1 h (SMD -0.67) (2 RCTs), and laryngospasm (SMD 1.09; 95%CI -2.11 to -0.07) (8 RCTs), and did not alter bleeding risk (3 RCTs). The sample sizes forthe subanalyses were not provided.
For scoliosis surgery, the addition of intraoperative Mg (50 mg/kg initial bolus and 8
mg/kg/h infusion) to ketamine (0.2 mg/kg initial bolus and 0.15 mg/kg/h
infusion)/remifentanil reduced postoperative PCA-morphine requirements by 29.5% (over0─48 h) (Jabbour 2014 Level II, n=50, JS 5). While, adding the same bolus and slightly higher dosingof intraoperative Mg (10 mg/kg/h) to remifentanil did not reduce 0─24 h hydromorphonerequirement vs remifentanil alone (0.38 ± 0.10 mg/kg vs 0.34 ± 0.11 mg/kg), where IV
methadone 0.1 mg/kg did (0.26 ± 0.10 mg/kg), with no difference in postoperative pain scoresin the three groups ( Martin 2018 Level II, n=60, JS 4).
For severe migraine, IV Mg bolus (max dose 1─2 g over 15─30 min) in the ED substantiallyreduced pain severity in 35-48% of paediatric patients (Orr 2018a Level IV SR, 21 studies [2 IV Mg], n[IV Mg]=57 [65 migraines]).
For tonsillectomy, the addition of peritonsillar Mg 2-5 mg/kg to local anaesthetic reduced
pain scores (4 RCTs) and the number of analgesic requests (WMD -0.68; 95% CI -1.17 to -0.18) (3RCTs, n=180) (Vlok 2017 Level I, 4 RCTs [Mg], n=230).
See also adult NMDA antagonists discussion of magnesium Section 4.6.1.3 and specific toadult Headache 8.6.5.1 , Migraine 8.6.5.2 and Paediatric Migraine 10.9.3.

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Ketamine
1. Perioperative low-dose intravenous ketamine bolus is similarly effective to opioids andsuperior to placebo in reducing early pain scores and analgesic requirements in children(U) (Level I [PRISMA]).
2. Perioperative low-dose intravenous ketamine bolus does not increase the postoperative
incidence of nausea and vomiting, sedation, agitation, dreams or hallucinations inchildren (S) (Level I [PRISMA]).
3. Peritonsillar infiltration and topical application of ketamine for paediatric tonsillectomy
reduces early pain scores and analgesic requirements versus placebo (S) (Level I [PRISMA]).
4. When added to multimodal analgesia, perioperative ketamine (bolus with or without
intra/postoperative infusion) in children is not opioid-sparing vs placebo (S), although
low postoperative pain scores and small sample sizes mean the meta-analysis isunderpowered (Q) (Level I [PRISMA]).
5. There is low level evidence that combination ketamine and opioid PCA improved painscores and PCA use post Nuss surgery (N) (Level II).
Magnesium
6. Magnesium (intravenous or peritonsillar infiltration) in children for tonsillectomy
reduces postoperative rescue medication use, and increases time to first analgesia
versus control; magnesium also reduces risk of postoperative emergence agitation andlaryngospasm (N) (Level I [PRISMA]).
7. Magnesium (locally infiltrated) in children reduces late (24 hour) but not early (<1 hour)
pain scores post tonsillectomy versus control (N) (Level I [PRISMA]).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: High-dose long term ketamine is neurotoxic in animal models. The neurodevelopmental
impact in children of subanaesthetic/analgesic doses of ketamine administered bybolus or postoperative infusion is unclear (U).
 The benefit of perioperative ketamine in preventing remifentanil induced hyperalgesia
has not been adequately assessed in paediatric surgery (U).

10.4.8 | Alpha-2 agonists
The alpha-2 agonists, clonidine and dexmedetomidine, are attractive for paediatric use with theiranalgesic, sympatholytic (anxiolytic, haemodynamic modulation), antinausea/antiemetic andbehavioural modification/sedative effects (Sottas 2017 NR). Administered as bolus and/or
infusion via various routes, both agents have been used in various paediatric settings.
Perioperative use• Preoperatively as premedication;• Intraoperatively for controlled hypotension and to modify anaesthetic/perioperative opioid
requirements; postoperative nausea and vomiting, shivering and emergence agitation; and• As local anaesthetic adjuvants (see Section 10.6 and 10.6.3.3).
5th Edition | Acute Pain Management: Scientific Evidence965Use in paediatric and neonatal intensive care units (PICUs/NICUs)
Particularly in ventilated patients (Piotrowski 2015 Level IV, n=33 [12 postoperative]; Nemergut 2013
NR; Gupta 2012 Level III-2; Playfor 2006 GL):
• For sedation and analgesia;• To modify distress or hypertensive response and escalating opioid requirements; and• To prevent and treat opioid withdrawal symptoms ( Honey 2009 Level IV SR, 9 studies, n=44;
Oschman 2011 NR;) and facilitate opioid weaning.
Use in other settings
For similar indications, these agents are used in paediatric ward settings and also for procedural
sedation and analgesia in the outpatient, ED and radiology settings ( Ter Bruggen 2017 Level I,
5 RCTs [paediatric], n=372; Jooste 2017 Level IV, n=90; McMorrow 2012 NR).
See also the adult Section 4.9 Alpha-2 agonists.
10.4.8.1 | Clonidine
Pharmacokinetics
Bioavailability of clonidine after rectal and epidural administration is high (100%) (Potts 2007 PK),but is erratic after nasal drop administration in supine anaesthetised children ( Almenrader 2009
PK, n=11). Oral bioavailability is lower in children than in adults at 55% when mixed with apple
juice (which may influence intestinal transport); thus PO doses greater than 4 mcg/kg should beconsidered (Larsson 2011 PK, n=8); nasal administration has higher bioavailability than oral andTmax occurs later (Blackburn 2014 PK, n=66). Clearance at birth is reduced and matures to achieve
82% of the adult rate at 1 y (Potts 2007 PK, n=72 [380 samples]).
The PKs of clonidine have also been assessed during sedation as an adjuvant to morphine andmidazolam infusion during ECMO in children, with simulation aiming for a target concentrationof 2 ng/mL, suggesting 3 boluses of 5 mcg/kg at 20 min intervals and infusion of 1 mcg/kg/h inchildren >12 y (Kleiber 2017 PK, n=22 [375 samples]). For mechanically ventilated patients, PK
simulation suggested optimal clonidine dosing for a target of 2 ng/mL was 2 mcg/kg bolus andinfusions up to 2 mcg/kg/h; this regimen should be halved in neonates (Hayden 2019 PK).
Efficacy
Clonidine has been used for the above indications for decades by various routes (Basker 2009 NR;
Nishina 2002 NR; Eisenach 1996 NR).
Preoperative clonidine 2-4 mcg/kg administration (PO in 10 RCTs, rectal in 1 RCT) reduces
postoperative pain scores, analgesic requirement and PONV vs midazolam and placebo, but not
fentanyl (Lambert 2014 Level I [Cochrane], 11 RCTs [comparators: 6 midazolam, 4 placebo and 1 fentanyl],
n=748). An earlier review draws similar conclusions (Dahmani 2010 Level I, 10 RCTs, n unspecified) (4RCT overlap). It additionally reports superiority of clonidine vs midazolam for sedation at induction(OR 0.49; 95%CI 0.27 to 0.89) (2 RCTs) and superiority vs diazepam for PONV (OR 0.34; 95%CI
0.13 to 0.94) (2 RCTs). The same review reports reduced emergence agitation incidence (OR 0.25;
95%CI 0.11 to 0.58) (3 RCTs). This is also confirmed for intraoperative IV clonidine administrationvs placebo (OR 0.5; 95%CI 0.26 to 0.95) (Pickard 2014 Level I, 2 RCTs [clonidine], n=170; Ydemann 2018
Level II, n=379, JS 5).
Typical bolus clonidine doses are 1─3 mcg/kg: IV, regionally, for nerve blocks and for
infiltration (see Section 9.6).
Clonidine has been infused in cardiac surgery and intensive care at widely ranging rates: 0.18
to 1─3 mcg/kg/h (Lambert 2014 Level I [Cochrane], 1 RCT: Hunseler 2014 Level II, n=213, JS 5; Basker
2009 NR).
Aerosolised IN clonidine 3─8 mcg/kg has unreliable sedative efficacy and time to onset of
effect (Larsson 2012 Level II, n=60, JS 5). This route has not been used for analgesic indications.

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10.4.8.2 | Dexmedetomidine
Dexmedetomidine is more alpha-2 selective than clonidine. Its off licence use has increased invarious paediatric settings (Sottas 2017 NR) (see below).
Pharmacokinetics
Dexmedetomidine PKs have been studied extensively in children. Population parameter
estimates [and between subject variability] for a 2-compartment model were: clearance (CL)42.1 L/h/70kg [31%], central volume of distribution (V1) 56.3 L/70kg [61%], inter-compartment
clearance (Q) 78.3 L/h/70kg [37%] and peripheral volume of distribution (V2) 69.0 L/70kg [47%](Potts 2009 PK, n=95 [730 observations]). Clearance matures with age and increases from 18.2
L/h/70kg at birth in a term neonate to reach 84.5% of the mature value by 1 y of age. Simulationof published infusion rates that provide adequate sedation for PICU patients found a target
therapeutic concentration of between 0.4 and 0.8 mcg/L. This estimate has been reviewed andan EC50 of 0.9 mcg/L (95%CI 0.45 to 2.34) for sedation proposed by modelling PK-PD data (Li 2018a
Level II PK, n=8 [3 way cross over study]). The equilibration half time between plasma and the effectcompartment was 3.3 min (95%CI 1.8 to 4.7), indicating that slow onset of effect after enteraldelivery is mostly due to slow absorption and not a delay between plasma concentration andeffect site.
Subsequent IV dexmedetomidine PK studies in children post 1-2 mcg/kg for bronchoscopy,
radiological imaging (Vilo 2008 PK, n=16), prior to (Liu 2017 PK, n=39), and during general surgery,following loading dose and infusion of 0.2─1.4 mcg/kg/h post liver transplantation (Weerink 2017
NR PK) are consistent with the earlier study (Potts 2009 PK, n=95). Hepatic function, assessed using
INR, may alter clearance. Clearance after liver transplantation varied widely and was associatedinversely with INR and not weight (Damian 2020 Level IV PK, n=20). Titration to clinical effect, rather
than weight-based dosing, was suggested for this population, with attention to changes in INR.
Bioavailability in adults is 82% after intranasal and buccal administration (Weerink 2017 NR PK)
with similar time to onset of 1 mcg/kg by atomiser (47.5 min; 95%CI 25 to 135) and drop
administration (60 min; 95%CI 30 to 75) vs IV (15 min; 95%CI 15-20) (Li 2018a Level II PK, n=8). In
children, after orogastric administration bioavailability was only 16% (Weerink 2017 NR PK); while
after IN atomiser administration, bioavailability was 84% (95%CI 70 to 98%) ( Miller 2018
Level III-1 PK, n=18) and lower with intranasal syringe administration (lying supine with headextended, where more pharyngeal run off possibly occurred) (Wang 2019a PK, n=13). Absorption
half time was 18 to 20 min in both studies.
Efficacy
Several overlapping reviews have been performed with similar findings mostly in favour ofdexmedetomidine. Data for emergence agitation is included here as severe pain in PACU may
mimic this. Following various paediatric surgery types (mostly tonsillectomy, but also ear,laparoscopic appendectomy and genitourinary surgery), dexmedetomidine:
IV/IN bolus only 0.15─2 mcg/kg intraoperatively vs placebo reduces• Postoperative pain (RR 0.51; 95%CI 0.32 to 0.81) (2 RCTs, n=138) (Schnabel 2013 Level I[PRISMA], 11 RCTs [10 IV, 1 IN], n=874) and pain in PACU (RR 0.41; 95%CI 0.25 to 0.65) (5 RCTs,
n=356) (Zhang 2014 Level I [PRISMA], 12 RCTs, n=812) (5 RCT overlap);• The need for rescue analgesia (OR 0.16; 95%CI 0.05 to 0.48) (3 RCTs, n=168) (Pickard 2014
Level I, 10 RCTs [dexmedetomidine], n=669) (7 RCT overlap) and for postoperative opioid
rescue (RR 0.4; 95%CI 0.26 to 0.62) (4 RCTs, n=249), but does not reduce overall morphine
requirement (2 RCTs, n=98) (Schnabel 2013 Level I [PRISMA] [10 IV, 1 IN], n=874);

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•

Emergence agitation (OR 0.22; 95%CI 0.14 to 0.33) (8 RCTs, n=499) (Pickard 2014 Level I, 10
RCTs [dexmedetomidine], n=669) (7 RCT overlap) (RR 0.35; 95%CI 0.26 to 0.45) (12 RCTs, n=812)(Zhang 2014 Level I [PRISMA], 12 RCTs, n=812) (5 RCT overlap).

IV bolus 0.15─2 mcg/kg with short term infusion 0.1─0.7 mcg/kg/h (in 8 RCTs) vs placebo
reduces:• Pain intensity in PACU (MD -1.18; 95%CI -1.88 to -0.48) (13 RCTs, n unspecified) and• Postoperative opioid consumption in PACU (RR 0.31; 95%CI 0.17 to 0.59) (11 RCTs,
n unspecified);• But does not reduce PONV (RR 0.67; 95%CI 0.41 to 1.08) (3 RCTs, n=290)(Bellon 2016 Level I [PRISMA], 14 RCTs, n=1,463) (6 & 7 RCT overlap).
In tonsillectomy only, IV dexmedetomidine 0.15─2 mcg/kg (intraoperative bolus or over
10 min and in 5 RCTs by infusion: pre, during or post surgery) vs mixed comparators (4 opioid,
10 placebo, 1 no therapy) reduces:• Postoperative pain scores in PACU (MD-1.82; 95%CI -2.5 to -1.13) (5 RCTs, n=480 [3 placebo,
1 opioid, 1 no therapy]);• Analgesic requirement in PACU (OR -0.59; 95%CI -0.89 to -0.3) (7 RCTs, n=680);• The need for rescue overall (OR 0.44; 95%CI 0.26 to 0.73) (11 RCTs, n=1,233); and• Emergence agitation score in PACU (MD -1.4; 95%CI -2.1 to -0.7) and incidence of EA (OR
0.28; 95%CI 0.21 to 0.36) and severe EA (OR 0.22; 95%CI 0.12 to 0.38) (Cho 2018b Level I,
15 RCTs, n=1,552) (3 & 4 RCT overlap).
Compared to intraoperative opioids, IV dexmedetomidine 0.75─4 mcg/kg reduces• Postoperative pain (RR 0.49; 95%CI 0.25 to 0.94) (3 RCTs, n=234);• But does not reduce the need for postoperative opioids (RR 0.77; 95%CI 0.6 to 1.1) (4 RCTs,
n=394) (Schnabel 2013 Level I [PRISMA], 11 RCTs [10 IV, 1 IN], n=874).
Subsequent RCTs or ones not included in the above reviews had similar findings. In
tonsillectomy, IV dexmedetomidine 0.3 mcg/kg reduced EA vs propofol 1 mg/kg and both wereeffective given IV 5 min before surgery cessation vs saline placebo (Cho 2018b Level I, 1 RCT: Ali
2013 Level II, n=120, JS 5). While, IV dexmedetomidine 1 mcg/kg given 10 min preoperatively vsplacebo had similar postoperative pain scores, reduced EA, with lower HR and stable mean
blood pressure intraoperatively (10 mmHg lower at all time points) ( Sharma 2019 Level II, n=60,
JS 4).
For myringotomy in children (1─8 y), post induction administration of IN dexmedetomidine
1 mcg/kg vs IN fentanyl 2 mcg/kg, with and without midazolam premedication, achieved similar
postoperative pain scores (Dewhirst 2014 Level II, n=100, JS 5) .
For strabismus surgery, intraoperative IV dexmedetomidine 1 mcg/kg bolus with 1 mcg/kg/h
vs IV ketamine 1 mg/kg bolus with 1 mg/kg/h similarly reduced EA and pain scores on the ward
(but not in PACU), with both superior to placebo (Chen 2013 Level II, n=84, JS 5).
For cardiac surgery, intraoperative dexmedetomidine infusion 0.5 mcg/kg/h reduced
postoperative fentanyl and inflammatory markers of the post surgery stress response, withsimilar pain scores vs placebo (Sun 2017 Level II, n=50, JS 4).
Following scoliosis surgery, postoperative IV dexmedetomidine infusion 0.4 mcg/kg/h (for 24 h)in addition to IV morphine PCA had no effect on morphine consumption or adverse effects(Sadhasivam 2009 Level III-2). In ventilated scoliosis patients, IV dexmedetomidine 0.4 mcg/kg/h vsIV midazolam 0.1 mg/kg/h reduced pain scores and modestly reduced low 24 h fentanyl
consumption (124 mcg  28 vs 165.8  33) (Aydogan 2013 Level II, n=32, JS 4).
Postalveolar bone graft surgery in children, dexmedetomidine 0.2─0.4 mcg/kg/h wasadministered for <24 h as an alternative to opioid infusion (Lopez 2018 Level III-3, n=54). Adjuvant

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infusion following craniosynostosis repair is also described (Kattail 2018 Level IV, n=4). For a 2 y old
child with chemotherapy-induced enterocolitis, adjuvant dexmedetomidine 0.05─0.2 mcg/kg/h
coadministration for 5 d improved pain control and allowed hydromorphone infusion reduction(Winton 2011 CR).
10.4.8.3 | Adverse effects of alpha-2 agonists
Haemodynamic effects
Hypotension and bradycardia are desirable effects with use of these agents for “controlled
hypotension” or blunting of pressor response. Alpha-2 agonists have provided cardiac
stability in the setting of paediatric cardiac surgery, intensive care patients (Gupta 2012
Level III-2; Sottas 2017 NR; Basker 2009 NR; Phan 2008 NR) and in supraventricular tachycardia
eg in neonates and children requiring cardiac surgery (Tobias 2013b NR). The haemodynamic
effects can be undesirable and are variably reported in RCTs and thus the reviews/meta analyses.
For systemic clonidine:• RCTs with clonidine 2─5 mcg/kg reported no difference overall in hypotension or
bradycardia incidence but interpretation was complicated by the use of atropine
pretreatment, with no comments made on the use of corrective interventions(Lambert 2014 Level I [Cochrane], 4 RCTs, n=279 ); two included trials of 2 vs 4 mcg/kg
clonidine vs placebo were underpowered to detect a difference for hypotension andbradycardia ─ defined as a 20% decrease from baseline, which occurred in 10 of 60
clonidine-treated vs 0 of 30 placebo-treated ( Mikawa 1996 Level II, n=90, JS 4) andhypotension defined as <70 mmHg and bradycardia defined as <60 beats/min
occurred in 4 of 30 clonidine-treated and 0 of 15 midazolam-treated (Cao 2009
Level II, n=45, JS 3).
For dexmedetomidine, significant change that requires medical intervention occurs
uncommonly:• The two largest reviews of IV administration do not comment on bradycardia andhypotension (Cho 2018b Level I, 15 RCTs, n=1,552; Bellon 2016 Level I [PRISMA], 14 RCTs,
n=1,463) (7 RCT overlap). Two earlier reviews stated no haemodynamic events werereported in the included RCTs (Zhang 2014 Level I [PRISMA], 12 RCTs, n=812; Pickard 2014
Level I, 10 RCTs [dexmedetomidine], n=669). One series documented bradycardia (>20%
decrease from baseline) in 4% of children who received dexmedetomidine 3 mcg/kg for
MRI sedation (Mason 2008 Level III-2, n=767 referenced in Pickard 2014 Level I, 10 RCTs
[dexmedetomidine], n=669);• One review documents 5 RCTs including haemodynamic outcomes (4 RCTs [placebo], n=180& 1 RCT [opioid], n=60) where 3 dexmedetomidine recipients had >30% change requiring
intervention: 1 received atropine for bradycardia and 2 saline bolus and isofluranedecrease for hypotension (1 RCT [placebo], n=26); while no patients needed rescue
treatment for bradycardia in the RCT with opioid comparator (Schnabel 2013 Level I[PRISMA], 11 RCTs, n=874).
Sedation and delay to discharge
The sedative effect is often useful and therapeutic in children but may be undesirable if delaying
discharge. Several small perioperative studies assessing the outcome of time spent in PACU ordelay in discharge have been incorporated in the systematic reviews summarised below.

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Clonidine RCTs conflict regarding time to discharge:• With delay (WMD 10.8 min; 95%CI 4.2 to 17.5) and increased sedation frequency post
discharge vs placebo (Pickard 2014 Level I, 1 RCT: Malviya 2006b Level II, n=120, JS 5);• And slightly earlier discharge vs placebo (1 RCT, n=46), with no difference vs midazolam(2 RCTs, n=194) (Lambert 2014 Level I [Cochrane], 11 RCTs, n=748).
While following IV dexmedetomidine, minimal clinical impact is reported on:• Time to extubation (WMD 0.6 min; 95%CI 0.28 to 0.96) (9 RCTs, n=555) and emergence(WMD 1 min; 95%CI 0.4 to 1.6) vs placebo (8 RCTs, n=548) (Zhang 2014 Level I [PRISMA],
12 RCTs, n=812);• Duration of PACU stay in 3 reviews (1 and 2 RCTs overlap): WMD 4.6 min (95%CI -0.08 to
9.275) vs placebo (3 RCTs, n=256) (Zhang 2014 Level I [PRISMA], 12 RCTs, n=812), SMD -0.37(95%CI -1.02 to 0.28) vs placebo or control (5 RCTs, n=792) (Cho 2018b Level I, 15 RCTs,
n=1,552) and 3 min vs placebo (4 RCTs, n=275) (Pickard 2014 Level I, 10 RCTs
[dexmedetomidine], n=669);• Time to discharge (2 RCTs, n=92) (Pickard 2014 Level I, 10 RCTs [dexmedetomidine], n=669).
Respiratory events
No oxygen desaturation or postoperative respiratory depression was reported fordexmedetomidine treated patients, while 3 children in the placebo group had bronchospasm(Zhang 2014 Level I [PRISMA], 12 RCTs, n=812) and one placebo recipient required oxygen
supplementation (5 RCTs, n=295) (Schnabel 2013 Level I [PRISMA], 11 RCTs, n=874);
Incidents of desaturation post tonsillectomy occurred less in dexmedetomidine treated vsplacebo or control (OR 0.40; 95%CI 0.21 to 0.77) (6 RCTs, n=843) (Cho 2018b Level I, 15 RCTs,
n=1,552).
Neurotoxicity
In contrast to most anaesthetic agents used, neuraxial clonidine has not been implicated inany reports or studies of neural toxicity/apoptosis and neither has epidural or intraperitoneal
dexmedetomidine in animal models ( Davidson 2013 NR; Walker 2012b NR). With
dexmedetomidine, some changes are seen with direct neural application of high dose inanimal studies. In rats who received a single injection brachial plexus block, the addition ofdexmedetomidine 60 mcg/kg to ropivacaine 0.5% reduced inflammatory cytokine (TNF-α andIL-6) amounts in the nerves vs saline (n=15) (Kang 2018 BS, n=39). While administration of highdose dexmedetomidine 60 mcg/kg alone increased inflammatory cytokines (including caspase
3, an important apoptosis protease) in the nerves of d 5 rat pups (neonatal equivalent), while
moderate dose 20 and 40 mcg/kg did not, in either d 5 or d 14 (child equivalent) rat pups
(n=24). In rabbits who received a femoral nerve CPNC infusion (for 72 h), the addition ofdexmedetomidine 3 mcg/mL to ropivacaine 0.25% was associated with myelin lamellar
structure changes; not seen with 1-2 mcg/mL added to ropivacaine, ropivacaine alone or
normal saline (Wang 2019b BS, n=30). Pre-emptive intraperitoneal administration ofdexmedetomidine ameliorated the effect of intrathecal administration of toxic doses of 10%
lidocaine in rats, an effect that was reversed by intraperitoneal injection of yohimbine or a
specific protein kinase C inhibitor (Xu 2018a BS, n=64). The neuroprotective effect ofdexmedetomidine in brain injury is not discussed here.

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1. Preoperative oral clonidine reduces postoperative pain scores and analgesic requirementin children compared to placebo or midazolam but not fentanyl (U) (Level I [Cochrane
Review]).
2. Preoperative oral clonidine reduces postoperative nausea and vomiting in children
compared to placebo or midazolam (U) (Level I [Cochrane Review]).
3. Preoperative intranasal dexmedetomidine reduces postoperative pain scores, rescue
analgesic requirements and emergence agitation with minimal adverse effects vsplacebo (N) (Level I [PRISMA]) and mixed comparators (N) (Level I).
4. Intraoperative dexmedetomidine reduces postoperative pain scores (U) (Level I[PRISMA]) and need for postoperative rescue analgesia (Q) (Level I) including opioid (U)(Level I [PRISMA]) in children compared to placebo, with minimal impact on time todischarge (N) (Level I [PRISMA]) via intravenous (S) (Level I [PRISMA]) and intranasal
routes (S) (Level I).
The following tick box represents conclusions based on clinical experience and expert
opinion: Alpha-2 agonists offer benefits in addition to analgesia in children in the perioperative,
intensive care and procedural settings. These benefits include anxiolysis, sedation (MAC
sparing), behavioural modification, prevention or treatment of opioid withdrawal(facilitating opioid weaning) (U) and reduction of emergence agitation (S).

10.4.9 | Alpha-2-delta ligands (gabapentinoids)
There is increased off licence use of alpha-2-delta ligands in children following the adultexperience in various pain states; paediatric data to support this is heterogeneous and limited(Egunsola 2019 Level III-3 SR [PRISMA], 7 RCTs, n=379). The meta-analysis includes the small studies
quoted below. They demonstrate efficacy for multi-day perioperative but not single preoperative
dosing.
Multi-segment scoliosis surgery
A single preoperative dose of gabapentin 600mg (≈11 mg/kg) did not reduce opioid consumption
over 24 h vs placebo (Mayell 2014 Level II, n=35, JS 5).
Gabapentin over 5 d (15mg/kg preoperatively then 15mg/kg/d) reduced total morphine
consumption in PACU, postoperative day (POD) 1 and 2 by 16-23% and pain scores in PACU andthe first postoperative morning only, with no differences in other outcomes vs placebo ( Rusy 2010
Level II, n=59, JS 3).
Gabapentin over 3 d (5─10mg/kg preoperatively then 7.5─22.5mg/kg/d [max 900 mg]/d)
reduced:• POD 1─3 pain scores and opioid use POD 1─2 (Trzcinski 2019 Level III-2, n=129);• The time required to meet physical therapy goals, but not length of stay [LOS] ( Thomas
2018b Level III-3, n=101); and• POD 1 (but not day of surgery) PCA opioid consumption by 40%, alone and in combination
with transdermal clonidine, with earlier PO intake, ambulation and for the combinationslight clinical impact on LOS (Choudhry 2017 Level III-3, n=127).
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Other surgery types and conditions
For tonsillectomy, preoperative gabapentin (dose 10-20 mg/kg in the 3 paediatric of 6 RCTs) andpregabalin (2 RCTs: 1 mixed, 1 adult) similarly reduce pain in the first 8 h, analgesic requirementsin the first 24 h and PONV without increasing adverse effects (Hwang 2016a Level I [PRISMA], 8 RCTs
[3 adult, 2 mixed, 3 paediatric], n=608).

In laparoscopic appendicectomy, varying doses of pre and postoperative gabapentin for 3 d(range 4.4─30.4 mg/kg/d) alone or with postoperative ketorolac reduced postoperative opioid
consumption for simple and complicated appendicitis with no difference in time to pain score≤3 or LOS (Baxter 2018 Level III-2, n=87).
For the Nuss procedure in adolescents, low dose gabapentin 100─200mg three times dailyfor 72 h has been used in combination with PCA hydromorphone, clonidine patch and local
anaesthetic via wound catheter with similar pain scores to those in thoracic epidural recipients(ropivacaine 0.2% with hydromorphone 10 mcg/mL) (Choudhry 2016 Level III-3, n=32).
In children with severe cerebral palsy (Gross Motor Function Classification System [GMFCS]
IV─V), gabapentin (7─18 mg/kg/dose or 900mg/d) improved pain (and dystonia) frequency andimpact (in patients co-receiving baclofen, diazepam and botulinum injections) (Harvey 2018
Level IV, n=11 doctors, 57 patients; Liow 2016 Level IV, n=82).
In paediatric burns, in addition to or instead of antihistamines (in inpatient and outpatientsettings), alpha-2-delta ligands reduced itch and pain: gabapentin 15 mg/kg/d (prescribedfor 53% of patients) (Nieuwendijk 2018 Level IV, n=413) and 24─34 mg/kg/d (where 23
patients poorly responded to gabapentin had pregabalin 3.7─6.5 mg/kg/d added) (Kaul 2018
Level IV, n=136).
In paediatric oncology, preoperative and therapeutic gabapentin use 900 mg/d for 30 d
reduced phantom limb pain incidence at 60 d (43 vs 77%) with similar reduction of early
perioperative pain scores vs placebo (Wang 2018 Level II, n=45, JS 5). Gabapentin 20─40mg/kg/d
for phantom limb pain is also described in 3 case series ( DeMoss 2018 NR). Pregabalin 1.25─2.5
mg/kg/d, as part of a multimodal analgesic regimen, has been used in a 4 y old girl with a severe
crush injury requiring foot amputation (Wossner 2017 CR).
In vincristine induced painful peripheral neuropathy (used for solid tumours and leukaemia),
8 weeks of pregabalin 150-300 mg (4─5.7 mg/kg)/d decreased mean pain score by 59% frombaseline with dose dependent effect (Vondracek 2009 Level IV, n=30). Gabapentin 15─70 mg/kg/d
pre-emptive and therapeutic use is described in a larger series of leukaemic patients (Anghelescu
2011b Level IV, n=112 [gabapentin-treated]).
In children with chronic pain from fibromyalgia and CRPS type 1, alpha-2-delta ligands havebeen used with some benefit (Cooper 2017c Level I [Cochrane], 2 RCTs, n=141) as well as in painful
restless legs syndrome (Frenette 2011 NR).
The use of alpha-2-delta ligands in prevention of chronic postsurgical pain in children has notbeen studied.
For alpha-2-delta ligands use in adults, see Sections regarding efficacy in acute 4.8.1.1 andchronic pain 4.8.2.1, and Section 1.4.6.3 for prevention of chronic postsurgical pain.

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1. Multi-day perioperative (but not single preoperative) gabapentin dosing reduces
postoperative morphine consumption vs placebo following multilevel posterior spinal
fusion for adolescents with idiopathic scoliosis (N) (Level II).
2. Multiday perioperative gabapentin reduces phantom limb pain incidence vs placebo in
paediatric oncology amputation surgery (N) (Level II).
3. Preoperative gabapentin and likely pregabalin improve analgesia after tonsillectomy inchildren and reduce PONV without increasing adverse effects (N) (Level I [PRISMA]).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Alpha-2-delta ligands use in children for acute (and chronic) pain conditions is
expanding based mostly on expert opinion and case series. The pain indications are
similar to those for adults with similar benefit and adverse event profiles (N).
 Gabapentin and pregabalin are used to manage pruritus and neuropathic pain
following burn injury in children (N).
 The use of alpha-2-delta ligands for the prevention of chronic postsurgical pain inchildren has not been studied (N).

10.4.10 | Corticosteroids
Systemic corticosteroids
The impact of systemic corticosteroid use on various outcomes in children post-surgery or withacute pharyngitis has been assessed; for data on corticosteroid use in combination with local andregional techniques see paediatric Section 10.6.2.6. See also Section 4.12.1 for use of systemic
corticosteroids in adults.
10.4.10.1 | Efficacy in painful medical conditions
Pharyngitis/Sore throat
For pharyngitis (proven bacterial or severe symptoms) presenting in the primary care or
emergency department setting, PO dexamethasone 0.6 mg/kg (max 10 mg) achieved onset ofanalgesia 5─24 h earlier than placebo (measured with three different scoring systems), with asingle dose as effective as a 3 d course (Sadeghirad 2017 Level I, 3 RCTs [paediatric], n=393) (seeSection 8.6.7.5 for adult data which includes information on steroid, as well as antibiotic andtopical treatments). Data is not available for systemic corticosteroid administration for post
extubation sore throat in children.
Septic arthritis
In low quality RCTs, 4 d of dexamethasone 0.15─0.2mg/kg 6─8 h reduces the number of days ofIV antibiotic treatment (MD -2.77; 95%CI -4.16 to -1.39) (Delgado-Noguera 2018 Level I [Cochrane],
2 RCTs, n=149). At 12 mth follow-up, dexamethasone may increase the proportion of patients
without pain (RR 1.33; 95% CI 1.03 to 1.72) (1 RCT, n=49) and with normal function of the affectedjoint (RR 1.32; 95% CI 1.12 to 1.57) (1 RCT, n=100). Small study numbers limit the capacity to assess
serious adverse effects.
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Henoch-Schonlein Purpura and abdominal pain
In case series and retrospective analyses only of patients with Henoch-Schonlein Purpura [HSP]and abdominal pain, corticosteroids reduced pain, usually within 24 h (Haroon 2005 NR). In HSP
associated pancreatitis, corticosteroid use (pulsed 2nd daily IV methylprednisolone 10─15
mg/kg/d, followed by PO prednisolone 1 mg/kg/d) for 2─3 wk reduced abdominal symptoms
including pain (Zhang 2018 Level IV, n=13).
10.4.10.2 | Efficacy in postoperative pain
Dental surgery
Following paediatric dental surgery under general anaesthesia, single-dose IV dexamethasone
0.3 mg/kg (max 8 mg) did not improve pain scores or oral intake but reduced postoperative
vomiting (McIntyre 2012 Level II, n=200, JS 5).
Strabismus surgery
The combination of single dose IV dexamethasone 0.15 mg/kg and intraoperative
superhydration (30 mL/kg/h until oral intake) vs single therapy reduced PONV, pain scores andparacetamol use with increased time to first analgesic request (Sayed 2016 Level II, n=120, JS 5).
Knee arthroscopy
In teenagers receiving femoral nerve block, neither adjuvant IM or perineural dexamethasone
further improved analgesia (Veneziano 2018 Level II, n=77, JS 5).
Adenotonsillectomy
Beneficial effects upon multiple outcomes are reported for single-dose dexamethasone inchildren 1 d following tonsillectomy (Steward 2011 Level I [Cochrane], 19 RCTs, n=1,756). Comparedto placebo, IV dexamethasone 0.15─1.0 mg/kg (max 8─25 mg) improved postoperative painscores (MD -1.1/10; 95%CI -1.7 to -0.4) (8 RCTs, n=652), reduced postoperative vomiting (RR 0.49;
95%CI 0.41 to 0.58) (15 RCTs, n=1,273) and resulted in an earlier return to soft diet (RR 1.45; 95%CI
1.15 to 1.83) (5 RCTs, n=452). A subanalysis to assess dose-dependent effect was not performed.
A subsequent systematic review of adult and paediatric RCTs includes RCTs with lower dosing to
0.05 mg/kg and PO and local infiltration routes (see below) (Titirungruang 2019 Level I, 64 RCTs [42paediatric], n=6,327) (16 RCT overlap). This meta-analysis has further comparisons of IV route withcomparator arms. There were consistent findings with IV administration preoperatively or attime of induction (in mostly paediatric RCTs, some including adults) reducing pain scores acrossfour time periods of <24 h (22 RCTs, n=1,868), 1 d (19 RCTs, n=1,520), 3 d (6 RCTs, n=346) and 7 d (5RCTs, n=266) and PONV (OR 0.24; 95%CI 0.18 to 0.33) (35 RCTs, n=3,415).
An RCT (excluded from the 2011 Cochrane review due to early termination) compareddexamethasone 0.05, 0.15 and 0.5 mg/kg (max 20 mg) and demonstrated a dose-dependent
effect for PONV (Czarnetzki 2008 Level II, n=215, JS 5). The reason for termination was a dosedependent increase in bleeding in dexamethasone-treated patients (above those ibuprofentreated) - see bleeding risk discussion below.
IV dexamethasone 0.5 mg/kg with IV ketamine 0.5 mg/kg reduced pain scores, analgesic
requirement and vomiting vs single agent therapy and placebo (Safavi 2012 Level II, n=120, JS 4).
IV dexamethasone 0.5 mg/kg (max 16 mg) was compared with infiltration with 2─4 mL LIA(2% lidocaine with 1:400, 000 adrenaline [6 mL], 0.5% bupivacaine [3 mL], 25 mcg fentanyl, 50
mcg clonidine). The LIA group had a lower incidence of PONV, pain on jaw opening andswallowing and reduced analgesic use POD 1─5 (Naja 2017 Level II, n=129, JS 5).
Following paediatric tonsillectomy, multiday PO prednisolone 0.25─0.5mg/kg (max 10-20mg/d) for 5─7 d did not reduce PONV, or pain at POD 3 or 7 (3 RCTs, n=441) (Titirungruang 2019
Level I, 3 RCTs [prednisolone], n=441).

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adjunctive PO prednisolone for 7d was inferior in pain relief, rescue analgesic use, PONV, sleep
and oral intake (Aveline 2015 Level III-3, n=1,231). Alternate day therapy with PO dexamethasone
in addition to ibuprofen and paracetamol reduced phone calls regarding pain and haemorrhage(Redmann 2018 Level III-3, n=1,200).
10.4.10.3 | Bleeding risk post-tonsillectomy
Five systematic reviews of dexamethasone have included the above early terminated RCT and havequalified the issue of bleeding (Titirungruang 2019 Level I, 64 RCTs [42 paediatric], n=6,327; Plante 2012
Level I, 29 RCTs [19 paediatric], n=2,674; Shargorodsky 2012 Level I, 12 RCTs [paediatric], n=1,180; Geva 2011
Level I, 14 RCTs [11 paediatric], n=1,429; Bellis 2014 Level III-1 SR, 15 RCTs, n=1,693 and 3 studies, n=2,088)(4 to 14 RCTs overlap). The included studies assess haemorrhage as primary or secondary, requiring

readmission, transfusion or reoperation and with 6 h to 14 d follow-up. The largest review of RCTs
reports an overall bleeding rate of 4.4% (Plante 2012 Level I, 29 RCTs [19 paediatric], n=2,674).
Dexamethasone does not increase the overall risk of bleeding post tonsillectomy (OR 0.96; 95%CI
0.66 to 1.40 for pooled adult and paediatric data, results comparable regardless of age). However,reoperation for bleeding is increased in children (OR 3.43; 95%CI 1.29 to 9.13) (8 RCTs, n=679), but
not in adults (4 RCTs, n=499). The most recent meta-analysis reports no increased odds for either
primary (15 RCTs, n=1,740) or secondary haemorrhage (23 RCTs, n=2, 440) (Titirungruang 2019 Level I, 64
RCTs [42 paediatric], n=6,327). A retrospective US paediatric cohort study found statistical, but
minimal clinical difference in revisits for bleeding in 30 d postoperatively in dexamethasone vs nondexamethasone treated (3.1 % vs 2.7, difference 0.4 %; 95% CI 0.13 to 0.67) with a small increaserisk seen across three age strata (Mahant 2014 Level III-2, n=139,715 [97,242 dexamethasone treated]). A
subsequent retrospective review with a prevalence of 2.8% secondary haemorrhage did not find arelationship of haemorrhage to dexamethasone (assessed with linear and quintile dose models)(Yiu 2017 Level IV, n=9,843). Older age (OR 1.08) and a primary haemorrhage (OR 2.89) werepredictors (See Section 10.4.2 Nonselective NSAIDs where age and chronic tonsillitis as theindication for surgery are predictors).
10.4.10.4 | Non-systemic corticosteroids
See Sections 10.6.2.6 for adjuvant use including infiltration, 10.6.5 for topical application and10.6.6 for comparator use in nerve blocks for tonsillectomy.

KEY MESSAGES
1. Single dose intravenous dexamethasone reduces pain post tonsillectomy, postoperative
vomiting and time to soft diet commencement in children (U) (Level I [Cochrane Review]).
2. Intavenous dexamethasone does not increase the overall risk of bleeding post
tonsillectomy but increases the risk of reoperation for bleeding in children (S) (Level I).
3. Oral dexamethasone (given in addition to antibiotics) shortens the time to onset of pain
relief in pharyngitis in children (U) (Level I).
4. Oral prednisolone multiday course post tonsillectomy does not reduce pain outcomes at
day 3 or day 7 or postoperative nausea and vomiting (N) (Level I).

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10.4.11 | Systemic lidocaine infusions
Systemic lidocaine infusions are used in the paediatric setting for patients experiencing severe
refractory pain. As per many analgesic interventions, this has been extrapolated from practice inadults (See Section 4.4.1.1). Paediatric hospital guidelines have been created based upon adultdosing (RCH 2017 GL)
In young children <6 y having laparoscopic inguinal hernia repair, intraoperative IV lidocaine
1.5mg/kg and 1 mg/kg/h (17 mcg/kg/min) reduced PACU pain scores vs placebo (Lee 2019 Level
II, n=66, JS 5).
In young children <6 y having abdominal surgery, IV lidocaine (initial 1.5mg/kg and infusion
1.5mg/kg/h (25mcg/kg/min) for <6 h) vs placebo reduced postoperative fentanyl requirement
on POD 1 and 2, time to return of bowel function 19 vs 23 h and hospital stay by 2 d (El-Deeb 2013
Level II, n=80, JS 5). Plasma concentrations at 0.5 and 4 h were ≈3 mcg/mL.
For various surgeries (including spinal fusion, Nuss surgery and nephrectomy) in older
children (median age 14 y), perioperative IV lidocaine infusion ≈0.86 mg/kg/h (14.4 mcg/kg/min)for 31  22 h has been used (Lemming 2019 Level IV, n=50). This case series did not provide detailof the patients’ multimodal analgesic therapy; adverse events were experienced by 22% of
patients (at various rates of 0.53−1.26 mg/kg/h (8.8−21 mcg/kg/min)), with discontinuation in
9% and dose reduction in 4%.
See also Sections 10.8.1, 10.9.3 and 10.9.5 where similar and higher dosing have been usedin paediatric cancer pain, migraine and sickle cell disease respectively.

KEY MESSAGES
1.

Perioperative intravenous lidocaine infusion in abdominal surgery in children improved
various pain and non-pain related postoperative outcomes (N) (Level II).

The following tick box represents conclusions based on clinical experience and expert
opinion: Dosing of perioperative lidocaine infusions have been extrapolated from use in
adults and pharmacokinetic study is warranted to determine safe dosing practices inchildren (N).

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10.5 | Opioid infusions and Patient Controlled Analgesia (PCA)
in children
This section incorporates the techniques of parenteral administration of opioids to children
via continuous infusion and patient controlled analgesia (PCA) devices, including a subsection
on nurse-controlled and parental proxy. As intermittent intramuscular (IM) injections are
distressing for children, parenteral administration via the intravenous (IV) route is preferred;
if peripheral perfusion is normal, the subcutaneous (SC) route can be used ( McNicol 1993
Level IV) with similar safety and efficacy to the IV route ( Doyle 1994a Level II, n=60, JS 3).
Procedure-specific dose recommendations and evidence for the use of these parenteral
techniques have been published (APAGBI 2012 GL). Large-scale audits (of >10,000 children)
provide data for serious clinical incidents and adverse effects associated with the use of theseparenteral opioid techniques (see individual subsections and Section 10.5.5 Overall safety atthe end of this section).

10.5.1 | Opioid infusions
10.5.1.1 | Pharmacokinetics of opioid infusions
Pharmacokinetic data has provided support for age-adjusted weight-based initial dosing
recommendations for morphine infusion for postoperative pain: 10 mcg/kg/h in neonates,
15 mcg/kg/h in toddlers and 25 mcg/kg/h in children >5 y (Taylor 2013 Level IV PK); 10–
40 mcg/kg/h are standard postoperative ward order parameters ( APAGBI 2012 GL). Titration andobservation of effect is the key as there is wide between subject variability with further impactof critical illness (Anderson 2014b NR PK). In ventilated children after cardiac surgery, PKs ofmorphine have been assessed (Valkenburg 2016 Level III-2 PK, n=38). Requirements were similar inchildren with and without Down’s syndrome: 32 mcg/kg/h guided by COMFORT B and observerNRS scoring. Body weight was the most predictive covariate; while Down’s syndrome was not.
10.5.1.2 | Efficacy of opioid infusions
Differences between intermittent bolus doses and continuous infusion of opioid relate more to
the total dose than to the administration method (Lynn 2000 Level III-2). Comparison in neonates
and young infants of the same total dose of morphine given via infusion (10 mcg/kg/h) or bolus(30 mcg/kg every 3 h) found no difference in pain scores (COMFORT and observer VAS)
(Bouwmeester 2003a Level II, n=68, JS 3; van Dijk 2002 Level II, n=181, JS 4) or stress response tosurgery (Bouwmeester 2001 Level II, n=204, JS 4). However, these doses were inadequate in children
aged 1–3 y, in whom additional bolus doses were required and the 3 h interval was less effective(possibly due to more rapid clearance) (van Dijk 2002 Level II, n=181, JS 4).
In ventilated postsurgical neonates, various morphine infusion regimens have been usedranging from 2.5–5 mcg/kg/h (Ceelie 2013 Level II, n=71, JS 5) to 10–30 mcg/kg/h (Olischar 2014
Level II, n=71, JS 5; Anand 2008 Level II, n=1,773, JS 5). Fentanyl has been increasingly used in PICUs;
seven centres varied widely in terms of initial opioid choice (fentanyl 64% vs morphine 36%) anddosing with peak infusion rates of 0.1─16 mcg/kg/h over a 14 d study period (converting
morphine rates to fentanyl equivalents using 1:80 dose ratio) ( Anand 2013b Level IV, n=419 [halfpostsurgical]). For control of acute procedural pain in ventilated neonates, continuous opioid
infusions have limited efficacy (Anand 2008 Level II, n=1,773, JS 5). Bolus opioid administration (eg

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977fentanyl) (Ancora 2013 Level II, n=131, JS 5) and other analgesic interventions are recommended(APAGBI 2012 GL) (see also Section 10.4.1).
Following ureteroneocystostomy, fentanyl loading of 1 mcg/kg and then infusion
0.17 mcg/kg/h was effective, although patients who received continuous ketorolac infusion
experienced less frequent bladder spasms (Jo 2011 Level II, n=52, JS 5).
10.5.1.3 | Adverse effects, complications and outcomes of opioid infusions
Major adverse events
A prospective multicentre audit has reported use of opioid infusions in children ( Morton 2010
Level IV, n=1,955 [infusions]). This audit reports only two cases of respiratory depression inassociation with continuous opioid infusion, one requiring naloxone. Sedation scores, oxygen
saturations and oxygen administration data were not collected. Programming or prescription
errors were the most common reported incidents with continuous opioid infusions ( n=9), noneof which led to patient harm (see also Section 10.5.2.3 for errors with PCAs).
Opioid infusions in neonates and later neurodevelopmental impact
The impact of the routine use of morphine infusion in ventilated neonates onneurodevelopmental and other outcomes has been studied and remains of concern ( Anand 2004
Level II, n=898, JS 4). A meta-analysis found no differences in mortality, duration of ventilation, or
improvements in short or long term neurological outcomes; but the analysed outcomes wereassessed by small, heterogeneous and usually single trials of low quality including 3 RCTs thatenrolled preterm and term neonates (Bellu 2008 Level I [Cochrane], 13 RCTs, n=1,505).
Detrimental effects of prolonged sedation and/or analgesia on preterm neonates have also
been a research focus (Anand 2004 Level II, n=898, JS 4; Anand 1999 Level II, n=67, JS 5). A 5 y followup of very preterm neonates found morphine and sedative exposure for >7 d was associatedwith poor neurodevelopmental outcome; this association was abolished once adjusted forgestational age and propensity scores (Roze 2008 Level III-2, n=1,572). A second author groupassessed long term outcomes of expreterm infants who were ventilated and participants in adual centre RCT comparing continuous morphine infusion 10 mg/kg/h for <7 d vs placebo (Simons
2003 Level II, n=150, JS 4). At 5 y follow-up, they suggested a negative association with morphine
use and the “visual analysis” intelligence quotient subtest, after adjusting for propensity scores(de Graaf 2011 Level II, n=90, JS 4). While at 8 y follow-up, no overall harm was found with positiveeffects of low-dose infusion 10 mcg/kg/h on higher executive function (WISC-III; de Graaf 2013
Level II, n=89, JS 4) and no adverse effects on thermal detection or pain thresholds (assessed withquantitative sensory testing (QST); vs 28 contemporary controls), chronic pain incidence oroverall neurological functioning (assessed by physical examination) (Valkenburg 2015 Level II, n=89
JS 4). At 2 y follow-up, expreterm toddlers, who as neonates were mechanically ventilated(mostly for lung indications) and received fentanyl infusion 1 mcg/kg/h (and boluses), had worse
hand eye coordination vs placebo infusion and fentanyl boluses (Ancora 2017 Level II, n=78, JS 5).
As studies vary in the degree and manner of correction for confounding factors, follow-up
at a later age focusing on higher-order neurocognitive function is necessary, ideally in alarger cohort.
Subacute opioid tolerance
Administration of parenteral opioids for as little as 5–7 d can produce opioid
tolerance/dependence. See Section 10.4.6 for discussion of opioid dependence, tolerance andwithdrawal in children, Section 10.4.7 for use of ketamine and 10.4.8 for use of alpha-2 agonists
for use in withdrawal, as well as the relevant adult Section 9.7.

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10.5.2 | Patient-controlled analgesia (PCA)
PCA can provide safe and effective analgesia for children aged as young as 5–6 y and compares
favourably with continuous morphine infusion (Morton 2010 Level IV n=5,605 [PCA] & 1,955[infusion]). PCA (and NCA) have been used for 2 decades in children (in 2016 at a single centre:
most commonly morphine 72%, hydromorphone 28% and rarely fentanyl 1% postoperatively)(Donado 2019 Level IV, n=32,338 [22 y]).
Patient selection is important and depends on the ability of the childand carers to understand the concepts of PCA and the availability of suitable equipment andtrained staff.
10.5.2.1 | Efficacy of PCA
Compared with continuous IV opioid infusions, opioid PCA provided greater dosing flexibility,
and similar analgesia. PCA has been associated with higher opioid consumption but the incidenceof adverse effects has varied, depending on the PCA dosing parameters ( Peters 1999 Level II, n=47,
JS 3; Bray 1996 Level III-2). PCA vs non-PCA techniques result in lower pain scores 9─10/100 over24─48 h, higher opioid consumption (7 mg ME) and pruritus, with similar incidence of otheradverse events (McNicol 2015 Level I [Cochrane], 49 RCTs [1 paediatric], n=3,412). The only paediatricstudy compared PCA bolus alone vs PCA bolus with background 15 mcg/kg/h for orthopaedic
surgery found equal efficacy but greater acceptability vs IM morphine (McNicol 2015 Level I[Cochrane], 1 RCT: Berde 1991 Level II, n=99, JS 3).
PCA can be particularly useful in children with altered opioid requirements. In children withsickle cell disease, postoperative PCA morphine requirements were almost double those ofnon-sickle children (Crawford 2006a Level III-3). Morphine PCA with bolus and background(mean rate 20 mcg/kg/h) has been used for paediatric sickle cell patients ( Jacob 2008 Level IV).
Opioid PCAs have been used by children with cancer including during their terminal phase andat home (Anghelescu 2015b Level IV, n=45 [69 PCAs]; Anghelescu 2015c Level IV, n=28 [44 PCAs];
Mherekumombe 2015 Level IV, n=33); see also sections 10.8.1.2 and 10.8.3.1 re pain managementin children with cancer.
Following scoliosis surgery, morphine and hydromorphone by PCA have been used ( McDonnell
2012 Level III-3; Ravish 2012 Level III-3; Milbrandt 2009 Level III-3; Matava 2014 Level IV). A high early
PCA demand ratio predicts higher pain scores, 24 h morphine consumption (Matava 2014 Level IV)
and the need to rotate to hydromorphone (McDonnell 2012 Level III-3). Intraoperative remifentanil
was associated with an increase in PCA morphine requirement in the 24 h post scoliosis surgery(Crawford 2006b Level II, n=30, JS 5), possibly due to acute opioid tolerance or opioid-induced
hyperalgesia.
Following pectus excavatum surgery, PCA morphine and hydromorphone have been
compared to epidural analgesia with minimal advantage of epidural analgesia with regard to painscores and no other differences (Stroud 2014 Level III-3 SR, 6 studies, n=403) (see also Section
10.6.2). PCA morphine with ketoprofen vs placebo has been trialled (Rugyte 2007 Level II, n=31,
JS 5) and morphine by PCA was similarly effective to morphine by continuous infusion ( Rugyte
2010 Level III-3). In addition to thoracic epidural infusion, paracetamol and ibuprofen, PCA (mostly
morphine; rotated to fentanyl in 7.4% of patients for side effects of PONV and pruritus) has beenused for a mean of 3 d with low POD 1 pain scores at rest (median 2 [IQR 2–3]) (Frawley 2016
Level IV, n=217).
Post tonsillectomy, PCA morphine 20 mcg/kg vs tramadol 0.2 mg/kg bolus were similarly
effective for 24 h (Ozalevli 2005 Level III-1).

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979For ureteroneocystostomy or pyeloplasty, PCA (and NCA) opioid has been compared withintrathecal (IT) morphine (mean dose 4.4 mcg/kg)  bupivacaine (Putnam 2015 Level III-2, n=128).
Overall pain scores were low; PCA/NCA patients required earlier and more systemic opioids withless pruritus and constipation. In the IT group, the technique failed in 7 patients and 2 patientsrequired naloxone, with one requiring ICU admission.
Post appendicectomy, PCA opioid was used for laparoscopic (49%) and open operations; pain
was improved by combination with diclofenac (Ousley 2016 Level IV, n=649 [552 PCA]).
Post neurosurgery in children aged 7─12 y, PCA fentanyl, morphine and tramadol wereeffective with similarly low pain scores and less ibuprofen and morphine rescue vs placebo PCA(Xing 2019 Level II, n=320 [195 PCA], JS 5).
Fentanyl is a useful alternative opioid via PCA, particularly for patients with renal impairment
or those experiencing morphine-related adverse effects (Tobias 1992a Level IV). Fentanyl PCA has
been used safely and effectively following neurosurgery (Chiaretti 2008 Level IV), pectus
excavatum surgery (Butkovic 2007 Level IV) and for acute cancer-related pain (Ruggiero 2007
Level IV) (see also Section 10.8).
Oxycodone PCA use in children is not reported to date; although paediatric centres
are including prescription recommendations in their pain management guidelines (CHW 2019 GL;
CHI 2019 GL).
As in adults, the use of pethidine should be discouraged in the paediatric setting (Benner
2011 NR). Pethidine does not have any advantage over other opioids and neurotoxicity from
norpethidine (normeperidine) accumulation has been reported in a healthy adolescent (Kussman
1998 CR) (see also Section 4.3.1.2).
See also Section 10.4.7.1 for the paediatric literature of ketamine addition to PCA opioid.
10.5.2.2 | PCA prescription
A survey of paediatric anaesthetists in the USA found significant variation in standard prescribing
practices for PCA (Nelson 2010 Level IV, n=294). Worldwide, morphine is the medicine used mostfrequently in paediatric PCA. A bolus dose of morphine 20 mcg/kg is a suitable starting dose
(APAGBI 2012 GL) and is associated with improved pain scores during movement vs 10 mcg/kg(Doyle 1994b Level II, n=40, JS 3).
The addition of a background infusion is more common in children than adults, tends to bereserved for more painful surgeries or conditions such as scoliosis and mucositis, and may betime limited postoperatively eg first 12–48 h or to night-time only. Morphine 0–4 mcg/kg/h isrecommended (APAGBI 2012 GL). Higher background rates are also prescribed (Nelson 2010
Level IV, n=294 [surveyed anaesthetists]). Although use of a background infusion was associated withincreased sleep disturbance in one audit (calculated from the number of hours PCA presses wererequired; OR 0.19), numbers were too small to fully investigate the contribution of the kind of
surgery (Kelly 2006 Level IV, n=126). Background infusions added to PCA of morphine 4─20
mcg/kg/h in children aged 5─20 y showed no difference in pain scores at 12 and 24 h after
surgery (5 RCTs, n=203), total opioid consumption (WMD 2.58; 95% CI −2.77 to 7.93) (7 RCTs, n=338)
and improved sleep duration (3 RCTs, n=165), with no difference in the number of night-timeawakenings (median of 3 per night in both bolus only vs bolus and background 20 mcg/kg/hgroups) (1 RCT, n=42) (Hayes 2016 Level I SR, 7 RCTs, n=338).
Morphine PCA 20 mcg/kg bolus with 5–20 mcg/kg/h background infusion has been used forchildren >7 y having laparoscopic appendectomy (Liu 2013 Level IV).
Surveyed anaesthetists reported fentanyl bolus prescriptions of 0.2–0.4 mcg/kg andhydromorphone of 1–3 mcg/kg (with similar background infusion rates) (Nelson 2010 Level IV, n=294).

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Hydromorphone was dosed in a paediatric series as IV PCA 3 mcg/kg boluses and had similar
efficacy and adverse effect profile to morphine 15 mcg/kg boluses (Karl 2012 Level III-1). IV
Hydromorphone PCA 2 mcg/kg bolus with 2 mcg/kg/h background has been compared with
PCEA bupivacaine/hydromorphone in scoliosis surgery (Gauger 2009 Level II, n=38, JS 3).
10.5.2.3 | Adverse effects, complications and outcomes of PCA
Recognition of potential complications of PCA use was enhanced by providing set instructions
for monitoring and by APS support (Wrona 2007 Level III-2). Audit and administrative analysis has
provided outcome data for this specialised technique (outlined below and also see Section
10.5.5).
PCA preparation, programming errors and device problems
Some adult hospitals have moved to pre-prepared syringe purchase for infusion and PCA
administration. While in paediatric centres, clinical staff generally remain responsible forpreparation of weight-based dosing in fixed syringe sizes, where 1─2 mL is then the standard
bolus size. An evaluation of syringe preparation in a single centre revealed excess syringe
volumes and deviations from stated label strength: usually in excess, with 21% of deviations>20% (Rashed 2016 Level IV, n=153 [syringe preparations]).
Programming error data (from a referenced tertiary adult centre report) has highlighted thecontribution of human factors such as nursing task interruption (Ocay 2018 NR). Errors occurred
infrequently: human programming 0.74% and device related 0.19%. Pump misprogramming hadserious consequences such as respiratory depression, over sedation or poorly treated pain. The
above Canadian paediatric centre has moved to staged implementation of standardisedmorphine PCA (and NCA) concentrations based on weights of 3 mg (≤3.9 kg), 10 mg (4 to 19.9 kg)
and 50 mg (≥20─25 kg) in 50 mL and found this has eliminated preparation errors and reduced
setup time (preparation and pump programming) and changed the PCA incidents from confusion
with or wrong dose to expiry date issues (Rashed 2019 Level III-2, n=175 syringes [157 children]).
Impact of background infusion addition to PCA in children
A meta-analysis reports that the addition of a background infusion increases the odds forrespiratory depression in adults (see Section 6.4.3), but not in children (George 2010 Level I, 14
RCTS, n=796 [3 paediatric, n=122]). A subsequent meta-analysis of low quality RCTs of mostly
children (5─20 y) comparing PCA alone vs PCA with background infusion showed no differencein adverse effects of PONV (18.8% vs 27.6: RR 1.2; 95% CI 0.8 to 1.8) (5 RCTs, n=239) or sedation(0 vs 8.5%: RR 3.5; 95% CI 0.4 to 29.3) (2 RCTs, n=81) (Hayes 2016 Level I, 7 RCTs, n=338) (3 RCT
overlap).
Major adverse events
A large UK audit has included prospective data for PCA (Morton 2010 Level IV, n=5,605 [PCA]). No
incident of permanent harm occurred, with a very low incidence (approximately 1 in 500) of“harm with full recovery”, including respiratory depression requiring naloxone (n=1), urinary
retention (n=4), nausea/vomiting (n=5) and itch (n=3). Sedation scores were not collected. These
adverse effects were defined by “requiring cessation of or change in technique”, which explains
why rates were lower than reported in case-control series and RCTs. Seven programming andprescribing errors that did not lead to harm were also reported.
Administrative data analysis of morphine recipients for non-surgical and surgical indicationsin 42 USA hospitals demonstrated a low incidence of interventions for PCA patients ( Faerber 2017
Level III-2, n=62,959 [PCA]); see below for detail of matched comparison with IV morphine recipients).

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Nausea and vomiting
Nausea and vomiting occurs in 30–45% of children using morphine PCA and can be reduced byprophylactic antiemetics (Carr 2009 GL). Adding antiemetics directly to PCA solutions for children
was not effective (Munro 2002 Level II, n=60, JS 5).
Pruritus
Addition of a low-dose naloxone infusion 0.25 mcg/kg/h did not impair analgesia but decreased
pruritus and nausea in postoperative children treated with PCA (Maxwell 2005 Level II, n=46, JS 5).
Naloxone 1 mcg/kg/h more effectively decreased pruritus than 0.25 mcg/kg/h in children requiringmorphine infusions during a sickle cell crisis (Koch 2008 Level IV). The suggested optimal dose of IV
naloxone by continuous infusion (determined by up titration from 0.05 to 1.65 mcg/kg/h) is≈1 mcg/kg/h (Monitto 2011 Level IV, n=59). Addition of naloxone to morphine PCA with backgroundinfusion (ratio 12 mcg: 1 mg) did not reduce pruritus incidence vs morphine PCA alone (22% vs 36:
difference -15%; 95% CI -33 to 4) (West 2015 Level II, n=92, JS 5).
Escalation of PCA use as a sign of compartment syndrome
Compartment syndrome in children occurs infrequently (1.3–3%), usually diagnosed at a meanof 19 h (range 1.5–65 h) post fracture or surgery of the limb (Ferlic 2012 Level IV, n=1,028). Pain as
one of the “5 P hallmarks” can be further qualified as pain escalation at rest as well as with
passive movement, unrelieved by plaster splitting and with increased analgesic request.
Escalation in PCA demands may occur, as reported in two paediatric patients (Yang 2010 Level IV).
See also later discussion regarding compartment sydrome and regional use in children 10.6.1.3.

10.5.3 | Nurse-controlled analgesia
In younger children and infants, “PCA” devices have been used by nurses to administerintermittent bolus doses (with or without a background infusion), a technique termed “nursecontrolled analgesia” (NCA). This technique may increase ease of administration particularly
prior to movement or procedural interventions, increase dose flexibility and improve parent andnurse satisfaction. Dose recommendations for morphine are generally 5–40 mcg/kg/h with
10–20 mcg/kg nurse-initiated boluses (Howard 2010 Level IV, n=10,000). NCA has also been used inolder children in intensive care who are unable to activate a conventional PCA device.
10.5.3.1 | Efficacy of NCA
Adequate analgesia comparable to PCA was reported but efficacy was dependent on accurate
nurse assessment of pain (Weldon 1993 Level III-2). The technique has been used in open vslaparoscopic Nissen fundoplication surgery (McHoney 2011 Level II, n=39, JS 5) and for fast-track
cardiac surgical patients (Iodice 2011 Level IV). In intubated patients post cardiac surgery,tramadol NCA in comparison to morphine NCA provided minor improvements in time to
extubation (Chu 2006 Level II, n=40, JS 4). In intubated children post cardiac surgery, fentanyl NCA
and remifentanil NCA (both with background) achieved similar pain and sedation scores, withless side effects but greater bolus requirement in the remifentanil treated ( Xiang 2014 Level III-1,n=60). Post neurosurgery, NCA fentanyl, morphine and tramadol were effective with similarly low
pain scores and less ibuprofen and morphine rescue required vs placebo NCA in children aged
1─6 y (Xing 2019 Level II, n=320 [192 NCA], JS 5).
In young children (<2 y) post ureteroneocystostomy, fentanyl NCA with paracetamol (orplacebo) has been used (Hong 2010 Level II, n=63, JS 5).

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10.5.3.2 | Adverse effects, complications and outcomes of NCA
Major adverse events
The incidence of adverse effects was similar in children self-administering conventional PCA andthose receiving NCA (Voepel-Lewis 2008 Level III-2, n=302; Morton 2010 Level IV, n=3,706 [NCA]).
Rescue events (requiring naloxone, airway management or admission to high dependency/ICU)
were more common in the NCA (and parental proxy) group but this group was also younger andhad a higher prevalence of comorbidities (Voepel-Lewis 2008 Level III-2). Cognitive impairment
and high opioid dose requirements on d 1 were associated with increased adverse effects. Twolarge prospective audits in institutions with APS oversight affirm NCA use (mostly morphine) as
safe and effective for postoperative analgesia in children ( Howard 2010 Level IV, n=10,000; Morton
2010 Level IV, n=3,706 [NCA]). The multicentre 2007–2008 UK audit reports one incident of harm
overall, which was with the NCA technique (cardiac arrest in a 2.5 kg neonate), andeleven respiratory depression events (0.3%) with “harm but full recovery”, six requiring
naloxone (Morton 2010 Level IV, n=3,706 [NCA]). The single centre 1996–2008 audit reports nodeaths but a similar rate of 0.4% for serious potentially life-threatening events of oversedation
or respiratory depression requiring active resuscitation and naloxone (Howard 2010 Level IV,
n=10,000). This audit provided rates for respiratory depression and sedation at 4.5% (with 91%
improving with temporary cessation or adjustment of technique), PONV 25% (severe for 14%)and pruritus 9.4% (severe for 4%). The incidences varied with age, morphine dose and type of
surgery. Notably both audits report higher incidences of serious adverse effects with NCA inneonates than children aged >1 mth: 0.8% vs 0.4 (Morton 2010 Level IV, n=3,706 [NCA]) and 2.5%
vs 0.27% (Howard 2010 Level IV, n=10,000).

10.5.4 | PCA by proxy
Administration by a nurse trained in pain assessment, rather than parents, is recommended inmost centres (Howard 2010 Level IV, n=10,000). Confusingly the term “PCA by proxy” has been used
to describe administration by both nurses and/or parents. The Joint Commission on
Accreditation of Healthcare Organisations issued a sentinel alert cautioning against the practiceof parental proxy in 2004. In response, some US centres ceased using parental proxy technique(reported by 11% of surveyed anaesthetists) (Nelson 2010 Level IV, n=294). However, many centres
continue this practice and, as for the conventional PCA technique, selection criteria, educationand guidelines should be followed (Chidambaran 2012 NR). In a prospective series of PCA by proxy(parents or health care providers), effective analgesia was achieved in 81–95% of children <6 yof age; 25% required supplemental oxygen and 4% required naloxone for respiratory depression(Monitto 2000 Level IV). In a retrospective series, PCA by proxy resulted in low pain scores, whilesomnolence or respiratory depression requiring naloxone occurred in 2.8% of children with
developmental delay (Czarnecki 2008 Level IV) and 1.9% of infants and preschoolers (Czarnecki 2011
Level IV). PCA by proxy vs conventional PCA in children with cancer pain was associated withcomparable (Anghelescu 2005 Level III-3) and lower complication rates in a follow-on series(Anghelescu 2012 Level IV). In children with developmental delay, no differences in outcomes wereseen when comparing postoperative use of parental/nurse controlled analgesia vs nurse
administered IV opioids (Czarnecki 2018 Level II, n=81, JS 2).
Comparison of morphine and hydromorphone via PCA, NCA and PCA by proxy (70% with abackground infusion) has been described (Voepel-Lewis 2008 Level III-3, n=302). Fentanyl PCA wasadministered by parental proxy (initial settings 0.075 mcg/kg bolus and background
0.3 mcg/kg/h) for toddlers for 48 h post cleft palate repair to establish an ED 50–95 of 0.63–
0.83 mcg/kg/h (Choi 2008 Level IV).
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10.5.5 | Overall safety of parenteral opioid use in children
Overall, parenteral opioid techniques are safe in children as long as administered in appropriate
settings. Of surveyed paediatric anaesthetists (representing 252 USA institutions with 51%
having APS oversight), 8 recalled deaths (in the preceding 5 y) in association with thesetechniques and 42 recalled cardiorespiratory events requiring naloxone (in the year prior;denominator unknown) (Nelson 2010 Level IV, n=294). The incidence rates of respiratory
depression in the various paediatric studies will vary depending upon how it is defined; degreeof desaturation, requirement for supplemental oxygen, suspension/cessation of opioids,
requirement for naloxone or respiratory intervention including ventilation. The studies done todate are generally underpowered to detect differences in the incidence of respiratory
depression. The large UK prospective audit of parenteral opioids delivered by the above
techniques reports an overall 1 in 10,000 incidence of serious harm and 0.13% incidence of
respiratory depression (requiring intervention with respiratory support, naloxone or opioid
cessation) (Morton 2010 Level IV, n=10,726). Importantly, these low rates occurred in UK centreswith 100% oversight by a paediatric APS and with institutional guidelines in place. Safety can be
improved through avoidance of concurrent sedatives or opioids by other routes, awareness ofcomorbidities posing extra risk and by careful dosing, with heightened monitoring in infants.
Opioid prescription and pump programming errors were an issue (1 in 631 infusions or 0.16%)
and can be minimised through adherence to guidelines and careful cross-checking (Morton 2010
Level IV, n=10,726).
Administrative data assessment from 42 USA hospitals revealed morphine by PCA vsmorphine by IV route was not associated with an increased risk of requirement for CPR or
mechanical ventilation (Faerber 2017 Level III-2, n=108,956 [PCA surgical n=11,220 & PCA non-surgicaln=6,030; each matched with an IV morphine group]); in the matched cohorts on day 1 of IV morphineuse, CPR events occurred in 0.89% of non-surgical and 0.45% of surgical patients. PCA exposure
had lower risk of requiring CPR in surgical (OR 0.56; 95%CI 0.45 to 0.70) and non-surgicalrecipients (OR 0.80; 95%CI 0.76 to 0.85).
A single institution reported use of PCA and NCA over 14 y as associated with 146 errors (1%),
of which two resulted in severe and preventable adverse events (Donado 2019 Level IV, n=16,806[PCA or NCA administrations with error reporting]).

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1. Addition of a low-dose background infusion to patient controlled analgesia (PCA) bolus
results in similar pain scores and total opioid consumption and improves sleep duration inchildren; numbers are inadequate to assess safety of adding a background (N) (Level I).
2. In ventilated preterm neonates, routine use of morphine infusions does not affectmortality, duration of ventilation or neurological outcomes (U) (Level I [Cochrane
Review]), including when followed up as older children (S) (Level II).
3. Postoperative intravenous opioid requirements vary with age in neonates, infants andchildren (U) (Level II).
4. Intermittent intramuscular injections are distressing for children and are less effective
for pain control than intravenous infusions (U) (Level III-1).
5. Patient-controlled analgesia (PCA) can provide safe and effective analgesia for children
as young as 5 years old (S) (Level III-3).
6. Intravenous opioids via continuous infusion, nurse-controlled analgesia and parental
proxy use of patient controlled analgesia (PCA) devices can be used effectively (U)(Level III-2) and safely (N) (Level IV) in children of all ages.
7. Nurse-controlled analgesia (U) (Level III-2) and parental proxy use of patient controlled
analgesia (PCA) devices in children (U) (Level III-3) may require more rescue
interventions (such as naloxone, airway management or intensive care) than PCA, but
this may reflect the younger patient population where this technique is offered.
8. Morphine by patient controlled analgesia (PCA) is at least as safe as intermittent nurse
administered intravenous morphine (N) (Level IV).
The following tick boxes represent conclusions based on clinical experience and expert opinion:
 Initial doses of opioid should be based on the age, weight and clinical status of the childand then titrated against the individual’s response (U).
 Effective patient controlled analgesia (PCA) prescription in children incorporates abolus that is adequate for control of movement-related pain (U).

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10.6 | Paediatric Regional Analgesia
Paediatric regional analgesia (PRA) incorporates peripheral nerve or neuraxial blocks andcatheter techniques. The efficacy of various PRA techniques for common paediatric surgicalconditions is described below. Differences between groups in RCTs can be difficult to detect withsmall sample sizes or when outcome measures are relatively insensitive (eg supplemental
analgesic requirements following procedures with low ongoing pain). This and the heterogeneityof studies and outcomes leads to systematic reviews with conclusions based often on single RCTs
(eg Kendall 2018 Level I [PRISMA], 40 RCTs, n=2,408). Previous prospective multicentre French and
UK audits (Ecoffey 2010 Level IV, n=29,870 PRA with GA & 1,262 PRA alone; Llewellyn 2007 Level IV,
n=10,633 [epidural]) and retrospective single centre Italian audit (Vicchio 2015 Level IV, n=18,279
PNBs) have been superseded by larger scale population safety data provided by the USA’s
Paediatric Regional Anaesthesia Network (PRAN) with more than 20 children’s hospitals
participating (Walker 2018 Level IV, n=104,393 blocks in 91,701 children). Data collection andpublication by PRAN is ongoing and informs our practices and information we can provide tofamilies during the consent process.
PRA safety under general anaesthesia, practice advisory and adjuvant use
PRA is typically performed in children under general anaesthesia. The safety of this has been
demonstrated in the PRAN audits and is comparable to placing blocks in awake adults ( Walker
2018 Level IV, n=104,393 [97,825 under GA]; Walker 2018 Level IV, n=2,017; Suresh 2018a Level IV,
n=40,121).

The European Society of Regional Anaesthesia and Pain Therapy (ESRA) and The American
Society of Regional Anaesthesia and Pain Medicine (ASRA) joint committee practice advisorygroup has published recommendations (Ivani 2015 GL):
1. Support for the performance of regional nerve blocks under deep sedation or GA;
2. Discretionary use of an adrenaline (epinephrine) containing test dose (as false negatives
occur);
3. Detection of epidural space with loss of resistance to either air or normal saline (or both)in small volumes;
4. Regional anaesthesia does not obscure or delay diagnosis of compartment syndrome.
This practice advisory has since been reaffirmed with dosing recommendations for neuraxial
blocks (Lonnqvist 2017 GL).
The addition of adjuvant medications to local anaesthetic agent can improve block qualityand duration (Forestier 2017 NR). Adjuvant agent addition to the regional or peripheral nerve
injectate should demonstrate a viable local mechanism of action beyond systemic
administration, be safe, tolerable and non-toxic via this route. See later sections 10.6.2.6 and10.6.3.3.

