Clinical Practice Guidelines
for the Management ofChronic Pain

The Committee for Clinical Practice Guideline
for the Management of Chronic Pain

The Japan Society of Acupuncture and Moxibustion
Japanese Association for the Study of Musculoskeletal Pain
Japanese Society of Orofacial Pain
The Japanese Headache Society
Japan College of Fibromyalgia Investigation
Japanese Association for the Study of Pain
Japan Society of Pain Clinicians
Japanese Association for the Study of Pain Rehabilitation
The Japanese Society for the Study of Chronic Pain
The Japanese Society for the Study of Low Back Pain

Publication Department, Shinko Trading Co. Ltd.

Preface

Preface
Not just in the lives we lead every day, but in every respect, such as our academic
and clinical activities, we have been largely affected by the COVID－19 pandemic in
2020 and as of February 2021, when this preface was written, although vaccinations
have begun, we still cannot foresee at the present time what future restrictions will be
like. Both various domestic and overseas conferences on pain which contribute towards
pain research and the ongoing development of pain management have also been largely
affected, forcing us to either cancel these conferences or hold them online. Under suchcircumstances, there is a large number of patients who are suffering from chronic pain
and intractable pain through daily treatment and our activities need to continue to constantly make further advances forward. We are praying that our daily living situation
will be restored as quickly as possible.
As mentioned in the preface to Clinical Practice Guidelines for Chronic Pain, published in 2018, research on pain has developed significantly over the past 40～50 years,
during which time a rich diversity of attractive theories, among other publications, havebeen published, closing in on the mechanisms of pain and the causes of chronic pain.
There have also been trials of drug discoveries based on what has been revealed about
these mechanisms. Of course, new drugs have certainly brought about major developments and changes to the management of pain, many of which have been outlined inthese guidelines. However, whether these new revelations about pain mechanisms havedirectly led to the development of actual drug discoveries and forms of treatment or
not, still remains problematic. We are still unable to eschew the viewpoint that pain asa target is unlikely to lead to groundbreaking drug discoveries or forms of treatment,
for various reasons. Some of these reasons include that pain is a subjective sensationand is therefore difficult to quantify, tends to undergo psychological and emotional embellishments, and our pain－receiving system tends to indicate changes in plasticity,
making it difficult for us to analyze and understand it.
Despite the existence of these various challenges, thanks to the hard work of a large
number of clinicians and researchers from all over the world, as well as campaigns toraise awareness, we have seen an incredible amount of change and progress in clinicalpain management over the past decade. Japan, which used to be decades behind theWest, has clearly made progress in the management of cancer pain and pain alleviation
treatment, saving a large number of patients. Without any doubt, what we clinicallyneed to tackle next is the extremely high number of patients suffering from chronic
non－cancer pain. A vast amount of national wealth has been lost due to chronic pain,
requiring us to tackle this issue effectively. Furthermore, it is not possible for us to save
individual patients unless we deal with chronic pain. The Japanese government has implemented administrative policies on various types of illnesses, such as for treating can-

279

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Prefacecer, lifestyle diseases, infectious disease, and mental illnesses, although the field of
chronic pain disease has been left out like an air pocket. However, thanks to the hard
work of a large number of people over the past decade and more, we are extremely delighted that measures on pain management are now being put forward as federal programs．
In this context, in 2018, ‘Research on Constructing a System for the Treatment and
Education of Chronic Pain Problems’ was put forward as a part of Health, Labour andWelfare Policy Research (Research on Chronic Pain) (Research Representative：Takahiro Ushida, MD, PhD) and in cooperation with a pain consortium, comprised of 7 academic committees, tackling chronic pain across the various disciplines, they devised the‘Clinical Practice Guidelines for Chronic Pain.’ In this revised edition, the guidelines
were created under ‘Research for the Uniform Accessibility to Chronic Pain Management Systems and Improved Healthcare Utilizing Pain Center Treatment Databases,’(Research Representative：Shoji Yabuki, MD, PhD), put forward by the MHLW Research Group as part of Health, Labour and Welfare Policy Research（Research on
Chronic Pain）, along with 8 academic societies and organizations belonging to the Union
of Pain－related Associations in Japan（Japanese Association for the Study of Musculoskeletal Pain, the Japanese Society of Orofacial Pain, the Japanese Headache Society, theJapanese Association for the Study of Pain, the Japan Society of Pain Clinicians, the Japanese Association for the Study of Pain Rehabilitation, the Japanese Society for the
Study of Chronic Pain（JSSCP）, and the Japanese Society of Lumbar Spine Disorders）
in addition to representatives from two societies and organizations（the Japan Societyof Acupuncture and Moxibustion, and the Japan College of Fibromyalgia Investigation（JCFI））as well as other observers and those involved in chronic pain. We received
positive feedback on the previous guidelines, more than we could have possibly everimagined, from a large number of physicians and with this revised edition, we havebeen able to provide updates and improve sections that we had been unable to cover inthe previous edition.
In closing, in creating these guidelines, we wish to take this opportunity to express
our heartfelt gratitude to everyone from the MHLW Research Group, all doctors andphysicians from the 10 societies and organizations, as well as everyone who was involved in the creation of this revised edition.
March, 2021
President of the Japanese Society for the Study of Pain（JASP）
President of the Hyogo College of Medicine
Koichi Noguchi, MD, PhD

281

Introduction
In 2020, the International Association for the Society of Pain（IASP）revised its definition of pain. Pain is “an aversive sensory and emotional experience typically causedby, or resembling that caused by, actual or potential tissue injury.” There has been nochange to the basic gist of what constitutes pain, but in the Japanese translation, we
have emphasized “aversive（unpleasant）experience.” Chronic pain, which is the subjectof these guidelines, refers to ‘pain that persists for a long time beyond the normal period required for healing trauma or disease that is the underlying cause of the pain.’ Asan unpleasant or aversive experience persists for a long period of time, it is easy for us
to imagine how this adversely affects work, school and daily life.
A large number of guidelines on treating or managing diseases have been published
to date, but there are hardly any guidelines on treating symptoms. In this context, theClinical Practical Guidelines for Chronic Pain were published in 2018, eliciting a large
response from its readers and this volume constitutes a revised edition of the 2018 edition.
Creation of the guidelines
The previous guidelines were created by experts from all over Japan, with contributions from 7 societies and associations：Japanese Association for the Study of Musculoskeletal Pain, Japanese Society of Orofacial Pain, Japanese Association for the Study ofPain, Japan Society of Pain Clinicians, Japanese Association for the Study of Pain Rehabilitation, the Japanese Society for the Study of Chronic Pain, and the Japanese Society
for the Study of Low Back Pain. Although it was no easy task for these cross－disciplinary societies and associations to collaborate and accomplish something together,through the cooperation of these 7 societies and organizations, they were able toachieve something remarkable. However, due to the limited amount of time prior to
publication, some aspects were unsatisfactory, such as citation analysis, deciding on evidence and determining the recommendation grades. This time round, in addition to the
7 previous societies and associations, the Japan Society of Acupuncture and Moxibustion, the Japanese Headache Society and Japan College of Fibromyalgia Investigation
were also included, meaning that a total of 10 societies and associations have participated in this project. Representatives from patients’ associations have also been included,
and where necessary we have referred to their opinions as well. I believe that we haveindeed created even deeper guidelines on chronic pain, encompassing a wider representation from all over Japan. In addition, learning from the past, our physicians involvedin the creation of these guidelines undertook workshops held by the Japan Council for
Quality Health Care Minds Guidelines Center（also known as ‘Minds’）. They were able
to learn about the current methods and policies for creating guidelines before proceed-

282

Introduction

ing with the creation of these guidelines. Furthermore, it was most reassuring to hear
the opinions of specialists from Minds on a variety of different occasions.
Our basic philosophy behind the creation of these guidelines
When making these guidelines, we discussed what kinds of chronic pain we would
address and decided to address adult chronic pain, but not chronic cancer pain. Moreover, we created items on frequently－occurring diseases, deciding to create guidelinesthat would be even more helpful for our readers. We have assumed that our readers
would consist of medical practitioners involved in treating or managing patients withchronic pain. As a wide variety of specialists from various professions are involved in
the management of chronic pain, we have aimed for something useful not only for physicians but for other medical staff as well. There are various forms of chronic pain treatment that are being implemented. We think that medical practitioners are choosing atreatment method that they themselves believe matches with the patient. However, unfortunately evidence has not always been established across the board. We have emphasized evidence in these guidelines. As there is a wide variety of patient diseases,
points of evaluation and patient background, there were many CQs in which we wereunable to summarize information through meta－analysis. In these cases, we conducted
qualitative synthesis and decided on a level of evidence, keeping in mind our effort tomake it helpful to readers. There were more than a few instances in which high－quality
helpful research papers were only available overseas. This does not necessarily meanthat all of the results from these overseas research papers match and conform with the
management of chronic pain in Japan. In meetings during which we decided upon arecommendation grade, we emphasized these points as well during our discussion. In
the CQs, there are cases where the recommendation grade is not high, even though the(quality of) evidence is, and vice versa. We kindly ask readers to understand that this isa result of our efforts to make the guidelines match and conform with the situation in
Japan．
Methods utilizedFirst of all, what we kindly ask from our readers is not to just look at the evidence
and recommendation grades and nothing else. Please make sure to read our answers
and commentary. Some may feel something odd about the evidence and recommendation grades provided in our CQs, depending on the type of profession, specialty, and thelevel of experience of the individual reader, but we believe readers should be able tounderstand the reasons and justifications for why a certain recommendation grade has
been listed. In some cases, the recommendation for the same type of treatment mayvary depending on the CQ. There are also some instances in which the results of research papers which have focused on chronic pain in general (overall chronic pain) andthose which have focused on specific diseases are different. As we have provided a283

Introduction

summary of these, in a certain sense, it is natural for the evidence and recommendation
grades to vary. We would like our readers to first refer to these guidelines and conduct
or implement treatments and diagnoses that are recommended and which have accumulated a high amount of evidence. However, each individual patient has a different
background and underlying causes for their pain. Ultimately, the medical practitioner
will choose a treatment method that (s)he thinks is best suited to the patient. This is because the medical practitioner attending to the patient knows that patient best. Afterconsidering the information contained in these guidelines, if our readers then think
about what would be best for their particular patients, then the makers of these guidelines will feel that their efforts have been rewarded．
Acknowledgements
These guidelines were created thanks to the cooperative efforts of a large number ofpeople. We received a large number of useful public comments from everyone belonging to the societies and associations. Thank you very much. I would especially like toacknowledge the efforts and hard work of Dr. Hisashi Date from the Sendai Pain Clinic,
as the committee leader in successfully completing these guidelines which encompass
all of Japan. There were some discussions in which it seemed like we had reached adeadlock, but Dr. Date skillfully brought these members together and pushed onwards.
Thank you sincerely.
Furthermore, I also cordially wish to thank Mr. Yukio Morita who checked and edited the manuscript from its incipient stages, Dr. Masako Watanabe of the Publication
Department of Medical Books, Shinko Trading Company（Ltd.）, Mr. Matthew McLaughlin who translated the original Japanese manuscript, which underwent numerouschanges, into English, and Ms. Kyoka Ito from the Department of Orthopaedic Surgery,
School of Medicine, Fukushima Medical University, who has worked behind the scenes
as the secretariat supporting this project.
It is our sincere wish that these guidelines will prove to be useful for everyone involved in the management of chronic pain and in future if some issues arise, we hopethat our next revised edition will offer even better guidelines including the latest available evidence．
March, 2021
Health, Labour and Welfare Policy Research Grants（research on chronic pain）
Research for the Uniform Accessibility to Chronic Pain Management Systems andImproved Healthcare Utilizing Pain Center Treatment Databases
Research Representative：Shoji Yabuki, MD, PhD

284

Preparative Method of these Guidelines
The Committee for Clinical Practice Guidelines for Chronic Pain
These guidelines act as a second volume, continuing on from Clinical Practice Guidelines for Chronic Pain, published in 2018. This volume features not only treatments forchronic pain but also a discussion of diagnosis, assessment and typical chronic pain illnesses. Just like with the previous volume, Clinical Practice Guidelines for Chronic
Pain, these guidelines are different from the various guidelines issued by the societies
and associations, as they have been constructed by the Committee for Clinical Practice
Guidelines for Chronic Pain, which is comprised of specialists from various pain－related
medical occupations and departments, and executed under the supervision of the
MHLW Research Group, as ‘Research for the Uniform Accessibility to Chronic PainManagement Systems and Improved Healthcare Utilizing Pain Center Treatment Databases.’
Basic structure of these guidelines
The structure of these guidelines was itemized in accordance with the medical－information service, ‘Minds Handbook for Clinical Practice Guideline Development 2017,’
adopting the basic structure of clinical questions（CQs）, answers, recommendation
grades, level of evidence, and commentary. For those CQS where we thought level ofevidence and recommendation grades were not necessary, we have limited our discussion to answers and commentary only.
Preparation of clinical questions（CQs）
The clinical questions were devised from the debate and discussion conducted
through ‘Plenary Sessions of the Committee for Clinical Practice Guidelines for Chronic
Pain’（Plenary Sessions）, comprised of members of the committee responsible for creating these clinical practice guidelines（CPG）, academic experts from Minds（observers）,
nursing representatives, and representatives from patient associations.
In our previous Clinical Practice Guidelines for Chronic Pain, we decided to conduct
evaluations by dividing the recommendation grades for CQs on pharmacotherapy into
‘Musculoskeletal Pain,’ ‘Neuropathic Pain,’ ‘Headache／Orofacial Pain,’ and ‘Fibromyalgia
Pain’（of the 7 IASP categories for chronic pain（Table A－1）,we excluded the 4 categories of ‘Cancer Pain’，‘Post－surgical ／ Traumatic Chronic Pain’ and ‘Chronic Visceral
Pain’）. However, in these guidelines, as evaluations were made according to the maindisease categories of chronic pain and also because some drugs did not fit or matchwith these categories, we decided on a recommendation grade through a holistic evaluation of the drugs．

Preparative Method of these Guidelines

Searching for citations
In line with the CQs that had been selected, our CPG committee in cooperation with
our systematic review team ran searches for references and citations. In principle,
searches ranged from between 2005 to 2020. In our search for references, our method
was to utilize MEDLINE, Cochrane and the NPO Japan Medical Abstracts Society to
extract citations listed in each CQ. With important references, we incorporated citations
from prior to 2005 and if the references were deemed to be important, we searched forthem manually and added them to the selection.
Levels of evidenceWith the levels of evidence for the CQs, we conducted a systematic review of eachoutcome, with the 5 important outcomes in mind for each CQ, and referred to for example the assessment sheet on the overall evidence of each research paper, their SoF（summary of findings）, and evidence to decision（EtD）frameworks and following the‘Minds Handbook for Clinical Practice Guideline Development 2017,’ we made decisions
after taking into consideration the discussion and debate that took place in the Plenary
Sessions.
The summations（overall strength of evidence regarding the general outcomes）of
the overall evidence for each CQ are as follows：A（high）
： We are very confident that the effect of the study reflects the actual effect；
B（moderate）
： We are quite confident that the effect in the study is close to the true
effect, but it is also possible it is substantially different；C（low）
： The true effect may differ significantly from the estimate；D（very
low）： The true effect is likely to be substantially different from the estimated effect.
Determining a recommendation grade
Recommendation grades were determined after taking into consideration a balance
between benefits（benefits, profits, usefulness）and risks（harm, disadvantages）. In
principle, forms of treatment that are covered under the scope of the Japanese healthinsurance system are considered but we decided to also recommend forms of treatmentthat were not covered by health insurance if they were believed to be useful overseas
or based on the evidence.
When deciding on a recommendation grade, votes were cast in the Plenary Session,
and we determined the grade when we reached a consensus rate of 80% or higher. If
votes did not reach a 80% consensus result, we would hold another discussion in a Plenary Session and cast a second round of votes. In cases where we failed to obtain 80%
consensus or higher, even after 3 rounds of voting（in cases where we had trouble
agreeing on the same point of view in the Plenary Session）,we then assigned a “no rec-

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Preparative Method of these Guidelines

ommendation” grade and also listed the final voting results. Furthermore, in cases
where there were no high－quality research papers, and we could not decide on astrength of recommendation, we assigned a “no recommendation” grade and also listed
the consensus rate. Therefore, in cases of “no recommendation,” in some cases, we had
a consensus rate of 80% or higher, but we were unable to decide upon a recommendation grade due to insufficient evidence, and in some cases where several recommendation grades were listed with the consensus rate, we were unable to agree upon a unified
point of view at the Plenary Session.
The way we listed the strength of our recommendations was conducted in accordance with the ‘Minds Handbook for Clinical Practice Guideline Development 2017,’ andare as follow.
1：（Non－）implementation is strongly recommended；
2：（Non－）implementation is weakly recommended.
Opinions from related societies & associations
This time we solicited public comments from the presidents, trustees, and membersof the 10 pain－related societies and associations who were involved in the creation of
the guidelines（The Japan Society of Acupuncture and Moxibustion, the Japanese Association for the Study of Musculoskeletal Pain, the Japanese Society of Orofacial Pain,
The Japanese Headache Society, Japan College of Fibromyalgia Investigation, Japanese
Association for the Study of Pain, Japan Society of Pain Clinicians, Japanese Association
for the Study of Pain Rehabilitation, Japanese Society for the Study of Chronic Pain, andthe Japanese Society of Lumbar Spine Disorders）. We also solicited public commentsfrom the Japanese Society of Neurological Therapeutics, Japanese Society of Psychosomatic Medicine, the Japanese Orthopaedic Association, The Japan Neurosurgical Society, and the Japanese Society of Anesthesiologists. We judged whether to accept or reject the opinions we had received during the Plenary Session and added some revisions
to certain sections.
Conflict of interest（COI）
All members who were involved in the creation of these guidelines were subject topotential conflict of interest and in accordance with the regulations on conflict of interest as outlined in the “the Policy of Conflict of Interest（COI）in Medical Research”
guidelines by the Japanese Association of Medical Sciences（JAMS）, in cases where information disclosure standards were exceeded, we have listed the names of the corporation or names of the committee members.
Indications for treatments
When devising these guidelines, we consciously tried to make them easy to utilize fora large number of chronic pain－related medical practitioners, nursing representatives

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Preparative Method of these Guidelines

and patient association representatives also participated in this project and therefore
we have consciously tried to reflect many of their comments as well.
When using these guidelines, we ask medical practitioners not to just read the recommendation grades；we ask you to read through the CQ main text, answers, and commentary sufficiently before considering whether, for example, to implement or prescribe. We would also greatly appreciate it if you could also refer to the guidelines issued by the various related societies and associations. Finally, we would like to clearlystate that these guidelines are something to be of clinical use for chronic pain and not
something to be used as materials for example in a court of law.
The Committee for Clinical Practice Guidelines for Chronic Pain
Chairman

Hisashi Date, MD, PhD

288

Contents

Clinical Practice Guidelines
for the Management of Chronic Pain
Contents
Preface 

279

Introduction 

281

Preparative Method of these Guidelines 

284

Contents 

288

Authors 

296

A．Overview 

303

CQ A-1：What kind of condition is chronic pain ?（How do we define304‘chronic pain’）? 
CQ A-2：What kinds of classifications are there for chronic pain ?  304
CQ A-3：What are the characteristics of patients with chronic pain ? 307
CQ A-4：What are the purposes and ultimate goals of chronic pain
308
management ? 
309
CQ A-5：Is there a placebo effect in chronic pain management ? 

B．Diagnosis & Evaluation 

313

CQ B-1：What points need to be kept in mind when diagnosing or 
evaluating patients with chronic pain ? 
314
CQ B-2：What kinds of tests are conducted to diagnose and evaluate
315
patients with chronic pain ? 
CQ B-3：Is a quantitative evaluation of physical function and activity
317
useful for evaluating the condition of chronic pain ? 
CQ B-4：Is the quantitative sensory test（QST）useful for assessing 
the condition of chronic pain ? 318
320
CQ B-5：Is thermography useful for evaluating chronic pain ? 
CQ B-6：Is there a test that is useful as a biomarker for chronic pain ?
（brain function, brain blood flow, blood, saliva, cerebrospinal fluid etc. ?）
321

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Contents

CQ B-7：What scales are used to diagnose and evaluate chronic pain ? 322
CQ B-8：Is the evaluation of pain intensity useful for chronic pain ?  322
CQ B-9：Is the evaluation of neuropathic pain useful for chronic pain ? 325
CQ B-10：Is the evaluation of ADL/QOL useful for chronic pain ?  327
328
CQ B-11：Is psychosocial evaluation useful for chronic pain ? 

C．Pharmacotherapy 

335

CQ C-1：Are nonsteroidal anti‒inflammatory drugs（NSAIDs）useful 
for chronic pain ? 
338
340
CQ C-2：Is acetaminophen useful for chronic pain ? 
CQ C-3：Is extract from inflamed cutaneous tissue of rabbits inoculated342with vaccinia virus useful for chronic pain ? 344
CQ C-4：Are Ca2＋ channel α2δ ligands useful for chronic pain ? 
CQ C-5： Are antiepileptic drugs（carbamazepine, sodium valproate）
347
useful for chronic pain ? 
348
CQ C-6：Is duloxetine useful for chronic pain ? 
350
CQ C-7：Are tricyclic antidepressants useful for chronic pain ? 
CQ C-8：Are anxiolytics（benzodiazepine type drugs）useful for chronic352
pain ? 
CQ C-9：Are centrally-acting muscle relaxants（tizanidine, eperisone）
354
useful for chronic pain? 356
CQ C-10：Is tramadol useful for chronic pain ? 358
CQ C-11：Are buprenorphine patches useful for chronic pain ? 
CQ C-12：Are opioid analgesics [strong] useful for chronic pain ?  359
CQ C-13：Is Kampo medicine（Chinese herbal medicine）useful for
361
chronic pain? 

D．Interventional Pain Treatment（Nerve Block）

369

CQ D-1：Are epidural injections useful for chronic pain ? 370
CQ D-2：Are nerve root block/transforaminal epidural injections useful373
for chronic pain ? 
CQ D-3：Are facet（zygapophyseal）joint injection and medial branch block useful for chronic pain ? 375
378
CQ D-4：Is stellate ganglion block useful for chronic pain ? 
380
CQ D-5：Is sympathetic ganglion block useful for chronic pain ? 
383
CQ D-6：Is a trigger point injection useful for chronic pain ? 
CQ D-7：Is a nerve block using radiofrequency thermocoagulation 290Contents（RF）useful for chronic pain ? 
384
CQ D-8：Is nerve block using pulsed radiofrequency（PRF）treatment387
useful for chronic pain ? 390
CQ D-9：Are intra-articular injections useful for chronic pain ? 

E．Interventional Pain Treatment（Low-Invasive
Surgery/Orthopedic Treatments）

399

CQ E-1：Is spinal cord stimulation（SCS）useful for intractable chronic pain ? 
400402
CQ E-2：Are intradiscal therapies useful for chronic pain ? 
CQ E-3：Are spring‒guide catheters and epiduroscopy useful for 
chronic low back and leg pain ? 404
CQ E-4：Is spinal fusion useful for chronic pain associated with spinal
406
diseases ? 
CQ E-5：Is surgical therapy useful for chronic pain associated with 
strangulated peripheral neuropathy ? 
408

F．Psychological Approach 
CQ F-1：Is psychoeducation useful for chronic pain ? 
CQ F-2：Is behavioral therapy（BT）useful for chronic pain ? 
CQ F-3：Is cognitive-behavioral therapy（CBT）useful for 
chronic pain ? 
CQ F-4：Is mindfulness useful for chronic pain ? 
CQ F-5：Is acceptance and commitment therapy（ACT）useful forchronic pain ? 
CQ F-6：Is hypnotherapy useful for chronic pain ? 
CQ F-7：Is autogenic training useful for chronic pain ? 
CQ F-8：Is progressive muscle relaxation useful for chronic pain ? 

G．Rehabilitation 

415
416
417
418
419
421
422
424
425

429

CQ G-1-1：Is general exercise therapy useful for chronic pain ? 
430
431
CQ G-1-2：Is motor control exercise useful for chronic pain ? 
CQ G-1-3：Is neuroscience-based rehabilitation（neurorehabilitation）
432
useful for chronic pain ? 
CQ G-1-4： Is exercise therapy used in combination with cognitive-
behavioral therapy（CBT）,patient education, and 
occupational therapy（OT）useful for chronic pain ? 
434
CQ G-2： Is mind-body exercise（yoga, pilates, Tai chi etc.）useful for
436
chronic pain ? 
437
CQ G-3：Is physical therapy useful for chronic pain ? 291Contents

CQ G-4：Is manual therapy useful for chronic pain ? 439
440
CQ G-5-1：Is cervical collars useful for chronic pain ? 
CQ G-5-2：Are lumbar corsets（lumbar fixation belts）useful for 
chronic low back pain ? 
441
CQ G-5-3：Are knee braces（knee corsets）useful for chronic knee joint442
pain due to knee osteoarthritis（OA）? 

H．Integrative Medicine 447

CQ H-1：Are acupuncture and moxibustion useful for chronic pain ? 

448
450
CQ H-2：Is massage useful for chronic pain ? 

I．Multidisciplinary Treatment 453

CQ I-1：What is the definition of multidisciplinary treatment ? 
454
CQ I-2：What are the individual approaches（therapeutic interventions）
455
included under multidisciplinary treatment ? 
CQ I-3：What kind of staff make up the multidisciplinary treatment
team for managing chronic pain ? And what roles do the staff play ? 456
461
CQ I-4：Is multidisciplinary treatment useful for chronic pain ? 
CQ I-5：What is the cost-effectiveness of multidisciplinary treatment for chronic pain ? 
464

J．Chronic Low Back Pain 

469

CQ J-1：How to define low back pain（LBP）
470471
CQ J-2：What is the pathology of low back pain（LBP）? 
CQ J-3：Is chronic low back pain（LBP）related to lifestyle habits ? 472
CQ J-4：Is there any relationship between chronic low back pain （LBP）and one’s occupation ? 
473
CQ J-5：Are psychosocial factors related to chronic low back pain （LBP）? 474
CQ J-6：Which elements are important when evaluating chronic 
low back pain（LBP）? 
476
CQ J-7-1：Are serotonin-noradrenaline reuptake inhibitors（SNRI）
478
useful for chronic low back pain（LBP）? 
479
CQ J-7-2：Is tramadol useful for chronic low back pain（LBP）? 
CQ J-7-3：Are nonsteroidal anti-inflammatory drugs（NSAIDs）useful 
for chronic low back pain（LBP）? 
480

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Contents

CQ J-8：Is exercise therapy useful for chronic low back pain（LBP）? 481
CQ J-9：Are patient education and behavioral psychology approaches482
useful for chronic low back pain（LBP）? 

K．Knee Osteoarthritis（Knee OA）491

CQ K-1：What kind of illness is knee osteoarthritis（knee OA）? 
492
CQ K-2：Are chondroitin and glucosamine useful for knee osteoarthritis
493（knee OA）? 
CQ K-3：Is an intra-articular injection of hyaluronic acid useful for 
knee osteoarthritis（knee OA）? 
495
CQ K-4：Is total knee arthroplasty（TKA）useful for knee osteoarthritis（knee OA）when conservative therapies are ineffective at a
496
progressed stage of the illness ? 

L．Chronic Neck and Shoulder Pain
（Katakori）

501

CQ L-1：What is the pathology of chronic neck and shoulder pain
502
（Katakori）
CQ L-2：Which elements are useful for diagnosing and evaluating 
chronic neck and shoulder pain（Katakori）? 503
CQ L-3：Is pharmacotherapy useful for chronic neck and shoulder pain
503
（Katakori）? 
CQ L-4：Are interventional treatments useful for chronic neck and505shoulder pain（Katakori）? 
CQ L-5：Which elements of non‒drug and non‒invasive therapy areuseful for treating chronic neck and shoulder pain （Katakori）? 506
CQ L-6：Is there a useful way to prevent chronic neck and shoulder507
pain（Katakori）? 