10.6.1 | Peripheral nerve blocks and catheters10.6.1.1 | Single injection peripheral nerve blocks (PNBs)
Single injection peripheral nerve blocks (PNBs) are effective and safe adjuncts for the
management of procedural, perioperative and injury related acute pain (PNBs: Walker 2018
Level IV, n=45,324; Ecoffey 2010 Level IV, n=20,576; Giaufre 1996 Level IV, n=4,090) (See also Section
5.8). The use of US-guidance for PNBs in children has grown significantly over the last decade,including in the ambulatory setting (Walker 2018 Level IV, n=45,324; : Suresh 2018a Level IV, n=40,121;986

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Kendall 2018 Level I [PRISMA], 40 RCTs, n=2,408; 1 RCT overlap with Lam 2016 Level IV SR [PRISMA], 23
studies [PNBs: including 10 RCTs], n=1,280). PRAN data have shown increase in the proportion of PNB
relative to neuraxial blocks: from 43.4 to 52.5% (Walker 2018 Level IV, n=86,328 [single injection];
Polaner 2012 Level IV, n=10,622).

Dosing
PRAN audit reveals PNB dosing practices vary 5−10 fold with volumes of 0.16 to 2.4 mL/kg anddoses of bupivacaine (means 0.5−1.25 mg/kg) or ropivacaine (means 0.42−1.42 mg/kg) (where
the upper 95%CI limit is less than the per kg max dose recommendations) ( Suresh 2018a Level IV,
n=40,121).
10.6.1.2 | Continuous peripheral nerve catheters
Continuous peripheral nerve catheters (CPNCs) for continuous local anaesthetic infusion havebeen used in all age groups (CPNCs: Walker 2018 Level IV, n=4,945; Walker 2015a Level IV, n=2,074;
Ecoffey 2010 Level IV, n=1,098). Within the PRAN dataset, the numbers of CPNCs inserted increased
gradually, and since 2012 have been stable relative to the more commonly inserted neuraxial
catheters (Walker 2018 Level IV, n=4,945 [CPNCs] vs 13,120 [neuraxial]). The majority of CPNCs wereinserted in older children >10 y; with ultrasound for the majority of catheter placements ( Walker
2015a Level IV, n=2,074).
Efficacy in hospital and post discharge
Case series report CPNC use in hospital and on discharge as an ambulatory option withelastomeric pumps (discharged home on POD 0─3 (Walker 2015a Level IV, n=2,074 [n discharged
unspecified]; Gurnaney 2014 Level IV, n=1,954 CPNCs in 1,700 patients [1,285 discharged]; Visoiu 2014b
Level IV, n=410 CPNCs in 403 patients [all discharged]; Ganesh 2007 Level IV, n=226 CNPCs in 217 patients[108 discharged]). High efficacy (as an adjuvant to oral analgesia including opioids) has beenreported in the above case series (balanced with low complication and failure rates per below).
Success rates were 93 to 98% when assessed by numerical rating (NRS) of pain control
satisfaction (parent, patient and nurse), pain scores in PACU vs at home and analgesic
consumption (Visoiu 2014b Level IV, n=403 [discharged]; Gurnaney 2014 Level IV, n=1,285 [discharged];
Visoiu 2014a Level IV, n=5 [paravertebral]). In PACU, 37% of patients with CPNCs in situ required no
opioid (Visoiu 2014b Level IV, n=403). Most patients required opioid at home: ≥1 dose for 96%(Visoiu 2014b Level IV, n=403), as needed by 64% vs regularly by 15% or 8% as needed which thenmoved to regular (Gurnaney 2014 Level IV, n=1,285).
CPNC dosing
Usual reported CPNC dosing were of plain ropivacaine 0.1−0.2% or bupivacaine 0.1−0.125% at
rates of 2−10 mL/h for 2 to 10 d ( Walker 2015a Level IV, n=2,074; Gurnaney 2014 Level IV, n=1,954[CPNCs]; Visoiu 2014b Level IV, n=410 [CPNCs]; Ganesh 2007 Level IV, n=226 [CPNCs]). The joint
practice advisory committees recommend CPNC local anaesthetic dosing based upon theabove audit data practices (with no PK-PD study) for peripheral nerve and fascial planes of
0.1−0.3 mg/kg/h for racemic bupivacaine, levobupivacaine or ropivacaine ( ESRA-Suresh 2018a
GL; ASRA-Lonnqvist 2017 GL). Lower dosing is suggested for neonates and younger children (withtheir differing PK profiles to ≈6 y) reflecting greater risk for local anaes thetic systemic toxicity(LAST) with higher free non protein-bound drug fractions and immature CYP3A4/7 enzyme
systems (Suresh 2018a GL; Johr 2015 NR). Some children have received higher thanrecommended local anaesthetic dosing without adverse events ( Walker 2015a Level IV, n=2,074;
Moriceau 2015 CR).

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10.6.1.3 | Safety and complications of PNBs and CPNCs
SafetySafety of PNB (PNBs: Walker 2018 Level IV, n=45,324; Ecoffey 2010 Level IV, n=20,576; Giaufre 1996
Level IV, n=4,090) are described below and in Section 10.6.2.4 under the individual block headings.
In the largest series, a low overall failure rate for PRA (PNB, CPNC and neuraxial single
injection and catheters) of 1% was reported (Walker 2018 Level IV, n=104,393). For two PNBs
(1 penile and 1 superficial cervical plexus block) broken needles required surgical retrieval and
one wrong-sided femoral PNB was performed (Walker 2018 Level IV, n=45,324). One wrong-sided
block has been reported in an Australian paediatric centre’s series (Drake-Brockman 2016 Level IV,
n=148 [PNBs]). Adoption of the ‘Stop Before You Block’ checklist ( Clebone 2017 GL; ANZCA 2015) asan anaesthesia time out (pre or post-induction of GA but preblock, ie before surgical time out)practice in paediatric centres world-wide is unknown. Some paediatric institutions havedeveloped additional local procedures to reduce this error (eg scrub nurses hand theanaesthetist the block needle after the anaesthesia time out) with focus on correct patient
identification, site marking, patient weight and safe drug dosing.
Safety of CPNC use has been confirmed by retrospective (CPNCs: Gurnaney 2014 Level IV,
n=1,954; Visoiu 2014b Level IV, n=410; Dadure 2009 Level IV, n=339; Ganesh 2007 Level IV, n=226 CNPCs)
and subsequent prospective PRAN audits (Walker 2015a Level IV, n=2,074 case overlap with Walker
2018 Level IV, n=4,945) and is described further below.
Complications related to CPNC technique
Primary failure rates of CPNC insertion were reported in the earlier audits (generally ≤2%; higher
for upper limb 7.6%).
Recognised vascular puncture rates vary between 2−3% (CPNCs: Gurnaney 2014 Level IV,
n=1,954; Dadure 2009 Level IV, n=339; Ganesh 2007 Level IV, n=226 CNPCs) and lower in prospective
data of 0.9% (95%CI 0.5 to 1.4) (Walker 2015a Level IV, n=2,074).
The most common adverse event for CPNC in all series were secondary failures of thecatheter (dislodgement, occlusion or disconnection) or of the delivery system.
In the PRAN audit, the secondary failure rate was 1.3% (95%CI 0.8 to 1.7); while catheters
were removed because of various complications on POD 0 to 2 in 6.1% patients; overall 7.3%
(95%CI 6.2 to 8.5) (Walker 2015a Level IV, n=2,074).This was independent of insertion while underGA, sedated vs when awake, insertion site or patient age. An earlier series reported similar rates
of secondary failure (1.9%) and excessive catheter leak in 1% ( Gurnaney 2014 Level IV, n=1,492
CPNCs). Another series reported catheter problems (6.9%) including elastomeric pump delivery
failure and leak (Visoiu 2014b Level IV, n=410).
Post discharge, CPNC related problems at home include motor block and difficult removal.
The families received education in catheter clamping in the event of adverse effects. With low
concentration and low infusion rates (see above), reported rates of motor block were 10%(Ganesh 2007 Level IV) to 20% (Dadure 2009 Level IV), resolving within 3 h of catheter clamping(Gurnaney 2014 Level IV, n=1,492). Most series reported difficult removal in a few patients only
(Walker 2015a Level IV, n=2,074 [2 difficult─1 attended ED]; Gurnaney 2014 Level IV, n=1,492 [2 difficult];
Visoiu 2014b Level IV, n=410 [1 difficult, 2 refusals by the patient]).
Anticoagulation and PNB/ CPNCs
Children rarely receive thromboprophylaxis after major surgery. There is no paediatric literature
pertaining to anticoagulation and PNBs; practice for paediatric patients receiving anticoagulants
generally follows adult recommendations. See discussion in adult Section 5.9.2 (and specific to
epidural haematoma and epidural catheters in adults in 5.9.1 and in children in 10.6.3.5).

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Local cutaneous infections related to CPNC use was lower (26/10,000; 95%CI 15 to 45) than withneuraxial catheters (60/10, 000; 95%CI 48 to 75) independent of insertion site ( Walker 2018
Level IV, n=4,945 [CPNCs] vs 13,120 [neuraxial]). An earlier overlapping series of CPNCs documented
superficial infection incidence of 0.9% (95%CI 0.5 to 1.4) associated with longer CPNC duration
4.5 d (range 3 to 7) vs 3 (1 to 3); 3 further catheters were removed in patients with fever only
(and no superficial infection) and no deep infections, abscesses or sepsis events were
documented (Walker 2015a Level IV, n=2,074). Retrospective studies report site infection requiring
antibiotics of ≤0.5−0.9% (Gurnaney 2014 Level IV, n=1,954; Dadure 2009 Level IV, n=339; Ganesh 2007
Level IV, n=226 CNPCs).
Local Anaesthetic Systemic Toxicity (LAST) with PNBs/CPNCs
The incidence of Local Anaesthetic Systemic toxicity (LAST) with PNBs has not changed over time
(OR 1.08; 95%CI 0.21 to 5.43) (Walker 2018 Level IV, n=45,324 PNBs). One severe LAST event(seizure) occurred in a teenager who received an infraclavicular PNB and was treated with lipid
emulsion with seizure resolution. While in a femoral fracture ED series of fascia iliaca
compartment blocks (FICNB) landmark technique with ropivacaine 0.5% 0.5─0.75 mL/kg (max 30 mL),
two patients had a seizure, one treated with intralipid and one (with known subarachnoid
haemorrhage) with benzodiazepine (Neubrand 2014 Level IV, n=158 [FICNB]).
With CPNCs, LAST incidence in the earlier series was ≤0.3/10,000 (Gurnaney 2014 Level IV,
n=1,954; Dadure 2009 Level IV, n=339; Ganesh 2007 Level IV, n=226 CNPCs) and 4/10,000 (95% CI 0.6
to 30) (Vecchione 2016 Level IV, n=625 CPNC [468 patients]). Early symptoms of LAST (ringing in theears or metallic taste) occurred in 0.5/10,000 ( Suresh 2018a Level IV, n=40,121 PNBs; Visoiu 2014b
Level IV, n=410 CPNCs) and 0.2/10,000 which resolved with clamping and CPNC removal (Gurnaney
2014 Level IV, n=1,492 children). One infant had LAST with a self-resolving seizure related
to paravertebral CPNC and chloroprocaine bolus: 0.8/10,000 (95%CI 0 to 4.8) (Walker 2018
Level IV, n=2,074).
Postoperative Neurological Symptoms (PONS) and PNBs/CPNCs
Prospective audit reports the incidence of neurological complication with PNBs has decreased
over time (OR 0.60; 95%CI 0.38 to 0.90) (Walker 2018 Level IV, n=45,324). No permanentneurological deficits (95%CI 0 to 0.4/10,000) and low risk of transient neurologic deficit of
2.4/10,000 (95%CI 1.6 to 3.6) were reported (Walker 2018 Level IV, n=104,393 blocks in 91,701
children). There was no difference in neurologic complication rate when comparing peripheral vsneuraxial blocks, CPNCs vs single injection (OR 0.63; 95%CI 0.21 to 2.74) or local anaesthetic type(bupivacaine vs ropivacaine).
Case reports have described prolonged neurological deficit (Drake-Brockman 2016 Level IV,
n=148 PNBs) and permanent injury (Walker 2018 NR; Ivani 2015 GL).
Acute compartment syndrome and PNB or CPNC
Acute compartment syndrome (ACS) associated with PNBs/CPNBs was not specifically reported
in the PRAN audit. There are reports where PNBs have masked ACS in adults with others where
PNB/CPNC did not, including three adolescents (Klucka 2017 Level IV [PRISMA], 15 studies, n=20; Ivani
2015 GL; Munk-Andersen 2013 CR; Walker 2012a CR; Cometa 2011 CR). This highlights the need for
frequent clinical monitoring and early review following high-risk injury or surgery (eg diaphysisof long bones, particularly tibia, and comminuted fracture) in the event of breakthrough pain
(particularly where analgesia including PRA has been previously effective).
In those deemed at risk, the Joint ASRA-ESRA Practice Advisory has suggested limiting the
drug dosing regimens to low concentrations/low volumes and avoiding adjuvants in PNBs,
neuraxial blocks and CPNCs (Lonnqvist 2017 GL).
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10.6.1.4 | Ultrasound guidance impact on safety and success of PNBS and CPNCs
PRAN has documented high use of ultrasound (US) guidance for CPNC placement: 78─90%(Walker 2015a Level IV, n=2,074) and increased use for PNB placement from ≈30% in 2007 to ≈90%
in 2015, with concomitant decrease in peripheral nerve stimulator use as sole assisting device(Walker 2018 Level IV, n=45,324 [PNBs]; Suresh 2018a Level IV, n=40,121). The joint committee practiceadvisory groups suggest lower dosing is required when using US-guidance (Suresh 2018b GL;
Lonnqvist 2017 GL). Although neurologic complications with PRA have decreased over time, USguidance has not impacted this: with 0/10,000 (95%CI 0 to 4.2) events with US use overlappingwith 3.6/10,000 (95%CI 2.1 to 6.0) without US (Walker 2018 Level IV, n=45,324 [PNBs]). Neither has
US use affected LAST incidence (95%CI −1.6 to 1.0/10,000), despite use being associated with
documented smaller local anaesthetic volumes.
A systematic review has summarised several heterogeneous RCTs without meta-analysis
showing similar or greater success rates vs nerve stimulation (1 RCT [axillary], n=40; 1 RCT[infraclavicular], n=50; 1 RCT [femoral], n=60) and landmark technique (2 RCTs [penile block], n=106),with variable effects on speed of block performance (vs landmark: faster (1 RCT [axillary], n=40) andslower (1 RCT [penile], n=40) and postoperative outcomes including pain scores and opioid
requirements (equivocal for transversus abdominus plane block (1 RCT [lap. appendicectomy], n=30) andrectus sheath block (1 RCT [umbilical hernia], n=52) vs positive vs wound infiltration for
ilioinguinal/iliohypogastric nerve block (2 RCTs [inguinal hernia], n=109)) (Lam 2016 Level IV SR [PRISMA],
23 studies [peripheral: including 10 RCTs], n=1,280). The earlier review by the same authors
summarised two earlier RCTs with similar findings: where US-guided ilioinguinal/iliohypogastric
block reduced the local anaesthetic dose given and PACU rescue paracetamol requirements vslandmark technique (Tsui 2010 Level IV SR [PRISMA], 1 RCT: Willschke 2005 Level II n=100 JS 3) andreduced block onset time for infraclavicular block vs nerve stimulator use ( Tsui 2010 Level IV SR[PRISMA], 1 RCT: Marhofer 2004 Level II, n=40, JS 3).
See sections 10.6.2.1 and 10.6.2.2 for discussion of US use in caudal and epidural insertion
respectively.

10.6.2 | Specific peripheral nerve blocks and catheters10.6.2.1 | Lower limb blocks in children
Lumbar plexus (or psoas compartment) block
For lower limb/hip surgery, lumbar plexus (or psoas compartment) single injection block (Gurkan
2017 Level IV, n=75; Walker 2011 Level IV, n=305) or CPNC (Walker 2018 Level IV, n=274 PNBs & 722
CPNCs) may be useful alternatives to neuraxial techniques (Omar 2011 Level II, n=40, JS 3; Villalobos
2019 Level III-2, n=61).
Lateral femoral cutaneous or femoral PNB or CPNC alone or in PNB combinations
For lateral thigh skin donor sites in burns surgery, an US-guided single injection lateral femoral
cutaneous nerve (LFCN) PNB and US-guided fascia iliaca compartment nerve block (FICNB) with
CPNC reduced postoperative pain scores vs local anaesthesia infiltration (Shank 2016 Level II, n=19,
JS 3). For femoral fracture or surgery, FICNB by landmark technique reduced pain scores (Paut2001 Level IV, n=20) and rescue analgesic use vs IV opioid (Suresh 2014 Level I [PRISMA], 1 RCT: Kim
2011 Level II, n=64, JS 3; Wathen 2007 Level II, n=55, JS 3; Neubrand 2014 Level III-2, n=259 [158 FICNB]).
For knee reconstructive surgery, FICNB vs femoral PNB were equivalent for postoperative
analgesia (Suresh 2014 Level I [PRISMA], 1 RCT: Farid 2010 Level II, n=23, JS 3) and femoral PNB (alone
or via CPNC) was effective vs IV opioid (Micalizzi 2014 Level III-2, n=93).

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5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENTFor femoral fracture and traction application, landmark and US-guided (Turner 2014
Level III-2, n=81) single injection femoral nerve blocks and CPNCs have been used effectively,
including in an infant (Frenkel 2012 CR) and PICU patients (Tobias 1994 Level IV, n=4; Johnson 1994
Level IV, n=23). In the latter, plasma concentrations during bupivacaine 0.125% infusion of 0.3
mL/kg/h at 10─92 h were 0.67─0.93 mg/L.
Three-in-one blocks have been used in iliac bone graft harvest in comparison with woundinfiltration and a wound catheter (Kumar Raja 2014 Level II, n=60, JS 5).
Following knee arthroscopic surgery, US-guided femoral and obturator blocks reduced painscores and analgesia requirements vs no block (Kendall 2018 Level I [PRISMA], 1 RCT: Marinkovic 2016
Level II, n=60 JS 2). In adolescents with skeletal dysplasia having arthroscopic knee surgery,femoral, femoral/sciatic or femoral/sciatic/obturator blocks were effective (Eiszner 2016 Level IV,
n=10 [PNB]). Combined femoral-sciatic nerve block offered better analgesia with fewer adverse
effects than IA infiltration with bupivacaine/clonidine/morphine in children undergoing anterior
cruciate ligament reconstruction (Tran 2005 Level II, n=36, JS 2).
Popliteal PNB and CPNC
For lower limb contracture surgery in cerebral palsy patients, US-guided popliteal vs sham block
reduced pain scores for 0─12 h (Kendall 2018 Level I SR [PRISMA], 1 RCT: Ozkan 2017 Level II, n=54, JS 5).
Following major foot and ankle surgery, popliteal CPNC with ropivacaine 0.2% 0.1 mL/kg/h achieved
comparable analgesia with fewer adverse effects (PONV, urinary retention, early discontinuation) vscontinuous epidural infusion 0.2% 0.2 mL/kg/h (Dadure 2006 Level II, n=52, JS 3).
10.6.2.2 | Upper limb blocks in children
Brachial plexus blocks
Traditionally the axillary approach to the brachial plexus was preferred in paediatric patientswith its relative safety when using the landmark technique. US-guidance has led to new
approaches in children for brachial plexus regional analgesia (Walker 2018 Level IV, n=5,636 [brachial
plexus PNBs/CPNCs]; Marhofer 2004 Level II, n=36, JS 3; De Jose Maria 2008 Level III-1, n=80; Dadure 2009
Level IV, n=31 [upper limb CPNCs]); Ergonenc 2017 CR).

Supraclavicular approach: single injection and CPNC
PRAN audit has documented increased use of this approach in children (Walker 2018 Level IV,
n=2,860 PNBs & 93 CPNCs [supraclavicular]). Following a single injection supraclavicular block, one
2 y old developed a pneumothorax which was managed conservatively.
For percutaneous fixation of supracondylar fractures, US-guided supraclavicular block
reduced the mean and peak pain score only in PACU vs IV opioids (Glover 2015 Level III-2, n=230[36 PNB]).
Infraclavicular approach: single injection and CPNC
Infraclavicular nerve block (ICNB) has been described in paediatrics with nerve stimulator (NS)(Ponde 2008 Level IV) and/or US-guidance (Walker 2018 Level IV, n=811 PNBs & 133 CPNCs[infraclavicular]). This approach is as safe as other brachial plexus approaches, with more reliablemusculocutaneous nerve block/less tourniquet pain vs the axillary approach ( Chin 2013 Level I[Cochrane], 3 RCTs [paediatric], n=156). For arm, forearm and hand surgery, US-guided low-volume0.25 mL/kg vs standard volume 0.5 mL/kg bupivacaine 0.25%/lidocaine 1% infraclavicular blockachieved similar sensory with shorter motor block duration (Kendall 2018 Level I [PRISMA], 1 RCT:
Ince 2017 Level II, n=60, JS 5).

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Axillary approach: single injection and CPNC
For forearm and hand surgery, axillary brachial plexus block provided satisfactory analgesia in
75−94% of cases (Gurnaney 2014 Level IV, n=2 [axillary]; Dadure 2009 Level IV, n=15 [axillary]; Fisher
1999 Level IV, n=185 [250 procedures]). US has assisted insertion of axillary catheters in children(Walker 2018 Level IV, n=981 PNBs & 9 CPNCs [axillary]) and single injection block for hand surgery insevere epidermolysis bullosa (van den Heuvel 2016 Level IV, n=9 [19 procedures]). Two fractionatednerve stimulator-guided axillary brachial plexus injections in children produced similar sensory
and motor block quality at 30 min to a single injection (Carre 2000 Level II, n=70, JS 2), unlike inadults (Chin 2016 Level I [Cochrane], 22 RCTs [adult], n=2,193). Selective block of themusculocutaneous nerve is recommended when a surgical procedure takes place in its territory.
Interscalene approach: single injection and CPNC
Interscalene single injection blocks and CPNCs use in children is documented in the PRAN audit(Walker 2018 Level IV, n=984 PNBs & 103 CPNCs). An earlier PRAN series assessed the safety of thetechnique where 88% were performed in teenagers (10−18 y) and usually under GA (75%)(Taenzer 2014a Level IV, n=518 [472 PNB & 46 CPNCs]). US-guidance in 88%, nerve stimulation with
US 11%, nerve stimulation alone 2.5% and rarely fluoroscopy assisted placement. One vascularpuncture and one superficial infection were documented and no other serious events (LAST,
neurological, cardiovascular or dural puncture) (95%CI 0 to 7.7/1,000). For forequarter
amputation, direct surgical placement and infusions via epineural CPNCs in the 3 brachial plexus
trunks (for 5 to 14 d) as part of a multi-modal regimen has been described (Kaddoum 2013
Level IV, n=4).
Wrist blocks
For distal hand surgery in anaesthetised young children, wrist block vs intraoperative alfentanil
reduced postoperative pain scores, PONV and recovery time ( De Windt 2010 Level II, n=60, JS 3).
For trigger thumb release, US-guidance increased median nerve block success rates vs landmark
technique (100 vs 74%) (Liu 2018 Level II, n=100, JS 3).
10.6.2.3 | Truncal blocks in children
Paravertebral block PVB and CPNC
Paravertebral block (PVB) or PV CPNC infusion has been reported in PRAN audit (Walker 2018 Level
IV, n=535 PVB & 550 PV CPNC). With US uptake and the advent of newer truncal plane blocks, therole and risk profile of the PVB technique is of interest, but the paediatric evidence base lacks
comparative trials. Of note, infant cadaveric studies suggested a single US-guided PVB 0.2−0.3
mL/kg at T12/L1 provides dose dependent coverage of T10 to L1 segments ( Albokrinov 2014 Level
III-2, n=20). Dosing in children for single and multi-injection reported in mg/kg ropivacaine
equivalents (not in mL/kg) was higher for infants at a mean of 1.47 and 2 respectively vs 1.25
and 1.75 for older children (Vecchione 2016 Level IV, n=2,390 in 871 children [1765 PVBs & 625 CPNCs]).
No complications were reported with single injection PVBs. While with PVB CPNC, 2 majorcomplications occurred: one was a LAST event in an infant relating to chloroprocaine 3% 1 mL/kg
bolus and one teenager with bilateral PV CPNCs developed a large paravertebral haematoma
with epidural extension that was conservatively managed (event rate for paravertebral CPNC:
18.2/10,000; 95%CI 0 to 113) (Walker 2018 Level IV, n=535 PVB & 550 PV CPNC). Minor complications
for PVB CPNCs recipients included: catheter dislodgement 4.9%, occlusion 1.5%, leakage 5.9%,
skin irritation 2.9% and minor bleeding in 1% (Vecchione 2016 Level IV, n=625).

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5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENTParavertebral block: single injection
Single injection PVB has provided effective analgesia following thoracoabdominal surgery inchildren.
In a systematic review of heterogeneous paediatric trials, single and multi-injection PVB
reduced pain scores at 4−6 h (SMD 0.85; 95%CI 0.12 to 1.58) and 24 h (4 RCTs, n=282) andsupplemental analgesia requirement (3 RCTs [inguinal; comparators no block, ilioinguinal block andcaudal] n=199) (OR 0.17; 95%CI 0.08 to 0.34) (Page 2017 Level I [PRISMA], 6 RCTs [PVB], n=358). PVBs
have also been effective for several hours (median 10 h to mean 22 h) following cardiac surgery
for aortic coarctation (Saleh 2018 Level II, n=50, JS 4; Turkoz 2013 Level IV, n=15) and PDA ligation(Chalam 2015 Level II, n=100, JS 4), Nuss procedure (vs no block; Kendall 2018 Level I [PRISMA], 1 RCT:Qi 2014 Level II, n=30, JS 2), infant pyloromyotomy (Mata-Gomez 2015 Level IV, n=3) and renal surgery(vs caudal Narasimhan 2019 Level II, n=50, JS 5; vs IV paracetamol Akinci 2019 Level II, n=40, JS 4; Berta
2008 Level IV, n=24).
Paravertebral block: CPNC
Compared with thoracic epidural catheter infusion, PVB CPNC infusion (US-guided; bilateral)provided equivalent analgesia for cardiac surgery via thoracotomy (nerve stimulator guided)with higher insertion success and less adverse events (El-Morsy 2012 Level II, n=60, JS 5) and wasequivalent for the Nuss procedure (Muhly 2019 Level III-2, n=331 [56 paravertebral, 114 epidural];Hall Burton 2014 Level III-2, n=20) or with higher pain scores and opioid use postoperatively (aswith intercostal nerve catheters) but shortest LOS (mean 2.0 vs 4.0 d vs 4.9) (Loftus 2016
Level III-2, n=137).
Surgically placed paravertebral CPNCs have been effective post-thoracotomy in children for
empyema decortication (bupivacaine 0.1% 0.3 mg/kg/h) ( Murphy 2016b Level IV, n=83), in infants
for congenital pulmonary malformations (ropivacaine 0.125% 0.2 mg/kg/h) (Di Pede 2014 Level III-3,n=40) and neonates for tracheo-oesophageal fistula (TOF) surgery (levo-/bupivacaine 0.0625%≈0.25 mg/kg/h for 43 h median) (Palmer 2012 Level IV, n=37).
Unilateral PVB CPNC ropivacaine infusion for 2 d provided equivalent analgesia vs single
injection caudal ropivacaine/morphine for upper abdominal surgery in infants (Sato 2017
Level III-2, n=21). Bilateral and unilateral US-guided PVB CPNCs have been used for various
thoracoabdominal procedures for 1−5 d (Boretsky 2013 Level IV, n=22) including including following
TOF repair (ropivacaine 0.08% 0.2 mg/kg/h for 4−5 d) (Thompson 2015 Level IV, n=2). Following
iliac crest bone graft harvest, paravertebral L2 CPNCs with elastomeric pump reservoir(ropivacaine 0.2%, 0.06─0.2 mL/kg/h) were effective for outpatient analgesia (Visoiu 2014a Level
IV, n=5).
Erector spinae plane block (ESPB)
It is debated whether the erector spinae plane block (ESPB) is a paravertebral variant withneuraxial spread (Tsui 2019 Level IV, n=242 [23 children]) vs a myofascial plane block: see thediscussion in adult Section 5.8.5.3. A median volume of 3.4 mL per dermatomal level is suggested
for ESPB dermatomal spread in adults (De Cassai 2018 NR); with no paediatric dosing
recommendation data specific to this block.
Erector spinae plane block: single injection
US-guided single injection ESPB has been described in various paediatric surgeries in children(6 mth to 16 y): at T1 for posterior chest wall surgery ( Hernandez 2018b CR), T5−8 for thoracic
surgery (Ueshima 2018 Level IV, n=2; Adhikary 2018 CR; Munoz 2017 CR), T7 for laparoscopiccholecystectomy (Aksu 2019b Level IV, n=3; Thomas 2018a CR), T12 for nephrectomy for Wilm’s
tumour (Aksu 2018b Level IV, n=2), and at L1 for laparoscopic or open lower abdominal surgeries(Aksu 2019a Level II, n=60, JS 4; Aksu 2019c Level IV, n=2) and inguinal hernia repair (Aksu 2018a
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Level IV, n=10), including in an ex-preterm infant (Hernandez 2018a CR). Post inguinal surgery, ESPB

at L1 vs quadratus lumborum block (transmuscular approach) reduced pain scores similarly (0−6h) with similar times to first analgesic rescue (Aksu 2019c Level II, n=60, JS 4).
Erector spinae plane block: continuous infusion
ESPB CPNC infusion is reported as used following thoracotomy (De la Cuadra-Fontaine 2018 CR),
video assisted thoracoscopic surgery (VATS) (Adhikary 2018 CR) and pyeloplasty (Munshey 2018 CR).
Intercostal nerve block single injection and CPNC
For ear reconstruction cartilage graft site pain, a surgically placed intercostal CPNC was superior
to IV analgesia in reducing pain scores at rest and on coughing (Woo 2016 Level II, n=66, JS 3). Whilea single injection intercostal block was inferior to a wound catheter infusion ( Niiyama 2016
Level II, n=48, JS 2).
Pectoralis nerves and serratus anterior plane PNBs
Ultrasound-guided pectoralis nerve (PECS) blocks and serratus anterior plane (SAP) blocks are
regional analgesia techniques of the thorax (for technique description see also adult Section
5.8.5.4). Following paediatric cardiac surgery via thoracotomy, PECS II and SAP block recipients
had clinically modest 0.5−0.9/10 difference in pain scores from 4−10 h with reduced fentanyl
requirement (by 0.5 and 0.6 mcg/kg) vs ICN block recipients (Kaushal 2019 Level II, n=108, JS 3).
Sternal bed block single injections
In paediatric cardiac surgical patients having a median sternotomy, parasternal 2 nd to 6thintercostal space injections of ropivacaine 0.5% 0.5−2 mL per level (total dose <5 mg/kg) reduced
pain scores (MD 2.6/10) and postoperative fentanyl requirement (MD 3 mcg/kg) vs placebo(Chaudhary 2012 Level II, n=30, JS 4).
Quadratus lumborum block (QLB) single injection and CPNC
US-guided quadratus lumborum block (QLB) is performed by four approaches: Type 1 (lateral),Type 2 (posterior), transmuscular (TM or anterior) (NYSORA 2020 GL) and intramuscular (IM). Use
has been described for various lower abdominal surgeries in the T12−L1 dermatomal
distribution. The PRAN data set provides no specific data for this block (presumed included in‘other truncal’) reflecting the low frequency of use in children ( Walker 2018 Level IV, n=256 [single
injection other truncal] & 20 [other truncal CPNCs]).
In children undergoing lower abdominal surgery, TM QLB reduced pain scores (0−24 h) andanalgesic requirements vs IM QLB (18.5 vs 48.1%), but with more quadriceps weakness (29.6 vs3.7%) (Hussein 2018 Level II, n=54, JS 3). Post ureteral reimplantation, US-guided Type 2 QLB
recipients had similar pain scores and similar vomiting incidence to US-confirmed caudal
ropivacaine 0.2% 1 mL/kg/morphine 30 mcg/kg block (Sato 2019 Level II, n=47, JS 5). Post inguinal
surgery, TM QLB vs ESPB at L1 were similarly effective (0-6h) (Aksu 2019c Level II, n=60, JS 4) andtype 2 QLB achieved statistically lower but clinically similar pain scores vs transversus abdominis
plane block (TAPB) (means <1 vs 2/10 for 0−24h), with reduced rescue requirement (12% vs 40)(Oksuz 2017 Level II, n=50, JS 5). TM QLB had utility in young children having day case inguinal
surgery (Aksu 2018c Level IV, n=10) and was used for congenital hip dislocation surgery (Ahiskalioglu
2018b Level IV, n=2).
The use in children of QLB CPNC infusion of levobupivacaine 0.1% 5 mL/h following radical
nephrectomy (Chakraborty 2015 CR) and ropivacaine 0.2% 5 mL/h following colostomy closure is
described (Visoiu 2013 CR).

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5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

Transversus abdominis plane block (TAPB)
Paediatric RCT data is limited (see below), surpassed by increasing numbers in the PRAN audit,
where no complications specific to TAPB were described (Walker 2018 Level IV, n=5,630 [TAPB] &n=199 [TAPB CPNCs]). An earlier PRAN TAPB subgroup analysis (95% US-guided) documented a low
incidence of complications 0.1% (95%CI 0.02 to 0.3%): including one vascular aspiration and one
peritoneal puncture without sequelae (Long 2014 Level IV, n=1,994). Notably, bupivacaine dosing
varied widely (mean 1 mg/kg; range 0.47 to 2.29) with 7% of patients receiving potentially toxic
doses (2 mg/kg) usually younger in age; this highlights the need to dose according to weight. No
LAST events were reported. US-guided TAPB in children provides abdominal wall sensory block
below T10 with 0.4 mL/kg local anaesthetic injection (Palmer 2011 Level IV, n=27 [38 TAPB]).
Transversus abdominis plane block: single injection
In a systematic review of heterogeneous RCTs, TAPB is superior to wound infiltration for painscores at rest at 8 h (7 RCTs, n=416) and 24 h (7 RCTs [2 paediatric], n=425) (Guo 2015 Level I [PRISMA],
9 RCTs [3 paediatric], n=500 [176 children]). In the paediatric RCTs, TAPBs vs wound infiltration
reduced paracetamol rescue use (1 RCT [inguinal], n=57), with no overall difference in morphine
requirements following open pyeloplasty (1 RCT [n=32) or laparoscopic appendicectomy wheremore TAPB recipients had complicated appendicitis (31 vs 11%) (1 RCT, n=87). In contrast,
ipsilateral TAPB reduced morphine requirements vs saline block in open appendicectomy, where
perforation and positive histopathology rates were similar ( Hamill 2016 Level I [PRISMA], 1 RCT:
Carney 2010 Level II, n=40 JS 4). Several subsequent studies are mostly positive:• Post laparoscopy, TAPB was superior to surgical site infiltration (Karnik 2019 Level II,
n=92, JS 4);• Post mixed abdominal surgery, TAPB was effective and more so with higher dose
bupivacaine 0.25% vs 0.125% (with adrenaline/epinephrine 5mcg/mL) 1 mL/kg (Suresh
2015b Level II, n=36, JS 5);• Following ureteral reimplantation, TAPB was effective (0.5 mL/kg) vs caudal block withless morphine (although higher initial PACU pain scores) (Baeriswyl 2018 Level I [PRISMA], 10
RCTs, n=505 [4 paediatric, n=195], 1 RCT: Bryskin 2015 Level II, n=45, JS 3);• Following colorectal procedures, TAPB was effective where 90% of infants had pain scoresof 0/7 for 24 h (Chen 2015 Level IV, n=10);• Following inguinal surgery, US-guided TAPB bupivacaine 0.25% 0.4 mL/kg vs no blockattenuated the surgical stress response (Abu Elyazed 2016 Level II, n=60, JS 2). TAPB was
more effective than surgical site infiltration (Kendigelen 2016 Level II, n=40, JS 2), similarly
effective vs caudal block (Baeriswyl 2018 Level I [PRISMA], 1 RCT: Sethi 2016 Level II, n=80, JS 3)
and both TAPB and caudal were more effective vs ilioinguinal-iliohypogastric nerve block(II/IHNB) (Sahin 2017 Level II, n=90, JS 3). In contrast, low volume US-guided TAPB 0.3 mL/kg
was inferior to US-guided ilioinguinal block in early rescue analgesic requirement(Fredrickson 2010 Level II, n=41, JS 3); and• Post robot assisted laparoscopic renal/urological procedures, neither TAPB nor caudal
provided additional benefit vs no block (Faasse 2015 Level III-2, n=120).
Transversus abdominis plane block: CPNCs
US-guidance is used for TAPB CPNC insertion (97% US-guided) (Walker 2015a Level IV, n=58 [TAP
CPNCs]). TAPB CPNC infusions have been employed in small children (weighing ≤10 kg) where
epidural use was contraindicated or refused (Bakshi 2017 Level IV, n=2; Visoiu 2012 Level IV, n=6).
Rectus sheath block (RSB)
Rectus sheath block (RSB) provides analgesia for midline abdominal procedures with block of the
7th to 11th intercostal nerve terminal branches (Visoiu 2015 NR). There has been wide variation in
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the dose and volume of local anaesthetic used for RSB: mean bupivacaine dose 0.72 mg/kg(95%CI 0.23 to 2.30) and ropivacaine 1.19 mg/kg (95%CI 0.39 to 2.43) (Suresh 2018a Level IV,
n=2,331 [RSB)).
Compared to systemic analgesia, RSB has longer time to first morphine rescue (MD 19 min;
95%CI 6 to 33) (3 RCTs [RSB], n=222) and reduces early postoperative morphine consumption at
6−8 h (MD -20 mcg/kg; 95%CI -30 to -10) (4 RCTs [RSB], n=235) (Hamill 2016 Level I [PRISMA], 5 RCTs
[RSB 4 umbilical & 1 laparoscopic appendicectomy], n=287; Suresh 2014 Level I [PRISMA]: 2 RCTs [RSB],n=65) (2 RCT overlap).
Subsequent RCTs show US-guided RSB is similarly effective vs surgical site infiltration forlaparoscopic assisted inguinal hernia repair (Uchinami 2017 Level II, n=34, JS 3) and for umbilicalsurgery vs both caudal and pre-incision surgical site infiltration (Relland 2017 Level II, n=39, JS 5),
independent of whether surgically or US-placed (Litz 2017 Level II, n=58, JS 3).
Ilioinguinal/iliohypogastric nerve block (II/IHNB)
The ilioinguinal/iliohypogastric nerve block (II/IHNB) is used for pain relief following inguinal
surgery in children. Dosing is variable per PRAN audit data where mean dose for bupivacaine was
0.68 mg/kg (95%CI 0.23 to 1.66) and for ropivacaine 0.95 mg/kg (95%CI 0.29 to 2.48) (Suresh 2018a
Level IV, n=3,892 [II/IHNB]). Of note, after II/IHNB landmark technique, weak hip flexion (inadvertent
FNB) occurred in 8.8% (95%CI 5.1-13.9%) (Lipp 2004 Level IV, n=182). Bowel puncture has been
described with resultant subserosal haematoma noted during appendicectomy without
consequence (Frigon 2006 CR), persistent superficial infection with skin flora (Johr 1999 CR) anddevelopment of intestinal obstruction resulting in laparotomy and bowel resection (Amory 2003 CR).
Single vs double injection II/IHNB landmark techniques have similar success rates of 72%(1 RCT, n=87), with similar efficacy of different needle insertion sites (1 cm inferomedial to ASIS;
1 to 2 cm medial to ASIS; 2 cm superomedial to ASIS) (1 RCT, n=132) (Suresh 2014 Level I [PRISMA],
15 RCTs [II/IHNB], n=1,046). US-guidance improves the success rate of II/IHNB to 94% with smaller
volumes of local anaesthetic administered (2 RCTs, n=166). With US study post landmark
technique demonstrating intramuscular injection was common (82%: iliac 18%, transversus 26%,
internal oblique 29% or external oblique 9%) and intraperitoneal uncommon (2%) ( Weintraud2008 Level III-2, n=62). The overall clinical block success rate was 61%: 100% success when
injectate was deposited in the correct plane vs 45% when injected into surrounding tissues.
For II/IHNB, the same dose at two concentrations/volumes was similarly effective (1 RCT,n=72) and higher doses were effective for longer (1 RCT, n=60) (Suresh 2014 Level I, [PRISMA], 2 RCTs
[II/IHNB dose], n=132). Similar analgesic efficacy following inguinal hernia repair has been foundwith wound infiltration, II/IHNB or caudal analgesia (Baird 2013 Level III-1 SR, 1 RCT: Machotta 2003
Level II, n=58, JS 4; Splinter 1995 Level II, n=200, JS 5).
After US-guided II/IHNB, plasma ropivacaine concentrations were higher and peaked earlierby ≈5 min at 1.78 mcg/mL (range 0.56-2.97) vs 1.23 mcg/mL with landmark technique (Suresh2014 Level I SR, [PRISMA], 1 RCT: Weintraud 2009 Level II, n=66, JS 3).
10.6.2.4 | Superficial head and neck blocks
Scalp blocks
Blocks of scalp branches of the frontal (supraorbital, supratrochlear), maxillary(zygomaticotemporal) and auriculotemporal nerves as well as branches of the superficial cervicalplexus (greater auricular and occipital nerves) have been used in a small number of children, as
an adjunct to postoperative opioids, following craniosynostosis repair ( Rothera 2014 Level III-2,
n=78; Pardey Bracho 2014 Level IV, n=32) and neurosurgery (Pardey 2008 Level IV, n=3) including in a
700 gm neonate (Suresh 2004b CR). See also Section 8.1.8.

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5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENTInfraorbital nerve block
In addition to use in cleft lip repair (Suresh 2012 NR) (see Section 10.6.6 below), infraorbital blockhas described applications for endoscopic maxillary sinus surgery (Higashizawa 2001 Level II, n=50,
JS 3) and trans-sphenoidal hypophysectomy (McAdam 2005 Level IV). Use of bilateral infraorbital
blocks with block of the external nasal branch of the anterior ethmoidal nerve has been used as
an alternative option for intra and postoperative pain management of nasal fracture repair ( Cok2015 CR).
Superficial cervical plexus block
Superficial cervical plexus block has provided relief in paediatric patients for internal jugularhaemodialysis catheter insertion (Ciftci 2014 Level IV), thyroplasty in an awake patient (Suresh
2004c CR) and cochlear implant (Merdad 2012 Level III-3, n=91), though there was association withpostoperative fever in the latter.
Blocks for ear surgery
Greater auricular nerve block (GANB) provided near equivalent analgesia with reduced PONV vs
IV morphine following tympanomastoid surgery (Suresh 2002 Level II, n=40, JS 4). Pre-incision GANB
vs placebo in addition to GANB performed at surgery completion did not affect postoperative
pain scores, analgesia requirements, time to rescue analgesia or PONV (Suresh 2004a Level II, n=40,
JS 4). For otoplasty, GANB with lesser occipital nerve block provided equivalent analgesia tosurgical site infiltration (Cregg 1996 Level II, n=43, JS 2) and local anaesthetic infiltration alone had
reduced PONV vs in local/general anaesthesia recipients (Lancaster 2003 Level III-3, n=85).
Following bilateral myringotomy and tube insertion, postoperative pain scores or PONV
did not differ with auricular (vagal nerve branch) block vs IN fentanyl ( Voronov 2008 Level II,
n=200, JS 4).
10.6.2.5 | Continuous local anaesthetic wound catheter infusions
The evidence for use of wound catheter infusions in children is limited (See adult Section 5.8.8).
One RCT was negative where, in children undergoing median sternotomy for ASD closure (withmediastinal drain), wound catheter ropivacaine 0.2% infusion ≈0.35 mg/kg/h vs placebo infusion
did not benefit pain scores, opioid consumption (0-72 h), PONV nor time to mobilisation (Mattila
2016 Level II, n=49, JS 5). The remaining RCTs have been positive:• Continuous wound catheter recipients had lower postoperative pain scores (2.5/10 vs3.5) (with 4-fold lower morphine use) after open appendicectomy vs systemic analgesia
and after laparotomy vs epidural analgesia (2.5/10 vs 3.0) (and 1.75 fold lower morphineuse) (Machoki 2015 Level II, n=71, JS 5). Wound catheter recipients mobilised earlier with nodifference in surgical site complications;• For ear reconstruction cartilage graft site pain, a surgically placed para-rectus 72 h woundcatheter infusion ropivacaine 0.2% 2−4 mL/h had extended analgesic benefits vs single
injection ICNB ropivacaine 0.75% (Niiyama 2016 Level II, n=48, JS 2). Mean plasma
concentrations of ropivacaine were low at 0.9 mg/L at 2 and 24 h and 0.7 at 48 h;• In children with spina bifida undergoing open urinary tract surgery, a wound catheter
infusion vs an opioid infusion or PCA (in conjunction with multimodal analgesia) achieved
similar pain scores with reduced morphine equivalent use by two thirds and reduced
antiemetic requirement (Chalmers 2015 Level III-2, n=36);• For Nuss surgery, wound catheter recipients (who also received hydromorphone PCA, lowdose gabapentin 100-200 mg three times daily and clonidine patch 50 mcg/d) had similar
pain scores to thoracic epidural infusion recipients (ropivacaine 0.2%/hydromorphone 10
mcg/mL) (Choudhry 2016 Level III-3, n=32). While in a study exploring the addition of
5th Edition | Acute Pain Management: Scientific Evidence997

preoperative self-hypnosis training, wound catheter recipients had higher pain scores but
lower PCA opioid requirement vs thoracic epidural recipients ( Manworren 2018 Level III-3,n=53). In a further study, wound catheter (ropivacaine 0.2%) recipients also had higher
mean postoperative pain scores vs thoracic epidural (bupivacaine 0.1%) recipients (3.8/10
vs 2.9) (Thaker 2019 Level III-3, n=124). In all three studies, wound catheter recipients had
shorter mean LOS: 2.9 d vs 4.1 (Choudhry 2016 Level III-3, n=32), 4.4 d vs 5.1 (Manworren
2018 Level III-3, n=53) and 4.9 d vs 5.6 (Thaker 2019 Level III-3, n=124);• In neonates following major thoraco-abdominal surgery, wound catheters infusing
levobupivacaine 0.125% 0.16mL/kg/h (0.2 mg/kg/h) were used in addition to paracetamol
and IV clonidine (Krylborn 2015 Level IV, n=20). Median plasma levobupivacaine
concentrations over 12−72 h were low [free 0.018 mg/L; total 1.305 mg/L], with 90% of
free concentration values remaining below 0.05 mg/L for the duration of the infusion.
10.6.2.6 | Adjuvants in PNBs
Multiple studies have been performed assessing the addition of various adjuvants in PNBs,
usually without systemic comparator, and are summarised below. See also adult Section 4.9.2.
Alpha-2 agonist adjuvant use in PNBs
Results of RCTs for adjuvant use of alpha-2 agonists are contradictory with small sample sizes,
variation in dosing and operation type (major vs minor). To date they have lacked a systemiccomparator arm.
Two overlapping SRs are contradictory. The first concludes alpha-2 agonists increase single
injection PNB duration with longer time to first rescue analgesic administration based on
predetermined pain score change (Lundblad 2016 Level I, 3 RCTs & 2 unpublished RCTs’ abstracts [4clonidine, 1 dexmedetomidine], n=283). The time until 25% of patients needed rescue analgesia was≈6 h longer with alpha-2 agonist/local anaesthetic vs local anaesthetic alone (HR 1.7; 95%CI 1.1
to 2.4) with no complications reported. The prolongation occurred across all the heterogeneous
PNBs assessed (Lundblad 2016 Level I, 3 RCTs & 2 unpublished RCTs’ abstracts, n=283). This finding was
also reported in an earlier study (Cucchiaro 2007 Level III-2, n=435) where motor block duration was
shorter for blocks without adjuvant clonidine (OR 0.33; 95%CI 0.16–0.69).
The second systematic review was negative: concluding clonidine 1−2 mcg/kg added to local
anaesthetic does not confer any additional benefit in postoperative pain outcomes for caudal or
II/IHNB for inguinal surgery or axillary block for arm surgery (Suresh 2014 Level I [PRISMA], 2 RCTs
[inguinal], n=160 & 1 RCT [axillary]: Trifa 2012 Level II, n=60, JS 5) (2 RCT overlap). A third nonoverlapping systematic review of paediatric tonsillectomy concludes no benefit with fixed doseclonidine 25mcg added to peritonsillar local anaesthetic infiltration (Vlok 2017 Level I, 2 RCTs
[clonidine], n=123).
Subsequent studies are positive with increased duration of analgesia with adjuvant clonidine
1 mcg/kg added to:• Local anaesthetic DPNB (Anouar 2016 Level II, n=40 JS 3) and to nerve stimulator-guided
pudendal nerve block for penile surgery (Naja 2013 Level II, n=80, JS 5); and• Bilateral infraorbital nerve blocks for cleft lip surgery (Feriani 2016 Level I [Cochrane], 1 RCT:
Jindal 2011 Level II, n=50, JS 5);
And adjuvant dexmedetomidine 1-2 mcg/kg added to:• Greater palatine nerve blocks for cleft palate repair (time to first analgesia mean 22h vs14.2) with no side effects (Obayah 2010 Level II, n=30, JS 3);• II/IH block where the addition doubled the time to first analgesic request following
inguinal surgery (Arirachakaran 2018 Level II, n=60 JS 5);998

5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT• TAPB reduced postoperative morphine requirements and reduced the EDmin forbupivacaine from 0.08% to 0.06% (assessed by haemodynamic changes to skin incision at
15 min) for inguinal surgery (Raof 2017 Level II, n=60, JS 5).
Adrenaline
Adrenaline as an additive has been used in various PNBs as described in this section; but has notbeen analysed as an adjuvant comparator in PNBs.
Opioids
Opioids are used frequently as part of multimodal analgesia and rescue therapy in patients
receiving PNBs. There are 2 RCTs where the addition of adjuvant opioids to the local anaesthetic
for infraorbital nerve block have been positive with increase in analgesia duration, without
systemic route comparator (see cleft lip Section 10.6.6).
Systemic and perineural steroids – dexamethasone
For tonsillectomy, a Cochrane review is positive for multiple outcomes (see Section 10.4.10 for
systemically administered dexamethasone). The below RCTs assess dexamethasone of varying
doses 0.1−0.5 mg/kg as an adjuvant to local anaesthesia in PVBs, by perineural and systemicroutes.
The adjuvant use of dexamethasone:• IV 0.5 mg/kg (max unspecified) vs placebo added to DPNB reduced pain scores with longer
time to rescue following hypospadias repair (Shirazi 2016 Level II, n=42, JS 3);• IV 0.15 mg/kg (max 8mg) added to glossopharyngeal nerve block provided superior
postoperative analgesia to either in isolation (Mohamed 2009 Level II, n=150, JS 3). However,glossopharyngeal nerve block in 2 children has been associated with postoperative airway
obstruction (Bean-Lijewski 1997 Level III-3, n=8);• Added to local anaesthetic for peritonsillar infiltration reduced analgesic use and PONV
incidence (RR 0.56; 95% CI 0.35 to 0.89) following tonsillectomy (2 RCTs, n=299) (Vlok 2017
Level I, 3 RCTs [dexamethasone: 2 paediatric], n=361 [309 children]). Infiltration of 0.5 mg/kg(max 8 mg) added to local anaesthetic reduced early and later (>12 h) pain scores vsbupivacaine alone and placebo, where all patients received IV dexamethasone 0.5mg/kg(max 16 mg) (Kilinc 2019 Level II, n=120, JS 5);• In US-guided PVB, expedited extubation by ≈5 h and reduced pain scores at 12 and 24 hfollowing coarctation repair in infants (Saleh 2018 Level II, n=50, JS 4);• While adding perineural or IM dexamethasone to FNB did not further improve analgesia
following knee arthroscopy in teenagers (Martin 2018 Level II, n=77, JS 5).
Ketamine
Adding IV ketamine 0.5 mg/kg to peritonsillar bupivacaine 0.25% was more effective than IV
placebo/peritonsillar bupivacaine infiltration, and IV placebo/placebo infiltration with lower painscores (1−24 h) and longer time to first analgesia (Inanoglu 2009 Level II, n=90, JS 5).
See Section 10.4.7.1 for summary of 3 overlapping systematic reviews assessing peritonsillar
ketamine administration as a comparator vs placebo and one RCT of peritonsillar administrationvs other systemic routes.
Magnesium
The addition of peritonsillar magnesium 2-5 mg/kg (max unspecified) to local anaesthetic
reduced pain scores (4 RCTs, n=230) and the number of analgesic requests (WMD −0.68; 95% CI−1.17 to −0.18) (3 RCTs, n=180) (Vlok 2017 Level I, 4 RCTs [Mg], n=230).

5th Edition | Acute Pain Management: Scientific Evidence999Tramadol
Tramadol has been assessed as a comparator arm in various RCTs by systemic administrationand infiltration and nerve block summarised in Section 10.4.4.12. See also below 10.6.6 for an
RCT of peritonsillar infiltration of tramadol as an adjuvant.
Midazolam
Midazolam has not been assessed as an adjuvant for PNBs.

10.6.3 | Neuraxial blocks
Central neuraxial blocks are used in paediatric patients to provide postoperative analgesia andto supplement intraoperative anaesthesia. Patient selection, technique, choice of medicines,
availability of experienced staff for performing blocks, an APS or outpatient resources andadequacy of follow-up vary between centres (Williams 2003 NR).
10.6.3.1 | Epidural analgesia
As the epidural space is relatively large with loosely packed fat in neonates, catheters can bethreaded from the sacral hiatus to lumbar and thoracic levels (Tsui 2004 Level IV). Accuracy of
caudal-epidural catheter placement in young infants (2 d to 5 mth) to the desired vertebral level
was improved with US-guidance vs external measurement in one study (Ponde 2017 Level IV,n=25). In older infants, various techniques have been suggested to improve correct placement
including US, nerve stimulation and ECG guidance (Willschke 2006 Level IV, n=64; Tsui 2004 Level IV,
n=10; Tsui 2002 Level IV). US provides visibility of the dura mater and ligamentum flavum,
especially in infants and younger children.
Insertion of epidural catheters at the segmental level required for surgery was more reliablein older children and has been shown to be safe in experienced hands with appropriately sized
equipment (Walker 2018 Level IV, n=13,120 [epidural catheters] & 854 single injection epidurals (notincluding caudal); Llewellyn 2007 Level IV, n=10,633 [epidural]; Giaufre 1996 Level IV, n=2,396 [epidural]).
Cephalad or caudad migration (assessed by x-ray) of caudal-thoracic epidural catheters occurredin 64% of patients (1 d to 10 mth old); however >1 level of migration occurred only in infants≤6 kg (Simpao 2019 Level IV, n=85). In older children with a thoracic epidural catheter, catheter
migration was also related to patient size: 1.1 level change in those <40 kg and less change of 0.3
level in those ≥40 kg (where catheters fell out in 10% of patients) (Strandness 2015 Level IV, n=59).
MRI anatomical studies have shown the largest dura to spinal cord distance is mid thoracic
at T5/6 and the smallest at the L2/3 region (Wani 2018 Level IV, n=88 patients). A formula for themean skin to epidural space distance at L3/4 in ≤6 y olds based on MRI data (9 + 0.62 x weight
kg=depth in mm) may be more accurate than previously reported formulas based on depth ofneedle insertion (Franklin 2015 Level IV, n=70).
Furthermore, MRI has shown spinal cerebrospinal fluid (CSF) volumes per kg are less inchildren (0─18 y) than previously predicted (Jang 2019 Level IV, n=500 [248 thoracolumbar]).
Thoracolumbar CSF volume (T1 to end of dural sac) reduced with increasing age (r 0.66: <1 ymean 1.95 mL/kg vs >12 y 0.99), height (r 0.72), and weight (r 0.73). In young children 0─3 y, MRI
study demonstrated the median epidural space volume per vertebral segment: the lumbar value
was 1.18 mL/kg (95%CI 0.94 to 1.43) and the thoracic value was half that at 0.60 mL/kg (95%CI
0.38 to 0.75) (Forestier 2017 Level IV, n=20).
Ultrasound can identify normal and abnormal spinal anatomy in children (6─12 y) post
myelomeningocoele repair, facilitating selection of the optimal intervertebral space for epidural
catheter placement (Ponde 2018 Level IV, n=12).

1000 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

Ultrasound is a reliable predictor of depth to loss of resistance (or depth of epidural space),
offers visibility of the needle and catheter, and may reduce bone contacts (Guay 2019a Level I[Cochrane], 1 RCT overlap with Tsui 2010 Level IV SR [PRISMA], 1 RCT: Tachibana 2012 Level II, n=20 JS 1).
US prescanning vs landmark technique in children (mean age 10 y) having a Nuss procedure
decreased the time to insert a thoracic epidural catheter (by ≈1 min: median 1.67 min vs 2.75)(not including pre-scanning time). Whilst continuous US scanning in neonates to 6 y olds reduced
epidural lumbar or thoracic catheter insertion time (mean 2.7 min vs 3.9) (Guay 2019a Level I[Cochrane], 1 RCT: Willschke 2006 Level II, n=64 JS 1).
Local anaesthetics
Continuous epidural infusions of bupivacaine are effective and safe in children (Walker 2018
Level IV, n=13,120 [epidural catheters]; Wong 2013a Level IV, n=3,152 [epidurals]; Ecoffey 2010 Level IV,
n=10,098; Llewellyn 2007 Level IV, n=10,633). In children <4 y having abdominal surgery, bupivacaine
0.25% epidural infusion (0.1 mL/kg/h) vs morphine infusion were similarly effective (Wolf 1993
Level II, n=32, JS 3). In children aged 7–12 y having lower extremity major orthopaedic surgery,patient-controlled epidural analgesia (PCEA) ropivacaine 0.2% vs continuous infusion bothachieved low pain scores (≤1/10) in the first 48 h postoperatively (Antok 2003 Level II, n=48, JS 2).
Total ropivacaine dose was reduced with PCEA (0.2 mg/kg/h vs 0.4 mg/kg/h) but no differencesin adverse effects were detected.
In neonates, due to reduced clearance and the potential for accumulation of bupivacaine,
the hourly dose should be reduced, and the duration of therapy limited to 24–48 h (Larsson 1997
Level IV; Ivani 2015 GL). Postnatal age and weight influence the pharmacokinetic profile oflevobupivacaine, with slower absorption and clearance in neonates and infants (Chalkiadis 2006
Level IV, n=86). Total plasma levobupivacaine concentrations after caudal epidural bolus in 3─6mth old infants peaked at 1 h post 2 mg/kg at 0.30 mg/L (range: 0.20─0.70) (Vashisht 2019
Level IV PK, n=8). During subsequent infusion of 47 h duration, the total plasma level increased(with rising alpha-1 acid glycoprotein); however free plasma concentrations plateaued at steadystate early, remained low at 0.03 mg/L and were cleared rapidly over ≈12 h post cessation. In
infants >6 mth, although plasma levobupivacaine concentrations increased, they remained low
after 24 h of epidural infusion (Lerman 2003 Level II, n=120, JS 5). Epidural infusions of ropivacaine
were effective and safe in neonates (Bosenberg 2005 Level IV) and children (Berde 2008 Level IV)
with minimal drug accumulation.
Postoperative continuous epidural infusion with chloroprocaine 1% (0.4─3 mL/h) or 1.5%
(0.25–1.5 mL/kg/h) for 7─118 h has been used in neonates, infants and children having various
surgeries, (Veneziano 2016 Level IV, n=21 [15 ≤6 mth]; Ross 2015 Level IV, n=18 [≤6 mth]; Kamata 2014CR), and was similarly effective to ropivacaine 0.1% in infants (≤6 mth) post-thoracotomy (Muhly
2015 Level III-2, n=54). No serious adverse events related to epidural analgesia were reported inany of the three studies. As an ester local anaesthetic which is rapidly metabolised in plasma at
all ages including neonates, chloroprocaine may have a lower risk of accumulation and LAST thanamide local anaesthetics in neonates and young infants with immature hepatic enzymes(Veneziano 2017 NR).
For infants (median age 59 d) having a Kasai portoenterostomy, epidural local anaesthetic (withvarious adjuvants: fentanyl or hydromorphone with clonidine in 56%) vs no epidural had lower painscores from 6─30 h (highest median score 0.2/10 vs 2.1), were more likely to be extubated intheatre (88% vs 59%) and had shorter LOS (median 6 d vs 8) (Phelps 2019 Level III-2, n=47).
In children (5 mth to 12 y) having ureteric reimplantation surgery, patients with a caudal
epidural catheter threaded 5─7cm vs lumbar epidural catheters (bupivacaine 0.125%/fentanyl
2 mcg/mL infusions at 0.1─0.3 mL/kg/h) had less interventions for bladder spasms (mean

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1001

1.8/patient vs 8) and wound pain (mean 8.8/patient vs 11.4) (Sommerfield 2016 Level III-2, n=135[catheter]).
In infants (<12 mth) having a laparotomy, epidural analgesia vs systemic analgesia resulted
in similar opioid administration 0─48 h and similarly adequate pain scores for 0─72 h
postoperatively but with less sedation (13% vs 30%) (Martin 2019 Level III-2, n=82).
Epidural opioids alone
Epidural opioids alone have a limited role. Epidural morphine provided prolonged analgesia but noimprovement in the quality of analgesia vs systemic opioids (Bozkurt 2004 Level II, n=32, JS 1). Withouta systemic or epidural local anaesthetic comparator, epidural morphine 0.1 mg/kg vs epidural
tramadol 2 mg/kg had similar pain scores and time to first rescue analgesic but with higher rates ofadverse effects (Demiraran 2005 Level II, n=80, JS 3). Epidural fentanyl 1 mcg/mL alone was lesseffective than both levobupivacaine 0.0625% and 0.125% alone and levobupivacaine/fentanyl
combined (Lerman 2003 Level II, n=114, JS 5). Bolus doses of epidural morphine 20–30 mcg/kg wereless effective than epidural infusions of fentanyl 1–2 mcg/mL and local anaesthetic (Reinoso-Barbero
2002 Level II, n=30, JS 1; Kart 1997 Level II, n=30, JS 5). IV Ketoprofen improved analgesia vs saline when
given in conjunction with epidural sufentanil (Kokki 1999 Level II, n=54, JS 5).
10.6.3.2 | Caudal analgesia
Despite innovation and increasing use of PNB, caudal analgesia remains a commonly performed
regional technique (comprising 27–40% of audited blocks), especially in the smaller paediatricpatient (Ecoffey 2010 Level IV, n=8,493 [caudal]; Walker 2018 Level IV, n=38,116 single injection caudal and
2,016 lumbosacral caudal catheters), although single injection caudal block has been used effectively
in older children weighing 30 to 50 kg (Keplinger 2016 Level IV, n=20). Single injection caudal blockprovides intra and postoperative analgesia and is generally used for surgery on the lower
abdomen, perineum and lower limbs (see Table 10.9 and for comparison with PNBs Section
10.6.2.1). Large series have reported a high success rate (particularly in children aged <7 y) and a
low incidence of serious complications (Walker 2018 Level IV, n=40,132 [PRAN]; Suresh 2015a Level IV,
n=18,650 [PRAN]; Ecoffey 2010 Level IV, n=8,493; Giaufre 1996 Level IV, n=12,111). The complication rate
for single injection caudal blocks was 1.9% (95%CI 1.7% to2.1): most commonly these were failure
1% (95%CI 0.8 to 1.1), blood aspiration 0.6% (95%CI 0.5 to 0.8) and a positive test dose indicating
intravascular injection 0.1% (95%CI 0.1 to 0.2) (Suresh 2015a Level IV, n=18,650). There was one
seizure (in a 1 mth old) and one cardiac arrest (in a 36 mth old), and no complications that led tolong term sequelae. Total plasma concentrations have been documented post administration ofropivacaine 3.1 mg/kg in larger children (30-50 kg) and were low, 1.16 mg/L (range 0.65 to 2.61),
peaking at 1 h (95%CI 0.5 to 1.5) (Keplinger 2016 Level IV, n=20).
Caudal bupivacaine, levobupivacaine and ropivacaine produced similar times to onset ofblock and quality of postoperative analgesia (Sharma 2018 Level II, n=90, JS 3; Praveen 2017 Level II,
n=60, JS 4; Cinar 2015 Level II, n=80, JS 2; Ingelmo 2006 Level II, n=86, JS 5; Frawley 2006 Level II, n=310,
JS 5; Ivani 2005 Level II, n=60, JS 5; Breschan 2005 Level II, n=182, JS 3).

Concentration-dependent differences have been noted for individual agents. Ropivacaine
0.175% was superior to lower concentrations and was as effective as a 0.2% solution but
produced less motor block (Khalil 2006 Level II, n=74, JS 5). In children aged 1–3 y having inguinal
surgery, six concentrations of levobupivacaine were administered (0.08–0.18%, 1 mL/kg) (Yao2009 Level II, n=60, JS 5); for caudal analgesia, this study established the EC 50 as 0.109% (95%CI
0.098 to 0.120) and the EC95 as 0.151% (95%CI 0.135 to 0.193).
The PRAN data provides information of large variation in local anaesthetic dosing practices
for caudal blocks (IQR, 1.23 to 1.98 mg bupivacaine/kg) (Suresh 2015a Level IV, n=17,867 [dosing
known]). This was not explained by weight differences (r 0.5; 95%CI 0.48 to 0.52). This may in part

1002 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

reflect the desire for differential block heights. Importantly, 25% recipients received doses >2 mg/kg
of bupivacaine equivalents and 5.4% received >2.5 mg/kg that could be potentially unsafe.
The volume administered directly influences the height of block achieved. The spread of
caudal block has been measured clinically (assessing dermatomes and myotomes) and thevertebral height measured by US, contrast and MRI studies (see Table 10.9). Dosing in volume
based on weight is practical. For effective caudal analgesia, volumes of 0.5–0.7 mL/kg are used
for sacral dermatome surgery and 0.8–1 mL/kg for lumbar and lower abdominal dermatome
surgery. Higher volume 1.2–1.5 mL/kg blocks are effective for abdominal and thoracic surgery;spread above the T12 dermatome occurs most reliably in neonates and infants.
Table 10.9 | Block height following caudal injection in children using different formulae
Surgery typePatient number andage

Local anaesthetic agent(%) and additives

Volume used vssuggested formula

Block heightachieved

ClinicalStudy

McGown 1982 Level IV, n=500

Upper abdominal;
lower abdominal;
lumbosacral; sacral
Height assessed in
n=360
aged 6 mth–10 y

Lidocaine 1% (withadrenaline 5 mcg/mL)

Outcome/conclusion

Volume/weight calculation successful for 430 (86%)

Study

Satoyoshi 1984 Level IV

Abdominal
Bupivacaine 0.25–
Paediatric cadaver
0.375% orradio-opaque
Mepivacaine 0.75–1.5%
contrast study: n=16
Clinical: n=21
aged 1 mth–11 y

1.65 mL/kg
1.1 mL/kg
0.55 mL/kg

1 mL/kg or Spiegel
formula (x1–1.5)
Developed new
formula: mL=[(cm indistance from C7 tosacral hiatus) – 13]

Range:
T2–T8
T8–T12
L1–S3

New formulaachieved T4–5
height: assessed byresponse to painfulstimulus

Outcome/conclusion

Reduced thoraco-abdominal musculature movement; abdominal
surgery successfully completed

Study

Coad 1989 Level II, n=60, JS 3

Inguinal
n=48 (including
2 failures);mean age 2  1 y

Bupivacaine 0.25%
Bupivacaine 0.25%
Bupivacaine 0.5%

Outcome/conclusion

No difference found for weight- vs formula-based dosing with similar
postoperative pain scores.

1 mL/kg vs formula([Age in years]+2)mL

5th Edition | Acute Pain Management: Scientific Evidence1003

Surgery typePatient number andage

Local anaesthetic agent(%) and additives

Volume used vssuggested formula

Study

Verghese 2002 Level II, n=50, JS 4

Orchidopexy
aged <6 yBupivacaine 0.25%
vsBupivacaine 0.2%
(both with adrenaline
5 mcg/mL and sodium
bicarbonate 8.4%
0.1 mL/10 mL)

Outcome/conclusion

Higher volume lower concentration had less response to spermatic cord
traction. The sample was too small to detect a difference in postoperative
rescue analgesia (fentanyl 7 vs 17% p=0.4; paracetamol 59 vs 74% p=0.37).

0.8 mL/kg
vs
1 mL/kg

Block heightachieved

35% to T 10
vs70% to T10(assessed with
spermatic cord
traction test)

UltrasoundStudy

Lundblad 2011 Level IV, n=50

Subumbilical surgery: Ropivacaine 0.2%
urogenital, anal,
foot, and inguinal
aged 0–4 y

All received 1.5 mL/kg
with volume/kg noted
once T12 reached:
Formula generated by US
was lower than studies
with dermatomal testing:mL per spinal segment=(0.154 x kg) minus
0.094

Outcome/conclusion

Inverse relationship with age (r 0.8) and weight (r 1.0).

StudyBrenner 2011 Level II, n=75, JS 5

Anal, penile andinguinal
median age 21–32
mth

Ropivacaine
0.2% if <12 mth
0.35% if >12 mth

Outcome/conclusion

Weak inverse correlation with weight, height, BMI.

0.7 mL/kg
1.0 mL/kg
1.3 mL/kg

Block ≥T12 vertebral
level on US in 93%
neonates, 73%
infants and 25%
young children.

Median vertebral
height L2; same forage <12 or >12 mth.

X-ray contrast study
Study
Orchidopexy
aged 1–5 yOutcome/conclusion

Hong 2009 Level II, n=73, JS 4
Ropivacaine 0.225% vsRopivacaine 0.15%

1 mL/kg
1.5 mL/kg

Median height (range)
T6 (T3–11)
T11 (T8–L2);

No difference in recovery times, postoperative pain scores or adverse
effects Higher volume/lower concentration had longer time toacetaminophen rescue (9.2 vs 6.1 h; p<001) and reduced requirement (50 vs76%; p=0.03).

1004 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

Surgery typePatient number andage

Local anaesthetic agent(%) and additives

Study

Koo 2010 Level III-2, n=87

Perineal, inguinal,
orchidopexyn=83 had caudal
aged 6 mth–4.5 yRopivacaine 0.2%

Outcome/conclusion

More segments were covered per mL administered with younger age: mean
number of segments (SD) of 1.3 (0.4) for <1 y, 1.1 (0.3) for 1–3 y and 0.8(0.4) for >3 y. Dosed according to surgical type; effective for surgery in
100%, with low median postoperative pain scores (>2 h), 4% required
analgesic rescue.

Study

Thomas 2010 Level III-2, n=45

Perineal/lower limb,
inguinal, abdominal
aged 1–7 yBupivacaine 0.25%

Outcome/conclusion

Contrast study 1 mL/kg of caudal injectate reliably achieved one vertebral
level higher than 0.5 mL/kg (L2 vs L3 for 93% of patients)

Study

Forestier 2017 Level IV, n=20

Outcome/conclusion

Block heightachieved

0.5 mL/kg
1 mL/kg
1.25 mL/kg

Median height (range)
L2 (L4–T12)
T12 (L1–T8)
T10 (L2–T7)

0.5 mL/kg
0.75 mL/kg
1 mL/kg

Normal MRIs of spine N/Aand sacrum assessed
to measure: volumeof spinal canal/
caudal space, duralsac, and spinal cord.
From this data
volume of epiduralspace and
cerebrospinal fluid
was calculated.

Volume used vssuggested formula

Median epidural volume
by weight
1.30 mL/kg
1.57 mL/kg
1.78 mL/kg
Median epidural volume
by height
0.146 mL/cm
0.172 mL/cm
0.204 mL/cm

Median height SEM
L2  0.44
L1  0.32
T12 0.43

Predicted height
L1
T10
T6

L1
T10
T6

The epidural space volume showed a linear relationship to both height (r0.83) and weight (r 0.82)

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Anatomical variations
Commonly used anatomical landmarks (posterior superior iliac spines and sacral hiatus) when
scanned by US do not form an equilateral triangle in children ≤7 y old ( Abukawa 2015 Level IV,
n=282) and infants (<9mth) (Mirjalili 2015 Level IV, n=26); the latter reported the sacral cornua wereidentifiable by US in all 26 infants, but could not be palpated in 4 (15%).
In an MRI study of children (<12 y), the distance between the sacro-coccygeal ligament andthe dural sac correlated with weight (r 0.77), height (r 0.77), age (r 0.76) and most strongly
with body surface area (r 0.80) (Lee 2017b Level IV, n=141). From this data, a formula to calculate
the sacro-coccygeal ligament to dural sac distance (95%CI lower limit) based on BSA wasdeveloped: 25 x BSA (mm). In a neonatal cadaveric study, the mean distance from the sacral
hiatus apex to the dural sac was 10.5 mm (range 4.9 to 26.2); there was a correlation between
neonatal length and distance from apex of sacral hiatus to dural sac (r 0.39) such that for every
1 cm increase in neonate length, the distance increased by 3.3% ( van Schoor 2018 Level IV, n=39).
In a further series of anaesthetised children, the dural sac ended below S2/3 in 7.6% of patients(Shin 2009 Level IV, n=317).
Ultrasound guidance
US allows the real-time visualization of local anaesthetic spread during caudal injection (Lam 2016
Level IV SR [PRISMA], 11 studies [caudal], n=1,101]). Continuous US scanning vs landmark techniquereduced time to perform a caudal (mean 2.42 min vs 2.73) (Lam 2016 Level IV SR [PRISMA], 1 RCT:
Wang 2013 Level II, n=140 JS 3). Two subsequent RCTs in children (1─12 y) found continuous USguided caudal injection vs landmark technique resulted in higher success on first puncture (80─93%
vs 63─66%) and lower rates of vascular puncture (0─1.5% vs 11─12%) and subcutaneous bulging(0% vs 8─12%), but with a similar success rate (no movement, HR and RR change ≤20%) and meantime to perform caudal (Karaca 2019 Level II, n=266, JS 3; Ahiskalioglu 2018a Level II, n=134 JS 3).
For the use of US and other techniques to facilitate caudal epidural catheter placement, see
Section 10.6.3.1 above.
10.6.3.3 | Adjuvants for epidural and caudal
Opioid and nonopioid adjuvants have been added to caudal local anaesthetic with the aim of
improving the efficacy or duration of analgesia. The neurotoxicity of nonopioid spinal additives
has not been systematically evaluated in neonates and children ( Walker 2012c NR). Preservativefree morphine and clonidine are registered drugs for use in the epidural space; the remaining
drugs listed below are used off label (Suresh 2018b GL). However, these recommendations by theEuropean/American Society of Regional Anaesthesia endorse clonidine, dexmedetomidine,preservative-free morphine and ketamine as neuraxial adjuvants.
Epidural adjuvants
Opioids
A combination of local anaesthetic and opioid is frequently used in epidural infusions but there
are limited data available to assess the relative merits of different regimens. Fentanyl 1–2
mcg/mL addition to local anaesthetic infusions had both improved analgesia (less IV opioid
rescue) (Lovstad 2001 Level III-2) and similar analgesic effect (Lerman 2003 Level II, n=114, JS 5) but
increased nausea and vomiting (Cho 2009 Level II, n=108, JS 5; Lovstad 2001 Level III-2). Addition offentanyl 5 mcg/mL to bupivacaine 0.1% provided similar analgesia but increased adverse effects
vs clonidine 1.2 mcg/mL with bupivacaine 0.1% (Cucchiaro 2006 Level II, n=47, JS 3). In children withcerebral palsy (mean age 11 y) having single event multi-level surgery (SEMLS), epidural
bupivacaine 0.125% (0.25 mL/kg/h initial rate) with fentanyl 2 mcg/mL vs clonidine 2.5 mcg/mL
was similarly effective over 72 h in terms of diazepam use, frequency and severity of muscle

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spasm, pain scores and epidural bolus requirement (Chalkiadis 2016 Level II, n=50, JS 4). Vomiting,antiemetic use and oxygen desaturations were more common with epidural fentanyl, whilst
blood pressure and heart rate were lower in epidural clonidine recipients. For children (3─12 yold) (86% with cerebral palsy) having lower limb orthopaedic surgery, an intraoperative epiduraldose of dexmedetomidine 1 mcg/kg vs fentanyl 1 mcg/kg in addition to ropivacaine 0.2% PCEA
achieved lower pain scores at 6 h (median 0/10 vs 1) but not at 12─48 h (Park 2017b Level II, n=60,
JS 5). Total ropivacaine dose, and the incidence of minor adverse effects (eg emergence agitationand nausea and vomiting) were similar. In cerebral palsy patients (3─17y) having SEMLS, adding
baclofen (3 mcg/kg bolus followed by 0.5 mcg/kg/h) to 0.1% bupivacaine (with clonidine in26─40% and fentanyl in 8─11% of patients) for continuous epidural infusion did not reduce
supplemental opioid or benzodiazepine administration, pain scores or length of stay (Nemeth2015 Level III-2, n=44).
Following a postoperative epidural infusion of ropivacaine 0.2% 0.15 mL/kg/h with fentanyl
0.375 mcg/kg/h (for median 38 h), fentanyl plasma levels reached a secondary peak 3─6 h post
cessation, and remained detectable for longer in infants and toddlers (3 mth – 3y) than in older
children (3─12 y) (mean residence time: 22.9 h vs 11.5) (Karas-Trzeciak 2015 Level IV PK, n=43).
There was marked variability in post-infusion fentanyl PKs, which was greater in infants andtoddlers than older children.
Epidural infusion of sufentanil (0.015 mcg/kg/mL)/ropivacaine 0.15% achieved similar painscores following paediatric urological surgery with reduced rescue analgesic use but with morepruritus vs fentanyl (0.1 mcg/kg/mL)/ropivacaine 0.15% (Cho 2008 Level II, n=64, JS 4).
The addition of morphine 10 mcg/mL to an epidural local anaesthetic infusion was more
effective than clonidine 0.6 mcg/mL (Cucchiaro 2003 Level II, n=26, JS 5), but higher doses ofclonidine improved analgesia when added to epidural ropivacaine infusion (De Negri 2001 Level II,
n=60, JS 4).
Tramadol 2 mg/kg has been added to ropivacaine 0.2% via the epidural route and wassuperior to ropivacaine alone (Inanoglu 2010 Level II, n=44, JS 5).
For the use of epidural morphine and hydromorphone in scoliosis surgery and pectus
excavatum repair, see Section 10.6.6.
Caudal adjuvants
Opioids
Addition of morphine to caudal local anaesthetic prolonged analgesia but dose-related adverse
effects were relatively common (Cesur 2007 Level II, n=135, JS 5; Bozkurt 1997 Level IV). Morphine
7.5 mcg/kg added to 0.125% levobupivacaine resulted in a lower incidence of vomiting thanhigher morphine doses and provided effective postoperative analgesia ( Dostbil 2014 Level II,
n=240, JS 5). Morphine 20 mcg/kg added to bupivacaine 0.166% (with adrenaline 1:600,000)
1 mL/kg was more effective (lower pain scores and fewer patients requiring rescue analgesics)
than bupivacaine/adrenaline alone or with clonidine 1 mcg/kg, although with higher rates of
PONV (Fernandes 2012 Level II, n=80, JS 5). Single injection caudal with bupivacaine 0.25% (1 mL/kg)
and morphine (30─50 mcg/kg) vs IV fentanyl for infants and children (0.5─12 y) having
laparoscopic surgery prolonged time to first rescue analgesia, and halved postoperative fentanyl
consumption (mean 24 h cumulative dose 1.1 mcg/kg vs 2.3) (Kundu 2015 Level III-2, n=65).
Clinically significant respiratory depression has been reported, particularly with higher
morphine doses and in younger patients (de Beer 2003 NR). Adverse effects are potentially fewerwith lipid soluble opioids but, while fentanyl may prolong caudal analgesia (Constant 1998 Level II,
n=59, JS 5), other RCTs have shown no benefit (Kawaraguchi 2006 Level II, n=35, JS 3; Baris 2003
Level II, n=75, JS 3; Joshi 1999 Level II, n=56, JS 2).

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1007Adrenaline (epinephrine)
Adding adrenaline (epinephrine) to bupivacaine has minimal effect on the duration of analgesia,
particularly in older children (Ansermino 2003 Level I, 3 RCTs, n=407). The influences of caudal
adrenaline and/or clonidine on the absorption characteristics of caudal levobupivacaine has
been evaluated (Chalkiadis 2013 Level IV, n=240). Adrenaline (5 mcg/mL) decreased the rate oflevobupivacaine systemic absorption, reducing peak concentration by half but with minimal
impact on levobupivacaine’s time-concentration profile. Adrenaline (2.5 mcg/mL) addition to
caudal ropivacaine slowed the Tmax, and reduced the peak ropivacaine concentration by 35% (Van
Obbergh 2003 PK).
Alpha-2 agonists
Addition of clonidine 1–2 mcg/kg to caudal local anaesthetic, as assessed by two systematic
reviews, prolongs analgesia (MD 3.7 h; 95%CI 2.7 to 4.7 and MD 4 h; 95%CI 2.8 to 5.1), with fewer
patients requiring rescue analgesics (RR 0.72; 95%CI 0.57 to 0.90 and OR 0.22; 95%CI 0.13 to0.37) (Schnabel 2011b Level I [PRISMA], 20 RCTs, n=993; Engelman 2013 Level I [PRISMA], 18 RCTs, n=782)(14 RCT overlap). In assessing the sedative effects of clonidine as a caudal additive, thesesystematic reviews conflict; one finding positive association (OR 2.48; 95%CI 1.63 to 3.69)(Engelman 2012 Level I [PRISMA], 3 RCTs [sedation], n unspecified) and the other none (RR 4.76; 95%
CI 0.24 to 93.19) (Schnabel 2011b Level I [PRISMA], 4 RCTs [sedation], n=142). Both found no reductionof PONV.
Subsequent studies of infraumbilical surgery in 1─12 y olds have similar findings for caudal
clonidine where:• 1, 2 and 3 mcg/kg dose dependently spared levobupivacaine: from 0.2% to ED50s of 0.11,
0.08 and 0.04% respectively (Disma 2011 Level II, n=120, JS 4). The optimal dose was
2 mcg/kg with longer time to first analgesic rescue, reduced rescue analgesic requirement
and less emergence agitation vs 1 mcg/kg, with more sedation in 3 mcg/kg recipients(30% vs 10 vs 0);• 2 mcg/kg vs fentanyl 1 mcg/kg added to ropivacaine were similarly effective, with more
adverse events (POV, desaturation and bradycardia) in fentanyl treated (Shukla 2011
Level II, n=90, JS 4). 1mcg/kg combined with fentanyl 1 mcg/kg was superior to caudal
fentanyl 1 mcg/kg (added to local anaesthetic) with prolonged analgesia duration andreduced pain scores from 1─12 h (by 0.5─1.8/13) (Jarraya 2016 Level II, n=40, JS 2);• 1 mcg/kg was superior to caudal midazolam 30 mcg/kg, with both superior to bupivacaine
alone with ≈2 fold increase in analgesic duration (12.1 h vs 10.1 vs 4.9) and less use of
3 rescue medications (4% vs 28 vs 60) (Sanwatsarkar 2017 Level II, n=75, JS 5). Intraoperative
haemodynamic changes and postoperative sedation were similar between groups,
however all received midazolam premedication;• In addition to caudal local anaesthetic, caudal clonidine 1 mcg/kg was superior to IV
clonidine and placebo in prolonging duration of analgesia (16.7 h vs 9.4 vs 4.2) andreducing the number of patients requiring rescue analgesia (0─24 h) (80% vs 96 vs 100%),
with no difference in sedation (Potti 2017 Level II, n=75, JS 4);• While clonidine (2 mcg/mL) differed from adrenaline with faster systemic absorption oflevobupivacaine; but both agents had minimal impact upon levobupivacaine’s timeconcentration profile overall (Chalkiadis 2013 PK).
Three overlapping systematic reviews document similar positive benefit of caudal
dexmedetomidine 1─2 mcg/kg as an adjuvant to local anaesthetic in children aged 0.5─12 yhaving various surgeries:• The duration of postoperative analgesia vs local anaesthetic alone is prolonged (WMD
8.2 h; 95%CI 5.0 to 11.4) (5 RCTs, n=270) (Trifa 2018 Level I [PRISMA], 21 RCTs, n=1,590; Tong

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2014b Level I [PRISMA], 6 RCTs, n=328) (6 RCT overlap) and (SMD 3.19; 95%CI: 2.16 to 4.22)(Tu 2019 Level I [PRISMA], 10 RCTs, n=691) (overlap 3 & 8 RCTs respectively). Subanalysis reveals

no difference between 1 mcg/kg (SMD 3.76; 95%CI 2.16 to 5.37) and 2 mcg/kg dose (SMD
1.73; 95%CI 1.73 to 2.89). Dexmedetomidine addition also reduces the need for rescue
analgesia vs bupivacaine alone at 6 h (RR 0.09; 95%CI 0.05 to 0.17), 12 h (RR 0.50; 95%CI
0.32 to 0.79) and 24 h (0.66; 95%CI 0.51 to 0.85), with no difference in PONV.
• A dose related increase in emergence time and sedation scores is consistently reported,
without increased risk of respiratory depression (Trifa 2018 Level I [PRISMA], 21 RCTs,
n=1,590). Compared to other caudal adjuvants, dexmedetomidine provides similaranalgesia to clonidine (2 RCTs) and dexamethasone (1 RCT), and is superior to opioids(fentanyl 4 RCTs; morphine 1 RCT) with longer duration of analgesia, lower use of rescue
analgesia and lower pain scores.
For unilateral inguinal hernia repair, the addition of dexmedetomidine 1 mcg/kg by caudal
or IV route to levobupivacaine was similarly effective vs placebo in doubling the median time
to first rescue analgesia (14.2 h vs 12.4 vs 6.0), reducing the number of patients requiring
rescue analgesia (63% vs 70% vs 93%) and reducing the incidence of emergence agitation (3%vs 3% vs 27%) (Yao 2018 Level II, n=90, JS 5). Emergence time was mildly delayed (by 6 and 7 min)vs placebo, with no difference in PACU LOS; no bradycardia, hypotension or motor block was
observed.
For hypospadias repair, caudal combinations of bupivacaine 0.25%/dexmedetomidine
1 mcg/kg/dexamethasone 0.1 mg/kg vs bupivacaine/dexmedetomidine 1 mcg/kg vsbupivacaine/dexamethasone 0.1 mg/kg increased the mean duration of analgesia (11.5 h vs 7.4
vs 4.5), lowered pain scores from 0.5 to 6 h, but with increased sedation in bothdexmedetomidine groups from 0.5 to 12 h postoperatively (Hassan 2018 Level II, n=63, JS 5).
Dexamethasone
Three systematic reviews have concluded that adjuvant dexamethasone caudally (0.1─0.2
mg/kg) or IV (mostly 0.5 mg/kg with one study 1.5 mg/kg) vs placebo prolongs the time to first
rescue analgesia following a single injection caudal block in children (mostly ≤10 y) having
lower abdominal/perineal or lower limb orthopaedic surgery (Zhu 2018a Level I [PRISMA], 7 RCTs,
n=647; Chong 2018 Level I [PRISMA], 14 RCTs, n=1,315; Kawakami 2017 Level I [PRISMA], 6 RCTs [IV only]
n=424) (6 & 4 RCT overlap). The largest review found prolongation with both caudal (WMD
5.4 h; 95%CI 3.5 to 7.3 9 RCTs) and IV routes (WMD 5.5 h; 95%CI 3.6 to 7.5) (5 RCTs) (Chong2018 Level I [PRISMA], 14 RCTs, n=1,315 ). Dexamethasone reduces pain scores postoperatively at
6 h (WMD -1.31; 95%CI -2.07 to -0.54) (6 RCTs) and 24 h (WMD -0.80; 95%CI -1.37 to -0.24)(5 RCTs), but not at PACU, 12 h, or 48 h. It reduces the number of patients needing rescue
analgesia in PACU (RR 0.30; 95%CI 0.18 to 0.51) (5 RCTs) and post PACU (RR 0.46; 95%CI 0.23
to 0.92) (9 RCTs), and reduces PONV (RR 0.47; 95%CI 0.30 to 0.73). No increased risk of adverse

effects with dexamethasone were reported in these reviews. Subsequent RCTs have similar
results for 0.1 mg/kg via caudal (Parameswari 2017 Level II, n=130, JS 3) and 0.25 mg/kg by IVroute (Salami 2017 Level II, n=94, JS 5). While a further RCT was positive for 0.1 mg/kg caudal
over IV route (Dongare 2018 Level II, n=60, JS 1).
Magnesium
Adding magnesium (Mg) 50 mg caudally vs control reduces the number of patients requiring
rescue analgesia postoperatively (RR 0.45; 95%CI 0.24 to 0.86) (Kawakami 2018 Level I [PRISMA],
6 RCTs [Mg], n=371). Duration of analgesia is prolonged with caudal magnesium (3/5 RCTs), with amixed effect on postoperative pain scores (6 RCTs); there were no serious adverse events
reported, with a similar rate of minor adverse events (eg shivering, sedation, motor block). In a
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further RCT, the combination of caudal Mg 50 mg/ dexmedetomidine 1 mcg/kg increased time
to first analgesic request vs Mg 50 mg alone vs dexmedetomidine alone which were also superior
to no adjuvant (Sayed 2018b Level II, n=120, JS 3). Dexmedetomidine recipients in both arms had
more sedation for 1─1.5 h.
Ketamine
The addition of caudal ketamine 0.25–0.5 mg/kg to local anaesthetic prolongs time to firstanalgesic request vs local anaesthetic alone (MD 5.6 h; 95%CI: 5.45 to 5.76) without prolonging
motor block (Schnabel 2011a Level I [PRISMA], 13 RCTs [paediatric], n=584), increases duration ofblock (with ketamine 0.5 mg/kg: SMD 2.25; 95%CI 1.53 to 3) and reduces postoperative analgesic
requirements (OR 0.26; 95%CI 0.1 to 0.7) (Dahmani 2011 Level I [QUORUM], 10 RCTs [caudal], n=686)(6 RCT overlap). Some adverse effects were more frequent in the ketamine group (eg sedation)
but not significantly different to placebo for PONV (OR 1.17; 95%CI 0.7 to 2) (Schnabel 2011a Level I[PRISMA], 13 RCTs [paediatric], n=584) or psychomimetic effects (OR 1.72; 95%CI 0.7 to 4.3) (Dahmani
2011 Level I [QUORUM], 10 RCTs [paediatric], n=686). A subanalysis of S-ketamine added to caudal
anaesthesia was performed showing similar prolongation of block vs racemic ketamine (Dahmani
2011 Level I [QUORUM], 4 RCTs [S-ketamine], n unspecified). A subsequent RCT found similar results(Aliena 2018 Level II, n=58, JS 4). A significant concern that continues to limit the use of neuraxial
ketamine is local neurotoxicity in vitro (Walker 2012c NR; Werdehausen 2011 BS).
Tramadol, neostigmine and midazolam
Caudal tramadol 1–2 mg/kg added to local anaesthetic prolongs the time to first rescue analgesic(4.5 h: 95%CI 2.8 to 6.1) at the expense of increased vomiting (OR 2.5; 95%CI 1.3 to 4.6) with no
IV comparator (Engelman 2012 Level I [PRISMA], 9 RCTs [tramadol], n=258). Caudal tramadol 2 mg/kg
added to bupivacaine and levobupivacaine was similarly effective for inguinoscrotal surgery(Sezen 2014 Level II, n=68, JS 5).
Caudal tramadol 1 mg/kg added to bupivacaine vs bupivacaine 0.25% alone prolonged durationof analgesia (9.6 h vs 7.2), reduced the amount of rescue paracetamol used to 24 h and had lower
rise of IL-6, CRP and cortisol over 24 to 72 h postoperatively (Sayed 2018a Level II, n=60, JS 5).
Tramadol 2mg/kg/bupivacaine 0.25% vs fentanyl 2 mcg/kg/bupivacaine 0.25% prolonged
duration of analgesia (10─18 h vs 7─11 h) with lower pain scores from 4─10 h, but more PONV
(8 vs 0%) (Solanki 2016 Level II, n=100, JS 2).
Neostigmine added in doses of 1–4 mcg/kg extends the time to first analgesic rescue request
by 2.5 times that of clonidine (MD 10 h; 95%CI 7.8 to 12.2) without any dose-dependent effectevident. This is at the expense of increased vomiting (OR 1.8; 95%CI 1.1 to 2.8) (Engelman 2012
Level I, 7 RCTs [neostigmine], n=533). Neostigmine (administered with adrenaline 5 mcg/mL) without
local anaesthetic demonstrated analgesic efficacy for 20–50 mcg/kg (but not 10 mcg/kg), with adose-dependent increase in PONV (Batra 2003 Level II, n=120, JS 2). Adding neostigmine 2 mcg/kg,
midazolam 50 mcg/kg or ketamine 0.5 mg/kg to bupivacaine 0.25% (1 mL/kg) for a single injection
caudal all prolonged duration of analgesia (21 h vs 18.3 vs 12.8 vs 7.2), and reduced postoperative
pain scores (mean 2.6/10 vs 3.1 vs 4.4 vs 5.6), but with increased vomiting with neostigmine andketamine (25% vs 15% vs 5% vs 5%) (Shirmohammadie 2019 Level II, n=80, JS 3).
Caudal midazolam 50 mcg/kg/bupivacaine vs caudal fentanyl 1 mcg/kg/bupivacaine vsbupivacaine alone had similar 0─24 h analgesic requirement, with higher sedation scores overthe initial 1.5 h (Baris 2003 Level II, n=75, JS 3). This dose added to bupivacaine prolonged time to
first rescue analgesic (similar to neostigmine 2 mcg/kg and ketamine 0.5 mg/kg) with nodifference in sedation scores over 24 h vs plain bupivacaine (Kumar 2005 Level II, n=80, JS 4).
Compared to plain bupivacaine, midazolam 50 mcg/kg vs morphine 50 mcg/kg added tobupivacaine prolonged the duration of analgesia (mean duration: 8 h vs 21 vs 15 respectively)
with similar prolongation of sedation to 12 h (Gulec 1998 Level II, n=60, JS 1).

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10.6.3.4 | Other outcomes of Paediatric Regional Analgesia
Stress response
Perioperative regional analgesia modifies the stress response to surgery in children (Nasr 2013
Level II, n=40, JS 3; Humphreys 2005 Level II, n=59, JS 2; Wolf 1998 Level II, n=26, JS 1). Suppression of
the stress response may necessitate a local anaesthetic block that is more intense or extensive
than required for analgesia, and therefore the risks of increased adverse effects or toxicity must
be balanced against any potential benefit (Wolf 1998 Level II, n=26, JS 1). Use of caudal opioids
alone (morphine 30 mcg/kg) was less effective than plain bupivacaine 0.25% in attenuating
cortisol and glucose responses following hypospadias surgery (Teyin 2006 Level II, n=28, JS 3).
Sufentanil added to bupivacaine modified the stress response to cardiac surgery (Sendasgupta
2009 Level II, n=30, JS 3).
Respiratory outcomes including apnoea
Improvements in respiratory outcome with regional analgesia have not been established incontrolled comparative trials. Reductions in respiratory rate and oxygen saturation were lessmarked during epidural analgesia vs with systemic opioids but the degree of difference was oflimited clinical significance (Wolf 1993 Level II, n=32, JS 2). Case series report improvements in
respiratory function and/or a reduced need for mechanical ventilation with regional analgesia
techniques (Raghavan 2008 Level IV; Aspirot 2008 Level IV; Hodgson 2000 Level IV; McNeely 1997
Level IV). A review summarises the use of awake caudal or combined spinal epidural vs epidural
as a supplement to general anaesthesia in 560 neonates having multiple surgery types withmultiple outcomes (surgical efficacy, postoperative respiratory events, other) (Maitra 2014 NR). A
meta-analysis of PRA (spinal, caudal or epidural) vs general anaesthesia for inguinal
herniorrhaphy in ex-premature infants reported a reduction in postoperative apnoea with PRA
when infants having preoperative sedation were excluded (RR 0.53; 95%CI 0.34 to 0.82) (4 studies
n=129); the groups did not differ in the need for postoperative ventilation (3 RCTs, n=98) (Jones
2015 Level I [Cochrane], 7 RCTs, n=203). A subsequent multicentre RCT assessing PRA (spinal, caudal,
or combined spinal and caudal) vs general anaesthesia (sevoflurane <1 h) for infants (≤60 wk
post-menstrual age) having hernia repair qualifies these findings (Davidson 2015 Level II, n=722,
JS 3). Prematurity was the strongest predictor of apnoea (OR 22; 95%CI 4 to 109), and PRA
reduced early (0 to 0.5 h) (1 vs 3%) (OR 0.20; 95%CI 0.05 to 0.91) but not late apnoea (0.5 to 12h). Neurodevelopmental outcomes did not differ between the regional anaesthesia and generalanaesthesia groups at 2 y (Davidson 2015 Level II, n=532, JS 3) and 5 y of age (McCann 2019 Level II,
n=447, JS 3).
10.6.3.5 | Safety and complications of Paediatric Regional Analgesia
Performance of PRA under general anaesthesia vs awake
The safety of performing paediatric regional anaesthesia (PRA) under general anaesthesia ordeep sedation has been demonstrated in six large prospective multi-regional audits (Walker
2018 Level IV, n=104,393; Taenzer 2014a Level IV, n=53,564; Wong 2013a Level IV, n=3,152; Polaner2012 Level IV, n=14,917; Ecoffey 2010 Level IV, n=31,142; Llewellyn 2007 Level IV, n=10,633; Giaufre
1996 Level IV, n=24,409) (see Table 10.10). Placement of regional anaesthesia/analgesia undergeneral anaesthesia is confirmed to be as safe as placement in sedated and awake children(Walker 2018 Level IV, n=104,393 in 91,701 children). The combined incidence for major adverse
events (LAST and neurological deficit together) was 2.2/10,000 (95%CI 1.5 to 3.4) for blocks
placed under GA and 15.2/10,000 (95%CI 7.8 to 28.4) for blocks placed when awake
or sedated.

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Overall complications
The earlier audits reported rates of overall complications for regional analgesia of 0.09% (Giaufre
1996 Level IV, n=24,409), 0.12 % (95%CI 0.09 to 0.17) (Ecoffey 2010 Level IV, n=31,142) and in PRAN
audits: 0.2% (Polaner 2012 Level IV, n=14,917) to 1.2% (95%CI 1.1 to 1.3) (Taenzer 2014b Level IV,
n=53,564); with the most recent providing specific adverse effect and not overall complication
incidence (Walker 2018 Level IV, n=104,393).
Younger age is associated with higher incidence of complications: neonates and infants vsolder children (OR 2.9; 95%CI 1.2 to 7.0) (Wong 2013a Level III-2, n=3,152); 1.13% for neonates vs0.3–0.8% older children, particularly dosing error (0.3% <12 mth vs 0.07% >12 mth) (Llewellyn
2007 Level IV, n=10,633); and 0.4% for infants <6 mth vs 0.1% >6 mth of age (Ecoffey 2010 Level IV,
n=3,860 [infant] vs 27,272 [older]). A higher incidence of complications with neuraxial catheters(inclusive of catheter malfunction, catheter contamination and vascular puncture) of 13.3%(95%CI 9.8 to 17.4%) was reported in neonates in a USA multicentre safety analysis (Long 2016
Level IV, n=307). No complications resulted in long term sequelae, and the risk of a serious
complication was estimated as 0.3/10,000 (95%CI 0.08 to 1.8). In young children having alaparotomy and epidural ropivacaine/sufentanil for postoperative analgesia, the epidural
catheter was removed early in 35%, the most common reasons being inadequate analgesia andtechnical failure; further adverse effects were documented in 16 patients (18%) (BravenboerMonster 2019 Level IV, n=90).
Table 10.10 | Incidence of adverse effects in large-scale audits of paediatric regional analgesia
Study

Walker 2018 Level IV

Denominator

104,393 blocks; 41,004 neuraxial
GA 94%,

Years audited

PRAN Apr 2007
– Sept 2015

Adverse effects type and incidence
LAST

LAST 0.76/10,000:
3 seizures;
4 cardiac arrests

Dural tap,
PDPH

rates of duraltap:
86/10,000
lumbar
66/10,000
thoracic and10/10,000 for
caudalapproach;
7/11 patientswith PDPH
had anepidural blood
patch

PONS

Permanent neurological deficits:
0/10,000 (95%CI 0 to 0.4)
Transient neurological deficits(primarily sensory): 2.4/10,000 (95%CI
1.6 to 3.6); 92% resolving by 3 mth

Drug error

NS

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Death, cardiorespiratory
event/ arrest

NS

Pressure sore

NS

Bleeding

0/10,000 haematomas associated withneuraxial catheters (95%CI 0 to 3.5);
1 epidural haematoma with aparavertebral catheter

Compartment
syndrome

NS

Infection

29/92 catheter associated infections
treated with antibiotics

Study

Wong 2013a Level III-2

Denominator

3,152 epidurals

Years audited

Jan 1997–Dec
2011

Adverse effects type and incidence
LAST

0 (1 intravascular catheter;
unrecognised)

Dural tap,
PDPH,
intrathecal
placement

1 PDPH;
blood patchNS;
1 IT
placementunrecognised

PONS

1/3,152 permanent with residual left
sided 3–4/5 weakness of L5─S1 (blood
staining of dural sac)

Drug error

3

Death, cardiorespiratory
event/arrest

1 fatal cardiac arrest; 1 respiratory
depression

Pressure sore

3

Bleeding

NS (bar that in patient with PONS
above)

Compartment
syndrome

1

Infection

11 local of skin: 5 required antibiotics

Study

Ecoffey 2010 Level IV

Denominator

31,142 blocks; 11,418 neuraxial
GA 96%

Years audited(ADARPEF II)
Nov 2005–Oct
2006

Adverse effects type and incidence
LAST

5.1/10,000 (95%CI 3 to 8):
1 convulsion; 15 cardiac: 2 ECGchange, 13 arrhythmia; (134 reports ofpositive test doses excluded fromadverse event assessment)

Dural tap,
PDPH, total
spinalanaesthesia

10 dural taps
0 PDPH
1 total spinal
anaesthesia

PONS

5 of short duration (18 h–3 wk);
0 permanent

Drug error

1 leading to
LAST in infant

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Death, cardiorespiratory
event/arrest

0 deaths/cardiac arrests; 1 total and2 high spinals: requiring short term
ventilation <12 h

Pressure sore

NS

Bleeding

NS

NS

Infection

1 localCompartment
syndrome

Study

Llewellyn 2007 Level IV

Denominator

10,633 epidurals

Years audited

Mar 2001–
Dec 2005

Adverse effects type and incidenceLAST

1 seizure post 2 boluses;
1 seizure/LAST at 24 h high end dosing

Dural tap,
PDPH, blood
patch

5 PDPH,
1 blood patch

PONS

1 permanent (peripheral nerve);
1 cauda equina; 5 resolved over 4–10
mth (2 concurrent spinal cord insult:
1 haematoma with rods, 1 impaired
blood supply)

Drug error

13

Death, cardiorespiratory
event/ arrest

0 deaths/cardiac arrests; 2 respiratoryarrests 1 total spinal and 1 with opioidand epidural bolus; ventilated <24 hPressure sore

33

Bleeding(1 possible haematoma mentioned in
PONS above in patient with
2 epidural catheters attributed to rod
placement in scoliosis surgery)

Compartment
syndrome

4 (not masked
by epidural)

Infection

2 epidural abscesses; 1 meningism;25 localStudy

Giaufre 1996 Level IV

Denominator

24,409 blocks; 15,013 neuraxial

Years audited

May 1993–
April 1994
(ADARPEF I)

Adverse effects type and incidence
LAST

7 LAST: 2 convulsions; 1 arrhythmia;
2 delayed arrhythmia (with overdose);2 “subclinical”

Dural tap,
PDPH

2 duralpuncture; 2
PDPH; 4 total
spinalPONS

2 transient <8 hDrug error

NS

Death, cardiorespiratory
event/ arrest

1 apnoea secondary to excess epiduralmorphine

Pressure soreNS1014 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

Bleeding

NS

Infection

1 local burn from skin preparation
solution/heated mattress; 1 rectal
puncture (with caudal) without
sequelaeCompartment
syndromeNS

Table 10.10 legend
ADARPEF = French-Language Society of Paediatric Anaesthesiologists; IT: intrathecal; LAST: local
anaesthetic systemic toxicity; NS: none specified; PDPH: postdural puncture headache;
PONS: postoperative neurological symptoms; PRAN: Paediatric Regional Anesthesia Network.

Local anaesthetic systemic toxicity
Accidental intravascular injection and LAST remain high-risk complications of caudal andepidural analgesia. It is reported to occur rarely: 0.76 to 5 in 10,000 (see Table 10.10) andmay be less common in paediatric populations than in adults (Neal 2018 GL ). As the sacrum islargely cartilaginous during infancy and early childhood, vascular puncture can occur (38 in
6,011) (Polaner 2012 Level IV) and there is an increased risk of injecting local anaesthetic into
the highly vascular medullary space of the sacrum (Veyckemans 1992 Level IV). Sevofluraneattenuated cardiovascular responses to adrenaline 0.5 mcg/kg IV less than halothane andmay be a better agent to facilitate detection (Kozek-Langenecker 2000 Level III-2). Changes in Twave amplitude can be observed in 91% of patients within 1 min of IV injection of 0.1 mL/kg
of lidocaine 1%/adrenaline 5 mcg/mL (and >25% change measured in 94%) (Varghese 2009
Level II, n=68, JS 4); this is a sensitive way of detecting intravascular injection. Almost all
regional blocks are performed under general anaesthesia in children but there is no clear
evidence that this obscures early signs of LAST (Taenzer 2014b Level IV; Bernards 2008 Level IV).
In the PRAN audit, 5 of 7 LAST events occurred in association with neuraxial block (see Section
10.6.1.3 for detail of the peripheral block associated events): 3 caudal single injections,
1 subarachnoid block and 1 thoracic epidural (Walker 2018 Level IV, n=59,069 [neuraxial]). Fourwere infants resulting in a greater risk of severe LAST for <6mth vs >6 mth of OR 7.4 (95%CI
1.3 to 39.3).
Paediatric patients with LAST (neonates to 18 y) have been successfully resuscitated with 20%
lipid emulsion (Presley 2013 Level IV SR [14 case reports]; Gitman 2019 NR). In conjunction withadvanced life support resuscitation, it is recommended as an early intervention (Neal 2018 GL;
AAGBI 2010 GL) (see also Section 4.4.3). Dosing recommendations are the same as for adults: if<70 kg, 1.5 mL/kg bolus (can be repeated twice every 5 min for persistent cardiovascularcollapse) and infusion 0.25 mL/kg/min (increased to 0.5 mL/kg/min if hypotension persists),
continuing for 10 min after attaining circulatory stability; the maximum cumulative
recommended dose is 12 mL/kg. Adverse effects when higher doses of 20% lipid emulsion wereused to treat LAST have been reported: hypoxia and V/Q mismatch occurred in a 3 y old child(dose 15.5 mL/kg) (Shenoy 2014 CR), and severe hyperlipidaemia, metabolic acidosis and raised
lactate associated with hypersomnolence, tachypnoea and tachycardia occurred in an 11 y oldgirl (dose 66 mL/kg) (Corwin 2017 CR); both patients made full recoveries.
Postoperative neurological symptoms
Neurological damage attributable to paediatric regional analgesia is rare (see Table 10.10). PRAN
publication has reported an overall event rate of no permanent neurological deficits (95%CI 0 to
0.4/10,000), and very low incidence of transient neurological deficits of 2.4/10,000, with similarrisk for neuraxial and peripheral blocks (Walker 2018 Level IV, n=104,393). The risk of transient
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neurological deficits or LAST combined was lower in patients having their blocks under generalanaesthesia vs awake/sedated, including when adjusted for age (OR 2.93; 95% CI 1.34 to 5.52)(Walker 2018 Level IV, n=104,393).
The prior UK audit reports a similar incidence of postoperative neurological symptoms(PONS) to PRAN audits, with two events with residual symptoms at 12 mth: one cauda equina
syndrome resulting from a drug volume error and one peripheral nerve injury (Llewellyn 2007
Level IV, n=10,633). Five other cases of peripheral or nerve root damage were of short duration:
three resolved spontaneously, two required chronic pain referral and gabapentin but resolved
by 10 mth. The two previous French audits report only transient PONS events (Ecoffey 2010
Level IV, n=31,142; Giaufre 1996 Level IV, n=24,509); a single centre audit reports one permanent
PONS event likely related to epidural insertion (Wong 2013b Level IV, n=3,152) and a survey reports
two permanent events in two infants (Flandin-Blety 1995 Level IV, n=2).
Care of insensate body regions is important post PRA as prolonged block/immobility may
result in nerve compression, accompanied by neurological deficit or neuropathic pain (Symons
2008 CR).
Infection
Local skin infection is variably reported (see Table 10.10), with Staphylococcus aureus the mostcommonly identified organism (Llewellyn 2007 Level IV, n=10,633 [paediatric epidurals]). This UK audit
reported three serious infections: two epidural abscesses and one meningism. The PRAN audit
reported one epidural abscess (in a 2 mth old with a lumbar epidural catheter removed on POD
4 that required surgical intervention and fully recovered) and 92 cases of local cutaneous
infection (53/10,000; 95%CI 43 to 64) (Walker 2018 Level IV, n=18,065 [catheters]). Most weretreated with catheter removal only; 29 were treated with antibiotics. Risk of infection was higher
with neuraxial vs peripheral catheters (60 vs 26/10,000) and increased by 6.7% per catheter day:the median catheter duration for cases of infection vs no infection was 4 d vs 2. There were no
infections reported with single injection blocks. Additional cases of epidural abscesses associatedwith epidural catheters in children ≤2 y old that responded to antibiotics are reported from theUK (Desai 2016b Level IV, n=2) and USA (Suchar 2016 CR).
Bacterial colonisation of catheters was more commonly associated with caudal than lumbar
catheters (Kost-Byerly 1998 Level IV), however, no difference was found in odds of superficial
infection for caudal vs lumbar epidural catheters, or caudal vs thoracic epidural catheters (Walker
2018 Level IV, n=18,065 [catheters]).
Acute compartment syndrome and pressure sores
There have been reports of acute compartment syndrome (ACS) in adult epidural recipients;
in 4 of 8, the epidural was not felt to have masked the ACS (Klucka 2017 Level IV [PRISMA], 15 studies,n=20). In children, 6 events have been reported felt to not have been masked by the single
injection caudal (Klucka 2017 Level IV [PRISMA], 15 studies, n=20 [1 caudal epidural]) or epidural
infusion (Wong 2013b Level IV, n=3,152 [1 ACS]) and (Llewellyn 2007 Level IV, n=10,633) with no eventsin the PRAN database (see Table 10.10). Avoiding unnecessarily dense sensory/motor blockallows full assessment and may prevent delay in diagnosis of compartment syndrome (Johnson
2009 Level IV).
Appropriate staff education regarding pressure care and vigilant monitoring for pressure
areas to prevent sores is essential for patients receiving continuous regional analgesia (Llewellyn
2007 Level IV).
Dural puncture and post-dural puncture headache (PDPH)
The audits report variably on dural puncture and resultant total spinal or post-dural puncture
headache (PDPH) and the need for respiratory or blood patch intervention (see Table 10.10). The

1016 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENTPRAN audit reported the risk of unintentional dural tap with an epidural needle for the different
approaches as 86/10,000 (95%CI 66 to 112) for lumbar, 66/10,000 (95%CI 46 to 95) for thoracic
and a low incidence 10/10,000 (95%CI 7 to 14/10,000) for caudal (Walker 2018 Level IV, n=54,124[single injection & catheters]). Eleven (7%) patients with an unintentional dural tap reported PDPH,
of which 7 had an epidural blood patch. An 11 mth old who required three attempts for an
epidural insertion developed a CSF cutaneous fistula following removal of the epidural catheter
on POD 3; this resolved following a sterile skin suture and occlusive dressing (Rusy 2018 CR).
Bleeding/epidural haematoma
Vascular puncture is reported in association with PRA, generally without consequence, andepidural haematomas are rare. One audit included removal of an epidural catheter in a
coagulopathic patient without comment on the consequence (Wong 2013a Level IV). Two audits
report on epidural/dural sac blood with neurological sequelae; the former related to surgical rod
placement (Llewellyn 2007 Level IV) and the latter attributed to epidural placement (Wong 2013aLevel IV). The PRAN audit has reported no epidural haematoma related to epidural catheter
insertion/infusion (Walker 2018 Level IV, n=18,065 [epidural]). Two reports of bleeding
complications and motor deficit with neuraxial blocks have required surgical intervention: ananterior spinal artery arteriovenous fistula/pseudoaneurysm related to an epidural needle andspinal cord trauma was reported in a 5 y old (who fully recovered over 20 mth) (Alnaami 2013 CR);
and an epidural haematoma in a 12 y old with sickle cell disease, choledocholithiasis and mildly
deranged coagulation with a thoracic epidural catheter (who fully recovered by 6 mth)
(Sathyamoorthy 2017 CR). Otherwise, epidural haematoma in children occurs more commonly
spontaneously (40–50%), associated with anticoagulants (25–30%) and rarely in association withtrauma (usually falls) (Sim 2010 CR) (see also Section 5.6.5).
Deaths associated with epidural use
One survey (Flandin-Blety 1995 Level IV, n=24,005) and one retrospective audit (Wong 2013a Level IV,
n=3,152) have reported deaths in association with neuraxial block insertions: three infants – one
related to LAST, one possibly due to cerebral air embolism, one due to spinal cord ischaemia –and one child aged 6 y with cerebral palsy and carnitine deficiency, who had cardiac arrest withintravascular catheter migration of an epidural catheter and presumed bupivacaine toxicity(Wong 2010 CR). No deaths have been reported in the large scale audits (see Table 10.10).
Physiological effects of caudal injection
Following caudal injection of local anaesthetic with adrenaline (1 mL/kg, max 20 mL injected over
1 min) in infants and children (2.3 mth to 8.6 y), there was a transient rise in epidural pressurethat returned to baseline within 60 s (Goeller 2016 Level IV, n=31). Caudal injection under generalanaesthetic of both 1 mL/kg and 1.5 mL/kg of ropivacaine 0.15% increased optic nerve sheath
diameter (a surrogate for intracranial pressure) with a similar peak of 14% and 19% respectively
10 min following injection, normalising at 30 min (Lee 2017a Level II, n=80, JS 5).
Complications of caudal analgesia
An attempted US-guided caudal block in a 1 mth old infant having an inguinal hernia repair failed
in the context of an ongoing cerebrospinal spinal fluid leak presumably secondary to a lumbar
puncture on d 13 of life (Bruce 2015 CR). Rectal puncture is a risk of caudal injection that may be
increased by the presence of faecal loading and rectal distension (Sathianathan 2015 CR).

10.6.4 | Intrathecal opioids
Following cardiac surgery, IT morphine 20 mcg/kg prolonged time to first analgesia anddecreased postoperative morphine requirements but did not alter time to discharge from5th Edition | Acute Pain Management: Scientific Evidence

1017

intensive care (Suominen 2004 Level II, n=80, JS 5). Addition of IT tetracaine and morphine to IV
remifentanil decreased pain scores and analgesic requirements after early extubation (Golianu
2005 Level II, n=45, JS 3). Spinal morphine 2 mcg/kg vs placebo added to bupivacaine increased
time to first rescue analgesic (12 h ± 3.2 vs 8 ± 3.5) and reduced need for supplementary
analgesia (17 vs 60%) following hypospadias repair (Apiliogullari 2009 Level II, n=54, JS 5). In 3─17 yolds having ureteroneocystostomy or pyeloplasty, IT morphine (mean 4.4 mcg/kg) vs opioid via
PCA/NCA resulted in less patients receiving rescue opioid 0─16 h postoperatively (0─8 h: 14% vs
96 and 8─16 h: 33% vs 92), less rescue opioid (oral morphine equivalents: 5 mcg/kg/h vs 10), andsimilar adverse event rates (eg nausea and vomiting, pruritus: 75% vs 67%) including hypoxia (asa surrogate for respiratory depression: 9% vs 8%) (Putnam 2015 Level III-3, n=128). In children andadolescents (0.5 to 20 y) having laparoscopic urological surgery, IT morphine (4─5 mcg/kg) vsbupivacaine infiltration of port sites resulted in similar perioperative systemic opioid
requirement (Srinivasan 2016 Level III-3, n=130). Early postoperative opioid requirements, adverse
effects and LOS were not reported.
In infants undergoing lower abdominal and urological surgery, addition of fentanyl 1 mcg/kg(but not lower doses) to IT local anaesthetic prolonged the duration of analgesia and reduced
supplemental analgesic requirements (Batra 2008 Level II, n=58, JS 5). Fentanyl 0.2 mcg/kg added
to local anaesthetic prolonged block duration and reduced analgesic requirements after hernia
repair in infants (Duman 2010 Level II, n=50, JS 4).
Dose-responsiveness for IT opioids is not evident in adults; studies are too few to assess thisin children.
For the use of IT morphine in scoliosis surgery, see Section 10.6.6.

10.6.5 | Topical therapies
As is the case for addition of adjuvant to injectate, topical application can lead to systemic
absorption. Thus for effective comparison, a systemic comparator arm is desirable but rarely
employed in the below summarised RCTs.
Studies relevant to photobiomodulation use in paediatric dental, cleft and tonsillectomy are
not discussed here but are included in the adult Section 7.4.
10.6.5.1 | Tonsillectomy
Following tonsillectomy, topical application of bupivacaine and ropivacaine reduces pain scores
at 4–6 h vs saline (-1.3/10; 95%CI -1.67 to -0.9) (Grainger 2008 Level I, 2 RCTs [paediatric], n=71).
Regular dosing with lidocaine spray (1 RCT, n=40) vs saline improves pain scores post
tonsillectomy in children until the third postoperative day (Fedorowicz 2013 Level I [Cochrane],
6 RCTs [1 adult, 1 mixed, 4 paediatric], n=593 [397 children]).
No benefit was seen following single topical application of tramadol 5% over 0─24 h, butthereafter pain scores were reduced for 7 d (Akbay 2010 Level II, n=40, JS 5). Single tonsillar
applications of tramadol 40 mg vs ketamine 20 mg were superior to placebo (artificial saliva),
with similar pain scores and rescue analgesic requirements (0─24 h) (Tekelioglu 2013 Level II, n=60,
JS 5). Tonsillar application of ketamine 20 mg vs morphine 20 mg alone and in combination weresuperior to placebo (artificial saliva) with reduced rescue paracetamol use (0─24 h), but painscores were only reduced in PACU (Canbay 2008 Level II, n=60, JS 5).
Cryotherapy (ice lollipop) over 4 h reduced pain post-tonsillectomy in children 2─12 y at 0.5
and 1 hr (Keefe 2018 Level I [PRISMA], 1 RCT: Sylvester 2011 Level II, n=87, JS 3).

1018 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

10.6.5.2 | Acute otitis media
Acute otitis media is common in children. Topical local anaesthetic drops (benzocaine/ antipyrine
or lidocaine) used in acute otitis media, in addition to PO analgesia, are effective vs saline at
10 min (RR 2.13; 95%CI 1.19 to 3.80) and 30 min after instillation (RR 1.43; 95% CI 1.12 to 1.81)(2 RCTs, n=117) (Foxlee 2011 Level I [Cochrane], 5 RCTs, n=391). Superiority of local anaesthetic(amethocaine/ antipyrine) vs naturopathic drops (3–4 herbal extracts in olive oil) is notestablished in three RCTs (in addition to paracetamol in one RCT and amoxicillin in one RCT)
(3 RCTs, n=274 [analysed]).
10.6.5.3 | Acute mouth ulceration
In painful acute mouth ulceration in children, topical viscous lidocaine 2% did not improve oral
intake, with similar requirement for rescue analgesic at 1 h vs placebo (Hopper 2014 Level II, n=100,
JS 5). Lidocaine 2% gel was massaged onto mouth ulcers and reduced pain by 19.7/100 (18.3)
at 3 min vs placebo in children prior to dental work (Coudert 2014 Level II, n=64, JS 5).
Topical therapies (commonly Maalox®: lidocaine, aluminium hydroxide combined with
diphenhydramine syrup) are used 2nd line (to paracetamol and/or ibuprofen) by 42% of USA
paediatric emergency physicians at 15 centres (MacLellan 2017 Level IV, n=150 [surveyed]).
10.6.3.4 | Nasogastric tube insertion
For efficacy of sweet solutions in nasogastric tube insertion in neonates see Section 10.7.1.5. For
evidence of efficacy of topical and nebulised local anaesthetic and IN ketamine in children see
Section 10.7.2.6.
10.6.3.5 | Circumcision
Ring block is more effective (across all operative stages) than DPNB and both are more effective
than EMLA® which is more effective than placebo in awake infant circumcision (1 RCT, n=54)(Suresh 2014 Level I [PRISMA], 5 RCTs [EMLA®], n=266). EMLA® has shorter time to analgesic rescue
vs DPNB (4 RCTs, n=212); including in older children who received general anaesthesia (Salgado
Filho 2013 Level II, n=41, JS 4). EMLA®/sucrose 25% 2 mL /lidocaine ring block was more effective
vs EMLA®/sucrose/DPNB and EMLA®/sucrose (Sharara-Chami 2017 Level II, n=70, JS 5).
One study measured methaemoglobin plasma concentrations after EMLA® 2 gm application
for 90 min; these were elevated at 6 h but did not require treatment (Suresh 2014 Level I [PRISMA],
1 RCT: Lander 1997 Level II, n=54, JS 1). Of note, a neonate who developed acquired
methaemoglobinaemia following circumcision with topical EMLA® cream (and lidocaine
infiltration) was successfully treated with methylene blue ( Kuiper-Prins 2016 CR).

10.6.6 | Use of Paediatric Regional Analgesia (PRA) in specific paediatric surgicalprocedures
There are numerous small observational and interventional studies of variable quality assessing
various PRA techniques for many surgeries as outlined below. Despite this body of work,
heterogeneity in interventional and control arms (in PRA technique, medication combinations
and dosing) makes comparison of studies and performing meta-analyses difficult. Two
qualitative systematic reviews by the same author group concluded that more evidence isneeded to establish the effects of PRA techniques, on the postoperative pain outcomes for

5th Edition | Acute Pain Management: Scientific Evidence1019specific procedures (Kendall 2018 Level I [PRISMA], 40 RCTs, n=2,408; Suresh 2014 Level I [PRISMA], 73
RCTs, n=5,125).
Penile surgery: circumcision and hypospadias repair
Policy statements from the Royal Australasian College of Physicians ( RACP 2010 GL), the British
Association of Paediatric Urologists (BAPU 2007 GL) and the American Academy of Pediatrics(American Academy of Pediatrics Task Force on Circumcision 2012 GL) emphasise the need for effective
analgesia for neonatal circumcision.
In boys (infants to adolescent) who also received a general anaesthetic, a dorsal penile nerve
block (DPNB) provides similar analgesia to a caudal block with similar need for rescue analgesia(RR 1.25; 95%CI 0.64 to 2.44) (4 RCTs, n=336) (Cyna 2008 Level I [Cochrane], 10 RCTs [5 RCTs DPNB],
n=721; Canakci 2017 Level II, n=60 JS 1), and is as or more effective with a longer duration than post
EMLA® cream application (Suresh 2014 Level I [PRISMA], 5 RCTs [EMLA®], n=266). PONV rates are alsosimilar (RR 1.88; 95%CI 0.70 to 5.04) (4 RCTs, n=336) with more leg weakness in caudal recipients(RR 10.7; 95%CI 1.3 to 86.1) (2 RCTs, n=110) (Cyna 2008 (Level I [Cochrane], 10 RCTs, n=721). However
in a single (PRAN participant) institution, DPNBs (landmark technique; surgically inserted at
cessation) were inferior to caudal blocks (often containing clonidine) with higher pain scores (OR2.7; 95%CI 1.7 to 4.4) and perioperative opioid requirement (OR 5.2; 95%CI 3.3 to 8.1) (Chan 2018
Level III-2, n=738). Caudal block vs parenteral analgesia does not reduce PONV (RR 0.61; 95%CI
0.36 to 1.05) or the need for early or later rescue analgesia (RR 0.41; 95%CI 0.12 to 1.43) (Cyna2008 Level I [Cochrane], 4 RCTs [parenteral], n=235). There is no clear analgesic intervention
recommendation; the clinical decision is influenced by perceived failure rates, risk/benefit ofparenteral analgesia and side effects especially leg weakness in children old enough to walk(Suresh 2014 Level I [PRISMA], 13 RCTs [circumcision]; Cyna 2008 Level I [Cochrane], 10 RCTs [caudal],
n=721; Brady-Fryer 2004 Level I [Cochrane], 35 RCTs [14 DPNB], n=1,984; Bellieni 2013 NR 14 RCTs [9DPNB], n=1,192) (2-3 RCT overlap).
Landmark technique DPNB has a failure rate of 10% (Faraoni 2010 Level II, n=40, JS 3) to 30%(O'Sullivan 2011 Level II, n=66, JS 5; Chan 2018 Level III-2). For US-guided DPNB there are at least
two described techniques ( Qian 2015; Sandeman 2007). Compared to landmark technique, USguided DPNB reduced postoperative pain scores and increased time to first analgesic 9.5 h vs
1 (Faraoni 2010 Level II, n=40, JS 3), reduced postoperative analgesic requirements (6 vs 38%),
with improved success rates (eg to 97%: O'Sullivan 2011 Level II, n=66, JS 5; Qian 2015) andreported increase in procedure time (Sandeman 2011 Level III-2, n=216 [101 DPNB] ) by ≈10 min(Faraoni 2010 Level II, n=40, JS 3).
There are insufficient controlled trials (DPNB vs placebo or sham, topical local anaesthetic orring block; local anaesthetic vs placebo or ring block; ring block vs no treatment) to rank theefficacy of local anaesthetic techniques for circumcision in awake neonates ( Brady-Fryer 2004
Level I [Cochrane], 35 RCTs, n=1,984; Bellieni 2013 NR) (2 RCT overlap). As topical local anaesthetic
cream only partially attenuates the pain response to circumcision, more effective analgesic
techniques are recommended. In one further RCT, EMLA® cream/PO sucrose 25% 2 mL/ lidocaine
ring block was more effective than EMLA®/PO sucrose/lidocaine DPNB (surgically inserted) andEMLA®/sucrose (Sharara-Chami 2017 Level II, n=70, JS 5).
For circumcision, nerve stimulator-guided pudendal nerve block vs DPNB had lower painscores, reduced analgesic requirement and provided longer duration of analgesia ( Naja 2011
Level II, n=60, JS 3) up to 18 h (Tutuncu 2018 Level II, n=85, JS 5). For hypospadias repair, nerve
stimulator-guided pudendal nerve block vs caudal block had lower pain scores, reduced analgesic
requirement and provided longer duration of analgesia vs local anaesthetic alone ( Kendigelen
2016 Level II, n=81 JS 5) and with clonidine 1 mcg/kg (Naja 2013 Level II, n=80, JS 5). Studies conflictin their results for DPNB vs caudal block for this surgery: a high success rate with both blocks was

1020 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

reported (DPNB 93% vs caudal 98%), with higher postoperative analgesic requirements for DPNB
vs caudal (70% vs 44%) (Seyedhejazi 2011 Level II, n=85, JS 2); while a second RCT had longer time
to first rescue analgesia for DPNB vs caudal (5 h vs 3.7) and reduced morphine requirement 0─48 h(Kundra 2012 Level II, n=54, JS 4).
An association has been suggested between caudal analgesia and postoperativecomplications including urethrocutaneous fistula or glanular dehiscence in hypospadias: 19% vs
0 DPNB recipients (Kundra 2012 Level II, n=54, JS4); aOR 13.4 (95%CI 1.8 to 101.8) (Taicher 2017
Level III-2, n=326 [230 caudal]); OR 2.1 (95% CI 1.14 to 3.8) for postoperative complications overall,but similar fistula incidence (Kim 2016 Level III-2, n=342 [216 caudal]) countered by OR 0.75 (95%CI
0.33 to 1.68) (Zaidi 2015 Level III-2, n=135 [45 fistulae]) and similar complication rates in hypospadias
surgical patients who received caudal vs DPNB (OR 2.4; 95%CI 0.9 to 6.4) (Braga 2017 Level III-2,
n=518 [367 caudal]) including vs GA alone (Splinter 2019 Level III-2, n=764 [825 procedures; 87%
caudal]). The latter studies proposed additional factors that were positively associated in theunivariate analysis such as hypospadias type (eg proximal meatus), surgery type and duration.
Caution must be exercised in interpreting these retrospective observational studies assessing
association for clinical significance, and the outcome scrutinised for biological plausibility.
Inguinal surgery
Inguinal surgery includes inguinal hernia repair, hydrocoele and testicular operations. Allabdominal wall truncal blocks and caudals have been used for this surgery (see earlier individual
sections for II/IHNB, PVB, ESPB, TAPB, TMQLB comparisons eg with surgical site infiltration andsee also Section 10.6.3.2 for caudal).
Two systematic reviews of inguinal surgery conflict in their conclusions on the analgesic
efficacy of single injection caudal block vs II/IH nerve block and/or wound infiltration. The firstfound single injection caudal block with local anaesthetic reduces the number of patientsrequiring rescue analgesia early 0─4 h (RR 0.81; 95%CI 0.66 to 0.99) (13 RCTs, n=789) and late 4─24 h(RR 0.81; 95%CI 0.69 to 0.96) (9 RCTs, n=532) on POD 0 (Shanthanna 2014 Level I [PRISMA], 17 RCTs,
n unspecified). In this setting, caudal block increases motor block (RR 2.59; 95%CI 1.29 to 5.20) (6RCTs, n=469) and urinary retention (RR 2.23; 95%CI 1.27 to 3.91) (5 RCTs, n=429). The parallel lower
quality systematic review found no difference in pain intensity at 1 h, or use of rescue analgesia(Baird 2013 Level III-2 SR, 13 studies n=733) (9 RCT overlap). The efficacy of different volumes of caudal
local anaesthetic has been assessed for inguinal surgery. One RCT found 0.75 mL/kg was more
effective than 0.5 mL/kg (Akpoduado 2017 Level II, n=56, JS 3); while another found no difference
between 0.6 vs 0.8 and 1 mL/kg (Marjanovic 2017 Level II, n=40, JS 2).
Failure rates for II/IHNB are variable (as they are for caudal see Section 10.6.3.2), reported as30─39% for landmark technique (Lim 2002 Level II, n=90, JS 3; Weintraud 2008 Level III-2, n=62). While
US-guidance may reduce failure rates for II/IHNB (eg to 6%: Weintraud 2009 Level II, n=66, JS 3;
Willschke 2005 Level II, n=100, JS 3) and possibly improve safety over the landmark technique(Suresh 2014 Level I [PRISMA], 15 [II/IHNB], n=1,046).
The effect of the addition of clonidine 1─2 mcg/kg to blocks for this surgery has not beenadequately assessed (Suresh 2014 Level I [PRISMA], 22 RCTs [inguinal: 2 clonidine], n=1,598; Seyedhejazi
2014 Level II, n=66, JS 2). See also PNB Adjuvant Section 10.6.2.6 and Neuraxial adjuvant Section
10.6.3.3.
Umbilical hernia repair
Analgesia for this common paediatric surgery is covered in the rectus sheath block (RSB) section(see 10.6.2.3), with no data specific to TAPB for this surgery to date.

5th Edition | Acute Pain Management: Scientific Evidence1021

Pectus excavatum repair
Pectus excavatum repair (including minimally invasive repair of pectus excavatum, Nuss andRavitch procedures) is painful surgery typically performed in adolescents. Thoracic epidural has
been shown to be effective (Frawley 2016 Level IV, n=217 [all epidural]), and similar or superior tosystemic analgesia. Epidural analgesia (bupivacaine or ropivacaine with fentanyl orhydromorphone) vs PCA (morphine, fentanyl or hydromorphone) for Nuss surgery reduced
postoperative pain scores at 12 h (WMD -1.12/10; 95%CI -1.61 to -0.62) (4 studies, n=196) and 48 h
(WMD -0.85; 95%CI -1.62 to -0.07) (6 studies, n=365) but not at other times; with no differences
between secondary outcomes (eg rescue analgesia, adverse events, LOS) (Stroud 2014 Level III-3
SR, 6 studies, n=430). While three epidural infusion regimens have been compared: bupivacaine
0.125%/fentanyl 5 mcg/mL was least effective with higher pain scores by ≈0.9/10 vs bupivacaine
0.125%/hydromorphone 10 mcg/mL vs ropivacaine 0.1%/hydromorphone 20 mcg/mL on POD 1,
but not later (Siddiqui 2016 Level III-2, n=72).
With the expansion of available regional analgesic techniques, there is no consensus on
postoperative pain management for pectus excavatum repair: 91% of respondents in aninternational survey (North America, Europe, Asia and Australia) reported thoracic epidural as
the primary analgesic modality for minimally invasive pectus excavatum repair or Nuss
procedure, with 27% concomitantly using PCA opioid ( Muhly 2014 Level IV, n=58). While USA
registry data reported less frequent use of epidurals (34%); pain scores and postoperative opioid
consumption were lower with an epidural catheter vs no regional analgesic technique or awound catheter, and achieved similar analgesia to paravertebral catheters (Muhly 2019
Level III-2, n=331 [114 epidural]; Stroud 2014 Level III-2, n=331). Epidural recipients had longer time
to ambulation (vs PVB CPNCs), higher rates of urinary catheterisation and longer LOS (median 4
d vs 3). While LOS was similar vs PCA only in a low quality RCT, where epidural failure rate was
22%, PCA was used during transition from epidural to orals for 19% and no detail of infusion
adjuvant or opioid use for either arm was provided (Desai 2016a Level II, n=110, JS 1). Longer LOS
for epidural recipients by 1─3 d is consistently reported in small and retrospective pectus
excavatum surgery studies below.
Pain outcomes were mixed where thoracic epidural infusion:• Provided equivalent analgesia vs PVB CPNC infusions (US-guided; bilateral) (Muhly 2019
Level III-2, n=331 [56 paravertebral, 114 epidural] Hall Burton 2014 Level III-2, n=20);• Resulted in lower pain scores and opioid use postoperatively vs PVB CPNCs and intercostal
nerve catheters, but LOS was shortest with PVB CPNCs (mean 2.0 d vs 4.0 vs 4.9) (Loftus
2016 Level III-2, n=137);• (With adjuvant hydromorphone 10 mcg/mL) achieved similar pain scores vs woundcatheter recipients (who also received hydromorphone PCA, low dose gabapentin
100─200 mg three times daily and clonidine patch 50 mcg/d) (Choudhry 2016 Level III-3,n=32);• Achieved lower pain scores vs wound catheter recipients (Kabagambe 2018 Level III-2, n=31;
Thaker 2019 Level III-3, n=124) but higher PCA requirements in a study exploring the additionof preoperative self-hypnosis training (Manworren 2018 Level III-2, n=53);• (With adjuvant hydromorphone) had higher (Keller 2016 Level III-2, n=52) or similar
postoperative opioid use and pain scores vs intercostal nerve cryoablation (Harbaugh
2018a Level III-2, n=32);• Had similar pain scores vs single injection intercostal nerve block (0.25% bupivacaine)
and/or PCA (Schlatter 2019 Level III-2, n=173);• Resulted in higher pain scores from POD 2─5 vs IV parecoxib 1 mg/kg (max 40 mg) BD(Yang 2015 Level III-2, n=120 [14 parecoxib]);

1022 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT• (With adjuvant clonidine 0.6 mcg/mL)/ketorolac/PCA had similar pain scores but greater
opioid use vs multimodal analgesia with no regional analgesia (paracetamol, NSAID, PCA,
gabapentin, clonidine patch, diazepam) (Man 2017 Level III-3, n=50); and• Resulted in greater postoperative opioid requirement and more minutes in severe pain(≥7/10) vs multimodal analgesia (including some receiving intraoperative methadone [0.1mg/kg max 7.5 mg]) (Singhal 2016 Level III-3, n=124). There was no difference in adverse
effects, although respiratory depression was not reported.
While two non-epidural studies show benefit for PRA in addition to PCA opioid, where USguided bilateral intercostal nerve blocks reduced early pain scores (0─6 h) and opioid
requirements in PACU and 0─24 h vs saline blocks (Luo 2017 Level II, n=62, JS 4) and US-guided
bilateral single injection thoracic PVB reduced pain scores by >2.5/10 vs PCA opioid alone at alltime points with lower PCA opioid use 0─48 h postoperatively (Qi 2014 Level II, n=30, JS 2).
Scoliosis surgery
Intrathecal and epidural opioids in posterior spinal fusion for idiopathic scoliosis
Studies of IT opioid dosing in children and adolescents having scoliosis surgery have used larger
doses on a per kg basis than adult studies. Doses of ≥9 mcg/kg are associated with respiratorycomplications and PICU admission.
IT opioids given preoperatively reduced blood loss and provided good analgesia in theimmediate perioperative period: morphine 5–15 mcg/kg and/or sufentanil 1 mcg/kg(Eschertzhuber 2008 Level II, n=46, JS 5) and morphine 12 mcg/kg (Lesniak 2013 Level III-3, n=256). IT
morphine (7.5 mcg/kg) vs extended release epidural morphine (150 mcg/kg) had similar time to
first PCA use and postoperative IV PCA morphine use 0─48 h (Cohen 2017 Level II, n=71, JS 4). Painscores differed relating to the kinetics of the epidural preparation and were lower with IT
morphine from 0─4 h, similar from 8─24 h, and lower with extended release epidural morphinefrom 28─36 h.
IT morphine prolonged time to first IV morphine: 22.9 h for ≥20 mcg/kg (mean 24) vs 16.7 h
for 9─19 mcg/kg (mean 14) vs 6.6 h with no IT morphine (Tripi 2008 Level III-2, n=407). This was at
the expense of respiratory depression (15.2% vs 2.7 vs 1.5) and PICU admission (17.4% vs 2 vs 0).
Pruritus (4─9%) and PONV incidence (25─30%) was similar. IT morphine (3–7 mcg/kg) combinedwith 2–5 d epidural infusion of ropivacaine and/or fentanyl (Ravish 2012 Level III-3, n=146) or
bupivacaine/hydromorphone epidural infusion (Milbrandt 2009 Level III-2, n=138) provided
superior analgesia vs IV PCA opioid alone.
Continuous epidural infusion with hydromorphone only 5 mcg/mL at 60─80 mcg/h (with10 mcg bolus q30 min prn) achieved adequate analgesia in 95% of adolescents (Hong 2016
Level IV, n=56). No serious adverse effects were reported but subsequently, the same groupcompared IT morphine vs a lower dose epidural hydromorphone infusion (40─60 mcg/h and5 mcg bolus q30 min prn), where 9 mcg/kg IT (Li 2018b Level III-3, n=56) reduced pain scores on
POD 0, while 12 mcg/kg IT (Hong 2017 Level III-2, n=40) only lowered PACU pain scores. In bothstudies, the IT group had shorter time to ambulation and urinary catheter removal.
Two serious adverse events occurred in the IT 9 mcg/kg group: one respiratory depression
and one with severe hypotension/bradycardia and both required ICU admission (Li 2018b
Level III-3, n=56).
Epidural local anaesthetic and or opioid in mixed scoliosis surgery
In children and adolescents having thoracolumbar spinal surgery (9 RCTs posterior spinal fusion [PSF]& 1 RCT anterior surgery for idiopathic scoliosis; 1 RCT of selective dorsal rhizotomy in cerebral palsy
patients), epidural analgesia (local anaesthetic, opioid or both) vs systemic analgesia reduces painscores at 72 h at rest (MDs -0.65/10 to -1.32) (5 RCTs, n=157) and on movement (MDs -1.07/10 to
5th Edition | Acute Pain Management: Scientific Evidence1023

-1.51) (2 RCTs [1 anterior; 1 posterior approach], n=60), with more patients opening their bowels
within 48 h (RR 11.5; 95%CI 2.4 to 56.3) (2 RCTs, n=60) (Guay 2019b Level I [Cochrane], 11 RCTs, n=559).
There was no difference in POV (0─48 h), time to ambulation or hospital LOS.
Dual epidural catheter techniques have been effective after anterior (Guay 2019b Level I[Cochrane], 1 RCT: Blumenthal 2006 Level II, n=30, JS 3), and posterior (Guay 2019b Level I [Cochrane], 1
RCT: Blumenthal 2005 Level II, n=30, JS 3; Lavelle 2010 Level III-2, n=55) spinal fusion with improved
dermatomal spread after combined surgical approach (Ekatodramis 2002 Level IV, n=23). PCEA has
been effective with a high level of patient satisfaction in selected cases (Saudan 2008 Level IV,n=98). There is however a significant epidural failure rate within 24 h of 8.5–37% due to incorrect
placement, patency issues and the long wound length (Guay 2019b Level I [Cochrane], 1 RCT: Gauger
2009 Level II, n=38, JS 3; Ravish 2012 Level III-3, n=146).
In a comparison of two epidural morphine administration techniques for PSF for idiopathic
scoliosis, patient-controlled intermittent epidural bolus (PCIEB) (50 mcg/kg initial bolus and q1 hprn) vs PCEA (20 mcg/kg initial bolus then 10 mcg/kg/h with 5 mcg/kg q30 min prn) had nodifference in pain scores with less morphine in 24 h (median 5 mg vs 12.5), PON (16% vs 50%),
POV (8% vs 35%) and pruritus (17% vs 40%) (Erdogan 2017 Level II, n=44, JS 5).
In patients with neuromuscular disorders and restrictive lung disease having PSF, epidural
analgesia with ropivacaine 0.2% (4─6 mL/h) and systemic analgesia vs systemic analgesia alone(NSAIDs and pentazocine) reduced pain scores and frequency of rescue analgesia use in the first
3 d postoperatively (Saito 2015 Level III-3, n=10).
Wound catheter use in scoliosis surgery
Continuous bupivacaine infusion via a wound catheter reduced basal morphine use in idiopathic
scoliosis surgery (Ross 2011 Level III-3, n=244 [129 wound catheter]).
Cardiothoracic surgery
In paediatric cardiac surgery, caudal injection of various medications and combinations reduced
intraoperative and postoperative analgesia vs control in 9 studies and pain scores in three of fivestudies (Maharramova 2019 Level IV SR [PRISMA], 17 studies, n=2,159). In two of three studies
caudal/general anaesthesia vs general anaesthesia alone reduced the perioperative stressresponse (cortisol, blood glucose or IL-6 levels), and caudal vs control reduced LOS in four of fourstudies; the authors concluded the data quality was too poor to make any recommendations forcaudal analgesia use in this surgery.
Tonsillectomy
The assessment and comparison of efficacy of analgesia in tonsillectomy trials is challenged by
the variation in surgical technique both within and between trials. Due to the proximity ofsignificant vascular structures and nerves, peritonsillar infiltration and nerve block have inherent
risks which can result in severe complications (Kang 2001 Level IV, n=2; Weksler 2001 CR). RCTs of
infiltration with agents that are effective systemically should have a systemic arm for comparison
that permits assessment of additive risk vs analgesic benefit.
For discussion of topical local anaesthetic and topical ketamine in children see Section 10.6.5
and adult Section 8.6.7.3
Local anaesthetic infiltration or application
Various local anaesthetics by infiltration (5 RCTs) or topical application (2 RCTs) produced modest
reductions in pain (SMD 7─19/100 mm) vs placebo following tonsillectomy; this is a pooled value
with no subgroup analyses for paediatric patients (Grainger 2008 Level I, 13 RCTs [7 RCTs paediatric,
n≈356]) (see also adult Section 8.6.7.3). Infiltration with local anaesthetic solutions containing
adrenaline may reduce blood loss (Johr 2015 NR). Compared to placebo, bupivacaine 0.25─0.5%
infiltration alone (3 RCTs) and with adrenaline (3 RCTs) results in fewer children requiring

1024 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

additional analgesia across 0─4 h postoperatively (RR 0.62; 95%CI 0.48 to 0.80) (4 RCTs, n=163)
and lower pain scores at 12─48 h (5 RCTs, n=204), but with no difference in PONV (3 RCTS, n=121)(Sun 2010 Level I, 7 RCTs, n=286) (2 RCT overlap). However, patients who received infiltration withbupivacaine 0.25% 5 mL vs pre-emptive administration of IV tramadol 3 mg/kg had higher
postoperative pain scores by 0.83/10 (95% CI 0.47 to 1.2) and required more postoperative
rescue analgesia (81% vs 57), with no difference in PONV (Teunkens 2019 Level II, n=200, JS 4).
Systemic or peritonsillar infiltration of dexamethasone
Peritonsillar infiltration pre-incision of dexamethasone as a comparator arm (and not as an
adjuvant) (in single doses of 0.3 to 1 mg/kg, with 0.5 mg/kg the most studied dose) was superior
to or equivalent to various active therapies, with all superior to placebo ( Titirungruang 2019
Level I, 7 RCTs [dexamethasone infiltration], n=728). In these heterogeneous RCTs, dexamethasone
infiltration vs placebo reduced postoperative pain at 0─24 h (OR -0.77; 95 %CI -1.02 to -0.53)(6 RCTs, n=528) and on POD 1 (OR -1.06; 95%CI -1.6 to -0.52) (7 RCTs, n=676) and reduced PONV
(OR 0.56; 95%CI 0.36 to 0.87) (7 RCTs, n=728).
Details of the active therapies in these RCTs reveals dexamethasone infiltration pre-incision:• Resulted in lower pain intensity vs IV 0.5 mg/kg (max 24 mg) with both routes superior toplacebo (Gao 2015 Level II, n=240, JS 4);• Was similar to bupivacaine 0.25% (3─5 mL) infiltration and postoperative topical lidocaine
spray (applied four times daily) with all treatment arms superior to placebo (Kaygusuz 2003
Level II, n=40, JS 2);• Lowered pain scores over 1 wk vs levobupivacaine infiltration 0.25% (with 5mcg/mL
epinephrine/adrenaline) with both superior to placebo; both active therapies increased
time to first analgesia similarly (Aysenur 2014 Level II, n=60, JS 4);• 0.3 mg/kg (max dose unspecified) was superior to placebo in lowering pain scores but
inferior to tramadol infiltration 0.1 mg/kg (with no systemic comparator) (Topal 2017
Level II, n=60, JS 2).
An earlier systematic review with 1 RCT overlap drew the same conclusions (Vlok 2017 Level I,
3 RCTs [2 paediatric, n=309]).