M．Orofacial Pain 

511

CQ M-1：How is chronic orofacial pain classified ? 
512
513
CQ M-2-1：What is the pathology of trigeminal neuralgia ? 
CQ M-2-2：What is the algorithm for diagnosing trigeminal neuralgia ? 514
CQ M-2-3：What kind of pharmacotherapy is useful for trigeminal
515
neuralgia ? 
CQ M-2-4：What other treatments, apart from pharmacotherapy, are518
useful for treating trigeminal neuralgia ? 293Contents

CQ M-3-1：What kind of disease is burning mouth syndrome（BMS）? 521
CQ M-3-2：What is the algorithm for diagnosing burning mouth 
syndrome（BMS）? 
522
CQ M-3-3：What kinds of pharmacotherapy are useful for burning523
mouth syndrome（BMS）? 
CQ M-3-4：What other forms of treatment, apart from pharmacotherapy, are useful for treating burning mouth syndrome （BMS）? 524
CQ M-4-1：What is the pathology of persistent idiopathic dentoalveolar
525
pain ? 
CQ M-4-2：What is the algorithm for diagnosing persistent idiopathic
527
dentoalveolar pain ? 
CQ M-4-3：What kinds of treatment are there for burning mouth 
syndrome（BMS）apart from pharmacotherapy ? 
528
CQ M-4-4：What are other ways to treat persistent idiopathic dentoalveolar pain, apart from pharmacotherapy ? 
529

N．Headache 533

CQ N-1：How is headache classified ? 534535
CQ N-2：How do we differentiate dangerous headaches ? 
538
CQ N-3：How can we treat medication-overuse headache ? 
CQ N-4-1：Are anti-CGRP antibodies and anti-CGRP receptor antibodies useful for preventing chronic migraine ? 541
CQ N-4-2：Are oral drugs useful for preventing chronic migraine ? 542
CQ N-5-1：Is non-invasive（percutaneous）vagus nerve stimulation
543
useful for chronic cluster headache ? 
CQ N-5-2：Is transcranial magnetic stimulation（TMS）useful for 
chronic migraine and chronic tension-type headache ?  544
CQ N-5-3：Is acupuncture useful for chronic migraine/chronic 
tension‒type headache ? 
545

O．Herpes Zoster-Related Pain 

551

CQ O-1：What kind of pathology is herpes zoster ? 
552
552
CQ O-2：How is herpes zoster-related pain categorized ? 
CQ O-3：Is vaccine useful for preventing herpes zoster and 
postherpetic neuralgia（PHN）? 
553
CQ O-4：Is the administration of antiviral drugs, after onset of herpes
554
zoster, useful for preventing postherpetic neuralgia ? 
CQ O-5-1：Is pregabalin useful for postherpetic neuralgia（PHN）? 294

Contents

556
CQ O-5-2：Is gabapentin useful for postherpetic neuralgia（PHN）? 556
CQ O-5-3：Is mirogabalin useful for postherpetic neuralgia（PHN）? 557
CQ O-5-4：Is amitriptyline useful for postherpetic neuralgia（PHN）? 558
CQ O-5-5：Is nortriptyline useful for postherpetic neuralgia（PHN）? 559
CQ O-5-6：Is tramadol useful for postherpetic neuralgia（PHN）?  559
CQ O-6：Is performing nerve block therapy soon after onset of herpes
zoster, useful for preventing postherpetic neuralgia （PHN）? 560
CQ O-7-1：Is pulsed radiofrequency of the dorsal root ganglion （DRG-PRF）useful for herpes zoster‒related pain ? 561
CQ O-7-2：Is applying pulsed radiofrequency to the peripheral nerves562
useful for herpes zoster-related pain ? 
CQ O-8：Is spinal cord stimulation useful for postherpetic neuralgia
563（PHN）? 

P．Painful Diabetic Peripheral Neuropathy 

569

CQ P-1：What kind of pathology is painful diabetic peripheral 
neuropathy（PDPN）? 
570
CQ P-2：What are the symptoms or painful diabetic peripheral 
neuropathy（PDPN）? 
571
CQ P-3：How is painful diabetic peripheral neuropathy（PDPN）
diagnosed ? 
572
CQ P-4-1：Is blood-sugar control useful for alleviating symptoms of574
painful diabetic peripheral neuropathy（PDPN）? 
CQ P-4-2：Is blood-sugar control useful for preventing the onset of574
painful diabetic peripheral neuropathy（PDPN）? 
2＋
CQ P-5-1：Are Ca channels and α2δ ligands useful for painful diabetic
575
peripheral neuropathy（PDPN）? 
CQ P-5-2：Are serotonin-noradrenaline re-uptake inhibitors useful for577
painful diabetic peripheral neuropathy（PDPN）? 
CQ P-5-3：Are tricyclic antidepressants useful for painful diabetic
578
peripheral neuropathy（PDPN）? 
CQ P-5-4：Are antiepileptic drugs useful for painful diabetic peripheral579
neuropathy（PDPN）? 
CQ P-5-5：Is tramadol useful for painful diabetic peripheral neuropathy
581（PDPN）? 295

Contents

CQ P-5-6：Are opioid analgesics〔strong〕useful for painful diabetic
582
peripheral neuropathy（PDPN）? 
CQ P-5-7：Is Kampo medicine useful for painful diabetic peripheral583
neuropathy（PDPN）? 
CQ P-6-1：Is nerve block useful for painful diabetic peripheral 
neuropathy（PDPN）? 
584
CQ P-6-2：Is transcutaneous electrical nerve stimulations（TENS）
useful for painful diabetic peripheral neuropathy（PDPN）? 585
CQ P-6-3：Is low level laser therapy（LLLT）useful for painful diabetic
585
peripheral neuropathy（PDPN）? 
CQ P-7：Is spinal cord stimulation（SCS）useful on intractable painful
586
diabetic peripheral neuropathy（PDPN）? 

Q．Fibromyalgia 593

CQ Q-1：What kind of pathology is fibromyalgia ? 594
CQ Q-2：What are the clinical symptoms of fibromyalgia in Japan ? 

595
597
CQ Q-3：What kinds of pathology coexist with fibromyalgia ? 599
CQ Q-4：Is pharmacotherapy useful for fibromyalgia ? 
601
CQ Q-5：Is exercise therapy useful for fibromyalgia ? 
601
CQ Q-6：Are alternative therapies useful for fibromyalgia ? 
603
CQ Q-7：Is multidisciplinary treatment useful for fibromyalgia ? Index 611

296

Authors for the Clinical Guideline for the Management of Chronic Pain

Representative of Study
Shoji Yabuki

Fukushima Medical University School of Health Sciences, Dean/Department of Pain
Medicine, Fukushima Medical University School of Medicine, Professor ※ A-8：① Hoshi
General Hospital

Chairman
Hisashi Date

Sendai Pain Clinic Center, Director※ NoneAcademic Advisor（Minds）
Toshio Morizane

Japan Council for Quality Health Care

Masahiro YoshidaDepartment of Hepato-Biliary-Pancreatic and Gastrointestinal Surgery, International
University of Health and Welfare School of Medicine, Professor ※ None

※ NoneAcademic Advisor
Hiroki Iida epartment of Anesthesiology and Pain Medicine, Gifu University Graduate School ofD
Medicine, Professor ※ Pfizer

Takahiro Ushida

Multidisciplinary Pain Center, Aichi Medical University School of Medicine, Director/
Professor ※ A-4：① Daiichi-Sankyo, A-7：① Boston Scientific Japan, ② Yotei-kai, ③ Zenki Clinic, C-2：①
Boston Scientific Japan, ② Yotei-kai, ③ Zenki Clinic, ④ Nipro

Shin-ichi Konno

 epartment of Orthopaedic Surgery, Fukushima Medical University School of MediD
cine, Professor ※ A-4：① Daiichi-Sankyo, ② Pfizer, ③ Shionogi Pharma, ④ Eisai, A-7：① Eisai, ② Stryker
Japan, ③ Asahi-Kasei

Takao Takeshima

Tominaga Hospital, Deputy President※ A-4：① Eisai, ② Eli Lilly Japan, A-6：① Eli Lilly Japan,② Eisai, ③ Otsuka Pharmaceutical, ④ Amgen, ⑤ Allergan Japan

Koichi Noguchi

 yogo College of Medicine, President/Department of Anatomy and Neuroscience, HyoH
go College of Medicine, Professor ※ None

Masako Hosoi

Department of Psychosomatic Medicine, Kyushu University Hospital, Clinical Associate Professor/Multidisciplinary Pain Center, Vice-Director ※ None

Toshihiko YamashitaDepartment of Orthopaedic Surgery, Sapporo Medical University School of Medicine,
Professor ※ A-6：Nipro, A-7：① Johnson & Johnson, ② Chugai Pharma, ③ Eisai, A-8：① Zimmer Biomet,② Smith ＆ Nephew

The Committee for the Clinical Practice Guideline for Managing of Chronic Pain
Masahiko Ikeuchi epartment of Orthopaedic Surgery, Kochi Medical School, Kochi University, ProfesD
sor and Chairman ※ Reffer to Note a

Masako IsekiDepartment of Anesthesiology and Pain Medicine, Juntendo University Faculty of
Medicine, Professor ※ A-5：Shionogi

Kazunori Itoh

Department of Acupuncture and Moxibustion, Meiji University of Integrative Medicine, Dean ※ A-6：Omron Healthcare

Noboru Imai

Department of Neurology, Japanese Red Cross Shizuoka Hospital, Director

Yoshiki Imamura

Department of Oral Diagnostic Sciences, Nihon University School of Dentistry, Professor ※ None

※ None297

Hiroshi Ueno

Department of Anesthesiology, Kyoto Prefectural University of Medicine, Associate
Professor ※ None

Satoshi Kasahara epartment of Anesthesiology and Pain Relief Center, The University of Tokyo HosD
pital, Staff Doctor ※ None

Yoshiharu Kawaguchi Department of Orthopaedic Surgery, University of Toyama, Professor and Chairman※ A-4：① Daiichi-Sankyo, ② Shionogi, ③ Eisai  A-７：① Medacta, ② Stryker, ③ Depuy

Motohiro Kawasaki

 ain Management Center, National Hospital Organizations: Shikoku Medical CenterP
for Children and Adults, Director ※ None

Shinji Kimura epartment of Rehabilitation Medicine, Niigata University Medical and Dental HospiDtal,  Hospital Professor ※ None

Shizuko Kosugi

 epartment of Anesthesiology, Keio University School of Medicine, Associate ProfesD
sor ※ None

Tetsuya Sakai

Department of Pain Clinic and Anesthesia, Sasebo Kyosai Hospital, Director

Eiji SakamotoDepartment of Dental Anesthesiology, Kyushu University Faculty of Dental Science,
Lecturer ※ None

Junya Sakamoto

Institute of Biomedical Sciences, Nagasaki University, Associate Professor

Yukiko Shiro epartment of Physical Therapy, Faculty of Rehabilitation Sciences, Nagoyga Gakuin
D
University, Associate Professor ※ None

Shogo TashiroDepartment of Pain Clinic, Maehara General Medical Hospital, Director

Toshimune Namba

Namba Acupuncture Clinic, Director

Takuya Nikaido

 epartment of Orthopaedic Surgery, Fukushima Medical University School of MediD
cine, Associate Professor ※ A-4：Daiichi-Sankyo

Shinsuke HamaguchiDepartment of Anesthesiology and Pain Medicine, Dokkyo Medical University Schoolof Medicine, Professor ※ A-4：Daiichi-Sankyo

Hiroki HosogoshiPsychology Major, Department of Sociology, Faculty of Sociology, Kansai University,
Associate Professor ※ None

Ko MatsudairaD epartment of Medical Research and Management for Musculoskeletal Pain, 22nd
Century Medical and Research Center, Faculty of Medicine, The University of Tokyo-Hospital, Professor ※ Reffer to Note b

Takako Matsubara epartment of Physical Therapy, Faculty of Rehabilitation, Kobe Gakuin University,
D
Professor ※ None

※ None※ None※ None※ NoneYasuhiko Matsumori

Sendai Headache and Neurology Clinic, Director

Kenji Miki aculty of Health Science, Osaka Yukioka College of Health Science, DistinguishedF
Professor ※ Reffer to Note c

Keisuke Watanabe

Department of Pain Clinic, Nara Medical University Hospital, Clinical Professor※ None※ NoneContributors
Shuntaro Aoki

 enter for Medical Education and Career Development, Fukushima Medical UniversiCty,  Assistant Professor ※ None

Koji AsoDepartment of Orthopaedic Surgery, Kochi Medical School, Kochi University, Assistant Professor ※ A-6：Eli Lilly Japan

Tomonori Adachi

 raduate School of Human Development and Environment, Kobe University, AssisG
tant Professor ※ None

Susumu AbeDepartment of Comprehensive Dentistry, Institution of Biomedical Sciences, Tokushima University Graduate School, Lecturer ※ None

298

Takashi Iida

 ivision of Oral Function and Rehabilitation, Department of Oral Health Science, NiD
hon University School of Dentistry at Matsudo, Lecturer ※ None

Masako Igawa

Department of Oral Surgery, Shizuoka City Shimizu Hospital

Shoichi IshigakiD epartment of Fixed Prosthodontics, Osaka University Graduate School of Dentistry,
Associate Professor ※ None

Shoko ItoIntensive Care Unit, Kagawa University Hospital, Clinical Assistant Professor

Masayuki InoueI nstitute of Physical Fitness, Sports Medicine and Rehabilitation, Aichi Medical University, Physical Therapist ※ None

Narihito Iwashita epartment of Anesthesiology, Shiga University of Medical Science, Senior AssistantD
Professor ※ None

Hironobu Uematsu epartment of Anesthesiology and Intensive Care Medicine, Osaka University GraduD
ate School of Medicine, Assistant Professor ※ None

Chie UsuiDepartment of Psychiatry, Juntendo University Nerima Hospital, Associate Professor※ None※ None※ NoneKiyoka Enomoto

Graduate School of Human Sciences, Osaka University, Graduate Student

Ayano Oiwa

Department of Anesthesiology, Toho University, Assistant Professor

Satoshi Oga epartment of Physical Therapy, Faculty of Rehabilitation, Kobe Gakuin University,
D
Assistant Professor ※ None

Yuse Okawa

 orinomiya University of Medical Sciences Acupuncture Information Center, AssisM
tant Professor ※ None

Yoshinori Okubo

Okubo Clinic, Director

Kazuo Okura epartment of Stomatgnathic Function and Occlusal Reconstruction, Institute ofD
Biomedical Sciences, Tokushima University Graduate School, Lecturer ※ None

※ None※ None※ NoneHiromichi Osumi

Graduate School of Health Science, Kio University, Associate Professor

Yuka Oono

 ivision of Dental Anesthesiology, Department of Diagnostic and Therapeutic SciencDes, Meikai University School of Dentistry, Associate Professor ※ None

Tetsuya Ohnou

Department of Anesthesiology, Kagoshima City Hospital, Manager

Hiroyuki Oka

Department of Medical Research and Management for Musculoskeletal Pain, 22nd
Century Medical and Research Center, Faculty of Medicine, The University of Tokyo-Hospital, Associate Professor ※ Reffer to Note b

Yusuke OkanoueDepartment of Orthopaedic Surgery, Kochi Medical School, Kochi University, Lecturer ※ None

Kentaro Ono

Division of Physiology, Kyushu Dental University, Professor

Akifumi Kanai

Division of Dolorology, Department of Research and Development Center for New
Medical Frontiers, Kitasato University School of Medicine, Professor ※ None

Tatsuya Kaneko

Department of Medical Research and Management for Musculoskeletal Pain, 22nd
Century Medical and Research Center, Faculty of Medicine, The University of Tokyo-Hospital, Researcher ※ Reffer to Note b※ None※ None※ NoneNaohisa Kikuchi

Chiba Rehabilitation Center, Director of Hospital

Katsuhito Kiyasu

 epartment of Orthopaedic Surgery, Kochi Medical School, Kochi University, LecturD
er ※ None

Natsue Kiyonaga

Department of Anesthesiology and Critical Care Medicine, Kagoshima University
Hospital, Assistant Professor ※ None

Hironori Saisu

Pain Center, Aichi Medical University Hospital, Assistant Professor※ None※ None299

Mie Sakai

Department of Anesthesiology and Intensive Care Medicine, Nagoya City University
Graduate School of Medical Sciences, Specially Appointed Assistant Professor ※ None

Yota Sakuma

Department of Orthopaedic Surgery and Spinal Surgery, Fukushima Medical University, Aizu Medical Center, Research Assistant ※ None

Ryo Sasaki

Department of Rehabilitation, Juzenkai Hospital, Physical Therapist

Tetsunori Satake

Department of Orthopaedic Surgery, Kochi Medical School, Kochi University, Assistant Professor ※ A-6：Eti Lilly Japan

Hitoshi Sato epartment of Oral and Maxillofacial Surgery, School of Dentistry, Showa University,
D
Lecturer ※ None

Toshiki Sato

Department of Orthopaedic Surgery and Spinal Surgery, Fukushima Medical University, Aizu Medical Center, Research Assistant ※ None

Mio ShinozakiDepartment of Anesthesiology and Pain Medicine, Dokkyo Medical University Schoolof Medicine, Lecturer ※ None

Akio ShimadaDepartment of Geriatric Dentistry, Osaka Dental University, Lecturer

Kazuhiro ShimoDepartment of Physical Therapy, Faculty of Rehabilitation, Kobe Gakuin University
Assistant Professor ※ None

Toru ShiraiDepartment of Anesthesiology, Kindai University Faculty of Medicine, Associate Professor ※ NoneYuh Sugiura

Sugiura Acupuncture Clinic, Director

Natsuki SugimuraDepartment of Orthopaedic Surgery, Kochi Medical School, Kochi University, Assistant Professor ※ None

Tomohiro Soga

Department of Community Medicine and Human Resource Development, Tokushima
University Graduate School of Biomedical Sciences, Specially Appointed Associate
Professor ※ None

Yumiko Takao

Department of Pain Medicine, Hyogo College of Medicine, Professor

Naoto Takahashi

Department of Pain Medicine, Fukushima Medical University School of Medicine, Professor ※ None

Noriyo Takahashi

Tokuyukai Home-Care Center, Manager of Center

Ayano TaniguchiDepartment of Pain Management & Palliative Care Medicine, Kyoto Prefectural University of Medicine, Clinical Assistant Professor ※ None

Kousuke Chujo

 epartment of Anesthesiology, Kagawa University School of Medicine, Associate ProD
fessor ※ None

Junpei Dan

Department of Orthopaedic Surgery, Kochi Medical School, Kochi University, Surgeon

Mitsuru Doi epartment of Dental Anesthesiology, Hiroshima University Graduate School of BioD
medical and Health Sciences, Assistant Professor ※ None

Yuji Tokiwa

Division of Physical Therapy, Department of Rehabilitation, Amagasaki Daimotsu
Hospital Physical Therapist ※ None

Ryoji Tominaga

Department of Orthopaedic Surgery and Spinal Surgery, Fukushima Medical University, Aizu Medical Center, Lecturer ※ None

Tetsuro Torisu

 agasaki University Hospital Prosthetic Dentistry Care Unit, Lecturer（Hospital AsN
sociate Professor） ※ None

Masayuki Nakagawa

Department of Pain Clinic, NTT Medical Center Tokyo, Head Physician

Takuya Naganawa

Digital Hollywood University Graduate School※ None※ None※ None※ None※ None※ None※ A-1：Mutsuu, A-2：Mutsuu※ None300

Yuichiro NakasoI nstitute of Physical Fitness, Sports Medicine and Rehabilitation, Aichi Medical University, Physical Therapist ※ None

Yuto Niwa

Faculty of Rehabilitation, Kobe Gakuin University Graduate School, Doctor’s Student

Noboru Noma

Department of Oral Diagnostic Sciences, Nihon University School of Dentistry,  Associate Professor ※ None

Kiyohiko Hatano

Fuji Clinic

Takafumi HattoriDepartment of Rehabilitation, Maehara Orthopedics Rehabilitation Clinic, Physical
Therapist ※ None

Yoshinori Hayashi

Department of Physiology, Nihon University School of Dentistry, Associate Professor

Yasuhiro Banno

Faculty of Health Science, Department of Rehabilitation, Physical Therapy Course,
Nihon Fukushi University, Associate Professor ※ None

Junichi Handa

 epartment of Orthopaedic Surgery, Fukushima Medical University School of MediD
cine, Assistant Professor ※ None

Yuki Hiraga

 epartment of Occupational Therapy, International University of Health and Welfare,D
School of Health Sciences at Fukuoka, Research Associate ※ None

Tomoko Fujii

 epartment of Medical Research and Management for Musculoskeletal Pain, 22nd CenD
tury Medical and Research Center, Faculty of Medicine, The University of Tokyo-Hospital, Project Researcher ※ Reffer to Note b

Aki Fujiwara

Department of Anesthsiology, Nara Medical University, Assistant Professor

Lynn Maeda

 epartment of Anesthesia and Pain Management, Nishinomiya Municipal Central
D
Hospital, Vice-Director ※ None

※ None※ None※ None※ NoneHiroto Makino

Department of Orthopaedic Surgery, University of Toyama

Yoichi Matsuda

 epartment of Anesthesiology and Intensive Care Medicine, Osaka University GraduD
ate School of Medicine, Associate Professor/Lecturer ※ None

Atsushi Mine

 epartment of Fixed Prosthodontics, Osaka University Graduate School of Dentistry,D
Lecturer ※ None

Wataru Muraoka

 epartment of Dentistry and Oral Surgery，Kawasaki Municipal Ida Hospital, MediD
cal Manager/Department of Dentistry and Oral Surgery, Keio University School of
Medicine, Lecturer ※ None

Ryo Motoya

School of Psychological Science, Health Sciences University of Hokkaido, Associate
Professor ※ None

Tadao Morino

 epartment of Bone and Joint Surgery, Ehime University Graduate School of MediD
cine, Lecturer ※ None

Yoshikazu Yanagisawa

Spinal Disease Center and Department of Orthopedic Surgery, Fukuoka Mirai Hospital ※ A-4：① Eli Lilly Japan，② Daiichi-Sankyo

Keisuke Yamaguchi epartment of Anesthesiology and Pain Clinic, The Juntendo Tokyo Koto GeriatricD
Medical Center, Professor ※ None

Shinobu YamaguchiDepartment of Anesthesiology and Pain Medicine, Gifu University Hospital, Lecturer※ None※ NoneTasuku YamazakiDepartment of Acupuncture and Moxibustion, Meiji University of Integrative Medicine, Assistant Professor ※ None

Yoko Yamazaki epartment of Orofacial Pain Clinic, Tokyo Medical And Dental University Dental
D
Hospital, Assistant Professor ※ None

Keiko Yamada

Department of Psychology, McGill University, Postdoctoral Fellow※ None301

Noritaka Yoshimura epartment of Anesthesiology and Pain Medicine, Gifu University Graduate School ofD
Medicine, Assistant Professor ※ None

Takahiko YoshimotoDepartment of Hygiene, Public Health and Preventive Medicine, Showa University
School of Medicine, Lecturer ※ None

Hiroyuki Wada

Department of Orthopaedic Surgery, Kochi Medical School, Kochi University, Surgeon※ NoneTranslator
Matthew McLaughlin

Master of Translation and Interpreting  （English-Japanese）（MAJIT）M. Sc. Ed.

ObserverYukari Takai

School of Nursing, Gunma Prefectural College of Health Sciences, Professor※ NoneThe Association for the Support of Patients with Intractable Pain（‘Goodbye Pain’） ※ None
※ Disclosure of Conflicts of Interest
Note a：※ A-6：Eli Lilly Japan, A-７： ① Kyocera, ② Stryker Japan, ③ Hosoki Hospital, ④ Kubokawa Hospital, ⑤ Suzaki Kuroshio Hospital,⑥ Kochi Takasu Hospital, ⑦ Fujiwara Hospital, ⑧ Atago Hospital, ⑨ Shiragikuen Hospital , ⑩ Nangoku Chuo Hospital, ⑪ Maeda Hospital
Note b：A-6：① Teijin-Frontier, ② Dai-ichi Life Foundation, ③ IASP・JASP・Pfizer, A-8：① Nippon Zoki Pharmceutical，② Ayumi Pharma,③ Ono Pharma, ④ SOMPO Japan, ⑤ MS & AD InterRisk Research & Consulting,Inc, ⑥ Chugai Pharma, ⑦ The Association for Preventive Medicine of Japan, ⑧ Shionogi Pharma , ⑨医療データサイエンティスト医療 AI 機器開発機構 , ⑩ MTG
Note c：A-1：シーエックスサービス，A-4：① Daiichi-Sankyo, ② Ayumi Pharma, ③ Eisai, ④ MSD, ⑤ Mochida Pharma, ⑥ Janssen Pharma,⑦ Mundipharma, A-6：① P Mind, ② Asahi-kasei, Pfizer, A-8：Nippon Zoki PharmceuticalChapter A．Overview：CQ A-1～CQ A-5
CQ A-1：What kind of condition is chronic pain ?（How do we
define “chronic pain” ?）CQ A-2：What kinds of classifications are there for chronic pain ?
CQ A-3：What are the characteristics of patients with chronic pain ?
CQ A-4：What are the purposes and ultimate goals of chronic pain
management ?
CQ A-5：Is there a placebo effect in chronic pain management ?

304

A．Overview

A．Overview
CQ A－1：What kind of condition is chronic pain ?（How do we define ‘chronic
pain’ ?）
Answer：Chronic pain refers to ‘pain that persists or recurs for more than 3months, or pain that continues beyond the normal period required for healing.’
Commentary：
IASP：International
Association for the
Study of Pain
pain sensitization：A
condition of exacerbated reactivity ofnociceptive neurons
to standard input andreaction to input
below the normal
threshold

The International Association for the Study of Pain（‘IASP’）defines pain as “anaversire sensory and emotional experience typically caused by, or resembling thatcaused by, actual or potential tissue injury.”1). Chronic pain refers to pain that typically persists for a period of three months or more, or pain that continues beyond
the normal period required for healing. On the other hand, because chronic pain
persists beyond the regular period of time of an acute disease or the appropriate
length of time required for tissue to heal, some believe that it follows no particularperipheral sensitization：A condition of
exacerbated reactivityof peripheral
nociceptive neurons
to a receptive fieldstimulus and reduced
thresholdlength of time. These guidelines do not define specifically designated illnesses ascentral sensitization：
Exacerbated reactivityof central nervous
system nociceptive
neurons to standard
centripetal input orthat below thethresholdchanges in nerve plasticity through repetitive stimulation.

chronic pain illnesses and we have decided to consider it as a condition, based upon
the IASP’s definition.
Pain sensitization（peripheral sensitization and central sensitization）is involvedin the pathology of chronic pain and its mechanism is believed to be caused byAnother thing is that pain that persists for an extended period of time can also
involve psychosocial issues and therefore it is considered to be an incredibly complex condition2).

plasticity：Originally aterm from physics,
meaning when an
extra external force isapplied, it is unable togo back to the originalstate even after theforce disappears. With
regards to nerves,
through repetitive
stimulation, thefunctions of thesensitive nerves
cannot be restored
even after the stimulus
disappears and asensitized statepersists

pain becomes chronic, its cause is seldom exclusively due to one of these three fac-mixed pain condition

tors and in many cases it is a complex mixed pain condition involving several caus-

CQ A－2：What kinds of classifications are there for chronic pain ?
Answer：Chronic pain is classified for example by pain syndrome and mechanism. Evaluating the pain syndrome or mechanism leads to both diagnosis andtreatment.
Commentary：
Chronic pain has several classifications. When classifying by pain factors, there
are nociceptive pain, neuropathic pain, psychosocial pain and others3). When theative factors.

A．Overview

305

Table A－1 IASP Chronic Pain Classifications（ICD-11）（Cited from References #4 and #5）
1．Chronic primary pain
1.1．Widespread chronic primary pain（including fibromyalgia syndrome）
1.2．Localized chronic primary pain（including non－specific low back pain, chronic
pelvic pain）
1.x．Other chronic primary pain
1.z．Chronic primary pain not otherwise specified
2．Chronic cancer pain
2.1．Chronic pain due to cancer and metastasesNote A1
2.2．Chronic chemotherapy－induced pain
2.3．Chronic pain due to cancer surgery
2.4．Chronic pain due to radiotherapy
2.x．Other cancer－related chronic pain
2.z．Chronic cancer pain not otherwise specified
3．Chronic postsurgical and posttraumatic pain
3.1．Chronic postsurgical pain
3.2．Chronic posttraumatic pain
3.x．Other chronic postsurgical and posttraumatic pain
3.z．Chronic postsurgical and posttraumatic pain not otherwise specified
4．Chronic neuropathic pain
4.1．Peripheral neuropathic pain
4.2．Central neuropathic pain
4.x．Other neuropathic pain
4.z．Neuropathic pain not otherwise indicated5．Chronic headache and orofacial pain
5.1．Chronic primary headaches
5.2．Chronic secondary headaches
5.3．Chronic orofacial pain
5.z．Chronic headache and orofacial pain not otherwise indicated
6．Chronic visceral pain
6.1．Chronic visceral pain from persistent inflammation
6.2．Chronic visceral pain from vascular mechanisms
6.3．Chronic visceral pain from obstruction ／ distension
6.4．Chronic visceral pain from traction ／ compression
6.5．Chronic visceral pain from combined mechanism
6.6．Chronic visceral pain referred from other locations
6.7．Chronic visceral pain from cancer
6.8．Functional or unexplained chronic visceral pain
6.x．Other chronic visceral pain
6.z．Chronic visceral pain not otherwise specified
7．Chronic musculoskeletal pain
7.1．Chronic musculoskeletal pain from persistent inflammation
7.2．Chronic musculoskeletal pain from structural osteoarticular changes
7.3．Chronic musculoskeletal pain due to diseases of the nervous system
7.4．Chronic non－specific musculoskeletal pain
7.x．Other chronic musculoskeletal pain
7.z．Chronic musculoskeletal pain not otherwise specified※ As the ICD-11 is revised regularly, readers should refer to the lastest version

Note A1：“2.1. Chronic pain due to cancer
and metastases”from
the table refers to cancer pain but in Japan
does not apply as a
type of‘chronic pain.’

306

A．Overview

Table A－2

Acute Pain and Chronic Pain, Intractable Chronic Pain（Cited from Reference #7）
Acute Pain

Chronic Pain
Chronic pain which is arepetition of acute pain
Intractable chronic pain
Chronic pain which is
protracted chronic pain

Cause of pain

Stimulation of nociceptors

Stimulation of nociceptors

Functional changes incentral nervous system
Modulation due topsychosocial factors

Duration

Does not exceed period fortissue repair

Slightly exceeds period
for tissue repair

Exceeds period for tissue
repair（3 months ＜）Main accompanying
symptoms

Hyperactive sympathetic
nerves（Hyperacuteperiod）

Sleeping disorders, loss ofappetite, constipation,
inhibition of daily living
activities

Sleeping disorders, loss ofappetite, constipation,
inhibition of daily living
activities

Main psychologicalsymptoms

Anxiety

Depression, anxiety,catastrophizing

Depression, anxiety,catastrophizing

Neuropathic

Nociceptive
Psychosocial

Figure A－1 Pain Model Diagram（Cited from Reference #8）
There are 3 factors related to pain : ‘nociceptive’ : ‘neuropathic’ : and ‘psychosocial’.

IASP recommends seven classifications of chronic pain to the ICD－114,5)（Table
IASP：International
Association for the
Study of Pain

pain and do not match with the classifications used in JapanNote 1. Sometimes anmultiple parenting

item overlaps with another item and this is recognized as multiple parenting6).

1）. One of these items includes ‘cancer pain’ but the other items are all non－cancer

For the classification based on the mechanism causing chronic pain, we have assumed the concepts in Table 27) and Figure 18). The modality is also involved inthese classifications and the stronger the psychosocial factors, the more frequently
it becomes difficult to treat.

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A．Overview

Table A－3

Factors which are related to Main Non－pain Symptoms ／ Signs Exhibited by Chronic Pain Patients

1．Cognitive ／ Emotional Factors
Depression, anxiety, loss of appetite, anger, catastrophizing, fear
2．Physical Factors
Sleeping disorders, decline in ADL（immobilization and disuse）
3．Social Factors
Decline in level of social activity（time off work, school, loss of employment）,
changes in family relationships, economic stress
4．Spiritual Factors
Decline in feelings of self－worth, decline in self－efficacy
5．Other Factors
Litigation, excessive expectations from medical institutions, dependence on
treatment（medication）

Neuropathy/tissue damage
・Disuse・Functional
disorder・Depression

Remission/
Recovery

e
tiv
ta
en rs
ev io
Pr havbeSense of alarm aboutpain/ avoidance
behavior

Anxiety

Able to face pain
optimistically

ive
ns s
fe iorDe havbeOversensitive
response to pain

Pain

Fear

Negative interpretation
Pain catastrophizing
Insomnia

State of noanxiety or
fear

・Recurring
・Perceive as expanding
・Sense of powerlessness
・Negative thoughts
・Threatening illness information (eg.‘this is untreatable
illness and we do not know the cause…’)

Figure A－2 Fear－avoidance model of pain（Partly cited from Reference #11）
This shows how pain becomes intractable and serious through a cyclical interaction
with psychosocial factors as the pain lingers.

CQ A－3：What are the characteristics of patients with chronic pain ?
Answer：Among patients with chronic pain, many display a variety of symptoms
and signs apart from pain.

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A．Overview

Commentary：
Chronic pain patients exhibit a wide variety of symptoms and signs as the duration of pain increases（Table A－3）
. Depression is a typical symptom. Conclusions
have yet to be reached on whether the stress caused by pain is triggering feelingsof depression or whether a state of depression is triggering the pain as a physicalsymptom9). When the pain lingers, it becomes intractable and serious through a cyclical interaction with psychosocial factors. As the fear－avoidance model of pain illustrates, when the pain becomes intractable, it often involves catastrophizing10). In
this way, signs such as immobilization and disuse appear, triggering a decline in acADL：activities of dailyliving11)
tivities of daily living（ADL）（Figure A－2）
. When pain persists over a long periodof time, it affects one’s work and academic life. Factors such as loss of fixed employment can also lead to a decline in the quality of social activity, a deterioration in
one’s sense of belonging in the family and economic stress leads to a deteriorationin perceptions of self－worth. As a result, this leads to a vicious cycle of a decline in

QOL：quality of life

quality of life（QOL）and the occurrence of lifestyle disorders12).

CQ A－4：What are the purposes and ultimate goals of chronic pain management ?
Answer：It is difficult to attain a pain－free condition in patients with chronic
pain. Reducing pain is one of the purposes and ultimate goals of chronic pain management but not the primary goal. The goal of medical practitioners should be to
QOL：quality of life

manage chronic pain while at the same time improving the patient’s QOL and ADL.
Commentary：

IASP：International
Association for the
Study of Pain

The IASP defines chronic pain as “pain that persists longer than the expectedperiod of time required to treat an illness or disease”13). There are no clear guidelines on duration but it is generally considered to be pain that persists for threemonths or more. In addition to a wide variety of organic factors involved in chronic
pain, non－organic factors, such as psychosocial factors, and central sensitization andcognition of the nervous system are also largely involved. Therefore, it is extremely
difficult to completely rid patients of a pain in which these complex factors overlap.

ASA：American
Society of Anesthesiologists
ASRA：American Society of Regional
Anesthesia and Pain
Medicine

The Guidelines for the Treatment of Chronic Pain14) by ASA and ASRA cite thefollowing four items as their treatment purposes and ultimate goals.
① Optimize pain management, recognizing that a pain－free state may not be attainable；② Enhance functional abilities as well as physical and psychological well－being；③ Enhance the quality of life（QOL）of patients；④ Minimize adverse outcomes.

A．Overview

309

In this way, we must manage pain while minimizing adverse outcomes（side effects）induced by treatment. Improving the patient’s QOL and ADL are the purposes and ultimate goals of chronic pain management.
Medical practitioner should set the treatment goals with their patients and confirming the degree to which these goals are attained is important to obtain soundtreatment outcomes. Therefore, feasible, positive and specific treatment goals are
set. Furthermore, psychological factors that modify pain such as depression, anxiety and dissatisfaction and a behavioral assessment should be conducted and if necessary, an emotional approach should be adopted to reduce these factors. In any
case, in order to have a diversity of expression to reflect aspects such as the patient’s living circumstances regarding pain, his／her behavioral patterns and individual character, we are required to set treatment goals that are finely tailored toeach individual case. External gains such as money and compensation are major
factors affecting pain behavior. Therefore, the medical practitioner must exercise
caution when observing whether or not such factors might be involved15).

CQ A－5：Is there a placebo effect in chronic pain management ?
Answer：A large number of previous papers indicate that there is a placebo effect in the management of chronic pain.
Commentary：The ‘placebo effect’ is a phenomenon by which a patient feels effects such as an
improvement in his／her symptoms through an intervention that is essentially believed to be medically ineffective（including administering medication, intravenous
injection, surgery, various forms of intervention, and alternative medicine）.
The placebo effect has come to be widely known following reports from the
1950s16). Pain is a subjective experience to the patient and it is believed that a large
percentage of placebo effects can be accounted for by treatments that have thepurpose of alleviating pain. However, before the placebo effect itself was able to beconsidered as something which brings about the effect of alleviating pain, it first
had to go through a long history of being treated as something of a nuisance17).
There have also been some reports that have cast doubt on the actual placebo effect18). However, recently, some researchers believe in actively utilizing the placebo
effect in the treatment of pain17,19,20).
In clinical settings, placebos are used to judge the effect of many analgesics andin many research studies, including randomized controlled trials（RCTs）,they have21)

acknowledged its analgesic effects . One research study also reported that a placebo arthroscopy（a surgical procedure）had the same effect as a synovectomy22).

RCT：randomized
controlled trial

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A．Overview

The trust relationship between a medical practitioner and patient contributes toenhanced patient willingness and increased placebo effect23). There have also beensome meta－analysis reports that patient expectation in treatment can positively affect pain alleviation24).
In terms of its mechanism, some placebo effects act as naloxone antagonists so it
is believed that the placebo effect is conveyed via endogenous brain opioids25－27). In
fMRI：functional magnetic resonanceimaging

addition, research studies using functional magnetic resonance imaging（fMRI）and

PET：positronemission tomographysystem may be implicated with analgesic effects due to a placebo28). Moreover, in

positron emission tomography（PET）suggest that the descending pain inhibitory
patients where the placebo proved to be effective, reports indicated asymmetry in
the emotional regions of the cerebral cortex limbic system and an increase in thesensory area of the cerebral cortex29). As seen above, there is a large number of research reports that are trying to scientifically determine the placebo mechanism.
References
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1939
2）‌Japanese Society of Neurological Therapeutics（Supervising Editors）: Treatment Guidelines Committee, ed : The standard neurological therapeutics :Chronic pain. Neurological Therapeutics 2010 ; 27 : 595－602
3）‌Inoue M, et al : 痛みの概念，定義．（Taguchi T, ed : 慢性疼痛疾患）．Saishin
Igakusha, Osaka, 2016 ; 8－14
4）‌Treede R－D, et al : A classification of chronic pain for ICD－11. Pain 2015 ; 156 :1003－1007 doi : 10.1097/j.pain.0000000000000160. PMID : 25844555
5）‌Nishie H : Over view of pain medicine : Epidemiology.（Japanese Association
for the Study of Pain, Core Curriculum for the Education of Pain Editorial
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6）‌Kitahara M : Definition of pain : Over view of pain medicine : Epidemiology.
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7）‌Kumazawa T “5
: 痛みの学術的アプローチへの提言”．（Sugahara T, supervising ed : 慢性疼痛はどこまで解明されたか），Showado, Tokyo, 2005
8）‌Kitahara M : Definition of pain : Over view of pain medicine : Epidemiology.
（Japanese Association for the Study of Pain, Core Curriculum for the Education of Pain Editorial Committee, ed.）: Multidisciplinary pain management :Core curriculum for education in pain. Shinko Trading Co. Ltd., Tokyo, 2016 ; 16
9）‌Nishihara M : Psychiatric aspects of pain and pain behavior. Pain Clinic（JPN）
2016 ; 37 : 741－747
10）‌Udo Y, et al : Predictive factors for degree of pain catastrophizing in patientswith chronic lower back pain. JJSPC 2017 ; 24 : 12－16
11）‌Leeuw M, et al : The fear－avoidance model of musculoskeletal pain : Current
state of scientific evidence. J Behav Med 2007 ; 30 : 77－94 doi : 10.1007/s10865－
006－9085－0. PMID : 17180640

A．Overview

12）‌Adachi T, et al : Effects of pain self－efficacy and other cognitive－emotional
factors on Health－related Quality of Life, and Pain Interference in Japanesechronic pain patients. The Journal of the Japanese Society for the Study ofChronic Pain 2015 ; 34 : 107－111
13）‌Merskey H, et al : Classification of chronic pain, 2nd ed : Descriptions ofchronic pain syndromes and definitions of pain terms. IASP, Seattle, 1994
14）‌American Society of Anesthesiologists Task Force on Chronic Pain Management : American Society of Regional Anesthesia and Pain Medicine : Practiceguidelines for chronic pain management : An updated report by the American Society of Anesthesiologists Task Force on Chronic Pain Management
and the American Society of Regional Anesthesia and Pain Medicine. Anesthesiology 2010 ; 112 : 811－833 doi : 10.1097/ALN.0b013e3181c43103. PMID :20124882
15）‌Marcus DA : Chronic pain : A preliminary care guide to practical management 2nd ed. New York, Humana Press, 2009 ; 15－34 doi : 10.1111/odi.12747
16）‌Beecher HK : The powerful placebo. J Am Med Assoc 1955 ; 159 : 1602－1606
doi : 10.1001/jama.1955.02960340022006. PMID : 13271123
17）‌Colloca L : The placebo effect in pain therapies. Annu Rev Pharmacol Toxicol
2019 ; 59 : 191－211 doi : 10.1146./annurev－pharmtox－010818－021542. PMID :3021674418）‌Hróbjartsson A, et al : Is the placebo powerless? An analysis of clinical trials
comparing placebo with no treatment. N Engl J Med 2001 ; 344 : 1594－1602
doi : 10.1056/NEJM200105243442106. PMID : 11372012
19）‌Finniss DG, et al : Biological, clinical, and ethical advances of placebo effects.
Lancet 2010 ; 375 : 686－695 doi : 10.1016/S0140－6736（09）61706－2. PMID : 20171404
20）‌Turner JA, et al : The importance of placebo effects in pain treatment and research. JAMA 1994 ; 271 : 1609－1614 doi : 10.1001. PMID : 788022121）‌Derry S, et al : Topical analgesics for acute and chronic pain in adults－an
overview of Cochrane Reviews. Cochrane Database Syst Rev 2017 ; 5 :CD008609 doi : 10.1002/14651858.CD008609.pub2. PMID : 28497473
22）‌Moseley JB, et al : A controlled trial of arthroscopic surgery for osteoarthritisof the knee. N Engl J Med 2002 ; 347 : 81－88 doi : 10.1056/NEJMoa013259.
PMID : 12110735
23）‌Nakano S, et al : Factors influencing placebo effects in patients with psychosomatic disorders : doctor－patient relationship, patient’s motivation and expectation for drug therapy. Rinsyoyakuri 1999 ; 30 : 1－7
24）‌Peerdeman KJ, et al : Relieving patients’ pain with expectation interventions : A meta－analysis. Pain 2016 ; 157 : 1179－1191 doi : 10.1097./j.pain.00000000
00000540. PMID : 26945235
25）‌Levine JD, et al : The mechanism of placebo analgesia. Lancet 1978 ; 8091 : 654－
677 doi : 10.1016/s0140－6736（78）92762－9. PMID : 80579
26）‌Benedetti F, et al : Mechanisms of the placebo response. Pulm Pharmacol
Ther 2013 ; 26 : 520－523 doi : 10.1016/j.pupt.2013.01.006 PMID : 23370213
27）‌Wager TD, et al : Placebo effects on human mu－opioid activity during pain.
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28）‌Eippert F, et al : Activation of the opioidergic descending pain control system
underlies placebo analgesia. Neuron 2009 ; 63 : 533－543 doi : 10.1016/j.neuron.
2009.07.014
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1038/s41467－018－05859－1

311

Chapter B．Diagnosis & Evaluation：CQ B-1～CQ B-11
CQ B-1：What points need to be kept in mind when diagnosing or
evaluating patients with chronic pain ?
CQ B-2：What kinds of tests are conducted to diagnose andevaluate patients with chronic pain ?
CQ B-3：Is a quantitative evaluation of physical function and activity
useful for evaluating the condition of chronic pain ?
CQ B-4：Is the quantitative sensory test（QST）useful forassessing the condition of chronic pain?
CQ B-5：Is thermography useful for evaluating chronic pain ?
CQ B-6：Is there a test that is useful as a biomarker for chronic
pain ?（brain function, brain blood flow, blood, saliva,
cerebrospinal fluid etc. ?）CQ B-7：What scales are used to diagnose and evaluate chronic
pain ?
CQ B-8：Is the evaluation of pain intensity useful for chronic pain ?
CQ B-9：Is the evaluation of neuropathic pain useful for chronic
pain ?
CQ B-10：Is the evaluation of ADL/QOL useful for chronic pain ?
CQ B-11：Is psychosocial evaluation useful for chronic pain ?

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B．Diagnosis & Evaluation

B．Diagnosis & Evaluation
CQ B－1：What points need to be kept in mind when diagnosing or evaluating
patients with chronic pain ?
Answer：An important point when diagnosing chronic pain patients is having an
accurate understanding of the patient’s condition and confirming whether any highly urgent diseases are present or not. The patient’s pain needs to be assessed holistically so that it leads to suitable treatment and care for each individual patient.
Commentary：
The most important thing when diagnosing chronic pain is taking the patient’s
history on their pain（including chief complaints, a history of their current illness,case history, family history, duration of pain, intensity of pain, pain patterns, aspects
and characteristics of their pain）and also conduct a physical examination（visualinspection, percussion, palpation, auscultation, neurological findings such as muscular strength, sensation or reactions）. In addition, where necessary, blood tests, diagnostic imaging, and neurological exams should be conducted to determine the root
cause of the pain and its pathology. In particular, attention should be paid to whether any underlying conditions such as inflammatory diseases and malignant tumors

Taking patient history
Main complaints, current history,
past history, family history
Conclusion

Since when, how,what is the cause

Examination
Inspection, palpation, auscultation
TherapeuticscienceDiagnostics

Conclusion

Exam
Blood test, image test
Simple X-ray, CT, MRI,
scintigraphy, PET etc.

Understand the pathology= diagnosis

Figure B－1

Method for diagnosing patients with chronic pain

B．Diagnosis & Evaluation315

are present when proceeding with the diagnosis.（Figure B－1）. Even when seeing
chronic pain patients over time, when new symptoms emerge, physical examinations and where necessary tests must be conducted to confirm the primary diseaserequiring treatment and any underlying pathologies that had not been apparent
before.1,2)
On the other hand, chronic pain can be divided into factors based on the pain
mechanism such as ‘nociceptive’，‘neuropathic’ and ‘psychosocial.’1）. However, inmany cases chronic pain is not caused by a single mechanism；these factors coexist and are intricately interrelated. Therefore, in order to select the suitable treatment and care required for each individual patient, there is need for a multifaceted
evaluation based on a biopsychosocial model. The items illustrated in Table B－1 arenecessary for a multifaceted evaluation3). Doctors needs to conduct an overall（holistic）evaluation of chronic pain patients.
Table B－1

Multifaceted Evaluation of Chronic Pain

1．Intensity, site, nature of pain, patterns, progression, changes throughout the day,enhancing and alleviating factors of pain
2．Psychological state : A questionnaire is used to take patient history regarding
matters such as anxiety, depression, angry emotions, fear, feelings of low self－
efficacy, a negative cognitive state called‘catastrophizing’, feelings of unfairness,feelings of distrust etc.
3．How one spends the day, degree of impairment in ADL, current sleeping habits
4．Development history, family history, family structure and current situation
5．Illnesses and clinical conditions in the field of psychiatry
6．History of substance dependence
7．Academic background, employment history, job details and conditions
8．Compensation and litigation
9．Exercise habits
10．Changes in diet and weight

CQ B－2：What kinds of tests are conducted to diagnose and evaluatepatients with chronic pain ?
Answer：It goes without saying that when diagnosing patients with chronic pain,
one needs to take a detailed history and tests in order to have an accurate understanding of the patient’s condition. However, because pain is a subjective experi4) Note B1
ence, much evaluation is conducted using an evaluation form（questionnaire）.

In recent years, a variety of tests have been conceived and developed in order toobjectively evaluate patients with chronic pain but at the current stage, there is insufficient evidence regarding its usefulness. Therefore, we expect this to be verified
in future.

Note B1：Refer to B-7

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B．Diagnosis & Evaluation

Table B－2

Examination & Testing for Diagnosing Chronic Pain

Taking history

History of disease & treatment, past injury, accidents, history ofsurgery, pre－existing conditions, employment history, history ofabsence from work, family history, family make－up, compensation,
litigation

Visual examination

Abnormal posture, gait disorder, edema, muscular atrophy,
involuntary movement,
Abnormal perspiration, changes in skin tone, presence of rash

Palpation

Tender points, muscle tension, psychroesthesia, sensations of heat

Neurological test

Dermatome,existence of sensation abnormalities［hypoesthesia,
hypersensitivity, allodynia］muscular strength, deep reflex,
pathological reflex

Blood test

Blood cell count, CRP, protein fractionation, electrolytes, sugar
metabolism, liver & kidney function, others

Imaging tests

X－ray, CT, MRI ／ MRA, ultrasound, scintigraphy etc.

Electrophysiological Peripheral nerve conduction velocity test, electromyogram,
testelectroencephalogram

Commentary：1）Diagnosing pain in patients with chronic pain
In many cases, patients have been suffering from pain over a long period of time,
have taken tests and received diagnoses from other facilities and have undergone
treatment. In order to avoid being misled by the diagnosis pronounced at otherhospitals and clinics, doctors need to re－examine patients once again for an accurate pathology and disease. In order to do this, patient history, a visual examinationand palpation need to be conducted in fine detail as well as neurological tests on
cranial, sensory and motor nerve, perception, muscular strength and reflexes, pain
provocation tests, range of motion（ROM）tests（on joints）, if necessary, blood test,
imaging tests（X－ray, CT, MRI, ultrasound, scintigraphy）, and electrophysiologicaltests（nerve conduction test, and electromyogram（EMG）etc.）should also be con5)
ducted（Table B－2）
. Careful attention needs to be paid to primary diseases thatshould be immediately treated such as malignant diseases, infections, bone fractures and neuromuscular diseases and if necessary, it is also important to consult a
specialist about them. On the other hand, with chronic pain, evaluations should proceed not only based on the anatomical changes obtained from these tests but also
by taking into account the multiple factors involved in each individual patient.
2）Attempts to Objectively Evaluate Chronic Pain Patients
Attempts are being made to objectively evaluate chronic pain patients. Thermography, which can visually catch a patient’s body surface temperature, allows us tomeasure the temperature on skin. This is used to investigate the differences be-

B．Diagnosis & Evaluation

317

tween a healthy side and the afflicted side, as well as changes in temperature at
the site of disease over time. However, skin temperature is prone to be affected by
the temperature of the（surrounding）environment. Therefore, caution is required
when comparing changes over time6) Note B2. A perception／pain quantitative analyti-

Note B2：Refer to B-5

cal device and current perception threshold（CPT）measuring devices are commercially available in the attempt to try and objectively measure the strength of pain.
Quantitative sensory testing（QST）is a quantitative evaluation method of psychophysically evaluating subjective pain, using static QST that investigates the senso-

QST：quantitative
sensory testing

ry receptivity of peripheral nerves to each form of stimulus, and dynamic QST thatinvestigates changes in pain perception repeatedly from a physical nociceptive
stimulus at（or near）the site of pain and at a site away from the site of pain7) Note

Note B3：Refer to B-4

B3. With evaluations of pain by quantitatively measuring physical function and phys-

ical activityNote B4, attempts are being made to shed light on pain through brain

Note B4：Refer to B-3function imaging tests such as MRI and PET. We have begun to understand phenomena such as the atrophy of gray matter from chronic pain on MRI, and that thedefault mode network（network of brain activity at rest）changes due to a chronic
pain state8－10). Research is also being conducted in which blood, saliva and spinal
fluid are being tested to reveal the biomarkers that can serve as indicators to evaluate painNote B5.

Note B5：Refer to B-6

CQ B－3：Is a quantitative evaluation of physical function and activity usefulfor evaluating the condition of chronic pain ?
Answer：Because physical function and physical activity are deeply involved in
the condition of chronic pain, conducting a specific evaluation of these factors will
extract issues and serve as indicators for making the suitable choice for treatment,intervention and management and their efficacy so it is useful for evaluating thecondition of chronic pain.
Commentary：
As the fear－avoidance model of pain indicates, physical function and physical activity are deeply involved in the development and exacerbation of chronic pain andhave a strong influence over not only pain but also ADL and QOL. Therefore, evaluating the physical function and activity in chronic pain patients is important forunderstanding their pathological condition11). To be more specific, evaluation forms（questionnaires）investigating patient－based outcomes are usedNote B6，which measure and evaluate actual physical function, exercise performance and the amount ofphysical activity.
When evaluating physical function and exercise performance, it is recommended

ADL：activities of dailyliving
QOL：quality of life
Note B6：Refer to B-10

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B．Diagnosis & Evaluation

to evaluate muscular strength, range of joint motion, balance function, movement
capabilities and ADL－related factors11,12). To be more specific, there is the one－legged standing（OLS）test and one－legged hop for evaluating patients’ balance
functions. The Time Up and Go（TUG）and the 10 Meter Walk Test（comfortable
walking speed and maximal walking speed）are widely used to asses movement capabilities. In addition, there is the Six Minute Walk Test to assess exercise tolerance and for assessing ADl－related performance, there are for example the 30－Second Chair Stand Test and the Stair Climb Test.
For evaluating the amount of physical activity, there are questionnaires such as
IPAQ：International
Physical Activity
Questionnaire

13,14)
the International Physical Activity Questionnaire（IPAQ）
and Physical Activity
15,16)
Scale for the Elderly（PASE）
to investigate activity within the home, work－re-lated activity, movement, leisure activity and non－active time. IPAQ is designed for
adults（15～69 years old）whereas PASE is for elderly patients. Also when evaluating the actual physical activity measured, the utilization of activity recording instruments such as activity meters and pedometers are recommended for measuring data such as time of activity, non－active time, number of steps and walking distance.

CQ B－4：Is the quantitative sensory test（QST）useful for assessing thecondition of chronic pain?
QST：quantitative
sensory testing

Answer：The quantitative sensory test（QST）indicates the different characteristics between patients with chronic pain and healthy subjects and there are many
clinical research studies that indicate its usefulness. However, the QST results provide insufficient evidence for categorizing the chronic pain pathology or for deciding on a method of treatment.
Commentary：
The QST is one form of psychophysical methods and can be broadly divided into
static QST and dynamic QST17). Static QST is a test that investigates the ‘condition’of receptivity, mainly in the peripheral nerves and serves as an indicator for somatic sensations such as tactile and vibratory perception, heat and cold as well as serving as a pain perception threshold such as with pressure pain and heat／cold pain.
On the other hand, the dynamic QST is a test that serves as an indicator of the‘function’ of pain modulation in locations above the peripheral nerves, and consists

TSP：temporalsummation of pain
CPM:：conditioned
pain modulationof temporal summation of pain（TSP）and conditioned pain modulation（CPM）.
The TSP is an indicator for the sensitization of abnormalities, like wind－up, in theascending pain transmission system, whereas the CPM serves as an indicator thatreflects dysfunctions in the descending pain inhibitory system.