In contrast to the Cochrane review of systemic use of dexamethasone presented in 10.4.10,
IV dexamethasone 0.5 mg/kg (max 16 mg)/saline block (a comparator arm) was less effective
than pre-emptive local anaesthetic infiltration/IV placebo which reduced pain scores andanalgesia requirements 0─24 h and PONV in PACU (3.1% vs 15.6%) and 24 h (9.2% vs 26.6%) (Naja2017 Level II, n=129, JS 5). The combination of glossopharyngeal nerve block with IV
dexamethasone 0.15 mg/kg (max 8 mg) for tonsillectomy provided superior postoperative
analgesia to either in isolation (Mohamed 2009 Level II, n=150, JS 3). However, glossopharyngeal
nerve block in 2 children has been associated with postoperative airway obstruction (which
terminated the proposed RCT) (Bean-Lijewski 1997 Level III-3, n=8).
Peritonsillar infiltration or systemic NMDA antagonists
Three systematic reviews of peritonsillar infiltration of ketamine for tonsillectomy (see Section
10.4.7.1) summarise between 3 and 10 RCTs with 2 to 10 RCT overlap. The effect for peritonsillar
infiltration is positive vs placebo for pain scores at 60 min (WMD -1.71/10; 95% CI -2.12 to -0.22)
and reduced analgesic rescue (RR 0.51; 95%CI 0.26 to 0.9), with no systemic arm for comparison(Tong 2014a Level I, 10 RCTs, n=522). Adding IV ketamine 0.5 mg/kg to peritonsillar bupivacaine
0.25% was more effective than IV placebo/peritonsillar bupivacaine infiltration, and IV
placebo/placebo infiltration with significantly lower pain scores from 1─24 h, and longer time to
first analgesia (Inanoglu 2009 Level II, n=90, JS 5). A subsequent study compared peritonsillar

5th Edition | Acute Pain Management: Scientific Evidence1025ketamine administration vs PR and IV routes vs IV tramadol with similar pain scores in all four
treatment arms (Yenigun 2015 Level III-1, n=120).
The addition of peritonsillar magnesium 2─5mg/kg to local anaesthetic reduced pain scores(4 RCTs, n=230) and the number of analgesic requests (WMD −0.68; 95% CI −1.17 to −0.18) (3 RCTs,
n=180) (Vlok 2017 Level I, 4 RCTs [Mg], n=230).
Peritonsillar tramadol and pethidine
Adjuvant use of peritonsillar infiltration of tramadol added to local anaesthetic was beneficial topain scores (0.25─24 h), with no difference in PONV (Vlok 2017 Level I, 1 RCT: Honarmand 2015
Level II, n=120, JS 5). Adjuvant use of peritonsillar infiltration of pethidine added to local
anaesthetic reduced pain scores (at 3 h) and increased time to first analgesic use (Vlok 2017
Level I, 1 RCT: Elhakim 1997 Level II, n=80, JS 4).
Ophthalmological surgery
Peribulbar block
Compared to intraoperative opioids, pre-emptive peribulbar block reduced the occurrence of
intraoperative oculocardiac reflex and PONV during strabismus ( Chhabra 2005 Level II, n=109, JS3)and other paediatric ophthalmic surgery with lower postoperative pain scores from 0.5─6 h(Subramaniam 2003 Level II, n=85, JS 3; Deb 2001 Level II, n=50, JS 1). A peribulbar block may eliminate
the need for opioid in children down to 5 wk of age undergoing vitreoretinal surgery (Patel 2012
Level IV, n=6).
Sub Tenon block
For vitreoretinal surgery, a sub Tenon block vs intraoperative opioids reduced the occurrence ofthe oculocardiac reflex with longer time to first rescue analgesic vs IV fentanyl ( Chhabra 2009
Level II, n=196, JS 5); with benefit (Ramachandran 2014 Level II, n=67, JS 3; Kachko 2010 Level II, n=79,
JS 1; Gupta 2007 Level II, n=45, JS 2; Steib 2005 Level II, n=40, JS 5) and no benefit to the reflex and
PONV for strabismus surgery (Tuzcu 2015 Level II, n=40, JS 3).
For strabismus surgery, a sub Tenon block yielded a small clinical improvement in early
postoperative pain scores at 30 min only (and not from 1─2 h) vs no block (Tuzcu 2015 Level II,
n=40, JS 3); with reduced postoperative analgesic requirements vs placebo (Steib 2005 Level II, n=40,
JS 5). Pain scores after sub Tenon block with bupivacaine did not differ vs topical lidocaine 3.5%
gel or placebo (Enyedi 2017 Level II, n=50, JS 5). Sub Tenon block reduced emergence agitation post
strabismus surgery vs placebo (10.4% vs 27.2%) independent of anaesthesia maintenance type(sevoflurane vs propofol/remifentanil) (Seo 2011 Level II, n=250, JS 5).
For paediatric cataract surgery, sub Tenon blocks were superior to IV opioid with reduced
oculocardiac reflex, lower pain scores and longer time to first analgesic (median 16 h [range
2─13] vs 4 [0.5─8.5]) (Ghai 2009 Level II, n=114, JS 5).
The relative risks of the different eye block approaches have not been fully evaluated and ameta-analyses for the various techniques has not yet been performed.
Cleft lip and palate repair
Infraorbital nerve block for cleft lip repair
For paediatric cleft lip repair, there is low quality evidence that an infraorbital nerve block withlidocaine or bupivacaine may reduce postoperative pain vs placebo (SMD -3.54; 95%CI -6.13 to 0.95) and vs IV analgesia (SMD -1.50; 95%CI -2.40 to -0.60) (Feriani 2016 Level I (Cochrane], 8 RCTs,
n=353). An infra-orbital nerve block vs surgical site infiltration reduces supplemental analgesia
requirements (RR 0.05; 95%CI 0.01 to 0.18) and prolongs analgesia duration (MD 8.26 h; 95%CI
5.41 to 11.11). The addition of clonidine 1 mcg/kg to bupivacaine in a bilateral infraorbital nerve
block prolonged duration of analgesia (11.1 h vs 9.3); with no systemic comparator ( Feriani 2016
Level I [Cochrane], 1 RCT: Jindal 2011 Level II, n=50, JS 5). Adding opioids to bupivacaine infraorbital

1026 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

nerve block (with no systemic comparators) increases duration of analgesia from 18 to 24 h forfentanyl and from 29 to 35 h for pethidine (Feriani 2016 Level I [Cochrane], 2 RCTs: Mane 2011
Level II, n=45, JS 5; Jonnavithula 2007 Level II, n=40, JS 2). Infraorbital nerve block reduces
postoperative opioid requirement and emergence agitation but not pain scores vs placebo(Kendall 2018 Level I [PRISMA] 1 RCT: Wang 2015 Level II, n=100, JS 4). Future studies should
standardise the observation time and the instruments used to measure outcomes, have larger
sample sizes and stratify children by age group (Feriani 2016 Level I [Cochrane], 8 RCTs, n=353).
Bilateral suprazygomatic maxillary nerve block and palatal block
For cleft palate repair, bilateral suprazygomatic maxillary nerve block (SZMNB) with ropivacaine
vs saline reduced postoperative opioid requirements (Mesnil 2010 Level III-3, n=33), halved the 48 h
IV morphine (mean 104 mcg/kg; 95%CI 69 to 140 vs 205 mcg/kg; 95%CI 131 to 280) and reduced
the need for morphine infusion postoperatively (3.6% vs 31) (Chiono 2014 Level II, n=57, JS 4). Minor
adverse events related to the SZMNB have been reported: bleeding at the puncture site,
localised swelling (Mostafa 2018 Level II, n=60, JS 4) and an infrazygomatic cheek haematoma whichappeared on POD 1 and resolved by POD 5 (Chiono 2014 Level II, n=57, JS 4). US-guidance permitted
confirmation of needle location and assessed local anaesthetic spread (Sola 2012 Level IV, n=25 [50blocks]). Levobupivacaine 0.2% and bupivacaine 0.2% SZMNBs provide equivalent postoperative
analgesia (Mostafa 2018 Level II, n=60, JS 4).
Palatal block (combined nasopalatine, greater and lesser palatine nerve block) vs no block
reduced pain scores following cleft palate repair, and delayed time to first analgesia (18 h vs 6)
with less demands for rescue analgesia (Jonnavithula 2010 Level II, n=45, JS 3). The addition ofdexmedetomidine 1 mcg/kg to bupivacaine 0.25% for greater palatine nerve blocks reduced painscores across 0─24 h vs bupivacaine 0.25% alone and prolonged time to first analgesia (mean 22 h
vs 14.2) with no side effects (Obayah 2010 Level II, n=30, JS 3).
Bilateral SZMNB vs bilateral infraorbital nerve block for cleft lip and vs palatal block for cleft
palate surgery achieved similar postoperative pain scores, opioid consumption, complication andfailure rates (Echaniz 2019 Level II, n=120 [102 children], JS 4).
Interventions for the iliac bone graft donor site for cleft palate repair are described in Section
10.6.2.1 lower limb blocks.
Dental procedures
Outpatient dental procedures
Topical anaesthetics should be used prior to local anaesthetic injection to minimise discomfort
with needle penetration and injection (Kuhnisch 2017 GL). Local anaesthetic infiltration reduced
pain following dental extractions (Anand 2005 Level III-2); adding morphine 25 mcg/kg to the local
anaesthetic did not improve the quality or duration of analgesia ( Bhananker 2008 Level II, n=42,
JS 3). There is low quality evidence suggesting similar efficacy for local anaesthetics during routine
dental treatments with articaine achieving slightly more pain score reduction than lidocaine postprocedure (SMD 0.37) (4 RCTs, n=397) (Tong 2018 Level I [PRISMA], 6 RCTs, n=541); while inferior
alveolar nerve block was superior to buccal infiltration for mandibular molar extraction (1 RCT,
n=113) (Klingberg 2017 Level I [PRISMA], 8 RCTs, n unspecified) (3 RCT overlap). Use of local anaesthesia
for dental work is documented in children with rare medical diseases (Dougall 2017 Level IV SR[PRISMA], 3 studies, n=83).
The use of a computer assisted injection devices delivery device vs conventional infiltration
was not painful, with high success rates (Giannetti 2018 Level IV, n=66; Sixou 2015 Level IV, n=278[421 procedures]) and similar onset of effect for submucosal and buccal injection for 1st permanentmolar work (Kandiah 2012 Level II, n=30, JS 3) and less painful for buccopalatal injection ( Feda 2010
Level II, n=40 JS 1). A vibrating device did not reduce pain scores during local anaesthetic injection(Raslan 2018 Level II, n=40, JS 2; Roeber 2011 Level II, n=90, JS 4). A needleless jet system was inferior
5th Edition | Acute Pain Management: Scientific Evidence1027

to standard local anaesthetic infiltration, as it required more local anaesthetic supplementationand more patients reported post procedure pain (Arapostathis 2010 Level III-2, n=87 [174 proceduressplit mouth design]).
Eutectic Mixture of Local Anaesthetics (EMLA®) with audiovisual aid distraction reduced painscores during needle insertion and was superior to EMLA® alone, or topical benzocaine (20%)
with and without audiovisual aid distraction (mean 4.7/10 vs 5.7 vs 5.9 vs 7.4) (Agarwal 2017 Level
II, n=120, JS 1). Acupuncture at L14 improved pain levels with local anaesthetic injection (buccal
infiltration, intraligament injection and block analgesia): mean 2.3/10 (95%CI 1.5 to 3.1) vs 3.9(95%CI 3.0 to 4.7) (Usichenko 2016 Level II, n=49, JS 4). A Cochrane review did not find positive
benefit for hypnosis (Al-Harasi 2010 Level I [Cochrane], 3 RCTs, n=69). The addition of preoperative
systemic analgesic prior to orthodontic separator placement (without general anaesthesia) islikely of benefit (Ashley 2016 Level I [Cochrane], 5 RCTs, n=190).
See also adult Section 8.6.7.2 Acute postoperative dental pain.
Dental procedures under general anaesthesia
RCTs of local anaesthetic for children undergoing dental work with a general anaesthetic were
heterogeneous regarding injection site (intra-ligamental vs surgical site infiltration vs topical) andvaried in supplemental analgesics and follow-up (Parekh 2014 Level I [Cochrane], 14 RCTs, n=1,152).
This precluded pooling of results, with a suggestion for further good quality RCTs. The additionof local anaesthetic to IV ketorolac in dental restoration or extraction under general anaesthetic
does not improve quality of recovery vs IV ketorolac alone and young children may bite or chew
the anaesthetic cheek or lip (Townsend 2009 Level II, n=27, JS 5). ‘Best Clinical Practice Guidelines’
by the European Academy of Paediatric Dentistry recommend the routine use of local
anaesthetic agents with vasoconstrictors to slow systemic absorption, prolong analgesic effectand provide additional haemostasis (Kuhnisch 2017 GL).

KEY MESSAGES
1. Topical local anaesthetic does not adequately control pain associated with circumcision
in awake neonates (U) (Level I [Cochrane Review]).
2. Caudal local anaesthetic, dorsal penile nerve block (U) (Level I [Cochrane Review]) andring block (N) (Level II) provide effective perioperative analgesia for circumcision in
infants to adolescents.
3. Caudal local anaesthetic in addition to general anaesthesia for circumcision does not
reduce postoperative nausea and vomiting or the need for early rescue or otheranalgesia in children (infants to adolescents) when compared to parenteral analgesia (U)(Level I [Cochrane Review]).
4. In acute otitis media, topical local anaesthetic drops are effective in children comparedto placebo and equivalent to naturopathic drops (S) (Level I [Cochrane Review]).
5. For paediatric cleft lip repair, infraorbital nerve block with lidocaine or bupivacaine may
reduce postoperative pain versus placebo; duration is increased when opioids are added(with no systemic comparator) (N) (Level I [Cochrane Review]).
6. Epidural analgesia compared to systemic analgesia after spinal surgery in children
improves pain up to 72 hours postoperatively (N) (Level I[Cochrane Review]).
7. Local anaesthetics (by infiltration or nerve block) reduce pain scores post dental
procedures (N) (Level I [PRISMA]).

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8. Ketamine added to caudal local anaesthetic for paediatric day-stay surgery prolongs
analgesia but not motor block (U) (Level I [PRISMA]); however concerns regarding
neurotoxicity remain.
9. Dexamethasone (caudal, perineural or IV) prolongs the duration of analgesia of local
anaesthetic caudal (N) (Level I [PRISMA]) and peripheral nerve blocks (N) (Level II).
10. Magnesium added to caudal local anaesthetic blocks improves analgesia in children (N)(Level I [PRISMA]).
11. Clonidine (U) and dexmedetomidine (N) improve analgesia in children when added to
local anaesthetic caudal blocks, epidural infusions (Level I [PRISMA]) and peripheral
nerve blocks (N) (Level II).
12. Peritonsillar dexamethasone or peritonsillar ketamine may reduce pain scores following
paediatric tonsillectomy compared to placebo (in trials with no systemic comparatorarms) (N) (Level I).
13. Ultrasound guidance for epidural catheter insertion is a reliable predictor of depth toloss of resistance (or of epidural space), offers visibility of the needle and catheter andmay reduce bone contacts (N) (Level IV SR).
14. In children having cardiac surgery, caudal injections with various medication
combinations vs control reduces postoperative analgesia requirements and pain scores(N) (Level IV SR [PRISMA]).
15. In children having scoliosis surgery, the addition of epidural local anaesthetic infusion to
intravenous PCA morphine improves pain scores and patient satisfaction (U) (Level I) anddecreases postoperative nausea (U) (Level II).
16. Peripheral nerve blocks (S) (Level I [PRISMA]), wound infiltration and caudal local anaesthetic
provide effective analgesia after day-stay paediatric inguinal surgery (S) (Level II).
17. Epidural infusions of local anaesthetic in children provide similar levels of analgesia
compared to systemic opioid infusion (U) (Level II) and intravenous PCA (U) (Level III-3 SR).
18. Epidural opioids alone are less effective than epidural local anaesthetic or combinationsof local anaesthetic and opioid in children (U) (Level II).
19. Intrathecal opioids provide prolonged analgesia after surgery in children and reduce
blood loss during paediatric spinal fusion (U) (Level II). High doses of intrathecal
morphine in children have been associated with respiratory failure and intensive careadmission (N) (Level III-2).
20. Paediatric regional analgesia (peripheral nerve and neuraxial blocks as single injections
and continuous catheters) are effective (Level II) and safe analgesic techniques inchildren (S) (Level IV); continous peripheral nerve catheters have been used in hospitaland following discharge, with low secondary failure rates (N) (Level IV).
21. Ultrasound guidance to assist peripheral block and catheter placement has increased
block success (Level II) but not impacted the incidence of local anaesthetic systemic
toxicity or neurological complications in children; the latter having decreased
independently over time (N) (Level IV).

5th Edition | Acute Pain Management: Scientific Evidence1029

22. Continuous wound catheter infusions of local anaesthetic are effective (N) (Level II) andsafe analgesic techniques (N) (Level IV).
23. Caudal local anaesthetic blocks provide effective analgesia for lower abdominal, perineal
and lower limb surgery (Level II) and have a low incidence of serious complications (S)(Level IV).
24. Continuous ultrasound-guided caudal injection versus landmark technique increases
success of first puncture and lowers risk of vascular puncture and inadvertentsubcutaneous injection (N) (Level II); while permitting real-time visualisation of injectate
spread (N) (Level IV).
25. Sub Tenon block for paediatric ocular surgery achieved longer time to first analgesic
administration versus placebo or intravenous opioid (N) (Level II).
26. Complications of epidural infusions are rare; the rates are slightly higher in neonates
and infants versus older children (S) (Level III-2).
27. Continuous epidural infusions provide effective postoperative analgesia in children of
all ages (U) (Level III-2).
28. Continuous epidural infusions are safe in children of all ages (S) (Level III-2) if
appropriate doses and equipment are used by experienced practitioners, withadequate monitoring and management of complications (U) (Level IV).
29. Thoracic epidural, paravertebral catheters, wound catheters and intercostal nerve
blocks all provide effective analgesia for pectus excavatum repair surgery, with longer
hospital stays in thoracic epidural recipients (N) (Level III-3).
30. Placement of paediatric regional analgesia (peripheral nerve and neuraxial blocks assingle injections and catheters) in children under general anaesthesia is not associatedwith an increased rate of complications (S) (Level IV).
The following tick boxes represents conclusions based on clinical experience and expert
opinion: An association between urethral fistula formation complicating hypospadias repair andcaudal block has not been consistently reported; variation in anatomical presentationand surgical technique are more biologically plausible risk factors (N).
 Lipid emulsion (20%) has been used in successful resuscitation of paediatric patients(neonates to 18 years) with local anaesthetic systemic toxicity; dosing
recommendations are the same as for adults and higher doses have led to adverse
effects (N).
 Dosing practices for peripheral nerve blocks vary and concerningly doses sometimes
approach or exceed the accepted safe dose limit; this occurs more commonly inyounger children (N).

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10.7 | Management of procedural pain in children
Procedure-related pain is a frequent and distressing component of medical care for children,
their families and hospital staff (Atkinson 2009 NR; Kennedy 2008 NR). Repeated interventions
are often required and the level of pain and memory of the first procedure affect the pain
(Taddio 2009 Level II, n=240, JS 5; Noel 2012 Level IV), fear (de Vos 2012 Level IV) and distress (Chen2000 NR) associated with subsequent procedures (Kennedy 2008 NR). Poorly managed
procedural pain may also result in greater anxiety, pain and avoidance of health care as adults(Young 2005 NR). Studies suggest that minor procedures are still undertaken in children,
particularly neonates and infants, in the elective and emergency hospital setting without
evidence-supported pain management interventions (Bueno 2017 Level IV SR, 68 videos; Cruz2016 Level IV SR, 18 studies, n=3,156; Ali 2014 Level IV; Codipietro 2011 Level IV; Losacco 2011 Level IV;
Hoyle 2011 Level IV; MacLean 2007 Level IV).

The aim of procedural pain management is to minimise physical discomfort, pain,
movement and psychological disturbance without compromising patient safety. Management
may include analgesic agents via different routes of administration, concurrent sedation or
general anaesthesia and nonpharmacological methods. The choice of technique will dependon the age and previous experience of the child, the type of procedure, the expected intensityand duration of pain, the treatment environment and available resources (Atkinson 2009 NR;
Murat 2003 GL). Sedation alone must not be seen as an alternative to appropriate analgesia,
particularly when pain is expected after completion of the procedure. Further information isavailable from evidence based guidelines produced by various anaesthetic, paediatric andemergency physician associations (Green 2019b GL; Lago 2017 GL; Cote 2016 GL; Mace 2008 GL;
RACP 2005 GL).

10.7.1 | Procedural pain in the neonate
10.7.1.1 | Blood sampling, skin puncture and intravenous cannulation
Effective pain management is a desirable standard of care for preterm and term neonates andmay improve their clinical and neurodevelopmental outcomes (Hall 2014 NR). Multiple
interventions have been assessed and their use is strongly supported; combining interventions
appears to be more effective and is recommended ( Lago 2017 GL). Neonates in NICUs require
frequent painful procedures (mean 7.5─17.3 per day) (6 studies); however pain management
strategies in these studies are inconsistently applied (Cruz 2016 Level IV, 18 studies, n=3,156). Many
studies continue to be published on interventions such as breastfeeding, sweet solutions,non-nutritive sucking (NNS) and kangaroo care (ventral skin to skin contact with an adult); wherethese studies do not alter the conclusions of published systematic reviews, they have notbeen referenced.
Different techniques of blood sampling
In term neonates, venipuncture is less painful than heel lance (HL) (SMD -0.76; 95%CI -1.00 to 0.52) (5 RCTs, n=288), including when a sweet solution is administered (SMD -0.38; 95%CI -0.69 to-0.07) (3 RCTs, n=170) with less pain behaviour exhibited during and after the procedure and fewer
attempts required (SMD 0.34; 95% CI -0.43 to -0.25) (4 RCTs, n=254) (Shah 2011b Level I [Cochrane],
6 RCTs, n=478). Spring-loaded automated devices for HL reduced the pain behaviour exhibited vsmanual lance (Shah 2003 Level II, n=80, JS 5).

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1031

Topical local anaesthesia
Evidence-based recommendations could not be made regarding the use of topical local
anaesthetics for the prevention of needle related procedural pain in newborns (Foster 2017
Level I [Cochrane], 8 RCTs, n=506). This includes for venipuncture, IV cannulation, arterial puncture,arterial cannulation, HL, lumbar puncture (LP), supra-pubic aspiration of urine, peripherally
inserted central catheter (PICC) placement and intramuscular injection. Subsequently, for infants(<3 mth), EMLA® vs placebo, sucrose or breastfeeding did not reduce pain during (6 RCTs, n=742)
or at the end (4 RCTs, n=226) of venipuncture (Shahid 2019 Level I [PRISMA], 10 RCTs, n=907) (1 RCT
overlap). None of the RCTs reported clinical symptoms of methaemoglobinaemia; in two RCTs
(n=134) methaemoglobin levels were <5%. However, acquired methaemoglobinaemia in aneonate following circumcision with EMLA® (dose unknown) and lidocaine infiltration, which was
successfully treated with methylene blue has been reported (Kuiper-Prins 2016 CR).
Breastfeeding, supplemental breastmilk and sweet solutions
Breastfeeding
In term neonates, breastfeeding reduces pain scores, behavioural (cry), and physiological (heartrate) responses to skin puncture procedures when compared to positioning (swaddling andplacement in a crib), holding by the mother, maternal kangaroo care, no intervention, placebo,
pacifier use and PO sucrose or both, topical local anaesthetics and music therapy ( Benoit 2017aLevel I [PRISMA], 21 RCTs, n=1,764; Shah 2012 Level III-1 SR [Cochrane], 10 RCTs [breastfeeding], n=1,076)(0 RCT overlap). The effect in preterm neonates is not clear; studies are of limited number, andpreterm neonates often cannot breastfeed and are more likely to receive repeated painfulprocedures.
Supplemental breastmilk
Studies of supplemental/expressed breast milk report mixed effects vs sweet tasting solutions(5 RCTs), placebo (6 RCTs) and no intervention (3 RCTs), and inferiority to pacifier use and rocking(1 RCT each) (Benoit 2017a Level I [PRISMA], 21 RCTs, n=1,764; Shah 2012 Level III-1 SR [Cochrane], 10
studies [supplemental breast milk], n=1,002) (0 study overlap).
Sweet solutions
A systematic review pooled data for meta-analysis on all sweet solutions (sucrose 106 studies,
glucose 62 studies, non-sucrose sweetener 2 studies, honey and fructose 1 study each ) for proceduralpain in neonates (Harrison 2017 Level III-1 SR [PRISMA], 168 studies, n unspecified). Sweet solutions
overall vs placebo reduced composite pain scores (SMD -0.90; 95%CI -1.09 to -0.70) (50 studies,
n=3,341) and cry duration (SMD -23.18 s; 95%CI -28.89 to -17.47) (29 studies, n=1,775).
The most frequently studied intervention for managing procedural pain in preterm and term
infants is sucrose with or without NNS. Studies vary in concentration and volume of sucrose
administered, comparison group intervention and outcomes measured, meaning meta-analysis
for each research question typically only combines a few studies or pool heterogeneous data.
Studies specific to sucrose mostly support an analgesic effect at higher concentrations (>20%)
for HL (39 RCTs), venipuncture (10 RCTs), and intramuscular (IM) injection (4 RCTs); this effect may
be greater when combined with other interventions (eg NNS, swaddling) (Stevens 2016 Level I[Cochrane], 74 RCTs, n=7,049). There is high quality evidence in this review for the following:• For HL, 24% sucrose (0.5─2 mL) with NNS or sucrose 0.5 mL orally vs placebo in preterm
and term infants reduces pain score at 30 s (WMD -1.70/21; 95%CI -2.13 to -1.26) (3 RCTs,
n=278) and 60 s post procedure (WMD -2.14/21; 95%CI -3.34 to -0.94) (2 RCTs, n=164);• 24% sucrose (2 mL) vs placebo for term neonates reduces pain score during venipuncture(WMD -2.79/21; 95%CI -3.76 to -1.83) (1 RCT, n=213);

1032 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT• 24% sucrose (2mL) vs placebo for term neonates reduces pain score during IM injection(WMD -1.05/21; 95%CI -1.98 to -0.12) (1 RCT, n=232);• Evidence for effectiveness of sucrose for arterial puncture (1 RCT) and SC injection (2 RCTs)
is inconclusive.
Debate continues as to the optimal dose and administration of sucrose with one RCT
documenting a minimum effective dose of 0.1 mL of 24% sucrose (Stevens 2018 Level II, n=248, JS 3).
A separate review focussing on the efficacy and safety of repeated sucrose over multiple
procedures in neonates found limited evidence supporting its use to reduce pain scores andbehaviours (cry), with no adverse effects reported; no meta-analysis was possible (Gao 2016
Level I [PRISMA], 8 RCTs, n=782).
Sweet non-sucrose solutions via dropper, syringe or pacifier have shown efficacy forprocedural pain in preterm and term infants (Bueno 2013 Level I [PRISMA], 38 RCTs [35 glucose;
artificial sweetener, fructose, glycine, honey, maltitol, 1 RCT each; 36 skin puncture], n=3,785):• Glucose 10─50% (0.2─2mL) vs no intervention or water reduces pain scores during and/or
after HL (6 RCTs, n=322; no meta-analysis);• Glucose 20─30% (1─2 mL) vs water for HL reduces pain scores (WMD −3.61/21; 95%CI 4.58 to -2.63) (2 RCTs, n=124);• Artificial sweetener, maltitol or fructose vs water or no intervention for HL reduces painscores (1 RCT each);• Maltitol, artificial sweetener or honey vs water for HL reduces cry duration (1 RCT each);• Glucose 25─30% (1─2mL) vs glucose 10%, water, no intervention or EMLA® reduces painscores for venipuncture (11 RCTs, n=1,250, no meta-analysis);• Glucose 25─50% (1─2 mL) vs water for venipuncture reduces cry response (RR 0.80; 95%CI
0.66 to 0.96: NNT 6; 95%CI 3 to 20) (3 RCTs, n=130).
A further systematic review of Chinese studies on all sweet solutions for neonatal proceduralpain found similar results to the above reviews ( Huang 2019 Level III-1 SR [PRISMA], 31 studies,
n=4,999) (0 study overlap).
Paracetamol
Paracetamol given 30─60 min prior vs placebo does not reduce pain with HL (3 RCTs), and findings
are conflicting for eye examination (2 RCTs) (for further discussion, see 10.7.1.4); no metaanalysis was possible due to study heterogeneity (Ohlsson 2016 Level I [Cochrane], 9 RCTs, n=728). A
subsequent RCT found paracetamol was not more effective than sucrose 24% for managing pain
during PICC placement in preterm neonates (Roofthooft 2017 Level II, n=60, JS 4).
Opioids
Background morphine infusions in ventilated neonates had limited efficacy for acute proceduralinterventions in intensive care (Bellu 2008 Level I [Cochrane], 2 RCTs [procedures], n=965). An RCT of
PO morphine (100 mcg/kg) vs placebo in non-ventilated premature infants for HL or eye
examination was stopped early due to a high rate of respiratory depression requiring
resuscitation (20% vs 0%) (Monk 2019 Level II, n=31, JS 5). IN Fentanyl (mean dose 1.3 mcg/kg) has
been used in neonates in NICU having painful procedures (78% PICC insertion); respiratory
depression occurred in 26% (McNair 2018 Level IV, n=23).
Combination intervention in neonates: pharmacologicalIn preterm neonates, topical local anaesthesia EMLA® combined with PO sucrose 30% was more
effective than sucrose alone in reducing venipuncture-related pain (Biran 2011 Level II, n=76, JS 3).
In term neonates, the addition of liposomal lidocaine for venipuncture to sucrose did not confer
additional benefit (Taddio 2011 Level II, n=330, JS 5).
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For PICC placement, IV morphine bolus with topical amethocaine provided more effective
analgesia than morphine or amethocaine alone in preterm neonates ( Taddio 2006 Level II, n=132,
JS 5). In ventilated term and preterm neonates pre-treated with EMLA®, a glucose 30% pacifier
combination was inferior to sevoflurane (Bueno 2013 Level I [PRISMA], 1 RCT [sevoflurane]: Michel
2010 Level II, n=59, JS 2).
Nonpharmacological intervention alone and in combination
Many nonpharmacological interventions have been studied for procedural pain in preterm andterm neonates including NNS, swaddling/tucking, rocking/holding and kangaroo care. However,study designs are heterogeneous and prone to bias due to difficulty blinding interventions;caution interpreting results is required. A systematic review assessed the efficacy ofnonpharmacological interventions on pain reactivity (behavioural responses within 30 s ofpainful procedure) and immediate pain regulation (behavioural response >30 s after painfulprocedure) (Pillai Riddell 2015c Level III-I SR [Cochrane], 63 studies [32 HL, 17 vaccination,
8 venipuncture], n=4,905). It found:• NNS vs control reduces pain reactivity in term neonates (SMD -1.20; 95%CI -2.01 to -0.38)(5 studies, n=270) and improves immediate pain regulation in preterm (SMD -0.43; 95%CI 0.63 to -0.23) (5 studies, n=260) and term neonates (SMD -0.90; 95%CI -1.54 to -0.25) (7studies, n=325);• Swaddling/facilitated tucking vs control reduced pain reactivity in preterm neonates(SMD -0.89; 95%CI -1.37 to -0.40) (8 studies, n=331);• Rocking and holding vs control improved immediate pain regulation in term neonates(SMD -0.75; 95%CI -1.20 to -0.30) (2 studies, n=81);• NNS with pacifier/sucrose appeared superior to NNS alone (1 study, n=24), and facilitatedtucking appeared to have an additive effect to NNS in preterm neonates (1 study n=45);• There were smaller benefits for the following interventions: environmental modification(eg low noise and lighting, clustering procedures) and touch/massage interventions inpreterm infants; swaddling/facilitated tucking and familiar odours (familiarisation withvanilla 24 h prior to procedure) in term infants;• Subsequent to this review, olfactory stimulation from lavender, breast milk and amniotic
fluid vs control for HL reduced pain scores (2.91/7 vs 3.31 vs 3.90 vs 5.20) (Akcan 2016 Level
II, n=102, JS 2).
For vaccination, individual studies report NNS to be inferior to PO sucrose 20% (Liaw 2011
Level II, n=165, JS 3) and glucose 25% (Lima 2017 Level II, n=78, JS 2), whilst external warming was
superior to NNS alone and PO sucrose 25% alone (Gray 2012 Level II, n=47, JS 3).
Two RCTs combined interventions for repeated HL in preterm infants. NNS/PO sucrose
provides better pain relief than NNS or PO sucrose alone (Gao 2018 Level II, n=91, JS 3), whilst PO
sucrose 20% is superior to facilitated tucking, but facilitated tucking/sucrose does not confer
additional benefit to sucrose alone (Cignacco 2012 Level II, n=71, JS 5).
Kangaroo care appeared to be safe and reduce pain response to HL, venipuncture, and IM
injections; however, the degree of benefit was difficult to estimate and may not be large(Johnston 2017 Level III-I SR [Cochrane], 25 studies, n=2,001). For all procedures on preterm neonates,
kangaroo care vs standard care reduced pain score at 30 s (MD -3.21/21; 95%CI -3.94 to -2.47)(6 studies, n=267) and 60 s (MD -1.64/21; 95%CI -2.86 to -0.43) (4 studies, n=156). No difference
was seen between mothers and alternative kangaroo care providers in preterm neonates. Single
studies in this review comparing kangaroo care with other active interventions demonstrated
similar efficacy to breastfeeding but superiority to PO dextrose and glucose solutions. Kangaroocare combined with breastfeeding, or PO sucrose/dextrose solutions was superior to kangaroo

1034 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

care alone. A subsequent RCT found kangaroo care remained efficacious across three procedures(HL) with similar efficacy to PO sucrose 24% (Campbell-Yeo 2019 Level II, n=242, JS 3).
For HL, passive music therapy (played lullaby) was superior to no music for preterm neonates
and, combined with NNS, was superior vs either alone, with lower pain and stress scores in bothpreterm and term neonates (Wright 2013 Level I, 2 RCTs [heel lance], n=87).
Acupuncture (invasive or non-invasive) for preterm and term neonates receiving HL did not
reduce pain intensity (Stadler 2019 Level I [PRISMA], 5 RCTs, n=265). Distress during acupuncture
itself was not reported. A subsequent RCT found auricular non-invasive magnetic acupuncturevs placebo reduced pain scores during (mean 5.9/21 vs 8.3) but not after HL in preterm and termneonates (Chen 2017a Level II, n=26, JS 3).
Applying mechanical vibration (5 s of 100 Hz) to the foot prior to HL, in addition to use of apacifier with sucrose and heel warming, did not impact upon pain scores vs pacifier and sucrose
alone (Baba 2010 Level II, n=20, JS 3).
For venipuncture, pre-recorded maternal voice was an effective intervention for reducing
term neonates’ physiological response to pain (Azarmnejad 2017 Level III-1, n=60).
10.7.1.2 | Lumbar puncture
For infant lumbar puncture (LP), surveyed clinicians working in paediatric EDs at five USA centres
reported frequent use of NNS (67%), with low use of other interventions (<30% for sucrose,
topical and injectable lidocaine) (Hoyle 2011 Level IV, n=156). A further USA centre audited local
anaesthetic use for LP in children aged 0─24 mth with 0% use in neonates, 54% in infants but
99% in toddlers (Gorchynski 2011 Level IV, n=223). A Canadian ED survey revealed minimal use of
PO sucrose in infants, and low use of topical local anaesthetic, across the paediatric age range(Ali 2014 Level IV, n=72 [EDs]). The poor translation of evidence into practice is disappointing withthe data known regarding the consequences of poor analgesia ( Kennedy 2008 NR) and thesuggested positive association of local anaesthetic use with increased first pass success andatraumatic taps (Kennedy 2014 NR).
EMLA® reduced the physiological and behavioural response with needle insertion for LP inpreterm and term neonates (Foster 2017 Level I [Cochrane], 1 RCT: Kaur 2003 Level II, n=60, JS 5).
10.7.1.3 | Urine sampling
EMLA® reduced pain scores in neonates and young infants undergoing suprapubic aspiration(Nahum 2007 Level II, n=52, JS 5). Oral sucrose 24% vs water reduced cry incidence (29 vs 78%) andpain scores during transurethral catheterisation in neonates (Stevens 2016 Level I [Cochrane], 1 RCT[catheterisation]: Rogers 2006 Level II, n=80, JS 5).
Four RCTs have compared pain from transurethral catheterisation to suprapubic aspiration.
Transurethral catheterisation after urethral application of lidocaine 2% was less painful thansuprapubic aspiration after skin application of EMLA® (Kozer 2006 Level II, n=58, JS 3). Transurethralcatheterisation with lubrication only was less painful than suprapubic aspiration without topical
local anaesthesia in preterm neonates (Badiee 2014 Level II, n=80 [uncircumcised males only], JS 2; ElNaggar 2010 Level II, n=48, JS 3) but not when compared to suprapubic aspiration with EMLA® in
preterm and term neonates (Ghaffari 2014 Level II, n=90, JS 3).
10.7.1.4 | Ocular examination for retinopathy of prematurity
Screening for retinopathy of prematurity (ROP) causes pain in neonates ( Belda 2004 Level IV).
Topical local anaesthetic reduces pain scores (Dempsey 2011 Level III-1 SR [Cochrane], 2 studies,

5th Edition | Acute Pain Management: Scientific Evidence1035n=168). A systematic review on the efficacy of sucrose found mixed results for eye examination(Stevens 2016 Level I [Cochrane], 7 RCTs [ROP], n=259):• Oral sucrose 24─33%/NNS is more effective than sterile water/NNS in reducing painscores (WMD -2.47/21; 95%CI -3.27 to -1.66) (3 RCTs, n=114);• Sucrose did not affect cry (2 RCTs) or HR (2 RCTs);• Two RCTs report short-lived reduction in oxygen saturation in PO sucrose treated infants,
during but not persisting after eye examination.
A review including lower level evidence concluded that topical local anaesthetic/sweet
tasting solution and a nonpharmaocological (adjunct) intervention was superior to topical local
anaesthetic alone (MD -3.67/21; 95%CI -5.86 to -1.47) (17 studies) (Disher 2018 Level III-1 [NMA], 29
studies, n=1,487) (2 & 7 study overlap with above). A fourth review included two RCTs comparing
paracetamol to placebo for eye examination which have conflicting results whilst a third RCTreported higher pain scores for paracetamol vs sucrose 24% (Ohlsson 2016 Level I [Cochrane], 3 RCTs
[ROP], n=213) (overlap 0, 0 & 3 RCTs).
10.7.1.5 | Nasogastric tube insertion
The evidence for efficacy of PO sucrose reducing pain from nasogastric/orogastric insertion isinconclusive (Stevens 2016 Level I [Cochrane], 3 RCTs [nasogastric], n=164 ). The highest quality
evidence is for sucrose 24% vs sterile water lowering mean pain score 30 s post orogastric tube
insertion (WMD -1.30/21; 95%CI -2.31 to -0.29) (1 RCT) but not during or 1 min post procedure(Pandey 2013 Level II, n=105, JS 5). A subsequent review that included lower level evidence
concluded sweet solutions (sucrose 24 to 30% or glucose 25%) vs no intervention or placebo
reduced pain score during or immediately after gastric tube insertion (MD -2.18/21; 95% CI 3.86 to -0.51) (4 studies, n=344) (Chen 2017b Level III-1 SR, 6 studies, n=441 [630 insertions] )(3 RCT overlap).
10.7.1.6 | Nasal CPAP prong insertion
Topical lidocaine 2% vs control did not reduce pain intensity or cortisol levels for preterm
neonates having nasal CPAP prongs inserted (Soliman 2016 Level II, n=60, JS 3).

10.7.2 | Procedural pain in infants and older children
10.7.2.1 | Venipuncture and intravenous cannulation
Venipuncture causes significant distress in many children ( Kennedy 2008 NR). Bothpharmacological and nonpharmacological interventions have supportive evidence.
Hospital initiatives
In a large children’s hospital, a system-wide initiative implemented a new standard of care forneedle procedures that required staff to consistently offer 4 strategies: topical anaesthetics; PO
sucrose or breastfeeding for infants 0─12 mth old; age-appropriate comfort positioning; and ageappropriate distraction (Friedrichsdorf 2018 Level III-3, n=20,758). This reduced wait times forservices and increased patient satisfaction. Staff concerns about implementation (such as wait
times) were allayed by the results. Using a similar multidisciplinary approach for venipuncture(including universal offering of EMLA®, child preparation, carer education, comfort positioning
and age-appropriate distraction), the majority of carers were satisfied (91%) with the process
and 82% reported the procedure eliminated the fear of needle-related procedures in theirchildren (Yamamoto-Hanada 2015 Level IV, n=132).

1036 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

Topical local anaesthesia
Topical local anaesthesia (via cream/gel, patch, iontophoresis and needleless compression
device delivery) reduces pain associated with venipuncture and IV cannulation in all age groups(Zempsky 2008 Level I, 52 RCTs, n unspecified).
Amethocaine (tetracaine) gel is more effective than EMLA® cream (RR 0.78; 95%CI 0.62 to0.98) with more rapid onset (Lander 2006 Level I [Cochrane], 6 RCTs, n=634), although does not
improve first time cannulation success rate (Pywell 2015 Level I [PRISMA], 3 RCTs, n=922) (1 RCT
overlap). A heated lidocaine/tetracaine patch was superior to both placebo ( 2 RCTs, n=109) andEMLA® (1 RCT, n=200) (Croxtall 2010 Level I, 3 RCTs [paediatric], n=309) and associated with a higher
first-time venipuncture/cannulation success rate than EMLA® (Cozzi 2017 Level II, n=356, JS 3).
Application of a heat pack after EMLA® does not increase first time success rate (Schreiber 2018
Level II, n=400, JS 3). EMLA® was more effective than a Valsalva manoeuvre in children (5─12y),both being more effective than control (1/10 vs 2.15 vs 2.55) (Akdas 2014 Level II, n=60, JS 2).
Iontophoresis of lidocaine 1─4% is superior to placebo (4 RCTs, n=420) and is equivalent to or
superior to EMLA® (2 RCTs, n=144) with a time to onset of 10 min (Zempsky 2008 Level I, 52 RCTs, nunspecified). Liposomal lidocaine 4% cream was similar with only 15 min application to placebo(Brenner 2013 Level II, n=120, JS 5), but after 30 min was both similar to amethocaine 4% ( Poonai
2012 Level II, n=60, JS 5) and superior to placebo (1 RCT, n=142) (Zempsky 2008 Level I, 52 RCTs, nunspecified). It had a more rapid onset, was as effective as EMLA® ( 3 RCTs, n=240) and was aseffective as buffered lidocaine (1 RCT, n=69) (Zempsky 2008 Level I, 52 RCTs, n unspecified).
Sonophoresis prior to application of liposomal lidocaine accelerated the onset time from 30 to
5 min (1 RCT, n=60) and sonophoresis/liposomal lidocaine was superior to sonophoresis/placebo
cream (1 RCT, n=77).
Intradermal delivery of powdered lidocaine (0.5─1 mg) under high pressure (20 bar) via aneedleless device (CO2 or helium driven) was effective within 3 min and produced more effective
skin anaesthesia than EMLA® in one RCT (Jimenez 2006 Level II, n=116, JS 3), but was less effective
than EMLA® in another (Stoltz 2017, Level II, n=150, JS 3). Powdered lidocaine 0.5 mg was more
effective than 0.25 mg (1 RCT, n=307) and placebo (2 RCTs, n=452) (Zempsky 2008 Level I, 52 RCTs,
n unspecified; Schmitz 2015 Level II, n=517, JS 5), and associated with infrequent mild adverse events
such as erythema and petechiae (Schmitz 2015 Level II, n=517, JS 5). In children (1─6 y) intradermal
needleless pressure-injected lidocaine was more effective than vapocoolant spray and placebo(Lunoe 2015 Level II, n=205, JS 3). A cooling and rapidly vibrating device (Buzzy®) combined withintradermal needleless pressure-injected lidocaine provided no benefit vs intradermal
needleless pressure-injected lidocaine alone, both for the administration of lidocaine andvenipuncture (Kearl 2015 Level III-2, n=356).
Nitrous oxide (N2O)
N2O at 20─75% reduced pain and anxiety associated with venipuncture/IV cannulation and, in
one study, shortened time to achieve access with fewer attempts (Tobias 2013a Level IV SR, 5
studies [venipuncture/cannulation], n unspecified). N2O 70% for 3 and 5 min reduced pain scores by>50% (Furuya 2009 Level II, n=73, JS 5). The combination of N2O 40─50% and topical EMLA® for IV
cannulation is more effective in reducing pain scores and increased satisfaction vs either method
alone (Pedersen 2013 Level I [PRISMA], 3 RCTs [IV cannulation], n=233). This systematic review also
included five large case series of N2O use in mixed minor procedures, supporting the safety ofN2O 50─70% administration in children. Minor adverse events were reported in 4─8% of patientsand serious or potentially serious adverse events were reported in less than 0.5% of patients.
(Pedersen 2013 Level IV SR [PRISMA], 5 studies, n=53,108).

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1037Dexmedetomidine
IN Dexmedetomidine (2 mcg/kg) 30 min prior reduced pain scores during venous cannulation
when given via mucosal atomisation device (MAD) vs dropper administration (Xie 2017b Level II,
n=106, JS 3).
Sweet-tasting solutions in older children
For school aged children, chewing sweetened gum before needle-related painful procedures(2 RCTs, n=111) or during the procedure (2 RCTs, n=103) did not reduce pain scores during theprocedure (Harrison 2015 Level I [Cochrane], 8 RCTs, n=808). In toddlers/preschool children (6 RCTs,
n=520) there was insufficient evidence of an analgesic effect for sweet tasting solutions or
substances during acutely painful procedures.
Combination pharmacological intervention
The combination of EMLA® and N2O 50% reduced procedure duration with more successful IV
placements than EMLA®/low-dose PO midazolam 0.3 mg/kg (max 15 mg) 40 min prior (Ekbom
2011 Level II, n=90, JS 4). Notably, the usual PO midazolam dose is 0.5 mg/kg and, at 40 min, offset
of effect is relevant.
Nonpharmacological intervention
Skin cooling techniques
Evidence on the use of skin cooling techniques in children is conflicting. Vapocoolant sprays did
not reduce pain from venipuncture or IV cannulation in children vs placebo or no treatment (3studies, n=387) (Hogan 2014 Level III-1 SR [PRISMA], 12 studies, n=1,266 [4 paediatric, n=509]). Pain or
discomfort from application of vapocoolant spray was not assessed in children. Two subsequentmeta-analyses of the same 2 paediatric RCTs (n=165, both RCTs included in the above review)similarly reported no pain reduction with vapocoolant sprays vs placebo (Zhu 2018b Level I, 11
RCTs, n=1,410; Griffith 2016 Level I [Cochrane], 9 RCTs, n=1,070). In two separate RCTs, a vapocoolant
spray (5-fluoropropane/4-fluoroethane: Painease®) applied 10 s prior to IV cannulation was
similarly effective to 3 min application of ice in older children (9─18 y) (Waterhouse 2013 Level II,
n=95, JS 4) and vapocoolant spray was superior to control but inferior to EMLA® ( Dalvandi 2017
Level II, n=40, JS 3). Ice application (0o C) for 3 min has previously been reported to improve painrelated behaviours in children aged 6─12 y undergoing venipuncture (Movahedi 2006 Level III-2).
With use of a metal applicator (Coolsense®: refrigerated to -2oC requiring 10 s application time),
94% of children aged 6─18 y rated their pain score during cannulation <3/10; patient and carer
satisfaction with the device was high (Ragg 2017 Level IV, n=100).
Vibration alone or combined with cooling
The efficacy of the Buzzy® device (vibration alone or combined with cooling) vs no intervention
for children (3─18y) having needle-related procedures has been assessed (Ballard 2019 Level I[PRISMA], 9 RCTs [7 IV cannulation/venipuncture, 2 vaccine injection], n=1,138). Buzzy® reduces:• Self-reported pain intensity (SMD -1.12; 95%CI -1.53 to -0.71) (6 RCTs, n=609);• Parent-reported pain intensity (SMD -0.94; 95%CI -1.62 to -0.27) (5 RCTs, n=398);• Observer-reported pain intensity (SMD -1.19; 95%CI -1.90 to -0.47) (4 RCTs, n=329).
Smaller meta-analyses suggest a beneficial effect on parent and observer-reported anxiety,but not success of procedure on first attempt, or adverse effects. Additionally, Buzzy® vsdistraction cards (1 RCT, n=110) and Buzzy®/topical anaesthesia vs vapocoolant spray/topicalanaesthesia (1 RCT, n=81) improve self and parent-reported pain intensity, whilst Buzzy®/comfort
plan is not superior to topical anaesthetic /comfort plan for IV cannulation (1 RCT, n=224).

1038 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENTThe following RCTs with mixed results were not included in the above review where Buzzy®:• Added to distraction cards for venipuncture was more effective than the hypnoanalgesic‘Magic Glove’ technique in 3─10 y olds (mean pain score 3.65/10 vs 4.67) (Susam 2018
Level II, n=64, JS 3);• Vs a handheld computer game for venipuncture resulted in similar median pain scores in4─12 y olds (3/10 vs 2) (Cozzi 2018 Level II, n=200, JS 3);• Vs virtual reality (VR) for venipuncture resulted in similar pain scores in 7─12 y olds (mean2.0/10 vs 1.5) (Gerceker 2018 Level II, n=121, JS 3);• Alone or combined with animated cartoons vs control for 5─12 y olds having venipuncture
did not reduce pain scores (Bergomi 2018 Level II, n=150, JS 3);• Was not as effective as EMLA® patch in reducing pain intensity for children (18 mth to 16 y)having IV cannulation (mean 8.5/18 vs 7.2) (Bourdier 2019 Level II, n=607, JS 3);• Resulted in lower pain scores than ShotBlocker®, bubble blowing or control in children
aged 5─10 y receiving IM injection in the ED (mean 3.87/10 vs 4.14 vs 4.75 vs 6.72) (Yilmaz
2019 Level II, n=160, JS 3).
A second review included lower level evidence and evaluated vibratory stimulation by any
method to reduce needle related procedure pain in children (0─18 y) (Ueki 2019 Level III-1, 21
studies, n=1,727) (7 RCT overlap). It found vibratory stimulation vs control reduced self-rated pain
intensity (SMD -0.55; 95%CI -0.92 to -0.18) (13 studies, n=1,589), observer-rated pain intensity(SMD -0.47; 95%CI -0.76 to -0.18) (16 studies, n=1,721) and observer-rated anxiety (SMD -1.03;
95%CI -1.85 to -0.20) (4 studies, n=624). There was no difference in success of procedure on firstattempt or adverse effects.
Distraction
A customised multimodal distraction device (Ditto®) designed for children aged 3─12 y provides
procedural preparation stories and distraction content. Compared to standard distraction,
combined Ditto® procedural preparation and distraction significantly reduced nursing staff andcarer reported pain and distress (Miller 2016 Level II, n=98, JS 3). Carers also reported combined
Ditto® procedural preparation and distraction as more effective than either in isolation.
Immersive virtual reality (Sony Snow World®) use in children aged 7─17 y significantly
reduced time spent thinking about pain, pain unpleasantness and worst pain; patients reported
more fun than controls (Atzori 2018 Level III-2, n=15). Patients aged 10─21 y used Bear Blast® with
VR goggles during venipuncture and experienced less pain and anxiety than controls ( Gold 2018
Level II, n=143, JS 3). Secondary analysis revealed patients with a high anxiety sensitivity
experienced less anxiety with VR vs control, while patients with low anxiety sensitivity did not.
For further discussion of distraction techniques including virtual reality see Section 10.7.5
Nonpharmacological Strategies in Adolescents and Children.
Other techniques
For older infants up to 36 mth having needle procedures, NNS improved immediate pain
regulation (behavioural response >30 s post procedure: SMD -1.34; 95%CI -2.14 to -0.54) (2studies, n=151) (Pillai Riddell 2015c Level III-2 SR [Cochrane], 63 studies, n=4,905). Touch/massagerelated strategies and structured non-parent involvement also improved immediate pain
regulation.
For pain during venipuncture in 6─12 y olds, acupressure and EMLA® reduced FLACC scores
similarly with both better than routine care (mean 2.65/10 vs 2.75 vs 7.75) (Pour 2017 Level II,
n=120, JS 3). Medical clowning (also termed clown care by therapeutic clowns or “clown doctors”)
for children aged 2─10 y reduced mean crying duration vs control (1.3 min vs 3.8) (Meiri 2016
Level III-1, n=100). Clowning also lowered parental assessment of child’s anxiety about future
blood tests assessed the following day vs both control and EMLA®, but did not reduce pain
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scores. In a further venipuncture study, medical clowning vs standard care reduced pain scoresin older 7─15 y old children (1.5/10 vs 2.7), but not in younger 4─6 y olds (Kristensen 2018
Level III-2, n=111).
Therapeutic dog presence for venipuncture in 4─11 y olds reduced observer-reported distressand patients’ cortisol levels, but not pain scores during the procedure or parental anxiety (Vagnoli
2015 Level II, n=50, JS 2).
Children with an intellectual disability having venipuncture or IV cannulation experienced
more pain and anxiety despite receiving more pain and anxiety interventions (eg EMLA®,
distraction, physical or verbal comforting) (Pascolo 2018 Level III-2, n=141).
10.7.2.2 | Lumbar puncture and bone marrow aspiration
Numerous techniques are used to alleviate the pain and distress occurring in children undergoing
lumbar puncture (LP) alone or combined with bone marrow aspiration (BMA) in the ED andoncology settings (Kennedy 2014 NR). Interventions have usually been assessed in isolation.
Despite positive benefits, use of analgesic intervention in EDs has penetrated poorly ( Ali 2014
Level IV). Combining techniques is recommended best practice: topical local anaesthesia, local
anaesthesia infiltration by slow injection, and PO sucrose with NNS in infants; and, for older
children, adding distraction (see Section 10.4.5) and anxiolysis with midazolam and/or further
analgesia with N2O (Kennedy 2014 NR). Deeper sedation techniques and general anaesthesia arealso used. The choice of intervention is best determined by the setting, the local resources andskills, and assessment of the individual child.
Topical local anaesthesia and nitrous oxide (N2O) (alone or in combination)
Several RCTs and case series have reported on the safety of N 2O 50─70% for mixed minor
procedures in children (see Section 10.7.2.1). Nitrous oxide is often co-administered with otheragents or strategies. For LP:• In infants <3 mth, needle-free jet injection of lidocaine vs saline resulted in lower painscores (mean 4.1/10 vs 4.8) and slightly reduced cry duration (by 10 s) (Ferayorni 2012
Level II, n=55, JS 5);• In infants <4 mth, needle free injection of lidocaine was of similar efficacy to EMLA® in
reducing pain intensity during needle insertion (Caltagirone 2018 Level II, n=58, JS 5);• For 3─21 y olds, topical local anaesthesia with EMLA® vs placebo reduced medianpropofol requirements 4 mg/kg (95%CI 3.5 to 4.4) vs 4.9 mg/kg (95%CI 4.3 to 5.6),
decreased movement at skin puncture (8% vs 84%) and reduced heart rate change (mean
1 bpm vs 8.3) (Whitlow 2015 Level III-2, n=25);• In 5─14y old children with leukaemia, self-administered N2O/oxygen mixture (ratio
unspecified) reduced self-reported pain intensity vs control (mean 1.05/10 vs 8) (Liu 2019
Level II, n=114, JS 5);• In an oncology LP clinic (2─29 y olds), N2O 40─70% with or without topical local
anaesthesia was 98% successful, with minimal sedation (Livingston 2017 Level IV, n=78 [LPsn=350]).
For LP and BMA:
• Coadministration of local anaesthesia and sedative/anxiolytic has been used bothinfrequently (18% and 8.2%) (Onody 2006 Level IV, n=3,964) and frequently (98.7% and64.5%) (Annequin 2000 Level IV, n=286 [LPs] & n=231 [BMAs]). The latter study described low
pain scores during LP and BMA (respective median procedural pain scores ─ patient 5/100
and 12.5; nurse 0/10 and 2) with a low need overall for restraint, 18.2% initially and 6%
during the procedure.

1040 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

Fentanyl alone
Oral transmucosal fentanyl is not licensed for paediatric use but 10─15 mcg/kg reduced painscores vs placebo dosette for LP/BMA (Schechter 1995 Level II, n=48, JS 4). As yet, IN use isunreported for this procedural indication.
Single or double agent sedation vs general anaesthesia
For oncology LP/BMA, general anaesthesia is considered by some to be best practice (eg withpropofol/fentanyl) (Ghasemi 2013 Level IV), while volatile-based general anaesthesia(sevoflurane/N2O) was preferred to sedation, with less distress and pain for children requiring
multiple procedures (Crock 2003 Level III-3). Propofol has been used by an ED physician-led
sedation team for these procedures (Lamond 2010 Level IV SR, 1 study [ED physician], n=87 [291procedures]). In two small cross-over trials of children with leukaemia undergoing LPs/BMAs,
adding IV fentanyl 1 mcg/kg to propofol sedation improved satisfaction, recovery time by 10 min(Cechvala 2008 Level II, n=22, JS 5) and analgesia (Nagel 2008 Level II, n=25, JS 5). The addition offentanyl 0.5─1 mcg/kg was propofol sparing with less movement during the procedure andshorter recovery times but no difference in post LP/BMA pain scores (Anghelescu 2013 Level II,
n=162, JS 5).
Oral or IV ketamine was effective and associated with less distress vs placebo or IV midazolam
during LP and/or BMA in children with cancer (Rayala 2019 Level II, n=52, JS 2; Tobias 1992b Level III-3;
Evans 2005 Level IV). In the ED setting, IV ketamine 1 mg/kg alone vs with IV midazolam 0.1 mg/kg
was similarly effective (Dilli 2008 Level II, n=99, JS 3), whilst for oncology patients, IV ketamine
1mg/kg/midazolam 0.1mg/kg vs IV pethidine 1mg/kg/midazolam 0.1mg/kg resulted in lower
median pain scores at the beginning of BMA/biopsy (3/10 vs 7) (Abdolkarimi 2016 Level II, n=57, JS
4). Adding ketamine 0.5 mg/kg to propofol (administered by non-anaesthetists) vs propofol
alone was propofol sparing, resulted in better observer scored intraprocedural pain scores andreduced recovery time (Chiaretti 2011 Level II, n=121, JS 3). In an outpatient oncology unit,
thiamylal/pentazocine vs ketamine/midazolam (routes unspecified) for LP/BMA was used bypaediatricians with similar efficacy, but with increased transient desaturation (36 vs 22%) andoxygen supplementation (82 vs 36%) (Nakagawa 2018 Level III-2, n=35 [268 procedures]).
Protocolised administration by non-anaesthetists of propofol sedation vs ketamine/midazolam
resulted in a higher sedation failure rate (12 vs 0%), but a lower rate of emergence symptoms(9.2 vs 50%) (Chayapathi 2018 Level II, n=152, JS 3). Pain outcomes were not assessed. A study of astandardised sedation procedure with IV midazolam and S(+) ketamine for BMA reported 2%
prevalence of hypoxia requiring intervention and 3% prevalence of minor complications (Sauer
2019 Level IV, n=107). The qualifications of the practitioner administering sedation were
not specified.
Nonpharmacological intervention
See also Section 10.7.5 for nonpharmacological techniques.
Child distress during a course of consecutive LPs/BMAs increased over time and was
positively related with parental distress (Caes 2014a Level IV, n=28 [242 procedures]). Additionally,parental distress about LPs/BMAs decreased over time with low-catastrophising parents but
remained high with high-catastrophising parents. In another study by the same group, parental
catastrophic thinking contributed to increased parental distress during, but less pain attending
behaviour before LP/BMA (Caes 2014b Level IV, n=46).
Massage therapy just prior to IT chemotherapy or BMA was associated with greater reduction
in children’s pain and anxiety vs control when evaluated prior to treatment and 20 min after(Celebioglu 2015 Level III-2, n=25). IV sedation was also given to both groups; however the amountof hypnoanalgesia administered was not reported.

5th Edition | Acute Pain Management: Scientific Evidence1041

Authors concluded that all youth with cancer having invasive medical procedures should
receive preparatory information to reduce distress and increase coping and compliance (lowquality evidence, strong recommendation), and psychological interventions such as distraction,
hypnosis, and combined cognitive behavioural therapy (CBT) interventions to reduce pain anddistress (high quality evidence, strong recommendation) (Flowers 2015 GL). Psychosocial
intervention (preparation and CBT) was associated with less mean anticipatory and total
behavioural distress ratings (OSBD-R) in patients receiving BMA or LP. Reduced behavioural
distress ratings from one procedure to the next were observed when psychosocial interventions(preparation and CBT) with a child-life specialist were given for the second procedure (Hsiao 2019
Level III-3, n=18).
Reduction of post-dural puncture headache (PDPH) incidence
Risk of PDPH after LP was higher with traumatic vs atraumatic needles (RR 2.14; 95%CI 1.72 to2.67) (36 RCTs, n=9,378); however the paediatric sub-analysis revealed no difference (2 RCTs,
n=315) (Arevalo-Rodriguez 2017 Level I [Cochrane], 66 RCTs, n=17,067 [3 paediatric, n= 475]). With the
exception of one adult RCT, there was no difference with different gauge traumatic needles(multiple sub-analyses, 10 RCTs [1 paediatric], n=2,288) or different gauge atraumatic needles (multiple
sub-analyses, 13 RCTs, n=3,134 [paediatric unspecified]). Subsequently, a lower risk of PDPH was
confirmed with atraumatic vs traumatic needles (RR 0.40; 95%CI 0.34 to 0.47) (n=24,901) but
again, no difference in the paediatric sub-analysis (2 RCTs, n=782) (Nath 2018 Level I [PRISMA], 110
RCTs [2 paediatric, unspecified number of mixed adult/paediatric], n=31,412 [1,065 paediatric]) (39 RCTs
overlap [2 paediatric]).
Lower level evidence have mixed findings. Following diagnostic LP in children, less PDPH
resulted with use of a 27-guage atraumatic vs 26-g traumatic needle (0.4% vs 4.5%) (Apiliogullari2010 Level III-2, n=414). In children having IT chemotherapy, the incidence of PDPH with a 22-g
traumatic vs 25-g atraumatic needle was similar (11 vs 7%) (Lowery 2008 Level III-2). With guidelinechange from 22-g spinal needles to 25-g (type unspecified) for diagnostic LPs/chemotherapy
administration and 27-g for spinal anaesthesia, epidural blood patch rates decreased from 0.8%
(5 y data) to 0.2─0.3% (10 y data) (Kokki 2012b Level III-3). Injected mean blood volumes of 0.27
mL/kg (range 0.16─0.53 mL/kg) for epidural blood patch achieved complete persistent resolutionof headache in 83% of 42 patients (see also Section 8.6.5).
The use of atraumatic needles for LP is strongly recommended in patients (including children)of all ages (Rochwerg 2018 GL).
10.7.2.3 | Botulinum toxin (intramuscular) or steroid (intra-articular) injection
IM botulinum toxin for spasticity and intra-articular steroid injections are acutely painfulprocedures, and general anaesthesia should be considered for these procedures, especiallywhen multiple injections are performed.
Nitrous oxide (N2O)
Use of N2O 70% in isolation reduced patient, parent and nurse-reported pain scores vs PR
midazolam 0.35─0.5 mg/kg (Zier 2008 Level II, n=50, JS 4). Using topical EMLA® and N2O 50% inchildren reduced pain in only 50% of the 51 procedures ( n=39) with the remainder experiencing
severe pain intensity (≥9/13) (Brochard 2009 Level IV). N2O 50%/oxygen treatment for botox or
joint injections was superior to inhaled nitrogen 50%/oxygen mix, with lower pain scores (by50%) and fewer patients requiring rescue with propofol or sevoflurane (18 vs 55%) (ReinosoBarbero 2011 Level II, n=100, JS 4). Use of N2O 50─70% in a small series of children having joint
injection achieved adequate analgesia in most (89%) children (Cleary 2002 Level IV, n=55).

1042 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

Local anaesthetic
Girls had lower post procedural pain scores with topical local anaesthesia (EMLA® or Numby®)plus subcutaneous buffered lidocaine vs topical local anaesthesia alone for corticosteroid knee
joint injections, but boys did not (Weiss 2015 Level II, n=63, JS 2).
The use of vapocoolant spray (used in 89%) or topical local anaesthetic (used in 2%), as well
as younger age, and body region injected (leg, thigh, hand) was associated with increased painwith botulinum toxin injection for spasticity (Fisher 2018b Level IV, n=249 [563 procedures]).
Other sedative agents
IV ketamine with or without midazolam in addition to topical local anaesthesia was successfully
used for botulinum toxin injection to treat spasticity with a low prevalence of minor adverse
effects (Chow 2016 Level IV, n=87 [152 procedures]). PR midazolam and ketamine in addition to
topical local anaesthesia has also been used successfully for botulinum toxin injection (Nilsson
2017 Level IV, n=61 [128 procedures]).
Impact of localisation techniques
For botulinum toxin injection, US-guidance may help localise muscles more accurately (Py 2009
Level IV) and reduce procedure related pain vs use of electrical stimulation with/ without USguidance (Bayon-Mottu 2014 Level III-2, n=107 [155 procedures]).
Nonpharmacological intervention
Medical clowning has been used for intra-articular steroid injections (Weintraub 2014 Level IV). For
botulinum toxin injections, results are mixed; medical clowning vs standard care was associatedwith lower pain scores in one study (Ben-Pazi 2017 Level III-2, n=45) but not in another (Houx 2019
Level III-2, n=88). Virtual reality has been used for botulinum toxin injection (Chau 2018 Level IV,n=14).
10.7.2.4 | Urethral catheterisation and micturating (voiding) cystourethrogramChildren with stronger medical fears were more anxious during the micturating
cystourethrogram (MCUG) as reported by their parents and examining technologists anddemonstrated more procedural distress as measured by their vocalisations (Fox 2016 Level IV,n=34).
Local anaesthesia — topical and installation
Lidocaine 2% gel is no better than non-anaesthetic gel in reducing pain from transurethral
bladder catheterisation (Chua 2017c Level I [PRISMA], 5 RCTs, n=369). A subsequent RCT similarly
reported lidocaine 2% gel was not better than usual care with high reported median pain scores(8/10 vs 9) and the authors thus emphasised that analgesia for this procedure needs to improve(Uspal 2018 Level II, n=73, JS 3); however high pain scores are not universally reported (Chua 2017cLevel I [PRISMA], 5 RCTs, n=369).
Nitrous oxide (N2O)
N2O use is associated with low pain and distress scores in children undergoing urethralcatheterisation and/or MCUG (Pedersen 2013 Level IV SR [PRISMA], 2 studies [catheterisation],n≈5,000).
Intranasal fentanyl alone
IN fentanyl 2 mcg/kg, administered slowly by dropper 10 min prior to catheterisation for MCUG,
with no distraction, resulted in similarly low pain scores vs water (mean 2.6/10 vs 2.9) (Chung2010 Level II, n=69, JS 5). Nasal irritation was reported by 6 and 14% respectively.

5th Edition | Acute Pain Management: Scientific Evidence

1043

Midazolam
Midazolam administered PO or IN vs no treatment for urinary catheterisation in 4─24 mth olds
was associated with lower parent and nurse-reported pain/distress (mean 33.6/100 vs 71.7) andshorter cry duration (median 0 s vs 240) (Weiser 2014 Level III-2, n=51).
SucroseSucrose 75% 4 mL vs water for children (3 mth─3 y) did not reduce pain intensity withtransurethral bladder catheterisation (London 2019 Level II, n=40, JS 5).
OtherPain scores were not different when olive oil/calcium hydroxide (oleocalcareous) liniment vs a
dry compress was used to aid removal of a urine collection bag (Lamy 2019 Level II, n=135, JS 3).
Nonpharmacological intervention
Preparing the child for the MCUG using a story booklet alone or with play preparation reduced
distress (Phillips 1998 Level III-2). Hypnosis was superior to play preparation, with reduced distressand procedure duration (Butler 2005 Level II, n=44, JS 3).
10.7.2.5 | Chest drain and intercostal catheter insertion and removal for thoracic surgery or
pneumothorax management
Chest drains and intercostal catheters are inserted for a variety of reasons perioperatively andfor management of pneumothorax.
The incidence of paediatric spontaneous pneumothorax is low; it can be primary [PSP] or
secondary [SSP] due to asthma, cystic fibrosis and congenital cystic adenomatoid malformations.
Pain is commonly present (along with dyspnoea); overall hospital admission rates for PSP and
SSP (reported by the British Thoracic Society) are 5.8 and 16.7/100 000 for women and men(respectively), without paediatric subgroup data (MacDuff 2010 GL). Most paediatric patients areadmitted (81% of 219 presentations) and have non-surgical management with oxygen, needle
aspiration (PSP 27% and SSP 9%) and/or intercostal catheter (ICC) insertion (PSP 48% and SSP
67%), with 38% PSP and 47% SSP requiring surgery (Robinson 2015 Level IV, n=162 children [120with PSP]).
Pain service involvement in patients with PSP/SSP in the acute phase of care has decreased
─ likely related to the use of less painful small bore or micro/pig tail catheters; duration of carepostoperatively has also shortened with change in surgical technique from open to limited
axillary (LATS) or video-assisted thoracic surgery (VATS) procedures. VATS had lower analgesic
requirement and shorter period of follow-up vs LATS (Butterworth 2007 Level III-3, n=31). Analgesic
intervention follows stepwise escalation with paracetamol, nsNSAID and opioids PO or IV
including by PCA. Following antibiotic or talc pleurodesis, nsNSAIDs are generally avoided (withno positive or negative data to support this practice) but are used post-bleb or apical pleuralabrasion or resection.
Removal of chest drains/ICCs can cause significant pain and distress. For chest drain/ICC
removal (inserted for various indications), IV morphine, topical anaesthesia with EMLA® andN2O reduced pain but did not provide adequate analgesia in children (and adults) (Bruce 2006aLevel III-2; Bruce 2006b Level IV SR, 14 studies, n=758 [1 study, 1 RCT, paediatric n=144] ). For children
aged <7 y having chest drain removal post cardiothoracic surgery, pain scores were similarlyhigh during the procedure (7/10) with EMLA® applied 3 h prior and IV placebo vs placebo
cream and IV morphine 0.1 mg/kg 30 mins prior (Rosen 2000 Level II, n=120, JS 2). IN Ketamine
0.5 mg/kg combined with IN sufentanil 0.5 mcg/kg has been used in children for drain removal(Nielsen 2014 Level IV).

1044 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

Following paediatric cardiac surgery, a nursing education program improved timely use of
periprocedural intervention including analgesic and nonpharmacological therapies for ICC
removal (Ring 2017 Level IV, n= 68 staff surveyed & 21 charts reviewed). Similarly, introduction of aprocedural treatment protocol (play therapist, topical local anaesthetic and targetedpharmacological intervention based on the tool’s estimate of risk) reduced the number ofpatients that were inconsolable after chest drain and pacing wire removal (Craske 2013 Level III-3,
n=163).
10.7.2.6 | Nasogastric tube insertion
Nasogastric tube (NGT) insertion causes pain and distress particularly in children (Juhl 2005
Level IV).
Topical local anaesthesia
In adults, topical gel and/or nebulised anaesthesia of the nose and pharynx reduces pain
associated with NGT insertion (OR 0.42; 95%CI 0.20 to 0.88) (Kuo 2010 Level I, 5 RCTs, n=212; Uri
2011 Level II, n=62, JS 5) and reduced NGT insertion time (Chan 2010 Level II, n=206, JS 5).
Lidocaine/phenylephrine spray (10 mg/1mg for 6─12 kg, 20 mg/2 mg for >12 kg) was not superior
to saline spray in infants and young children (6 mth─5 y) (median 9/10 vs 9) (Craig 2019 Level II,
n=107, JS 5). An RCT in children aged 1─5 y of nebulised lidocaine was terminated early due to the
distress associated with nebulisation; this may outweigh its potential benefit (Babl 2009 Level II,
n=36, JS 5).
Ketamine
In adults, IN ketamine 50 mg reduced pain scores vs placebo for NGT insertion (Nejati 2010 Level II,
n=72, JS 5). In mostly preschool aged children having NGT insertion (for repeat gastric aspirates),
IN ketamine 2 mg/kg and IN midazolam 0.5 mg/kg (max 10 mg) vs placebo achieved sedation for
71 min (95%CI 64 to 80) and reduced pain scores and the need for physical restraint (4% vs 100),with low post-procedure agitation rates (11% of procedures) (Buonsenso 2014 Level II, n=36 [108procedures], JS 5).
10.7.2.7 | Dental procedures
For pharmacological interventions see the various analgesic subsections in 10.4 and for local
anaesthetic interventions see Section 10.6.6
Nonpharmacological interventions for dental procedures
In children <18 y having dental procedures, distraction techniques including music, virtual reality,
magic tricks, exposure to positive dental images and relaxation training have been studied with
mixed results for pain, anxiety and behaviour outcomes (Goettems 2017 Level I, 13 RCTs,
n unspecified) including during local anaesthetic infiltration (Sridhar 2019 Level II, n=66, JS 3) andpulpotomy (Shetty 2019 Level III-1, n=120). Acupuncture (at the LI 4 meridian point bilaterally) inchildren and adolescents (4─18 y) reduced self-reported pain intensity (2.3/10 vs 3.9) during local
anaesthetic injection for dental treatment (Usichenko 2016 Level II, n=49 [98 injections], JS 3).
10.7.2.8 | Intraosseous pin removal
Topical local anaesthetic vs placebo in children (3─16 y) having interosseous pin removal did not
reduce pain intensity (Dulai 2016 Level II, n=281, JS 5).

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10.7.2.9 | Burns dressingsChildren who have sustained burns injuries often require repeated, painful and distressing
dressing changes (see also Section 8.5). Considerable interindividual variation occurs andanalgesia needs to be titrated to effect as requirements differ according to the surface area
involved, the location, the stage of healing and need for grafts, and the child’s previous
experiences (Palmer 2014 NR). It is important to consider significant coexistent post-traumaticstress symptoms or disorder (Stoddard 2011 Level III-1; Stoddard 2006 Level IV) and anxiety anddepression (van Baar 2011 Level III-2). Additionally, parental post-traumatic stress symptoms andparental guilt predict more child distress, and parental general anxiety/depression predict lesschild coping (Brown 2019 Level IV, n=87). Long term post-traumatic stress symptoms may be
reduced by adequate early opioid administration (Sheridan 2014b Level IV). In the early phases,
general anaesthesia may be preferred for dressing changes, stepping down to proceduralinterventions on the ward and then as outpatients ( Palmer 2014 NR).
Burn dressing types
Numerous dressings for superficial and partial thickness burns have been assessed and the
optimal choice is unclear (Wasiak 2013 Level I [Cochrane], 6 RCTs [paediatric], n=364). In paediatricpatients, biosynthetic dressings are superior to silver sulphadiazine in reducing daily opioid
requirements (1 RCT, n=20), the time to healing, number of dressing changes and hospital stay
(2 RCTs, n=109) but were similar to hydrocolloid dressing (Duoderm®) in terms of pain scores andtime to healing (1 RCT, n=72).
Pharmacological interventions for burn dressing
Opioids
Opioids are frequently required and prescribed for burns dressing changes, with little publisheddata. Compared to placebo, oral transmucosal fentanyl (≈10 mcg/kg) compared favourably withPO morphine (Robert 2003 Level II, n=8, JS 4), PO hydromorphone 60 mcg/kg (Sharar 1998 Level II,
n=14, JS 4) and PO oxycodone 0.2 mg/kg in reduction of pain associated with dressing changes(Sharar 2002 Level III-2). IN fentanyl 1.4 mcg/kg reduced pain scores similarly with similar recovery
time vs PO morphine 1 mg/kg in paediatric burns dressing change (Borland 2005 Level II, n=28, JS 4).
Ketamine
IN Ketamine 0.5 mg/kg combined with IN sufentanil 0.5 mcg/kg has been used in children forburn dressing change (Nielsen 2014 Level IV, n=7). IV Ketamine administration by nonanaesthetists was audited, where doses of 6─800 mg were given to children weighing 3─111 kg
for procedures of 1─105 min duration (Owens 2006 Level IV, n=347). Ten events occurred that
required intervention (2.9% incidence): eight were airway related and responded torepositioning, supplemental oxygen or bag-mask ventilation and two hypotensive events
responded to fluid administration.
For burns dressing changes in children aged 1─5 y, PO ketamine 5 mg/kg with midazolam
0.5 mg/kg vs combination PO midazolam 0.5 mg/kg/paracetamol 10 mg/kg/codeine 1 mg/kg
may provide superior analgesia: mean pain scores 7.4/13 (95%CI 4 to 12) vs 8.9 (95%CI 4 to 13)(Norambuena 2013 Level II, n=60, JS 4).
Dexmedetomidine
IN dexmedetomidine 2 mcg/kg has been used as premedication prior to burns reconstructive
surgery (Talon 2009 Level II, n=50, JS 3) but no conclusion can be drawn as to the impact upon pain
outcomes. Use in deep sedation is described below.