B．Diagnosis & Evaluation① Knee osteoarthritis
In knee osteoarthritis, researchers have indicated the possibility that pressure
pain threshold and TSP are related to the degree of severity of pain symptoms.
However, there is insufficient evidence indicating its relationship with the cold pain
threshold18) . In addition, some studies have shown that CPM was reduced in patients with knee osteoarthritis compared with healthy subjects18). With the prognostic predictions using QST, one study showed that in cases indicating a clear decline in CPM, analgesic effects were low19), in cases of exacerbated TSP, pain tended to be protracted after prosthetic joint replacement surgery20）, and in cases
showing a recognizable decline in the pressure pain threshold over a wide area, patients’ response to exercise therapy as a form of treatment was low21).
② Non－specific chronic low back pain
Systematic reviews comparing the QST values for non－specific chronic low backpain with healthy subjects showed a decline in the pressure pain threshold in remote sites including the upper and lower limbs, and exacerbated TSP in the lumbar area. However, there are few reports related to CPM and in addition, there is alack of uniformity among the protocols, meaning that a fixed point of view has not
yet been obtained22).
③ Fibromyalgia
Cases of fibromyalgia have a lower heat pain threshold than healthy subjects,
with reports that their cut－off value is a sensitivity of 39.1 ℃, with a sensitivity of
63.5%, and specificity of 78.9%. The cut－off value for CPM is －1.0（amount ofchange in VAS）with a sensitivity of 45.7% and specificity of 78.9%23). Furthermore, in systematic reviews comparing TSP and CPM with healthy subjects, they
indicated exacerbated TSP, and reduced CPM but there is an extremely small
number of research studies using them as tools in diagnosing fibromyalgia and formaking prognostic predictions meaning it does not provide us with conclusive evidence24).
In this way, there have been various reports on chronic pain patients regarding
a reduced heat pain threshold18,22,23), exacerbated TSP, reduced CPM and dysfunction18,22,24,25). On the other hand, systematic reviews that considered the correlations
between factors such as CPM, pain intensity and impaired function were unable toestablish a significant correlation between them25). Therefore, at the current stage,
we have been unable to ascertain the validity of QST（especially dynamic QST）asa clinical and experimental pain biomarker. Future research needs to strongly focus on for example establishing a standardized measuring method25,26) and multiple
verifications, which incorporates several forms of QST（for example ones that are
TSP and CPM based）
.

319

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B．Diagnosis & Evaluation

CQ B－5：Is thermography useful for evaluating chronic pain ?
Answer：Thermography measures the distribution of temperature on the surfaceof the body using infrared light and is one type of physiological method that displays data visually. In chronic pain, it is used to assess the degree of severity of the
primary illness and the effects of treatment. However, in terms of the usefulness ofthermography, there is insufficient evidence for it to be used to give a definite diagnosis of chronic pain and for classifying its level of severity. At the current stage,
RCT：randomized
controlled trial

we expect randomized controlled trials（RCTs）to be conducted using it in future
on a variety of illnesses and pathologies.
Commentary：
To date, there have been several observational studies that conducted exploratory evaluations of changes in skin temperature using thermography as an indicatorof pathologies and outcomes for some diseases, while no RCTs had verified the usefulness of thermography.
As vasomotor disturbances and changes in skin temperature occur in complex

CRPS：complex
regional pain
syndrome

regional pain syndrome（CRPS）due to the impaired function of sympathetic

IASP：International
Association for the
Study of Pain

IASP’s criteria27) for assessing CRPS includes the differences in skin temperaturenerves, thermography has long been utilized as an auxiliary diagnostic tool. The
between the affected and contralateral areas. In a joint multicenter study28) that examined 296 CRPS patients following the IASP’s diagnostic criteria, researchers utilized infrared thermography imaging to assess the difference in skin temperature（⊿T）between the affected limb and non－affected limb. The average ⊿T ± standard deviation（SD）was －0.72±1.65 ℃. The ⊿T was under 1 ℃ in 131 patients,
failing to achieve the assessment criteria（⊿T＞1 ℃）advocated by the IASP29).
Furthermore, there has been no correlation between the duration of symptoms and⊿T. With CRPS, it cannot be used to assess skin temperature on regular occasions
but some are of the opinion that it should be used to measure body temperaturewhen the sympathetic nerves are stimulated when conducting whole-body cooling.
However, there are limits to its usefulness in actual clinical conditions30). Therefore,
for the purpose of making a diagnosis, the diagnostic accuracy of using a thermography alone need to be considered31).
There exist some observational studies on herpes zoster, investigating the changes in skin temperature according to the stage of the disease, in its acute phase, sub－acute phase, and chronic phase32).
There have been reports on low back pain（LBP）and tension type headache inwhich the site of pain matched with the site of skin temperature abnormality33).
Furthermore, skin blood flow increases through treatment interventions such as rehabilitation and trigger point injections and some reports have assessed its effects

B．Diagnosis & Evaluation321

as a treatment34).
Researchers have acknowledged that in chronic pain that comes with impaired
blood flow such as from thromboangiitis obliterans and arteriosclerosis obliterans,
there is a decline in skin temperature due to reduced blood flow. Furthermore,
thermography is used to assess the effects of sympathetic nerve block and to confirm improvements in impaired blood flow.35).

CQ B－6：Is there a test that is useful as a biomarker for chronic pain ?（brain
function, brain blood flow, blood, saliva, cerebrospinal fluid etc. ?）Answer：At the current stage, there are no verified biomarkers that can be used
to detect the prevention, early diagnosis, or relapses of chronic pain. However,there are reports on tests that could potentially be considered according to eachdisease.
Commentary：
In randomized controlled trials（RCTs）conducted since 2010, several biomarkers
have been used, in an explorative manner, as indicators for the treatment outcome

RCT：randomized
controlled trialof chronic pain.
In a systematic review that considered the effects of exercise therapy on chronic
pain, blood－based biomarkers were used as indicators of outcomes in 4 RCTs36). As
chronic pain is thought to be a malfunction of the immune system, proinflammatory
and anti－inflammatory markers were used. In research that introduced exercise
therapy on patients with knee osteoarthritis（OA），researchers observed a reduction in Interleukin－6（IL）, a proinflammatory cytokine, and also tumor necrosis fac-knee OA：knee
osteoarthritis

tor（TNF）
α －receptors 1 and 237,38). In addition, in a research study examining theeffects of exercise therapy on subjects with low back pain, showed found that catechol－O－methyltransferase（COMT）genes and single nucleotide polymorphism（SNP）were related to pain, anxiety and depression39).
There have been no RCTs or systematic reviews on biomarkers in the saliva forchronic pain, only 2 case control research studies and a pilot research study40,41).
A systematic review on CRPS reported an increase in the concentration of IL-1β
and IL-6 and a decrease in soluble intercellular adhesion molecule-1（sICAM-1）inthe cerebrospinal fluid of CRPS patients42).
No systematic reviews exist on the relationship between chronic pain and brain
blood flow but there have been reports of 2 RCTs43,44). There have been numerous
reports on the relationship between changes in functional connectivity and severityof pain and psychological factors in various chronic pain patients using functional
magnetic resonance imaging（fMRI）, but the usefulness of fMRI as a biomarker

fMRI：functional magnetic resonanceimaging322

B．Diagnosis & Evaluation

have yet to be established45,46）.
A systematic review on proton magnetic resonance spectroscopy（1H-MRS）that
could quantitatively measure the level of neurometabolites（glutamic acid, γ‒aminobutyric acid）indicated that 1H-MRS is expect to develop as a biomarker by improving measurement techniques47）.
In addition, a meta‒analysis that assessed the relationship between the length
patterns of the third finger, and OA and chronic joint pain reported that the Type-3
pattern (the ring finger ＞ the index finger) was related to symptomatic knee andhand OA and indicated the possibility of adopting it as a non-invasive biomarker
for identifying the risks of such diseases48).

CQ B－7：What scales are used to diagnose and evaluate chronic pain ?
Answer：Since chronic pain involves multiple factors, it is hard to assess it by an
unified scale. Scales that diagnose and evaluate chronic pain include ones for the intensity and nature of pain, dysfucntion, ADL/QOL, and pain affect/cognition, which
are used in accordance with the objectives.
Commentary：
At the current stage, there is no single scale that has been certified as being able
to express actual pain itself49). In particular, chronic pain includes multiple factors
so currently the situation is that a diverse range of scales are being used in combination to diagnose and evaluate pain（Table B－3）. However, each indicator records
pain over time so patients are able to evaluate how their pain changes and the effects of treatment3). When utilizing the scales, attention must be paid to how theymight be influenced by age, culture, language, cognitive ability or communication
ability. As a basic premise, one should choose a scale which is easy for patients tocomprehend, and of which reliability and validity has already been tested50). In addition, one should listen attentively to patients’ complaints and at the same time observe their behaviors and attitudes；it is necessary to integrate all the informationthat is useful for making a decision about the treatment policy.

CQ B－8：Is the evaluation of pain intensity useful for chronic pain ?
Answer：Pain intensity is one of the most general items used in clinical evaluations. Self－reports from patients are widely used as a method to evaluate the painand evaluation tools including for example the visual analogue scale（VAS）,numerical rating scale（NRS）, verbal rating scale（VRS）and the Faces Pain Scale－Re-

B．Diagnosis & Evaluation

Table B－3

Pain－related Questionnaires & Scales

1．Pain Intensity
・NRS : numerical rating scale
・VAS : visual analogue scale
・FRS : Wong－Baker Faces pain rating scale
2．Nature of Pain
・MPQ : McGill Pain Questionnaire
・SF－MPQ : Short－Form McGill Pain Questionnaire
・Pain drawings
3．Neuropathic Pain
・Neuropathic Pain Screening Questionnaire・painDETECT・Spine painDETECT
・DN4 : the Douleur Neuropathique en4 questions
・NPSI : Neuropathic Pain Symptom Inventory
・LANSS : the Leeds Assessment of Neuropathic Symptoms and Signs ／S－LANSS : Short versions of the LANSS
・NPQ : Neuropathic Pain Questionnaire
4．Evaluation of Dysfunction（illness ／ site specific evaluation）
・DASH : Disabilities of the Arm, Shoulder and Hand
・WOMAC : Western Ontario and McMaster Universities Osteoarthritis Index
・JOACMEQ : Japanese Orthopaedic Association Cervical Myelopathy Evaluation
Questionnaire
・JOABPEQ : Japanese Orthopaedic Association Back Pain Evaluation Questionnaire・RDQ : Roland－Morris Disability Questionnaire
・ODI : Oswestry disability index
・NDI : Neck disability index
・HIT－6 : Headache Impact Test
・DC ／ TMD : Questionnaires from Diagnostic Criteria for Temporomandibular Disorders
・DC ／ BMS : Questionnaires from Diagnostic Criteria for Burning Mouth Syndrome
5．Evaluation of ADL ／ QOL
・BPI : Brief Pain Inventory related items
・MPI : Multidimensional Pain Inventory related items
・PDAS : Pain Disability Assessment Scale
・SF36 : Short－Form36－Item Health Survey
・EQ－5D : EuroQol5 Dimension
6．Evaluation of Pain Affect ／ Cognition
・HADS : Hospital Anxiety and Depression Scale
・STAI : State－Trait Anxiety Inventory
・BDI : Beck Depression Inventory
・POMS : Profile of Mood States
・PCS : Pain Catastrophizing Scale
・TSK : Tampa scale for kinesiophobia
・FABQ : Fear－Avoidance Beliefs Questionnaire
・BS－POP : Brief Scale for Psychiatric Problems in Orthopaedic Patients・PSEQ : Pain Self－Efficacy Questionnaire
・MPI : Multidimensional Pain Inventory
・SCL－90 R : Symptom Check List 90 Revised

323

324

B．Diagnosis & Evaluation

vised（FPS－R）. It is recommended to not only evaluate intensity of pain in chronic
pain examinations, but to include it alongside other evaluation items and conduct acomprehensive evaluation.
Commentary：
Because pain is an internal and personal experience, self－reports are currently
accepted as a form of measurement of pain, in a wide sense. Intensity of pain is themost general item in clinical evaluations of pain51).
VAS：visual analogue
scale
NRS：numerical rating
scale
VRS：verbal rating
scale
FPS-R：face pain
scale-revised

VAS, NRS, VRS and FPS－R are widely used as scales to represent intensity of
pain. Of these, VAS and NRS have a strong correlation and both are considered tobe superior to VRS52). Writing materials are not necessary to measure using NRS
and methods such as phone interviews and asking patients to directly type in responses into a computer database can also be handled. In systematic reviews53,54)
comparing the usefulness and practicality of each respective scale, when evaluating
intensity of pain in a one－dimensional manner, NRS is believed to be the easiest
one to use in terms of sensitivity, convenience and a high level of compliance.
VAS is hard to comprehend compared with other scales and in particular, suitable results are unobtainable in elderly patients. On the other hand, as it is a continuous scale, it is possible to use it for comparing data.
Just like with VRS, NRS and VAS, there is a strong correlation with otherscales53). VRS utilizes adjectives to represent different levels of pain and because
respondents have to read the whole list included on the scale, it is more time－consuming than other methods but it has an equal or superior level of compliance toother methods. Because the expressions used in VRS might sometimes be interpreted differently by individual respondents and as it depends on the circumstances（for example, pre－and post－surgery comparisons, and comparisons between respondents etc.）, it may not be suitable for comparing two phenomena or events.
FPS－R is recommended for children or patients who have limited language abilities53).
There are several research reports that have investigated the minimal clinicallyimportant changes（MCID）of each scale in cases of chronic pain disease. A study
reported an MCID was of approximately 20mm55) on the VAS in patients withchronic low back pain, and another reported that an MCID was 2 points decrease（or 30% reduction）56) on the NRS in chronic pain patients who were treated withpregabalin. In a study on patients with chronic musculoskeletal pain, they reported
a 1 point decrease（or 15% decrease）in NRS as an MCID57), and on top of this, inthe same research study, a 2 point, or 33% decrease on the NRS matched with apatient’s improved condition which was “far greater”（than compared with before）.
Compared with NRS, VAS, VRS and FPSR have been reported to be more influenced factors other than pain intensity, such as pain-related interference and dis-

B．Diagnosis & Evaluation

comfort58）.
When evaluating the intensity of pain, there is a possibility that the current pain
data we are getting from the above scales are not accurately reflecting the overallpain of the patients. Scales such as the Brief Pain Inventory（BPI）and Graded
Chronic Pain Scale（GCPS）are designed to self-report the maximum, minimum
and average pain intensity during a fixed period of time（for example over the past53)
24 hours or over the past 1 week）.

Although the scales above are widely used in clinical settings, in chronic paincare, there are no research studies that investigate the usefulness of evaluating
pain intensity. When evaluating chronic pain, it is recommended that doctors do
not just evaluate pain intensity but make a comprehensive judgement by incorporating other evaluation factors as well.

CQ B－9：Is the evaluation of neuropathic pain useful for chronic pain ?
Answer：In chronic pain care, evaluation of neuropathic pain is useful for deciding on a treatment policy. Screening questionnaires are utilized to identify patients
who might be suffering from neuropathic pain. A diagnosis of neuropathic pain is
ascertained through taking patient history, conducting a neurological examinationand tests to diagnose neurological disease and lesions, following an algorithm.
Commentary：
Various factors are implicated when chronic pain arises. As the treatment policy
for neuropathic pain is different from that of other diseases and pain, it is necessary
to confirm the presence or absence of neuropathic pain in order to have the appropriate treatment59).
The screening questionnaire is used to distinguish between patients who haveneuropathic（especially non－specific）pain. For example, there is the Leeds Assessment of Neuropathic Symptoms and Signs（LANSS）and the Short Version of the
LANSS （S－LANSS）, Neuropathic Pain Questionnaire （NPQ）, Douleur Neuropathique Pain Questionnaire（DN4）, painDETECT, ID Pain59)，and the reliability
and validity of each respective questionnaire has been proven but each of them is
supported by a low amount of evidence60). Each questionnaire has been translated
into many languages, and Japanese versions have been developed for the LANSS,
DN4, and PainDETECT questionnaires. In Japan, they have developed the Neuropathic Pain Screening Questionnaire61) and Spine painDETECT for evaluating spinal disease－derived neuropathic pain.62)
Although a screening questionnaire is useful in terms of how it simply distinguishes between patients who have neuropathic pain and those who do not, there

325

326

B．Diagnosis & Evaluation

is no information on the questionnaire the clinical course of pain and the sensory
examination is either extremely simplified or an abbreviated version. Therefore,
the screening questionnaire should be utilized as the first stage in the diagnostic
process and when the results do suggest neuropathic pain, it is recommended that
doctors take patient history and perform neurological tests in order to confirm thepresence（or absence）of neurological legions or disease63). The Neuropathic Pain
Special Interest Group（NeuPSIG）of the International Association for the study of
IASP：International
Association for the
Study of Pain

Pain（IASP）have displayed a diagnostic algorithm mainly based on nerve lesions
and disease64), and so we recommend taking patient history, conducting neurological examinations and confirmation tests stage by stage, when proceeding with a diagnosis（Figure B－2）.

Diseasehistory

History related to neurological lesions and disease& presence of pain according to neuroanatomical
distribution
Yes
Possible
Neuropathic Pain

Neurologicalexamination

Pain accompanying neuropathy in region consistent
with anatomical innervation
Yes
Probable
Neuropathic Pain

Conﬁrmation
test

Diagnostic test to determine somatosensory
nervous system lesions or disease causing the painYes
DeﬁniteNeuropathic Pain

Figure B-2 F lowchart of Neuropathic Pain Scoring（Cited from References #5）

Evaluation or assessment questionnaires are also used as a tool to complement
the screening questionnaire. Evaluation questionnaires either provide a numericvalue or categorization for the syndrome of neuropathic pain patients and include
for example the Neuropathic Pain Scale（NPS）, Neuropathic Pain Symptom Inventory（NPSI）, Short－form McGill Pain Questionnaire 2（SF－MPQ－2）,and Pain Quality Assessment Scale（PQAS）. Of these, the reliability and validity of the Japanesetranslation of the NPSI and SF－MPQ－2 have been certified. Evaluation questionnaires can be utilized for understanding the syndrome and characteristics of pa-

B．Diagnosis & Evaluation

327

tients with neuropathic pain and also for assessing their responses to therapy ortreatment and there are reports that they are a more accurate reflection of pain
syndromes, rather than a measurement of pain intensity in neuropathic pain65).

CQ B－10：Is the evaluation of ADL/QOL useful for chronic pain ?
Answer： Patients who suffer from chronic pain have limited physical activity
due to their fear of pain. It goes without saying that the ultimate goal of chronic
pain treatment is not just alleviating the pain but also an improvement in ADL and
QOL. Therefore, evaluating ADL/QOL as well as evaluating the severity of pain
are useful for evaluating treatment outcomes. When evaluating ADL/QOL that accompanies pain, there is an evaluation of chronic pain in general and a disease－specific evaluation, so it is recommended that doctors select a combination of evaluation methods depending on the disease or condition.
Commentary：
The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials（IMMPACT）which was designed by US pain specialists, have indicated 4 domainsthat can serve as indicators for clinical trial outcomes on chronic pain treatment：
pain intensity, physical function, mental function and general overall level of improvement11）. The alleviation of pain through treatment of chronic pain is not necessarily associated with an improvement in physical function；evaluations of ADL,
QOL and social engagement are also important for evaluating in a wider sense theefficacy of treatment. Most evaluations of ADL/QOL use patient self－reported
scales, an evaluation of chronic pain in general, and also disease－specific evaluations
that correspond to the particular site of pain or disease. In terms of the evaluationof chronic pain in general, the Brief Pain Inventory66,67), Multidimensional Pain Inventory related items68), the Pain Disability Assessment Scale69), and the related
67,70)
items of the 36－Item Short Form Health Survey（SF－36）
are widely used toevaluate treatment intervention outcomes. On the other hand, for patients with low
back pain, not just comprehensive evaluations discribed above, but disease－specificevaluations such as the Roland－Morris Disability Questionnaire and Oswestry Disability Index, are often used to evaluate treatment outcomes67,71). When using a patient self－reported scale, doctors should use questionnaires in which the reliability
and validity of the Japanese version has been certified and approved. Furthermore,
after taking into consideration the site of the patient’s pain or disease and considering their cognitive ability and burden, it is recommended that doctors evaluate
them using a combination of comprehensive and disease－specific evaluations.

ADL：activities of dailyliving
QOL：quality of life

328

B．Diagnosis & Evaluation

CQ B－11：Is psychosocial evaluation useful for chronic pain ?
Answer：There is a strong relationship between chronic pain and psychological
function. Psychological changes such as anxiety, depression and anger can arise
due to pain. On the other hand, the degree of psychological distress and negative
thoughts can be a predictor for the prognosis of chronic pain. Therefore, psychosocial evaluation are useful for predict the prognosis of treatment and for decide interventional methods for chronic pain.
Commentary：
It should be noted that evaluating psychosocial factors of chronic pain is not identifying and/or ruling out psychiatric diseases. In a painful state, such negative emotions develop a vicious cycle, in which the pain persists and worsens. On the other
hand, researchers have indicated that the prevalence rate of anxiety disorders anddepression is higher among chronic pain patients than the prevalence rate among
the general population72). There have also been reports on the relationship between
strength of anxiety, depression and catastrophizing and response to chronic pain
treatment, opioid dependence and treatment prognosis73－75). Therefore, psychological assessment plays an important role in predicting prognosis and in deciding on asuitable treatment intervention.
In clinical research on chronic pain patients, scales such as the Hospital Anxiety
and Depression Scale（HADS）and State－Trait Anxiety Inventory are widely usedas scales for measuring anxiety. An observational study on patients with chronic
low back pain（LBP）showed that higher intensity of pain, a higher degree of disability, and a higher risk of opioid analgesic abuse were seen in subjects with highanxiety than in those with low anxiety73,74). HADS, the Beck Depression Inventory（BDI）, and Profile of Mood States（POMS）, are used as scales to measure depression. In addition to evaluating general psychological distress such as anxiety anddepression, the evaluation questionnaire has also been developed to assess thethoughts that specifically arise in a state of pain. Of these scales, the Pain CatastroPCS：Pain Catastrophizing Scale

phizing Scale（PCS）and Pain Self－Efficacy Questionnaire have been used in many
clinical and research studies on chronic pain to date. A systematic review on chronic musculoskeletal pain indicated that there were a significant relationship between
the degree of pain catastrophizing and the severity of pain and physical impairment76). Futhermore, a systematic review on chronic musculoskeletal pain showedthat there were significant relationships between high self-efficacy and high degreeof physical function, QOL, work efficiency, and satisfaction77). The fear－avoidancemodel is a vicious－circle model which explains how pain becomes chronic and intractable；the cause of their pain being the patient’s psychological behavior inwhich they fall into an avoidance of exercise out of fear of pain. The Fear－Avoid-

B．Diagnosis & Evaluation

329

patients’ specific fear－avoidance beliefs and the reliability and validity of the Japa-

FABQ：Fear-Avoidance Beliefs Questionnaire

nese version of the FABQ has been certified. Similarly, the Tampa Scale for Kinesi-

LBP：low back pain

ance Beliefs Questionnaire（FABQ）is a questionnaire which evaluates chronic LBP

ophobia（TSK）, which is a scale evaluating their fear－avoidance thoughts, was initially developed to evaluate their fear of exercise and the validity of this scale formusculoskeletal pain other than LBP has also been certified.
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Chapter C．Pharmacotherapy：CQ C-1～CQ C-13
CQ C-1：Are nonsteroidal anti-inflammatory drugs（NSAIDs）
useful for chronic pain ?
CQ C-2：Is acetaminophen useful for chronic pain ?
CQ C-3：Is extract from inflamed cutaneous tissue of rabbits
inoculated with vaccinia virus useful for chronic pain ?
CQ C-4：Are Ca2＋ channel α2δ ligands useful for chronic pain ?
CQ C-5： Are antiepileptic drugs（carbamazepine, sodium
valproate）useful for chronic pain ?
CQ C-6：Is duloxetine useful for chronic pain ?
CQ C-7：Are tricyclic antidepressants useful for chronic pain ?
CQ C-8：Are anxiolytics（benzodiazepine type drugs）useful forchronic pain ?
CQ C-9：Are centrally-acting muscle relaxants（tizanidine,
eperisone）useful for chronic pain ?
CQ C-10：Is tramadol useful for chronic pain ?
CQ C-11：Are buprenorphine patches useful for chronic pain ?
CQ C-12：Are opioid analgesics [strong] useful for chronic pain ?
CQ C-13：Is Kampo medicine（Chinese herbal medicine）usefulfor chronic pain ?

336

C．Pharmacotherapy

Table C-1
Drug name

Route ofadministration

Drugs Used to Manage Chronic Pain

Dosage / Usage

Diseases covered
under health insurance

Nonsteroidal Anti-inflammatory Drugs（NSAIDs）（only typical drugs listed） ➡
disclofenac

oral / suppository 25～100 mg／day

ibuprofenoral

600 mg／day

loxoprofenoral

60～180 mg／day

celecoxib

oral

200 mg／day

Acetaminophen➡

acetaminophen

CQ C-1

osteoarthritis/LBP/
cervicobrachial syndrome/
periarthritis of the shoulder /other general pain

gastrointestinal disorders, renal
dysfunction, edema，cardiovascular events, asthma

general pain

liver dysfunction

CQ C-2oral

600～4,000 mg／day

Extract from Inflamed Cutaneous Tissue of Rabbits Inoculated with Vaccinia Virus
extract frominflamed cutaneous
tissue of rabbits
inoculated withvaccinia virus

Side effects / Precautions➡

CQ C-3oral

4 capsules（16 units）／day

postherpetic neuralgia (PHN),
nausea, rash
LBP, cervicobrachial syndrome,
periarthritis of the shoulder,osteoarthritis

injected drug

3.6 units intravenous/
intramuscular/
subcutaneous injection

LBP, cervicobrachial syndrome, drowsiness, rashsymptomatic neuralgia, itchaccompanying skin disease

Ca2+ Channel α2δ Ligands（Gaqbapentinoid） ➡

CQ C-4pregabalin

oralstarting dosage
50～150 mg／day
maintenance dosage
300～600 mg／day

neuropathic pain, fibromyalgia

gabapentin

oral

starting dosage
400～600 mg／day
maintenance dosage
600～1,800 mg／day

refractory epilepsy, neuropathic drowsiness, dizziness, weightpain（public application）
gain

mirogabalin

oralstarting dosage 10 mg／day
maintenance dosage
20～30 mg／day

peripheral neuropathic pain

drowsiness, dizziness, weight
gain, edema

Antiepileptic Drugs➡

carbamazepineoralstarting dosage
200～400 mg／day
maintenance dosage
600～1,200 mg／day

trigeminal neuralgia, epilepsy,
manic depression（bipolar
disorder）

drowsiness, dizziness, liver
dysfunction, rash, cytopenia

sodium valproateoral

400～1,200 mg／day

Migraine prevention, epilepsy,
manic depression（bipolar
disorder）

drowsiness, dizziness, liver
dysfunction, pancreatitis

Antidepressants➡

drowsiness, dizziness, weight
gain, edema

CQ C-5

CQ C-6, 7

Tricyclic Antidepressants
amitriptyline

oral(for peripheral neuropathic pain) depression, enuresis, peripheral drowsiness, dizziness, sense of
initial dosage 10 mg／day
neuropathic pain
fatigue, nausea, dry mouseincreased when necessary,
max. dosage 150 mg／day

impramine

oral(for depression)
starting dosage
25～75 mg／day
gradually increased whennecessary maintenancedosage up to
200～300 mg／day

depression, bed-wetting

dry mouse, dizziness,
drowsiness, constipation

nortriptyline

oral(for depression)
starting dosage
30～75 mg／day
gradually increased whennecessary
maintenance dosage up to
150 mg／day

depression

dry mouse, drowsiness,
constipation

337

C．Pharmacotherapy

Drug name

Route ofadministration

Dosage / Usage

Diseases covered
under health insurance

Side effects / Precautions

Tetracyclic Antidepressantsmaprotiline

oral

starting dosage
10 mg／day
maintenance dosage
30～75 mg／day

depression

drowsiness, dizziness, sense of
fatigue, nausea

Serotonin-Noradrenaline Reuptake Inhibitors（SNRI）
duloxetine

oral

starting dosage
20 mg／day
maintenance dosage
20～60 mg／day

depression, fibromyalgia,
diabetic neuropathy, chronic
LBP, knee OA

nausea, drowsiness, dry mouse,headache, sense of fatigue（when used for pain, one shouldcarefully judge whether applicableor not considering the risk ofincidence of mental symptoms
such as suicidal thoughts, suicidal
tendencies, hostility,
aggressiveness etc.）

Anxiolytics（benzodiazepine drugs） ➡

CQ C-8clonazepam

oral

starting dosage
0.5～1.0 mg／day
maintenance dosage
2～6 mg／day

epilepsy（minor motor seizure,
psychomotor seizure,autonomic seizure）

drowsiness, dizziness,light headedness, hypotonia,
dependence

alprazolam

oralstarting dosage
0.4～1.2 mg／day
maintenance dosage
0.4～2.4 mg／day（not to exceed 1.2 mg／day
in elderly patients）

anxiety in psychosomatic
illness, tension, depression,
sleeping disorder

drowsiness, dizziness,light headedness, hypotonia,
dependence, withdrawal
symptoms

Central Muscle relaxants➡

CQ C-9tizanadineoral

starting dosage
3 mg／daymaintenance dosage
6～9 mg／day

cervicobrachial syndrome,
improved muscle tension in
LBP, spastic paralysis

drowsiness, dizziness, drop inblood pressure, dry mouse

eperisoneoral

150 mg／day

cervicobrachial syndrome,
periarthritis of the shoulder,improved muscle tension in
LBP, spastic paralysis

drowsiness, dizziness,light headedness

Opioid analgesics➡

CQ C-10, 11, 12

tramadoloral

starting dosage
50～100mg／day
maintenance dosage
50～300mg／day

chronic pain, cancer pain

drowsiness, dizziness, nausea/ vomiting, constipation

tramadol /acetaminophen
combination tablet

oral

starting dosage
75～150mg／day
maintenance dosage
150～300mg／day ※ 1

chronic pain, post-dental pain

drowsiness, dizziness, nausea/ vomiting, constipationbuprenorphinetransdermal patch

transdermal
patch（for 7 days）

starting dosage
0.12mg／day
maintenance dosage
0.12～0.48mg／day

osteoarthritis, chronic LBP

drowsiness, dizziness, nausea/ vomiting

morphineoral（rapidrelease agent）

starting dosage
10～30mg／day
maintenance dosage
30～90mg／day ※ 2chronic pain, cancer pain

nausea / vomiting,constipation, respiratory
depression，mental
dependence / abuse / misusefentanyl transdermal transdermal
starting dosage
patch
patch
12.5～25 μg／hour（for 1 or 3 days） maintenance dosage
25～37.5 μg／hourchronic pain, cancer pain

nausea / vomiting, constipation,
respiratory depression, mental
dependence / abuse / misuse

oxycodone

chronic pain（added as eligible nausea / vomiting, constipation,
for coverage as of October
respiratory depression, mental
2020）cancer pain
dependence / abuse / misuseoral（chronic pain）
10～60mg／day（cancer pain）
10～80mg／day※ 1 Starting dosages and maintenance dosages indicate amount of Tramadol they contain※ 2 If we assume that the upper dosage limit is 90 mg/day, then it is recommended that a dosage of 60 mg/day be used

338

C．Pharmacotherapy

C．Pharmacotherapy
CQ C－1：Are nonsteroidal anti－inflammatory drugs（NSAIDs）useful forchronic pain ?
NSAIDs：nonsteroidal
anti-inflammatory
drugs

Answer：Nonsteroidal anti－inflammatory drugs（NSAIDs）alleviate chronic low
back pain（LBP）and osteoarthritic pain but they have a small effect on chronic
LBP. It is not effective in improving fibromyalgia. There is a risk of side effects

COX-2：cyclooxygenase-2

from selective COX－2 inhibitors on the upper digestive tract and cardiovascularsystem so long－term use, without any clear purpose in mind, should be avoided.
Recommendation Grade & Summary of Overall Evidence
Recommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 92.9%〕

Summary of overall evidence：B（moderate）
Commentary：
NSAIDs is a collective name for drugs that provide analgesic effect, reduce fever
and act on inflammation, among other effects, by blocking the production of prostaPG：prostaglandins

glandins（PG）by blocking cyclooxygenase（COX）in the arachidonic acid cascade.
There are 6 systematic reviews and 1 guideline that have been adopted for verifying the efficacy of NSAIDs on chronic pain.
In a systematic review1) of the efficacy of NSAIDs on chronic low back pain
（LBP）
, researchers found that compared with the placebo, NSAIDs significantly
improved pain（MD －6.97, 95%CI －10.74 ～－3.19）according to patients’ VAS（visual analogue scale）scores（displaying 0～100 mm）up to the 16 th week.
NSAIDs overall also significantly improved physical function, compared with theplacebo, up to the 12th week（MD －0.85, 95%CI －1.3～－0.4）according to theirevaluations on the Roland Morris Disability Questionnaire（RMDQ）（0～24）. However, in each case it had a small effect, making it hard to establish if its effects areclinically significant and the reliability of the evidence is low.
In a systematic review2) comparing the effects of each type of NSAID on osteoar-

OA：osteoarthritis

thritis（OA）by dosage, the usefulness of NSAIDs was confirmed in 76 placebo－
controlled research studies and network meta－analysis is comparing and considering the usefulness of each type of these drugs. NSAIDs that are accessible in Japanand that have indicated a high analgesic effect include diclofenac, naproxen, andibuprofen. Of these drugs, 150mg of diclofenac／day displayed the largest effect onpain（Effect size：－0.57, 95%CI －0.69 ～－0.45）and physical function（EffectC．Pharmacotherapy

339

size：－0.51, 95%CI －0.65～－0.37）.
In a systematic review3) that considered the effects of local administration of
NSAIDs on knee OA, they holistically evaluated the effects on pain and improvement of physical function, and found that the difference in the rate of clinical efficacy between weeks 6 and 12 when they were administered, compared with the placebo（adhesive skin patch and drug administered as a base）, was 10.2% for diclofenac（RR 1.2, 95%CI 1.12 ～ 1.29）and 14.6% for Ketoprofen RR 1.22, 95%CI
1.03～1.45）；a significant improvement in either case. In addition, the difference in
the incidence rate of local side effects, such as skin symptoms, compared with theplacebo was significantly higher at 6.4% for diclofenac（RR 1.84, 95%CI 1.54 ～2.21）
but a significant difference was not recognized for Ketoprofen with a difference of 2.5%（RR 1.04, 95% CI 0.85～1.27）.
Because there was no difference in the frequency of incidence of full－body complications such as gastrointestinal tract disturbance compared with the placebo, local administration of NSAIDs is useful on knee OA pain.
According to the American Academy of Neurology（AAN）and American Headache Society（AHS）guidelines

4)on the prevention of migraine, they recommend

fenoprofen（yet to be approved in Japan）, ibuprofen, and naproxen as first－line

AAN：American Academy of Neurology
AHS：the American
Headache Society

NSAIDs to treat acute－stage migraine. In addition, in a systematic review5) verifying
the effects of aspirin in preventing migraine, based on the results of their analysisof 8 RCTs（dosage of aspirin ranged from 50～650 mg／day）, they concluded thatoral administration of 325 mg／day of aspirin is required to prevent migraine pain.

RCT：randomized
controlled trial

In a systematic review verifying the effects of NSAIDs on fibromyalgia（FM）, FM：fibromyalgia
the difference compared with the placebo in those who experienced a 30% improvement in pain with NSAIDs was －3.6％（RD －0.04, 95% CI －0.16～0.08）whereas the difference compared with those who experienced a 50% improvement in
pain was －6.9％（RD －0.07, 95%CI －0.18 ～ 0.04）; a significant difference was
not recognized6).
According to a systematic review1) of chronic low back pain（LBP）, they foundthat the incidence rate of side effects in all NSAIDs up until the 16th week was
3.4%（RR 1.04, 95% CI 0.92～1.17）compared with the placebo, failing to recognize
a significant difference in the frequency of side effects. However, many of these research studies used a small sample size over a short period of time so we need toconsider that the only side effects they detected were subjective symptoms.
In a systematic review7) of the safety of selective COX－2 inhibitors, in a meta－
analysis of selective COX－2 inhibitors on OA, researchers found a significantly
higher frequency in general side effects from selective COX－2 inhibitors（RR 1.26,
95%CI 1.09～1.46）, compared with the placebo. In particular, they found that withthe risk of incidence of upper digestive tract symptoms（RR 1.19, 95%CI 1.03 ～1.38）and cardiovascular system side effects, the risk of high blood pressure（RR

340

C．Pharmacotherapy

1.45, 95%CI 1.01～2.10）, edema and cardiac arrest（RR 1.68, 95%CI 1.22～2.31）
were significantly elevated.
When administering NSAIDs, careful attention needs to be paid to the incidenceof gastrointestinal mucosal damage, renal dysfunction and cardiovascular events,
when using selective COX－2 inhibitors. Therefore it is important to rigorously monitor for side effects and take measures when needed, and avoid any long－term administration without any clear purpose in mind.
PeriodDatabase
Words
searched

P
I／C

Limitations
Selection summary

2005～2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
chronic pain
NSAIDs administered group／non－administered group
Limited by publication type,PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, other（cases of50＋）etc
Of the 303 search hits, we narrowed it down to31, and in the end used 7 search hits whichmatched with the set PICOCQ C－2：Is acetaminophen useful for chronic pain ?
Answer：There is a lack of evidence indicating the effects of acetaminophen on
musculoskeletal pain（pain due to low back pain or osteoarthritis）, so its usefulness
remains unclear. On the other hand, it is highly useful in alleviating pain due totension－type headache（TTH）or migraine. Although severe side effects are rare,
one needs to be careful of impaired liver function due to high－dose administration.
Recommendation Grade & Summary of Overall Evidence
Recommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100%〕

Summary of overall evidence：B（moderate）
Commentary：
The analgesic－acting mechanism of acetaminophen is unclear. It has weak anti－
inflammatory effects and is assumed to mainly express its analgesic effects via thecentral nervous system. Three systematic reviews have been adopted to consider
the usefulness of acetaminophen on chronic pain.
According to a systematic review8) that considered the usefulness of acetaminophen on musculoskeletal pain, even when 4,000 mg of acetaminophen was used in
1 day to treat low back pain（LBP）, according to the VAS scores（on a range from
0～10）in which subjects evaluated their pain, researchers did not recognize the effect of acetaminophen compared with the placebo over a short period of time（lessthan 2 weeks）（MD：－0.5, 95%CI －2.9～1.9）or a medium－length period of time
SF-12：Short-Form
12-Item Health Survey（2 weeks＋but less than 3 months）（MD：1.4, 95%CI －1.3～4.1）. Furthermore,on the Short－Form 12－Item Health Survey（SF－12）（0 ～ 100）according to their

C．Pharmacotherapy

341

evaluations, there was no recognizable effect on physical function either over the
short term（MD：0.4, 95%CI－1.7～2.5）or medium term（MD：－1.9, 95%CI－4.8～1.0）compared with the placebo. Of the 3 randomized controlled trials（RCTs）that
were included in this systematic review, only one of them researched chronic low

RCT：randomized
controlled trial

back pain, and apart from this, almost no high－quality RCTs exist that consider theusefulness of acetaminophen on chronic low back pain（LBP）.
In the same systematic review, acetaminophen significantly reduced OA pain,

OA：osteoarthritis

compared with the placebo, both over the short term（MD －3.3, 95%CI －5.5～－
1.9）and mid－term（MD －3.7, 95%CI －5.8～－0.8）. However, they used WOMAC（0～100）for the majority of pain evaluations, which makes it difficult for us tosay whether the improvement was clinically significant or not. In addition, there
was also a change in physical function over the short term MD －2.9, 95%CI －4.9～－0.9）and mid－term（MD －1.7, 95%CI －6.0 ～ 2.6）but the significant improvement over the short term showed only a slight effect, whereas the improvement over the mid－term was not significant. The usefulness of acetaminophen for
OA is negative.
According to a systematic review9) that considered the usefulness of acetaminophen for tension－type headache（TTH）, researchers found that among patients
suffering from frequently－recurring tension－type headache（a headache that occurs at a frequency of between 1～15 times a month）in the acute stage, the difference in the number of patients whose pain subsided or disappeared 2 hours laterwas 9.8% higher for those administered with 1,000 mg of acetaminophen compared with those given a placebo（RR 1.21, 95%CI 1.15～1.28）,displaying a significant improvement. On the other hand, the difference between those administeredwith 560～650 mg of acetaminophen and those given a placebo was 5.8%（RR 1.11,
95% CI 0.90 ～ 1.37）, failing to yield a significant improvement. The difference in
the incidence rate of side effects between those who orally took 1,000 mg of acetaminophen and those given a placebo was 1.4%（RR 1.12, 95%CI 0.94～1.32）；the
difference was not significant, meaning its usefulness in actual clinical settings ishigh.
According to a systematic review10) that considered the usefulness of acetaminophen on migraine, the difference in the % of patients who experienced an improvement in pain 1 hour later was 19.2%（RR 1.97, 95%CI 1.52 ～ 2.55）comparing
those administered with 1,000 mg of acetaminophen with those given a placebo,and the difference in improved physical function 2 hours later was 10.3%（RR 1.76,
95%CI 1.24～2.48）for the acetaminophen group compared with the placebo group,
indicating a significant improvement in either case. The difference in the incidence
rate of side effects, compared with the placebo, was 4.7%（RR 0.78, 95%CI 0.64～
0.95）, meaning it is also highly useful in actual clinical settings.
According to a systematic review8) of side effects related to musculoskeletal pain,

WOMAC：Western
Ontario and McMaster
University Osteoarthritis Index

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the difference in the incidence rate of some form of side effects from acetaminophen was 2%（RR 1.0, 95%CI 0.9－1.1）compared with the placebo, and the percentage of those who discontinued administration due to side effects was 0.9%（RR
1.2, 95%CI 0.9－1.5）, showing that the difference was not significant. In addition,
the frequency in which severe side effects occur is low and no difference was recognized compared with the placebo（RR 1.2, 95%CI 0.7－2.1）,However, in terms ofliver function abnormality, it has a high risk compared with the placebo（RR 3.8,
95%CI 1.9－7.4）, therefore caution is required.
Impaired liver function due to acetaminophen is caused by the metabolite NAPQI
but it carries a high risk when taken in high dosages. According to the Food andFDA：Food and Drug
Administration

Drug Administration（FDA）the daily dosage of acetaminophen is limited to 4,000
mg／day（in Japan as well）, and many OTC common－cold medicines contain acetaminophen as well. Therefore, unexpected overdoses can happen meaning doctors
need to carefully pay attention to monitoring administration.
Moreover, the long－term administration of acetaminophen elevates the risk ofgastrointestinal haemorrhage（GIH）and it has become clear that there is a mild increase in systolic blood pressure11).
PeriodDatabase
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Limitations
Selection summary

2005～2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
chronic pain
acetaminophen, paracetamol administered group／non－administered group
Limited by publication type,PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane search filter, other（cases of 50＋）etc
Of the 375 search hits, we narrowed it down to 21, and in the end used 4 which matched withthe set PICOCQ C－3：Is extract from inflamed cutaneous tissue of rabbits inoculated withvaccinia virus useful for chronic pain ?
Answer：Extract from inflamed cutaneous tissue of rabbits inoculated with vaccinia virus may possibly by useful for low back pain, cervico－omo－brachial syndrome and postherpetic neuralgia. Severe side effects are rare and so because it ishighly safe, it is considered for use, in cases where patients fail to respond to standard treatment.
Recommendation Grade & Summary of Overall Evidence
Recommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 84.6%〕

Summary of overall evidence：D（very low）
Commentary：
Extract from inflamed cutaneous tissue of rabbits inoculated with vaccinia virus

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343

is a type of drug containing non－protein type physiologically－active substances extracted from the inflamed cutaneous tissue of rabbits. Experiments conducted onanimals have confirmed that it exhibits analgesic effects through activation of thedescending pain inhibitory system, anti－inflammatory action, inhibiting the releaseof excitatory neuropeptides, inhibiting the excitation of sympathetic nerves, improving blood flow, and neuroprotective action, and in other ways12).
Three RCTs have been conducted on each type of chronic pain disease to consider the usefulness of extract from inflamed cutaneous tissue of rabbits inoculated

RCT：randomized
controlled trial

with vaccinia virus on chronic pain.
In a placebo－controlled RCT13) targeting 120 patients with low back pain（LBP）,
researchers found that patients experienced a moderate improvement in pain or
better while moving, 2 weeks after administration, in 43.6% of patients administered with the drug compared with 24.1% of patients in the placebo group, indicating a significant effect.
More over in a placebo－controlled RCT14) conducted on 164 patients with cervico－omo－brachial syndrome, researchers reported a moderate improvement or betterin spontaneous pain, 3 weeks after administration, in 44.4% of patients administered with the drug compared with 28.4% in the placebo group, indicating a significant effect.
In another placebo－controlled RCT15) conducted on 238 patients with postherpetic neuralgia（PHN）, they reported a moderate improvement in pain or better, 4weeks after administration, in 34.3% of those who had been administered with the

PHN：postherpetic
neuralgia

drug compared with 19.6% of those in the placebo group, indicating a significant
effect.
In addition, in each of these RCTs, researchers recognized that it was effective in
improving patients’ ADL and QOL. However, each of these RCTs is old, having
been conducted in the 1980s, were small in scope and had a short observation period, and so because their recruitment criteria and the way they evaluated analgesic
effects were vague, there is a high risk of bias and the quality of evidence is low.
In terms of safety, the incidence rate of side effects in these RCTs was between
5.1～12.1% among patients in the group administered with the drug, failing to indicate a significant difference compared with the placebo group. Specific side effects that were observed include digestive symptoms such as gastric distress, constipation, loss of appetite, diarrhoea, and nausea and drowsiness but in each ofthese RCTs, symptoms were mild and the drug was discontinued due to side effects in around 0 ～ 4% of cases, indicating a high level of safety. However, there
have also been reports of severe side effects such as shock, anaphylactic－like symptoms, impaired liver function and jaundice so caution should be exercised when thisdrug is being used16).
According to the Clinical Guidelines of Pharmacotherapy for Neuropathic Pain

ADL：activity of dailyliving
QOL：quality of life

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17)（Revised 2nd edition）
released by the Japan Society of Pain Clinicians, they highly

evaluate the fact that the safety and usability of extract from inflamed cutaneous
tissue of rabbits inoculated with vaccinia virus were assessed in Japan and position
this substance as a second－line drug in the pharmacotherapy of neuropathic pain.
The quality of evidence on the efficacy of extract from inflamed cutaneous tissueof rabbits inoculated with vaccinia virus for treating chronic pain is not high but it
is highly safe so in the event where chronic pain disease does not improve understandard treatment, its usage should be considered. In future, in order to confirm
the efficacy of extract from inflamed cutaneous tissue of rabbits inoculated withvaccinia virus, there is a need for researchers to accumulate further evidence
through conducting high－quality RCTs.
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Selection summary

2005～2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
chronic pain
Neurotropin（inflamed cutaneous tissue of rabbits inoculated with vaccinia virus, neurotropin）
administered group／non－administered group
Limited by publication type, PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, other（cases of50＋）etc
Of the 227 search hits, we narrowed it down to12, and in the end used 5 which matched withthe set PICO, and 1 additional document, brining it to a total of 6 which we used. With the
NPO Japan Medical Abstracts Society searches, we expanded our search back to the 1980s

CQ C－4：Are Ca2＋ channel α2δ ligands useful for chronic pain ?
Answer：Ca2＋ channel α2δ ligands（pregabalin, gabapentin, mirogabalin）areuseful on postherpetic neuralgia（PHN）and painful diabetic neuropathy（DN）.Pregabalin is effective on fibromyalgia. The main side effects from Ca2＋ channel α2δ ligands are drowsiness, dizziness, edema, increase in weight, and so dosages need tobe adjusted for senior patients and those with renal dysfunction.
Recommendation Grade & Summary of Overall Evidence
Recommendation grade：1（strong）：Implementation is strongly recommended〔Consensus 85.0%〕
Summary of overall evidence：B（moderate）
Commentary：
By binding to voltage－dependent Ca2＋ channel α2δ subunits in the central ner-vous system, Ca2＋ channel α2δ ligands（gabapentinoids）inhibit the release of excitatory neurotransmitters, exhibiting an analgesic effect. Currently, there are three
Ca2＋ channel α2δ ligands that can be used in Japan：pregabalin, gabapentin, andmirogabalin.
RCT：randomized
controlled trial

There are 4 systematic reviews and 2 RCTs that have considered the usefulness
of Ca2＋ channel α2δ ligands on chronic pain.

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345

In systematic reviews18,19) on the effect of pregabalin and gabapentin on neuropathic pain, they considered their usefulness on postherpetic neuralgia（PHN）and
painful diabetic neuropathy（DN）.

PHN：postherpetic
neuralgia

With PHN, researchers observed that the difference in the % of patients whose
pain decreased by 50% or more through pregabalin（300 mg／day）compared withthe placebo was 19.5％（RR 2.52, 95%CI 1.86 ～ 3.42）and through gabapentin（1,200～3,600 mg／day）was 14.4％（RR 1.69, 95%CI 1.43～2）, compared with theplacebo, marking a significant improvement. Evaluations of patients’ satisfactionlevels using the Patient Global Impression of Change（PGIC）indicated that the %of those showing a large level of improvement over the placebo was 17.1%（RR

PGIC：the Patient
Global Impression of
Change2.13, 95%CI 1.54～2.94）for patients administered with pregabalin and 10.3% for
those administered with gabapentin（RR 1.32, 95%CI 1.16～1.5）, indicating a significant improvement over the placebo.
With painful diabetic neuropathy（DN）, the difference in the % of patients whose
pain had decreased by 50% or more compared with the placebo was 7.0%（RR 1.3,
95%CI 1.15 ～ 1.46）in patients administered with pregabalin, 15.2％（RR 1.69,
95%CI 1.41 ～ 2.02）in patients administered with gabapentin, indicating a significant improvement. According to PGIC, evaluations from patients administered withpregabalin were 20.3％（RR 1.75, 95%CI 1.51～2.03）, and 20.3％（RR 1.66, 95%
CI 1.36 ～ 2.03）for those administered with gabapentin, indicating significantly
higher scores than the placebo.
In addition, in RCTs published since 2017, researchers have considered the usefulness of pregabalin for both post－traumatic neuropathic pain20) and peripheral
neuropathic pain due to oxaliplatin21), respectively. Both of these placebo－controlled
research studies examined over 100 cases but did not recognize a significant improvement in pain or QOL.
In a systematic review22) that verified the usefulness of antiepileptic agents onchronic low back pain, researchers did not recognize that Ca2＋ channel α2δ ligands
were useful in improving pain and physical function, from the 2 months～up to 12
months stage, in chronic low back pain（LBP）and lumbar radiculopathy, comparedwith the placebo. In standard LBP, researchers did not recognize a significant improvement in pain（evaluations standardized from 0～10）, at the 2 week～3 monthstage, in patients administered with gabapentin（MD 0.0, 95% CI －0.3 ～ 0.3）,
compared with the placebo and in patients with lumbar radiculopathy administeredwith pregabalin（300～600 mg／day）, they did not recognize that it was effective incausing a significant improvement in pain MD －0.1, 95%CI －0.3～0.2）or physicalfunction（evaluations standardized from 0～10）, compared with the placebo.
In a systematic review23) of the usefulness of pregabalin on fibromyalgia, researchers considered the usefulness of administering patients with pregabalin indosages of 150～600 mg／day. In terms of side effects, as the incidence of dosage de-FM：fibromyalgia

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pendence becomes increasingly more frequent, both the rate of improvement ofpain at 450 mg／day and patient satisfaction levels have increased and the % of patients who experienced a 50% reduction in pain or higher was 10.4%（RR 1.75,
95%CI 1.44 ～ 2.13）compared with the placebo, indicating a significant improvement. Furthermore, the % of those who indicated a high level of improvement inpatient satisfaction through the evaluations of the Patient Global Impression of
Change（PGIC）was 8.8%（RR 1.33, 95%CI 1.16～1.52）, significantly higher thanthe placebo.
The main side effects from using Ca2＋ channel α2δ ligands are drowsiness, dizziness, weight gain, and peripheral edema23). The difference in the incidence of side
effects was 9.4% for pregabalin（300 mg／day）（RR 1.21, 95%CI 1.15～2.28）and
13.2% for gabapentin（1,200～3,600 mg／day）（RR 1.28, 95%CI 1.22～1.36）compared with the placebo, indicating that it was significantly higher. The incidence
rate of severe side effects was 3.0% for pregabalin and 3.1% for gabapentin, andthere was no significant difference compared with the placebo, but the % of patients for whom oral administration was discontinued due to side effects, was 4.2%
for pregabalin（RR 1.86, 95% CI 1.49～2.33）and 3.3% for gabapentin（RR 1.38,
95%CI 1.14～1.67）compared with the placebo；making it significantly higher18,19）.
For this reason, patients should be rigorously monitored after commencing administration. Of the side effects, drowsiness and dizziness are frequent so during administration, patients should be advised not to drive a car and with elderly patientsin particular, one must be careful of bone fractures due to a fall. Moreover, Ca2＋
channel α2δ ligands are excreted by the kidneys as an unmetabolized drug, so it isimportant to adjust the dosage in accordance with a patient’s kidney function24).
In April 2019, Japan led the world in making mirogabalin available for use. In
phase III clinical trials（RCTs）, researchers considered the usefulness of mirogabalin on peripheral neuropathic pain（postherpetic neuralgia（PHN）, painful diabetic
neuropathy）, compared with a placebo25,26). They examined 671 patients with postherpetic neuralgia（PHN）and at the 14th week stage, they found that 30 mg／dayof mirogabalin significantly improved their pain（MD －0.77, 95%CI －1.10 ～－0.44）compared with the placebo. They also examined 834 patients with painful diabetic neuropathy and found that at the 14th week stage, 30 mg／day of mirogabalinsignificantly improved their pain（MD －0.50, 95%CI －0.82 ～－0.17）comparedwith the placebo. However, they did not observe a significant improvement inphysical function. Side－effects include nasopharyngitis, drowsiness, dizziness, peripheral edema, and weight gain. Around 90% of these participants were able tocomplete the clinical trial, right through to the end in each case, indicating its tolerability. In future, there is need for further verification in actual clinical settings anda need to accumulate evidence on its usefulness.
According to the Clinical Guidelines of Pharmacotherapy for Neuropathic Pain

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347

17)
（Revised 2nd edition）
released by the Japan Society of Pain Clinicians, pregabalin

and gabapentin are positioned as first－line drugs in the management of neuropathic
pain. However, one comment was added to the revised text：“mirogabalin can beused in the same manner as pregabalin.”27)
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Selection summary

2005～2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
chronic pain
pregabalin, gabapentin, mirogabalin, gabapentinoid administered group ／ non－administeredgroup
Limited by publication type,PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, other（cases of50＋）etc
Of the 663 search hits, we narrowed it down to 50, and in the end, we used 9 of them whichmatched with the set PICO as well as 1 additional document and 1 website bringing it to a total of 11 which we used

CQ C－5：Are antiepileptic drugs（carbamazepine, sodium valproate）usefulfor chronic pain ?
Answer：Carbamazepine is useful for trigeminal neuralgia, and sodium valproateis useful in preventing migraine attacks. There is no evidence indicating its usefulness on other forms of chronic pain. We need to be careful of its side effects whichmainly include drowsiness, dizziness, light-headedness, nausea, and impaired liverfunction.
Recommendation Grade & Summary of Overall Evidence
Recommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 84.6%〕

Summary of overall evidence：B（moderate）
Commentary：
Carbamazepine exhibits its pharmacological effect by blocking Na＋ channels andsodium valproate by blocking Ca2＋ channels and inhibiting GABA.
We have used 3 systematic reviews that consider the usefulness of antiepileptic
drugs（carbamazepine, sodium valproate）on chronic pain.
In a systematic review28) considering the usefulness of carbamazepine on neuropathic pain, researchers found that the % of patients with trigeminal neuralgia administered with carbamazepine（100～2,400 mg／day）who experienced improved
symptoms was 60.6%（RR 6.02, 95%CI 2.82～12.85）compared with the placebo,indicating that their pain had significantly improved. The incidence rate of side effects among those administered with carbamazepine compared with the placebo
was 38.2%（RR 2.4, 95%CI 1.85～3.12）, indicating that the risk of incidence is significantly higher and researchers recognized that they suffer from drowsiness, dizziness, light－headedness, skin rash and impaired liver function but there were no

GABA：γ -aminobutyric acid

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reports of severe side effects. However, when using carbamazepine, one should also
pay attention to severe side effects such as liver dysfunction, granulocytopenia,
aplastic anemia, toxic epidermal necrolysis（TEN）,and Stevens－Jonson syndrome.
Carbamazepine is the gold standard for pharmacotherapy when treating trigeminal neuralgia29), and even according to the guidelines on trigeminal neuralgia by the
AAN：American Academy of Neurology

American Academy of Neurology（AAN）and the Federation of European Neuro-

FENS：Federation ofEuropean Neuroscience Societies

strong evidence.