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Deep sedation/analgesia
Three doses of PR ketamine (4, 6 and 8 mg/kg) with PR midazolam 0.5mg/kg for burns woundcare sedated children with low pain scores (median 0 vs 0 vs 0) and a dose dependent effect onrecovery time (mean 25 vs 27 vs 36 min) (Grossmann 2019 Level II, n=201, JS 4). Propofol
2mg/kg/ketamine 1mg/kg was comparable to propofol 2mg/kg/remifentanil bolus 0.1 mcg/kg
and infusion 0.05 mcg/kg/min for burns dressing changes, but with longer recovery time (median
22.5 min (IQR 20.3─25) vs 10.3 (IQR 9.1─11.5)); pain outcomes were not reported (Seol 2015 Level
II, n=50, JS 5). IV Ketamine 0.8─2 mg/kg with propofol 0.8─2.5 mg/kg or dexmedetomidine
0.4─1.2 mcg/kg has also been used for short duration (10 min) dressing change ( Canpolat 2012
Level III-1).
Nonpharmacological interventions for burn dressing
Nonpharmacological strategies such as distraction, virtual reality (VR), preparation, parental
presence and hypnosis may be effective (see also Section 10.7.5). Studies vary substantially inthe specifics of interventions and comparison groups and are difficult to blind.
Child life therapy
Child life (previously termed educational play) therapy (preparation, education and distractiondelivered by a therapist) for pain and anxiety management vs standard care for initial burndressing change reduced a combined scaled pain and anxiety score (mean 1.7/20 vs 2.9) and painscores alone (median 5.3/13 vs 6.0), but not anxiety scores alone (Children’s Fear Scale); nor did
it improve wound outcomes or reduce need for grafting (Hyland 2015 Level II, n=100, JS 3). In acohort of patients with low procedural pain scores, directed medical play vs standard
preparation reduced maximum pain score during burns dressing change (median 2/10 vs 3)(Moore 2015 Level III-1, n=21).
Distraction
The use of therapeutic clowning increased compliance with dressing change vs standard careassessed by behavioural response (mean 4.8/15 vs 11.0) (Yildirim 2019 Level II, n=50, JS 3).
Child life therapists using computer tablet distraction vs their standard intervention duringhydrotherapy for burns dressing changes in 4─12 y olds did not reduce self-reported pain scores,
but reduced nurse-reported pain and emotional response during and after the procedure (BurnsNader 2017 Level II, n=30, JS 3).
Multimodal procedural preparation (video shown on screen device: “Bobby got a burn”) andmultimodal distraction (screen device using games: “touch and find” stories with multisensory
visual, auditory, and vibratory feedback: Ditto®) lowered pain scores (child by 20─27%, parent
by 29─37% and nursing staff by 16─34%) vs a hand-held video game device or standard
distraction (varied use of TV, video games, stories, toys, nursing staff soothing and care giversupport) (Miller 2010 Level II, n=80, JS 3). Across three procedures, multimodal distraction reduced
pain scores, while multimodal procedural preparation, video or standard distraction did not.
Ditto™ vs standard distraction (in addition to varying pharmacological agents) did not impact
significantly on pain or anxiety ratings during the first three dressing changes ( Brown 2014b
Level II, n=117, JS 3).
Adding animated cartoon watching to PO ibuprofen vs ibuprofen alone was not associatedwith improved pain scores during burns dressing change (Feng 2018 Level III-2, n=54).
A multidisciplinary group of clinicians identified barriers to routine iPad® use for distraction
during burns dressing change including competing demands of clinicians, differing views on therelevance of distraction, and lack of experience and confidence with iPad® use (Green 2018
Level IV, n=15). The authors suggested that effective use of iPads in this context required training
and guidelines for clinicians.
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Immersive VR gaming vs standard distraction reduced nurse observer-rated pain scores(mean 2.9/10 vs 4.7) and rescue use of N 2O (15 vs 43%) ( Kipping 2012 Level II, n=41, JS 3).
Augmented reality gaming achieved lower patient pain scores vs basic cognitive therapy
intervention (2.9/10 vs 5.4) ( Mott 2008 Level III-1). When immersive VR games were added toroutine analgesia, patient pain scores with burn dressing changes decreased ( Das 2005
Level IV, n=7).
Other nonpharmacological interventions
Pain scores with burn dressing changes reduced with music (“active alternate engagement”)(Klassen 2008 Level III-2 SR, 1 RCT [paediatric burn dressing change], n=14; Fratianne 2001 Level II, n=24,
JS 3) and massage therapy (O'Flaherty 2012 Level IV; Hernandez-Reif 2001 Level IV). Twice weekly
massage for 15─20 min for 5 wk lowered heart and respiratory rate, with a positive response(becoming relaxed or falling asleep in 93%, verbally requesting more in 20%) (O'Flaherty 2012
Level IV) and decreased pain and anxiety by 58% vs no change in patients receiving standard care(Parlak Gurol 2010 Level III-1).
Hypnosis had no effect on pain and wound healing for burn dressing changes, but reduced
preprocedural anxiety on the second of three burns dressing changes (MD -0.8/10; 95%CI -1.5
to -0.1) (Chester 2018 Level II, n=62, JS 3).
Nonpharmacological interventions for physiotherapy in burns rehabilitation
Use of PlayStation II EyeToy™ to facilitate body movement vs standard therapy in 5─18 y olds did
not increase range of motion gains; as rehabilitation progressed, standard therapy did increase
pain scores while EyeToy™ did not (r 0.18 vs 0.05) (Parry 2015 Level II, n=17 [31 limbs], JS 1). Xbox
Kinect™ plus standard physiotherapy in 5─12 y olds achieved greater improvements in active
range of motion between discharge and follow-up vs standard physiotherapy and had higher fun
and enjoyment scores; pain outcomes were not reported (Lozano 2018 Level III-2, n=66).
In adult and paediatric burn patients having physiotherapy, immersive VR SnowWorld®
reduced mean worst pain intensity by 20% (54/100 ± 3 vs 44 ± 4), pain unpleasantness by 26%(41/100 ± 4 vs 30 ± 3), and time spent thinking about pain by 37% (47/100 ± 4 vs 30 ± 3) (Sharar2007 Level II, n=88 [66 children], JS 3). Repeated use of SnowWorld® in addition topharmacotherapy by children with burns having physiotherapy reduced cognitive, sensory andaffective pain scores (by 44, 27 and 32%) with patients experiencing three-fold more fun thanwhen no immersive VR was used, although there was no difference in the maximum range of
motion achieved (Schmitt 2011 Level II, n=54, JS 3).
Distraction through purposeful activity with play and games vs “exercise by rote” modulated
the pain experience and improved range of motion achieved during physiotherapy for handburns in children (Omar 2012 Level II, n=30, JS 2).

10.7.3 | Vaccine injection pain in infants and children
Vaccine injections are the most commonly performed medical procedures worldwide, andconcern about pain caused by vaccine injection is a barrier to future vaccine uptake; managing
vaccine injection pain therefore has immediate and long term implications for the health andwellbeing of individuals and populations (Taddio 2015a NR). There is supportive evidence forvarious interventions. Most studies focus on assessing the effects of a single intervention in an
RCT or quasi-randomised study design, and control groups often include active treatments.
Outcomes assessed depend on stage of development and include patient distress (using
behavioural pain/distress scales, cry duration and/or physiological variables), by carer, healthprofessional or researcher, and self-reported pain and fear at different time points, typically prior
to injection, in the acute phase (usually within 1 min of injection) and recovery phase (usually

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1─3 min post injection). Translation of evidence to practice is slow but can be improved with a(telephone-based) educational outreach program (Schechter 2010 Level IV), assessment of lay andmedical perceptions and practice (Harrison 2014 Level IV) and then use of innovative techniques
to effect change eg social media (Center for Pediatric Pain Research NR). Guidelines for evidencebased recommendations across the lifespan are available (McMurtry 2016 GL; Taddio 2015c GL;
WHO 2015 GL). Work is also being done to develop painless modes of vaccine delivery (eg IN, PO,transdermal) (Garg 2018 NR).
10.7.3.1 | Procedural modifications
Procedural modifications were assessed in a systematic review with the following findings (Taddio
2015d Level III-1 SR, 31 studies, n unspecified):• IM injection without aspiration vs with aspiration reduces acute distress in infants(18 mth) (SMD -0.82; 95%CI -1.18 to -0.46) (2 studies, n=313);• Simultaneous vs sequential injections reduces acute distress in infants (<1 y) (SMD -0.56;
95%CI -0.87 to -0.25) (2 studies, n=172);• Injecting the most painful vaccine last reduces acute distress in infants (6 mth) (SMD
-0.69; 95%CI -0.98 to -0.40) (2 studies, n=196);• Vastus lateralis vs deltoid injection reduces acute and recovery phase distress in infants(<1 y) (SMD -0.7; 95%CI -1.0 to -0.4) (1 study, n=185);• Subsequently, term infants (<4 mth) who received HBV vaccine first vs DTwP vaccine first
had lower pain scores (MD -4.13/7; 95%CI -1.9 to -6.4) and HR, and higher oxygen
saturation (Kumar 2016 Level II, n=130, JS 4).
A wider (23-guage 25 mm vs 25-g 25 mm) needle reduces pain intensity (MBPS: MD 0.70/15;
95%CI 0.39 to 1.01) and cry duration (MD 8s; 95%CI 2.86 s to 13.14) in infants (<6 mth) receiving
DTwP vaccines in the thigh; however this effect is probably not clinically relevant, and thegeneralisability of this result is uncertain (Beirne 2018 Level I [Cochrane], 1 RCT: Bharti 2010 Level II,
n=320, JS 3). Longer needles of 25 mm (23 or 25-g) vs 16 mm (25-g) resulted in both fewer severe(NNT=25) and non-severe (NNT=5-6) reactions (Beirne 2018 Level I [Cochrane], 1 RCT: Diggle 2006
Level II, n=458, JS 3). Applying pressure has a positive effect in adults and may be of use in children(Schechter 2007 NR, 1 negative RCT, 2 positive unpublished RCTs, n unspecified). In an additional RCT,
fast injection vs slow injection in infants (2-6 mth) receiving DTaP-IPV-Hib (0.5 mL) reduced mean
pain scores (MBPS: 6/15 vs 7.4) but not cry duration or parent-reported pain (Taddio 2016
Level II, n=120, JS 3).
Evidence based guidelines strongly recommend not aspirating on vaccine injection andinjecting the most painful vaccine last for all children (18 y); weaker recommendations include
simultaneous injection for 1 y but not 1-3 y olds, and vastus lateralis (rather than deltoid)
injection site for 11 mth (Taddio 2015c GL).
10.7.3.2 | Topical local anaesthesia
Topical local anaesthesia for infants and children (0-12 y) is recommended (Taddio 2015c GL). For
infants (age unspecified), topical local anaesthesia (EMLA® in 12 of 13 studies) vs control(placebo in 6 of 13 studies) reduced acute distress from vaccine injection (SMD -0.91; 95%CI 1.36 to -0.47) (13 studies, n=1,424), but not for children (4-12 y), although this finding was qualified
by a positive result if one study (n=39) at high risk of bias was removed from the meta-analysis(SMD -0.47; 95%CI -0.73 to -0.21) (2 studies, n=230) (Shah 2015 Level III-1 SR, 55 studies, n unspecified).
Meta-analyses for adolescents (12 y) was not possible; two included studies had conflicting
results. Despite this, selective use of topical local anaesthesia has been recommended in older
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children (Taddio 2015c GL; Schechter 2007 NR). Topical local anaesthesia vs placebo in infants andchildren did not affect immune response to vaccines (MMR, DTaP-IPV-Hib HBV, BCG vaccines) as
measured by antibody response (4 studies, n=833) (Shah 2015 Level III-1 SR, 55 studies, n unspecified).
10.7.3.3 | Sweet solutions
Two systematic reviews (14 study overlap) support efficacy of sweet solutions for vaccination
injection in infants <2 y old:
• For 1─12 mth olds, PO sucrose (12─75%) and glucose (30─40%) 1-2 mL vs water, saline or
no treatment reduces incidence of cry and crying duration (MD -13.5; 95%CI -16.8 to 10.2) (Kassab 2019 Level III-1 SR [Cochrane], 14 studies, n=1,551);• PO sucrose vs control for <2 y olds was associated with lower acute distress (SMD -0.37;
95%CI -0.67 to -0.06) (18 studies, n=881) and acute and recovery distress (SMD -0.76; 95%CI-1.19 to -0.34) (18 studies, n=2,071); PO sucrose 2 mL was typically given (15 of 18 studies) 2
min prior to injection (15 of 18 studies) and was effective in concentrations of 20-33% (9/18
studies) but not 12% (Shah 2015 Level III-1 SR, 55 studies, n unspecified);• PO glucose 1─2 mL (25─50%) vs control for <1 y olds reduces acute + recovery distress(SMD -0.69; 95%CI -1.03 to -0.35) (6 studies, n=818) (Shah 2015 Level III-1 SR, 55 studies, nunspecified);• Sweet solutions combined with NNS (1 study) or breastfeeding (1 study) in infants <3 mth
was not superior to either intervention alone (Shah 2015 Level III-1 SR, 55 studies, nunspecified).
In further individual studies not included or subsequent to the above reviews:• PO glucose 25% 2 mL vs NNS in neonates receiving HBV vaccine reduced pain score (mean
3.3/7 vs 5.6) and crying time (mean 10.9 s vs 33.9), however increased HR (147 vs 137)
(Lima 2017 Level II, n=78, JS 2);• Infants (2─4 mth old) who received oral rotavirus vaccine (contains 71.5% sucrose) vssucrose 24% prior to vaccine injection had no difference in observer-reported pain scores(mean 7.4/15 vs 7.7), parent or clinician reported pain scores, or cry duration (Taddio
2015b Level II, n=120, JS 5);• For 2─6 mth old, high-dose PO sucrose 50─75% (2 mL) was equivalent to water in termsof pain scores and crying time (Curry 2012 Level II, n=113, JS 5);• For older infants (15 mth MMR vaccination) sucrose 30% vs water reduced cry duration(mean 18 s vs 33) (Despriee 2016 Level II, n=114, JS 3).
Sweet solutions (sucrose or glucose) are strongly recommended for infants (2 y) receiving
vaccines, with weaker recommendations to combine with NNS or breastfeeding (Taddio 2015cGL). In older children, there is insufficient evidence to support the use of sweet solutions(sucrose) in 1─4 y olds (6 studies, n=520), and no evidence of analgesic effect of sweet solutions(sweetened chewing gum) in school aged children (2 studies, n=111) (Harrison 2015 Level III-1 SR, 8
studies, n=808 [n vaccination unspecified]).
10.7.3.4 | Nonpharmacological intervention for vaccine injection
Preparation and education
A systematic review found supportive evidence for the following nonpharmacologicalinterventions (Pillai Riddell 2015b Level III-1 SR, 13 studies, n=972 [children] & 53 [nurses] & 197[expectant parents]):

1050 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT• Educating nurses administering vaccines improved use of pain management interventions(SMD 0.66; 95%CI 0.47 to 0.85) (1 study: Chan 2013 Level III-1, n=53 [459 procedures]);• Parental presence reduced pre-vaccine injection distress in infants and children (1─7 y)(SMD -0.85; 95%CI -1.35 to -0.35) (3 studies, n=67);• Parental education before vaccination day improved use of interventions pre-vaccination(RR 2.08; 95%CI 1.51 to 2.86) (2 studies, n=300) and reduced acute distress (SMD -0.35;
95%CI -0.57 to -0.13) (3 studies, n=350) in infants 2 y old;
• Parental education on vaccination day improved use of interventions (SMD 1.02; 95%CI
0.22 to 1.83) (4 studies, n=183), (RR 2.42; 95%CI 1.47 to 3.99) (4 studies, n=239) and reduced
periprocedural distress (SMD -0.48; 95%CI -0.82 to -0.15) (4 studies, n=262) in infants andchildren 6 y old.
The effect of information provision has been assessed in further RCTs:• Information provision to new mothers prior to leaving hospital on vaccine pain
management given by factsheet vs control (baby general health information) did not
improve knowledge scores or utilisation of pain management interventions 2 mth later(Taddio 2014 Level II, n=120, JS 3);• Post-natal education for parents with a pain pamphlet and/or pain video vs general vaccine
information increased the use of pain management interventions (breastfeeding, sucrose,
topical local anaesthesia) at infant (6 mth) vaccination (pain pamphlet + pain video 63%, pain
pamphlet only 61%, general vaccine information 53%) (Taddio 2018 Level II, n=2,549, JS 3);• Excluding toddler (18 mth) pain scores during the regulatory phase of vaccine injection,
parental psychological distress (assessed by BSI-18) had no moderating effect on theimpact of a parent education video (ABCDs of pain management) when assessing various
outcomes (parental soothing behaviours, parental worry, infant (6 mth) and toddler
reactivity and regulatory phase pain scores) (Gennis 2018 Level II, n=128, JS 5);• For parents of older children (4─6y), automated parent-training via a 10 min interactive
computer program + distraction, vs distraction only vs no treatment did not reduce child
distress or pain. However, it did improve parental knowledge, parents’ behaviours during
vaccination, and children’s engagement in distraction and deep breathing during
vaccination (Cohen 2015 Level II, n=90, JS 3).
Parents who were educated on pain management strategies for an RCT most commonly usedstrategies such as acting calm, holding the child and distraction, whilst strategies such as PO
sucrose, topical local anaesthetic cream and pacifier use were uncommon; reasons cited for thisincluded parents thinking these strategies were unnecessary, forgot to use strategy, or they were
not easily accessible at the vaccine clinic (McNair 2017 Level IV, n=130).
In a review of YouTube videos of children receiving vaccination injections, 73% of infants(<12 mth) received at least one pain management strategy during injection, with distraction(66%) the most common strategy; no videos showed breastfeeding or the use of a sweet solution(Harrison 2014 Level IV SR, n=142 [videos]).
Feeding interventions
Two systematic reviews found supportive evidence for breastfeeding in infants <12 mth old ( Shah2015 Level III-1 SR, 55 studies, n unspecified) and beyond the neonatal period (Harrison 2016
Level III-1 SR [Cochrane], 10 studies, n=1,066) (6 study overlap):• For infants <12 mth, breastfeeding during vaccination injection vs control reduces acutephase distress (SMD -1.78; 95%CI -2.35 to -1.22) (8 studies, n=792), and acute and recovery
phase distress (SMD -1.89; 95%CI -3.19 to -0.59) (n=424) (Shah 2015 Level III-1 SR, 55 studies,n unspecified);
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• For infants <12 mth, breastfeeding before vaccination injection (if not used during) vscontrol reduces acute phase distress (SMD -1.43; 95%CI -2.14 to -0.72) (2 studies, n=100)
and acute and recovery phase distress (SMD -1.47; 95%CI -2.05 to -0.90) (Shah 2015
Level III-1 SR, 55 studies, n unspecified);• Beyond the neonatal period (mostly 1─6 mth old), breastfeeding vs water or no treatment
reduces cry time (MD -38 s; 95%CI -50 to -26) (6 studies, n=547), and pain scores (SMD 1.7; 95%CI -2.2 to -1.3) (5 studies, n=310) but not HR (2 studies, n=186) (Harrison 2016
Level III-1 SR [Cochrane], 10 studies, n=1,066);• Additionally, there was supportive evidence for breastfeeding reducing cry time and painscores vs massage and cuddling, PO glucose 25%, topical local anaesthesia (EMLA®) andvapocoolant spray (1 study each) (Harrison 2016 Level III-1 SR [Cochrane], 10 studies, n=1,066).
Subsequent RCTs continue to support a beneficial effect of breastfeeding (Dar 2019 Level II,
n=60, JS 3; Gad 2019 Level II, n=120, JS 2; Fallah 2017 Level II, n=120, JS 3; Hashemi 2016 Level II, n=131,
JS 2). Additionally, formula feeding of infants (4─10 wk) during vaccine injection vs no treatment
reduced cry duration (MD -32.9 s; 95%CI -58.0 to -7.8) and recovery phase pain scores (MD-3.78/7; 95%CI -2.52 to -5.05) (Bos-Veneman 2018 Level II, n=48, JS 2).
Physical interventions
Various physical interventions have been assessed in a systematic review (Taddio 2015d Level III-1
SR, 31 studies, n unspecified):• In neonates, kangaroo care vs lying supine reduces acute and recovery phase distress(SMD -0.65; 95%CI -1.05 to -0.25 and SMD -0.89; 95%CI -1.26 to -0.52 respectively) (3studies, n=736);• Excluding one high risk bias study, for infants (6 wk─6 mth) holding by parent during
vaccination vs lying supine and not being held reduces acute distress (SMD -1.25; 95%CI 2.05 to -0.46) (2 studies, n=181);• For infants (0─4 mth) holding by parent after vaccination (if not held during) reduced
acute and recovery distress (SMD -0.65; 95%CI -1.08 to -0.22) (2 studies, n=417);• For infants (0─4 mth), NNS reduces acute distress (SMD -1.88; 95%CI -2.57 to -1.18) (2studies, n=186);• Manual tactile stimulation (pressure, rubbing/stroking, tapping) vs no treatment does not
reduce acute distress in infants (3 studies, n=301), or self-reported pain in older children
and adults (3 studies, n=893);• For children (4─6 y), sitting upright vs lying supine reduces fear (SMD -0.39; 95%CI -0.77
to -0.01) (1 RCT: Lacey 2008 Level II, n=107, JS 2) but not pain;• For children (4─7 y) vibrating device with cold reduces pain (SMD -1.23; 95%CI -1.58 to 0.87) (2 studies, n=145) but not fear;• For vaccination for older children (7 y) and adults, a muscle tension intervention reduces
risk of fainting during injection (RR 0.11; 95%CI 0.02 to 0.79) (2 studies, n=38).
Application of cold and vibration (using the Buzzy® device) vs no treatment reduced selfreported pain scores in paediatric patients receiving vaccination (3─18y) (SMD -0.76; 95%CI -1.09
to -0.43) (2 RCTs, n=144) (Ballard 2019 Level I [PRISMA], 9 RCTs, n=1,138) (1 RCT overlap), whilst
vapocoolant sprays were not effective in reducing pain for infants (3 mth old) (1 study, n=74)
or older children (3─17 y) (4 studies, n=228) (Shah 2015 Level III-1 SR, 6 studies [vapocoolant in children],n unspecified).

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Further studies to the above reviews have been published on physical interventions:• Facilitated tucking vs holding in supine position in term neonates receiving HBV vaccine
reduces pain score (mean 2.83/7 vs 6.47) but not HR, RR or oxygen saturation (Kucukoglu
2015 Level II, n=60, JS 2);• White noise vs no intervention for premature neonates (born at 28─32 wk) receiving their
2nd dose of HBV vaccine reduced pain scores (mean 8.14/21 vs 14.35) and peak HR (mean154/min vs 166) and RR (mean 50/min vs 61) (Kucukoglu 2016 Level III-1, n=75);• ShotBlocker/swaddling vs swaddling alone for healthy term neonates receiving HBVvaccine reduces pain scores during (mean 1.64/7 vs 2.96) and 3 min after (mean 0.74/7
vs 1.42) injection, but not HR or RR (Caglar 2017 Level II, n=100, JS 3);• Maternal kangaroo care vs swaddling for infants (ex-term and preterm) reduces painscores at 1 min (median 2.5/7 vs 5 ) and 5 min (0/7 vs 4) post vaccine injection, as well as
cry duration (median 42.5 s vs 135) (Pandita 2018 Level II, n=61, JS 3);• Holding infants (6─12 wk post-natal age) in the supine vs upright position reduced crying(52 vs 70%), irritability (43 vs 58%) and distressed facial expression (46 vs 60%) 30 s after
vaccine injection (Yin 2017 Level III-2, n=282);• There was no difference in pain scores, and cry duration between infants (4─6 mth)
receiving 10 s manual pressure, rapid injection without aspiration, or both; all study
groups were superior to standard care (Gol 2017 Level II, n=128, JS 3);• In older children (4─12 y) ShotBlocker vs placebo and typical care was not found to be
more effective in reducing self-reported or observer-reported pain scores, distressbehaviours (crying, screaming or requiring adult restraint) or observer-reported distress(Cobb 2009 Level II, n=89, JS 2).
Physical interventions that are strongly recommended include kangaroo care for 1 mthold, breastfeeding during vaccination injection for 2y old, holding for 3 y old, and sitting up
for 3─18y olds; weaker recommendations include to use NNS during vaccination injection for2 y olds, vibrating device with cold for 3─18 y olds, and muscle tension for 7─18 y olds, andrecommend against manual tactile stimulation and warming the vaccine for all ages (Taddio
2015c GL).
Psychological interventions
Parental responses during injection such as excessive reassurance, criticism or apology increase
distress, whereas humour and distraction tend to decrease distress ( Schechter 2007 NR, 4 studies,n unspecified). Parental stress promoting behaviours had a stronger relationship than soothing
behaviours and emotional availability with infant reactivity (immediate response) and regulation(non-immediate response), suggesting that teaching parents what not to do may be at least as
important as teaching parents what to do (Badovinac 2018 Level IV, n=220). Furthermore, caregiver behaviour and poorer pain regulation at 12 mth vaccination predicted forward to preschool vaccination coping, and care-giver behaviour also showed relationships to broader childcognitive behavioural abilities (Campbell 2018 Level IV, n=760). Healthcare staff can also influencea child’s vaccination experience, and should purposefully use coping promoting strategies (Pedro2016 Level IV, n=220 [4─7y]).
Three systematic reviews have assessed psychological interventions for vaccine injection:• For 0─3 y olds, directed video distraction vs control reduces acute and recovery phase
distress (SMD -0.68; 95%CI -1.04 to -0.32) (4 studies, n=126) and pre-vaccination distress(SMD -0.49; 95%CI -7.6 to -0.22) (4 studies, n=216) (Pillai Riddell 2015a Level III-1 SR, 10 studies,
n=1,259);

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1053• Directed toy distraction vs control for 0─3 y olds reduces peri-vaccination distress (SMD 0.47; 95%CI -0.91 to -0.02) (1 study, n=81), whilst non-directed toy distraction vs control
does not reduce acute distress as the confidence interval includes zero (SMD -0.93; 95%CI-1.86 to 0.00) (4 studies, n=290) (Pillai Riddell 2015a Level III-1 SR, 10 studies, n=1,259);• Verbal distraction vs control reduces distress in children (3─7 y) (SMD -1.22; 95%CI -1.87
to -0.58) (2 studies, n=46) but not pain (Birnie 2015 Level III-1 SR, 22 studies, n 1,717);• Breathing with a toy reduces pain in children (3─9 y) (SMD -0.49; 95%CI -0.85 to -0.13) (6studies, n=368) but not fear (Birnie 2015 Level III-1 SR, 22 studies, n=1,717);• Video distraction vs control reduces distress in children (2─12 y) (SMD -1.22; 95%CI -1.87
to -0.58) (5 studies, n=328) but not pain (Birnie 2015 Level III-1 SR, 22 studies, n=1,717);• Music distraction vs control reduces pain in children (3─7 y) (SMD -0.45; 95%CI -0.71 to-0.18) (4 studies, n=417) but not in adolescents (1 study n=118) (Birnie 2015 Level III-1 SR, 22
studies, n=1,717);• There is no benefit for breathing techniques without a toy for pain or fear in children (3─7 yolds) (2 studies, n=136), coughing with injection for pain in 4─5 y olds (1 study n=136), false
suggestion for pain or distress in 4─7 y olds (2 studies, n=240) or repeated reassurance for pain,
distress or fear in 3─7y olds (2 studies, n=82) (Birnie 2015 Level III-1 SR, 22 studies, n=1,717);• Psychological interventions for needle-related procedural pain in older children andadolescents (2─19 y) are effective (11 unique RCTs studying immunisation or injection:
distraction 7 RCTs, combined CBT 6 RCTs, suggestion 1 RCT), but a sub-group analysis on vaccine
injection was not done (Birnie 2018 Level I [Cochrane], 59 RCTs, n=5,550) (0 & 10 RCT overlap).
Further studies published on psychological interventions for vaccine injection pain found:• Parent participation to deliver distraction during vaccination in 4─6 y olds vs medical
assistant delivered distraction did not change self-reported pain or satisfaction scores,
parent-reported pain or satisfaction scores, or observer-reported pain scores (Franck 2015
Level II, n=76, JS 3);• Music therapy for children (4─6 y) vs no treatment did not reduce parent ratings of child’s
pain but did reduce child distress behaviours during and after vaccination and parent
distress promoting behaviours before, during and after vaccination (Yinger 2016 Level II,
n=58, JS 2);• Relaxation therapy and guided imagery had similar effects on cortisol reactivity, selfreported stress, pain intensity and pain unpleasantness in females (11─12 y) receiving theHPV vaccine (Nilsson 2015 Level III-2, n=37).
There is no data for needle phobia interventions alone; in vivo exposure based therapy forchildren (7─17y) with other phobias reduced specific fear (SMD -1.71; 95%CI -2.72 to -0.70)(4 studies, n=235), whilst imagined exposure based therapy in children (7─17y) reduced specificfear post-treatment (SMD -0.88; 95%CI -1.7 to -0.05) (2 studies, n=41) and at 3 mth (SMD -0.89;
95%CI -1.73 to -0.04) (1 study, n=24) (McMurtry 2015 Level III-1 SR, 11 studies, n=620).
The following psychological interventions are recommended: verbal signal of impending
procedure, suggestion and reassurance for all children (0─17 y); directed video distraction,
directed or non-directed toy distraction for 3 y; verbal, video or music distraction and breathingwith a toy for 3─12 y olds; and recommend against a planned cough during injection for 3─17 yolds (Taddio 2015c GL). For patients with high levels of needle fear in vivo exposure-based therapy,
and if this is not used, non-in vivo (imagined) exposure-based therapy is strongly recommended
for children 7─17 y old (McMurtry 2016 GL).

1054 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

Combination intervention
Various combinations of interventions have been studied in vaccine injection pain. Further
reviews and studies are summarised here:• In infants <3 mth, topical anaesthesia with breastfeeding vs topical anaesthesia alone
reduced acute and recovery phase distress (SMD -0.83; 95%CI -1.36 to -0.30) (Gupta 2013
Level II, n=90, JS 3), whilst there was no benefit for sweet tasting solutions with NNS vseither alone (1 study), or breastfeeding and sweet tasting solutions vs either alone (1 study)(Shah 2015 Level III-1 SR, 55 studies, n unspecified);• PO sucrose, oral tactile stimulation (with a pacifier or a bottle) and parental holding
reduced the duration of crying in infants (2 mth) receiving multiple immunisations (Reis
2003 Level II, n=116, JS 5);• EMLA® combined with N2O 50% was superior to either alone for observed pain in infants(<24 mth) during and post vaccination injection (Carbajal 2008 Level II, n=55, JS 5);• EMLA® and breastfeeding was similarly effective to vapocoolant spray and breastfeeding,and both combinations were superior to breastfeeding alone in terms of cry duration(36 s vs 33 s vs 68 s) and pain intensity at 1 min (mean 1.4/6 vs 1.8 vs 3.2) and 3 min (mean0.9/6 vs 0.6 vs 2.3) post vaccine injection (Gupta 2017 Level II, n=90, JS 3);• Combination of video/ sucrose/topical lidocaine administered to infants at each of theirvaccinations up to 12 mth old reduced pain scores during vaccine injection vsvideo/sucrose, video alone and placebo (mean 6.3/15 vs 6.7 vs 6. 7 vs 6.7 respectively)
suggesting benefit from this combination of interventions was derived from topicallidocaine only (Taddio 2017b Level II, n=352, JS 5);• The same four groups all received video/sucrose/topical lidocaine for vaccinations at 15
mth old, and there was no difference in pain scores across groups before, during and after
vaccination injection, suggesting consistency in vaccine pain management interventionsin the first year of life does not confer benefit at 15 mth (Taddio 2017a Level II, n=352, JS 5).

10.7.4 | Procedural pain management in the emergency department
Clinical guidelines from various bodies have been developed for procedural pain management in
the ED. The American College of Emergency Physicians has published a guideline for unscheduled
procedural sedation in children and adults; it focusses on safety of delivering sedation in thiscontext rather than on individual drug efficacy, and is applicable to the use of various sedatives(Green 2019b GL).
10.7.4.1 | Laceration repair
All oral agents as specified in Sections 10.4.1 to 10.4.3 have been used in children having
laceration repair, usually to supplement topical or injected local anaesthetic. IN fentanyl use is
not yet specifically reported for laceration repair.
Topical local anaesthesia
Topical local anaesthetic application for wound closure can avoid the distress caused byintradermal injection; importantly cocaine-containing preparations are no longer recommended(Tayeb 2017 Level III-1 SR [Cochrane], 25 RCTs [2 paediatric, 19 mixed paediatric/adult], n=3,278 [paediatricunspecified]). Numerous topical local anaesthetic agents have been assessed. Only a descriptive
analysis is possible as studies have high risk of bias, mostly involve only single comparisons andonly 15 of 25 RCTs report pain scores. The most widely used topical agent applied to paediatricwounds is lidocaine-adrenaline-amethocaine (tetracaine) preparation (abbreviated to ALA in
Australia and LAT or LET in the USA). This combination appears as effective as tetracaine5th Edition | Acute Pain Management: Scientific Evidence

1055adrenaline-cocaine (3 RCTs, n=341), buffered lidocaine-adrenaline infiltration (1 RCT, n≈66),
infiltrated lidocaine (1 RCT, n=40) and as a gel or solution with no other comparator (1 RCT, n=194).
Topical ALA solution applied to wounds at triage reduced treatment time by 31 min vscontrols (Priestley 2003 Level II, n=161, JS 4) and pain associated with subsequent intradermal
injection of lidocaine (Singer 2000 Level II, n=43, JS 5).
Local anaesthesia infiltration
In mainly adult patients, pain on injection of local anaesthesia is reduced by warming (to37─43oC) (Hogan 2011 Level I [PRISMA], 1 RCT [paediatric], n=44) or buffering with sodium
bicarbonate (increasing the pH of lidocaine to ≥7.35) (Cepeda 2010 Level I [Cochrane], 2 RCTs [mixedage], n=165 and 1 RCT [paediatric], n=7) (see also Section 4.4.2).
Alternatives to suturing: tissue adhesives and hair apposition
Tissue adhesives vs suturing for simple lacerations produce similar cosmetic results (9 RCTs,
n=889), and less parent-reported pain (WMD -13.4/100; 95%CI -20 to -6.9) (5 RCTs, n=434) withshorter procedure time (WMD -4.7 min; 95%CI -7.2 to -2.1) (6 RCTs, n=584) and may be more
acceptable to children (Farion 2003 Level I [Cochrane], 13 RCTs [paediatric], n unspecified). The risk ofdehiscence is increased slightly with tissue adhesive vs standard wound care (NNH 40; 95%CI 20
to 1,168) but it is offered to parents as a preferred initial intervention. Hair apposition was aseffective as suturing for simple scalp lacerations (Hock 2002 Level II, n=189, JS 3), and can be
performed effectively by doctors and nurses (Ong 2008 Level II, n=164, JS 3).
Children who received topical local anaesthetic (ALA) prior to tissue adhesive application
were more likely to have a pain-free procedure vs placebo by self or observer report (RR 0.54;
95%CI 0.37 to 0.80) (Harman 2013 Level II, n=221, JS 5).
Midazolam
Midazolam is a useful adjunct in the procedural sedation pharmacotherapy armamentarium forlaceration repair in younger or noncooperative children. IN administration stings and the PO
route is generally preferred, although efficacy may be more variable (influenced by first-passmetabolism and duration of fasting). Compared to PO route or aerosolised buccal delivery prior
to laceration repair in young children (0.5─7 y), aerosolised delivery IN had faster onset andachieved adequate sedation, at the expense of nasal irritation and being less readily accepted
than the PO route (Klein 2011 Level II, n=169, JS 5). PO midazolam 0.7 mg/kg vs PO ketamine
5 mg/kg for children (1─10 y) having laceration repair resulted in similar parent-reported painscores (3.7/10 vs 5.1) (Rubinstein 2016 Level II, n=68, JS 5).
Nitrous oxide (N2O) and ketamine alone or in comparison
Inhaled N2O 50─70% (with oxygen) is commonly used for laceration repair and minor surgery inchildren and reduces pain and anxiety, with large case series affirming the utility and safety ofthe technique for this and other indications (Tobias 2013a Level I SR, 1 RCT [laceration], n=30;
Pedersen 2013 Level IV SR [PRISMA], 1 RCT [laceration], n=204 & multiple studies [laceration],n unspecified; Heinrich 2015 Level IV, n=210; Babl 2010 Level IV, n=504). Ketamine is also commonlyused as dissociative sedation and analgesia for laceration repair. Common doses used as soleagent in the ED are 0.5─1 mg/kg IV and 3─5 mg/kg IM; coadministration of atropine or
benzodiazepine is no longer recommended (Green 2011 GL). PO and IN routes are also used (seebelow).
For facial laceration repair in the ED by a plastic surgeon, in children and adolescents (1─16 y;
60% unfasted), N2O 50% with lidocaine infiltration vs lidocaine infiltration alone reduced painscores during lidocaine infiltration (mean 1.9 /10 vs 9.7) and suturing (2/10 vs 8.8); in controls
forceful restraint was applied in 100% vs patients receiving N2O where only 15% required mild
restraint (Bar-Meir 2006 Level III-2, n=60). Minor adverse effects (mostly nausea) occurred in 29%1056 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

of patients receiving N2O. N2O 50─70% and IV ketamine 2 mg/kg had similar analgesic efficacy,with deeper sedation and longer median duration by 13.5 min in those ketamine treated (Lee2012 Level II, n=32, JS 3). The addition of PO ketamine 5 mg/kg to PO midazolam 0.5 mg/kg vsmidazolam alone for laceration repair, resulted in similar pain scores during local anaesthetic
injection (parent and researcher: 4/10), with increased sedation and time to discharge for the
combination group (MD 65 min; 95%CI 22 to 107) (Barkan 2014 Level II, n=60, JS 5). IN Ketamine
9 mg/kg achieved adequate sedation for laceration repair in young children, whilst doses of
3mg/kg and 6 mg/kg did not (Tsze 2012 Level II, n=12, JS 2).
The safety of ketamine has been documented in a large paediatric ED series ( n=8,282) withlow rates of emergence reactions (clinically important 1.4 vs “any” 7.6%), vomiting 8.4% andrespiratory events 3.9% (Green 2009c Level IV). Variables independently associated with increased
risk of respiratory effects included age <2 y (OR 2.00; 95%CI 1.47 to 2.72) and ≥13 y (OR 2.72;
95%CI 1.97 to 3.75), high IV dosing (initial dose ≥2.5 mg/kg or total dose ≥5.0 mg/kg) (OR 2.18;
95%CI 1.59 to 2.99) and co-administered anticholinergic (OR 1.82; 95%CI 1.36 to 2.42) or
benzodiazepine (OR 1.39; 95%CI 1.08 to 1.78). Oropharyngeal procedures, ASA class ≥3 and useof IV vs IM route were not associated with increased risk.
10.7.4.2 | Closed fracture reduction
Closed fracture reduction is a major procedure, which may be performed in EDs with a variety ofanalgesic techniques including N2O (Pedersen 2013 Level IV SR [PRISMA], 4 studies, total n=45,120),
ketamine IV or IM (Babl 2010 Level IV, n=2,002 [1,622 N20 & 340 ketamine]), opioids (IV morphine, INor IV fentanyl and IV alfentanil), propofol or combinations of these agents ( Migita 2006 Level I SR,
5 RCTs, n=526; Hoeffe 2017 Level IV, n=90; Schofield 2013 Level IV). The majority of studies assess
procedural pain scores and not postprocedural impact. Paediatric guidelines for procedural
sedation have been produced by the American College of Emergency Physicians (Green 2019b GL).
Different regimens may result in no or mild sedation through to heavy sedation or evenanaesthesia. Comparison of specific regimens studied are summarised below:
Ketamine• With PO oxycodone 0.2 mg/kg pre-treatment, IV ketamine 1 mg/kg with IV midazolam
0.1 mg/kg vs N2O 50% and haematoma block (1% buffered lidocaine 2.5 mg/kg) had
similar parental and child pain scores, but later readiness for discharge (mean 83 min vs16); minor adverse effects were frequent in both groups (vomiting 24% vs 26; headache
11% vs 13) with the ketamine/midazolam group reporting more ataxia (24% vs 9)
nightmares (20% vs 7) and hallucinations (29% vs 4) (Luhmann 2006 Level II, n=102, JS 3);• IV Ketamine/midazolam vs IV etomidate/fentanyl achieved lower observer pain scores,
similar amnesia and greater parental satisfaction, despite longer recovery time (LeeJayaram 2010 Level II, n=23, JS 5);• In children (3─14 y) receiving IV midazolam 0.2 mg/kg (max 10 mg), IV morphine 0.1 mg/kg
and 0.05 mg/kg prn (max 5 mg) vs IV ketamine 2mg/kg (max 70 mg) resulted in similar
pain scores following the procedure (median 2/10 vs 2); sedation scores were notreported (Barcelos 2015 Level II, n=25, JS 3);• An ED dose finding study for IV ketamine for procedural sedation/anaesthesia in 3─18 yolds (71% fracture/dislocation reduction) suggested similar median sedation depth(Ramsay sedation scores 5.5─6/6) and duration (23─24.5 min) with an initial dose of 1.5
or 2 mg/kg vs 1 mg/kg, but greater need for redosing with 1 mg/kg (16% vs 3% with
1.5mg/kg and 5% with 2 mg/kg) (Kannikeswaran 2016 Level II, n=125, JS 5);

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1057

• In another dose finding sedation study, the ED 95 dose for bolus IV ketamine for closed
forearm fracture reduction was estimated at 0.7 mg/kg for 2─5 y olds and 6─11 y olds,
with 0.8 mg/kg for 12─17 y olds (Chinta 2015 Level IV, n=60);• Following ED intervention for fracture reduction, laceration repair and other painfulprocedures (where procedural pain scores were not assessed), ketamine mostly single
agent (or combined with midazolam) vs fentanyl/midazolam had similar vomiting rates(20% vs 14), low incidence of emergence reaction (1% vs 0) and lower incidence of posthospital behavioural disturbance (McQueen 2009 Level III-3, n=554 [294 fracture reductions]).
Intranasal and inhaled analgesia• IN fentanyl 1.5 mcg/kg added to N2O 70% did not improve analgesia over N2O alone inchildren (2─16 y) with low procedural pain scores and short procedure duration (mean3.62 min; 84% fracture manipulation) (Seiler 2019 Level II, n=402, JS 5);• IN diamorphine 0.1 mg/kg with N2O 50% has been used successfully for closed fracture
reduction in the ED (Kurien 2016 Level IV, n=100);• Inhaled N2O for closed fracture reduction in children and adolescents is safe but its
efficacy is reported to be mixed (Pedersen 2013 Level IV SR [PRISMA], 6 studies, n=54,127[closed fracture reduction unspecified]; Babl 2010, n=2,002 [393 closed fracture reduction];
Hennrikus 1995 Level IV, n=100; Hennrikus 1994 Level IV, n=54);• Methoxyflurane via Penthrox® inhaler in children (5─13 y) requiring mostly upper
extremity fracture reduction was an effective analgesic with rapid onset (<30 s), butvariable effectiveness for procedural sedation; minor adverse events (eg cough, agitation,
blurry vision) occurred in 5 of 14 patients (Babl 2007 Level IV, n=14);• Dexmedetomidine IN or IV use is not yet reported for this indication (McMorrow 2012 NR).
For children and adolescents (21 y old) with a forearm or lower extremity fracture, the useof procedural sedation (23% vs 18) by paediatric and general ED physicians was similar.
Paediatric ED physicians were more likely to use fentanyl (62% vs 19), the IV route (91% vs 67),
and a combination of agents (90% vs 44) (Cimpello 2004 Level III-2, n=718). Patient age andcharacteristics of a displaced fracture (but not ethnicity: African-American or Caucasian) werepredictors of use of conscious sedation (midazolam and fentanyl, or ketamine) for closed
forearm fracture reduction in children and adolescents (18 y) presenting to a paediatric ED(VanderBeek 2006 Level IV, n=503).
Opioid/propofol and ketamine/propofol combinations
Opioid/propofol or ketamine/propofol (ketofol) combinations for deeper procedural sedation
are increasingly used in paediatric EDs. In various paediatric procedural sedation settings,
adverse effects of propofol use (of 0.5─2mg/kg and higher) have been reported at rates of:cardiovascular (hypotension 15.4% and bradycardia 0.1%); respiratory (desaturation 9.3%,
apnoea 1.9%, assisted ventilation 1.4%, unplanned intubation 0.02%, laryngospasm 0.1%); andpost-procedure vomiting (0.14%) (Lamond 2010 Level IV SR, 60 studies, n=17,066). Of the sevenincluded ED studies, six were for fracture reduction ( 2 RCTs, n=204; 4 case series, n≈610) withcoadministration of opioid (morphine or fentanyl) and supplemental oxygen. Desaturation rates
varied from 5─31%, with lower rates of airway intervention (such as jaw manoeuvres and bagmask assistance) and no intubations. Ketofol has been compared to propofol only (with andwithout opioid pre-treatment) for fracture reduction with focus upon satisfaction withprocedural sedation, and respiratory (9─28% depending how defined) and other adverse effects(Weisz 2017 Level II, n=183, JS 3; Shah 2011a Level II, n=140, JS 5; David 2011 Level II, n=220, JS 5).
Pharmacokinetic modelling has been done for ketofol with dosing recommendations for longer
duration procedures (Coulter 2014 PK).

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Regional anaesthesia/analgesia
Haematoma blocks and Bier’s block (or IV regional anaesthesia/block [IVRA/IVRB]) are used for
closed forearm fracture reduction in the ED. A survey of orthopaedic surgeons and paediatric ED
physicians found 78% of respondents had used a local anaesthetic technique for closed reductionof a forearm fracture but only 17% reported frequent use; of respondents who had used local
anaesthetic techniques, haematoma blocks (93%) and Bier’s blocks (20%) were the mostcommon (Constantine 2007 Level IV, n=85). A subsequent survey of paediatric ED physicians foundthat 35% of respondents had used a Bier’s block and 4% a haematoma block ( Schofield 2013 Level
IV, n=111). Local anaesthetic IVRB is highly effective and safe (Migita 2006 Level I SR, 3 RCTs [IVRB],
n=560; Murat 2003 Level III-3 SR, 5 studies, n=1,178; Chua 2017a Level IV, n=1,788) but data on optimal
dosing, safety and comparisons of efficacy are limited, and serious complications may arise withfaulty equipment, inappropriate local anaesthetic use, or inadequate monitoring and training ofstaff.
Trans-arterial axillary brachial plexus block (1% lidocaine with adrenaline 0.7 mL/kg) achieved
similar procedural pain scores to ketamine/midazolam deep sedation in children (>8 y) having
closed reduction of a forearm fracture in the ED (mean 6.4 /13 vs 7.5); 11/20 blocks wereassessed as incomplete (residual motor block) (Kriwanek 2006 Level II, n=43, JS 2).
Ultrasound (US)-guided ulnar, radial, and median nerve blocks in the forearm for hand
injuries managed procedurally in the ED (fractures, dislocations, crush injuries, complex
lacerations) have been used successfully in children and adolescents (7─17 y old) (Mori 2019
Level IV, n=6; Frenkel 2015 Level IV, n=10). US-guided intra-articular lidocaine injection to the
glenohumeral joint has been used successfully for analgesia to reduce an anterior shoulder
dislocation in a 17 y old male (Breslin 2014 CR).
10.7.4.3 | Psychological interventions
In addition to pharmacological interventions, procedural planning for children in the ED should
include age-appropriate psychological interventions, such as distraction techniques (see below
Section 10.7.5).

10.7.5 | Nonpharmacological strategies in children and adolescents
For further information on nonpharmacological strategies for specific procedures, see sections
10.7.1─4 above.
Distraction
Distraction can be passive (eg listening to music, being read a book, watching a screen,
kaleidoscope, distraction boxes) or active (eg guided imagery, handheld video games, nonimmersive or immersive virtual reality). Distraction reduces self-reported needle-related
procedure pain (SMD -0.56; 95% CI -0.78 to -0.33) (30 RCTs, n=2,802), and self-reported needlerelated distress (SMD -0.82; 95%CI -1.45 to -0.18) (4 RCTs, n=426) (Birnie 2018 Level I [Cochrane], 59
RCTs, n=5,550). Further reviews including lower level evidence generally support distraction
techniques for various needle procedures, laceration repair and bone marrow aspiration (Bukola
2017 Level III-I SR, 7 studies, n=312; Wente 2013 Level III-2 SR, 10 studies, n=1,164; Koller 2012 Level III-2
SR, 37 studies, n=1,575; Landier 2010 Level III-2 SR, 26 studies, n=1,675).

A systematic review assessed immersive virtual reality for 21 y olds undergoing medical
procedures (Eijlers 2019 Level III-1 SR [PRISMA], 17 studies, n=859). It found immersive VR vs usual
care reduced:• Self-reported pain scores (SMD -1.30; 95%CI -0.68 to -1.91) (14 studies);• Self-reported anxiety (SMD -1.32; 95%CI -0.21 to -2.44) (7 studies);

5th Edition | Acute Pain Management: Scientific Evidence1059• Carer (SMD -0.47; 95%CI -0.22 to -0.72) (4 studies), and professional-reported pain scores(SMD -0.82; 95%CI -0.48 to -1.15) (3 studies);• Self-reported pain scores in burns care (SMD -0.66; 95%CI -0.40 to -0.91) (5 studies) andvenous access (SMD -0.32; 95%CI -0.01 to -0.62) (2 studies) but not oncological care
(3 studies).
Subsequently, VR vs standard of care reduced pain scores in 4─11 y having venipuncture in
the ED (Chan 2019a Level II, n=123, JS 3) and pathology (Chan 2019a Level II, n=131, JS 3), whilst,
immersive VR was not superior to nurse led distraction in 7─16 y olds for venous cannulation but
had higher satisfaction (100% vs 85) (Walther-Larsen 2019 Level II, n=64, JS 3).
A retrospective series analysed three comfort measures (distraction, positioning andmedication) and used number of attempts to complete a procedure (IV cannulation,
gastrointestinal tube placement, incisional procedures, urinary catheterisation) as a measure ofefficacy in minimising distress (Dastgheyb 2018 Level IV, n=74,276). Higher success rates occurredwith distraction in younger children, particularly <1 y, whilst in older children (>4 y) higher
success rates occurred with positioning; however, differences between comfort measures foreach procedure and age group were generally small.
Hypnosis
Hypnosis requires the skills of a trained health professional and time for the child to learn thetechnique. Hypnosis vs control for needle-related procedural pain reduces pain scores (SMD 1.4; 95%CI -2.32 to -0.48) (5 RCTs, n=176), distress scores (SMD-2.53; 95%CI -3.93 to -1.12) (5 RCTs,
n=176) and behavioural measures of distress (SMD -1.15; 95%CI -1.76 to -0.53) (6 RCTs, n=193)(Birnie 2018 Level I [Cochrane], 59 RCTs, n=5,550). For children undergoing cancer-related
procedures, hypnosis is an effective pain-control technique (Tome-Pires 2012 Level I SR, 10 RCTs
[cancer procedural pain], n=394) (5 RCT overlap). A subsequent review of oncology patients foundhypnosis reduced pain scores vs usual treatment (pooled effect size Cohen’s d 2.16; 95%CI 1.41
to 2.92) and controls having attention focus (Cohen’s d 2.24; 95%CI 1.66 to 2.82) but not vs active
control groups (eg music, play, audiobooks) (Nunns 2018 Level I [PRISMA], 15 RCTs, n=585 [8 hypnosis,
n=337]) (6 RCT overlap with above reviews).
Cognitive behavioral therapies (CBT)Combined CBT (defined as combining at least one cognitive strategy with at least one behavioral
strategy) may include parent coaching, parent positioning, child distraction and suggestion ( Birnie
2018 Level I [Cochrane], 59 RCTs, n=5,550):• Reduces observer-reported pain (SMD -0.52; 95%CI -0.73 to -0.30) (4 RCTs, n=385) andbehavioral distress (SMD -0.40; 95%CI 0.67 to -0.14) (11 RCTs, n=1,105);• Does not reduce self-reported pain (14 RCTs, n=1,359), self-reported distress (6 RCTs, n=234)
observer-reported distress (6 RCTs, n=765) or behavioral measures of pain (2 RCTs, n=95);• The same review found breathing interventions reduced self-reported pain (SMD -1.04;
95%CI -1.86 to -0.22) (4 RCTs, n=298), however preparation and information (4 RCTs, n=313),
and suggestion (3 RCTs, n=218) showed no effect for any pain or distress outcome. No
conclusion could be made on memory alteration (1 RCT, n=15).
A second systematic review further explored memory reframing interventions in children(3─18 y) (Noel 2018 Level III-1 SR, 3 studies, n=158). It found a memory reframing intervention vscontrol on the day of a subsequent needle procedure did improve memory of fear (SMD -0.60;
95%CI -1.05 to -0.15) but did not improve memory of pain, anticipatory fear or acute fear (2studies, n=50 [oncology LP] & 45 [dental injection]); memory reframing intervention following aneedle procedure (immediately and at follow-up) did improve memory of pain (SMD -0.53;

1060 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

95%CI -1.03 to -0.02) (1 study, n=63 [vaccination]); outcomes regarding subsequent procedures
were not assessed.
Relaxation and biofeedback vs control for 12 y olds receiving venipuncture did not lower pain
intensity during the procedure (Forsner 2014 Level III-2, n=109).
In children (8─14 y) having cancer-related procedures, a 4-session intervention of
preprocedural relaxation plus biofeedback was associated with progressively reduced stateanxiety across the sessions, and improvement in heart rate variability; 81% of participants
reported the combination of relaxation and biofeedback helped them feel in control of theirbodies prior to the procedure (Shockey 2013 Level IV, n=12). Of patients (7─18 y) undergoingneedle-related procedures (venipuncture, IV cannula insertion and Botox injection), 83.3% of
those who used ‘Brighthearts’ (a biofeedback assisted relaxation application) reported the app
was helpful and would use it again, 100% of parents and 96% of healthcare providers indicatedthey would use it again, and 64% of the healthcare providers perceived that it assisted with easeof procedure performance (Burton 2018 Level IV, n=107 [30 patients 27 parents 50 healthprofessionals]).
Music therapyMusic therapy includes passive listening to recorded or played music and active participation of
the patient with music. In children aged 1 mth─20 y, music therapy has a positive impact on pain
(8 RCTs, n=882) and anxiety (6 RCTs, n=324) or both (5 RCTs, n=279) with various procedures(venipuncture/IV cannulation, bone marrow aspiration, dental/oral and other surgery) ( Klassen
2008 Level I, 19 RCTs [5 active, 14 passive], n=1,513). On meta-analysis, music therapy reduces pain
(SMD -0.39; 95%CI -0.66 to -0.11) (5 RCTs, n=465) and anxiety (SMD -0.39; 95%CI -0.76 to -0.03)(5 RCTs, n=284). A further RCT on IV cannulation in the ED shows the addition of passive music
therapy to standard care (topical local anaesthetic, nurse explanation and reassurance) achieves
lower pain and anxiety scores vs standard care alone (Hartling 2013 Level II, n=42, JS 3).
Other nonpharmacological interventions
Inviting parental presence for procedures (with and without sedation) is common practice. A
child being positioned vertically and held by a parent vs being restrained by staff supine on an
exam table reduced distress during IV cannulation (Sparks 2007 Level II, n=118, JS 4). During
venipuncture, fearful parental expression and being reassured uninformatively (told “don’t
worry”) increased children’s fear, while informative reassurance and distraction use decreasedit (McMurtry 2010 Level IV, n=100). Preprocedural preparation of the parent and child in adevelopmentally appropriate way is considered best practice and is being incorporated within
hospital and national guidelines (Duff 2012 GL), as is staff and parent training in the use of
nonprocedural talk (RACP 2005 GL) and use of child-friendly language for preparation/explanation(Stock 2012 GL). Nurse or play therapist coaches or hospital employed “child life interventionists”
are also being employed to educate, distract and plan procedural intervention strategies forchildren and their parents informally and formally (LeBlanc 2014 NR).

5th Edition | Acute Pain Management: Scientific Evidence

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KEY MESSAGESNeonates
1. In term neonates, venipuncture is less painful than heel lance (N) (Level I [Cochrane Review]).
2. Sucrose (S) (Level I [Cochrane Review]) and non-sucrose sweet solutions (mostly glucose)(N) (Level I [PRISMA]) reduce pain scores and behavioural response for skin-breaking
procedures in neonates.
3. Providing physical comfort measures, including kangaroo care (maternal or alternative skinto skin provider), non-nutritive sucking (alone or combined with sweet-tasting solutions),
facilitated tucking (swaddling) or rocking and holding (N) reduces pain experienced by termand preterm neonates having skin-breaking procedures (S) (Level I [Cochrane Review]).
4. Pain from ocular examination for retinopathy of prematurity is reduced by sucrose andnon-nutritive sucking (N) (Level I [Cochrane Review]) and topical local anaesthetic (N)(Level III-1 SR [Cochrane Review]).
5. Kangaroo care (or skin to skin contact) in neonates reduces the distress of vaccine
injection (N) (Level III-1 SR).
6. Sucrose reduces distress after gastric tube placement in neonates (N) (Level III-1 SR).
Infants and children
7. Breastfeeding (<2 years of age) reduces pain intensity and crying duration for skin-breaking
procedures including vaccine injection compared to positioning, holding by mother,maternal skin to skin contact (<1 months), topical anaesthetics, music therapy, pacifier use(<4 months), placebo, no intervention and/or oral sucrose (S) (Level I [Cochrane Review]).
8. Non-nutritive sucking reduces pain after needle-related procedures in infants and young
children (<3 years) (N) (Level I [Cochrane Review]).
9. Oral sucrose and glucose reduce cry incidence and duration (U) (Level III-1 SR [Cochrane
Review]) and distress (N) (Level III-1 SR) of vaccine injection in infants.
10. Distraction in infants and young children (<3 years) reduces vaccine injection pain (N)(Level III-1 SR).
11. Procedural modifications reduced distress of vaccine injection including injection without
aspiration (18 months), simultaneous injection of multiple vaccines (12 months) andinjection of most painful vaccine last (6 months) (N) (Level III-1 SR).
12. Topical local anaesthetic reduces distress of vaccine injection in infants (N) (Level III-1 SR).
13. Parental presence reduces prevaccine injection distress in infants and children (N)(Level III-1 SR).
14. Parental education before or on vaccination day increases use of evidence-based pain
management strategies and reduces distress in infants and children (N) (Level III-1 SR).
15. Physical interventions including holding by parent (during or after) and non-nutritive
sucking in infants (0─4 months) reduces the distress of vaccine injection (N) (Level III-1 SR).
16. The efficacy of supplemental/expressed breast milk for procedural pain management isunclear (N) (Level III-1 SR).
17. Needle-free pressure injected lidocaine is quick in onset and reduces pain from
subsequent needle-related procedures in infants and children (N) (Level II).

1062 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENTChildren and adolescents
18. EMLA® is an effective topical local anaesthetic for children but amethocaine is superior
for reducing needle-insertion pain (U) (Level I [Cochrane Review]).
19. Topical local anaesthetic application (U) (Level I [Cochrane Review]), inhalation of
nitrous oxide 50─70% or the combination of both (U) (Level I [PRISMA]) provides
effective and safe analgesia for minor procedures in children.
20. Distraction (including with video, toys, music or stories) and hypnosis reduces needle
related pain (S) and distress (N) in children and adolescents (Level I [Cochrane Review]).
21. Buzzy® (which combines vibration and cold) (N) (Level I [PRISMA]) and vibration by othermethods (S) (Level III-1 SR) reduces needle-related procedure pain, including vaccine
injection in children.
22. Active and passive music therapy reduces pain and anxiety associated with various
needle-related procedures in children (U) (Level I).
23. Immersive virtual reality reduces pain of medical procedures including wound dressing
care and venipuncture (N) (Level III-1 SR [PRISMA]).
24. Immersive virtual reality for medical procedures in children reduces self-reported pain
and anxiety (N) (Level III-1 SR).
25. Ketamine is effective for paediatric procedural pain management (Q) (Level IV).
26. Hospital wide initiatives to implement evidence-based standards of care for needle
related procedures can improve service delivery and patient satisfaction (N) (Level IV).
The following tick boxes represent conclusions based on clinical experience and expert opinion:
 Using combinations of evidence-supported single pain management strategies for
painful procedures is strongly recommended (N). Non-pharmacological intervention
should always be incorporated (N).
 It is of concern that minor procedures are still undertaken in children, particularly
neonates and infants, in the elective and emergency hospital setting with minimal orno pain management intervention (N).
 Inadequate monitoring, lack of adequate resuscitation skills and equipment, and theuse of multiple medicine combinations has been associated with major adverse
outcomes during paediatric procedural analgesia and sedation (U).
 Pain caused by injection is a barrier to vaccine uptake; thus managing vaccine injection
pain has immediate and long term implications for the wellbeing and health ofindividuals and society (N).
 Based on data from other specific phobias, exposure-based therapy (in vivo or
imagined) is recommended for children and adolescents (7─17 years) with needle
phobia receiving vaccine injections (N).
 Hypnosis requires teaching by a trained professional, but distraction can be readily
provided by staff or parents and should be routinely offered in the paediatric setting (U).
 For children and adolescents, sitting upright may reduce procedural pain and distress (N).

5th Edition | Acute Pain Management: Scientific Evidence1063

10.8 | Acute pain in children with cancer
Acute pain in children with cancer may be due to tissue destruction from the cancer itself, itsconsequences (eg infection), or from its treatment (eg chemotherapy, radiotherapy, painfulprocedures, surgery), and may be primarily nociceptive or neuropathic. It is a common symptom
in children with cancer (Ye 2019 Level IV, n=205; Tutelman 2018 Level IV, n=230; Friedrichsdorf 2014
NR; Fortier 2014 Level IV, n=45) and may be more common in children from low-income households(64% vs 42) (Ilowite 2018 Level IV, n=78). It is associated with significant fear and distress (Ljungman
1999 Level IV), and difficulty in pursuing and achieving personal goals ( Schwartz 2017 Level III-2,
n=199). Self-reported pain scores by children with cancer have been of higher intensity thannurse-reported pain scores (2 studies), whilst agreement with parent/carer-reported pain scoresvaried (9 studies) (Cheng 2018 Level III-2 SR, 33 studies, n=3,063 [children paired with parents/nurses]).
Use of symptom self-report wherever possible is recommended.
Compared with adults (see Section 8.9), the pattern and sources of acute pain differ
significantly in children with cancer. The WHO guideline Pharmacological Treatment of Persisting
Pain in Children with Medical Illnesses (WHO 2012 GL) addresses pain in cancer and other medical
conditions (such as HIV/AIDS, sickle cell disease, burns, trauma and phantom limb pain). It
recommends a two-step analgesic management approach, abolishing the middle step that
previously contained codeine. In 2019, this guideline was withdrawn by the WHO, however it
remains endorsed by organisations in Australia, New Zealand and internationally until it isreplaced.

10.8.1 | Cancer-related pain
10.8.1.1 | Tumour-related pain
Pain due to tumour is present at diagnosis in the majority of children ( Miser 1987 Level IV) andoften resolves with initial disease modifying therapy. Systematic reviews for cancer pain
management have not identified any paediatric RCTs of paracetamol (Wiffen 2017b Level I[Cochrane], 3 RCTs [0 RCTs in children]), NSAIDs (Cooper 2017b Level I [Cochrane], 0 RCTs), opioids(Wiffen 2017a Level I [Cochrane], 0 RCTs) and pharmacological interventions (Eccleston 2019 Level I, 0
RCTs [cancer]) and pharmacokinetic, pharmacodynamic and pharmacogenomic data on
commonly used drugs in children with cancer is limited (Constance 2017 NR). Thus,
recommendations for their use are based on low quality evidence, extrapolation from different
populations, and expert opinion.
Breakthrough pain
Breakthrough cancer pain in children is usually of sudden onset, severe and of short duration(Friedrichsdorf 2014 NR; WHO 2012 GL). For incident and breakthrough pain treatment, IR opioids
are recommended at 10─15% of total daily dose. Commonly PO or IV morphine is used but allother opioids have been administered including via more rapid onset routes eg fentanyl
transmucosally, SL or IN (Triarico 2019 NR; Coombes 2017 Level IV, n=26). “End of dose” pain ismanaged with escalation of background dosing, as in adults.
Background pain
For background pain, morphine is the most commonly used opioid; hydromorphone IR andoxycodone IR and controlled or extended release use starting at typical initial doses has also
been described (Snaman 2016 NR). Transdermal buprenorphine has been used in 2─17 y olds withsuggested weight-based doses starting at 8.75 mcg/h (<15 kg), 17.5 mcg/h (15─30 kg) and 35

1064 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

mcg/h (>30 kg), titrated up to a maximum of 70 mcg/h (Ruggiero 2013 Level IV, n=16; Michel 2011
Level IV SR, 2 studies [cancer pain], n=4). Use of SL buprenorphine (2.5─10 mcg/k 12 hly) has also
been described (Michel 2011 Level IV SR, 1 study, n=13).
Transdermal fentanyl has been used for cancer-related pain in previously opioid-tolerant
children (2─19 y old in and outpatients) receiving a minimum of 30 mg/day PO morphine for avariable time period prior (Finkel 2005 Level IV, n=199 [132 cancer]; Hunt 2001 Level IV, n=41; Noyes
2001 Level IV, n=13; Collins 1999 Level IV PK, n=13). Opioid naïve cancer patients with pain (notcontrolled by paracetamol/ibuprofen) were admitted for TD fentanyl uptitration ( Othman 2016
Level IV, n=64). They commenced 12 mcg/h (if <15 kg) or 25 mcg/h (if >30 kg or 15─30 kg withsevere pain) with IV morphine rescue administration 50─100 mcg/kg; 16% required up titration
within 15 d (max dose reached 50 mcg/h) (Othman 2016 Level IV, n=64). Transdermal fentanyl
mean clearance and volume of distribution were similar to adults in older children (7─18 y)(Collins 1999 Level IV PK, n=13).
Opioid rotation/switch (mostly from morphine, hydrocodone or hydromorphone) tomethadone has been described in children and adolescents (1─18 y) as both inpatients andoutpatients (Madden 2018 Level IV, n=52; Mott 2018 Level IV, n=16; Davies 2008 Level IV, n=17).
Inpatient rotation/switch is usually done in more opioid-tolerant patients and with moreaggressive dosing. Initial dose calculations include 0.1 mg/kg/dose or using conversion ratios(usually 10 to 25:1) dependent on the context (eg pain intensity, inpatient vs outpatient andmorphine equivalent daily dose). Methadone has also been used as an adjunct opioid (typicalinitial dose 1 mg nocte) (Mott 2018 Level IV, n=16). QTc prolongation in small case series withoutcomplication has been reported; the clinical significance is unclear (Madden 2019 Level IV, n=42;
Madden 2017 Level IV, n=25; Anghelescu 2016 Level IV, n=37). There are single case reports ofhypoglycaemia (Gjedsted 2015 CR) and central sleep apnoea (Amos 2013 CR) in children with cancer
on methadone. For further discussion re methadone also adult Section 4.3.1.
IV bisphosphonates (mostly zoledronate) have been used for pain related to bone metastases
and primary bone malignancies (Anghelescu 2019a Level IV, n=35).
Lidocaine infusions can be considered in patients with cancer pain that is refractory to opioid
escalation (Berde 2016 NR). However it has a narrow therapeutic range and is not titratable topain intensity; infusion rates >2 mg/kg/h (33 mcg/kg/min) or plasma concentrations >6 mcg/mL
are likely to carry a substantial risk of seizures, and many factors (eg hepatic or renal dysfunction)
may confer risk at lower infusion rates or plasma concentrations (see also 10.4.11 Systemic
lidocaine infusions).
Epidural and subarachnoid infusions (mostly opioid, local anaesthetic and/or baclofen),through a tunnelled indwelling catheter connected to an external pump, are the most commonly
reported regional techniques for invasive tumour pain, where systemic analgesia has become
ineffective or intolerable (Rork 2013 NR). Fully implantable systems have been used in adolescents(Rork 2013 NR; Bengali 2014 CR). Other reported regional techniques include local anaesthetic
delivered by tunnelled femoral nerve and brachial plexus catheters (Rork 2013 NR). Neurodestructive techniques, such as coeliac plexus or splanchnic nerves blocks with neurolytic agents(Rork 2013 NR), surgical cordotomy (Steel 2017 CR) and stereotactic mesencephalotomy (Ivanishvili2016 CR) have been reported.
Neuropathic pain
Neuropathic pain in children is often treatment-related (see below); cancer-related neuropathic
pain usually occurs with invasion or compression of nerves, plexus or spinal cord (by sarcomas)
or following limb-sparing surgery (Collins 1995 NR). It requires multimodal and adjuvant therapy(alpha-2-delta ligands, antidepressants and opioids; see respective sections in adult Section 4
and paediatric 10.4.4 and 10.4.9) including nonpharmacological approaches (see Section 10.7.5)
5th Edition | Acute Pain Management: Scientific Evidence1065with physiotherapy and psychology (Friedrichsdorf 2014 NR; Anghelescu 2014 Level IV). Methadone
has been used in the acute setting for new onset neuropathic pain, to assist weaning andpostoperatively (Anghelescu 2011a Level IV).
Nonpharmacological interventions
Various nonpharmacological therapies have been studied in children and adolescents withcancer pain including creative art therapy (1 RCT), aromatherapy (1 study), physical activity (1study), massage and touch therapy (3 studies) (Jibb 2015 Level IV SR, 32 studies [6 cancer pain], n=1,171[n=143 cancer pain]) and scrambler (TENS-like) therapy (Park 2017a CR) with mixed results.
A web-based intervention (C-TIPS) delivering information to carers of children with cancer intheir home focussed on pharmacological and nonpharmacological pain management and coping
strategies (Chung 2018b Level IV, n=30). An electronic tablet device in 8─18 y olds (Fortier 2016 Level
IV, n=12) and a smart phone application in 12─18 y olds (Jibb 2017 Level IV, n=40) aimed at children
and adolescents with cancer-related pain have been developed to provide real-time pain selfmanagement support.
10.8.1.2 | Pain in the terminal stages
In the terminal stages of cancer, pain is common (Wolfe 2015 Level IV, n=104; Goldman 2006
Level IV, n=185; Wolfe 2000 Level IV, n=103) and poorly managed pain is associated with higher
levels of long term parental grief (van der Geest 2014 Level IV, n=89; Kreicbergs 2005 Level IV, n=449).
Feeding back to patients, families, and health providers of self- and carer-reported childsymptoms and health-related quality of life did not improve child distress or health-related
quality of life (Wolfe 2014 Level II, n=90, JS 3).
Opioid requirements may escalate (Hewitt 2008 Level IV, n=185; Sirkia 1998 Level IV, n=100), andbenefit has been reported with the use of PCA opioids to allow rapid dose titration (Anghelescu
2015b Level IV, n=159; Schiessl 2008 Level IV), with the addition of low dose IV ketamine infusion(Taylor 2015 Level IV, n=14; Finkel 2007 Level IV, n=11) and intervention with continuous nerve
catheter infusions (Anghelescu 2010 Level IV, n=10) (see Sections 10.4.5, 10.5 and 10.6). Outpatient
PCA opioids have also been administered (using the Computerised Ambulatory Drug Delivery
device CADD), enabling children to stay at home during the terminal stages of their illness(Mherekumombe 2015 Level IV, n=37 [33 cancer]; Anghelescu 2015c Level IV, n=45). Methadone has
been used in small series of children/young adults with cancer for terminal care and pain
unresponsive to escalation of other opioids (Mott 2018 Level IV, n=16; Anghelescu 2011a Level IV;
Davies 2008 Level IV).

10.8.2 | Procedure-related painChildren, their parents, physicians and nurses all rate procedural interventions and treatment asa significant source of pain (Ljungman 1999 Level IV; Ljungman 1996 Level IV). Multiple diagnostic
and therapeutic interventions are required during the course of treatment and require pain
management matched to the procedure type and needs of the child.
10.8.2.1 | Lumbar punctures, bone marrow aspirations, blood sampling
See Sections 10.7.2 for pharmacological intervention and 10.7.5 for nonpharmacologicalintervention used in paediatric oncology care.

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10.8.2.2 | Central venous port access
For pain relief during central venous port access in children with cancer, EMLA® was evaluatedas superior to placebo (Miser 1994 Level II, n=47, JS 5). When added to topical anaesthesia with
EMLA® for port access, neither PO morphine 0.25 mg/kg (Heden 2011 Level II, n=50, JS 5) nor PO
paracetamol 40 mg/kg (maximum 2 g) (Heden 2014 Level II, n=51, JS 5) impacted upon pain, fearand distress scores, which were equally low in placebo treated patients. Outcomes for secondand subsequent procedures were improved if adequate analgesia was provided for the firstprocedure (Weisman 1998 Level III-2). Individual studies suggest various modes of distraction (egvirtual reality, bubble blowing, book reading) are equivalent or superior to active controls forport access (4 studies [age 2─19 y]) (Jibb 2015 Level IV SR, 32 studies, n=1,171).
Parents showed increased non-verbal caring behaviours with repeated port accessprocedures (Bai 2018 Level IV, n=43 [105 procedures]), which can reduce child distress during theprocedure (Bai 2017 Level IV, n=43).