RCT：randomized
controlled trial

30)
science Societies（FENS）, it is considered to be the first－line drug based on

In a systematic review31) considering the usefulness of sodium valproate on neuropathic pain, researchers mention 2 RCTs that examined painful diabetic neuropathy and 1 RCT that examined postherpetic neuralgia（PHN）but the scope of eachof these studies was small and there is a discrepancy in the results so its usefulness
has not been validated by meta－analysis. There is insufficient evidence indicating
the usefulness of sodium valproate on neuropathic pain and therefore it is not a
first－line drug for managing neuropathic pain.
In a systematic review32) that considered the usefulness of sodium valproate inpreventing migraine attacks, oral administration of sodium valproate（800＝1,500
mg／day）reduced the frequency of migraines（MD －4.31, 95% CI －8.32～－0.3）,
compared with the placebo. The same systematic review reported that side effects
from taking sodium valproate include, sense of fatigue, nausea, drowsiness, dizziness and impaired liver function. The difference in the incidence rate（of adverse
events）compared with the placebo was 6.8%（RR 0.03, 95%CI －0.08－0.13）；thedifference was not significant. Individual side effects were sense of fatigue（RD0.07, 95% CI －0.03～0.17）, dizziness（RD 0.07, 95% CI 0.01～0.13）, nausea（RD0.15, 95% CI 0.04～0.26）, and trembling（RD 0.07, 95%CI 0.01～0.13）but severeside effects are rare, meaning that it has high tolerability.
PeriodDatabase
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Limitations
Selection summary

2005～2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
chronic pain
carbamazepine, valproic acid, valproate administered group／non－administered group
Limited by publication type,PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, other（cases of50＋）etc
Of the 105 search hits, we narrowed it down to 19, of which we ended up using 5 whichmatched with the set PICOCQ C－6：Is duloxetine useful for chronic pain ?
Answer：Duloxetine improves pain and physical function in painful diabetic neuropathy（DN）, fibromyalgia, osteoarthritis, and low back pain（LBP）and patientsatisfaction is high. There are many types of side effects that arise but severe side
effects are rare.

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349

Recommendation Grade & Summary of Overall Evidence
Recommendation grade：1（strong）：Implementation is strongly recommended〔Consensus 80.0%〕
Summary of overall evidence：A（high）
Commentary：
Duloxetine is one of the serotonin－noradrenaline reuptake inhibitors（SNRI）, andits analgesic effect is due to an activation of the descending pain inhibitory system.

SNRI：serotonin-noradrenaline reuptake
inhibitor

Duloxetine is also used as an antidepressant but its antidepressive effect and its analgesic effect each have their own respective mechanism. The analgesic effects ofduloxetine arise faster and in lower dosages than its antidepressive effects33).
There are 2 systematic reviews and 1（PASS）posthoc analysis that examined
the usefulness of duloxetine on chronic pain.
A systematic review33) on painful diabetic neuropathy and fibromyalgia evaluatedthe severity of patients’ pain, physical function, mental function, and patient satisfaction between weeks 8～12 after being administered with 60 mg／day of duloxetine. The rate of patients whose pain reduced by 50% or more after taking duloxetine was 20.4%（RR 1.73, 95%CI 1.44～2.08）and 13.1%（RR 1.57, 95%CI 1.2～
2.06）for painful diabetic neuropathy and fibromyalgia, respectively, compared withthe placebo. Their physical function and mental function were evaluated using the
Short－Form 36－Item Health Survey（SF－36）and found that the difference in the
average change from the baseline compared with the placebo for physical aspects

SF-36：Short-Form
36-Item Health Survey

was 2.65（95%CI 1.38～3.92）, and 1.28（95%CI －0.33～2.89）,whereas for mental
aspects it was 1.08（95%CI －0.32～2.48）and 3.11（95%CI 0.59～6.02）, showingthat some had significantly improved. Patient satisfaction was evaluated using thePatient Global Improvement－Inventory（PGI－I）, and researchers found that the average difference from the control was －0.6（95% CI －0.07～－0.44）, and －0.45

PGIC：Patient Global
Impression of Change（95% CI：－0.37 ～－0.18）, indicating that in either case it had improved significantly.
In a systematic review on OA34), the rate of patients whose pain reduced by

OA：osteoarthritis

more than 50% between weeks 10～14 after being administered with 60～120 mg／
day of duloxetine, was 17.9%（RR 1.62, 95%CI 1.30～2.02）higher than the placebo. Patients’ physical function was evaluated using WOMAC, and they found thatthe difference between the control in average change from the baseline was －5.43（95%CI －6.87～－3.99）, indicating a significant improvement. The average change
compared with the control in patient satisfaction according to the Patient Global
Impression of Change（PGIC）was －0.48（95% CI －0.59～－0.37）, showing that it
had improved significantly.
35)
A posthoc analysis（PASS）
that evaluated its efficacy on low back pain（LBP）

evaluated patients’ severity of pain and physical function at weeks 12～14, after be-

WOMAC：Western
Ontario and McMaster
University Osteoarthritis Index

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ing administered with 60 ～ 120 mg ／ day for duloxetine. The relative difference inthe average change from the baseline in the severity of pain was －0.29（95% CI－0.41～－0.16）, showing a significant improvement. Their physical function was
evaluated using the Roland Morris Disability Questionnaire（RMDQ）, and the relative difference in the average change from the baseline was －0.15（95% CI －0.29～－0.01）, indicating that it had significantly improved.
According to a systematic review on the side effects from taking duloxetine forchronic pain, the side effects from this drug include nausea, dry mouth, dizziness,
somnolence, fatigue, insomnia, headache, constipation, decreased appetite and hyperhidrosis, although side effects do not occur as frequently as with tricyclic antidepressants33). The incidence rate of side effects is related to dosage dependence,with an incidence 8.9%（RR 1.15, 95%CI 1.1～1.2）higher when taking duloxetine
than the placebo, and the rate of patients who discontinued taking it orally due toside effects was high at 5.3%（RR 1.95, 95% CI 1.6～2.37）. Severe side effects are
rare；there was no significant difference compared with the placebo（RR 0.81, 95%
CI 0.53 ～ 1.25）. As duloxetine is a serotonin－noradrenaline reuptake inhibitor（SNRI）, there is considerable risk of onset of serotonin syndrome. The frequency of
onset is low at normal dosages but as there is an elevated risk of serotonin syndrome due to an overdose or when using a serotonin agonist such as tramadol in
combination, caution is advised. Drug infomation advises caution；it mentions paying attention to their mutual effect on pain and when administering this drug for
pain, one must consider the risk of mental symptoms arising in patients, such as
suicidal thoughts, suicidal tendencies, hostility and aggressiveness, when making a
careful judgment whether it is suitable to administer this drug or not.
PeriodDatabase
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Selection summary

2005～2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
chronic pain＊
Duloxetine administered group／non－administered group
Limited by publication type, PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, other（cases of 50＋）etc
Of the 137 search hits, we used 11 which matched with the set PICOCQ C－7：Are tricyclic antidepressants useful for chronic pain ?
Answer：Tricyclic antidepressants are useful in reducing neuropathic pain andfibromyalgia－related pain. It is not useful in improving low back pain（LBP）. Amitriptyline causes a variety of side effects and caution is especially required whentreating older patients and those with heart disease.
Recommendation Grade & Summary of Overall Evidence
Recommendation grade：2（weak）：Implementation is weakly recommended

C．Pharmacotherapy

351〔Consensus 100.0%〕

Summary of overall evidence：C（low）
Commentary：
Analgesic effects of tricyclic antidepressants manifest in a shorter period of timeand in lower dosages than antidepressants. Its main analgesic effect mechanism isthe activation of the descending pain inhibitory system by blocking re-uptake of serotonin and noradrenaline, but other mechanisms, such as N－methyl－D－aspartate（NMDA）receptor antagonism and blockade of sodium channels, and the effect on
β2 adrenergic actions is proposed36).
We have adopted 5 systematic reviews and 1 meta－analysis on the usefulness oftricyclic antidepressants on chronic pain.
A systematic review37) has evaluated changes in the intensity of pain in patientswith painful diabetic neuropathy, postherpetic neuralgia, and mixed neuropathic
pain administered with 10 ～ 200 mg of amitriptyline ／ day over a period of 4 ～ 9
weeks. The rate of patients whose pain was reduced by more than 50% was 19.7%
higher in amitriptyline patients compared with the placebo（RR 2.0, 95%CI 1.5～
2.8）
. In a systematic review38) conducted by the Special Interest Group on Neuropathic Pain（NeuPSIG）of the International Association for the Study of Pain
（IASP）, they evaluated the analgesic effects of tricyclic antidepressants（amitriptyline, desipramine, imipramine, nortriptyline）on neuropathic pain, and calculated
that the number needed to treat（NNT）to reduce pain by 50% was 3.57（95%
CI：3 ～ 4.4）
. As this value is lower than other drugs, it gives us the impression

NNT：number needed
to treatthat tricyclic antidepressants have the strongest effect on neuropathic pain. However, the majority of research on the effects of tricyclic antidepressants on neuropathic pain was conducted prior to the year 2000, and the period of observation was under 1 month, and because indicators such as physical function and mental function
and level of patient satisfaction have not been evaluated, in light of the above, careful attention needs to be paid to how the quality of each RCT ranges from low to
medium and the level of evidence is not high.
In a systematic review39) that evaluated the usefulness of amitriptyline on fibromyalgia, researchers indicated that the rate of patients administered with 25～50
mg of amitriptyline／day over a period of 8～24 weeks whose pain reduced by morethan 50% was 24.6%（RR 2.88, 95%CI 1.69～4.91）higher than the placebo.
In a systematic review that evaluated its usefulness on low back pain（LBP）, researchers evaluated changes in the intensity of pain when patients were administered with tricyclic antidepressants（maprotiline, desipramine, imipramine）over a
period of 4 ～ 12 weeks. The difference in the average change in intensity of painfrom the baseline compared with the control was 0.1（95% CI －0.51～0.31）, indicating that there was no significant improvement compared with the placebo40,41).

FM：fibromyalgia

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According to a meta－analysis evaluating the side effects on patients with chronic
pain who were administered with antidepressants, the incidence of side effects
from amitriptyline was 43.4%（RR 2.9, 95% CI 0.67～12.58）higher than the placebo. There is a variety of side effects, including dry mouth（RR 18.95, 95% CI 1.19
～301.39）, weight gain（RR 8.74, 95%CI 1.12～68.32）,irritability（RR 8.19, 95% CI
0.45～147.47）, blurred vision（RR 6.37, 95% CI 0.34～119.6）, headache（RR 3.39,
95% CI 0.92～12.55）, dipsia（RR 3.14, 95% CI 1.10～8.94）, edema（RR 1.8, 95%CI
0.18 ～ 18.21）, constipation（RR 1.60, 95%CI 1.19 ～ 2.15）, drowsiness（RR 1.60,
95%CI 0.52～4.91）, and palpitations（RR 1.55, 95%CI 0.29～8.24）. The incidence
rate of patients in which oral administration was discontinued due to side effects
42)
was high at 10.8%（RR 4.09, 95% CI 1.31～12.82）.

Because tricyclic antidepressants can cause sinus tachycardia through their anticholinergic effects, caution is advised when administering them to patients withischemic heart disease. It also elevates the risk of sudden cardiac death when 100
mg ／ day is administered43). Therefore, older patients and those in which ischemic
heart disease is suspected must be screened with an electrocardiogram（ECG）prior to administration and any medical history of ischemic heart disease needs to bethoroughly taken as well.
PeriodDatabase
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Limitations
Selection summary

2005～2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
chronic pain＊
Tricyclic antidepressants administered group／non－administered group
Limited by publication type, PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, other（cases of50＋）etc
Of the 246 search hits, we used 21 of them which matched with the set PICOCQ C－8：Are anxiolytics（benzodiazepine type drugs）useful for chronic pain ?
Answer：Of the anxiolytics（benzodiazepine type drugs）, clonazepam is useful
BMS：burning mouth
syndromefor burning mouth syndrome and alprazolam has a limited usefulness on tension－
type headache. There is no evidence on the usefulness of benzodiazepine typedrugs on chronic low back pain（LBP）, neuropathic pain and fibromyalgia. As benzodiazepine type drugs have a high incidence rate of side effects such as drowsiness and tend to be habit－forming, one should refrain from using them for chronic
pain, long－term use or careless concomitant use with opioid analgesics should be
avoided.
Recommendation Grade & Summary of Overall Evidence
Recommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 94.1%〕

Summary of overall evidence：C（low）

C．Pharmacotherapy

353

Commentary：
Benzodiazepine type drugs are mainly used to fight anxiety, as a sedative, and topromote sleep. Furthermore, it is effective as a muscle relaxant, and its expected
analgesic effects are used for example on low back pain and stiff shoulders.
We have adopted 4 systematic reviews in order to consider the usefulness of antianxiety drugs（benzodiazepine type drugs）on chronic pain.
According to the pharmacotherapy guidelines40) by The American College ofPhysicians（ACP）, 2 placebo－controlled RCTs conducted on the usefulness oftetrazepam（yet to be approved in Japan）on chronic low back pain（LBP）as a
benzodiazepine type drug, did not recognize a significant improvement when administered for 5～7 days and when administered for 10～14 days（RR 0.71, 95% CI
0.54～0.93）（RR 0.82, 95% CI 0.72～0.94）, indicating low evidence of its usefulness.
In a systematic review44) on the treatment of burning mouth syndrome（BMS）,a
meta－analysis was conducted on 22 RCTs to consider the usefulness of various
drugs on BMS. As a result, local administration of clonazepam significantly improved pain（on a 0～10 scale）compared with the placebo（MD 1.64, 95%CI 1.23
～2.05）, and compared with the placebo, the difference in which an improvementof 50% or more occurred was 52.9%（RR 6.92, 95%CI 2.92～16.39）,which was significantly higher. Side effects were drowsiness, a burning sensation inside themouth, and dryness inside the mouth, but there was no difference compared withthe placebo. Based on these results, we believed that it is clinically useful.
In a systematic review45) on the prevention of tension－type headache（TTH）, in
1 RCT that was used, there was no recognizable reduction in the frequency of
TTH in 62 patients with TTH who were administered with alprazolam comparedwith the placebo but their overall symptoms tended to improve（evaluated on aheadache index from 0～100）（RR 2.0, 95% CI 0.65～6.2）so its effect is limited.
Furthermore, the incidence rate of side effects was 16.67％ .
In a Cochrane review46) which considered the usefulness of clonazepam on neuropathic pain and fibromyalgia, 3 research studies were raised as possible candidates
but the quality of the research in each case was low, and because they were not eligible for analysis, no evidence on its usefulness was obtained.
There have been many reports of central nervous system type side effects
caused by benzodiazepine type drugs, compared with the placebo, such as drowsiness, a feeling of lethargy and lightheadedness. In addition, many patients withchronic pain use benzodiazepine type drugs in combination with opioid analgesics
but because they are habit－forming, withdrawal from these drugs is difficult, andthere is an elevated risk of drug abuse. Long－term administration of benzodiazepine type drugs, without any specific aim in mind, should be avoided47).

ACP：The American
College of Physicians

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PeriodDatabaseWordsearched

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Limitations
Selection summary

2005～2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
chronic pain
benzodiazepine, clonazepam, diazepam administered／not－administered group
Limited by publication type, PubMed CER randomized controlled trials ／ systematic reviews
search filter, Cochrane RCT search filter, other（number of cases50＋）etc
Narrowed down from 230 to 21 searches, and ultimately 5 were used that matched with theset PICOCQ C－9：Are centrally－acting muscle relaxants（tizanidine, eperisone）usefulfor chronic pain ?
Answer：The usefulness of centrally－acting muscle relaxants （tizanidine,
eperisone）on chronic low back pain remains unclear. Attention needs to be paid tocentral nervous system side effects such as drowsiness, dizziness and exhaustionand symptoms of the digestive organs such as dipsia, nausea and vomiting, andpain in the fovea centralis.
Recommendation Grade & Summary of Overall Evidence
Recommendation grade：No recommendation〔Consensus 88.2%〕
Summary of overall evidence：D（very low）
Commentary：
In Japan, the centrally－acting muscle relaxants tizanidine and eperisone are used
to improve myotonia in subjects with low back pain（LBP）. Tizanidine displays amuscle－relaxing effect through stimulation of central α 2 adrenergic receptors,
whereas eperisone acts by inhibiting reflexes in the spinal cord.
We used 1 systematic review and 2 RCTs that were included under that review
in order to consider the usefulness of centrally－acting muscle relaxants（tizanidine,
eperisone）on chronic pain.
In a systematic review48) that considered the usefulness of eperizone on LBP, 7
research studies, that included 5 RCTs, were eligible for analysis but of these, only
2 of the RCTs targeted chronic LBP so here we considered each respective RCT.
In an RCT49) that investigated how eperizone affects blood flow in the paraspinal
muscles, researchers considered the usefulness of oral administration of eperizone
in 74 patients with chronic LBP, compared with patients who only received standard physiotherapy as the control group. When they measured the blood flow inthe paraspinal muscles at week 4 after administering eperizone, they found thatoxyhemoglobin had risen more significantly in the eperizone group than the physiotherapy group. Pain improved by approximately 14 points（VAS：on a scale from0 ～ 100）in both groups；there was no recognizable difference. In addition, there
was no recognizable improvement in either group in mental function when evaluat-

C．Pharmacotherapy

ed on the SF－36.
In the other RCT50), 60 subjects with chronic LBP and with spasticity in theirparaspinal muscles were randomly assigned into 2 groups and in addition to the
100 mg／day of tramadol, they were also administered with eperizone and tizanadine, respectively, and researchers investigated improvement in pain. At day 5 andday 30 after administration, at rest, pain had improved in both groups by approximately 40 points on the VAS scale（on a scale from 0～100）, but no significant difference in improvement effect was observed between the two groups.（eperizone
group：average 63（SD 12）→ 22（SD 11）, tizanadine group：average 69（SD 11）→ 23（SD 11）. As for side effects, drowsiness was significantly higher in the tizanadine group（43.3%）than the eperizone group（16.6%）. Administration was discontinued due to side effects in 9 cases due to tizanadine and in 5 cases due to eperizone；it was significantly higher in the tizanadine group.
Based on the above, there is little evidence indicating the usefulness of central－
acting muscle relaxants（tizanadine, eperizone）on chronic LBP.
According to a systematic review48) on LBP mentioned above, researchers reported side effects such as digestive organ symptoms（nausea, vomiting, pain in
the fovea centralis）, dizziness, and drowsiness, in patients administered with eperizone. However, compared with diazepam and thicolchicoside（yet to be approvedin Japan）, the difference in the frequency of side effects was significantly lower
from eperizone at 25.3%（RR 0.25, 95% CI 0.15～0.41）. Common side effects fromtizanadine are dipsia, exhaustion and dizziness but in most cases it is mild and if
oral administration of tizanadine is discontinued, these symptoms will disappear.
Caution is advised with tizanadine because overdoses can cause low blood pressure
and bradycardia. Moreover, in some cases researchers have observed elevated liver
enzymes and if necessary, monitoring of liver function should be taken into account51).
There has been much research considering the usefulness of central－acting muscle relaxants on multiple sclerosis（MS）and muscle contracture after spinal cord
injury and researchers have evaluated its usefulness. However, there is little high－quality evidence regarding its effect on chronic pain and so in future there is aneed to verify its efficacy through RCTs and accumulate evidence.
PeriodDatabase
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Limitations
Selection summary

2005～2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
chronic pain
central muscle relaxant, Tizanidine, Eperisone administered／non－administered group
Limited by publication type,PubMed CER randomized controlled trials, systematic review
search filter, Cochrane RCT search filter, other（number of cases50＋）etc
Narrowed down from 190 to 15 searches, and ultimately 4 were used that matched with theset PICO. With NPO Japan Medical Abstracts Society, we expanded our search back to 1990

355

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CQ C－10：Is tramadol useful for chronic pain ?
Answer：Tramadol significantly improved pain and physical function in neuroOA：osteoarthritis

pathic pain, low back pain（LBP）,and osteoarthritis（OA）.There is insufficient evi-

FM：fibromyalgia

dence of its usefulness on fibromyalgia（FM）. In Japan, it is not designated as anarcotic so it is easy to prescribe but considering that it is an opioid, long－term administration of this drug without any clear aim should be avoided.
Recommendation Grade & Summary of Overall Evidence
Recommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100%〕

Summary of overall evidence：B（moderate）
Commentary：
Tramadol is not designated as a narcotic in Japan. It is a dual drug, which bothacts on μ－opioid receptors and inhibits the reuptake of serotonin and noradrenaline. Tramadol is metabolized to O－desmethyltramadol（M1）, which has analgesic
effects, by CYP2D6. The unchanged compound tramadol and the M1 metabolitebond with the μ －opioid receptor and act as an opioid analgesic but M1 displays ahigher analgesic effect than the unchanged compound tramadol. The second metabolite N, O－desmethyltramadol（M5）are also activated and involved in the analgesic
effect. In this way, the main analgesic effects of tramadol are M1 and M5 so havebeen called a prodrug52).
We have adopted 4 systematic reviews on the usefulness of tramadol on chronicpain.
A Cochrane review53) evaluated changes in the intensity of pain in patients withneuropathic pain by administering them with 100～400 mg／day of tramadol over 4～6 weeks. The rate of patients who experienced more than 50% reduction in pain
was 23% higher（RR 2.16, 95%CI 1.02～4.58）in the tramadol group than in theplacebo group.
A Cochrane review54) which investigated its usefulness on LBP evaluated changes in the intensity of pain and physical function when patients were administeredwith 150～300 mg／day of tramadol over a 28～90 day period. The difference in the
average change in the intensity of pain from the baseline was－0.5（95%CI －0.66～－0.44）compared with the control；a significant improvement. Physical function
was evaluated on the Roland Morris Disability Questionnaire（RMDQ）, and the difference in the average change in the intensity of pain from the baseline was－0.18（95%CI －0.29～－0.07）compared with the control；indicating that it had significantly improved.
A Cochrane review55) on OA evaluated changes in intensity of pain and physicalC．Pharmacotherapy357

function when patients were administered with 100～400 mg／day of tramadol over
2 weeks ～ 91 days. The difference in the average change in the intensity of painfrom the baseline was －0.25（95%CI －0.32 ～－0.18）compared with the control；a significant improvement. Physical function was evaluated by the Western
Ontario and McMaster Universities Index（WOMAC）and the difference in the average change from the baseline was －0.20（95%CI －0.29 ～－0.12）comparedwith the control；a significant improvement.
In a systematic review56) that considered 3 RCTs on subjects with fibromyalgia（FM）, researchers evaluated changes in the intensity of pain and quality of life
（QOL）in patients who were administered with tramadol only, those administered

QOL：quality of life

with tramadol and acetaminophen in combination, and those administered with tramadol and amitriptyline in combination. The average change in intensity of painfrom the baseline was －13（95% CI －25.37～－0.63）, －12（95% CI －18.77～－
5.23）, and －13（95% CI －19.08～－6.92）respectively；pain had improved. QOL
was evaluated using the Fibromyalgia Impact Questionnaire（FIQ）, and the average change on the FIQ from the baseline for tramadol／acetaminophen was －6.00（95%CI －9.55 ～－2.45）, showing an improvement but no significant effect wasseen when tramadol was administered alone at －2.9（95% CI －10.86 ～ 5.06）.
Based on the above, tramadol is not sufficiently useful.
Side effects from tramadol include nausea, constipation and drowsiness but theincidence rate for each of these side effects was 9%（RD 0.09, 95%CI 0.05～0.13）,
5%（RD 0.05, 95%CI 0.02～0.09）, and 6%（RD 0.06, 95%CI －0.01～0.13, higher
than the placebo, respectively54). In the United States, the number of prescriptions
for tramadol has increased more than for any other opioid analgesic. The reason forthis is believed to be related to people’s awareness that tramadol carries a low riskof drug dependence／abuse52). In Japan, tramadol is not designated as a narcotic or
psychotropic drug. Furthermore, physician do not have a duty to take an e－learning course upon prescription and it is not essential to obtain a treatment consent
form from patients either57). However, the risk of dependence／abuse is not nil, so
long－term administration without any clear aim in mind must be avoided. Tramadol, which had been an unregulated opioid analgesic up until this point, was designated as a regulated opioid（Schedule IV）by the US Food and Drug Administration（FDA）in 2014.
PeriodDatabase
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Limitations
Selection summary

2005～2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
chronic pain*
Tramadol administered group／non－administered group
Limited by publication type, PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, other（cases of50＋）etc
Of the 322 search hits, we used 12 which matched with the set PICOFDA：Food and Drug
Administration

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CQ C－11：Are buprenorphine patches useful for chronic pain ?
Answer：Buprenorphine patches are useful in reducing low back pain（LBP）andosteoarthritic pain. On the other hand, there is no evidence indicating their efficacy
on neuropathic pain. Compared with other opioid analgesics, they tend to have few
side effects and are recommended for older patients with many complications.
Recommendation Grade & Summary of Overall Evidence
Recommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100%〕

Summary of overall evidence：B（moderate）
Commentary：
Buprenorphine is pharmacologically a partial agonist of μ－opioid receptors but
also a complete agonist of μ－opioid receptors in concentrated use in clinical settings, with no noticeable ceiling effects as an analgesic. On the other hand, it does
have ceiling effects in respiratory depression58). Buprenorphine has low molecularweight just like fentanyl and high liposolubility so it is suited for percutaneous andtransmucosal administration59). Approximately 2／3 of buprenorphine is not metabolized, the remaining 1／3 is metabolized by CYP3A4 in the liver to norbuprenorphine. It has low pharmacological activity as a metabolite. As an unchanged compound, buprenorphine and 2／3 of its metabolite are excreted in the feces. Because
there is very little involvement with the kidneys, when kidney function deteriorates
it is possible to use the same dosage as that used in patients with standard kidney
function. In the case of impaired liver function, its half－life lingers but it does notreally have much impact on patients clinically. Buprenorphine is recommended forolder patients because they often have decreased kidney and liver function60,61).
We have adopted 3 systematic reviews on the usefulness of buprenorphine
patches on chronic pain.
In a Cochrane review54)on low back pain（LBP）, researchers evaluated changes
in the intensity of pain and physical function in subjects administered with buprenorphine patches containing 5～40 μg／hr over a period of 4～12 weeks. The difference in the average change from the control in intensity of pain from the baseline was－2.47（95% CI －2.69 ～－2.25）；a significant improvement. Physicalfunction was evaluated using the SF－36, and the difference in the average change
from the baseline was －0.14（95% CI－0.53 ～－0.25）, indicating that there wasno significant improvement compared with the placebo.
OA：osteoarthritis

In a Cochrane review62) on osteoarthritis（OA）,researchers evaluated changes inintensity of pain and physical function in subjects administered with buprenorphine
patches containing 5～20 μg／hr over a period of 4～24 weeks. Compared with the

C．Pharmacotherapy

controls, the difference in the average change in pain intensity from the baseline
was －0.19（95% CI －0.30～－0.09）；a significant improvement. Physical function
was evaluated using the Western Ontario and McMaster Universities Index（WOMAC）, and compared with the controls, the difference in the average change fromthe baseline was －0.23（95% CI －0.40～－0.05）；a significant improvement.
In a Cochrane review63) on patients with neuropathic pain, 11 research papers
were cited as possible candidates for inclusion but in all papers the quality of theresearch was low so they were excluded from the eligibility criteria for analysis
and there was no discussion on their usefulness.
The incidence rate of side effects from buprenorphine patches was 18.3%（RR
1.25, 95% CI 1.09～1.42）higher than the placebo62), but compared with other opioid analgesics, there is low risk of side effects such as constipation and nausea andlow risk of dependence／abuse or death due to overdose64,65). Buprenorphine patches
are an opioid analgesic which is not designated as a narcotic in Japan but before
prescribing one, a physician are required to take an e－learning course.
PeriodDatabase
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Limitations
Selection summary

2005～2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
chronic pain
Buprenorphine administered group／non－administered group
Limited by publication type, PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, other（cases of50＋）etc
Of the 380 search hits, we used 12 that matched with the set PICOCQ C－12：Are opioid analgesics [strong] useful for chronic pain ?
Answer： Opioid analgesics [strong] improve pain and physical function, for ashort period of time, in low back pain（LBP）, osteoarthritis（OA）, and neuropathic
pain. However, there is no evidence indicating their usefulness over a long periodof time. Because long－term administration of opioid analgesics [strong] elevates therisk of dependence/abuse and death due to overdose, they become highly disadvantageous to patients. In Japan, there are almost no facilities which can manage patients with opioid dependence abuse. Therefore, before beginning to administer
these drugs, rigorous patient screening should be conducted and we do not recommend undergoing treatment by anyone other than a pain management specialist
who can conduct rigorous monitoring.
Recommendation Grade & Summary of Overall Evidence
Recommendation grade：No recommendation〔Consensus 100%〕
Summary of overall evidence：B（moderate）

359

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Commentary：
At the current stage, a variety of opioid analgesics [strong] are used in Japan but
the only opioid analgesics [strong], which patients with chronic non－cancer pain areable to get a prescription for, are morphine formulations, fentanyl patches and oxycodone extended－release tablets. On the other hand, a large number of formulations
can be used overseas and their usefulness has been considered in several RCTs.
We have adopted 3 systematic reviews to consider the usefulness of opioid analgesics [strong] for chronic pain.
In a Cochrane review54) on low back pain, they evaluated changes in pain intensity and physical function when patients were administered with an opioid analgesics[strong]（tapentadol, oxycodone, morphine, oxymorphone）over a period of 2 ～ 12weeks. Compared with the control, the difference in the average change in pain intensity from the baseline was －0.43（95% CI －0.52 ～－0.33）；a significant improvement. Physical function was evaluated using the Roland Morris Disability
Questionnaire（RMDQ）and SF－36, and compared with the control, the differencein the average change from the baseline was －0.26（95% CI －0.37～－0.15）, indicating that it had significantly improved.
OA：osteoarthritis

In a Cochrane review62) on osteoarthritis（OA）,researchers evaluated changes inpain intensity and physical function when administered with each type of opioid
analgesic [strong] over a period of 1～15 weeks. Compared with the control, the difference in the average change in pain intensity from the baseline was －0.22（95%CI －0.42～－0.03）for fentanyl, 0.04（95% CI －0.19～0.28）for hydromorphone,－0.25（95% CI －0.42～－0.09）for morphine, －0.31（95% CI －0.47～－0.15）foroxycodone, －0.39（95%CI －0.58～－0.21）for oxymorphone, and －0.31（95% CI－0.46 ～－0.16）for tapendatol, indicating a significant improvement except forwith hydromorphone. Physical function was evaluated using the Western Ontario
and McMaster Universities score（WOMAC）, and compared with the control thedifference in the average change（in physical function）from the baseline was－0.28（95% CI －0.48～－0.09）for fentanyl, －0.20（95% CI －0.38～－0.02）formorphine, －0.30（95% CI：－0.58～－0.01）for oxycodone, －0.38（95% CI －0.56～－0.19）for oxymorphone, and －0.26（95%CI －0.35～－0.17）for tapendatol；asignificant improvement.
A systematic review conducted by the Spinal Interest Group on Neuropathic

IASP：International
Association for the
Study of Pain

38)
Pain（NeuPSIG）of the International Association for the Study of Pain（IASP）,

evaluated the analgesic effects of opioid analgesics [strong] on neuropathic pain, andthey calculated that the number needed to treat（NNT）to reduce pain by 50% was
4.3（95% CI 3.4～5.8）.
The incidence rate of side effects from opioid analgesics [strong] administered fora short period of time, compared with the placebo, was 27.7%（RR 1.5, 95%CI 1.33
～1.81）for fentanyl, 4.7%（RR 1.10, 95%CI 0.89～1.35）for morphine, 34.4%（RR

C．Pharmacotherapy

1.69, 95%CI 1.47～1.95）for oxycodone, and 16.3%（RR 1.39, 95%CI 1.17～1.66）
higher for tapendatol62).
There are several research papers indicating the usefulness of opioid analgesics[strong] for chronic pain but most of them are limited to short－term evaluations.
Because there are no research papers which have evaluated the usefulness of opioid analgesics used for a period of over 1 year, caution is required for such treatment interventions. Opioid analgesics not only generate an analgesic effect but also
euphoria, and dependence/abuse can arise and the risk of death due to overdose
increases with dose dependent effects66). If the original disease causing chronic pain
is low back pain（LBP）, osteoarthritis, or neuropathic pain, one can expect thesedrugs to give a slight improvement in analgesic effect and QOL if limited to a shortperiod of time（within 3 months）. However, there is a high possibility that the benefits（analgesic effects）of long－term administration might be outweighed by its
disadvantages（dependence/abuse, death）. Furthermore, at the current stage in Japan, there are almost no institutions which can manage patients with opioid dependence／abuse. Therefore, rigorous patient screening must be conducted prior to administration and after administration commences, if rigorous monitoring is not conducted, then opioid dependence/abuse may occur. A high level of knowledge about
opioid dependence and abuse is required when administering opioid analgesics[strong] for chronic pain. Therefore, we do not recommend that undergoing treatment with opioid analgesics〔strong〕by anyone other than a pain management
specialist.
PeriodDatabase
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Limitations
Selection summary

2005～2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
chronic pain*
Strong opioid（opioid strength）administered group／non－administered group
Limited by publication type, PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, other（cases of 50＋）etc
Of the 405 search results, we used 11 which matched with the set PICOCQ C－13：Is Kampo medicine（Chinese herbal medicine）useful for chronic
pain ?
Answer： As there is insufficient evidence indicating that Kampo medicine（Chinese herbal medicine）is effective on chronic pain, it remains unclear at the current
stage. However the fact that in Japan patients can be insured if treated with Kampo medicine is also a factor, so many medical practitioners do positively evaluate its
utility to some degree.
Recommendation Grade & Summary of Overall Evidence
Recommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 94.1%〕

361

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Summary of overall evidence：C（low）
Commentary：
In Western medicine, the main purpose is to treat a specific illness and so theymainly use medication that proves to be effective against the sites of lesions or
their associated symptoms. On the other hand, in Kampo medicine（Chinese herbal
medicine）, they understand the whole picture of each individual patient’s body andfocus on treating patients by fixing the body’s overall condition and restoring imbalances and distortions inside the body. This is how Western medicine and Kampo
medicine are different in their approach. With pain conditions, in Kampo medicine
treatment, they do not directly reduce the pain by ascertaining the organic causeof the patient’s pain, but restore the factors which aggravate the pain as “distortions”.
There has been much published research which has considered the usefulness of
Kampo medicine on chronic pain but the majority of this has been case studies orcase series studies and at the current stage there are no RCTs with high－quality
research. However it should be noted that, in Japan, Kampo medicine can be used
as a form of treatment which is covered by insurance and so many doctors in clinical settings are prescribing them and to a certain degree have positively evaluatedtheir usefulness. In a retrospective research study67) targeting 221 patients withchronic pain, researchers administered Kampo medicine（such as gosha－jinki－gan,
shakuyaku－kanzo－to, yokukan－san）and reported a decrease in pain in 77.9% of
the patients（highly effective：26.3%, moderate improvement：12.7%, slight improvement：38.9%）.
In a randomized open－label study on 58 spinal canal stenosis patients with painful muscle cramp, the frequency of painful muscle cramps decreased to less than
50% in 81.2% of patients who were administered with 7.5g of shakuyaku－kanzo－to／day（2.5～7.5g／day）, indicating that there was no statistically－significant difference in the frequency of occurrence according to the dosage68). In a non－randomized comparative trial targeting 83 patients with knee osteoarthritis（OA）, compared with the control group, the group who had been administered withshakuyaku－kanzo－to had a lower frequency of painful muscle cramp incidence but
statistically speaking, the difference was not significant. However, the rate ofchange in muscular stiffness in the gastrocnemius muscle did significantly decrease69).
In a case series study, they have reported on the utility of various Kampo medicines on chronic pain. In 15 patients with postherpetic neuralgia who were administered with 7.5 g of keishi－kajutsu－bu－to／day and 1～5 g of bushimatsu（processed
aconite root）／day in combination, 80% of these patients were able to continue taking them internally, and in 91% of these patients, pain intensity decreased by 50%

C．Pharmacotherapy

or more70). In a retrospective study considering the usefulness of gosha－jinki－gan
on 28 patients with LBP, pain improved in 35% of the patients. The conditions thatthe researchers cited for improvements were the absence of spinal canal stenosis
and regular administration of the Kampo medicine71). A retrospective study considering the usefulness of Kampo medicine on 151 patients with pain from spinal canalstenosis and intermittent claudication clearly showed that the the dosage of pregabalin and opioid analgesics had decreased in the group administered with Kampo
medicine（for example gosha－jinki－gan, hachimi－jio－gan）compared with non-administration group72). In a prospective cohort study that considered the usefulnessof hachimi－jio－gan on 14 patients with arteriosclerosis obliterans（ASO）, researchers indicated a decrease in pain and patients were able to walk longer distances73).
Side effects from Kampo medicine（Chinese herbal medicine）include pseudohyperaldosteronism from licorice root, drug－induced interstitial pneumonia fromScutellaria root, excessive β－stimulating effect from the Ephedra herb, and aconite
poisoning from aconite tuber. Kampo formulations are composed of various herbal
medicines and therefore attention should be paid to the herbal medicines ingredients of which they are composed when administering them to patients.
PeriodDatabase
Words
searched

P
I／C

Limitations
Selection summary

2005～2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
chronic pain*
kampo medicine administered group／non－administered group
Limited by publication type, PubMed CER randomized controlled group ／ systematic review
search filter, Cochrane RCT search filter, other（cases of50％＋）etc
Of the 170 search hits, we used 18 of them which matched with the set PICO

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Chapter D．Interventional Pain Treatment（Nerve Block）：CQ D-1～CQ D-9
CQ D-1：Are epidural injections useful for chronic pain ?
CQ D-2：Are nerve root block/transforaminal epidural injections
useful for chronic pain ?
CQ D-3：Are facet（zygapophyseal）joint injection and medial
branch block useful for chronic pain ?
CQ D-4：Is stellate ganglion block useful for chronic pain ?
CQ D-5：Is sympathetic ganglion block useful for chronic pain ?
CQ D-6：Is a trigger point injection useful for chronic pain ?
CQ D-7：Is a nerve block using radiofrequency thermocoagulation（RF）useful for chronic pain ?
CQ D-8：Is nerve block using pulsed radiofrequency（PRF）
treatment useful for chronic pain ?
CQ D-9：Are intra-articular injections useful for chronic pain ?

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D．Interventional Pain Treatment（Nerve Block）
CQ D－1：Are epidural injections useful for chronic pain ?
Answer： Epidural injections are mainly useful for spinal diseases, and in particular it is useful to administer steroids for radiculopathy due to lumbar or cervicaldisc herniation.
Recommendation Grade & Summary of Overall Evidence
1）Lumbar spine disease
・Epidural steroid injection for radiculopathy due to lumbar disc herniationR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 83.3%〕
Summary of overall evidence：B（moderate）
・Epidural injections for lumbar spinal canal stenosis, discogenic painR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 88.2%〕
Summary of overall evidence：C（low）
・Caudal block for failed back surgery syndromeR ecommendation grade：No recommendation〔Consensus：Implementation is weakly recommended 41.2%, No recommendation 58.8%〕

Summary of overall evidence：C（low）
2）Cervical diseases
・Epidural steroid injection for radiculopathy due to cervical disc herniationR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕
Summary of overall evidence：B（moderate）
・Epidural injection for cervical spinal stenosis, axial painR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 82.4%〕
Summary of overall evidence：C（low）
Commentary：
Epidural injections are an interventional therapy frequently used to manage pain.
There are 3 pathways in which it is administered：interlaminar epidural, transforaminal epidural（nerve root block）and caudal blocks but here we will discuss epidural injections in general. Transforaminal epidural injection will be described indetail on the following page.
1）Lumbar spine disease

D．Interventional Pain Treatment（Nerve Block）

In a meta－analysis of 8 RCTs on the efficacy of epidural steroid injections（interlaminar, transforaminal, caudal）for lumbar disc herniation, researchers found that371

RCT：randomized
controlled trial

it indicated significant analgesic effect 1－month and 3－months afterwards comparedwith those who were only injected with standard saline solution and local anesthetic. In another meta－analysis on 3 RCTs that was conducted one year later, researchers indicated a slight significance but there was no statistical difference interms of improvement of ADL1).
In a meta－analysis of 5 RCTs on lumbar radiculopathy including lumbar spinal
stenosis, there was no statistical difference in analgesic effect and improvement in
ADL compared with the placebo control2), However, in the RCTs in question, theresearch did not clearly display a diagnosis of radiculopathy and the method of epidural injection and the site of injection vary greatly from one research study to thenext and because they included research in which only the placebo group was prescribed an analgesic and research in which an epidural standard saline solution injection was used as the placebo, we have some doubts whether this meta－analysis
is able to evaluate the usefulness of epidural injection or not.
There is a large number of RCTs that have considered the usefulness of epiduralsteroid injections on lumbar spine diseases but the control used in the majority ofthem is a local anesthetic and injection of standard saline solution or a different approach method. There are mixed results, some showing a significant difference,others not but in both the control group and steroid injection group, they showed
analgesic effect over a short period of time. A systematic review of 52 research papers3), contains an RCT on caudal blocks for patients with lumbar spinal canal stenosis（steroid injection）over a short period of time（12 weeks）and the usefulness
of interlaminar epidural injection over a 2－year period, and both indicating analgesic effect and an improvement in ADL. Similarly, there exist respective RCTs on
the 2－year usefulness of a caudal block and interlaminar epidural injection for discogenic pain as well as caudal block for failed back surgery syndrome（FBSS）. FBSS：failed backBased on the above, the evidence is limited but we believe that epidural injections
are useful on lumbar spine diseases. Some cases of FBSS include strong psychosocial factors and therefore as careful judgment is required when applying a caudal
block, we decided on assigning a ‘no recommendation’ grade.
2）Cervical spine disease
As there have been reports of lethal complications from cervical transforaminal
epidural injection（nerve root block）, only the interlaminar approach is subject tothese guidelines. There are several RCTs but the conditions vary so no meta－analysis has been conducted. According to a systematic review4), 4 RCTs have shownstrong evidence of its usefulness in providing analgesic effect and improving ADL
over the long term（1～2 years）in cases of cervical disc herniation. There are also
respective RCTs, displaying the same level of usefulness, on cases of axial pain, andsurgery syndrome

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spinal canal stenosis.
3）Regarding steroid injections
One of the causes of spinal disease pain is inflammation surrounding the epiduralspace. Theoretically, it is believed that steroid injections are useful. There havebeen attempts to investigate the superiority of steroid injections but apart fromlumbar disc herniation, its usefulness has not been proven compared with local anesthetic injections used alone5). The reason for this is believed to be, for example
how the saline solution is useful by washing away the inflammatory substances. As
for lower back and leg pain, a meta－analysis that considered whether lumbar spine
surgery could be avoided or not by comparing an epidural steroid injection with
only a local anesthetic injection, 5 RCTS showed that it did have the effect of slightly reducing the risk of surgery within 1 year but 16 of the RCTS indicated that it
did not have an effect for over 1 year6). Considering side effects such as impaired
glucose tolerance, frequent injections of steroid should be avoided.
Furthermore, in a systematic review on the difference in the effects of steroid injections according to particulate or non－particulate steroids, there was no superiority with particulate steroids7). When we consider the dangers of spinal cord infarction and cerebral infarction due to intravascular administration, non－particulate
steroids should be used, unless there is some specific reason.
4）Adverse effects
With reports of fatal complications such as spinal cord infarction due to intravascular injection of particulate steroids in cervical transforaminal approach, intravascular injections in interlaminar approach should be avoided as well. There are reports recommending that real－time contrasts be conducted under fluoroscopic control at all sites, as well as prohibiting injections at postoperative wounds8). Considering the situation with pain clinic treatment in Japan, injections at lumbar sites
should be conducted, as much as possible, under fluoroscopic control and at cervicalsites, it is essential that epidural injections be conducted under fluoroscope.
Considering fluoroscope control, it is believed that intravascular injections occur
0.5% at lumbar sites, 4.1% occurring at cervical sites, and dural punctures occurring 0.5% of the time9). In a retrospective look at cervical epidural injections underfluoroscope in 4,396 patients, research reported that the incidence rate of dural
puncture was 1.3% but there was no incidence of spinal cord injury or postdural
10)puncture headache（PDPH）. There were almost no reports of severe side effects,

and as long as the injection is made under fluoroscopic control caudally from C6／7,
and as long as a nonparticulate steroid injection is used, it is a relatively safe procedure.
It is believed that there is no difference in efficacy between a lumbar injection
performed under ultrasound guidance and one performed under fluoroscope. Furthermore, the operation can be shortened with a caudal injection. However, consid-

D．Interventional Pain Treatment（Nerve Block）

ering the inability to check intravascular injections and the lack of visibility in deep
lumbar sites when performed under ultrasound, lumbar epidural injections（interlaminar／transforaminal）conducted under fluoroscope should be prioritized11).
PeriodDatabase
Words
searched

P
I／C

Limitations
Selection overview

2005～2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
chronic pain,neck pain, Complex Regional Pain Syndromes, Phantom Limb, Neuralgia, zoster
associated pain, Peripheral Vascular Diseases, back pain, low back pain, postherpetic neuralgia
Epidural Injections, caudal block
Limited by publication type,PubMed CER randomized controlled trials ／ systematic review
search filter, Cochrane RCT search filter, other（cases of50＋）etc
Of the 523 searches, we used 18 that matched with the set PICOCQ D－2：Are nerve root block／transforaminal epidural injections useful forchronic pain ?
Answer：Nerve root blocks are useful on lumbar spine diseases, and in particular
steroid injections are useful on radiculopathy due to disc herniation. There havebeen severe complications with cervical sites so its use is limited.
Recommendation Grade & Summary of Overall Evidence
1）Lumbar spine disease・Transforaminal epidural steroid injection for lumbar disc herniation
Recommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 82.4%〕
Summary of overall evidence：B（moderate）
・Transforaminal epidural injection for lumbar spinal canal stenosis
Recommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 88.9%〕
Summary of overall evidence：C（low）
2）Cervical diseases
・Nerve root block under limited conditions such as ultrasound guidanceRecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 83.3%〕
Summary of overall evidence：C（low）
Commentary：
In Japan, nerve root block is a technique of injecting into the nerve sheath andsome think that it is different from transforaminal epidural injection but this concept is not consistently agreed upon. Based on the extent of our search, most research has reported on using transforaminal epidural injections for the purpose oftreatment, but as they have been unable to clearly distinguish between the two, wewill treat them as one and the same technique.

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D．Interventional Pain Treatment（Nerve Block）

1）Lumbar spine diseases
RCT：randomized
controlled trial

In a systematic review of 18 RCTs on transforaminal epidural injection3), most of
the research that was utilized did not show any difference between the groups interms of the drug that was administered or the pathway via which it was administered, and researchers showed significant analgesic effect for lumbar spine diseases
and improvement in ADL in the control group and the group administered withthe steroid. In 4 RCTs on radiculopathy due to lumbar disc herniation, researchers
showed long－term efficacy（1 ～ 2 years）. In 3 of the RCTs, researchers showed
short－term effects on lumbar spinal canal stenosis but the evidence was limited
and no high－quality RCTs exist on discogenic low back pain（LBP）or failed backsurgery syndrome（FBSS）. In another RCT that was published after that on unilateral leg pain due to lumbar disc herniation, in which physiotherapy and pharmacology were used as the controls, researchers found that when transforaminal epidural injection（steroid injection）was added, there was a significant improvement in
pain and ADL 1 month later12).
Theoretically, we expect transforaminal epidural injections to be more effective
than interlaminar epidural injections and caudal blocks because the advantage isthe steroid can be directly injected into the inflamed area around the nerve root. Ina systematic review of 12 research studies on lumbar disc herniation, in comparison
with interlaminar epidural injection, several reports clearly indicated that transforaminal epidural injection were more highly effective but the results of a meta－
analysis of 5 RCTs, which were uniform, did not show any significant difference inanalgesic effect or improved ADL13). Similarly, in a meta－analysis of 3 RCTs, it was
not found to be superior when compared with a caudal block14). In conclusion, there
is limited evidence indicating that transforaminal epidural injection is more usefulthan interlaminar epidural injection and caudal block for treating lumbar disc herniation but considering things like the possibility of root arterial injury during atransforaminal epidural injection and a feeling of discomfort at the time of the steroid injection, we need to judge which form of treatment to choose.
We would like to refer you to the epidural injection（CQ D－1）for deciding
whether to add a steroid injection or not. Researchers have demonstrated the statistical superiority of a steroid injection over just a local anesthetic injection for
lumbar disc herniation1), but there is another RCT that failed to show the statisticaldifference for other types of lumbar spine diseases5). Furthermore, in a meta－analysis of 4 RCTs comparing injections of particulate and non－particulate steroids forlumbar transforaminal epidural injection, researchers did not find any difference inanalgesic effect nor any difference based on the type of steroid used15). When it
comes to actually using non－particulate steroid, we should limit the frequency of its
usage.
2）Cervical spine diseases

D．Interventional Pain Treatment（Nerve Block）

There have been reports that cervical transforaminal epidural injection may result in rare, but severe complications, What researchers have thought could be possible mechanisms causing this include brainstem／spinal cord infarction mainly due
to an intravenous particulate steroid injection and also vascular spasm due to thepuncture needle. Therefore, in recent years there have been few high－quality reports. In a systematic review of transforaminal epidural injections conducted underfluoroscope to treat radiculopathy, 16 research papers indicated that it was effective（provides analgesic effect, and avoidance of surgery）but the evidence waslimited. In addition, there is a case report of 23 severe complications, including 13
cases of death, so we recommend conducting the interlaminar approach16).
In a retrospective consideration of nerve root block conducted under ultrasoundguidance and epidural injection（interlaminar）conducted under fluoroscope control17), a nerve root block conducted under ultrasound guidance was a shorter procedure but there was no difference in analgesic effect or improved ADL. In an epidural injection, there was some blood reflex in 8% of cases at the time of absorption
but this phenomenon did not occur in a nerve root block conducted under ultrasound guidance. An angiography detected 11% during epidural injection. A nerve
root block conducted under ultrasound guidance offered superior visibility of theblood vessels in the area surrounding the puncture site and therefore may possibly
be safer but we should also keep in mind the danger of being unable to confirm an
intravascular injection. There have been no reports of severe complications fromnerve root block under ultrasound guidance but it is recommended to have somesafety measures in place when using non－particular steroids such as using realtime fluoroscopy concomitantly as much as possible.
PeriodDatabase
Words
searched

P
I／C

Limitations
Selection outline

2005～2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
chronic pain,neck pain, Complex Regional Pain Syndromes, Phantom Limb, Neuralgia, zoster
associated pain, Peripheral Vascular Diseases, back pain, low back pain, postherpetic neuralgia
Epidural Injections
Limited by publication type,PubMed CER randomized controlled trials ／ systematic review
search filter, Cochrane RCT search filter,other（case number of50＋）etc
Of the 523 search hits, we utilized 9 that matched with the set PICOCQ D－3：Are facet（zygapophyseal）joint injection and medial branch blockuseful for chronic pain ?
Answer：We can expect medial branch block to provide analgesic effect and improved QOL for facet joint－derived chronic low back pain（LBP）,cervical pain, andthoracic back pain. There is a possibility that giving or not giving patients a steroid
injection may not even have an influence. Facet（zygapophyseal）joint injection is
widely used to treat facet joint－derived chronic low back pain（LBP）,cervical pain,
and thoracic back pain but evidence indicating its usefulness is limited.