10.8.3 | Treatment-related pain
Pain during active treatment is common (Levine 2017 Level IV, n=258), worse than post-treatment
pain (Tutelman 2018 Level IV, n=230), and a source of high distress and suffering to children withcancer (Levine 2017 Level IV, n=258; Ljungman 2000 Level IV; Collins 2000 Level IV). Parental
acceptance of pain has been shown to predict decreased child distress, and an instrument tomeasure parental acceptance of pain during their child’s treatment has been developed (Thorsell
Cederberg 2017 Level IV, n=243). Parental trait anxiety predicts a higher frequency of parentreported pain episodes, lower child health-related quality of life and increased parental
solicitous behaviours (Link 2016 Level IV, n=353 [parents] & n=137 [children]).
10.8.3.1 | Mucositis
Oral mucositis is a common painful condition occurring in 52─80% of children receiving
chemotherapy (Mazhari 2019 Level III-3 SR [PRISMA], 9 studies, n=504; He 2018 Level III-3 SR [PRISMA],
8 studies, n=373). It can be difficult to assess (Tomlinson 2008 NR), and is a frequent indication for
IV opioid therapy. Opioid requirements are often high and escalate with the severity of mucositis(Coda 1997 Level II, n=119, JS 5; Dunbar 1995 Level IV).
Opioids
A systematic review concludes that morphine by PCA or continuous infusion provides similaranalgesia (no difference in pain scores), and PCA use results in reduced hourly and overallmorphine intake and duration of pain by 1.9 d (95%CI 0.25 to 3.5) with a stated concern of bias
due to drop out rates in these studies (Clarkson 2010 Level I [Cochrane], 3 RCTs [1 paediatric], n=184).
PCA morphine and pethidine (Oudot 2011 Level II, n=29, JS 5) and PCA morphine andhydromorphone had similar efficacy (Collins 1996 Level II, n=10, JS 4) but PCA sufentanil was lesseffective than PCA morphine or hydromorphone (Coda 1997 Level II, n=199, JS 5). Prolonged
administration is often required (6─74 d) (Dunbar 1995 Level IV). If excessive or dose-limiting
adverse effects occur, rotation to another opioid (morphine to fentanyl or fentanyl tohydromorphone) can produce improvement in the majority of patients, without loss of pain
control (Drake 2004 Level IV).
Ketamine
Ketamine 20─40 mcg/kg/mL improved pain scores when added to PCA/NCA morphine (James2010 Level IV) and also decreased morphine consumption when patients were requiring ≈1 mg/kg
of morphine per day (White 2011 Level III-3). In a small case series of children with mucositis,
5th Edition | Acute Pain Management: Scientific Evidence1067topical morphine 0.025─0.4 mg/kg was used in a dose-response study and reduced pain scoresby ≥36% in six of seven children (Nielsen 2012 Level IV). Plasma levels were low, suggesting
minimal systemic absorption.
Laser and photodynamic therapy
Low level laser therapy for oral mucositis, both as a prophylactic and therapeutic intervention inchildren and adolescents (<18 y) has been shown to be effective, however its effect on pain fromoral mucositis is variably reported and unclear (Mazhari 2019 Level III-3 SR [PRISMA], 4 studies [lowlevel laser therapy], n=504 [n=244]; He 2018 Level III-3 SR [PRISMA], 8 studies, n=373) (8 study overlap).
Photodynamic therapy (methylene blue + low level laser therapy) was not superior to low level
laser therapy alone in children (<18 y) (Ribeiro da Silva 2018 Level II, n=29, JS 3).
Honey
Honey was not superior to control for moderate to severe mucositis in teenagers, despite
showing benefit in adults (Yang 2019 Level I [PRISMA] [NMA], 17 RCTs [5 paediatric], n=1,265 [276paediatric]).
Cryotherapy, cytokines and growth factors
Systematic reviews on the use of cryotherapy (Riley 2015 Level I [Cochrane], 14 RCTs [1 mixed adultand children], n=1,280) and cytokines and growth factors (Riley 2017 Level I [Cochrane], 35 studies [4paediatric], n=3,102) for the prevention of mucositis found insufficient evidence to support theiruse in children and adolescents.
Other therapies
Palifermin (IV keratinocyte growth factor) reduced the incidence (OR 4.1; 95%CI 2.4 to 7.0) (5studies) and severity (SMD 0.64; 95%CI 0.30 to 0.97) (3 studies) of oral mucositis in children (<18 y)(Mazhari 2019 Level III-3 SR [PRISMA], 9 studies [5 palifermin], n=504 [n=260]) and one RCT found that
Mucosyte® mouthwash (verbascoside, polyvinylpyrrolidone, sodium hyaluronidate) vs placebo
reduced pain intensity (D 3 median 1/10 vs 2; D 8 median 0/10 vs 1) and analgesic requirements in
5─18 y olds with mild to moderate oral mucositis (Bardellini 2016 Level II, n=56, JS 3).
There is limited evidence in children that topical vs ingested vitamin E improved mucositis (1RCT, n=40), while debridement in addition to standard care reduced severity and days toresolution (1 RCT, n=80) (Clarkson 2010 Level I [Cochrane], 32 RCTs [4 paediatric], n=1,505 [n=176]).
For further reading, see adult section 8.9.8.2 regarding acute mucositis pain.
10.8.3.2 | Neuropathic pain
Neuropathic pain during treatment can occur acutely secondary to chemotherapy, where it may
be dose limiting (eg vincristine) or after surgery (Anghelescu 2019b NR). It may be more common
than expected and poorly documented. In an adolescent and young adult cohort (13─39 y,
median 18 y) screened for neuropathic pain, 26% of patients receiving treatment and 11% post
treatment had neuropathic pain, and only 26% had the diagnosis documented in their medical
record (Acquazzino 2017 Level IV, n=78). Of patients undergoing definitive surgery (amputation or
limb sparing, mostly lower limb) for osteosarcoma, 81% were diagnosed with neuropathic pain(based on pain descriptors eg tingling, burning, shooting and pins and needles); mean durationof documented neuropathic pain was 6.5 wk (Anghelescu 2017 Level IV, n=37).
Gabapentin (reported doses ≈10─45 mg/kg/d) and amitriptyline or nortriptyline (reported
doses ≈0.3─0.45 mg/kg/d) are the recommended first line agents for neuropathic pain in children
with cancer; reported doses are typically lower than in adults (on a per kg basis) (Anghelescu 2019bNR). Opioids (Windsor 2019 NR) including methadone, ketamine infusions and lidocaine (patch orinfusion) (Anghelescu 2019b NR) have also been used, as have multimodal interventions including

1068 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

pharmacological (mostly with an opioid and gabapentin) and nonpharmacological therapy(Anghelescu 2014 Level IV, n=66).
Anti-glycolipid disialoganglioside (GD)-2 agents (typically given over 10─20 h/d for severaldays) have improved outcomes in patients with high-risk neuroblastoma. However, neuropathic
pain (thought to be due to complement activation) during infusion can be severe and dose
limiting. Morphine by NCA/PCA (Ari 2018 Level IV, n=16) and hydromorphone/dexmedetomidine
infusions (Gorges 2015 Level IV, n=6) have been used in a ward environment to manage thisneuropathic pain. Anti-GD2 therapy with Hu14.18K322A monoclonal antibody that causes lesscomplement activation resulted in lower opioid requirements over 4 d (IV morphine equivalent,
median 1.57 mg/kg vs 2.41) (Anghelescu 2015a Level III-3, n=28).
10.8.3.3 | Postoperative pain
Postoperative pain related to surgical procedures for diagnostic biopsies, insertion of long term
IV access devices and tumour resection is also a frequent source of treatment-related pain.
Analgesic intervention using all modalities including preoperative gabapentin and postoperative
wound and CPNC local anaesthetic infusions have been described for limb salvage surgery(Anghelescu 2010 Level IV, n=150) and for upper limb forequarter amputation ( Kaddoum 2013
Level IV, n=4). Subsequently, in children and adolescents (10─17 y) having a lower limb
amputation for osteosarcoma, perioperative gabapentin (300 mg three times daily for 30 d) (aspart of a multimodal analgesic regimen) vs placebo resulted in similar reduction of early
perioperative pain scores, and reduced the incidence of phantom limb pain at 60 d
postoperatively (43% vs 77%) (Wang 2018 Level II, n=45, JS 5). (See also adult Section phantom limb
pain 8.1.5)
In children with cancer requiring morphine infusions, the highest rate of breakthrough pain
was found in postoperative cases, of which 92% had solid tumours ( Flogegard 2003 Level IV). In
children with thoracic, abdominal or lower limb cancer, supplemental IV opioid boluses (either
nurse-administered or via PCA) were safely combined with epidural bupivacaine and fentanyl
infusion to control postoperative pain. Of 117 patients, 1 developed respiratory depression (dueto a dosing error) but patients were closely monitored and had pre-existing tolerance to opioids(Anghelescu 2008 Level IV).
10.8.3.4 | Vertebral compression fracture
Balloon kyphoplasty has been used to manage intractable pain in teenagers from vertebral
compression fractures secondary to chemotherapy and steroid-induced osteoporosis/
osteopaenia (Hoashi 2017 Level IV, n=3). For further reading, see adult Section 8.9.7.6.

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KEY MESSAGES
1. PCA and continuous opioid infusions are equally effective in the treatment of pain in
mucositis in children, but opioid consumption and duration of pain is less with PCA (U)(Level I [Cochrane Review]).
2. Topical local anaesthetic application for children having central venous port access iseffective and analgesia is not further improved by oral analgesics (morphine orparacetamol) (U) (Level II).
3. Self-reported pain scores by children with cancer were higher in intensity compared withnurse-reported pain scores, with variable agreement with parent/carer-reported painscores (N) (Level III-2 SR).
4. There is limited evidence that low-level laser therapy reduces the severity of mucositis inchildren (U) (Level III-2 SR [PRISMA]).
5. QT interval prolongation with methadone in children with cancer has been reported
without complication; the clinical significance is not clear (N) (Level IV).
6. Poorly managed pain in children during the terminal stages of cancer is associated withhigher levels of long term parental grief (N) (Level IV).
7. Outpatient intravenous PCA opioid has been used to help children in the terminal stagesof cancer stay at home (N) (Level IV).
8. Transdermal fentanyl patch use may be appropriate in opioid tolerant children withcancer (N) (Level IV).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: In paediatric cancer pain management, the same therapeutic approaches as in adults
are used, although evidence is limited (U).
 The World Health Organization has removed codeine from the management
approach to paediatric cancer pain reducing the number of tiers from three to two:with tier one including nonopioid analgesics and adjuvants and tier two including
strong opioids; in 2019 the WHO withdrew the reference document, but it remains
endorsed by organisations throughout Australia, New Zealand and internationally
until it is replaced (Q).
 Caution must be taken during uptitration of transdermal systems due to thepharmacokinetic profile of transdermal delivery that has slow penetration and delayed
uptake from the stratum corneum (N).

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10.9 | Other acute pain conditions in children
10.9.1 | Management of pain due to trauma in children
10.9.1.1 | Early and prehospital trauma pain
Prehospital care of paediatric patients suffering moderate to severe trauma is administered bya range of people with varying levels of healthcare expertise including parents, carers or family
members, childcare or school staff, and emergency medical services. The provision of first aid is
an important component of pain management. Administration of analgesics (and sedatives) by
emergency medical services is strongly recommended ( ACEP 2016 GL; Gausche-Hill 2014 GL).
Despite this, and evidence that it is effective, administration of analgesia for moderate to severe
trauma in the prehospital setting is reported to be low. In a systematic review on the efficacy
and safety of analgesics used for injured children and adolescents (<18 y) in the prehospitalsetting only a descriptive review was possible (Samuel 2015 Level IV SR, 19 studies [13 paediatric, 6
mixed adult/paediatric], n>67,287). The authors made the following conclusions:• Overall rates of analgesic administration were low;
• Fentanyl 1-3 mcg/kg (route unspecified) had an accepted efficacy, and although otheranalgesics have a documented benefit (eg morphine, methoxyflurane, nitrous oxide), no
comparisons could be made;• Rates of reported adverse effects in studies and large case series are low, but there isinsufficient evidence to assess the safety profile of analgesics in this setting.
Further studies report variable documentation of pain assessment (18-81%) and consistently
low administration rates of any analgesics (6.4-45%), despite a high prevalence of moderate tosevere pain intensity (up to 74%) when it is documented (Browne 2016a Level III-3, n=7,340; Hewes
2018 Level IV, n=276,925; Schauer 2018 Level IV, n=3,439; Lord 2016 Level IV, n=38,167; Murphy 2016aLevel IV, n=6,371; Rutkowska 2015 Level IV, n=1493; Johnson 2014 Level IV, n=5,057). There were two

exceptions, where an ambulance service gave an analgesic agent to 79−92% of children (<15 y)
who reported pain (Jennings 2015 Level IV, n=15,016; Galinski 2011 Level IV, n=433). Younger age(Hewes 2018 Level IV, n=276,925; Lord 2016 Level IV, n=38,167; Murphy 2016a Level IV, n=6,371; Johnson
2014 Level IV, n=5,057; Watkins 2006 Level IV, n=45), and in two USA studies, non-white ethnicity(Hewes 2018 Level IV, n=276,925; Johnson 2014 Level IV, n=5,057) were associated with less pain score
documentation and provision of analgesics.
Children (≤17 y old) compared to adults were less likely to have their pain assessed (OR 0.80;
95%CI 0.76 to 0.85) (Ramgopal 2018 Level III-2, n=371,746) and be administered opioid analgesia byan ambulance service (Bendall 2011b Level III-2, n=97,705; Hennes 2005 Level III-2, n=5,383). A further
study found factors associated with opioid administration in children were vascular access (OR11.89; 95%CI 7.33 to 19.29), longer patient transport time (OR 1.07; 95%CI 1.04 to 1.11) and painscore documentation (OR 2.23; 95%CI 1.40 to 3.55) (Browne 2016b Level IV, n=1,368).
Barriers to managing acute pain in children identified by paramedics include
concern/difficulty administering analgesia (by IV, PO or inhalational route) to a distressed anduncooperative child, difficulty assessing pain in children, limited education, training, andexperience managing children, as well as risk of adverse reactions with analgesics (Whitley 2017
Level IV, n=127; Rahman 2015 Level IV, n=191; Murphy 2014a Level IV, n=16; Williams 2012 Level IV, n=16;
Watkins 2006 Level IV, n=52 [surveyed]).

Self-reported self-efficacy scores in ambulance officers for assessing pain in toddlers andchildren improved immediately following the implementation of a pain management protocol(self-report pain scale and analgesic dosing guide) in one RCT, with some improvement
5th Edition | Acute Pain Management: Scientific Evidence1071maintained 13 mth later (Jaeger 2017 Level II, n=264, JS 2). Education combined with protocol
implementation was not superior to protocol implementation alone. However, an attempt toimprove the assessment of pain and provision of analgesia by implementing prehospital pain
management protocols (use of age appropriate pain scales, decreased minimum age for opioid
administration and updated fentanyl dosing) was unsuccessful in another study (Browne 2016aLevel III-3, n=7,340).
The most commonly reported analgesics used by Australian prehospital emergency medical
services for children and adolescents with acute pain were inhaled methoxyflurane, IN fentanyl
and IV morphine; all have been found to be effective analgesics in this setting (Bendall 2011a Level
III-2, n=3,312; Murphy 2017 Level IV, n=94; Lord 2016 Level IV, n=38,167; Jennings 2015 Level IV, n=15,016;
Babl 2006 Level IV, n=105). The most frequently administered analgesic was methoxyflurane with

one study reporting no serious adverse effects with its use; mild adverse effects occurred in 36%(mostly drowsiness) with deep sedation occurring in 33% of patients under 5 y (Babl 2006 Level
IV, n=105). Ketamine has also been used with doses of 0.25−1 mg/kg via IV and IN routes and ahigher IM dose of 5 mg/kg (Schauer 2018 Level IV, n=3,439; Bredmose 2009a Level IV, n=164). IN Sketamine 0.45−1.25 mg/kg has been used in 7−17 y olds (Johansson 2013 Level IV, n=6 [paediatric]).
In children with acute pain (mostly from limb injury) presenting to the ED, the majority ofparents and carers (72-78%) reported trying to manage their child’s pain, but only 28-56%
administered an analgesic (Conrad 2019 Level IV, n=338; Whiston 2018 Level IV, n=743; Rogovik 2007a
Level III-2, n=310; Maimon 2007 Level IV, n=214). Reasons reported for not giving analgesics included
concern about masking signs and symptoms, the child not showing signs of pain, not wanting todelay being seen by a physician, no analgesics available and did not have time (Conrad 2019
Level IV, n=338; Whiston 2018 Level IV, n=743; Maimon 2007 Level IV, n=214).
10.9.1.2 | Trauma pain in hospital
The majority of literature on hospital management of paediatric trauma focuses on ED
management of isolated limb injuries; literature on multi-trauma pain management is limited.
This section is on management of pain from a traumatic injury; for management of proceduralpain with closed fracture reduction or laceration repair see Section 10.7.4.
Multi-trauma
In children and adolescents (<18 y) with severe trauma (injury severity score [ISS] 12/75), only
32% received analgesia during resuscitation in the ED (mostly opioids; 67% during primary
survey) (Anantha 2014 Level III-2, n=203). Patients who received analgesia vs those who did not
were more likely to be in a car accident (58% vs 42), and have parents present duringresuscitation (17% vs 6), had a higher median ISS (22/75 vs 17), shorter duration in the ED(141 min vs 195) and longer ICU (median 3 d vs 1) and hospital stay (median 6 d vs 4).
Isolated limb injuries
For children with suspected fractures presenting to the ED, fast-tracking is occurring to facilitate
rapid analgesic administration and direct referral for X-ray from triage. To avoid the distressassociated with IV access or IM injection, alternative administration routes for analgesics arebeing increasingly used in this setting. Despite this, reported analgesic administration is variable.
In children and adolescents (3─18 y) with a limb or clavicle area injury (62% fractures), analgesic
administration rate was low (29%) and sufficient analgesia (assessed as adherence to protocol
for paediatric ED analgesia) was only prescribed in 16.4% of patients; the median time toinitiation of an analgesic medication after arrival in the ED was 2 h ( Rogovik 2007a Level III-2,
n=310). In children and adolescents (<18 y) with a closed long bone fracture, mean time to firstanalgesia was 70 min, and severity of pain assessed at triage did not influence the provision of1072 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

analgesia (Weng 2010 Level IV, n=211). In a cohort of children and adolescents (<18 y, 90% withextremity fracture) presenting to USA EDs, 72% received analgesia, and 55% of these patients
received opioids; younger age (<3 y) and children who were admitted to hospital were less likely
to receive analgesics in the ED (Yackey 2018 Level IV, n=1,341). Further evidence suggests younger
children may be at increased risk of poorly managed pain: when presenting to the ED with anisolated painful injury (82% long bone fracture), infants (6─24 mth) vs school age children (6─10 y)were more likely to receive no analgesia (65% vs 48) and less likely to receive opioid analgesia(17 vs 44%) (Alexander 2003 Level III-2, n=180).
Ethnicity, and its association with pain and its management in the ED has been assessed. In
children (mean age 7.6 y) with a long bone fracture presenting to two USA EDs, mean initial painscores were not statistically different across ethnic groups (4.7─7/10), except for patients who
identified as Somali, who reported lower pain scores (4/10) (Ortega 2012 Level IV, n=880). In thesame cohort, patients were less likely to receive a discharge prescription for an opioid analgesic
if they identified as biracial (RR 0.45), African-American/non-Hispanic (RR 0.59) or
Hispanic/Latino (RR 0.61) vs patients who identified as white/non-Hispanic (Ortega 2013b Level IV,
n=878). In Northern Israel, Arabic and Jewish patients (3─15 y olds) presenting to a paediatric ED
with severe pain (7/10) from a fracture or dislocation received opioid analgesia at similar rates(99%, mostly PO oxycodone) through a nurse driven pain protocol; ethnicity of the nurse did not
influence opioid administration (Shavit 2016 Level III-2, n=3,782).
In an ED, 91% of carers consented to their child (4─17 y; 70% musculoskeletal injury) receiving
an analgesic (Whiston 2018 Level IV, n=743). Of those who refused, the most common reason wasthat their child refused the medication. Thus, carer refusal was not thought to be a major barrier
to children’s pain management in this context.
System interventions to improve pain management have been studied with mixed results:• A physician pain reminder (pain scale form added to chart) did not enhance theprescription of analgesics to children and adolescents (3─18 y) with a limb or clavicle area
injury (62% fractures, mean pain score on arrival: 4.4/10) (Rogovik 2007b Level III-2, n=310);• In children (mean age 6 y) presenting to the ED with a supracondylar fracture,
implementation of a medical directive to triage nursing staff (to assess and document
pain scores and administer paracetamol or ibuprofen for pain 7/10) increased rate ofanalgesic administration within 60 min of presentation from 15 to 54% and reduced
median time to analgesic administration from 72.5 min to 11 min; rate of opioid
administration was not reported (Porter 2015 Level III-3, n=184). Increasing awareness of
splinting through posters aimed at medical staff in the ED did not increase the rate of backslab application before X-ray (29% vs 33);
• A computerised reminder triggered with X-ray ordering increased splint application prior
to X-ray (from 22% to 49) in patients (<16 y) with a forearm fracture requiring
manipulation (Mills 2016 Level III-3, n=298). However, this did not change analgesia
provision within the first hour of presentation;• Implementation of a pain protocol for triage nurses to assess pain, document intensity
and administer paracetamol for suspected long bone fractures reduced median time to
first analgesia from 71.5 to 26 min; the initial analgesic was paracetamol in 52% (mediantime to paracetamol 20 min) and an opioid in 47% (77% IN fentanyl) (median time to
opioid analgesia 29 min) (Schuman 2018 Level III-3, n=1,011).
Various combinations of opioids (PO, IN, or IV), sedatives, NSAIDs and paracetamol for
fracture pain management in the ED have been studied; these studies are summarised below.
Also see Section 10.4.4 Conventional and Atypical opioids.

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Intranasal fentanyl
IN Fentanyl for fracture pain has been studied to assess its analgesic efficacy and speed of onset,
whilst the effects of introducing an IN fentanyl protocol to the ED on quality of care has also beenassessed:• Following limb fracture, IN fentanyl 1─2 mcg/kg effectively reduces pain in the ED (Murphy
2014b Level I [Cochrane], 3 RCTs, n=313; Setlur 2018 Level IV SR [PRISMA], 6 studies [limb injury],
n=2081; Mudd 2011 Level IV SR, 3 studies [limb injury], n=150) (2 & 2 study overlap). It is effectivein the usual concentration 50 mcg/mL vs high concentration 300 mcg/mL (lower volumes
required) (1 RCT, n=189), and is equivalent to IV (1 RCT, n=65) and IM morphine (1 RCT, n=45)
with more rapid onset;• IN Fentanyl 1.5─2 mcg/kg achieves similar pain score reduction to IN ketamine 1─2 mg/kg
at 15─30 min; minor adverse effects (eg dizziness, bad taste) were less common with IN
fentanyl (41─61% vs 78─100%)(Frey 2019 Level II, n=90, JS 5; Reynolds 2017 Level II, n=87, JS 3;
Graudins 2015 Level II, n=80, JS 5).
• Introduction of an IN fentanyl protocol for suspected fracture pain reduced time to opioid
analgesia vs IV morphine by 8.5─29 min (Schoolman-Anderson 2018 Level III-3, n=132;
Schacherer 2015 Level III-3, n=94; Holdgate 2010 Level III-3, n=181; Borland 2008 Level III-3,
n=617). Reduced rates of unnecessary IV cannulation ( Schoolman-Anderson 2018 Level III-3)
and length of ED stay (Schacherer 2015 Level III-3, n=94) were also reported;• In a paediatric ED with an IN fentanyl pain pathway for children and adolescents (3─21 y)with a long bone fracture, where the pathway could have been utilised, 41% did notreceive IN fentanyl, with consequences including unnecessary IV cannulation for IV
morphine administration (Arnautovic 2018 Level IV, n=1,374).
Transmucosal/nebulised fentanyl• Transmucosal (transbuccal) fentanyl 10─15 mcg/kg was equi-efficacious vs IV morphine
0.1 mg/kg over 15─75 min (Mahar 2007 Level II, n=95, JS 3);• Nebulised fentanyl 3─4 mcg/kg was similarly effective vs IV fentanyl 1.5 mcg/kg (Miner2007 Level II, n=41, JS 3) and vs IV morphine 0.1 mg/kg (Furyk 2009 Level II, n=77, JS 4) (both
RCTs in Thompson 2016 Level I [PRISMA], 7 RCTs [2 paediatric limb injury], n=475 [n=118]).
Paracetamol, NSAIDs and oral opioids• Ibuprofen for fracture pain in the ED was superior (Clark 2007 Level II, n=300, JS 3) or similar
to (Friday 2009 Level II, n=68, JS 3) paracetamol/codeine and similarly effective toibuprofen/codeine (Le May 2013 Level II, n=81, JS 5), oxycodone and oxycodone/ibuprofen(Koller 2007 Level II, n=66, JS 5);• In a further study, children and adolescents (6─17 y) presenting to ED with a
musculoskeletal injury (38% fracture) analgesia with PO morphine 0.2 mg/kg/ibuprofen
10 mg/kg vs morphine/placebo vs ibuprofen/placebo did not provide adequate analgesia
in 70% of patients (Le May 2017 Level II, n=456, JS 5);• PO oxycodone was more effective and produced less itching than codeine but earlyadministration at triage was required as having X-rays, rather than examination or casting,
was identified as the most painful period (Charney 2008 Level II, n=107, JS 5);• PO morphine 0.5 mg/kg alone and combined with SL midazolam 0.2 mg/kg for displaced
long bone fractures reduced pain scores similarly, but at the expense of increased
sedation for 59% patients with combination treatment vs 23% with morphine alone (WilleLedon 2011 Level II, n=58, JS 5);1074 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT• SL Ketorolac 0.5 mg/kg vs SL tramadol 2 mg/kg were both effective for moderate tosevere fracture pain; the lack of comparison with other analgesics limits the usefulness of
this study (Neri 2013 Level II, n=131, JS 5).
See also paediatric Section 10.4.2 and adult Section 4.2.1 on NSAIDs, including effects onbone healing.
Diamorphine and hydromorphone
IN Diamorphine 0.1 mg/kg drops and spray provide rapid effective analgesia for fracture pain
(Regan 2013 Level III-3, n=297; Kendall 2015 Level IV, n=226) with similar efficacy but more rapid onset
vs IM morphine 0.2 mg/kg (Kendall 2001 Level II, n=404, JS 3). A pharmacokinetic study has been
done of IV vs IN diamorphine in children with fractures (Kidd 2009 PK, n=24).
IN Hydromorphone 0.03─0.06 mg/kg has been used to treat acute pain (49% limb fracture
requiring closed or open reduction) in the ED (Tsze 2019b Level IV, n=35)
Ketamine
IN Ketamine 1─2 mg/kg achieves similar pain reduction to IN fentanyl 1.5─2 mcg/kg but withmore frequent minor adverse effects (see fentanyl section above) (Frey 2019 Level II, n=90, JS 5;
Reynolds 2017 Level II, n=87, JS 3; Graudins 2015 Level II, n=80, JS 5). In children (3─13 y) with anisolated limb injury (75% fractures) and moderate to severe pain intensity at triage, IN ketamine(mean total dose 1 mg/kg) reduced pain scores from baseline to 30 min post ketamine (median74.5/100 vs 30) which was maintained at 60 min (median 25/100) ( Yeaman 2013 Level IV, n=28).
All patients were rated as awake or mildly sedated (University of Michigan Sedation Scale 0─1),
and minor side effects were common (dizziness 36%, bad taste 29%, dysphoria 14%).
Methoxyflurane (Penthrane®)
Although no longer used as an anaesthetic agent (Brown 2012 NR), methoxyflurane is available as aself-administered Penthrox® inhaler which dispenses 0.2─0.4% methoxyflurane (Medical
Developments International 2001). In adolescents who presented with minor trauma and moderate
pain to the ED, methoxyflurane was effective vs placebo (Coffey 2014 Level II, n=300 [90 adolescents],
JS 5). In smaller series, methoxyflurane reduced pain scores associated with extremity injuries by
2.5─4.7/10 with high satisfaction, but did not provide analgesia for subsequent fracture
manipulation (Grindlay 2009 Level IV SR, 6 studies, n=293) (see also Section 4.5.2).
Regional analgesia
The following studies have reported on the efficacy of regional analgesia for limb injuries in the
ED and during hospital admission:• Children and adolescents (15 mth−18 y) who received a fascia iliaca block with ropivacaine
0.5% (0.5─0.75 mL/kg) vs IV morphine 0.1 mg/kg for femoral fracture in the ED had alower rate of failure of analgesia (failure to achieve pain score <4/10) 30 min postintervention, lower combined pain scores to 6 h (difference 15%; 95%CI 6 to 24%), andlonger duration of analgesia (median time to next analgesic administration 313 min vs 60)(Black 2013 Level II SR [Cochrane], 1 RCT: Wathen 2007 Level II, n=55, JS 3);• In patients (15 mth─22 y) presenting to a paediatric ED with a femoral fracture, 61%received a fascia iliaca compartment nerve block (FICNB; landmark technique) for pain
management (Neubrand 2014 Level III-2, n=259). Those who received a FICNB/systemic
analgesia vs systemic analgesia alone were older (median age 8.0 y vs 5.3), and in the 6 h
post-intervention had lower pain scores (median 1/10 vs 2.5) and parenteral medicationuse (median doses 1 vs 2). There was no difference in the prevalence of adverse events,
however, two patients receiving FICNB had seizures: one patient had an intracranial
haemorrhage; the other resolved with intralipid;
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1075• In patients presenting to ED with an isolated femoral fracture, single shot US-guided
femoral nerve block vs systemic analgesia resulted in longer time to next analgesic dose
(6.1 h vs 2.2), lower subsequent analgesic dose frequency (0.15 vs 0.30/h), and lower
morphine requirements (6.5 vs 14.8 mcg/kg/h, route unspecified) ( Turner 2014 Level III-3,n=81);• A single shot femoral nerve block has been used for femoral fracture management ininfants as young as 3 mth old (Frenkel 2012 CR);
• Continuous femoral nerve blockade in children (15 mth─14 y) with femoral fractures for
up to 6 d has been used successfully (Johnson 1994 Level IV, n=23; Tobias 1994 Level IV, n=4).
Alpha-2-delta ligands
Pregabalin 1.25─2.5 mg/kg/d, as part of a multimodal analgesic regimen, has been used in a 4 y
old girl with a severe crush injury requiring foot amputation ( Wossner 2017 CR).
See also paediatric alpha-2-delta ligands Section 10.4.9.
10.9.1.3 | Trauma pain post-discharge
Nearly 60% of patients (mean age 7.6 y) presenting to two USA EDs with a long bone fracture
were given an opioid prescription on discharge (Ortega 2018 Level IV, n=873). Socioeconomic status(measured by household income) did not influence this; however, the rate of over the counter
analgesic (paracetamol and ibuprofen) prescription decreased as household income increased.
In a similar cohort from the same centre, fracture severity and opioid discharge prescription
provision were lower in younger children (<4 y), but in children requiring closed reduction of
their fracture in the ED, analgesic discharge prescription did not differ with age ( Ortega 2013aLevel IV, n=877).
For fracture pain management post discharge from the ED, ibuprofen (either regularly or asneeded) was similarly effective to paracetamol (Shepherd 2009 Level II, n=72, JS 3),
paracetamol/codeine (Drendel 2009 Leve II, n=336, JS 5) and PO morphine (Poonai 2014 Level II,
n=134, JS 5) with less minor adverse effects (eg nausea, vomiting, drowsiness) than codeine (30%
vs 51) and morphine (31% vs 56).
Carer administered analgesia
For children (5─10 y) treated in the ED with an extremity or clavicle fracture, parent administeredanalgesia in the first two days post-discharge was low (65% received ≤1 dose/d) (Zisk 2008
Level IV, n=50). Analgesia administration correlated with parental postoperative pain scores on
d 1 (r 0.41) and d 2 (r 0.23) and child pain report only on day 2 (r 0.22). However, active and loudbehaviour tool items correlated more strongly with analgesia administration than the quiet
withdrawn behaviours items suggestive of pain.
Both a web-based module and an online video were superior to standard of care (verbal
instructions) in improving caregiver knowledge about pain management of a child’s fracture but
did not improve functional outcomes (eg number of school or carer work days missed) (GoldenPlotnik 2018 Level IV, n=311).

10.9.2 | Management of acute burn injury in children
Following the initial injury, burn patients experience both background and procedural pain; itchis also a significant symptom (Nelson 2019 NR). Higher acute pain intensity is associated withdelayed re-epithelialisation (Brown 2014a NR) and may influence psychological outcomes. Somechildren require treatment throughout the rehabilitation phase including reconstructive

1076 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

surgeries, and physical and occupational therapies for months or years, and may experience painwith these treatments (Nelson 2019 NR).
Children who sustain a burns injury in early childhood can have long term changes insomatosensory and pain processing, including reduced stress-induced activation of endogenous
pain inhibitory mechanisms (Pardesi 2017 NR). Furthermore, on quantitative sensory testing, 9─16 yolds who had sustained a moderate burn injury (5─10% total body surface area, mostly 2nd
degree) in infancy (6─24 mth) had altered responses to mechanical (increased detection
threshold, lowered pain threshold, greater perceptual sensitisation), but not thermal (warm)
stimuli. In contrast, severe burn injury (>10% total body surface area, mostly 2nd or 3rd degree)
only showed perceptual sensitisation to a tonic heat stimulus and no difference in response tomechanical stimuli (Wollgarten-Hadamek 2009 Level III-2, n=72).
See also the adult Section 8.5.
10.9.2.1 | Early and prehospital burn pain
First aid measures reduce pain from burn injury in the initial stages (Varley 2016 NR; ANZBA 2014 GL).
Placing the burnt area under cool running water for ≥20 min should be performed (up to 3 h post
initial burn) with application of longitudinally (not circumferentially) placed thin film plastic “cling”
wrap (or clean sheets, if unavailable). Additionally, analgesic medication is recommended as partof the initial resuscitation management of severe burns (ANZBA 2014 GL). In children andadolescents (0─15 y) admitted to a burns centre within 24 h of injury, pre-burn centre analgesic
administration (paracetamol, NSAID and/or opioid) increased over time (68 to 79% from2002─2004 to 2007─2008); flame burns and more extensive burns were predictors of receiving preburn centre analgesics, whilst transfer/referral by ambulance services or general practitioners werepredictors of not receiving pre-burn centre analgesics (Baartmans 2016 Level III-3, n=622). In children(0─4 y) with burns, median pain scores reduced with treatment by an ambulance service (initial
6.5/10 vs final 1/10); in addition to nonpharmacological measures, 49% were administeredanalgesics (paracetamol, ibuprofen, methoxyflurane or morphine) by PO, IM, IV or inhaled routes(Fein 2014 Level IV, n=117). Most patients (83%) received no analgesia prior to ambulance arrival.
10.9.2.2 | Background burn pain
Psychological impact
The full impact of children and adolescents’ acute pain experience whilst recovering from aburn injury is unknown, but it may influence psychosocial function both immediately and longterm (Nelson 2019 NR). Burn injured children (8─17 y) who use internalisation as a pain coping
strategy may be more vulnerable to the development of a long term anxiety disorder (Rimmer
2015 Level IV, n=187). Girls were more likely than boys to use internalisation or seeking social
support as coping strategies, whilst children whose burn injury occurred at 10 y old weremore likely to use information seeking and positive self-statements vs <5 y olds. Posttraumatic stress symptoms and post-traumatic stress disorder are common in youth following
burn injury (18─25% prevalence) and can be observed in children as young as 12 mth (Nelson
2019 NR). In children and adolescents admitted to hospital with burn injuries, higher morphinedoses during admission correlated with a reduction in post-traumatic stress symptoms over3─6 mth in young children (age 1─4 y: r -0.32) (Stoddard 2009 Level IV, n=11), 6 mth in older
children (age 6─16 y: r -0.44) (Saxe 2001 Level IV, n=24) and 4 y (age range 1.5─17.1 y; survival
curves stratified according to number of opioid units and size of burn) ( Sheridan 2014b Level IV,
n=147). Separation anxiety, but not pain intensity, may be a mediator between increased
morphine doses during admission and a reduction in post-traumatic stress symptoms 3 mth
post burn injury (age 6─18 y) (Saxe 2006 Level IV, n=61).
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Patterns of pain and analgesic prescribing practices
In 0─4 y olds with a small mean total body surface area burn (6.3%), observer-reported mean
background pain scores were low. However, 21─28% of morning and afternoon pain scores weremoderate for background pain and 25% had moderate and 66% severe procedural pain scores(de Jong 2014 Level IV, n=168).
A survey of burn centres treating children and adolescents (18y) found the most commonlyused analgesics for inpatient background and breakthrough pain were: IV morphine (49─65%),
paracetamol with codeine (41─52%) and paracetamol alone (29─49%); for outpatient pain
management, paracetamol with codeine and paracetamol alone were most commonly used(Martin-Herz 2003 Level IV, n=111). Sustained release opioids were used in school age children
and adolescents by 27% and 46% of respondents respectively, whilst antipruritics (mostly
antihistamines) and anxiolytics were used in 53─66% and 17─40% of respondents across all
age groups. Distraction was the most common nonpharmacological strategy used (36─67% of
respondents), with other strategies including music/art therapy (27─29%), relaxation(13─42%) and massage (7─11%). In a survey of centres that care for critically ill paediatric burns
patients, the most common sedatives and analgesics used were midazolam, fentanyl,
morphine, ketamine and diphenhydramine; routine use of scoring systems to assess pain andsedation were common (90%), but only 63% of centres had a sedation policy, and only 54% of
respondents reported noticing withdrawal signs and symptoms in their patient population(Singleton 2015 Level IV, n=41 [centres]).
Children and adolescents (mean age 5.3 y, range 0.5─16) with severe burns (mean total bodysurface area [TBSA] burned: 48.3%, range 10─95%) and ventilated in intensive care (meanduration 25 d, range 8─112) received morphine and midazolam infusions for background pain
and anxiety which reached mean peaks of 0.40 mg/kg/h and 0.15 mg/kg/h respectively, on
average 14 d after admission; at extubation, mean morphine and midazolam infusion rates were0.22 mg/kg/h and 0.10 mg/kg/h respectively ( Sheridan 2001 Level IV, n=28). Ketamine infusion(40─200 mcg/kg/h) as part of a multimodal analgesic regimen has been used for 37 d in a 9 y old
with severe burns (White 2007 CR). IV clonidine has been used in an 11 y old burns patient as partof a multimodal analgesic regimen (Lyons 1996 CR).
Development and implementation of a paediatric pain and anxiety guideline resulted inadequate background and procedural pain and anxiety scores with no complications related toovermedication of patients (Sheridan 1997 Level IV, n=125).
Perioperative analgesia
Tumescent local anaesthesia (high volume/low concentration 0.05%─0.1% lidocaine: 7 mg/kgmax) for surgical acute burn management resulted in all patients requiring no opioid or ketamine(0─24 h) postoperatively, and 80% of patients required no analgesia at all ( Bussolin 2003 Level III3, n=60). For burns contracture release surgery with lateral thigh donor sites, a single injection
lateral femoral cutaneous nerve (LFCN) US-guided peripheral nerve block (PNB) and US-guided
fascia iliaca compartment nerve block (FICNB) with continuous infusion reduced postoperative
pain scores vs local anaesthesia infiltration in 6─9 y olds (Shank 2016 Level II, n=19, JS 3). Dual
peripheral nerve catheters (axillary and sciatic) successfully managed postoperative pain for toe
to hand transfer reconstructive surgery following severe burns in a 3 y old (Dadure 2004 CR). The
combined bupivacaine maintenance infusion dose was 5 mg/kg/d for 48 h and serial plasmabupivacaine levels remained below toxic levels.

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Procedural interventions
See Section 10.7.2.9
Subacute interventions
There was no difference in observer-rated pain scores in patients (5 wk─13 y) admitted to a burns
unit having massage sessions with a carrier oil or aromatherapy oil vs standard nursing care (vanDijk 2018 Level II, n=284, JS 3).
Regular massage therapy (15 min twice a wk) vs standard treatment reduced the severity ofpain, itch and less so state anxiety in adolescents (12─18 y) post burn over a 5 wk period (Parlak
Gurol 2010 Level III-2, n=63).
Similar to previously published prevalence rates in paediatric non-burn populations,phantom limb pain following amputation for burn injury occurred in 38% of patients, where
amitriptyline was commonly used (Thomas 2003 Level IV, n=34). See also adult Section 8.1.5.
10.9.2.3 | Pruritus
Pruritus is a common symptom following burn injury in children that often presents in the acutephase of recovery. A behavioural post-burn pruritus scale (Toronto Pediatric Itch Scale) has beendeveloped for infants and children 5 y old (Everett 2015 Level IV EH, n=30 patients [3 raters]). A selfreport tool (Itch man scale) has been validated in children 6 y old (Morris 2012 Level IV, n=45). Ina cohort of paediatric burn survivors (mean age 7.8 y; mean TBSA 41%), pruritus was present in
93% at discharge with a mean intensity of 5.7/10, decreasing to 63% and 2.5/10 respectively at
2 y follow-up (Schneider 2015 Level IV, n=430). In a subsequent cohort, 72% of patients (13 y)reported itch following burns injury, predictors of itch included time since burn, depth of injury,
TBSA burned and skin grafting (Nieuwendijk 2018 Level IV, n=413). In preschool children with minor
burns (mean age 1.6 y; mean TBSA burn 4%) assessed within 32 d of injury, parents reported
pruritus in 47%, with the majority (78%) being mild; weak correlations were found between
pruritus and ethnic minorities (Black, Latino/Hispanic, Asian or other), greater TBSA of burn, andmore days elapsed since burn (Stewart 2019 Level IV, n=256). Significant improvements in multiple
outcomes following burn injury including itch and pain have been observed in children (meanage 7 y) over 2 y (Wurzer 2017 Level IV, n=167) and preschool children (<5 y) up to 4 y, with thegreatest rate of recovery occurring in the first 6 mth (Kazis 2016 Level IV, n=456).
In addition to, or instead of antihistamines in paediatric burns (inpatient and outpatientsettings), alpha-2-delta ligands reduced itch and pain: gabapentin 15 mg/kg/d (prescribed for
53% of patients) (Nieuwendijk 2018 Level IV, n=413) and 24─34 mg/kg/d (where 23 patients poorly
responding to gabapentin had pregabalin 3.7─6.5 mg/kg/d added) (Kaul 2018 Level IV, n=136).
Evidence based guidelines for post-burn pruritus recommend cetirizine and cimetidine as firstline and loratadine as second line peripherally acting agents, gabapentin as a first line centrally
acting agent, and laser therapy and pressure garments as possible nonpharmacologicalinterventions (Goutos 2010 GL). Combination therapy is commonly used and should be
implemented in a judicious stepwise fashion that includes peripherally acting, centrally acting
and nonpharmacological interventions early.

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KEY MESSAGES
1. For paediatric trauma patients in the prehospital setting, frequency of administration ofanalgesics is low (N) (Level IV SR) and documentation of pain assessment is variable (N)(Level IV).
2. Intranasal fentanyl is equivalent to intravenous or intramuscular morphine in reducing
pain associated with paediatric fracture presenting to the emergency department (U)(Level II).
3. Intranasal ketamine (1─2 mg/kg) achieves similar pain reduction to intranasal fentanyl(1.5─2 mcg/kg) for isolated limb fracture pain, but with an increased frequency of minorside effects (eg dizziness, bad taste) (N) (Level II).
4. The introduction of an intranasal fentanyl protocol for limb injury can reduce the time to
first analgesia in the emergency department, compared to intravenous morphine (N)(Level III-3).
5. Single shot fascia iliaca compartment block is effective in managing femoral fracture pain(N) (Level III-3).
6. Methoxyflurane, intranasal or intravenous fentanyl and intravenous morphine are
effective and commonly used prehospital to manage pain from trauma (N) (Level IV);
intravenous or intranasal ketamine is also an effective analgesic in the prehospitalsetting (U) (Level IV).
7. Younger children (<3 years) with an isolated limb injury receive less analgesia in theemergency department than older children (N) (Level IV).
8. In children and adolescents admitted to hospital with burns, higher morphine doses
during admission predict reduced post-traumatic stress symptoms (N) (Level IV).
9. Pruritus following burn injury in children is common; predictors for pruritus include
greater total body surface area of burn and greater number of days since burn injury (N)(Level IV).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Administration of analgesia by emergency medical services and emergency
departments for trauma patients (including those with burns) is strongly recommended
as part of the initial resuscitation along with first aid measures such as cooling anddressings for burns and splint application for trauma (N).
 Gabapentin and pregabalin are used to manage pruritus and neuropathic pain
following burn injury in children (N).

1080 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

10.9.3 | Paediatric migraine
Migraine is common in children: 9.1% over all age ranges, more prevalent in girls (10.5%) vs boys
(7.6%); with increased prevalence in both female and male adolescents (aged >14 y) by 2.7% and1.3% respectively (IHS 2018 GL; Wober-Bingol 2013 Level IV, n=210,524). However, headache is an
infrequent presentation to the paediatric ED (1%) (Orr 2018c NR; Sheridan 2014a NR). Of paediatric
ED headache presentations, primary headache makes up 27–40%, and migraine accounts 34–
74% of primary headaches (Hsiao 2014 Level IV, n=43,913; Conicella 2008 Level IV, n=55,273). Of
migraineurs presenting to the ED, 85% of children and adolescents were discharged home; withlow re-presentation rates: 5.5% return within 3 d (Bachur 2015 Level IV, n=32,124). Paediatric vsadult migraine may be shorter in duration (2–72 h vs 4–72 h), bilateral and typicallyfrontotemporal (IHS 2018 GL; Sheridan 2014a NR). The general management principles of acutepaediatric migraine are the same as for adults (see Section 8.6.5): environmental modificationand nonpharmacological/psychological intervention should be considered (see below 10.9.3.3
and Section 10.7.5).
Guidelines for the treatment of migraine in children and adolescents acknowledge the lackof large paediatric efficacy and safety studies, summarise the same trials and make similar
recommendations (Oskoui 2019 GL; Gelfand 2018 GL; Rastogi 2018 GL; NICE 2015 GL; Alfonzo 2015 GL;
Sheridan 2014a NR). Triptan trials in children and adolescents have led to licensed use ≥6 y for
rizatriptan in the USA and ≥12 y for the other triptans in the USA, Canada and Europe (Faber 2017
NR). The New Zealand and Australian product information statements (Medsafe and Australian
Register of Therapeutic Goods) for the various triptans state there is inadequate data for children<18 y, without specifying a licensing age cut off.
The challenges in assessing efficacy of various agents include the high placebo response rate
(eg 28–58% for pain freedom at 2 h), trials using different enrichment strategies (longer timesince migraine diagnosed, longer duration of untreated headache [eg 4 h] and placebo
administration with exclusion of placebo responders) and the use of different outcomes:
headache relief vs pain freedom or if recurs vs relief of other symptoms (see below and also
Section 8.6.5.2 for definitions of outcomes used in the below studies).
10.9.3.1 | Oral and Intranasal therapies
The evidence available for the standard of care first line abortive therapy using simple PO
analgesia for acute paediatric migraine is limited. Trial data for triptans is of better quality;
triptans (with NNT 6 for adolescents and NNT 13 for children) are recommended in mostguidelines as either first line, in combination or second line abortive therapy.
A Cochrane review of acute migraine treatments in children (<12 y) and adolescents (12–17 y)assessing the primary outcome of pain freedom at 2 h post intervention is summarised below
according to child vs adolescent age groups (Richer 2016 Level I [Cochrane], 27 RCTs, n=9,158):
Children (<12 y)• Paracetamol 15 mg/kg is not superior to placebo (RR 1.40; 95%CI 0.75 to 2.58); there isno difference in headache relief, rescue medication use, headache recurrence or adverse
events (1 RCT, n=88);• Ibuprofen 7.5─10 mg/kg is superior to placebo (RR 1.87; 95%CI 1.15 to 3.04: NNT 4)(2 RCTs, n=172). It also improves headache relief (RR 1.49; 95%CI 1.11 to 2.00) (2 RCTs,
n=125), but not rescue medication use (2 RCTs, n=164) or headache recurrence (1 RCT, n=38);• Triptans are superior to placebo (RR 1.67; 95%CI 1.06 to 2.62: NNT 13) (3 RCTs, n=345).
However, there was no difference in secondary outcomes of headache relief (3 RCTs,

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n=345), rescue medication use (2 RCTs, n=145), nausea (3 RCTs, n=345), vomiting (3 RCTs,
n=345) or adverse events (3 RCTs, n=420).

Adolescents (12–17 y)• Ibuprofen has not been adequately assessed. One RCT found it is not superior to placebo
for pain freedom at 2 h, headache recurrence, rescue medication or adverse events, butdoes achieve superior headache relief (RR 2.5; 95%CI 1.02 to 6.10) (1 RCT, n=32);• Triptans are superior to placebo for pain freedom at 2 h (RR 1.32; 95%CI 1.19 to 1.47: NNT
6) (21 RCTs, n=6,761), but with increased minor adverse events (risk difference 0.13; 95%
CI 0.08 to 0.18: NNH 8) (21 RCTs, n=7,876);• Triptans are also superior to placebo for headache relief (RR 1.14; 95%CI 1.04 to 1.24) (20
RCTs, n=6,182), rescue medication use (RR 0.79; 95%CI 0.72 to 0.87) (18 RCTs, n=5,066) andheadache recurrence (RR 0.79; 95%CI 0.68 to 0.93) (15 RCTs, n=2,463); there is nodifference in nausea (RR 0.94; 95%CI 0.79 to 1.12) (17 RCTs, n=4,975) or vomiting (RR 0.73;
95%CI 0.48 to 1.12) (14 RCTs, n=4,037);• Subgroup analysis reveals individual triptans are superior to placebo in achieving pain
freedom at 2 h◦ PO Rizatriptan 5 mg (RR 1.34; 95%CI 1.13 to 1.60) (4 RCTs, n=1,438);◦ Sumatriptan PO 25, 50, 100 mg and IN 5, 10, 20 mg (RR 1.27; 95%CI 1.10 to 1.48) (10
RCTs, n=2,299);◦ Zolmitriptan PO 2.5, 5 , 10 mg and IN 0.5, 2.5, 5 mg (RR 1.66; 95%CI 1.16 to 2.38)(4 RCTs, n=1,480);◦ Whilst PO almotriptan (1 RCT), eletriptan (1 RCT) and naratriptan (1 RCT) have notdemonstrated superiority to placebo;
The authors concluded it is not possible to recommend one triptan over another.
Subsequent to the above Cochrane review, in adolescents (12–17 y) IN zolmitriptan 5 mg vsplacebo achieved pain-freedom at 2 h (30% vs 17), headache relief at 2 h (51% vs 39) and reduced
rescue medication use up to 24 h post-treatment (20.3% vs 31.6) (Winner 2016 Level II, n=798, JS 4).
Mild to moderate adverse events were more common with zolmitriptan (25.5% vs 9.9%); mostcommonly disturbed taste.
Three dose combinations of sumatriptan/naproxen (10/60, 30/180 and 85/500 mg) inadolescents (12–17 y) achieved pain freedom at 2 h for 29, 27 and 24% vs 10% of placebo treatedpatients (Derosier 2012 Level II, n=589, JS 5). The higher 85/500 mg dose has shown efficacy in two
subsequent repeated use studies of adolescents (12–17 y) with recurrent migraine. When
instructed to take early (within 1 h) vs placebo, pain freedom at 2 h was higher (37% vs 18); there
was no difference in sustained pain-free response up to 24 h (86% vs 78), but more adverse
effects (eg neck spasm/tightness, drowsiness, throat tightness) with sumatriptan/naproxen(10.8% vs 3) (Winner 2015 Level II, n=94 [347 migraines], JS 4). While in a case series, 42% achieved
pain freedom at 2 h (McDonald 2011 Level IV, n=622 adolescents [12,957 exposures]).
Pharmacokinetics of triptans in adolescents
Iontophoretic sumatriptan patch (6.5 mg delivered over 4 h to upper arm or thigh skin) inadolescents (12–17 y) resulted in similar systemic exposure vs adults (Gutman 2016 Level III-3 PK,n=37). IN zolmitriptan (5 mg) in adolescents (12─17 y) and adults resulted in similar plasma
concentrations of zolmitriptan and its active metabolite (Zhou 2017 Level IV PK, n=30). The authors
used a simulation model to predict dosing in young children, but absorption kinetics from thesmaller nasal mucosa is unknown making the model’s clinical application questionable.

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10.9.3.2 | Intravenous (IV) therapies
Intravenous (IV) therapies for acute childhood migraine are administered in the ED, outpatient
infusion clinics or during inpatient admission. In practice, they are usually second or third line
interventions in varying combinations given to patients who have not responded adequately to
PO/IN intervention. Various medications and combinations have been reported as mostly level
III and IV evidence making assessment of efficacy difficult.
Second line single and combination IV therapies
In 5–17 y olds, IV fluid bolus 10 mL/kg (0.9% sodium chloride) alone or with nurse administeredplacebo reduced migraine intensity 30 min post bolus (-12.5/100; 95%CI -17.2 to -7.8);
expectation of additional drug treatment did not influence the effectiveness of IV fluid bolus(Richer 2014 Level II, n=47, JS 3). After failing at home treatments, IV prochlorperazine 0.15
mg/kg (max 10 mg) was superior to IV ketorolac 0.5 mg/kg (max 30 mg) in 5–18 y olds withcomplete resolution within 1 h in 85% vs 55% (SMD 30%; 95%CI 8 to 52%) ( Brousseau 2004
Level II, n=62, JS 5).
When used in the ED for children and adolescents (<19 y) with ketorolac and usuallydiphenhydramine (given to 65–89%), treatment failure (defined as subsequent opioid
administration) occurred less following IV prochlorperazine vs IV metoclopramide vs IV
promethazine (8.7% vs 25 vs 43) (Sheridan 2018b Level III-2, n=67).
For paediatric patients, a standardised IV regimen including fluid bolus 20 mL/kg (0.9% sodium
chloride: max 1 L)/ketorolac 0.5 mg/kg (max 30 mg)/prochlorperazine or metoclopramide
0.15 mg/kg (max 10 mg) or diphenhydramine 1 mg/kg (max 50 mg) vs a combination of various
other regimens reduced pain scores (by 6.9/10 vs 5.3), ED LOS (4.4 h vs 5.3) and hospital
admission rate (3% vs 32) without changes in ED return rate ( Leung 2013 Level III-3, n=252).
In 12–21 y olds who received an IV fluid bolus 20 mL/kg (± ketorolac), the addition of IV
prochlorperazine (dose unspecified) vs IV chlorpromazine 0.1 mg/kg (max unspecified) had lower
treatment failure (15% vs 40), hospital admission (4.7% vs 16) and rescue medication use (9.9%vs 29.3) (Kanis 2014 Level III-3, n=349).
In children, adolescents and young adults (mean age 15 y) attending an outpatient infusion
centre, headache resolution was achieved 30 min post combination IV therapy with fluid
bolus/ketorolac/metoclopramide or prochlorperazine and/or dexamethasone in 79% of visits;
treatment success was less likely in those with increasing frequency of migraine headaches andmedication overuse headache (Orr 2018b Level IV, n=543 [837 visits]). For severe migraine in <18 yolds, IV prochlorperazine 0.15 mg/kg (max 10 mg) and IV diphenhydramine 0.5 mg/kg (max 25mg) administered in the ED resulted in a 14 and 21% treatment failure rate (further rescue
therapy, hospitalisation or return visit to the ED within 48 h) (Trottier 2012 Level IV, n=79; Trottier2010 Level IV, n=92). For 6─18 y olds with a step-up protocol dependent on medications taken
prior, ED discharge rates were higher after intervention with combination IV ketorolac /IVantiemetic (prochlorperazine or ondansetron) (77% of 300 visits) vs IV ketorolac alone (56% of
39 visits) vs IV antiemetic alone (58% of 50 visits) vs PO or IN therapies (47% of 285 visits)(Aravamuthan 2017 Level IV, n=700 visits).
Third line IV therapies for refractory or status migrainosus
IV dihydroergotamine 0.1–1.0 mg/kg 6–8 hly and IV antiemetic (prochlorperazine,
metoclopramide or ondansetron) administered to inpatients (<18 y) achieved complete or nearcomplete headache resolution in 21─80% in 3 case series (Nelson 2017 Level IV, n=124 [145admissions]; Kabbouche 2009 Level IV, n=32; Linder 1994 Level IV, n=30). Minor adverse effects werecommon (34–91%), including nausea and vomiting despite coadministered antiemetic therapy.

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Mean length of stay was 3–3.7 d; one series reported mean admission cost of $US 7,569 (Nelson2017 Level IV, n=145 [admissions]).
IV magnesium bolus 1–2 g max over 15─30 min administered in the ED substantially reduced
pain severity in 35–48% of paediatric patients with severe migraine (Orr 2018 Level IV SR, 21 studies[2 magnesium IV, n=65]). See adult sections for NMDA antagonists Section 4.6.1.3 and Headache
8.6.5.1 and Migraine 8.6.5.2.
IV sodium valproate has been used in three case series: IV bolus 500–1000 mg in children andadolescents (<19 y) in the ED (Sheridan 2015 Level IV, n=12; Reiter 2005 Level IV, n=58) and IV bolus
20 mg/kg and infusion 1 mg/kg/h for 24 h in admitted children and adolescents (<18 y) ( Zafar
2018 Level IV, n=83). In the first two series, pain scores reduced by a mean of 36 and 40% with low
prevalence of minor adverse events (0 and 14%) eg dizziness and nausea. The third series
reported complete resolution of migraine in 66% of patients, with nausea (8.4%) and vomiting(2.4%) the only adverse effects.
IV lidocaine (mean bolus 2.9 mg/kg and mean maximum infusion 1.6 mg/kg/h) administeredin PICU for status migrainosus in children and adolescents (10–19 y) achieved 50% reduction in
migraine pain intensity at 16.3 h (mean) with resolution at 19.3 h (mean) ( Ayulo 2018 Level IV,n=31). Complete resolution occurred in 90.3% with one non-serious event (self-resolving chest
pain and anxiety) and no serious side effects (see also Section 10.4.11 Systemic lidocaine
infusions).
Low dose bolus IV propofol 0.25 mg/kg (1–5 doses) added to IV fluid bolus 20 mL/kg vsstandard IV combination therapy of IV fluid bolus/ ketorolac 0.5 mg/kg (max 30 mg)/
diphenhydramine 1 mg/kg (max 50 mg)/metoclopramide 0.1 mg/kg (max 10 mg) in 7–19 y olds
in the ED achieved similar pain reduction (51% vs 59) with less rebound headache at 24 h (7% vs25) (Sheridan 2018a Level II, n=74, JS 2). This study was limited by the 5 minutely titration of
propofol to a pain score of <4/10 and does not specify sedation scores or the mean dose or range
given vs the fixed dosing of standard therapy.
10.9.3.3 | Nonpharmacological interventions for headacheStress is considered a common trigger for headaches in children and adolescents ( Bougea 2018
NR). Various preventive stress management strategies have been studied including yoga,
relaxation therapy, biofeedback, hypnosis, massage therapy and acupuncture. Although many ofthese studies have positive results, their design is limited by small sample sizes, absence ofcontrols and lack of follow-up. Whilst these strategies can be used for acute migraine
management, many require skills that need to be developed with time and there is a literature
gap on their use in this context.
Psychological interventions are effective as a preventive strategy for headache ( Trautmann2006 Level I, 23 RCTs [10 migraine/12 migraine & tension type/1 tension type only], n=999). Individualand group relaxation training, including progressive muscle relaxation (16 RCTs with 4 including
stress/pain management strategies), biofeedback (7 RCTs) and cognitive behavioural therapy (10RCTs) reduce the intensity of headache by ≥50% in 70% of adolescents vs 30% of waitlist controls.
Treatment success is maintained for at least 1 y, although comparative efficacy withpharmacological treatments has not been investigated. An overlapping Cochrane review draws
a similar conclusion for reduced headache frequency (RR 2.4; 95%CI 1.7 to 3.3) (15 RCTs, n=644)(Fisher 2018a Level I [Cochrane], 47 RCTs [23 headache], n=2,884) (14 RCT overlap). No impact on
disability is demonstrated (6 RCTs, n=446). A meta-analysis on biofeedback only for prevention in
paediatric (<18 y) migraine has been performed (Stubberud 2016 Level I, 5 RCTs, n=137) (1 & 3 RCT
overlap). Biofeedback (EMG, peripheral skin temperature and blood-volume pulse biofeedback)vs waitlist control reduces migraine frequency (MD -1.97; 95%CI -2.72 to -1.21) (3 RCTs, n=72),
attack duration (MD -3.94; 95%CI -5.57 to -2.31) (2 RCTs, n=48) and headache intensity (MD -1084 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

1.77/10; 95%CI -2.42 to -1.11) (2 RCTs, n=52), but is not superior to active treatment arms oreffective as an adjuvant therapy.
Use of mind body techniques of transcendental meditation and hypnotherapy vs progressive
muscle relaxation had similar reduction in headache frequency at 3 (37–44%) and 9 mth(42–53%) (Jong 2019 Level II, n=131, JS 3).
Following insertion of gold auricular acupuncture needles in 8─18 y olds presenting to the EDwith severe migraine, mean pain scores reduced (from 7.63/10 to 0.55) only at 15 min, with
4 patients refusing treatment and 2 withdrawing post treatment initiation ( Graff 2018 Level IV,n=19).

KEY MESSAGES
1. In children (<12 years), effective acute migraine treatments include ibuprofen andtriptans (Q) (Level I [Cochrane]), however there is a significant placebo response rate inthis setting.
2. In adolescents (12–17 years), triptans are effective acute migraine treatments, however
there is a significant placebo response rate in this setting. One triptan cannot berecommended over another (Q) (Level I [Cochrane]).
3. Nonpharmacological preventive therapies including relaxation training and cognitive
behavioural therapy reduce the frequency and intensity of headache in adolescents for
1 year (S) (Level I [Cochrane]). Biofeedback also reduces migraine attack duration (S)(Level I).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Guidelines for the treatment of migraine in children and adolescents recommend
environment modification, paracetamol, ibuprofen, naproxen (or other nonselective
NSAIDs), dopamine antagonists (if nausea prominent), fluid therapy and triptans (U).
 Evidence is limited for standard of care second line therapies (single and multiple IVtherapies including fluids and antiemetics) and third line therapies (such as IV
dihydroergotamine, magnesium, sodium valproate, lidocaine or propofol) for acutechildhood migraine (N).
 The use of psychological interventions and stress management strategies have notbeen assessed in acute migraine episodes; it must be recognised that many of theseskills need to be developed over time (N).

10.9.4 | Acute abdominal pain in children
All medical causes of acute abdominal conditions are discussed in adult Section 8.6.1 (including
renal and ureteral stones, biliary colic and acute pancreatitis, dysmenorrhoea, irritable bowel
syndrome and colic). These also affect children and teenagers but are not reviewed separately
here. The data for recurrent abdominal pain is presented below.
As for adults, early pain relief (usually in the form of opioids) does not interfere with thediagnostic process in acute abdominal pain in children ( Green 2005 Level II, n=108, JS 5; Kim 2002
Level II, n=60, JS 5).
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1085For abdominal pain associated with Henoch-Schonlein Purpura, see 10.4.10.1; and for the
principles of management of abdomincal pain associated with haematological disorders see
10.9.5.
For CAMT interventions for infantile colic see Section 10.11.4.
10.9.4.1 | Recurrent abdominal pain (abdominal migraine)
Recurrent abdominal pain (RAP) or abdominal migraine presents to primary care and EDs and isfunctional and a diagnosis of exclusion (Brusaferro 2018 NR). It occurs usually in male school-aged
children, sometimes adolescents, rarely in adults. RAP is characterised by recurrent attacks ofacute abdominal pain, nausea, vomiting and often headaches.
There is currently no good evidence for the efficacy of any pharmacological treatment(tricyclic antidepressants, antibiotics, 5-HT4 receptor agonists, antispasmodics, antihistamines,
H2 receptor antagonists, serotonin antagonists, selective serotonin re-uptake inhibitors,
dopamine receptor antagonists, and hormones) in RAP in children (Martin 2017 Level I [Cochrane],
16 RCTs, n=1,024).
Probiotics are effective in improving pain in children with RAP vs placebo (NNT 8) ( 7 RCTs,
n=722), however, based on moderate quality evidence ( Newlove-Delgado 2017 Level I [Cochrane] 19
RCTs, n= 1,453). There is no convincing evidence that fibre-based interventions improve pain inchildren with RAP.
Cognitive Behavioural Therapy (CBT) (4 RCTs, n=175) and hypnotherapy/guided imagery (4RCTs, n=146) reduce pain (in part or fully) in the short term (immediately to 1 or 3 mth) in children
and adolescents presenting with RAP ( Abbott 2017 Level I [Cochrane], 18 RCTs [10 CBT, 4 hypnosis],n=928).

KEY MESSAGES
1. Probiotics improve pain in children with recurrent abdominal pain versus placebo (N)(Level I [Cochrane Review]) with no good evidence for positive effect of various
pharmacological treatments (N) (Level I [Cochrane Review]).
2. Cognitive behavioural therapy (CBT) and hypnotherapy reduce pain short term (over1 to 3 months) in children and adolescents with recurrent abdominal pain (N) (Level I[Cochrane Review]).

10.9.5 | Acute pain associated with haematological disorders in children
10.9.5.1 | Sickle Cell Disease (SCD) in Children
Sickle cell disease (SCD) affects all age groups. Neonatal sceening is routinely available inresource rich countries with moderate prevalence, with some impact on global disease burden.
Highest prevalence countries do not have the funds to screen. As is the case for adults, there isinterindividual variability in the impact of SCD upon paediatric patients. Hydroxyurea
prophylaxis, transcranial doppler and red cell exchange transfusion programs have had positive
benefit, reducing vaso-occlusive crises (VOC) and emergency department (ED) presentation
frequency and mortality (Lovett 2017 NR; Yawn 2015 GL), with subsequent reduced need for in
hospital pain service input. The majority of ED visits and hospital admissions for patients with
SCD are pain related (Glassberg 2017 GL).

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The principles of care are the same as for adults and involve individual care plans and stepup analgesic administration for at home and in hospital analgesic escalation, combined withsimultaneous treatment of the precipitants of infection, dehydration and hypoxia ( Glassberg 2017
GL; Yawn 2015 GL; NICE 2012 GL). Paediatric centres have developed clinical care pathways eg thosefromwww.chop.edu/clinical-pathway/sickle-cell-disease-with-pain-clinical-pathway
and(Kavanagh 2015 Level III-2, n=289 [ED visits for VOC]). With clinical pathway introduction in an urban
paediatric centre, time to first analgesic medication, time to first opioid and use of IV ketorolac
improved (Ender 2014 Level III-2, n=68). Early achievement of maximum opioid analgesia improved
hospitalisation outcomes in children (Payne 2018 Level III-3, n=108 [236 admissions]).
See adult Section 8.6.4 Acute pain associated with haematological disorders.
Pharmacogenomics relevant to SCD
There is increased prevalence of poor CYP2D6 metaboliser phenotype in populations of African
descent. Children with sickle cell disease have had CYP2D6 geno-phenotyping where 44% hadintermediate and 5.3% poor phenotype (Yee 2013 Level IV, n=75). This is an importantconsideration when choosing analgesic therapies for this patient group, where 27% of children≤17 y with SCD have received codeine (Han 2018 Level IV, n=581 ≤ 19 y [opioid recipients]).
NSAIDs and opioid use in children with SCD
The use of an oral at home opioid protocol reduced the number of ED visits, time spent in the ED
and hospital admissions over 12 mth for sickle cell pain (Conti 1996 Level IV, n=9; Friedman 1986
Level IV, n=15). Admission rates were lower following an initial paediatric ED intervention with
nsNSAID/opioid combination vs opioid only (33% vs 64) (Cacciotti 2017 Level III-3, n=176). A
paediatric ED treatment protocol administering PO paracetamol 15 mg/kg/ibuprofen
10 mg/kg/morphine 0.3 mg/kg for pain scores >5/10 reduced the number of patients requiring
subsequent IV insertion for parenteral therapy, length of stay in the ED and hospital admission(Paquin 2019 Level IV, n=97 [147 visits]). Sustained-release PO morphine for children admitted with
VOC was as effective as a continuous IV morphine infusion ( Jacobson 1997 Level II, n=56, JS 5).
However, in children treated with PO morphine vs IV morphine infusion, incidence of acute sickle
chest syndrome and plasma concentrations of morphine and morphine-6-glucuronide (M6G)
were significantly higher (Kopecky 2004 Level II, n=50, JS 4).
IV morphine PCA with bolus and background (mean 20 mcg/kg/h) has been used for children
admitted with VOCs (Jacob 2008 Level IV, n=10 [48 admissions]). Postoperative PCA morphine
requirements in children with SCD were almost double those of nonsickle children ( Crawford
2006a Level III-3, n=22 [12 SCD]).
Acute kidney injury in SCD
Children with VOC with acute kidney injury had longer LOS; the risk of developing AKI increased
for every additional day of ketorolac treatment (OR 1.63; 95%CI 1.08 to 2.47) (Baddam 2017
Level III-3, n=33 AKI patient events vs 164 without AKI).
Pruritus management related to opioid infusions
For children receiving morphine infusions for sickle cell crises, naloxone 1 mcg/kg/h more
effectively decreased pruritus than 0.25 mcg/kg/h (Koch 2008 Level IV, n=16).
Intranasal opioid analgesia in SCD
IN fentanyl has been incorporated into clinical practice guidelines for VOC paediatric ED
presentations (Carden 2018 Level IV, n=60; Kavanagh 2015 Level III-2, n=289 visits). IN fentanyl was a
suitable alternative with reduced time to initiation of opioid analgesia (Kelly 2018 Level III-2, n=105[487 visits]; Kavanagh 2015 Level III-2, n=128 [289 visits]). IN fentanyl vs placebo decreased pain scoresat 20 min only (and not at 10 or 30) (Fein 2017 Level II, n=49, JS 5). IN fentanyl use increased the
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proportion of patients discharged from the ED and reduced time to initiation of subsequent IV
opioid including by PCA (Kavanagh 2015 Level III-2, n=289 visits); however in another study it did not
reduce the need for IV opioid analgesia (Kelly 2018 Level III-2, n=487 visits).
IN diamorphine has been used for sickle cell crises and was effective in reducing pain scores(Telfer 2009 Level IV, n=21). It was introduced in an ED protocol as initial therapy 0.1 mg/kg (withoptional IV morphine 100 mcg/kg). Subsequently the protocol was revised to coadministration
with PO morphine 0.4 mg/kg (which could be repeated at 1 h) to reduce need for IV insertion.
Chronic opioid use in SCD including methadone
Over a 5 y period, children with SCD aged 0–9 y had a low prevalence of opioid use 8.5% vsteenagers 46.3% and vs adults 48.7 to 58.3% (Han 2018 Level IV, n=3,882 [2,123 ≤19 y]). Most
patients (87% of children and 55% of adults) used <5 mg PO MED, but some used >30 mg PO
MED (3% paediatric and 23% of adults). A subgroup of patients experience frequent painful VOCs
with subsequent increased ED presentations and hospital admissions with pain recurrence that
may require daily opioids. Adolescents with frequent recurrent (chronic) pain related to SCD
were treated for several months with methadone (commenced at 12.5 mg, uptitrated to 30 mg/dmax), with reduced hospitalisations from 0.35± 0.19 to 0.19 ± 0.17/mth (LeBlanc 2018 Level IV,n=16).
Corticosteroid use in SCD
In children, a 2 d course of IV methylprednisolone 15 mg/kg/d vs placebo decreased the durationof severe pain associated with acute VOCs; but patients who received methylprednisolone had
more rebound attacks after therapy was discontinued ( Dunlop 2006 Level I [Cochrane], 1 RCT(paediatric): Griffin 1994 Level II, n=36 [116 VOCs], JS 5).
Ketamine infusion in SCD
Beneficial use of low-dose IV ketamine infusion 0.05–0.4 mg/kg/h is described for children andadolescents with VOC usually in addition to or to replace opioid IV PCA (Puri 2019 Level IV, n=4;
Sheehy 2015 Level IV, n=7; Zempsky 2010 Level IV, n=5) with reduction in pain scores and opioid
requirement (Nobrega 2018 Level IV, n=80 [181 infusions]). A single dose given over 10 min of IV
ketamine 1 mg/kg was non-inferior to IV morphine 0.1 mg/kg for VOC pain in children (Lubega
2018 Level II, n=240, JS 5). Both therapies impacted similarly on change in maximal pain scores by
66.4% vs 61.3; the reduction was achieved earlier for ketamine (at 20 min vs 34), but was shorterin duration (60 min vs 120) with increased transient side effects (37.5% vs 3.3).
Dexmedetomidine infusion in SCD
In children with refractory pain due to VOC despite nsNSAID/IV opioid/ketamine 0.1–0.3
mg/kg/h infusion, dexmedetomidine infusion 0.2–0.4 mcg/kg/h for up to 6 d duration has beenused (Sheehy 2015 Level IV, n=3).
Inhaled nitric oxide
Nitric oxide deficiency or defective nitric oxide-dependent mechanisms may underlie many ofthe processes leading to vaso-occlusion. An early paediatric study suggested inhaled nitric oxide
may be of benefit in painful acute VOC (Weiner 2003 Level II, n=25, JS 4); however, in young adults
admitted with VOC, there was no difference between inhlaed nitric oxide vs nitrogen placebo intime to VOC resolution or LOS (Gladwin 2011 Level II, n=150, JS 5).
Inhlaed nitrous oxide (N2O)
Despite the frequency of use of inhaled N2O in paediatrics, there is no current data on the use ofthis agent specifically in VOC in children.

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Rehydration
Hydration supplementation of patients with VOC is commonly practiced. Most children (84%)
with VOC in the ED received fluids; a subanalysis of those who received normal saline bolus
revealed less pain score improvements (Carden 2019 Level IV, n=400 [261 bolus]).
OxygenOxygen supplementation is a standard of care despite old trials not supporting efficacy (see adult
Section 8.6.4.1). Nocturnal oxygen desaturation was associated with a higher rate of painful VOC
in children (Hargrave 2003 Level IV). Comorbid obstructive sleep apnoea (OSA) in children isassociated with serious complications of SCD (Katz 2018 Level III-3, n=272 SCD [136 OSA]); a 6 wk
pilot trial reports no rebound pain on CPAP cessation ( Marshall 2009 Level II, n=24, JS 3).
Magnesium
Magnesium IV or PO therapy has no effect on reducing pain or LOS in adults or children with VOC(Than 2019 Level I [Cochrane], 5 RCTs [3 paediatric & 2 mixed], n=386).
Lidocaine infusion
IV lidocaine 1–2 mg/kg/h (17-33 mcg/kg/min) for 2 d has been used for VOC (resistant to PCA
morphine) with analgesic benefit (Puri 2019 Level IV, n=2 [3 occasions]).
Vitamin D supplementation
Vitamin D deficiency has been associated with vaso-occlusive crises and acute pain in children
and adolescents (1–20 y) with sickle cell disease (Adegoke 2017 Level IV, n=123; Lee 2015 Level IV,n=95). Vitamin D supplementation for acute pain management in this population has not beenstudied.
Nonpharmacological interventions
Psychological therapies such as relaxation, hypnosis and cognitive behavioural therapy (CBT)
reduce pain immediately after treatment for other recurrent acute pain presentations; but 2─4sessions of CBT in patients with SCD focusing on coping skills (1 RCT), pain management (1 RCT)or a family intervention (1 RCT) were not beneficial at 1–12 mth follow-up (Fisher 2018a Level I[Cochrane], 3 RCTs [SCD], n=174). In a further Cochrane review, CBT for adolescents with SCD did
not reduce pain frequency (1 RCT, n=53) or health care utilisation (2 RCTs, n=68) (Anie 2015 Level I[Cochrane], 5 RCTs [adolescents & young adults], n=260) (2 RCT overlap). Internet delivered CBT was
feasible and the impact on pain burden vs control (internet delivered pain education) can beassessed (Palermo 2018 Level II, n=25, JS 3). Although adherence to use of a smart phone app toguide CBT was low (12%), if the app was used on a day of high pain, next-day pain was reduced
vs waitlist controls (Schatz 2015 Level II, n=46, JS 3).
Massage therapy in youth with SCD improved function and reduced pain, depression andanxiety (Lemanek 2009 Level II, n=34, JS 1). However, the parents (who performed the massage
therapy) had higher levels of anxiety and depression following the intervention. In children
admitted with VOC, yoga vs listening to relaxing music reduced pain but not anxiety scores withthe first but not subsequent sessions (Moody 2017 Level II, n=73, JS 2).
Prevention of painful VOC in children
Hydroxyurea (or hydroxycarbamide) 15─25 mg/kg for 10–24 mth vs placebo improved pain
outcomes: pain scores (1 RCT n=193) with reduced frequency of pain crises (4 RCTs, n=577), acutechest syndrome (RR 0.43; 95% CI 0.29 to 0.63) (2 RCTs, n=492) and hospitalisations (1 RCT, n=60)(Nevitt 2017 Level I [Cochrane], 8 RCTs [6 paediatric only & 2 mixed], n=899). Hydroxyurea improves
only fetal haemoglobin level vs control (observation: 1 RCT [paediatric], n=22) or when added to

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magnesium therapy (1 RCT [mixed], n=44). Guidelines based upon this data as to when to institutehydroxyurea therapy in children (and adults) are available (Qureshi 2018 GL).
Zinc supplementation reduces the incidence of painful VOC in children and adults (Nagalla
2018 Level I [Cochrane], 1 RCT [zinc], n=145). While the evidence in children for piracetam isinsufficient to support its use (Al Hajeri 2016 Level I [Cochrane], 3 RCTs, n=169) and is negative forprasugrel (Heeney 2016 Level II, n=341, JS 5).
10.9.5.2 | Haemophilia
As in adults, pain in children with haemophilia A (Factor VII) and B (Factor IX deficiency) is either
recurrent acute, related to spontaneous or injury-related bleeding into joints, muscles (andrarely viscera), or chronic with secondary painful arthropathies. Preventative use of recombinantfactor concentrates has had greater positive impact on pain management in affected children vsacute ‘on demand’ treatment (Usuba 2019, Level III-3, n=401).
There is no data or evidence base specifically for haemophilia but guidelines as referenced in
the adult Section (See 8.6.4.2) are available (Holstein 2012 Level IV, n=1,678 children & 5,103 adults).
The principles involve rest, ice, compression and elevation, paracetamol and escalated therapy
at home or in hospital including adjuvants and nonpharmacological intervention. The use ofanalgesic medication needs to be encouraged (Rambod 2016 Level IV, n=154), possibly througheducation of parents of young affected children and guideline creation by haematologists inconjunction with primary care and pain specialists.

KEY MESSAGES
Sickle cell disease
1. Hydroxyurea decreases the frequency of acute vaso-occlusive crises, life-threatening
complications and hospitalisations in children with sickle cell disease (S) (Level I[Cochrane Review]).
2. Intravneous or oral magnesium does not reduce pain of vaso-occlusive crises associatedwith sickle cell crises or length of hospital stay (N) (Level I [Cochrane Review]).
3. Attention must be paid to acute kidney injury risk in sicker inpatients with sickle celldisease receiving multiple doses of nsNSAID (N) (Level III-3).
4. Parenteral corticosteroids reduced the duration of severe pain in children with vasoocclusive crises in sickle cell disease at the expense of more rebound attacks post
cessation (Q) (Level II).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: It is standard of care for oral and IV paracetamol, nsNSAIDs and opioids to form part ofan individual at home or hospital care plan for children with vaso-occlusive crises.
Upon admission this is escalated to parenteral nsNSAID and opioid therapy (N).
 There is no evidence that fluid replacement therapy reduces pain in children with VOC,
although it is common practice (N).
 The impact on painful vaso-occlusive crises of oxygen supplementation in patients withand without obstructive sleep apnoea and CPAP in patients with obstructive sleep
apnoea requires assessment (N).

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 Most children with sickle cell disease are not on opioids for chronic or frequent
recurrent pain (while adolescents are, at similar rates to affected adults). In patientswith sickle cell disease, postoperative opioid requirements may be higher (N).
 Adjunctive low-dose ketamine and IV lidocaine infusions reduce pain intensity andopioid requirements in refractory pain of acute vaso-occlusive crisis in children withsickle cell disease (N).
Haemophilia
 In children with haemophilia, on demand and preventative use of recombinant factor
concentrates has improved pain-related quality of life measures. Otherwise theprinciples of pain management in acute bleeds in affected children and adults involverest, ice, compression and elevation and stepwise escalation of analgesia. Parents ofyoung affected children need education regarding analgesic medication (N).

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10.10 | The overweight or obese child or adolescent10.10.1 | Definitions of obesity
Obesity in childhood has been defined in various ways. The ideal definition based on percentage
body fat is not practical for epidemiological use (Cole 2000 Level IV, n=192,727). Body mass index[BMI] is widely used but has limitations. In children, it varies substantially with age and sex(Chidambaran 2018 NR), does not discriminate between lean and fat mass, provides poor heightstandardisation for weight, and is not a consistent marker of body fat across ethnic groups (Hudda
2019 Level IV). Internationally, BMI cut-offs used for overweight and obesity vary. Both Australia(ABS 2018 Level IV) and New Zealand (NZ MoH 2018 Level IV) use the International Obesity Taskforce
cut-offs developed for children aged 2─18 y (Cole 2000 Level IV, n=192,727). These are linked toadult BMI cut-offs at 18 y which have been related to health risk. The WHO defines cut-offs foroverweight and obesity in SD: for 0-5 y, using the WHO median growth standard weight for
length/height (overweight  2 SD; obese  3 SD) (de Onis 2010 Level III-3); for 5-19 y, using the
WHO median growth reference of BMI for age (overweight  1 SD; obese  2 SD) (de Onis 2007
Level IV, n=30,018).

10.10.2 | Prevalence of childhood obesity
Global age standardised obesity prevalence increased in girls and boys respectively from 0.7 and
0.9% in 1975 to 5.6 and 7.8% in 2016 (NCD-RisC 2017 Level IV). The latter equates to 50 million
obese girls and 74 million obese boys worldwide. In several countries, the prevalence of obesity
was ≥20% such as the Middle East, North Africa, the Caribbean and Polynesian region and >30%
in the Pacific Islands. The trends in mean BMI have accelerated in South East Asia, with flattening
for North Western Europe and the high income English speaking countries.
In the USA, childhood (2─19 y) obesity prevalence increased from 5.5% (1976─1980) to 17.1%(2003─04) and 18.5% (2015─16) (National Center for Health Statistics 2019 Level IV). In Australia and
New Zealand, the increase in obesity has been less marked. In Australia, obesity prevalence in5─17 y olds increased from 5% (1995) to 8% (2007─08) (ABS 2009 NR); when combined with thoseoverweight, the prevalence rates were 22% in 1995 increasing to 25% in 2007─08 and haveremained stable since (ABS 2018 Level IV). In New Zealand, the prevalence of obesity in 2─14 yolds has increased from 8.4% (2006─07) to 12.4% (2017─18); when combined with thoseoverweight the total prevalence was 21% in 2006─07, increasing to 31.9% in 2017─18 (NZ MoH
2018 Level IV).

10.10.3 | Morbidity associated with paediatric obesity
Obesity is a risk factor for morbidity in children including: sleep-disordered breathing [SDB]
incorporating obstructive sleep apnoea [OSA], dyslipidaemia, hypertension, atherosclerosis, left
ventricular hypertrophy, impaired glucose tolerance and type 2 diabetes mellitus, metabolic
syndrome, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (Chidambaran 2018
NR). The most immediately relevant condition to acute pain management is SDB/OSA, and theincreased risk of ventilatory impairment with opioids and other sedative/hypnotics. The
prevalence of OSA varied from 13─36% in obese children and adolescents, and was 24─77% in
obese children and adolescents with symptoms of SDB (Baker 2017 Level IV, n=224 [148 obese];
Verhulst 2008 NR, 6 case series, n=269).

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See also Section 10.4.4.5 for information regarding mortality in obese children related tocodeine and for adults see sections 9.4 and 9.5.

10.10.4 | Medication dosing in paediatric obesity
When dosing a medication, its volume of distribution (Vd), clearance (CL) and pharmacodynamics
should be considered (Anderson 1997 NR); however this can be challenging to apply in practice.
Furthermore, obesity can influence pharmacokinetics (PKs) through its effects on body size, bodycomposition and organ function, as well as being a risk factor for comorbid disease. Its influence isunpredictable and can place the patient at risk of both underdosing and overdosing of medication(Samuels 2016 NR). For example, the Vd for lipophilic drugs may be increased, unchanged or
reduced, and for hydrophilic drugs may be unchanged or reduced (Chidambaran 2018 NR). In
paediatrics, the influence of maturation and growth on Vd, CL and pharmacodynamics must also
be considered.
Barriers to appropriate drug dosing in overweight and obese children include: a paucity of
paediatric bariatric pharmacokinetic data (Chidambaran 2018 NR); the range of doses calculated
for a given drug from the many size descriptors that have been proposed (Chidambaran 2018 NR);a requirement to use different size descriptors for initial dosing and maintenance dosing forsome drugs (Anderson 2017a NR PK); and cumbersome dosing calculations that may lead totemptation for arbitrary or “educated guess” dose adjustment in the clinical setting ( Callaghan
2015 Level III-2). Given the barriers to accurate dosing in overweight and obese children, authors
have emphasised the importance of judicious dosing and titration to effect wherever possible(Baines 2011 NR; Samuels 2006 NR).
Lean body mass (LBM) and ideal body weight (IBW) have been recommended for dosing
many drugs in overweight and obese patients. A nomogram (https://onlinelibrary.wiley.com/
doi/full/10.1111/anae.12860) developed from UK data of children >5 y was created to facilitate
calculations of LBM and IBW in a perioperative setting or urgent drug dose calculation scenario(Callaghan 2015 Level III-2). It was quicker to use, with less mistakes and similar accuracy comparedto calculations using equations. Other proposed size descriptors for various drugs have included:
total body weight, dosing weight, adjusted body weight, predicted body weight, PK mass, fat freemass, normal fat mass, body surface area and BMI (Anderson 2017a NR). For some medications,
LBM may work eg for maintenance dosing of remifentanil or dexmedetomidine and for others
ideal body weight may fit eg for benzodiazepines, while for further medications (eg paracetamol)
neither may be appropriate.
Total body mass can be partitioned into fat and fat-free components. The relative influenceof fat mass compared with fat free mass on a drug’s pharmacokinetics differs for each drug. The
size descriptor “normal fat mass” is based on allometric theory and accounts for the relative
influence of fat mass. It calculates a drug and PK parameter specific mass that can range from fat
free mass to total body weight (Anderson 2017a NR PK). Calculating normal fat mass for drug
dosing has been proposed as a principle-based approach that accounts for size and bodycomposition effects on PKs of all drugs in children and adults of all sizes.
Concerns have been raised about increased risk of toxicity in obese patients when weightbased dosing exceeds the recommended maximum dose. An important example is paracetamol,
where CYP2E1, the enzyme responsible for metabolising paracetamol to its toxic metabolite Nacetyl-p-benzoquinone-imine (NAPBQI), may be induced in obesity with potentially increased
NAPBQI production (Hakim 2019 Level IV PK), although this concern remains poorly documented.
Available data suggest uncompromised clearance and low plasma concentrations of paracetamol
were achieved in obese adolescents when given routine doses (1 g 6 hly) (Hakim 2019 Level IV PK).
There are few paediatric data available, despite one unpublished coroner reported death due to
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1093hepatic failure of an obese child who received paracetamol dosed per kg without allometricscaling. The influence of obesity on paracetamol toxicity, if any, is unknown.
Obesity has been described as a chronic inflammatory state and associated with otherchanges in the enzyme activity of metabolic and elimination pathways (Brill 2012 NR). However,the clinical relevance of many of these changes is questionable. In the absence of data, dosing
by IBW for age is considered reasonably safe, but capping at usual adult maximums will likely
result in underdosing. Pharmacokinetic and pharmacodynamic study for individual drugs isrequired to establish whether this provides effective analgesia in the overweight and obese.

10.10.5 | Weight/mass adjusted dosing for individual drugs
The terms weight and mass are used interchangeably in the literature (eg ideal body mass = ideal
body weight). Due to limited data in overweight and obese children and adolescents, suggestions
are typically based on studies of obese adults and normal weight children (See Table 10.11).
Table 10.11 | Dosing suggestions for common analgesics relevant to body weight
Analgesic

InitialdosingMaintenancedosingMorphine

Ideal BW

Ideal BW

Dosing not specified as
initial or maintenanceMortensen 2011

Ideal BW
Fentanyl

Total BW

Total BW

Total BW

Lean BW

Lean body mass/Ideal BW
Nil data

Nil data

Lidocaine

Total BW

Ideal BW

Chidambaran 2018
Mortensen 2011

Lean BW

Ketamine

Chidambaran 2018
Mortensen 2011

Total BW
Total BW

Remifentanil

Chidambaran 2018
Mortensen 2011

Lean BW
Lean BW/Total BW

Sufentanil

Chidambaran 2018
Mortensen 2011

Lean BW
Lean body mass/PK mass

Alfentanil

References

Chidambaran 2018

Chidambaran 2018

Paracetamol

Total BW with allometricscaling (single dose only)

Hakim 2019

Ibuprofen

Total BW with allometricscaling (multidose)

Anderson 2019

BW=body weight

1094 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENTKEY MESSAGESThe following tick boxes represent conclusions based on clinical experience and expert
opinion: When dosing medication in the overweight or obese child or adolescent, age of thepatient, each individual drug and the dose type (initial or maintenance) must be
considered (N).
 Given the barriers to accurate dosing in overweight and obese children, judicious
dosing and titration to effect wherever possible is recommended. This requiresconsideration of both pharmacokinetic and pharmacodynamic factors (N).
 Young and obese children with history of obstructive sleep apnoea syndrome/sleepdisordered breathing are at higher risk of developing serious opioid-induced ventilatory
impairment and death (U) (Level IV).

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10.11 | Complementary and alternative medicines and therapies
in children
Complementary medicines and therapies are defined as evidence-based health care approaches
developed outside of conventional Western medicine; they are used in conjunction withconventional care (McClafferty 2017 NR). Alternative medicines and therapies are used in place of
conventional care. Complementary and alternative medicines and therapies (CAMTs) arecommonly used in communities. Increasingly, complementary medicines and therapies are usedas part of integrative approaches to hospital-based healthcare in the paediatric population.
Therefore, there is a need for health care professionals managing acute pain to be informed
about CAMTs and, where relevant, their potential drug interactions. The evidence for CAMTs islimited by the large degree of heterogeneity of the various interventions and small sample sizes
resulting in low level power to detect differences.
See also adult Section on CAMs 4.14. Studies relevant to photobiomodulation use inpaediatric dental, cleft and tonsillectomy are not discussed here but are included in the adult
Section 7.4.

10.11.1 | Natural products
Aromatherapy
Studies on aromatherapy for paediatric acute pain show mixed results (Dimitriou 2017 Level I[PRISMA], 9 RCTs [2 paediatric], n=644 [112]; Lakhan 2016 Level III-3 [PRISMA], 12 studies [3 paediatric],
n=1,019) (2 study overlap):• In 6─12 y olds post-tonsillectomy, lavender essential oil (in addition to paracetamol every••6 h) rubbed onto the palms and inhaled 6 h prn did not reduce pain intensity, but did
reduce paracetamol use (1 RCT: Soltani 2013 Level II, n=48, JS 2);
In infants (3─36 mth) following craniofacial surgery, massage with mandarin oil vs
massage with a carrier oil did not reduce pain scores, HR or mean arterial pressure (1 RCT:de Jong 2012 Level II, n=60, JS 3);
In 3─6 y olds having various surgery types (mostly thoraco-abdominal), rosa damascena
essential oil vs sweet almond oil (placed on a small pad, adjacent to the head)
postoperatively every 3 h for 12 h reduced mean pain scores 3─12 h postoperatively (1RCT: Marofi 2015 Level II, n=64, JS2).

Melatonin
Melatonin is a neurohormone synthesised endogenously by the pineal gland from the amino acidtryptophan. Antinociceptive effects of melatonin have been demonstrated in animal models and,in addition to acting on melatonin receptors (MT1/MT2), other proposed analgesic mechanisms
include modulation of opioid, benzodiazepine, alpha adrenergic, serotonergic and cholinergic
receptors (Srinivasan 2012 NR). Although exogenous melatonin is commonly used in paediatrics,
clinical studies on its use as an analgesic in children are lacking (Marseglia 2015a NR). In children
1─14 y, PO melatonin 0.5 mg/kg (max 5 mg) vs placebo 30 min prior to venipuncture reduced
preprocedural anxiety (mean 1.3/5 vs 2.2) and pain scores during venipuncture (for ≤3 y olds,
mean 2.5/10 vs 3.2; and for >3 y olds, mean 1.2/10 vs 2.1) (Marseglia 2015b Level II, n=60, JS 5).
Honey
Honey in children vs placebo reduces pain and analgesic use for up to 5─10 d post-tonsillectomy;
regimens of honey administered varied substantially in volume (4─15 mL), frequency (daily to1096 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

hourly) and duration (1─10 d) (Lal 2017 Level I [QUOROM], 8 RCTs, n=545; Hwang 2016b Level I[PRISMA], 4 RCTs, n=264) (4 RCTs overlap). The analgesic medication regimens used in included
studies was not clear. An RCT not included in the meta-analyses found that onset to pain relief
was faster, pain severity was lower and the need for rescue analgesia was less in the honeyrecipients vs controls (Mohebbi 2014 Level II, n=80, JS 2).
For neonates having a heel lance, honey vs water reduced cry duration (Bueno 2013 Level III-1[PRISMA], 1 study: Ramenghi 2001 Level III-1, n=15).
See Section 10.7.1─2 for use of sweet solutions in procedural pain in children.
Turmeric and Ginger (Zingiberaceae)
Zingiberaceae include Curcuma longa (turmeric), Zingiber officinale (ginger), Curcuma
zanthorrhiza (Javanese ginger) and Alpinia galanga (galangal). Curcumin (diferuloyl methane) isthe principal curcuminoid of the Indian spice turmeric, while the anti-inflammatory components
of ginger are gingerol and zingerone. The available systematic reviews have assessed efficacy for
pain in adults. There have been no peer reviewed publications in children regarding analgesic
efficacy, although conference abstracts reflect growing interest for use of turmeric in juvenile
arthritis. Efficacy of ginger in nausea and vomiting is not presented here.
Supplements and vitamins
Fish oil (500 mg/d) and vitamin B1 (100 mg/d) alone or in combination vs placebo improved pain
intensity and reduced duration of pain in 13─18 y old girls with dysmenorrhoea; comparisons
between active arms were not reported (Hosseinlou 2014 Level II, n=240, JS 3). In adolescents withdysmenorrhoea, zinc 50 mg/d during menstruation reduced the mean duration of pain in 3
menstrual cycles, and mean pain scores in two of three menstrual cycles (Zekavat 2015 Level II,
n=120, JS 5).
Perioperative enteral docosahexaenoic acid (DHEA) 37.5 mg/kg two times daily vs sunflower
oil in neonates (>34/40 wk gestational age) having cardiovascular surgery (without
cardiopulmonary bypass eg Blalock-Taussig shunt or aortoplasty) reduced postoperative IVbuprenorphine requirements (14.6 mcg/kg vs 25.2) and duration (2 d vs 4.5) (Bernabe-Garcia 2016
Level II, n=35, JS 4).
Vitamin D supplementation for acute pain management in children has not been studied(see paediatric sickle cell disease Section 10.9.5.1 for comment on Vitamin D deficiency in sickle
cell disease).

10.11.2 | Acupuncture
Acupuncture (invasive [skin breaking] or non-invasive eg pressure, laser or transcutaneouselectrical) for preterm and term neonates receiving heel lance does not reduce pain intensity(Stadler 2019 Level I [PRISMA], 5 RCTs, n=265). Individual RCTs found mixed results: two RCTs showed
reduced pain scores with acupuncture, one RCT showed no difference vs control, and two RCTs
showed increased pain with acupuncture. A subsequent RCT found auricular non-invasive
magnetic acupuncture vs placebo reduced pain scores during (mean 5.9/21 vs 8.3) but not afterheel lance in preterm and term neonates (Chen 2017a Level II, n=26, JS 3).
Perioperative acupuncture (including electroacupuncture) vs control in children andadolescents (<18 y) having tonsillectomy reduces pain intensity (4─48 h) (4 RCTs, n=234 [3paediatric, n=201]) and analgesic consumption postoperatively (4 RCTs, n=232 [3 paediatric, n=199])(Cho 2016 Level I [PRISMA], 12 RCTs, n=1,025 [11 paediatric, n=910]). Similar results are reported by anoverlapping systematic review of RCTs and non-RCTs (Pouy 2019 Level IV SR, 9 RCTs and 3 studies,n=910 children) (9 RCT overlap).

5th Edition | Acute Pain Management: Scientific Evidence

1097For bilateral myringotomy and tympanostomy tube insertion, intraoperative acupuncture vscontrol in 1─6 y olds reduced postoperative pain, agitation and analgesic use, with increased
time to first analgesic request (Lin 2009 Level II, n=60, JS 3).
For percutaneous kidney biopsy in 7─26 y olds, there was no difference in pain scores
between laser acupuncture vs placebo groups (during or after the procedure) where all painscores were low (<2/10) (Oates 2017 Level II, n=66, JS 5). Change in self-reported pain scores fromduring the procedure to after the procedure were mildly greater with laser (-0.8/10 vs -0.5).
For dental treatment, acupuncture (at the LI4 point bilaterally) in children and adolescents
4─18 y reduced self-reported pain intensity (2.3/10 vs 3.9) during local anaesthetic injection(Usichenko 2016 Level II, n=49 [98 injections], JS 3).
For 8─18 y olds presenting to the ED with severe migraine, pain scores reduced (mean from
7.63/10 to 0.55) at 15 min following insertion of gold auricular acupuncture needles, with 4 patientsrefusing treatment and 2 withdrawing post treatment initiation (Graff 2018 Level IV, n=23).
Acupuncture has been used in postoperative patients 0.5─18 y admitted to intensive care(Wu 2009 Level IV, n=20) and in 10─17 y olds with appendicitis in the ED (Nager 2015 Level IV, n=6);
however efficacy was not adequately assessed.
For further discussion of acupuncture for acute pain in adults see Section 7.3.

10.11.3 | Mind-body practices
10.11.3.1 | Hypnosis
Hypnosis encompasses a variety of interventions (eg self-hypnosis, hypnotic guided imagery),and requires the skills of a trained health professional and time for the child to learn thetechnique. It has been studied mostly for procedural pain management. Hypnosis vs control forneedle-related procedural pain reduces pain intensity (SMD: -1.4; 95%CI -2.32 to -0.48) (5 RCTs,
n=176), distress (SMD: -2.53; 95%CI -3.93 to -1.12) (5 RCTs, n=176) and behavioural measures of
distress (SMD: -1.15; 95%CI -1.76 to -0.53) (6 RCTs, n=193) (Birnie 2018 Level I [Cochrane], 59 RCTs,
n=5,550). For children undergoing cancer-related procedures hypnosis is an effective pain-control
technique (Tome-Pires 2012 Level I, 10 RCTs [cancer procedural pain], n=394) (5 RCT overlap). A
subsequent review of oncology patients found hypnosis reduces pain scores vs treatment as
usual (Cohen’s d 2.16; 95%CI 1.41 to 2.92) and vs controls having attention focus (Cohen’s d 2.24;
95%CI 1.66 to 2.82) but not vs active control groups (eg music, play, audiobooks) (Nunns 2018
Level I [PRISMA], 15 RCTs [8 hypnosis], n=585 [337]) (6 & 6 RCT overlap).
Hypnosis had no effect on pain and wound healing for burn dressing changes but reduced
preprocedural anxiety on the second of three burns dressing changes (MD -0.8/10; 95%CI -1.5
to -0.1) (Chester 2018 Level II, n=62, JS 3).
Hypnosis interventions have been studied for postoperative pain (including Nuss procedure,
spinal fusion, tonsillectomy) with mixed results, and no conclusions on its efficacy can be drawn
in this setting (Accardi 2009 Level III-3 SR, 13 studies [3 postoperative], n=528; Duparc-Alegria 2018
Level II, n=120, JS 2; Manworren 2018 Level III-2, n=53). See also adult section 7.1.4 Hypnosis.
10.11.3.2 | Mindfulness-based interventions (attention and meditation)
Mindful attention vs guided imagery helped children 10─14 y focus their attention on
experimental pain (cold pressor) without increasing pain intensity or decreasing tolerance ( Petter2013 Level II EH, n=82, JS 2). While in adolescents 13─18 y, mindful attention vs guided imagery
prior to experiencing experimental pain (cold pressor) did not change pain intensity or tolerance
overall; however in the subgroup who meditated regularly, mindful attention did reduce pain
intensity (Petter 2014 Level II EH, n=198, JS 2).

1098 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

Instructor taught Mantram meditation (commenced prior to infusion commencement) has
been used successfully by children 3─14 y with high risk neuroblastoma experiencing pain fromanti-glycolipid disialoganglioside (GD)-2 monoclonal antibody infusions (Ahmed 2014 Level IV,n=34). See also adult sections 7.1.3 Mindfulness-based interventions and 7.1.5 Attentional
techniques.
10.11.3.3 | Guided imagery, relaxation and biofeedback
Postoperative guided imagery (at least 3 times a week)/standard care vs standard care alone
reduced pain intensity following spinal fusion surgery for scoliosis in 11─20 y olds (Charette 2015
Level II, n=40, JS 3). Preoperative relaxation-guided imagery vs control in 6─12 y olds (having
inguinal hernia repair, phimosis repair or endoscopy) reduced mean pain scores 2 hpostoperatively (4.5/10 vs 7.7) (Vagnoli 2019 Level II, n=60, JS 3).
Relaxation and biofeedback vs control for 12 y olds receiving venipuncture did not lower pain
intensity during the procedure (Forsner 2014 Level III-2, n=109). Relaxation therapy and guided
imagery had similar effects on cortisol reactivity, self-reported stress, pain intensity and pain
unpleasantness in females 11─12 y receiving the HPV vaccine (Nilsson 2015 Level III-2, n=37).
In children 8─14 y having cancer-related procedures, a 4-session intervention of
preprocedural relaxation plus biofeedback progressively reduced state anxiety across thesessions, with improvement in heart rate variability; 81% of participants reported the
combination of relaxation and biofeedback helped them feel in control of their bodies prior to
the procedure (Shockey 2013 Level IV, n=12). In patients 7─18 y undergoing needle-related
procedures and using ‘Brighthearts’ (a biofeedback assisted relaxation application), 83%
reported the app was helpful and would use it again, 100% of parents and 96% of healthcare
providers indicated they would use it again, and 64% of the healthcare providers perceived thatit assisted with the ease of performing a procedure (Burton 2018 Level IV, n=107 [30 patients, 27
parents, 50 health providers]).
10.11.3.1 | Physical and other complementary therapies
Other complementary therapies have been assessed for acute pain management with studies
reporting mixed results: massage therapy (Staveski 2018 Level II, n=60, JS 3; de Jong 2012 Level II,
n=60, JS 3), Therapeutic Touch (Johnston 2013 Level II, n=55, JS 2), Reiki (Kundu 2014 Level II, n=38, JS
5), yoga (Moody 2017 Level II, n=70, JS 3), reflexology (Koc 2015 Level II, n=60, JS 2) and Korean handtherapy (Ochi 2015 Level IV, n=29). Conclusions on their effectiveness cannot be made due to small
samples and study designs prone to bias.
See also adult sections regarding massage and yoga in 7.5 Physical therapies.

10.11.4 | Infantile colic
Infantile colic can be defined as excessive crying in the first few months of life; the most citedclinical diagnostic criteria is the rule of 3s: crying for longer than 3 h/d for ≥3 d/wk for at least 3
wk (Biagioli 2016 Level III-1 SR [Cochrane], 18 RCTs, n=1,014). In mothers who had usedcomplementary medicine (mostly homeopathic remedies, probiotics or herbal medicines) totreat their infant’s colic where 73% was alongside conventional medicine treatments, 66% felt it
was effective and 47% reported no side effects (Di Gaspero 2019 Level IV, n=152).
Oral herbal, antifoaming, sweet solution or anticholinergic agents
Various pain-relieving agents to treat colic have been studied: herbal agents (defined as plantderived remedies), (6 studies, n=427), simethicone (4 studies, n=166), sweet solution [sucrose or
5th Edition | Acute Pain Management: Scientific Evidence1099glucose] (3 studies, n=120), dicyclomine (5 studies, n=137) and cimetropium bromide (2 studies,n=126) (Biagioli 2016 Level III-1 [Cochrane], 18 RCTs, n=1,014). Although some of these studies foundpositive results, reported benefits are inconsistent, and study designs are prone to bias, with theauthors concluding that none of these agents could be recommended. Additionally, a
subsequent systematic review of systematic reviews found supporting evidence specifically forfennel extract, but methodological issues with studies call this result into question ( Perry 2019
Level I [PRISMA], 16 SRs [5 herbal medicine SRs], n RCTs unspecified).
Probiotics
Three systematic reviews have reported on the efficacy of probiotics for infantile colic. These
draw the same conclusion: Lactobacillus reuteri (108 colony forming units daily for 21 or 28 d) is
effective at reducing cry/fuss time >50%: RR 2.34 (95%CI unspecified) (5 RCTs, n=317) (Schreck Bird
2017 Level I [PRISMA], 5 RCTs, n=388); RR 1.67 (95%CI 1.10 to 2.81) (6 RCTs, n=391) (Dryl 2018 Level I[PRISMA], 7 RCTs, n=471); RR 1.71 (95%CI 1.35 to 2.15) (4 RCTs, n=293) (Sung 2018 Level I [PRISMA], 4
RCTs, n=345) (4 RCT overlap). Most infants included in these RCTs were breastfed (although not all
exclusively). There is insufficient evidence for probiotics in formula fed infants (Sung 2018 Level I[PRISMA], 1 RCT [formula fed], n=66 (21 d)]. A systematic review of systematic reviews identified afurther 4 older reviews that drew similar conclusions (Perry 2019 Level I [PRISMA], 16 SRs [7probiotic], n RCTs unspecified). A Cochrane review assessed probiotics for prevention of colic in
infants (<1 mth old at recruitment) where probiotics vs placebo did not reduce the number of
new cases of infantile colic (3 RCTs, n=1,148), but did reduce the duration of crying (MD -32.6
min/d; 95%CI -55.6 to -9.54) (3 RCTs, n=707); there was no difference in the incidence of serious
adverse effects (6 RCTs, n=1,851) (Ong 2019 Level I [Cochrane], 6 RCTs, n=1,886) (0 RCT overlap).
Dietary modifications
Various dietary modifications for infantile colic have been studied including maternal low
allergen diets for breastfed infants (2 studies), lactase enzyme supplementation (3 studies), andhydrolysed formula (6 studies) (Gordon 2018 Level III-1 [Cochrane], 15 studies, n=1,121). The authors
concluded that reported benefits for hydrolysed formula were inconsistent, and overall, due tosmall samples and high risk of bias, no intervention was able to be recommended.
Skeletal manipulation
Individual studies report positive outcomes for skeletal manipulative therapies to treat infantile
colic. However, studies were small and methodologically biased and these flaws make the resultsinconclusive; only one study assessed for adverse effects and reported none ( Perry 2019 Level I[PRISMA], 16 SRs [6 manipulation]; Dobson 2012 Level I [Cochrane], 6 RCTs, n=325).
Acupuncture
There is no conclusive evidence to support the safety and efficacy of acupuncture to treat colic
in infants (1–25 wk old) (Skjeie 2018 Level I [PRISMA], 3 RCTs, n=307; Lee 2018 Level I, 4 RCTs, n=357)(3 RCT overlap).

1100 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENTKEY MESSAGES
1. Hypnosis for needle-related procedural pain (including for cancer-related procedures)
reduces pain intensity (S) and distress (N) versus control (Level I [Cochrane Review]).
2. Preventive use of probiotics does not reduce infantile colic incidence, but does reduce
crying duration versus placebo (N) (Level I [Cochrane Review]).
3. The probiotic Lactobacillus reuteri reduces cry/fuss time in breastfed infants with colic;there is insufficient evidence in formula fed infants (N) (Level I [PRISMA]).
4. Oral administration of honey versus control in children reduces pain and analgesic use
after tonsillectomy (N) (Level I [PRISMA]).
5. Perioperative acupuncture (including electroacupuncture) versus control in children
having tonsillectomy reduces postoperative pain intensity (in the first 48 h) and analgesic
consumption (N) (Level I [PRISMA]).
6. Acupuncture (invasive or non-invasive) versus control for preterm and term neonates
receiving heel lance does not reduce pain intensity (N) (Level I [PRISMA]).
The following tick boxes represent conclusions based on clinical experience and expert
opinion: Complementary and alternative medicines and therapies encompass a wide variety ofinterventions with common use in the community; complementary medicines andtherapies are increasingly used as part of integrative approaches to hospital-based
healthcare in the paediatric population (N).
 The evidence on complementary and alternative medicines and therapies ischaracterised by small sample sizes and study designs prone to bias and caution isurged in interpreting results. Additionally, the safety and potential drug interactions ofmany complementary and alternative medicines and therapies have not beenadequately assessed (N).

5th Edition | Acute Pain Management: Scientific Evidence

1101

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Pharmacol 70(4): 479–82.
Zafar MS, Stewart AM, Toupin DN et al (2018) Continuous Intravenous Valproate as Abortive Therapy for PediatricStatus Migrainosus. Neurologist 23(2): 43-46.
Zaidi RH, Casanova NF, Haydar B et al (2015) Urethrocutaneous fistula following hypospadias repair: regional
anesthesia and other factors. Paediatr Anaesth 25(11): 1144-50.
Zamzmi G, Kasturi R, Goldgof D et al (2018) A Review of Automated Pain Assessment in Infants: Features, Classification
Tasks, and Databases. IEEE Rev Biomed Eng 11: 77-96.
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1174 5th Edition | Acute Pain Management: Scientific Evidence10.0 | THE PAEDIATRIC PATIENT

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5th Edition | Acute Pain Management: Scientific Evidence

1175Appendix A: The Editorial Working Party and Contributors
Editorial Working Group
Editors
Prof Stephan A.
Schug (Chair)

Emeritus Professor and Senior Honorary Research Fellow
Anaesthesiology and Pain Medicine, Medical School,
University of Western Australia
Perth, Western Australia

A/Prof Greta M.
Palmer(Chair PaediatricVolume)Staff Anaesthetist and Specialist Pain Medicine Physician
The Royal Children’s and Royal Melbourne Hospitals
Deputy Head of the Children’s Pain Management Service
Royal Children’s Hospital
Research Associate, Murdoch Childrens Research Institute
Associate Professor
Faculty of Medicine, Dentistry and Health Sciences, University of
Melbourne
Melbourne, Victoria

Prof David A. Scott

Specialist Anaesthetist and Specialist Pain Medicine Physician Directorof the Department of Anaesthesia and Acute Pain Medicine
St. Vincent’s Hospital Melbourne
Professor
Faculty of Medicine Dentistry and Health Sciences, University of
Melbourne
Melbourne, Victoria

Dr Mark M. Alcock

Staff Anaesthetist and Specialist Pain Medicine Physician, Departmentof Anaesthesia and Pain Management and Clinical lead, Queensland
Interdisciplinary Paediatric Persistent Pain Service,Children's Health Queensland Hospital and Health Service
Senior lecturer,
Faculty of Medicine
University of Queensland,
Brisbane, Queensland

Dr Richard
HalliwellDeputy Director of Anaesthesia and Director of Acute Pain Service
Westmead Hospital, Sydney
Clinical Senior Lecturer, Discipline of Anaesthesia,
Sydney Medical School.
Sydney, New South Wales

Dr Jeffrey F. Mott

Staff Anaesthetist and Specialist Pain Medicine Physician, Clinical lead
Acute Pain Service,Redcliffe Hospital
Senior lecturer, Faculty of Medicine,
University of Queensland
Brisbane, Queensland

1176 5th Edition | Acute Pain Management: Scientific Evidence

APPENDIX A

Editorial Advisory Group
Representative of FPMRCA:Dr Mark Rockett

Consultant Anaesthetist and Specialist in Pain Medicine
University Hospitals Plymouth NHS Trust
Honorary Associate Professor
University of Plymouth, Faculty of Health
Plymouth, UK

Representative of Hong
Kong College ofAnaesthesiologists:
Dr Sze Ming Wong (Clara)

VMO Specialist Pain Medicine Physician
Barbara Walker Centre for Pain Management, St Vincent's
Hospital, Melbourne
VMO Anaesthetist, Eastern Health, Melbourne
Specialist Pain Medicine Physician, Pain Specialist Australia
Melbourne, Victoria

Contributors Volume I: Adults (Chapters 1 to 9)
Dr Luke Arthur

Clinical Associate Lecturer, The University of Adelaide
Adelaide, South Australia

Dr Ali M AsghariPain Management Research InstituteSydney Medical School - Northern, University of Sydney atRoyal North Shore Hospital
St Leonards, New South Wales

Professor Michael
Barrington

Senior Staff Anaesthetist, Department of Anaesthesia andAcute Pain Medicine, St Vincent’s Hospital
Professor, Centre for Integrated Critical Care
Department of Medicine & Radiology, Melbourne Medical
School, Faculty of Medicine, Dentistry and Health Sciences,
The University of Melbourne
Melbourne, Victoria

Dr Carolyn Berryman

NHMRC Postdoctoral Fellow
School of Medicine, The University of Adelaide
Adelaide, South Australia

Prof Alex Brown

Aboriginal Health Equity Theme Leader,South Australian Health and Medical Research Institute
Professor of Medicine
Aboriginal Health, University of Adelaide
Adelaide, South Australia

Dr Frank Buchanan

VMO Anaesthetist Epworth Healthcare
Director, Elgin Pain Management
Honorary Research Fellow,
Melbourne Clinical School, The University of Notre Dame
Melbourne, Victoria

5th Edition | Acute Pain Management: Scientific Evidence

1177

Dean Bunbury

Consultant Anaesthetist & Prehospital Physician
Anaesthesia and Pain Medicine, Counties Manukau HealthHonorary Senior Lecturer, University of Auckland
Auckland, New Zealand

Dr Jared M. Campbell

Research Fellow, Graduate School of Biomedical Engineering
Centre for Nanoscale Biophotonics, University of New
South Wales
Randwick, New South WalesProf Antonio Celenza

Head, Division of Emergency Medicine
University of Western Australia and Sir Charles Gairdner
Hospital
Nedlands, Western Australia

Dr Phoon Ping Chen

Consultant
Department of Anaesthesiology & Operating Services
Alice Ho Miu Ling Nethersole Hospital & North District
HospitalHong Kong

A/Prof Catherine Cherry

Infectious Diseases Physician and Clinical Epidemiologist
The Alfred Hospital, Burnet Institute and Monash
University
Melbourne, Victoria

Dr Myles Conroy

Staff Anaesthetist, Barwon HealthSenior Clinical Lecturer
Deakin University, University Hospital Geelong
Geelong, Victoria

Prof Tomas Corcoran

Director of Research, Department of Anaesthesia and Pain
Medicine
Royal Perth Hospital
Adjunct Clinical Professor
School of Public Health and Preventive Medicine, Monash
University
Clinical Professor
Medical School, University of Western Australia
Perth, Western Australia

Dr Jennifer Curnow

Director of Clinical Haematology
WSLHD, Westmead Hospital
Director of Westmead Haemophilia Treatment Centre
Westmead Hospital
Sydney, New South WalesProf Rob Delcanho

Adjunct Professor in Orofacial Pain Medicine
School of Medicine, Notre Dame University, Perth
Clinical Associate Professor
School of Dentistry, University of Sydney
Perth, Western Australia

1178 5th Edition | Acute Pain Management: Scientific Evidence

APPENDIX ADr Christina Denman

Staff Specialist, Department of Anaesthesia andPerioperative Medicine
Royal Brisbane and Women’s Hospital
Brisbane, Queensland

Ms Alison Duncan

Clinical Pharmacist, Infectious diseases/HIV
The Alfred Hospital
Melbourne, Victoria

Dr Reginald Edward

Consultant Anaesthetist & VMO
Latrobe Regional Hospital
Honorary Lecturer
Monash University
Traralgon, Victoria

Dr Paul Emery

Provisional Fellow in Anaesthesia
Royal Darwin Hospital, Top End Health Service
Darwin, Northern Territory

Dr A. Reza Feizerfan

Specialist Pain Medicine Physician and Specialist Anaesthetist
Departments of Anaesthesia and Pain Management, Royal
Perth Hospital
Perth, Western Australia

A/Prof Damien Finniss

Department of Anaesthesia & University of Sydney PainManagement Research InstituteRoyal North Shore Hospital
Sydney, New South Wales
School of Allied Health Sciences, Griffith University,
Queensland

A/Prof Ray Garrick

Consultant Neurologist, St Vincent’s Hospital
Associate Professor of Medicine
University of Notre Dame Australia
Darlinghurst, New South WalesProf Stephen J Gibson

Director of Research
Caulfield Pain Management and Research Centre
Professorial Associate
National Ageing Research Institute
Melbourne, Victoria

A/Prof Paul Gray

Director, The Professor Tess Cramond Multidisciplinary Pain
CentreRoyal Brisbane and Women’s Hospital
Brisbane, Queensland

Prof Mark Hutchinson

Director, Australian Research Council Centre of Excellence
for Nanoscale BioPhotonics
University of Adelaide,
Adelaide, South Australia

5th Edition | Acute Pain Management: Scientific Evidence

1179

Dr Christine Huxtable

Anaesthetic Consultant, Royal Adelaide Hospital
Adelaide, South Australia

Dr Thomas Judd

Anaesthetic Registrar, Counties Manukau District Health
Board
Auckland, New ZealandDr. Karin Jones

Anaesthetist and Pain Medicine Specialist,
Royal Melbourne Hospital and Royal Women’s Hospital
Parkville, Victoria

A/Prof Benny Katz

Geriatrician, St Vincent’s Hospital Melbourne
Associate Professor
Faculty of Medicine, Dentistry and Health Sciences,
University of Melbourne
Melbourne, Victoria

Prof Janet R Keast

Professor and Chair of Anatomy and Neuroscience
Department of Anatomy and Neuroscience, University of
Melbourne
Melbourne, Victoria

Dr Peter Keogh

Specialist Anaesthetist and Pain Physician
Alfred Hospital
Adjunct Lecturer
Department of Anaesthesia and Perioperative Medicine,
Monash University
Melbourne, Victoria

Dr Charles Kim

Staff Specialist in Anaesthesia and Pain Medicine
Department of Anaesthesia and Pain Management, The
Royal Melbourne Hospital,
Barbara Walker Centre for Pain Management
St Vincent’s Hospital
Senior Clinical Lecturer
Faculty of Medicine, Dentistry and Health Sciences,
University of Melbourne
Melbourne, Victoria

Dr Jeff Kim

Staff Specialist Anaesthetist
Nepean and Blue Mountains LHD, NSW Health
Clinical Lecturer
Nepean Clinical School, University of Sydney
Sydney, New South WalesDr Brian Lee

Specialist Anaesthetist and Specialist Pain Medicine Physician
Department of Anaesthesia and Pain Management, Royal
Perth Hospital
Perth, Western Australia

Dr Chuan-Whei Lee

Specialist Anaesthetist and Pain Medicine Physician
Royal Melbourne Hospital
Melbourne, Victoria

1180 5th Edition | Acute Pain Management: Scientific Evidence

APPENDIX A

Dr Daniel J Lee

Consultant Physician in Rehabilitation and Pain Medicine,
Melbourne Pain Group, Victorian Rehabilitation Centre
Glen Waverley, Victoria

Dr Yee Chi Lee

Associate Consultant, Director of Pain Service
Department of Anaesthesiology & Operating Services
Alice Ho Miu Ling Nethersole Hospital & North District
HospitalHong Kong

Ms Monita Mascitti-Meuter

Cultural Diversity Program Coordinator, St Vincent’s Hospital
Melbourne, Victoria

Dr Benjamin Moran

Intensive Care and Anaesthetic Specialist
Central Coast Local Health District
Conjoint Senior Lecturer
University of Newcastle
Gosford, New South Wales

Dr Irene Ng

Staff Anaesthetist, Department of Anaesthesia and PainManagement, Royal Melbourne Hospital
Honorary Fellow
Faculty of Medicine, Dentistry and Health Sciences,
University of Melbourne
Melbourne, Victoria

Prof Michael K Nicholas

Director, Pain Education and Pain Management Programs,
Pain Management Research Institute, Sydney Medical
School - Northern, University of Sydney at Royal North
Shore Hospital
St Leonards, New South WalesDr Yin Ling Or

Associate Consultant, Director of Acute Pain Service,
Department of Anaesthesiology & Operating Services
Alice Ho Miu Ling Nethersole Hospital & North District
HospitalHong Kong

Dr Peregrine B Osborne

Senior Research Fellow
Department of Anatomy and Neuroscience, University of
Melbourne
Melbourne, Victoria

Dr Tuong D Phan

Senior Staff Specialist Anaesthetist, Department ofAnaesthesia and Acute Pain Medicine
St Vincent’s Hospital
Honorary Senior Clinical Lecturer
Faculty of Medicine, Dentistry and Health Sciences
University of Melbourne
Melbourne, Victoria

5th Edition | Acute Pain Management: Scientific Evidence1181

Dr Lindy Roberts AM

Specialist Anaesthetist and Pain Medicine Physician,
Departments of Anaesthesia and Pain Management,
Sir Charles Gairdner Hospital
Perth, Western Australia

Prof Edward A Shipton

Academic Head, Department of Anaesthesia
University of Otago
Christchurch, New ZealandProf Philip Siddall

Director, Pain Management Service
HammondCare, Greenwich Hospital
Conjoint Professor in Pain Medicine
Sydney Medical School – Northern, University of Sydney
Sydney, New South WalesProf Helen Slater

Clinical Researcher and Specialist Physiotherapist,
School of Physiotherapy & Exercise Science, Faculty of
Health Sciences, Curtin University
Perth, Western Australia

Prof Andrew Somogyi

Discipline of Pharmacology
Adelaide Medical School, University of Adelaide
Department of Clinical Pharmacology
Royal Adelaide Hospital
Adelaide, South Australia

Dr Anna Steer

Anaesthesia Registrar - Advanced Trainee
Victorian Anaesthesia Training Scheme
Melbourne, Victoria

Dr Andrew Stewart

Senior Staff Anaesthetist, Co-ordinator Acute Pain Service,
Department of Anaesthesia and Acute Pain Medicine
St Vincent’s Hospital
Melbourne, Victoria

Dr Sonya Ting

Anaesthetist and Pain Specialist, Department of Anaesthesia
and Pain Medicine,King Edward Memorial Hospital for Women
Perth, Western Australia

Dr Zoe Vella

Anaesthetist and Pain Medicine Registrar,
Professor Tess Cramond Multidisciplinary Pain Centre,
Royal Brisbane and Women’s Hospital
Brisbane, Queensland

Dr Yanyi Wang

Discipline of Chinese Medicine
School of Health and Biomedical Sciences, RMIT University
Bundoora, Victoria

A/Prof Laurence Weinberg

Director of Anaesthesia, Austin Health
Melbourne, Victoria

Dr Leigh White

Anaesthetics Registrar, Sunshine Coast University Hospital
Sunshine Coast, Queensland

1182 5th Edition | Acute Pain Management: Scientific Evidence

APPENDIX A

Dr Noam WinterAnaesthetist and Specialist Pain Medicine Physician
Princess Alexandra and Queen Elizabeth II Jubilee Hospitals
Brisbane, Queensland

Dr Maggie Wong

Consultant Anaesthetist, Department of Anaesthesia
The Royal Women’s Hospital, Melbourne
Department of Anaesthesia and Acute Pain Medicine
St Vincent’s Hospital
Melbourne, Victoria

Dr Andrew Zacest

Neurosurgeon and Clinical Associate Professor
Department of Neurosurgery and University of Adelaide
Royal Adelaide Hospital
Adelaide, South Australia

Dr Melanie Zeppel

Honorary Senior Research Fellow
Department of Biological Sciences, Faculty of Science andEngineering
Senior Research Fellow
GenIMPACT, Centre for Economic Impacts of Genomic
Medicine, Macquarie Business School, Macquarie
University
North Ryde, New South Wales

A/Prof Zhen Zheng

Discipline of Chinese Medicine
School of Health and Biomedical Sciences, RMIT University
Bundoora, Victoria

5th Edition | Acute Pain Management: Scientific Evidence

1183

Contributors Volume II: Paediatric (Chapter 10)
Dr Harith Al-Rawi

Paediatric Emergency Physician,Emergency Department, Royal Children’s Hospital
Honorary Clinical Lecturer
University of Melbourne
Melbourne, Victoria, Australia

Prof Brian Anderson

Paediatric Anaesthetist and Intensivist
Starship Children’s HealthProfessor of Anaesthesiology
University of Auckland
Auckland, New Zealand

A/Prof Peter Barnett

Paediatric Emergency Physician,Emergency Department, Royal Children’s Hospital
Department of Paediatrics,
University of Melbourne
Research Fellow
Murdoch Childrens Research Institute
Melbourne Victoria, Australia

Dr Sarah Brew

Staff Anaesthetist
Department of Anaesthesia and Pain Management
Barwon Health University Hospital
Geelong, Victoria, Australia

Dr Laura Burgoyne

Senior Staff Specialist Anaesthetist,
Department of Paediatric Anaesthesia, Women’s and Children’s
Hospital
Clinical Senior Lecturer
University of Adelaide
Adelaide, South Australia, Australia

Dr Kathleen CookeSpecialist Anaesthetist and Specialist Pain Medicine Physician
Chair, Statewide Persistent Pain Management Network Queensland
Director, Support Kids in Pain (SKIP)
Brisbane, Queensland, Australia

A/Prof Dianne Crellin

Nurse Practitioner,
Emergency Department, Royal Children’s Hospital
Senior Lecturer
Department of Nursing, University of Melbourne
Research Fellow
Murdoch Children's Research Institute
Melbourne Victoria, Australia

1184 5th Edition | Acute Pain Management: Scientific Evidence

APPENDIX ADr Paul Davies

Staff Anaesthetist
Department of Anaesthesia and Pain Management, RoyalChildrens Hospital
Research Fellow
Murdoch Children's Research Institute
Melbourne Victoria, Australia

Dr Jonathan De Lima

Senior Staff Specialist in Anaesthesia and Pain Medicine,
Department of Anaesthesia and Pain Management, Children’s
Hospital at Westmead (Sydney Children’s Hospital Network);
Senior Clinical Lecturer
University of Sydney
Sydney, New South Wales, Australia

Dr Alexandra
Donaldson

Senior Staff Specialist Anaesthetist
Clinical lead, Procedural Anxiety and Oncology
Department of Anaesthesia and Pain Management, QueenslandChildren’s Hospital
Brisbane, Queensland, Australia

Dr Kate Drummond

Staff Specialist Anaesthetist and Pain Medicine Specialist,
Department of Anaesthesia and Pain Management, Albury Base
Hospital and Albury Wodonga Health (Wodonga Campus)
Albury, New South Wales, Australia

Dr Jacqueline Duc

Staff Specialist,
Paediatric Palliative Care Service, Children's Health Queensland
Hospital and Health Service
Senior lecturer
University of Queensland
Brisbane, Queensland, Australia

Dr Susan Hale

Staff Specialist Anaesthetist
Department of Anaesthesia and Pain Management, Children’s
Hospital at Westmead (Sydney Children’s Hospital Network)
Sydney, New South Wales, Australia

Dr Sarah Johnson

Staff Specialist Anaesthetist
Department of Anaesthesia and Pain Management, Children’s
Hospital at Westmead (Sydney Children’s Hospital Network)
Sydney, New South Wales, Australia

Dr Su May Koh

Staff Anaesthetist
Department of Anaesthesia and Pain Management, RoyalChildrens Hospital
Melbourne, Victoria, Australia

Dr Caroline Mann

Paediatric Anaesthetist,
Starship Children’s Health
Auckland, New Zealand5th Edition | Acute Pain Management: Scientific Evidence

1185

Dr Christine Mott

Staff Specialist,
Paediatric Palliative Care Service, Children's Health Queensland
Hospital and Health Service
Medical lead, Hummingbird House, Brisbane
Senior Lecturer
University of Queensland,
Brisbane, Queensland, Australia

Dr Vanessa Rich

Staff Specialist Anaesthetist
Department of Anaesthesia and Pain Management, QueenslandChildren’s Hospital
Senior Lecturer
School of Clinical Medicine - Children's Health Queensland
Clinical Unit
Brisbane, Queensland, Australia

Dr Derek Rosen

Staff Specialist Anaesthetist
and Clinical lead, Acute Pain Service
Department of Anaesthesia and Pain Management, QueenslandChildren’s Hospital;
Visiting Specialist Anaesthetist,
Sydney Children’s Hospital, Randwick and Liverpool Hospital,
SydneySenior Lecturer
University of Queensland
Brisbane, Queensland and Sydney, New South Wales, Australia

Dr Stuart Ross

Staff Specialist Anaesthetist
Department of Anaesthesia and Pain Management, Children’s
Hospital at Westmead (Sydney Children’s Hospital Network)
Sydney, New South Wales, Australia

Dr David
Sommerfield

Staff Specialist Anaesthetist and Specialist Pain Medicine Physician
Department of Anaesthesia and Pain Management, PerthChildren’s Hospital,
Adjunct Clinical Senior Lecturer
University of Western Australia Medical School
Perth, Western Australia, Australia

Dr Dana Weber

Staff Specialist Anaesthetist
Department of Anaesthesia and Pain Management, PerthChildren’s Hospital,
Adjunct Clinical Senior Lecturer
Medical School, University of Western Australia
Perth, Western Australia, Australia

Dr Nicole Wylie

Staff Specialist Anaesthetist
Department of Paediatric Anaesthesia, Women’s and Children’s
Hospital,
Adelaide, South Australia

1186 5th Edition | Acute Pain Management: Scientific Evidence

APPENDIX ADr Jordan Wood

Paediatric Anaesthetist and Specialist Pain Medicine Physician
Department of Anaesthesia and Pain Management, Christchurch
Hospital,
Clinical Senior Lecturer
University of Otago,
Christchurch, New Zealand

Dr Angela Yeo Siok
Hoong

Consultant Anaesthetist and Pain Medicine Specialist
Department of Paediatric Anaesthesia,
Kandang Kerbau Women's and Children's Hospital,
Singapore

5th Edition | Acute Pain Management: Scientific Evidence

1187

Multidisciplinary consultative committee
Area of expertise

MemberAffiliation

Aboriginal andTorres Strait Islander
LiaisonDr Claire Fenwick

Senior Lecturer,
Mount Isa Centre for Rural & Remote Health(MICRRH) and James Cook University
Townview, Queensland

Addiction Medicine(Drug and Alcohol)

Dr Richard O’Regan

Director Clinical Services
Next Step Drug and Alcohol Services, Mental
Health Commission
Perth, Western Australia

Australian
Medicines
Handbook

Louise Quinn

EditorAustralian Medicines Handbook Pty Ltd
Adelaide, South Australia

Burns and Plastic
Surgery

Prof Fiona WoodAM

Director of the Burns Service of WA and
Director of the Burn Injury Research Unit of
UWA.
Perth, Western Australia

Chiropractic

Professor Simon
FrenchProfessor of Musculoskeletal Disorders
Department of Chiropractic
Faculty of Science and Engineering,
Macquarie University
North Ryde, New South Wales

ClinicalPharmacology

Prof Paul Rolan

Clinical Professor
Faculty of Health and Medical Sciences
The University of Adelaide
Adelaide, South Australia

Consumer
representative

Helen Maxwell
WrightConsumer Representative
ANZCA
Melbourne, Victoria

Emergency
Medicine

Professor Anthony
Bell

Clinical Associate Professor
Director Clinical Services,
Rockingham Peel Group, SMHS
Cooloongup, Western Australia

General Practice

Dr Stephen Leow

General Practitioner
GP Axis Munno Para
South Australia

1188 5th Edition | Acute Pain Management: Scientific Evidence

APPENDIX A

GI and Trauma
Surgery

Dr Sudhakar Rao

Director of Trauma Service, Royal Perth HospitalState Director of Trauma Western Australia
Perth, Western Australia

Neurosurgery

Dr Andrew Zacest

Clinical Associate Professor, University of
Adelaide
Consultant Neurosurgeon Department of
Neurosurgery, Royal Adelaide Hospital
Adelaide, South Australia

Nursing

Julie Hodgson

CNC, Acute/Persistent Pain, Department ofAnaesthesia and Pain Medicine, Royal Perth
Hospital
Perth, Western Australia

Orthopaedic Surgery

Dr OwenWilliamson

Orthopaedic Surgeon and Specialist Pain
Medicine Physician
JPOCSC Pain Clinic
Fraser Health Authority
Surrey, BC, Canada

Pain Medicine

Dr James Jarman

Pain medicine specialist physician andanaesthetist
Joondalup Hospital and St. John of God
Midland Public Hospital
Perth, Western Australia

Palliative Medicine

Dr Kevin Yuen

Consultant in Palliative CareRoyal Perth Hospital
Perth, Western Australia

Pharmacology

Professor Maree
Smith

Director, Centre for Integrated Preclinical Drug
Development
Emeritus Professor of Pharmacy,
The University of Queensland, St Lucia Campus
Brisbane, Queensland

Pharmacy

Penelope Tuffin

Advanced Practice Pharmacist, Pain/Palliative
Care
Royal Perth, Fiona Stanley and Bethesda
Hospitals
Perth, Western Australia

Physiotherapy

Professor Lorimer
Moseley

Professor of Clinical Neurosciences,
Foundation Chair in Physiotherapy, Director,
IIMPACT in Health
University of South Australia
Adelaide, South Australia
5th Edition | Acute Pain Management: Scientific Evidence

1189

Psychiatry

Dr Newman L
HarrisClinical Senior Lecturer
University of Sydney
St Leonards, New South Wales

Rehabilitation
Medicine

A/Professor Carolyn
ArnoldHead Pain Management Services, Alfred
Health,Monash University Department ofAnaesthesia & Perioperative Medicine,
Melbourne, VIC Australia

Rheumatology

Dr Raj Vinod Anand

Rural and Remote
Medicine

Dr. Jonathan
Ramachenderan

1190 5th Edition | Acute Pain Management: Scientific Evidence

Rural General Practitioner – Anaesthesia &Palliative Care
Albany Health Campus
Albany, WA

Appendix B: Process report
This is the fifth edition of the book Acute Pain Management: Scientific Evidence. The first edition
was written by a multidisciplinary committee headed by Professor Michael Cousins andpublished by the National Health and Medical Research Council (NHMRC) in 1999.
The second and third editions were written by multiple contributors and a working groupchaired by Professor Pam Macintyre. The editions were approved by the NHMRC and published by
the Australian and New Zealand College of Anaesthetists (ANZCA) and its Faculty of Pain Medicine(FPM) in 2005 and 2010. They were also endorsed by other major organisations worldwide.
As guidelines and key sources of information should be revised as further evidence
accumulates (ideally every 5 years), a fourth edition was written by multiple contributors and aworking group chaired by Professor Stephan Schug and published by ANZCA and its FPM in 2015.
In view of the NHMRC changing its criteria, this edition was not submitted for NHMRC approval,
but it was widely endorsed by many significant national and international organisations - theInternational Association for the Study of Pain (IASP), the Royal College of Anaesthetists and its
Faculty of Pain Medicine, the American Academy of Pain Medicine, the Australian Pain Society,
Australasian College of Sport and Exercise Physicians, the Australasian Faculty of Rehabilitation
Medicine, the College of Anaesthesiologists of the Academies of Medicine of Malaysia andSingapore, the College of Intensive Care Medicine of Australia and New Zealand, the European
Society of Regional Anaesthesia and Pain Therapy (ESRA), the Faculty of Pain Medicine of theCollege of Anaesthetists of Ireland, the Hong Kong College of Anaesthesiologists, the Hong Kong
Pain Society, the Malaysian Association for the Study of Pain, the New Zealand Pain Society, thePain Association of Singapore, PainSA (South Africa), PROSPECT (Procedure SpecificPostoperative Pain Management), the Royal Australasian College of Physicians, the Royal
Australian and New Zealand College of Psychiatrists, the Royal Australasian College of Surgeons
and the South African Society of Anaesthesiologists.
Since the fourth edition was published in 2015, a sizeable amount of new evidence relating
to the management of acute pain has been published. The aim of this fifth edition is, as with thefirst four editions, to combine a review of the best available evidence for acute pain managementwith current clinical and expert practice, rather than to formulate specific clinical practicerecommendations. Accordingly, the document aims to summarise, in a concise, accessible, andeasily readable form, the substantial amount of evidence currently available for the managementof acute pain in a wide range of patients and acute pain settings using a variety of treatment
modalities. It aims to assist those involved in the management of acute pain with the best current(up to at least August 2019) evidence-based information.
It is recognised that while knowledge of current best evidence is important, it plays only apart in the management of acute pain for any individual patient and many factors in addition toscientific evidence should be considered if such treatment is to be effective.
Evidence-based medicine has been defined as “the conscientious, explicit and judicious useof current best evidence in making decisions about the care of individual patients” and that must
“integrate research evidence, clinical expertise and patient values” (Sackett 1995 NR). Therefore
evidence, clinical expertise and, importantly, patient participation (ie including the patient as
part of the treating and decision-making team, taking into account their values, concerns andexpectations) are required if each patient is to get the best treatment. The information provided
in this document is not intended to over-ride the clinical expertise of health professionals. Thereis no substitute for the skilled assessment of each individual patient’s health status,
circumstances and perspectives, which health professionals will then use to help select thetreatments that are relevant and appropriate to that patient.

1192 5th Edition | Acute Pain Management: Scientific Evidence

APPENDIX B

This report provides examples of the decision-making processes that were put in place todeal with the plethora of available evidence under consideration.

Development process
An editorial working group was convened to coordinate and oversee the development process,to edit the reference and also contribute updates to some sections – members were Prof
Stephan Schug, A/Prof Greta Palmer, Prof David Scott, Dr Mark Alcock, Dr Richard Halliwell, andDr Jeff Mott. While all members of the working group contributed to the whole document,
A/Prof Greta Palmer and Dr Mark Alcock provided specific input and expertise to the paediatricsection. This section will remain as Chapter 10 in the PDF of the book, but In view of the largely
increased amount of information in the paediatric section, it will be published as a separate
volume II of the hardcopy of the book.
The editorial working group was assisted by an editorial advisory group comprising Dr MarkRockett, nominated by the Faculty of Pain Medicine, Royal College of Anaesthetists in the United
Kingdom, and Dr Clara Sze Ming Wong, nominated by the Hong Kong College ofAnaesthesiologists.
A large panel of contributors was enlisted to draft sections of the document and amultidisciplinary consultative committee was chosen to review late drafts and contribute more
broadly as required. A list of panel members is attached in Appendix A, together with a list ofcontributing authors and editorial working group members.
Structures and processes for the revised edition were developed, and within theseframeworks, contributors were invited to review the evidence and submit content for specificsections according to their area of expertise. All contributors were given specific instructions
about the process of the literature search and the requirements for submission of their section,
were referred to the website of the NHMRC document How to Use the Evidence: Assessment andApplication of Scientific Evidence (NHMRC 2000 GL), received an electronic copy of the respective
contribution in the fourth edition and were directed to the ANZCA website for copies of the full
fourth edition of the document.
Members of the editorial working group were responsible for the initial editing of eachsection, the evaluation of the literature submitted with the contributions and checking for
further relevant references. In a series of meetings, the editorial working party compiled andedited an initial draft. Once the draft of a section had been prepared, it was returned to therespective contributor for comment before being redrafted for public consultation as well as
review by members of the multidisciplinary panel. To ensure general applicability, there was avery wide range of experts on the contributor and multidisciplinary committee, including
medical, nursing, allied health and complementary medicine clinicians and consumers (seeAppendix A).
Acute Pain Management: Scientific Evidence 5th Edition (Volumes I and II) is based on the
NHMRC’s recommendations for guideline development. That is, this review of the best available
evidence for acute-pain management focuses on improving patient outcomes, includes
statements concerning the strength of levels of evidence underpinning recommendations anduses a multidisciplinary approach involving all stakeholders (including consumers).
Competing interests
Conflicts of interest were managed by the members of the working party responsible for writing
the content of the document by completing an International Committee of Medical Journal
Editors Uniform Disclosure Form for Potential Conflicts of Interest. A list of conflicts of interest isprovided below:
5th Edition | Acute Pain Management: Scientific Evidence

1193Member

Conflicts of interest

Prof Stephan A.
Schug (Chair)

Emeritus Professor and Honorary Senior Research Fellow inAnaesthesiology and Pain Medicine, Medical School, University ofWestern Australia, PerthPrevious Chair of Anaesthesiology at University of Western Australia(retired October 2019); previous Director of Pain Medicine at Royal
Perth Hospital (retired October 2019).
Previous Member of Board of FPMANZCA and various committees of
ANZCA and FPMANZCA (retired May 2020).
Vice Chair of SIG Acute Pain of IASP and previous Chair of SIG AcutePain of ACECC (retired May 2020).
Member of Advisory Board of PROSPECT group, of Faculty of 1000
(F1000), of IASP Taskforce for ICD-11 (Pain), previous Executive
Secretary and member of Board of AOSRA (retired May 2020).
Current recipient of competitive research funding from ANZCA and NHMRC.
The Anaesthesiology Unit of the University of Western Australia
chaired by Prof Schug has received research and travel funding andspeaking and consulting honoraria until October 2019, from then on
Prof Schug personally, from Aspen, bioCSL, Bionomics, Biogen, Emerge,
ESA, Foundry, Gruenenthal, HealthEd, iX Biopharma, Indivior, Janssen
Pharmaceuticals, Luye Pharma, Mundipharma, Pfizer, Seqirus,
Socratec, Therapeutic Guidelines and Xgene over the last 5 years.

A/Prof Greta M.
PalmerPaediatric and Adult Specialist Pain Medicine Physician and Specialist
Anaesthetist, Royal Children’s and Royal Melbourne Hospitals; Deputy
Head of the Children’s Pain Management Service, Royal Children’s
Hospital; Research Associate, Murdoch Childrens Research Institute;
Associate Professor, University of Melbourne, Melbourne.
Travel funding and consultation honorarium from Gruenenthal for
attendance at an international tapentadol paediatric research advisory
meeting.
No further industry support has been received in the last 5 years.

Prof David A. Scott

Professor, University of Melbourne; Director of the Department ofAnaesthesia and Acute Pain Medicine, St. Vincent’s Hospital
Melbourne; Elected Councilor (honorary) to May 2020. Chair ANZCA
Research Committee.
No industry support or funding, either directly or indirectly, has been
received in the last 5 years. Current recipient of competitive researchfunding from ANZCA and the NHMRC.

Dr Mark Alcock

Paediatric Specialist Pain Medicine Physician and Anaesthetist,
Queensland Children’s Hospital; Clinical lead of the Queensland
Interdisciplinary Paediatric Persistent Pain Service, QueenslandChildren’s Hospital; Senior Lecturer, University of Queensland.
No industry support has been received in the last 5 years.

1194 5th Edition | Acute Pain Management: Scientific Evidence

APPENDIX B

Dr Richard
HalliwellDeputy Director of Anaesthesia, Westmead Hospital, Sydney; Directorof Acute Pain Service Westmead Hospital; Clinical Senior Lecturer,
Discipline of Anaesthesia, Sydney Medical School.
No industry support has been received in the last 5 years.

Dr Jeff Mott

Staff Anaesthetist and Specialist Pain Medicine Physician, Clinical lead
Acute Pain Service, Redcliffe Hospital, Senior lecturer, Faculty of
Medicine, University of Queensland
No industry support has been received in the last 5 years.

Editorial Advisory Group
Representative of
FPMRCA:

Consultant anaesthetist and specialist in pain medicine, Plymouth
University Hospitals, Plymouth, UK.

Dr Mark Rockett

Honorary Associate Professor, University of Plymouth, Faculty of
HealthSpeaking and/or consultative honoraria from Pfizer, Grunenthal andAstellas Pharma within the last 5 years. Recipient of competitive
research funding from NIAA and NIHR.

Representative of
Hong Kong CollegeofAnaesthesiologists:
Dr Clara Sze Ming
Wong

Consultant Anaesthetist, Eastern HealthSpecialist in Pain Medicine, Pain Specialists Australia
Melbourne, Australia
No conflicts of interest declared

No disclosures of interests were requested from contributors. Contributors conductedsearches and summarised the new literature and had no influence on the content or thedecisions about inclusion or exclusion of material.

Review of the evidenceThis document is an extensive revision of the fourth edition of Acute Pain Management: Scientific
Evidence published in 2015. Therefore, most of the new evidence included in this fourth edition
has been published from August 2014 onwards, which was the cut-off date of literature inclusionin the fourth edition. Literature was considered when published between this date and the cutoff date for this fifth edition (August 2019). However, in rare circumstances, references publishedafter this cut-off were considered but only if of high relevance and encountered in the editorial
process. These were identified by team members. High-quality evidence-based guidelines had
been published independently by a number of organisations in the areas of acute back andmusculoskeletal pain and recommendations relevant to the management of acute pain weredrawn directly from these.
Search strategies
Searches of the electronic databases Medline or PubMed, Embase and Cochrane wereconducted for each of the main topics included in the review, from August 2014 until August
2019. Searches were limited to articles concerning humans and basic science literature for somesubsections. Included literature was required to be full text, written in English language.
5th Edition | Acute Pain Management: Scientific Evidence

1195The initial searches were inevitably broad, given the very wide scope of the topic. “Pain”,“acute pain”, “postoperative pain” or “analgesia” was searched with the key headings of thevarious sections and subsections of the document such as “neuropathic”, “patient-controlled”,“epidural”, “paracetamol” and so on. For drugs and techniques, a search was also made for“efficacy”, “complications” and “adverse effects”. Hand searches were also conducted of a large
range of relevant journals from August 2014 onwards and bibliographies of relevant papers werechecked to identify references that may not have been identified from database search.
Levels of evidence
Levels of evidence were documented according to the NHMRC designation ( NHMRC 1999 GL) and,as for the second and third edition of this document, clinical practice points have been added.
Levels of evidence
I

Evidence obtained from a systematic review of all relevant randomised controlled
trials.

II

Evidence obtained from at least one properly designed randomised controlled trial

III-1

Evidence obtained from well-designed pseudo-randomised controlled trials (alternate
allocation or some other method)

III-2

Evidence obtained from comparative studies with concurrent controls and allocation
not randomised (cohort studies), case-controlled studies or interrupted time series
with a control group

III-3

Evidence obtained from comparative studies with historical control, 2 or more singlearm studies, or interrupted time series without a parallel control group

IV

Evidence obtained from case series, either post-test or pre-test and post-test

Clinical practice points


Recommendedjbest practice based on clinical experience and expert opinion

Foreign language evidence
Where new systematic reviews or meta-analyses were identified with an English abstract, but
written substantially in another language, these were considered for inclusion if there wasenough information in the abstract to establish it as valid NHMRC Level I evidence. In thisinstance, these were included and then classified as Level I evidence for this review. Similarly,
where relevant, studies with lower hierarchies in a foreign language were also considered, if
there was enough information in the English abstract to establish study validity (eg criticalappraisal score and relevant findings). If there was insufficient information in the abstract toestablish its validity then such references were excluded. Where available in the review team,speakers of the language would be engaged for translation.
Preferred evidence
A review of acute pain management requires a broad focus on a range of topics (eg postoperative
pain, musculoskeletal pain, migraine, pain associated with spinal cord injury etc). This broad
focus inevitably produces a very large number of research publications. In order to provide thebest information to inform practice, it was important to concentrate on the highest ranked,
highest quality evidence where available (eg Cochrane review).

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APPENDIX B

Secondary evidence: High-quality systematic reviews of RCTs (NHMRC Level I) were thepreferred evidence source. Reference lists of such designated Level I evidence were thenscanned for the included RCTs. If these RCTs had also been identified in the literature search,
they were excluded from subsequent analysis as their findings had already been accounted forin the Level I evidence. Relevant RCTs identified in the search, which had not been included in
the systematic reviews or meta-analyses and relevant RCTs published since the cut-off date forliterature inclusion in the systematic reviews or meta-analyses, were included in the update, toprovide additional primary evidence. In case of multiple systematic reviews or meta-analyses
published in parallel, or a lower-ranked meta-analysis published after a previous higher-ranked
one (eg an older Cochrane Review), their results were considered after identification of thenumber of overlapping studies. Cochrane Reviews, which had been withdrawn due to age andlack of an update, were considered in conjunction with subsequently published Level I evidence.
Systematic reviews or meta-analyses that included non-randomised controlled studies wereassigned the level of evidence of their lowest level component studies, as outlined in the NHMRC
designation of evidence levels (NHMRC 1999) and identified by SR following the level of evidenceeg (Roberto 2014 Level III-2 SR).
Primary evidence: Where Level I reviews were not available, the next preferred level ofevidence was RCTs (NHMRC Level II). Where these were not available, other experimental
evidence or case series were accepted as the best available evidence by the guideline developers(reflecting NHMRC Level III and Level IV). According to NHMRC guidelines, Level IV evidence isobtained from case series, either post-test or pretest and post-test; these levels refer to evidence
about interventions (NHMRC 1999 GL). Publications describing results of audits or surveys werealso included as Level IV evidence in the absence of any other higher-level evidence.
Expert opinion: In the few instances where no relevant published evidence was available,
expert opinion was included as the best available information. Narrative reviews containing such
evidence are identified by NR following the reference eg (Graham 2013 NR). Where no opinionbased reviews were available, the guideline writing team (working group) provided expert input.
Other evidence types: Not all evidence relating to the management of acute pain isintervention-based. In a number of instances, best practice has been derived from studies suchas record audit, quality processes or single case reports, pharmacokinetic studies, humanexperimental data and basic science or animal data. These studies were included where relevant
and identified by a research identifier following the reference. Thus readers will find CR (for casereport) eg (Madadi 2010 CR), GL for clinical practice guidelines eg (Kowalski 2011 GL), BS if
presenting basic science or animal data eg (LaCrois-Fralish 2011 BS), PK if presenting
pharmacokinetic studies eg (Holford 2012 PK) and EH if presenting human experimental dataeg (Saxena 2013 EH). The latter two were also assigned an evidence level in line with NHMRC
hierarchy if suitable eg (Williams 2002 Level II PK, n=96, JS 4).
Quality scoring
Systematic reviews and meta-analyses: These studies were not directly assessed for quality
using a critical appraisal instrument by the guideline development team. The quality assessment
was based on the quality criteria that were reported to underpin the review. These were rated
and reported in the following manner, on the assumption that if the study was reported as having
been conducted along the lines of a specific quality approach, then the methodological qualityof the study could be assumed.
• Reviews performed by the Cochrane Collaboration are identified as [Cochrane] in the texteg (Derry 2013 Level I [Cochrane]);• Reviews that overtly state that the review conformed with an evidence-based minimum
set of items for reporting referred to as Preferred Reporting Items for Systematic Reviews
5th Edition | Acute Pain Management: Scientific Evidence

1197

and Meta-Analyses (PRISMA) (Liberati 2009) are identified as PRISMA eg (Moore 2014 Level I[PRISMA]);• Reviews that overtly state that the review conformed with standards previously publishedas Quality of Reporting of Meta-analyses (QUOROM) (Moher 1999), a precursor of PRISMA,
are identified as QUOROM eg (Macedo 2006 Level I [QUOROM]);• Non-Cochrane meta-analyses that did not provide evidence of using PRISMA or QUOROM
quality and reporting methods are only labelled Level I eg (Thorlund 2014 Level I).
• Network meta-analyses are identified as [NMA] eg (Martinez 2017 Level I (NMA),
135 RCTs, n=13,287).
For all systematic reviews and meta-analyses, the number of RCTs for Level I and the numberof studies for all other levels is reported as well as the number of subjects included in these, if
reported or immediately obvious eg (Rabbie 2013 Level I [Cochrane], 9 RCTs, n=4,473); if this is not
the case, the term unspecified is used eg (Hughes 2011 Level IV SR, 5 studies, n unspecified).
Randomised controlled trials: The Jadad scoring instrument was used to score the quality of
all RCTs (Jadad 1996).

Considering the reporting of dropouts throughout trials, a Jadad score point was withheld if
the numbers randomised were greater than the numbers analysed and insufficient explanation
was provided. No dropouts were assumed if the text did not state this, but the descriptive
reporting was comprehensive (ie 60 started, 60 finished, 60 analysed, therefore assume no
dropouts). If there were obvious dropouts (i.e. 60 in, 56 completed), reviewers sought
information on the percentage completing the study, and the analysis approach, which wastaken to account for the dropouts.
In addition to the Jadad score, the number of patients randomised (prior to dropouts) is
reported for all Level II references eg (Chan 2010 Level II, n=4,484, JS 5).
No quality evaluation was undertaken for lower ranked evidence (Level III and Level IV), when
this was the highest available level of evidence. However, the number of patients or events
included is reported if obvious in the publication and the size of the study subtracts from, or adds
to, the quality of the evidence eg (Morton 2010 Level IV, n=5,065).

1198 5th Edition | Acute Pain Management: Scientific Evidence

APPENDIX B

Thus, this document is underpinned by the highest level, highest methodological quality
evidence available for each review question.
Conflicting evidence
If evidence was consistent, the most recent, highest hierarchy and highest quality referenceswere used. If evidence was conflicting, the same approach was taken (identifying highest level,
highest quality evidence), however examples were given of differences within the literature sothat readers could appreciate the ongoing debate. In some instances, particularly in acute pain
management in various patient populations, evidence was limited to case reports only, which
was made clear in the document as the best available evidence in this instance.
Cost analyses
The area of acute-pain management remains remarkably deficient in research on costs andhealth economics, one obvious example is the costs associated with the adverse effects oftreatment. Where available, relevant health economic information was reported to assist
clinicians to better manage both pain and some of the adverse effects of treatment, as well as
better individualise treatment for each patient, and to minimise overall expenditure. This is again
noted as an area warranting further research.
Key messages
These levels of evidence were also used for the key messages, which are presented in order oflevel of evidence from the highest to the lowest. Key messages referring to information extracted
from Cochrane meta-analyses or systematic reviews were marked “Level I [Cochrane Review]”,
and these were listed first, followed by those marked “Level I [PRISMA]” and “Level I[QUOROM]”. The listing of key messages continued then with those derived from systematic
reviews not adhering to these standards, which were marked “Level I” and then followed by key
messages in descending level of evidence. At each level, key messages based on systematic
reviews or meta-analyses are listed before those based on studies at this level, eg key messages
based on “Level III-2 SR” were listed before those based on “Level III-2” studies.
Updating the evidence base from the fourth edition of the guidelines
There is no standard approach to updating wording or strength of evidence of existing guideline
recommendations (Vernooij 2014 GL). The system used by Johnston et al, as applied to the
updating process in the fourth edition of these guidelines, was again used in this update to reflect
the implications of new evidence on clinical recommendations when reviewed and changed as
required (Johnston 2003). The guideline team found this approach to be simple andstraightforward when considering the implications of new research, layered onto existing
recommendations. To indicate New, Unchanged, Strengthened, Weakened, Qualified andReversed in the key messages, the bolded letters N, U, S, W, Q and R respectively were used —see table below for examples.

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1199

Review and revision of key messages
New

New evidence leads to new key message(s).

Unchanged

The new evidence is consistent with the data used to formulate the original
key message. The key message in the original report remains unchanged.

Strengthened

The new evidence is consistent with the data used to formulate the original
key message. The key message in the original report remains unchanged or
expanded. The level of evidence and/or content of the key message in theoriginal report has been strengthened to reflect this additional evidence.

Weakened

The new evidence is inconsistent with the data used to inform the original
key message(s). However, the new evidence does not alter the key
message but weakens the level of evidence.

Qualified

The new evidence is consistent with the data used to formulate the original
key message. The key message in the original report remains unchanged
but applicability may be limited to specific patient groups/ circumstances.

Reversed

The new evidence is inconsistent with the data used to inform the original
key message(s). The strength of the new evidence reverses the conclusionsof the original document.

Note

Clinical and scientific judgment informed the choices made by the Working
Party members; there was no mandatory threshold of new evidence (egnumber of studies, types of studies, magnitude of statistical findings) that
had to be met before classification of categories occurred.
The first letter of each of the words (N for New, U for Unchanged etc) wasused to denote the classification, and changes (if any) from the last editionof this document.

An example of the use of this system is taken from the key messages in Section 4.2.3.

KEY MESSAGES
1. Topical NSAIDs are effective in treating acute strains, sprains or sports injuries withsystemic adverse effects comparable to placebo; gel formulations show superior efficacy
over creams (S) (Level I [Cochrane Review]).
2. Topical NSAIDs are of limited analgesic efficacy for traumatic corneal abrasions, but
reduce rescue analgesia requirements (W) (Level I [Cochrane Review]).
3. Topical NSAIDs reduce anterior chamber inflammation and thereby pain after cataract
surgery (N) (Level I [PRISMA]).
4. The efficacy of NSAIDs for peri- or intra-articular injection as a component of local
infiltration analgesia compared with systemic administration remains unclear (U)(Level I [PRISMA]).

1200 5th Edition | Acute Pain Management: Scientific Evidence

APPENDIX B

Where the new evidence led to reversal of a conclusion and key message, this was noted ina green text box and labelled R in the key message. For example, this appears in the text:
Note: reversal of conclusion
This reverses the Level I key message in the previous edition of this document; a precedingmeta-analysis had described no effect of hypnosis on postoperative pain scores.
and the related key message reads:
3. Hypnosis may reduce … postoperative pain (R) (Level I) …. .
Drug names
This document uses the generic names of drugs that apply in Australia and New Zealand(Australian Approved Names [AAN]); the Therapeutics Goods Administration (TGA) has updated
medicine ingredient names in 2015 and where applicable, the new names in accordance withthis update have been used (TGA 2015 GL). Where this name differs from the International
Nonproprietary Name (INN) or the United States Adopted Name (USAN), these are given inbrackets on first use within each of the chapters.

Bibliographic citations
Citations and bibliographic style are based on a modified Harvard (Author-Date) style. In-text
citations use the format “First Author” then “Year of Publication” eg ( Madden 2012). A decision
was made to omit “et al” for in-text citations that had more than one author, for brevity andimproved readability. Multiple references supporting one statement are listed in order of levelof evidence and within each level from newest to oldest eg (Chan 2011 Level II, n=423, JS 5; Wylde
2011 Level IV, n=1,334; Haroutiunian 2013 NR; Macrae 2008 NR; Kehlet 2006 NR).
Small letters further qualify multiple publications by the same first author in the same year
in in-text citations eg (Anderson 2014a) (Anderson 2014b) as in the reference lists eg
Anderson BJ & Dare T (2014b) We need to confirm, not relearn old information. Paediatr Anaesth 24(6): 549–52.

Web pages are shown with their uniform resource locator (URL) and the date assessed by amember of the Working Group.

Public consultation
Following finalisation of the draft its availability was advertised through ANZCA and FPMANZCA
by direct e-mail to all fellows and through college and faculty publications and social media.
The public consultation period was from 16 September 2020 to 16 October 2020. The draft wasmade available on a website (https://www.anzca.edu.au/news/top-news/acute-painmanagement-scientific-evidence-5th-edit) and Colleges of many of the contributors andmultidisciplinary consultative committee members were notified of the availability of the draft
and asked to disseminate this information to their members.

5th Edition | Acute Pain Management: Scientific Evidence

1201

Submissions and comments were received from the following 18 individuals, some of them
representing organisations:Name

Affiliation

Dr Caroline Ariaens

Specialist Anaesthetist, Waikato Hospital
Hamilton, New Zealand

Dr Richard Barnes

Melbourne, Victoria

Dr Kirsty Belfrage

Bendigo, Victoria

Dr Michael Clifford

Consultant Anaesthetist & Paediatric Intensivist
Department(s) of Paediatric Intensive Care, Anaesthesia
and Pain Management, The Royal Children's Hospital
Melbourne, Victoria

Michele Cree

Pharmacist Lead – Critical Care
Queensland Children’s HospitalSouth Brisbane, Queensland

Dr Suran Dhanapala

Pain Specialist, Ballarat Hospital
Ballarat, Victoria

Dr Darren Emerick

VMP, Sunshine Coast Hospitals
Queensland

Dr Sarah Flint

Medical Lead, Critical Care and Perioperative Services
The Queen Elizabeth Hospital
Adelaide, South Australia

Dr Mike Foss

Specialist Anaesthetist and Pain Physician, Waikato
Hospital
Hamilton, New Zealand

Dr Chris Hattingh
Dr Kim Hattingh

Pain Physician, Bendigo Health
Bendigo, Victoria

Dr Christine Huxtable

Consultant Anaesthetist
Acting Head, APS,
Royal Adelaide Hospital, South Australia

Dr Anju Tessa James

Consultant in Pain Medicine, The Townsville Hospital,
Townsville, Queensland

1202 5th Edition | Acute Pain Management: Scientific Evidence

APPENDIX B

Prof Pam Macintyre

Professor of Anaesthesia and Pain Medicine, University of
Adelaide,
Consultant in Anaesthesia and Pain Medicine, Royal
Adelaide Hospital,
Adelaide, South Australia

Claire Morgan

Associate Director, Medical Affairs
Seqirus (Australia) Pty Ltd
Melbourne, Victoria

Prof Michael Paech

Emeritus Professor of Obstetric Anaesthesia, University ofWestern Australia
Perth, Western Australia

Dr Alette Roux
Michael Sargent

AFT Pharmaceuticals
Takapuna, New Zealand

Topics raised
The main topics raised in these submissions and comments related to:•

Additional websites with information about breastfeeding;•

Additional information re paediatric dosing and use of units;•

Additional information on changed medication names;•

Correction of typographical errors and suggestions for improved layout;•

Improvement of information and inclusion of additional references on perioperative
methadone;•

Effects of NASAIDs on healing;•

Information on TGA regulated Good Manufacturing Practice compounded solutions
available in Australia under Schedule 5a;•

Neurotoxicity and IT use of clonidine in labour analgesia;•

Combinations of paracetamol and NSAIDs;•

Use of slow release opioids in acute pain including suggestions of additional references;•

Toxicity of alpha-2-delta agonists including suggestions of additional references.

These submissions and comments and additional submissions and comments by the membersof the multidisciplinary advisory committee (see listing in Appendix A) were considered by theeditorial working group and resulted in changes to the document presented for public
consultation if appropriate and necessary before finalising this edition.

5th Edition | Acute Pain Management: Scientific Evidence1203

Implementation, dissemination and revision
The Australian and New Zealand College of Anaesthetists (ANZCA) and its Faculty of Pain
Medicine (FPM) will be responsible for the dissemination, implementation, and updating of thisdocument. The document will be initially available on the internet via the ANZCA website(formatted to allow for downloading and printing as a PDF) as well as later in hard copy.
ANZCA will also notify other Colleges and professional groups and organisations of theavailability of the document and ask them to disseminate the information to their members. In
addition, information will be sent to relevant national and international organisations with therequest to endorse this document and to distribution this information to their members. This isfurther expected to heighten awareness of the availability of this document. It will also be
promoted at relevant professional meetings and conferences and by editorials in professional
journals.

References
Jadad AR, Moore RA, Carroll D et al (1996) Assessing the quality of reports of randomized clinical trials: is blinding
necessary? Control Clin Trials 17(1): 1–12.
Johnston ME, Brouwers MC & Browman GP (2003) Keeping cancer guidelines current: results of a comprehensive
prospective literature monitoring strategy for twenty clinical practice guidelines. Int J Technol Assess Health Care19(4): 646–55.
Liberati A, Altman DG, Tetzlaff J et al (2009) The PRISMA statement for reporting systematic reviews and meta-analysesof studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339: b2700.
Moher D, Cook DJ, Eastwood S et al (1999) Improving the quality of reports of meta-analyses of randomised controlled
trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet 354(9193): 1896–900.
NHMRC (1999) A guide to the development, evaluation and implementation of clinical practice guidelines.
https://www.nhmrc.gov.au/guidelines-publications/cp30 Accessed 29 August 2015
NHMRC (2000) How to use the evidence: assessment and application of scientific evidence.
https://www.nhmrc.gov.au/guidelines-publications/cp69 Accessed 29 August 2015
Sackett DL & Rosenberg WMC (1995) The need for evidence-based medicine. Journal of the Royal Society of Medicine
88(11): 620–24.
TGA (2015) Updating medicine ingredient names - list of affected ingredients. https://www.tga.gov.au/updatingmedicine-ingredient-names-list-affected-ingredients Accessed 13 June 2020
Vernooij RW, Sanabria AJ, Sola I et al (2014) Guidance for updating clinical practice guidelines: a systematic review ofmethodological handbooks. Implement Sci 9: 3.

1204 5th Edition | Acute Pain Management: Scientific EvidenceAcronyms and abbreviations
5-HT

5-hydroxytriptamine (serotonin)AA

auricular acupuncture

AAN

Australian Approved Names

AAP

American Academy of Paediatrics

AAPD

American Academy of Paediatric Dentistry

AAPM

American Academy of Pain Medicine

ACB

adductor canal blockACE

angiotensin-converting enzyme

ACT

acceptance and commitment therapy

ACTH

adrenocorticotrophic hormone

ADH

antidiuretic hormone

ADHD

attention deficit hyperactivity disorderAHI

apnoea-hypopnoea index

AIDS

acquired immunodeficiency syndrome

AKI

acute kidney injury

ALA

adrenaline, lignocaine, amethocaine

AMPA

α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate

ANZCA

Australia and New Zealand College of Anaesthetists

APS

acute pain service

ASA

American Society of Anesthesiologists

ASIC

acid-sensing ion channel

ASRA

American Society of Regional Anesthesia and Pain Medicine

ATPadenosine triphosphatebd

twice daily dosing

BDNF

brain-derived neurotrophic factor

BIS

Bispectral Index (depth of anaesthesia)

BK

bradykinin

BMI

body mass index

BPS

Behavioural Pain Scale

CABG

coronary artery bypass graft

CAGE“cut-annoyed-guilty-eye” screening questionnaire for problematic alcohol use

CAIPchannelopathy-associated insensitivity to pain

CaLD

culturally and linguistically diverse

CAM

complementary and alternative medicine

CB1cannabinoid type 1

CB2

cannabinoid type 2

CBT

cognitive behavioural therapy

1206 5th Edition | Acute Pain Management: Scientific Evidence

ACRONYMS AND ABBREVIATIONS

CCKcholecystokinin

CCL3chemokine (C-C motif) ligand 3

CGRP

calcitonin gene-related peptide

CHEOPSChildren's Hospital of Eastern Ontario Pain Scale

CIPA

congenital insensitivity to pain with anhydrosis

CIPN

chemotherapy-induced peripheral neuropathy

CKD

chronic kidney disease

Cmax

maximum serum concentration

CNCP

chronic non-cancer related pain

CNS

central nervous system

CO2carbon dioxide

COMT

catechol-O-methyltransferase

COPD

chronic obstructive pulmonary disease

COX-2

cyclooxygenase-2

CPAP

continuous positive airway pressure

CPM

continuous passive movement

CPNB

continuous peripheral nerve block

CPNC

continuous peripheral nerve catheters

CPOT

Critical-Care Pain Observation Tool

CPSP

chronic postsurgical painCR

controlled-release

CRIES

Cries, Requires oxygen, Increased vital signs, Expression, Sleeplessness

CRPS

chronic regional pain syndrome

CSE

combined spinal epidural

CSF

cerebrospinal fluid

CSI

central sensitisation inventoryCTcomputer tomography

CTG

cardiotocograph

d

day

DALY

disability-adjusted life years

DAMP

damage-associated molecular patternDHE

dihydroergotamine

DIS

daily interruption of sedation

DLF

dorsolateral funiculus

DN 4

Douleur Neuropathique 4

dNCR

delayed neurocognitive recovery

DNIC

diffuse noxious inhibitory control

DRG

dorsal root ganglia

DRtdorsal reticular nucleus
5th Edition | Acute Pain Management: Scientific Evidence

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EA

Electro acupuncture (in paediatrics: Emergence agitation)

EBP

epidural blood patch

EC50

Half maximal effective concentration

ECF

extracellular fluid

ECG

electrocardiogramED

emergency department

EDIN

Échelle Douleur Inconfort Nouveau-Né

EEG

electroencephalogrameg

for example (exempli gratia)

EMA

European Medicines Agency

EMG

electromyelographERAS

enhanced recovery after surgery

ERCP

endoscopic retrograde cholangiopancreatography

ERD

erosive reflux disease

EREM

extended-release epidural morphineESeffect size

ESA

European Society of Anaesthesiology

ESI

epidural steroid injection

ESPB

erector spinae plane block

ESRA

European Society of Regional Anaesthesia and Pain Medicine

EVENDOL

Evaluation ENfant DOuLeur

FANS

Faceless Acute Neonatal Pain Scale

FAS

Functional Activity Scale

FBSF

fentanyl buccal soluble film

FBT

fentanyl buccal tablets

FDA

Food and Drugs Administration (USA)FLACC

Faces, Legs, Activity, Cry and Consolability

fMRI

functional magnetic resonance imaging

FNB

femoral nerve block

FPM

Faculty of Pain Medicine

FPS

Faces Pain Scale

FPS-R

Faces Pain Scale-Revised

g

gram

G

Gauge

G-CSF

granulocyte-colony stimulating factor

GABA

gamma-amino butyric acid

GANB

greater auricular nerve block

GDNF

glial-derived neurotrophic factor

GFR

glomerular filtration rate

1208 5th Edition | Acute Pain Management: Scientific Evidence

ACRONYMS AND ABBREVIATIONS

GM-CSF

granulocyte macrophage-colony stimulating factor

H3Ghydromorphone-3-glucuronide

h

hour

HIV

human immunodeficiency virus

HLheel lance

HRVheart rate variability

HSAN

hereditary sensory and autonomic neuropathyIA

intra articular

IASP

International Association for the Study of Pain

ICintercostal

ICB

intercostal block

ICD

International Classification of Diseases

ICF

intracellular fluid

ICU

intensive care unit

ICV

intracerebroventricularID

intellectual disability

iethat is (id est)ILinterleukinIMintramuscular(ly)INintranasal(ly)INNInternational Nonproprietary Name

INR

International Normalised Ratio

INRS

Individualised Numeric Rating ScaleIR

immediate-releaseITintrathecal(ly)IVintravenous(ly)IVRAintravenous regional anaesthesia

JIA

juvenile idiopathic arthritis

LANSS

Leeds Assessment of Neuropathic Symptoms and Signs

LAST

local anaesthetic systemic toxicity

LBP

low back pain

LEA

lumbar epidural analgesia

LIA

local infiltration analgesia

LLLT

low-level laser therapy

LMWH

low molecular weight heparin

LTP

long-term potentiation

M1

O-desmethyltramadol

M3G

morphine-3-glucuronide

M6G

morphine-6-glucuronide
5th Edition | Acute Pain Management: Scientific Evidence

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MAM

monoacetylmorphine

MBI

mindfulness-based interventions

mcg

microgram(Note: In handwritten scripts microg or microgram should be used to
avoid errors in line with NSQHS standards)

MDMA

N-Methyl-3,4-methylenedioxyamphetamine (ecstasy)

MDR

multidrug resistance protein

MEDmorphine equivalent doseminminutemg

milligrammGluR

metabotropic glutamate receptor

MHRA

Medicines and Healthcare Products Regulatory Agency (UK)mL

millilitre

MLAC

minimum local anaesthetic concentration

mm

millimetreMMEmorphine mg equivalents

MPQ

McGill Pain Questionnaire

MRImagnetic resonance imaging

MS

multiple sclerosis

N-PASS

Neonatal Pain, Agitation and Sedation Scale

mth

month

N2O

nitrous oxide

NAC

N-acetylcysteine

NAPBQI

N-acetyl-p-benzoquinone imineNAS

neonatal abstinence syndromeNCA

nurse-controlled analgesia

NCAPC

Non-Communicating Adult Pain Checklist

NCCPC-PV Non-Communicating Children’s Pain Checklist — postoperative version
NCCPC-R

Non-Communicating Children’s Pain Checklist

NFCS

Neonatal Facial Coding Scalengnanogram

NGF

nerve growth factor

NHMRC

National Health and Medical Research Council

NICU

neonatal intensive care unit

NIPS

Neonatal Infant Pain Scale

NIRSnear infrared spectroscopy

NK1

neurokinin-1

NMDA

N-methyl-D-aspartate

NNH

number needed to harm

NNS

non-nutritional sucking

1210 5th Edition | Acute Pain Management: Scientific Evidence

ACRONYMS AND ABBREVIATIONS

NNT

number needed to treat

NOAC

new oral anticoagulant

NPQ

Neuropathic Pain Questionnaire

NRS

numerical rating scale

NSAID

nonsteroidal anti-inflammatory drug

NSAID-ERD NSAID-exacerbated respiratory diseasensNSAID

nonselective non-steroidal anti-inflammatory drug

OCT1

organic cation transporter

ODI

Oswestry Disability Index

ODT

orally disintegrating tablet

OHS

obesity hypoventilation syndrome

OIH

opioid-induced hyperalgesia

OIVI

opioid-induced ventilatory impairment

ONJ

osteonecrosis of the jaw

OPRM1

opioid receptor mu-1

ORT

opioid risk tool

OSA

obstructive sleep apnoea

OST

opioid substitution therapy

OTFC

oral transmucosal fentanyl citrate

OUD

opioid use disorder

P2X3

purinergic receptor subtype

PaCO2

Partial pressure of carbon dioxide in arterial blood

PACU

postanaesthesia care unit

PAG

periaqueductal grey

PaO2

Partial pressure of oxygen in arterial bloodPAR

proteinase-activated receptor

PBM

photobiomodulation

PCA

patient-controlled analgesia

PCC

percutaneous cervical cordotomy

PCEA

patient-controlled epidural analgesia

PCINA

patient-controlled intranasal analgesia

PCS

Pain Catastrophising Scale

PDA

patent ductus arteriosus

PDMP

Prescription Drug Monitoring Program

PDPH

postdural puncture headache

PET

positive emission tomography

PGB

pelvic girdle pain

PGE2

prostaglandin E2

PGI2

prostacyclin
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PICC

peripherally inserted central catheter

PICU

paediatric intensive care unit

PIEB

programmed intermittent boluses

PIPP

Premature Infant Pain Profile

PMA

postmenstrual age

PNB

peripheral nerve block

PND

perioperative neurocognitive disorders

PNS

peripheral nerve stimulationPO

per ora (oral route)

POCD

postoperative cognitive dysfunction

POD

postoperative day

PON

postoperative nausea

PONS

postoperative neurological symptoms

PONV

postoperative nausea and vomiting

POV

postoperative vomiting

PPDA

postoperative pain days averted

PPI

proton pump inhibitor

PPP

Paediatric Pain Profile

PPPM

Parents Postoperative Pain MeasurePR

per rectum (rectal route)prn

pro re nata (as needed)

PROSPECT PROcedure-SPECific postoperative pain management
PSF

posterior spinal fusion

PTA

Polymyxin E, tobramycin and amphotericin B

PTSD

post-traumatic stress disorder

PVB

paravertebral block

QALY

quality-adjusted life years

QI

quality improvementqidfour times daily dosing

QoL

quality of life

QoR

quality of recovery

QST

quantitative sensory testing

RANKL

receptor activator of nuclear factor kappa-B ligand

RAP

recurrent abdominal pain

RASS

Richmond Agitation-Sedation Scale

RCT

randomised controlled trial

REMS

Risk Evaluation and Mitigation Strategy

RFIDradiofrequency identification

RID

relative infant dose

1212 5th Edition | Acute Pain Management: Scientific Evidence

ACRONYMS AND ABBREVIATIONS

ROP

retinopathy of prematurity

RSB

rectus sheath blockrTMS

repetitive transcranial magnetic stimulation

RVM

rostroventromedial medullassecondSACD

subacute combined degeneration

SAS

Sedation-Agitation Scale

SC

subcutaneous(ly)SCCspinal cord compression

SCD

sickle cell disease

SCI

spinal cord injury

SDB

sleep-disordered breathing

SF-36

Short Form 36 of Medical Outcomes Study

SF-MPQ

Short Form of McGill Pain Questionnaire

SHORE

Social and Health Outcomes Research and Evaluation

SIADH

Syndrome of inappropriate antidiuretic hormone secretion

SIP

Sickness Impact ProfileSL

sublingual(ly)SNPsingle-nucleotide polymorphism

SNRI

serotonin–norepinephrine-reuptake inhibitors

SOAPP-R

Screener and Opioid Assessment for Patients with Pain-Revised

SPID

summed pain intensity differenceSRslow-release

SRE

skeletal related events

SRW

standardised regression weights

SSRI

selective serotonin-reuptake inhibitor

SSTS

sublingual sufentanil tablet system

SUD

substance use disorder

SUNCT

Short-lasting Unilateral Neuralgiform headache attacks with Conjunctival injection
and Tearing

t1/2keotime taken to achieve 50% effect-site concentration (with plasma concentrations at
steady state) or defined in paediatrics as the equilibration halftime between
plasma and effect compartment

TAPB

transversus abdominis plane block

TBSA

total body surface area

TCA

tricyclic antidepressantTDtransdermal(ly)TdP

Torsades de Pointes

tds

three times daily dosing (ter die sumendum)

TEA

thoracic epidural analgesia
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TEAS

transcutaneous electrical acupoint stimulation

TENS

transcutaneous electrical nerve stimulation

TGA

Therapeutic Goods Administration

THA

total hip arthroplasty

THC

tetrahydrocannabinol

TIRF

transmucosal immediate-release fentanyl medicines

TKA

total knee arthroplasty

Tmax

time to reach maximum serum concentration

TMD

temperomandibular disorder

TMJ

temporomandibular joint

TNF

tumour necrosis factor

TNS

transient neurological symptoms

TOTPAR

total pain relief

TrkA

tyrosine kinase receptor

TRP

transient receptor potential

TRPV1

transient receptor potential vanilloid 1

TTH

tension-type headache

URL

uniform resource locatorUSultrasoundUSA

Unites States of America

US$

USA dollar

USAN

United States Adopted Name

VATS

video-assisted thoracic surgery

VAS

visual analogue scale

Vdvolume of distribution

VDS

verbal descriptor scale

VIGOR

Vioxx Gastrointestinal Outcomes Research

VNRS

verbal numerical rating scaleVOC

vaso-occlusive crisis

VPL

ventral posterolateral nucleus of the thalamus

VPM

ventral posteromedial nucleus of the thalamus

VRvirtual reality

VZV

varicella-zoster virus

WBFPRS

Wong-Baker Faces Pain Rating Scale

WHO

World Health Organization

WISP

withdrawal-associated injury site pain

wk

week

WOMAC

Western Ontario and McMaster Universities Osteoarthritis Index

y

year

1214 5th Edition | Acute Pain Management: Scientific Evidence

ACRONYMS AND ABBREVIATIONS

Methodological and statistical terms
aHR

adjusted hazard ratioaORadjusted odds ratioaRRadjusted relative risk

BSbasic science or animal data

CCTcase-controlled trial

CI

confidence interval

CPG

clinical practice guidelineCRcase report

EH

experimental human studiesGLclinical practice guidelineHRhazard ratio

IRR

incidence rate issue

JS

Jadad Score

MD

mean difference

NMA

network meta-analysis

NNH

number-needed-to-harm

NNT

number-needed-to-treatNRnarrative review

ORodds ratioPKpharmacokinetic study

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

QUOROM Quality of Reporting of Meta-analysesrcorrelation coefficient

RCT

randomised controlled trialRDrisk difference

RR

relative risk

SMD

standardised mean differenceSRsystematic review

SRW

standardised regression weights

WMD

weighted mean difference

5th Edition | Acute Pain Management: Scientific Evidence

1215Indexabdominal aortic surgery ........................................................ 319

anticoagulants................................................................. 361–364

abdominal migraine ..............................................................1086

anticonvulsants ................................................................ 194-199
herpes zoster .................................................................. 534
older patients .................................................................. 764
multiple sclerosis ............................................................ 560
spinal cord injury pain ..................................................... 515

abdominal pain................................................................ 529–533
analgesia and the diagnosis ............................................ 529
acute ....................................................................... 529–533
children
acute......................................................................1085
recurrent [abdominal migraine] ............................1086
emergency department .................................................. 611
prehospital analgesia ...................................................... 621
Aboriginal and Torres Strait Islander
peoples............................................................................ 772–776
acetaminophen see paracetamol
acupuncture and acupressure ......................................... 444–451
children ............................................................... 1097–1098
pelvic–girdle pain ........................................................... 721
acute pain services ..............................................................90–93
economic evaluation ...................................................95–96
addiction ......................................................................... 806-823
adductor canal block ....................................................... 346–347
adjuvants
caudal .................................................................. 1007–1010
epidural ............................................................... 1006–1007

antiemetics ....................................................... 143-146, 409-410
migraine .......................................................................... 549
antiviral ................................................................................... 535
anxiety ...................................................................... 12-15, 17-19
anxiolytics ............................................................................... 628
arnica ...................................................................................... 228
assessment see pain assessment
asthma ............................................................................ 116, 711
attention ................................................................................... 12
attention deficit hyperactivity disorder ................................... 916

adrenaline (epinephrine) ........................................................ 203
children .........................................................................1008

attentional techniques .................................................... 436–437
children ............................................................... 1098–1099

agitation .......................................................................... 605–606

autism spectrum disorder ....................................................... 901

alcohol dependence ............................................................... 827

back pain ....................................... 83-84, 112, 192, 219, 328, 578
acupuncture and acupressure .................................. 444-448
pregnancy ....................................................................... 721
TENS ................................................................................ 443

alfentanil (paed) ..................................................................... 938
allergic reactions [hypersensitivity]
childrencoxib ....................................................................... 927
nsNSAIDs ................................................................ 924
paracetamol ........................................................... 914
coxibs ............................................................................. 120
NSAIDs ............................................................................ 116
nsNSAIDs ........................................................................ 116

balloon kyphoplasty (paed) ................................................... 1069
beliefs .................................................................................. 12-15
benzodiazepine ............................................................... 632-635
dependence .................................................................... 828
biliary colic .............................................................................. 531

allodynia ................................................................................... 64

biofeedback ............................................................................ 732
children ......................................................................... 1099

allometric dosing/scaling(paed) .................................................... 910, 926, 930, 944, 1094

bisphosphonates ............................................................. 208, 595

alpha-2 agonists .............................................................. 200–206
children ................................................................... 965–971
alpha-2-delta ligands see gabapentin, pregabalin
alvimopan............................................................................... 146
amantadine ............................................................................ 186
amitriptyline
antidepressant......................................................... 191–193
cancer ............................................................................. 588
children .........................................................................1068
phantom limb pain ......................................................... 487
analgesic rebound headache .................................................. 557
anastomotic leakage
coxibs ............................................................................. 121
epidural analgesia........................................................... 316
nsNSAIDs ........................................................................ 117
antibiotics ......................................................... 565, 568, 570-571

i1

antidepressants ............................................................... 191-193
cancer pain ...................................................... 586, 588-589
fibromyalgia .................................................................... 192
neuropathic pain ..................................................... 191–193
older patients .......................................................... 763–764
postoperative pain .......................................................... 191
spinal cord injury pain ............................................. 514–515

5th Edition | Acute Pain Management: Scientific Evidence

blood sampling in neonates ........................................ 1031–1036
bone cancer See cancer painbone healing
coxibs .............................................................................. 120
NSAIDs .................................................................... 116, 964
bone marrow aspiration in children ............................ 1040–1042
botulinum toxin ...................................................................... 225
children ......................................................................... 1042
bowel obstruction, malignant ................................................. 596
breastfeeding/supplemental breastmilk[as an analgesic intervention] (paed) ................................... 1032
breast pain .............................................................................. 751
buccal route ............................................................................ 311
bupivacaine...................................................................... 166-173
children ......................................................................... 1001
labour pain ...................................................................... 728
combined with opioids .................................... 153, 159–160

INDEX

buprenorphine ........................................................ 133–135, 832
children ................................................................... 944–945
perineural ....................................................................... 160
sublingual ................................................................ 294, 312
transdermal ......................................................295, 304-305
burns injury pain ............................................................. 524–528
children .........................................................................1076
analgesic prescribing practices ..............................1078
background ............................................................1077
nonpharmacological interventions ........................1079
nonpharmacological interventions forphysiotherapy ........................................................1077
patterns of pain .....................................................1078
prehospital ............................................................1077
pruritus ..................................................................1079
psychological impact .............................................1077
caesarean section ............................................................ 733–739
calcitonin ........................................................................ 207–208,
cancer pain ..................................................................... 596
phantom limb pain ......................................................... 487
cancer pain ...................................................................... 580–602
assessment ..................................................................... 580
bone cancer ............................................................. 591–596
breakthrough pain ............................................311-312, 587
children ............................................................... 1064–1070
ketamine ..........................................................183, 585-586
neuropathic .................................................................... 585
postoperative ................................................................. 592
principles of management ....................................... 580–581
procedural .......................................................................590

dexmedetomidine ................................................... 967–969
hypnosis ........................................................................ 1098
ketamine ................................................................. 959–965
lumbar puncture ........................................................... 1035
migraine .............................................................. 1081–1085
mucositis ............................................................. 1067–1068
nsNSAIDs ......................................................................... 918
opioids ............................................................................ 928
infusions .......................................................... 977–985
nurse-controlled analgesia .............................. 982–983
patient-controlled analgesia............................ 979–982
patient-controlled analgesia by proxy ................... 983
safety of parenteral use ........................................ 984
pain assessment ...................................................... 891–906
cognitive impairment .............................................. 899
composite scales ............................................. 904–905
intellectual disability ............................... 899–902, 906
observational and behavioural scales ...................... 895
self report ....................................................... 896, 905
paracetamol .................................................................... 907
dosing.............................................................. 910–911
procedural pain ................................................... 1031–1063
regional analgesia ................................................. 986–1030
topical therapies ........................................................... 1018
tramadol ................................................................. 938–943
chlorhexidine .......................................................................... 329
chronic postsurgical pain ................................... 21–32, 36, 97-98
characteristics ................................................................... 23
epidemiology ......................................................... 21, 24-27
prevention .............. 28-31, 164-165, 175, 182, 320, 348-349
syndromes ............................................................... 489-493
circumcision ............................................................................ 189

cancer surgery ................................................................. 316–317

cleft lip/palate surgery (paed) ............................................... 1026

cannabinoids ................................................................... 209–213
addiction ........................................................................ 828
spinal cord injury pain .................................................... 515

clonidine .......................................................................... 200-205
children ........................................................................... 966
intrathecal ........................................................ 201-206, 341

carbamazepine ................................................................ 198, 563

cluster headache ..................................................................... 553

cardiac effects of systemic opioids .................................. 142–143

CNS-stimulant drugs ............................................................... 829

cardiac pain ..................................................................... 538–539
prehospital analgesia ...................................................... 629

Codeine ................................................................... 127, 293, 584
breastfeeding .......................................................... 127, 743
children ........................................................................... 932
metabolism ....................................................................... 47
neurosurgery............................................................ 506-507

cardiac surgery ................................................................ 320–321
acupuncture ................................................................... 446
children .........................................................................1024
cardiovascular adverse effects
childrennsNSAIDs ................................................................ 924
paracetamol ........................................................... 913
coxibs ...................................................................... 119–120
nsNSAIDs ........................................................................ 115
opioids ..................................................................... 142-143
catastrophising ......................................................... 12–14, 24-25
caudal analgesia in children ......................................... 1002–1006
adjuvants .......................................................................1007
channelopathy-associated insensitivity to pain ........................ 43
chemotherapy-induced peripheral neuropathy ................... 589–590
chest drain removal in children .............................................1044
childrenacupuncture ........................................................ 1097–1098
cancer pain .......................................................... 1064–1070
clonidine ..........................................................................966
complementary and alternative medicines ........ 1096–1101
consequences of early pain and injury ..................... 888–890
corticosteroids ......................................................... 973–975
coxibs ...................................................................... 926–928
developmental neurobiology of pain ....................... 885–887

cognitive-behavioural interventions ....................... 434, 437–438
children ............................................................... 1060–1061
cognitive impairment ................................................ 70, 756-757
children .................................................................... 899-900
compartment syndrome ......................................................... 419
children ......................................................................... 1016
complementary and alternative medicine ...................... 227–231
children ................................................................ 1096-1101
aromatherapy ....................................................... 1096
DHEA ..................................................................... 1097
fish oil.................................................................... 1097
ginger .................................................................... 1097
turmeric ................................................................ 1097
vitamin B 1 ............................................................ 1097
vitamin D ............................................................... 1097
zinc ........................................................................ 1097
continuous positive airway pressure ................................ 779-784
cooling therapy ............................................................... 460–462
coping strategies .......................................................... 10-15, 438
corticosteroids ................................................................ 214–218

5th Edition | Acute Pain Management: Scientific Evidencei2children
systemic .......................................................... 973–975
intraarticular injection ...........................................1042
herpes zoster .................................................................. 535
pharyngitis ...................................................................... 570
regional ................................................................... 218–222
sickle cell disease ............................................................ 541
sinusitis........................................................................... 571
systemic.......................................................................... 214
coxibs .............................................................................. 112–122
children
NSAID exacerbated respiratory ............................... 927
gastrointestinal effects ........................................... 927
hypersensitivity ...................................................... 921
overdose ................................................................. 927
platelet effects and bleeding .................................. 927
renal effects ............................................................ 928
cranial neurosurgery....................................................... 507
short-stay surgery ........................................................... 495
intramuscular ................................................................. 302
intravenous ............................................................. 298–299
older patients .......................................................... 761–762
oral ................................................................................. 293
pharyngitis ...................................................................... 570
vascular effects ............................................................... 115
cranial neurosurgery ....................................................... 506–508
cryotherapy ............................................................................ 461
culturally responsive care ................................................ 768–772
CYP2D6 polymorphism .................. 46-48, 127, 131, 137-138, 745
CYP3A4 ..................................................................................... 46
day-stay or short-stay surgery ......................................... 494–505
delirium ........................................................................... 756–757
children ...........................................................................999
emergence agitation and magnesium ......................964
and alpha-2 agonists ................... 966–968, 1008–1009
and regional block ...................................... 1026–1027
denosumab ..................................................................... 595–596
dental pain ...................................................................... 565–567
acupuncture and acupressure ........................................ 450
dental surgery (paed) .................................................. 1027–1028

duloxetine ....................................................................... 191–193
dysaesthesias .................................................................... 64, 483
dysmenorrhoea ....................................................................... 532
acupuncture and acupressure ................................. 449–450
complementary and alternative medicine................ 227-230
transcutaneous electrical nerve stimulation ................... 441
economic considerations .................................................... 94–98
patient-controlled analgesia ........................................... 404
education ............................................................................ 80–88
patient .............................................................................. 80
patient-controlled analgesia ........................................... 419
staff ................................................................................... 84
web-based (paed) .......................................................... 955
elderly patients See older patients
EMLA cream .................................................................... 355, 908
emergency department .................................................. 611–620
acupuncture and acupressure ......................................... 447
children ......................................................................... 1055
enhanced recovery after surgery [ERAS] ........................ 481-482
epidural abscess .............................................................. 325–328
children ......................................................................... 1016
epidural analgesia ................................................... 316–332, 517
caesarean delivery .......................................................... 735
children ............................................................... 1000–1002
adjuvants............................................................... 1006
deaths ................................................................... 1017
infection ................................................................ 1016
postoperative neurological symptoms .................. 1015
complications ........................................................... 325-330
labour pain ...................................................................... 726
local anaesthetic opioid
combinations .................................................................. 167
local anaesthetics .................................................... 167–170
older patients .................................................................. 765
sickle cell disease ............................................................ 542
spinal surgery .................................................................. 513
epidural blood patch .............................................................. 555
children ............................................................... 1017, 1042

depression ................................................................... 13–14, 520

epidural haematoma ........................................ 325–326, 361-365
children ......................................................................... 1017

developmental neurobiology (paed) ............................... 885–887

epinephrine See adrenaline

devil’s claw ............................................................................. 229
dexamethasone ........................................ 214, 567-568, 596, 728
children ....................................... 973–975, 999, 1009, 1025
spinal surgery ................................................................. 510
dexmedetomidine .................................... 200-206, 500, 508, 510
children ................................................................... 967–969
intensive care ................................................................. 608
labour ...................................................................... 734-735

erector spinae plane block .............................................. 349–350
children ........................................................................... 993
ergot derivatives /dihydroergotamine .............549, 552, 557, 752
children ......................................................................... 1083
exercise therapy ...................................................... 455, 619, 721
faces pain scales...................................................................... 624
children ........................................................... 897, 902, 905

dextromethorphan ................................................................. 184
phantom limb pain ......................................................... 486

facial expression (paed) .......................................................... 894

dextropropoxyphene .............................................................. 128

fast-track surgery .................................................................... 481

diamorphine [diacetyl morphine, heroin] .............................. 128
children ................................................................. 938, 1075

femoral nerve block ................................................ 343, 345, 359

dihydrocodeine ...................................................................... 128
discharge medications .............................. 31, 85-86, 97, 631–640
day-stay or short-stay surgery ........................................ 503
discharge opioid prescribing (paed) ....................... 947, 1076
distraction ....................................................................... 436, 527
children ............................................................... 1039, 1047
droperidol ....................................................................... 143–145

i3drug metabolism ................................................................. 46–48

5th Edition | Acute Pain Management: Scientific Evidence

facial recognition software...................................................... 898

fentanyl ........................................................................... 128–129
buccal.............................................................................. 311
cancer breakthrough pain ............................................... 311
children ................................................................... 930–931
cancer breakthrough ............................................. 1064
intranasal
in sickle cell ................................................... 1087
intranasal ........................................................................ 315

INDEX

oral ................................................................................. 315
patient-controlled analgesia ........................................... 406
sublingual . ..................................................................... 311
transdermal .................................................................... 304
fibromyalgia ...................................................... 10, 192–193, 197
forceps delivery ...................................................................... 733

information provision ............................................................. 432
inguinal hernia repair ............................................................. 445
children ........................................................................ 1021
injury response ................................................................... 38–39
intellectually disabled see cognitive impairment

fractured neck of femur ......................................................... 619

intensive care . ................................................................. 603-610
children .......................................................................... 888

functional activity scale [FAS] ................................................... 69
children .......................................................................... 899

intellectually disabled see cognitive impairment

gabapentin ............................................................................. 198
children ................................................................... 971–983
chronic postsurgical pain .................................................. 30
neuropathic pain ............................................................ 198
phantom limb pain ......................................................... 486
pregnancy ................................................................ 714–715
spinal surgery ................................................................. 509
tonsillectomy pain .......................................................... 568
gastrointestinal adverse effects
coxibs ............................................................................. 118
nsNSAIDs ................................................................. 114, 963
opioids ..................................................................... 143-147
genetics ...............................................................................43–48
giant cell arteritis ............................................................. 556–557
guided imagery ....................................................................... 619
children ........................................................................1099
Guillain-Barre syndrome ......................................................... 609
gynaecological surgery ................................................... 319, 442,
acupuncture ................................................................... 446
haematological disorders. ............................................... 540–544
children ............................................................... 1086–1090
haemophilia .................................................................... 542–543
children .........................................................................1090
haloperidol ............................................................................. 145
headache......................................................................... 545–559
acupuncture and acupressure ........................................ 450
childrennonpharmacological intervention ..........................1044
migraine ............................................................ 1041-4
intravenous therapies ............................................1043
postdural puncture .................................. ..976–7, 1002
hepatic disease ................................................................ 801–805
hepatic surgery ................................................................ 318–319
hepatotoxicity of paracetamol ............................................... 110
children .................................................................. 912–913
hereditary sensory and autonomic neuropathy syndromes ..... 43
herniotomy ............................................................................ 491
see also inguinal hernia repair/inguinal surgery
herpes zoster ................................................................... 534–536
HIV pain ........................................................................... 575–577
honey ..................................................................................... 230
children .........................................................................1096
hydrocodone (paed) ................................ 935-936, 949-949, 1065
Hydromorphone ..................................................................... 129
children .......................................................................... 936
patient-controlled analgesia ........................................... 406
hyperalgesia ..................... 3, 64, 148-150, 180-187, 525, 808-810
hyperbaric oxygen therapy. .................................................... 551
hypersensitivity see allergic reactions
hypnosis .......................................................................... 435, 732
children ............................................................... 1060, 1098
hysterectomy. ........................................................................ 492
infantile colic (paed) .................................................... 1099-1100

interscalene block ........................................................... 343–344
intra-articular analgesia .................................................. 353–354
clonidine ......................................................................... 205
dexmedetomidine ........................................................... 206
NSAIDs ............................................................................ 123
intramuscular route ........................................................ 302–303
intranasal route ...................................................................... 308
children ........................................................................... 971
patient-controlled analgesia ........................................... 414
intrathecal analgesia ....................................................... 333–341
labour pain ...................................................................... 730
older patients .................................................................. 765
intravenous cannulation ......................................................... 463
children ............................................................... 1036–1040
neonates ............................................................. 1031–1035
intravenous regional anaesthesia
clonidine ......................................................................... 205
dexmedetomidine ........................................................... 205
nsNSAIDs ................................................................. 123–124
intravenous route ........................................................... 298–301
irritable bowel syndrome ........................................................ 532
ketaminecancer pain...................................................................... 585
children ................................................................... 959–965
chronic postsurgical pain................................................... 29
emergency department .................................................. 614
intranasal ........................................................................ 308
older patients .................................................................. 763
oral .................................................................................. 313
patient-controlled analgesia ........................................... 410
phantom limb pain .......................................................... 486
prehospital .............................................................. 627–628
regional ........................................................................... 188
sickle cell disease. ........................................................... 541
spinal cord injury pain ..................................................... 514
spinal surgery .................................................................. 510
sublingual ....................................................................... 313
systemic. ................................................................. 181–184
transdermal..................................................................... 230
labour pain ...................................................................... 723–742
acupuncture and acupressure. ........................................ 449
laceration repair in children ........................................ 1055–1059
lacosamide .............................................................................. 199
lactation .......................................................................... 742–750
migraine .......................................................................... 546
lamotrigine.............................................................................. 199
laparoscopic colectomy........................................................... 318
learning processes. ................................................................... 11
lidocaine ......................................................................... 163–165
children ................................................................. 976, 1089
postsurgical pain ............................................................... 30
lipid emulsion therapy .................................................... 172–173
children ................................................................. 989, 1015
local anaesthetics
continuous wound catheter infusions ............................. 354
children ........................................................... 997–998

5th Edition | Acute Pain Management: Scientific Evidencei4cranial neurosurgery................................................ 506–507
day-stay or short-stay surgery ........................................ 495
epidural .......................................................................... 323
intensive care ................................................................. 610
intrathecal ...................................................................... 333
older patients ................................................................. 763
peripheral ...................................................................... 168
regional .................................................................. 166–170
systemic.......................................................................... 163
children ............................................... 976, 1083, 1089
systemic toxicity
children ............................ 987, 989, 1090, 1092, 1095,
1101, 1111–1114, 1115–1117
tonsillectomy pain .......................................................... 568
topical............................................................................. 355
children .................................................................1037
tumescent (paed) ..........................................................1078
local infiltration analgesia [LIA] ........123, 169, 221, 322, 353–354
lower limb blocks ................................................................... 344
children ................................................................... 990–991
low-level laser therapy [LLLT] .......................................... 452–454
children ............................................................... 1068, 1070
lumbar puncturechildren ............................................................... 1040–1042
infants ...........................................................................1035
magnesiumcaudal (paed) .................................................................1029
intrathecal ..................................................................... 340
migraine ......................................................................... 550
children .................................................................1084
peritonsillar (paed) ........................................ 964, 999, 1026
regional .......................................................................... 189
scoliosis surgery (paed) ...................................................964
sickle cell disease (paed)................................................1089
spinal surgery ................................................................. 510
systemic................................................................... 185–186
children ...................................................................964
Māori peoples ................................................................. 776–778
massage .......................................................................... 459–460
mastectomy ........................................................................... 490
medical clowning/clown doctors (paed) ............. 1039, 1043, 1047
medical pain .................................................................... 529–577
meditation ....................................................................... 227, 434
children ............................................................... 1098–1099
melatonin ...................................................................... 230, 1096
children .........................................................................1096
memantine ............................................................................. 186
membrane stabilisers
spinal cord injury pain .................................................... 514
systemic.......................................................................... 163
menstruation-related migraine .............................................. 552
meperidine See pethidine
meralgia paraesthetica ........................................................... 722
methadone ...................................................................... 129–130
children .......................................................................... 937
cancer ................................................ 1065–1066, 1068
neonatal abstinence ........................................ 937, 945
paediatric sickle cell disease ..................................1088
pectus excavatum ..................................................1022
poisonings .............................................................. 949
scoliosis surgery .......................................................964
sickle cell disease ...................................................1088
withdrawal prevention and treatment ................... 958
metabolism....................................................................... 47
patient–controlled analgesia .......................................... 407
methoxyflurane ....................................................... 177–179, 627

i5

5th Edition | Acute Pain Management: Scientific Evidence

childrenburn ...................................................................... 1077
prehospital ........................................................... 1072
trauma .............................................. 1071–1072, 1085
methylnaltrexone............................................................ 146, 338
methylprednisolone ................................................................ 214
childrenHenoch-Schonlein Purpura abdominal ................... 974
sickle cell disease .................................................. 1088
midazolam .............................................................................. 223
children .................................... 971, 1010, 1041, 1044, 1056
migraine ........................................... 443, 450, 546–552, 616–617
children ............................................................... 1081–1085
pregnancy ....................................................................... 552
mind-body practices (paed) ........................................ 1098–1099
mindfulness-based interventions ............................................ 434
children ................................................................ 1098-1099
morphine ........................................................................ 130–132
children ........................................................................... 929
patient–controlled analgesia ........................................... 406
phantom limb pain .......................................................... 486
mucositis ......................................................................... 571–572
children ............................................................... 1067–1068
multimodal postoperative pain
management ........................................................... 476–478
multiple sclerosis. ................................................................... 560
musculoskeletal pain............................................................... 579
music therapy ......................................................................... 436
children ............................................ 1032, 1035, 1054, 1061
nalbuphine ...................................................................... 147, 408
children ........................................................................... 946
naloxone ................................................................................. 410
children ................................................................... 947, 982
naltrexone....................................................................... 833–834
nasogastric tube insertion
children ......................................................................... 1045
neonates ....................................................................... 1036
nausea and vomiting ............................................... 143–146, 339
children .................................................... 960, 981, 971, 982
neonatal abstinence syndrome ............................... 135, 713, 743
children ........................................................... 937, 942, 944
neonates
pain assessment ...................................................... 891–895
measurement tools ......................................... 903–904
procedural pain ................................................... 1031–1036
neostigmine ............................................................................ 224
neuraxial block
adrenaline ....................................................................... 203
anticoagulants ......................................................... 361–364
cancer pain.............................................................. 598–599
children ............................................................... 1000–1017
clonidine ......................................................................... 201
dexmedetomidine ........................................................... 202
herpes zoster .................................................................. 536
prevention of chronic postsurgical
pain ................................................................................... 28
neurokinin-1 receptor antagonists .......................................... 150
neurodevelopmental disorders (paed) also see
cognitive impairment and autism............................................ 900
neurodevelopmental outcomes .............................................. 714
children ....................................................... 890, 1011, 1031
neurological disorders ..................................................... 560–564
neurological injury .................................................................. 325

INDEX

neuropathic pain
acupuncture and acupressure ........................................ 450
antidepressants ....................................................... 191–192
cancer pain .............................................................. 587–588
gabapentin ..................................................................... 198
ketamine ........................................................................ 183
local anaesthetics ........................................................... 163
measurement ................................................................... 69
membrane stabilisers .............................................. 142–143
postoperative ................................................................. 483
pregabalin ...................................................................... 198
spinal cord injury. ........................................................... 513
neurostimulation .................................................................... 487
neurotoxic/neurotoxicity .................. 158, 170, 201, 224, 329, 500
children ....................................... 963, 970, 980, 1006, 1010
nicotine .................................................................................. 305
nitrous oxide [N2O] ..................................................174-177, 626
children ..................................1037, 1040, 1042, 1056, 1088
chronic postsurgical pain .................................................. 32
emergency department .................................................. 619
labour pain ..................................................................... 740
prehospital ..................................................................... 625
sickle cell disease ............................................................ 541
NMDA-receptor antagonists ............................................ 180–187
See also amantadine, dextromethorphan, ketamine,magnesium, memantine
regional ......................................................................... 188
systemic.......................................................................... 180
nocebo effect. .....................................................................16–20
nociceptive pathways ..............................................................2–9
nonpharmacological interventions
acupuncture and acupressure ................................. 444–451
burns injury pain............................................................. 527
children .........................................................................1059
emergency department .................................................. 619
intensive care ................................................................. 606
labour pain ..................................................................... 740
phantom limb pain ......................................................... 487
postoperative dental pain .............................................. 567
prehospital ..................................................................... 628
spinal cord injury pain .................................................... 515
TENS ............................................................................... 441
NSAID-exacerbated respiratory
disease .................................................................... 116, 120
NSAIDs............................................................................. 112-125
cancer pain ..................................................................... 581
emergency department .................................................. 611
intranasal........................................................................ 308
lactation ......................................................................... 744
metabolism ...................................................................... 48
nonsystemic ................................................................... 123
postoperative dental pain .............................................. 565
pregnancy ....................................................................... 711
prehospital ..................................................................... 625
rectal .............................................................................. 307
sickle cell disease ............................................................ 540
spinal surgery ................................................................. 509
tonsillectomy pain .......................................................... 568
nsNSAIDs ......................................................................... 112–122
children ................................................................... 918–925
bone healing effects ............................................... 924
cryptorchidism ........................................................ 916
exacerbated respiratory disease[including Aspirin] ............................................ 921–922
gastrointestinal effects ........................................... 923
hypersensitivity ...................................................... 921
patent ductus closure ...................................... 918–919

platelet effects and bleeding ................................... 922
premature ductus closure ....................................... 916
renal effects ............................................................ 923
vascular effects ....................................................... 924
cranial neurosurgery . ..................................................... 507
day-stay or short-stay surgery ......................................... 494
intramuscular .................................................................. 302
intravenous ..................................................................... 298
older patients .................................................................. 761
oral .................................................................................. 293
pharyngitis ...................................................................... 570
numerical rating scales ............................................................. 67
children .......................................................... 896, 905, 906
nurse-controlled analgesia .............................................. 982–983
obesity ............................................................................ 787–794
children ............................................................... 1092–1094
definitions ............................................................. 1092
dosing.......................................................... 1093–1094
morbidity ................................................................ 992
prevalence............................................................... 992
obstructive sleep apnoea ................................................ 779–786
children ......................................................................... 1092
ocular examination in neonates ............................................ 1035
older patients .................................................................. 753–767
epidural analgesia ........................................................... 765
intrathecal analgesia ....................................................... 765
medicines ................................................................ 760–767
pain assessment ...................................................... 755–758
patient–controlled analgesia ........................................... 764
pharmacokinetics and pharmacodynamics ............. 758–760
ondansetron ................................................................... 143–145
ophthalmological ............................................................ 124–125
childrensurgery .................................................................. 1026
examination ................................................ 1035–1036
opioid-induced hyperalgesia ............. 148-150, 808, 818, 822, 824
opioid-induced ventilatory impairment [OIVI]......................................... 140–142, 156, 196, 295, 336, 408
children ................................................................. 946, 1095
discharge medications .................................................... 632
opioids ............................................................................ 126–152
addiction ................................................................. 825–826
buccal.............................................................................. 311
burns injury procedural pain ........................................... 525
cancer pain.............................................................. 582–583
children ................................................................... 928–947
adverse effects ........................................ 932, 935–936
adverse events ........................................................ 949
intrathecal ................................................... 1017–1018
longterm use ........................................................... 950
and misuse ...................................................... 951–952
medication prescribing errors ................................. 929
related deaths ................................................. 948–949
safe storage ...................................................... 953-954
tolerance and withdrawal ................................ 956-958
cranial neurosurgery ....................................................... 506
day-stay or short-stay surgery ......................................... 496
emergency department .................................................. 612
epidural ........................................................................... 153
herpes zoster .................................................................. 535
immediate–release ......................................................... 293
intra–articular ................................................................. 159
intramuscular .................................................................. 302
intranasal ........................................................................ 307
intrathecal ....................................................................... 153
intravenous. .................................................................... 299
labour pain ...................................................................... 723

5th Edition | Acute Pain Management: Scientific Evidencei6lactation ......................................................................... 744
metabolism ...................................................................... 47
migraine ......................................................................... 549
neuraxial ......................................................................... 152
obstructive sleep apnoea ............................................... 781
older patients ................................................................. 762
oral ................................................................................. 293
patient–controlled analgesia .......................................... 405
perineural ....................................................................... 160
peripheral ....................................................................... 159
pharyngitis ...................................................................... 570
pregnancy ....................................................................... 712
prehospital ..................................................................... 625
pulmonary ...................................................................... 313
rectal .............................................................................. 307
sickle cell disease ............................................................ 540
slow-release ............................................................ 295, 638
spinal cord injury pain .................................................... 514
spinal surgery ................................................................. 509
subcutaneous ................................................................. 302
sublingual ....................................................................... 311
systemic................................................................... 126–152
topical............................................................................. 161
transdermal .................................................................... 304
opioid tolerance and withdrawal .................... 148–150, 806–823
children ................................................................... 956–958
oral route. ....................................................................... 288–297
patient–controlled analgesia .......................................... 411
table of analgesic efficacy ............................................... 289
oral ulceration ................................................................. 571–572
children .........................................................................1019
organisational requirements .................................................... 89
orofacial pain.......................................................................... 565
orthopaedic ............................................................................ 321
acupuncture ................................................................... 445
childreninjury ...................................................................... 924
scoliosis surgery ...................................................1023
surgery........................................... 930, 945, 953, 1001
total hip arthroplasty. ..................................................... 446
Total knee arthroplasty .................................................. 446
otitis media ............................................................................ 571
outcome measures ................................................................... 72
oxcarbazepine ........................................................................ 199
oxycodone ................................................................................ 47
children .......................................................................... 934
metabolism ...................................................................... 47
patient–controlled analgesia. ......................................... 407
Paediatric Regional Anaesthesia Network (PRAN) ..................986
paediatric spinal fusion [scoliosis surgery]................... 1023–1024
pain
adverse physiological effects .......................................38–40
adverse psychological effects ........................................... 41
effects on injury-induced dysfunction .............................. 40
functional impact.........................................................68–69
physiology .....................................................................2–10
older patients .......................................................... 753–755
psychological factors ...................................................11–15
pain assessment ..................................................................64–66
cancer pain ..................................................................... 580
children ................................................................... 891–902
composite scales.............................................. 904–905
multidimensional ..................................... 899, 903–904
observational .......................................................... 906
self-report................................................ 896–897, 905
unidimensional (FPS/CAS/VAS) ........................ 897, 903
intensive care ................................................................. 603

i7

5th Edition | Acute Pain Management: Scientific Evidence

neonates ................................................................. 891–895
behavioural measures. ............................................ 894
measurement tools ......................................... 903–904
physiological measures ........................................... 892
older patients .................................................................. 755
opioid tolerant patients .................................................. 815
pain history ....................................................................... 65
prehospital ...................................................................... 624
pain measurement .............................................................. 66–71
See also outcome measures
categorical scales .............................................................. 67
multidimensional measures .............................................. 69
neuropathic pain ............................................................... 69
numerical rating scales. ..................................................... 67
older patients .......................................................... 757–758
patients with special needs ............................................... 70
unidimensional measures ................................................. 67
pain perception ..................................................................... 2–10
older patients .................................................................. 753
pain trajectories (paed) ........................................................... 994
pamidronate ................................................................... 208, 595
pancreatitis ............................................................................. 531
paracetamol .................................................................... 108–111
cancer pain...................................................................... 581
children ................................................................... 907–917
asthma .................................................................... 915
atopy ....................................................................... 915
cardiovascular effects.............................................. 913
cryptorchidism ........................................................ 916
hepatotoxicity ......................................................... 912
hypersensitivity ....................................................... 914
neurobehavioural outcomes ................................... 916
patent ductus closure .............................................. 913
premature ductus closure ....................................... 916
cranial neurosurgery ....................................................... 507
day-stay or short-stay surgery ......................................... 495
emergency department .......................................... 611–612
herpes zoster .................................................................. 535
intensive care .................................................................. 607
intravenous ..................................................................... 298
lactation .......................................................................... 744
older patients .......................................................... 761–762
oral .................................................................................. 292
pharyngitis ...................................................................... 570
postoperative dental pain ....................................... 565–566
pregnancy ....................................................................... 710
prehospital ...................................................................... 625
rectal ....................................................................... 306–307
spinal surgery .................................................................. 509
tonsillectomy pain ........................................................... 568
paravertebral block ......................................................... 348–349
children ................................................................... 992–993
Parkinson’s disease ......................................................... 561–562
paroxysmal hemicrania ........................................................... 554
patient controlled epidural analgesia [PCEA] .................. 404–422
anxiety ........................................................................ 14–15
children ................................................................... 979–982
economic evaluation ......................................................... 95
education .......................................................................... 81
equipment .............................................................. 417–418
medicines ................................................................ 405–411
older patients .................................................................. 764
patient factors ................................................................. 419
psychological aspects .................................................. 14–15
safety ...................................................................... 415–416
staff factors ..................................................................... 419

INDEX

patient-controlled epidural
analgesia ................................................................. 324–352
pelvic-girdle pain .................................................................... 517
peptic [gastrointestinal] ulceration ........................................ 113
childrencoxibs ..................................................................... 927
nsNSAIDS ................................................................ 923
percutaneous vertebroplasty ................................................. 594
periarticular analgesia ............................................................ 353
perineal pain ................................................................... 750–751
perineural catheters /continuous peripheral nerve catheters(CPNCs) (paed) ........................................................................987
peripheral nerve block..................................................... 343–353
anticoagulants ................................................................ 364
cancer pain ..................................................................... 598
children ...........................................................................986
adjuvants ....................................................... 998–1000
head and neck .........................................................996
ilioinguinal/iliohypogastric.......................................996
clonidine ......................................................................... 200
day-stay or short-stay surgery ....................................... 497
dexmedetomidine .......................................................... 200
pethidine ................................................................................ 132
children ................................................................. 980, 1026
phantom limb pain ................................................................. 486
pharmacogenomics .................................................................. 43
children ........................................................... 929–930, 933
pharyngitis.............................................................................. 570
children ...........................................................................973
phenytoin ............................................................................... 199
photobiomodulation ....................................................... 452–454
physical comfort measures (paed).........................................1062
physical therapies ............................................................ 455–456
children .........................................................................1099
vibration ...................................................... 1038–1039
placebo effect......................................................................16–20
platelet function
coxibs ............................................................................. 120
nsNSAIDs ................................................................. 115–116
children .................................................................. 922
play therapy/child life interventionists (paed) .......................1061
porphyrias ....................................................................... 543–544
postamputation pain. ............................................................. 485
postdural puncture headache ................................................ 554
children .........................................................................1042
postherniotomy pain syndrome ............................................. 490
postherpetic neuralgia .................................................... 534–537
antidepressants .............................................................. 191
prevention ...................................................................... 536
post-hysterectomy pain syndrome ......................................... 492
post-mastectomy pain syndrome ........................................... 490
postoperative pain .......................................................... 476–512
acupuncture and acupressure ........................................ 444
antidepressants ....................................................... 191–192
clonidine ......................................................................... 200
dexmedetomidine ............................................................ 20
gabapentin ..................................................................... 194
local anaesthetics ........................................................... 163
membrane stabilisers ..................................................... 163
physical therapies ........................................................... 455
pregabalin ...................................................................... 194
poststroke pain ...................................................................... 562

post-thoracotomy pain syndrome ........................................... 489
prednisolone ........................................................................... 214
children ................................................................... 984–985
pre-emptive analgesia ......................................................... 33–37
pregabalin ............................................................................... 194
chronic postsurgical pain................................................... 32
postoperative dental pain ............................................... 565
pregnancy. ...................................................................... 721
spinal surgery .................................................................. 509
tonsillectomy pain ........................................................... 569
pregnancy ....................................................................... 710–752
addiction ......................................................................... 837
medicines and fetal risk .......................................... 715–716
migraine .......................................................................... 552
prehabilitation ........................................................................ 457
prehospital analgesia .............................................................. 621
pressure sores (paed)............................................................ 1016
preventive analgesia ........................................................... 33–37
probiotics ................................................................................ 229
children ..................................................... 1086, 1099, 1100
procedure-related pain
cancer patients................................................................ 590
children ............................................................... 1031–1063
intensive care .................................................................. 610
neonates ....................................................................... 1031
pruritus ................................................................... 147, 337–338
children ....................................................... 982, 1079, 1087
psychological interventions ............................................. 432–440
children ........................................... 1042, 1053–1054, 1059,
pulmonary route ............................................................. 313–314
pulse oximetry ........................................................................ 785
quadratus lumborum block ..................................................... 352
children ........................................................................... 994
radiation therapy .................................................................... 593
rectal route ............................................................................. 306
regional analgesia
anticoagulation .............................................. 356, 361–365
blocksadductor canal block ............................................... 345
brachial plexus blocks.............................................. 344
fascia iliaca block ..................................................... 345
femoral nerve block ................................................ 345
head and neck blocks .............................................. 353
lumbar plexus block ................................................ 347
sciatic nerve block ................................................... 347
children ................................................................. 986–1030
donor site pain in burns injury ........................................ 527
infection ......................................................................... 358
nerve injury .................................................................... 356
prehospital ..................................................................... 628
prevention of chronic postsurgical
pain ................................................................................... 28
toxicity ........................................................................... 357
rehabilitation
physical therapies ................................................... 458–459
postoperative pain .................................................. 481–482
relaxation ................................................................................ 433
remifentanil ............................................................................ 133
children ........................................................................... 938
renal adverse effects
coxibs .............................................................................. 119
nsNSAIDs ......................................................................... 114
renal colic ................................................................................ 529
emergency department .................................................. 616

5th Edition | Acute Pain Management: Scientific Evidencei8renal disease ................................................................... 795–805
respiratory depression (paed) ................. 930, 933, 944, 948, 981
Reye’s syndrome .................................................................... 744
Children .......................................................................... 922
rib fractures ............................................................................ 321
root-cause analysis ................................................................... 92
ropivacaine ............................................................................. 173
sciatic nerve block .................................................................. 347
scoliosis surgery (paed) ....................................... 971, 1023–1024
shingles see herpes zoster
shoulder dislocation ........................................................ 617–618
sickle cell disease............................................................. 540–542
children ............................................................... 1086–1090

transcutaneous electrical nerve stimulation see TENStransdermal route ........................................................... 304–305
children ................................................ 932, 944, 1064, 1070
patient-controlled analgesia ........................................... 415

sinusitis .................................................................................. 571

transverse abdominis plane block ................................... 160, 222

skin cooling (paed) ................................................................1038

trigeminal autonomic cephalalgias.......................................... 553

sleep-disordered breathing .................................... 779–786, 813
children ......................................................... 929, 946, 1092

trigeminal neuralgia ................................................................ 563
triptanschildren ............................................................... 1081–1082
cluster headache ............................................................. 553
migraine .......................................................................... 548
truncal blocks .................................................................. 348–352
children ................................................................... 992–996
ultrasound/ultrasound guided regional analgesia .................. 342
children ............................ 990, 994, 1000–1001, 1029, 1059

sodium valproate ................................................................... 197
spinal cord compression .................................................. 591–592
spinal cord injury ............................................................. 513–516
taxonomy ....................................................................... 513
spinal surgery .................................................................. 509–512
steroids
injection in children .......................................................1042
postoperative dental pain .............................................. 565
tonsillectomy pain .......................................................... 568
St John’s wort ......................................................................... 227
subcutaneous route ............................................................... 302
patient-controlled analgesia ........................................... 414
sublingual route .............................................................. 311–315
patient-controlled analgesia ........................................... 414
sucrose/sweet solutions .................................... 1032–1033, 1038
sufentanil ........................................................................ 133, 161
children .......................................................................... 937

umbilical surgery ..................................................................... 996
upper limb blocks ............................................................ 343–344
children ........................................................................... 991
urethral catheterisation in children....................................... 1043
urinary retention ............................................................. 147, 339
children ................................................................... 147, 339
urine sampling in neonates and infants ................................ 1035
urological surgery ................................................................... 320
circumcision and penile surgery (paed) ....................... 1020
uterine pain ............................................................................ 752

SUNCT .................................................................................... 554

vaccination injection pain (paed) ................................ 1048–1055

symphysial diastasis ............................................................... 722

valproate ................................................................................. 199
vapocoolant ............................................................................ 461
children ........................................................................... 991
venipuncture [blood sampling] .............................................. 461
children ..................................................... 1031, 1036, 1061

tanezumab ............................................................................. 592
tapentadol .............................................................................. 135
children ........................................................... 938, 943–944
taxane acute pain syndrome .................................................. 590
temporomandibular disorders ............................................... 569
TENS ................................................................................ 441–443
children .........................................................................1066
tension-type headache ........................................................... 545
thoracic surgery...................................................................... 441
children ....................................................... 993, 1003, 1044
pectus excavatum repair .......................................1022
thoracotomy........................................................................... 489
children ........................................... 889, 937, 944, 993–994
thought processes .................................................................... 12
tonsillectomy ........................................................... 568–569, 573
tolerance ................................................................ 148–150, 158,
children ................................................................... 956–959
topical therapies
children ............................................................... 1018–1019
local anaesthetics ........................................................... 355
NSAIDs ............................................................................ 124
tramadol ................................................................................. 115
children .......................................................................... 938
emergency department .................................................. 613
herpes zoster .................................................................. 535

i9

intravenous ..................................................................... 300
lactation .................................................................. 743, 746
metabolism ....................................................................... 46
migraine .......................................................................... 550
older patients .................................................................. 763
oral .................................................................................. 297
patient-controlled analgesia ........................................... 406
postoperative dental pain ............................................... 566
prehospital ...................................................................... 625
rectal ............................................................................... 307
spinal cord injury pain ..................................................... 514

5th Edition | Acute Pain Management: Scientific Evidence

verbal numerical rating scales ................................................... 67
children ........................................................................... 901
vertebral compression fracture ............................... 207–208, 458
children ......................................................................... 1069
virtual reality .......................................................................... 437
children ..................................................... 1048, 1059, 1067
visual analogue scales ............................................................... 68
children ........................................................................... 897
warming and cooling intervention .......................................... 460
web-based education ................................................................ 84
children ................................................................. 955, 1066
whiplash injury .......................................................................... 83
white willow bark .................................................................... 229
withdrawal .............................................................. 557, 820, 828
children ........................................................................... 958
wound catheters infusions see local anaesthetic
wound infiltration ................................................................... 123
children ................................................ 990, 995, 1021, 1029
day-stay or short-stay surgery ......................................... 494
wounds ................................................................................... 618