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D．Interventional Pain Treatment（Nerve Block）

Recommendation Grade & Summary of Overall Evidence
1）Medial branch blockR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 94.1%〕
Summary of overall evidence：C（low）
2）Facet（zygapophyseal）joint injectionR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 83.3%〕
Summary of overall evidence：C（low）
Commentary：1）Medial branch block
When one suspects facet joint－derived chronic low back pain（LBP）, cervicalpain, or thoracic back pain, a nerve root block is conducted on the posterior rami of
the spinal nerves, which are the sensory nerves of the facet joints, for the purposesof diagnosis and treatment. Research on medial branch block is conducted on thepremise of evaluating research being carried out for a rigorous diagnosis of facet
joint－derived pain. A systematic review22) has been conducted, and there are 4
RCT：randomized
controlled trial

RCTs that investigated the usefulness of medial branch block on chronic LBP, cervical pain, and thoracic back pain18－21). There is no research comparing it againstsham treatments. In all 3 RCTs（lumbar18), cervical19), thoracic20)）comparing thedifference in effect of a medial branch block by the drug used（local anesthetic vs.
local anesthetic＋steroid）, each displayed analgesic effect and improved QOL overthe short－term and long－term, irrespective of the type of steroid used. The resultsof a follow－up study conducted over 2 years were that pain had improved at 14～
19 weeks after the 1 medical branch block, and after conducting 5～6 blocks over a
2－year period, it maintained a reduction in pain over the long term. In another
RCT21) on LBP, compared with radiofrequency thermocoagulation of the medial
branch of posterior ramus of which there is much evidence of its efficacy, lumbar
medial branch block provides inferior analgesic effect over the short and long term,
and there was no difference in improved QOL. Also in these RCTs, there was not 1
report of any severe complications.
Based on the above, we do recommend medial branch block as a form of treatment which we expect can provide analgesic effect and improved QOL for facet
joint－derived chronic LBP, cervical pain, and thoracic back pain. However, as there
is no high－quality research comparing it against sham treatments, the certainty of
its evidence is low.
2）Facet（zygapophyseal）joint injection
Facet（zygapophyseal）joint block is a widely－used form of treatment with thesame purpose as the medial branch block mentioned above. Research on facet（zy-D．Interventional Pain Treatment（Nerve Block）

gapophyseal）joint injection is conducted under the premise of evaluating research
being carried out for a rigorous diagnosis of facet joint－derived pain. There are 5
23－27)
RCTs（4 lumbar, 1 cervical）
on the usefulness of facet（zygapophyseal）joint

injection on chronic low back pain（LBP）, cervical pain, and thoracic back pain, anda systematic review has been conducted22). When we evaluate a quantitative synthesis of 2 RCTs23,24) that compare a facet（zygapophyseal）joint injection for LBP
with a sham treatment（saline solution, hyaluronic acid）, there was found to be nodifference in analgesic effect over the short term, and over the long term, analgesic
effect was slightly superior from the facet（zygapophyseal）joint injection and nodifference in improved QOL. In a research study25) on long－term analgesic effectand improved QOL comparing a facet（zygapophyseal）joint injection with radiofrequency thermocoagulation of the medial branch of posterior ramus（for which alarge number of evidence its efficacy exists）, researchers did not find any difference in efficacy or degree of effect. In another research study26) comparing short－term analgesic effect and improved QOL in a facet（zygapophyseal）joint injectiongroup with a NSAIDs（only）group and a NSAIDs＋facet（zygapophyseal）joint injection group, the results showed that analgesic effect and improved QOL weresignificantly higher in the NSAIDs＋facet（zygapophyseal）joint injection group（1st）＞ the facet（zygapophyseal）joint block group（2nd）＞ the NSAIDs group（3rd）, in that order. Furthermore, in another research study27) comparing analgesic
effect on patients with cervical pain across 2 groups：one group receiving analgesic＋home exercise management and an additional facet（zygapophyseal）joint injection
and one group without the injection, researchers found that only those in the groupto which a facet（zygapophyseal）joint injection was added experienced a significant reduction in pain over the short and long term, compared with prior to treatment. These RCTs did not report any cases of severe complications.
Based on the above, facet（zygapophyseal）joint injection is a widely－used formof treatment for facet joint－derived chronic low back pain（LBP）,cervical pain, andthoracic back pain but there have been reports of results that contradict these effects, meaning there is poor grounds on which we are able to strongly recommend
it as a form of treatment from which one can expect analgesic effect and improved
QOL, and the certainty of its evidence remains low.
PeriodDatabase
Words
searched

P
I／C

Limitations
Selection summary

2005～2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
chronic pain, low back pain, neck pain, back pain
facet block, facet blocks, facet joint block, facet joint blocks, zygapophyseal joint block, zygapophyseal joint blocks, medial branch block, medial branch blocks, facet injection, facet injections, facet joint injection, facet joint injections, zygapophyseal joint injection, zygapophyseal
joint injections, medial branch injection, medial branch injections／no particular specifications
Limited by publication type,PubMed CER randomized controlled trials,／systematic reviews／
meta－analysis search filter,Cochrane RCT search filter, other（English, Japanese）etc
Of the 169 search hits, we utilized 10 searches that matched with the set PICO

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D．Interventional Pain Treatment（Nerve Block）

CQ D－4：Is stellate ganglion block useful for chronic pain ?
Answer：Apart from its effects in preventing postherpetic neuralgia（PHN）from
SGB：stellate ganglion
block

herpes zoster, there is no high－quality evidence on stellate ganglion block（SGB）.
However, it is widely used to alleviate head and neck pain and sympathetic nerve－
dependent pain, and there are reports indicating its efficacy. One needs to give
each case plenty of consideration about its applicability and when performing thisblock, one needs safety measures such as performing it under ultrasound guidance.
Recommendation Grade & Summary of Overall Evidence

CRPS：complex
regional pain
syndrome

1）CRPS in the upper limbs
Recommendation grade：No recommendation〔Consensus 81.3%〕
Summary of overall evidence：C（low）
2）Prevention of postherpetic neuralgia（PHN）for herpes zosterR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 86.7%〕
Summary of overall evidence：C（low）
3）Orofacial painR ecommendation grade：No recommendation〔Consensus：47.1% implementation is
weakly recommended；52.9% no recommendation〕

Summary of overall evidence：D（very low）
Commentary：
Stellate ganglion block（SGB）is used for various types of chronic pain such as
PHN：postherpetic
neuralgia

complex regional pain syndrome（CRPS）,postherpetic neuralgia（PHN）,headache,and orofacial pain, and also for disease other than pain such as blood circulation disorder in the upper limbs, facial（nerve）paralysis, drug－refractory ventricular arrhythmia, hot flashes which is a symptom of menopause in women, and post－trau-

PTSD：post-traumaticstress disordermatic stress disorder（PTSD）. In recent year, researchers have reported on using
guides, such as X－ray fluoroscopy and ultrasound, in order to increase the efficacy
and safety of this procedure.
1）CRPS in the upper limbs
In a Cochrane review28) on sympathetic nerve block using local anesthetic for
CRPS, researchers claimed they were unable to reach a conclusion on the efficacy
and safety of this intervention due to insufficient evidence. In a CRPS review published in 201129), they gave SGB a weak recommendation for CRPS in the upper
limbs. In addition, other researchers reported on an observational research study
on the efficacy of early－stage SGB in treating CRPS in the upper limbs, recognizing
a significant improvement in pain and range of motion（ROM）in the hand joints
through SGB and also reported a more significant improvement in pain in the

D．Interventional Pain Treatment（Nerve Block）

group with a shorter interval between onset of the condition and when they began
the SGB compared with the other group with a longer interval between onset and
SGB30). Furthermore, in another study31) researchers reported that the effect of
SGB was weak either when 16 weeks or more had passed since the time of onset
or in cases where skin blood flow had decreased by more than 22% compared with
the normal side. They reported a correlation between how early treatment began
using SGB and the effects of the treatment and also that the effects of SGB werehigh if treatment began by the 12th week after onset31).
Some cases of CPRS include strong psychosocial factors and therefore careful
judgment is required when applying SGB and we recommend performing it at an
early stage after onset.
2）Prevention of postherpetic neuralgia（PHN）for patients with herpes zoster
According to a double－blind RCT on the possibility of preventing the transition
32)
from acute－stage herpes zoster of the head to postherpetic neuralgia（PHN）, re-searchers reported that the frequency of transitions to PHN had significantly decreased. We recommend performing SGB at an early stage after onset. Similarly,
SGB is considered to be useful for herpes zoster at an early stage, but there is nothigh－quality evidence.
3）Orofacial pain
No high－quality RCTs or observational studies exist on the effects of SGB on orofacial pain. There are reviews33) and case series34) indicating the efficacy of SGB on
orofacial pain, and case reports35) for example that SGB was effective on atypical facial pain. Performing SGB should be considered when the effects from other formsof treatment have proven to be insufficient.
4）Using guides
There is no high－quality evidence verifying the superiority of one guide, by comparing the landmark method, X－ray fluoroscopy, and ultrasound guidance. In a review36) on SGB－related complications, researchers reported that the method used
for performing SGB in cases where complications arose were the landmark method
at 48.5%, X－ray fluoroscopy at 26.9%, and ultrasound guidance at 24.6%. Under ultrasound guidance, the blood vessels and other tissue can be visualized, and therefore this may improve its safety. There is 1 RCT37) indicating the usefulness of ultrasound guidance compared with the landmark method, for treating CRPS in theupper limbs. In addition to this, there are also some observational research studies
indicating the usefulness of ultrasound guidance compared with X－ray fluoroscopy.38,39)

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PeriodDatabase
Words
searched

P
I／C

Limitations
Selection summary

2005～2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
chronic pain, neck pain, complex regional pain syndromes, zoster associated pain, herpetic
pain, atypical facial pain, phantom limb
stellate ganglion block, cervical sympathetic ganglion block
Limited by publication type, PubMed CER randomized comparative trials,／systematic review
search filter, Cochrane RCT search filter, etc.
Of the 192 search hits, 13 were utilized that matched with the set PICOCQ D－5：Is sympathetic ganglion block useful for chronic pain ?
Answer：Thoracic sympathetic ganglion block and lumbar sympathetic ganglion
block have often been used in clinical settings for the purpose of alleviating ischCRPS：complex
regional pain
syndrome

emic pain in peripheral vessel disease, complex regional pain syndrome（CRPS）,
and pain due to sympathetically maintained pain（SMP）, and there are also many
reports indicating its usefulness. However, there is little high－quality evidence.
Recommendation Grade & Summary of Overall Evidence
1）Thoracic sympathetic ganglion block
・CRPS in the upper limbs
Recommendation grade：No recommendation〔Consensus 84.6%〕
Summary of overall evidence：C（low）
・Pain due to vascular disorders in the upper limbs
R ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 92.3%〕
Summary of overall evidence：D（very low）

PHN：postherpetic
neuralgia

・Post－traumatic syndrome, PHN, brachial plexus syndromeR ecommendation grade：No recommendation：〔Consensus：Implementation is
weakly recommended 33.3% No recommendation 66.7%〕

Summary of overall evidence：D（very low）
2）Lumbar sympathetic ganglion block・Pain due to vascular disorders in the lower limbs
R ecommendation grade：2（weak）： Implementation is strongly recommended〔Consensus 92.3%〕
Summary of overall evidence：C（low）
・CRPS in the lower limbs
Recommendation grade：No recommendation〔Consensus 91.7%〕
Summary of overall evidence：D（very low）
FBSS：failed backsurgery syndrome

・Lumbar spinal canal stenosisR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 83.3%〕
Summary of overall evidence：D（very low）

D．Interventional Pain Treatment（Nerve Block）

Commentary：
In the management of chronic pain, sympathetic ganglion block is often used inclinical settings for the purpose of alleviating ischemic pain in peripheral vessel disease. We have already talked about stellate ganglion block（SGB）at CQ D－4 sohere we will discuss thoracic sympathetic ganglion block and lumbar sympathetic
ganglion block.
1）Thoracic sympathetic ganglion block
There are few reports about its effects on pain－related diseases and the evidence
is limited.
In an RCT40) that investigated the effects of thoracic sympathetic ganglion blockon 36 cases of CRPS type I of the upper limbs, researchers found that intensity ofpain displayed significantly lower scores in the thoracic sympathetic ganglion blockgroup 12 months later according to their McGill Pain Questionnaire Scores, theNeuropathic Pain Symptom Inventory, and Hospital Anxiety and Depression Scale.
In a crossover test on 15 patients with CRPS in the upper limbs, which included
SGB and thoracic sympathetic ganglion block at a high position of T2 , patients had
a more definite effect（rise in upper limb temperature, reduced pain）with the T2
block41). Furthermore, in a retrospective study42) focusing on 51 patients and investigating the usefulness of thoracic sympathetic ganglion block（at the high positionof T3 using 5 ml of 0.25% [w ／ v] levobupivacaine）on chronic upper－limb pain
（CRPS, post－traumatic syndrome, PHN, brachial plexus disorder）, researchers
found it to be effective when assessed 2－weeks later in 52.9% of patients. When it
was performed within 1 year after onset it was found to more effective than casesthat had occurred over 1 year ago. In a 2016 Cochrane review28), there was a lackof high－quality reports on thoracic sympathetic ganglion block using local anesthetic for CRPS patients and therefore they were unable to conclude that it was effective. Intervention treatment for CRPS requires caution because CRPS patients havepossibility to have strong association with psychosocial factors. Thus, we decided toassign a “no recommendation” grade.
In a comparative research study43) on thoracic sympathetic ganglion block radiofrequency thermocoagulation for treating vascular disorders in the upper limbs, researchers divided and compared 50 patients with Raynaud’s disease into a groupthat underwent radiofrequency coagulation at T2 and T3 and a group in which coagulation was only performed at T2, receiving an injection of 6％ [v／v] phenol and
0.5 ml of water. In both groups, researchers acknowledged a significant reduction
in pain and a rise in skin temperature in the upper limbs, as well as improved QOL
but there was no recognizable significant difference between the groups apart fromthe time required to perform the procedure. Just like above, the evidence was insufficient and in a 2011 systematic review41), they were unable to come to a clear
conclusion about its usefulness. As there are few severe side effects, physicians

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should consider performing this when the effects of other forms of conservative
treatment prove to be insufficient.
2）Lumbar sympathetic ganglion block
Lumbar sympathetic ganglion block is applied to pain caused by vascular disorders of the lower limbs. There is 1 RCT45) on blocks using a neurolytic agent totreat vascular disorders of the lower limbs. Researchers targeted 41 limbs in 37 patient with chronic ischemic limbs and when comparing a phenol group with a local
anesthetic group, researchers found that pain had significantly reduced in the phenol group after 6 months. In addition to this, there are also some reports46,47) indicating the efficacy of lumbar sympathetic ganglion block using a neurolytic agent
on ischemic diseases of the lower limbs. In a neurolytic agent－type block, although
there are complications such as inflammation of the genitofemoral nerve, the frequency of severe complications is low, and if other forms of conservative treatment
are insufficiently effective, it is useful in terms of alleviating pain and preventing
amputation of the diseased limb.
There is an extremely small number of high－quality research reports indicating
the usefulness of lumbar sympathetic ganglion block using local anesthetic, and in a2016 Cochrane review28), due to a lack of high－quality reports on lumbar sympathetic ganglion block using a local anesthetic for patients with CRPS, researchers
were unable to conclude whether it was useful or not.
When expecting long－term effects, apart from a neurolytic agent－based block,
another choice is to use the method of physical destruction of nerves using radiofrequency thermocoagulation（RF）. There is a report48) indicating that the usefulRF：radiofrequency
thermocoagulation

ness of lumbar sympathetic ganglion block using RF was inferior to neurolytic
agents and also a report49) indicating that both treatment had the same usefulness.
In a comparison of the effect of using radiofrequency thermocoagulation（RF）andphenol in a lumbar sympathetic ganglion block（temperature rise, and preventionof sweating）, on patients with CRPS type I, caused for example by injuries to theknee, shin, and leg joints, they found that it had 89% efficacy at 8 weeks after theblock had been conducted on the phenol group, whereas it was only 12% for the
RF group48). On the other hand, in a comparative research study conducted on 20
patients with CRPS type I, allocating 10 patients into each group, researchers reported a significant reduction in pain from the baseline in all patients in bothgroups when evaluated 4 months later. Lumbar sympathetic ganglion block using
RF and phenol had an equal efficacy49). For the reasons mentioned above, we alsodecided to assign a “no recommendation” grade for CRPS of the lower limbs.
There are no RCTs which have considered the effect of lumbar sympathetic ganglion block on lumbar spinal canal stenosis. In terms of reports indicating its usefulness, there is a report50) indicating that it might possibly be effective on patients
who have been suffering from cauda equina syndrome for a short period of time,

D．Interventional Pain Treatment（Nerve Block）

383

and its efficacy rate on 62 patients with lumbar spinal canal stenosis was 48.4%
and had a high efficacy rate on patients with coldness in the lower limbs51), andthere are also reports in which there was a recognizable improvement in intermittent claudication51,52,).
PeriodDatabase
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Limitations
Selection summary

2005～2020
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
chronic pain
Sympathetic ganglion block chemical（alcohol）, physical（RF）blockage ／ local anesthetic,chemical（alcohol）
Limited by publication type,PubMed CER randomized comparative trial ／ systematic review
search filter,Cochrane RCT search filter, limited number of RCTs,important observational research, cases series included
Of the 37 PubMed search hits, 126 Cochrane CENTRAL search hits, from 42 NPO Japan Medical Abstracts Society search hits, we utilized 14 search hits that matched with the set PICOCQ D－6：Is a trigger point injection useful for chronic pain ?
Answer：Although evidence indicating the usefulness of a trigger point injection（local anesthetic）for myofascial pain syndrome（MPS）has been accumulating, it
still remains insufficient. As long as it is performed by an experienced pain man-

MPS：myofascial pain
syndrome

agement specialist, then it is a relatively safe and easy procedure and can help
treat pain. Attention should be paid to complications during the procedure and wemust consider how frequently to make the procedure and type of the drug should
be administered.
Recommendation Grade & Summary of Overall EvidenceRecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 94.1%〕

Summary of overall evidence：B（moderate）
Commentary：
There is a systematic review53) which conducted a meta-analysis of the analgesic
effects of a trigger point injection（TPI）on myofascial pain syndrome（MPS）including tension-type headache（TTH）. They divided patients into a local anesthetic
injection group and an ‘other intervention’ group（saline solution, topical local anesthetic, dry needling, acupuncture and moxibustion, stabilization sprint, and stretches, etc）
. They found that the local anesthetic group experienced significant pain relief 16 weeks after the procedure compared with the other intervention group. Furthermore, in the meta－analysis from the same systematic review, botulinum toxin
injection had an inferior analgesic effect than the local anesthetic injection. However, due to a high lack of uniformity among the research studies, in order to draw
conclusions, there is need for further research in future, taking into account the research design, type of drug used and its concentration, whether there was an addi-

TPI：trigger point
injection

384

D．Interventional Pain Treatment（Nerve Block）

tional steroid drug or not, the site of injection, and any concomitant treatments（stretches, muscle strengthening exercises, stabilization spring, manipulation, etc）.
At the current stage, there is no strong evidence54) supporting the usefulness ofbotulinum toxin and steroid drugs, and there is a need to consider side effects andthe problem of treatments which are ineligible to be covered under health insurance.
There are a few reports on complications, for example subcutaneous bleeding,dizziness and injection site pain, but the majority of them are local and temporary
so TPI is considered to be a relatively safe procedure.
If performed by a highly－experienced physician, the procedure is highly safe andis widely used in clinical settings. However, when performing this procedure, its effects must constantly be evaluated and should not be performed over a long periodof time without some clear aim in mind. In addition, for TPI’s effects on stiff shoulders in particular, we wish to refer you to CQ L－4.
PeriodDatabase
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2005～2019
PubMed,Cochrane CENTRAL, NPO Japan Medical Abstracts Society
tension type headache, Temporomandibular Joint Disorders, Musculoskeletal Pain, neck pain,back pain, myofascial pain syndrome, chronic pain
Trigger point injection
Limited by publication type,PubMed CER randomized controlled trials ／ systematic review
search filter, Cochrane RCT search filter, other（cases of50＋）etc
Of the 138,215 search hits, we utilized 21 of them which matched with PICOCQ D－7：Is a nerve block using radiofrequency thermocoagulation（RF）
useful for chronic pain ?
Answer：We expect that nerve block using radiofrequency thermocoagulation
RF：radiofrequency
thermocoagulation（RF）, provides short－ and long－term pain relief and short－term improved QOL for
patients suffering from chronic low back pain（LBP）originating in the facet andsacroiliac joints. Furthermore, we expect it to provide short－ and long－term pain
relief for patients with trigeminal neuralgia but we recommend that the form oftreatment be selected keeping in mind that there is a risk of complications in patients who are resistant to drug therapy. It also has the possibility of being usefulover the short－and long－term for chronic pain in patients with knee osteoarthritis（OA）.
Recommendation Grade & Summary of Overall Evidence
1）Chronic low back pain originating in the facet and sacroiliac jointsR ecommendation grade：1（strong）：Implementation is strongly recommended〔Consensus 83.3%〕
Summary of overall evidence：A（high）
2）Trigeminal neuralgia

D．Interventional Pain Treatment（Nerve Block）

Recommendation grade：2（weak）：Implementation is strongly recommended〔Consensus 100.0%〕
Summary of overall evidence：C（low）
3）Chronic pain in knee OA
Recommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 90.5%〕
Summary of overall evidence：B（moderate）
Commentary：1）Chronic low back pain（LBP）originating in facet and sacroiliac joints
Radiofrequency thermocoagulation（RF）is performed on the dorsal rami of the
spinal nerve, which is a sensory nerve of the facet joints, for patients with chronic
low back pain（LBP）originating in the facet joints and sacroiliac joints, as well as
the L5（＋L4）dorsal ramus and S1－3 dorsal rami of the sacral nerve. In addition toevaluating their symptoms, it is also important to assess whether it is suitable toperform treatment or not through a rigorous diagnostic nerve block23).
There are many RCTs that have investigated the usefulness of RF for treating
chronic low back pain originating in the lumbar facet joints and sacroiliac joints
and in 2019, researchers reported a meta－analysis55). We conducted a new meta－
analysis on 16 RCTs including the paper in the previous meta-analysis and new research papers that were found by our search for these guidelines56)（short－term
pain relief：13 RCTs, long－term pain relief：7 RCTs, short－term improvement in
QOL：5 RCTs, long－term improvement in QOL：3 RCTs, incidence rate of severe
complications：14 RCTs）. Although we saw a wide dispersion between the resultsof each research study, a quantitative synthesis, indicated that short－ and long－term pain relief and improved QOL could be expected. The incidence rate of severe complications was low at 0.92%（injection, mild burns, vagal reflex）, with nocomplications that leave patients with long－term impairments. In addition, because
there was no difference in the incidence rate as compared with the control treatment, we strongly recommend it as being a highly safe, form of treatment, which
we can expect to be useful.
2）Trigeminal neuralgia
With trigeminal neuralgia patients who are resistant to drug therapy, radiofrequency thermocoagulation（RF）is conducted on trigeminal ganglion（Gasserian
ganglion or semilunar ganglion）and the peripheral branches of the trigeminal
nerve（supraorbital nerve, supratrochlear nerve, maxillary nerve, infraorbital
nerve, mandibular nerve, mental nerve）.
There are 2 systematic reviews57,58) on interventional treatments of trigeminal
neuralgia. They used RCTs that were subject to this research, and including new
research papers59,60) that were found while searching for references for these guide-

385

386

D．Interventional Pain Treatment（Nerve Block）

lines, 5 RCTs in total were applicable. There is no research which compares itagainst sham treatments or other forms of treatment apart from nerve block.
There have been comparisons based on the target of treatment（trigeminal gangliPRF：pulsed
radiofrequency

on vs. peripheral branch）, a comparison with pulsed radiofrequency（PRF）and acomparison with RF + PRF and in terms of outcomes, they were only able to evaluate pain relief. In a research study comparing trigeminal ganglion RF with RF of
the peripheral branches of the trigeminal nerve, in both instances, they reported ahigh pain relief rate over the short and long term. In a research study comparing
RF and PRF of the trigeminal ganglion, RF showed a marked decrease in trigeminal neuralgia pain over the short term but there was no effect from PRF. In another research study that compared RF of the trigeminal ganglion against RF＋PRF
of the trigeminal ganglion, both reduced trigeminal neuralgia pain over the shortand long term but researchers indicated the possibility that the effect was slightly
superior in the RF＋PRF group. There is need to conduct further research into theconcomitant use of RF and PRF.
In a large－scale case series study61) on the incidence rate of severe complications
on 1,600 patients, researchers reported an incidence rate of 0.6～5.7%, including
complications such as anesthesia dolorosa, dysesthesia, loss of corneal reflex, keratitis, masseter muscle weakness, and diplopia（double vision）. As the data were old,
it is possible that the incidence rate would be even lower using current procedures
but before conducting the procedure, it is necessary for doctors and patients to sufficiently discuss（informed consent）the risks of complications first.
In light of the above, for severe cases of patients resistant to drug therapy, aftersufficiently considering the risks of complications, we believe that RF for trigeminal
neuralgia would prove to be highly effective.
3）Chronic knee pain in knee osteoarthritis（knee OA）
There are some RCTs comparing RF treatment of the genicular nerve with other forms of treatment（sham treatments, knee joint injection, taking NSAIDs internally）to treat chronic knee pain in patients with knee OA, and in 2019, researchersreported a meta－analysis62). Along with the research papers that were subject tothis meta－analysis, we also found and included new research papers63) when searching for references for these guidelines, and when we conducted a new meta－analysis on 4 RCTs in total（short－term pain relief：4 RCTs, long－term pain relief：2
RCTs, short－term improvement in QOL：4 RCTs, long－term improvement in
QOL：N／A, incidence rates of severe complications：4 RCTs）, it indicated that we
can expect short－ and long－term pain relief. There was a dispersion in QOL de-

WOMAC：Western
Ontario and Mcaster
Universities Oateioarthritis Index

pending on the evaluation method used（2 research papers used WOMAC to evaluate, 2 used OKS）but it is possible that it improves QOL over the short term. Not
even 1 severe complication arose in these RCTs so it has been evaluated as a safe
form of treatment.

D．Interventional Pain Treatment（Nerve Block）

387

In light of the above, RF on the knee joint nerve in patients with chronic knee
pain from knee OA is a form of treatment which we can expect to be effective but
the number of cases in this research remains small, and as this has not yet been
positioned as a standard form of treatment in Japan, we weakly recommend it.
PeriodDatabase
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I／C

Limitations
Selection Summary

2005～2019
PubMed,Cochrane CENTRAL, NPO Japan Medical Abstracts Society
chronic pain, low back pain, neck pain, back pain, trigeminal neuralgia, osteoarthritis, CRPS,
sympathetically, sympathetic, ischemic
radiofrequency／no specifications
Limited by publication type, PubMed CER randomized controlled trials ／ systematic review ／meta－analysis search filter, Cochrane RCT search filter, other（English, Japanese）etc
Of the 502 search hits, we utilized 10 searches that matched with PICOCQ D－8：Is nerve block using pulsed radiofrequency（PRF）treatment usefulfor chronic pain ?
Answer：Of the diseases that may give rise to chronic pain, nerve block using
pulsed radiofrequency（PRF）is believed to be a form of treatment that can be selected for treating postherpetic neuralgia（PHN）and chronic shoulder joint pain
and researchers have shown its short－term and long－term efficacy（for at least 3
months）and its high level of safety. In some cases, it may also be applicable fortreating radiculopathy, lumbar facet joint－derived pain, knee OA, and idiopathic trigeminal neuralgia.
Recommendation Grade & Summary of Overall Evidence1）Postherpetic neuralgia（PHN）
Recommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 85.7%〕
Summary of overall evidence：B（moderate）
2）Chronic joint pain・Chronic shoulder joint pain
Recommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 95.2%〕
Summary of overall evidence：B（moderate）
・Chronic knee joint pain
Recommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 85.0%〕

Summary of overall evidence：C（low）
3）Radiculopathy
Recommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 81.0%〕

Summary of overall evidence：B（moderate）

PRF：pulsed
radiofrequency
PHN：postherpetic
neuralgia

388

D．Interventional Pain Treatment（Nerve Block）

4）Lumbar facet joint－derived painR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 90.0%〕
Summary of overall evidence：C（low）
5）Idiopathic trigeminal neuralgiaR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕
Summary of overall evidence：C（low）
Commentary：
RCT：randomized
controlled trial

There are many RCTs and prospective controlled trials and in a meta－analysis
and systematic review researchers indicated its safety and that just from one procedure, patients experienced analgesic effect persisting for at least 12 weeks, particularly for PHN and chronic shoulder joint pain. Therefore, nerve block using
PRF is a form of treatment that should be chosen to treat chronic pain, mainly thepathologies mentioned above. Furthermore, the temperature of the needle tip ismaintained at 42 ℃ and below in PRF so there is a low possibility that it will destroy nerves, and because there have been no reports of complications to date, it
can be called a highly－safe form of treatment64－68). Therefore, performing PRF inclinical settings on pathologies other than those mentioned above（radiculopathy,
lumbar facet joint－derived pain, chronic knee joint pain, idiopathic trigeminal neuralgia）will not be hampered；we expect further research to be conducted in future. However, there is little evidence available on the optimal amount of time forthe procedure, the site of treatment, and parameters, and there for it requires further consideration.
1）Postherpetic neuralgia（PHN）
In a double－blind placebo－controlled RCT on PHN69), researchers compared andconsidered patients with chest PHN；48 cases underwent peripheral nerve（intercostal nerve）PRF while another 48 cases underwent a sham stimulation over a period of 6 months. Researchers reported a significant decline in VAS scores and significant improvement in QOL（SF－36）in the PRF group. In a meta－analysis67) on
the efficacy of PRF targeting patients with neuropathic pain, researchers comparedpatients who underwent a nerve block using local anesthetic as well as drug therapy such as pregabalin for PHN, and results indicated that PRF was highly useful.
Furthermore, there is another report70) that showed that we can expect even better analgesic effects for patients when PRF is used in combination with pregabalin.
Based on the above, we can say that PRF can be selected to treat PHN. However,regarding the site for performing PRF, we wish to refer you to CQ O－7.
2）Chronic joint pain
In a double－blind RCT71) conducted over 3 months on patients with frozen shoul-

D．Interventional Pain Treatment（Nerve Block）

389

der, they compared a group（68 cases）that underwent PRF of the suprascapularnerve with a sham stimulation group（68 cases）, and reported a significantly higher improvement in pain and shoulder joint disorders. Moreover, there is a systematic review66) that discussed 5 RCTs on the effects of PRF on chronic shoulder joint
pain, and researchers found that PRF on the suprascapular nerve was effective forat least 12 weeks or more on chronic shoulder joint pain and with no reports ofcomplications, indicating that it is highly safe. Therefore, we recommend PRF on
the suprascapular nerve for treating patients with chronic shoulder joint pain.
However, it is not clear whether PRF is superior over conventional forms of treatment such as intra－articular steroid injection, physiotherapy, and nerve block using
a local anesthetic and therefore further consideration is required. Although there isa report72) indicating the efficacy of PRF on chronic knee joint pain, there are nohigh－quality retrospective－looking studies that we can cite as references and so because the evidence is not clear, we only give it a weak recommendation.
3）Radiculopathy
In a 2015 meta－analysis67) on the efficacy of PRF on patients with neuropathic
pain, they were unable to indicate its efficacy on radiculopathy. However, according
to a recent meta－analysis on cervical radiculopathy65), performing a single dorsal
root ganglion（DRG）PRF may possibly mitigate pain from the short term to the73)

long term（6 months）. Furthermore, in a double－blind RCT

on lumbar radiculop-

DRG：dorsal root
ganglion

athy, researchers indicated that compared with an epidural injection using a local
anesthetic, the analgesic effect and functional improvement effects from DRG PRF
lasted for a longer period of time. Therefore, although the evidence on the efficacyof DRG PRF on radiculopathy is limited, it could be considered as an option for patients who show resistance to treatments such as epidural injection.
4）Lumbar facet joint－derived pain
In a systematic review64) of 3 RCTs comparing the effects of PRF and radiofrequency thermocoagulation（RF）on lumbar facet joint－derived pain, the results indicated that the effects of a medial branch of the posterior ramus PRF persisted fora shorter duration than a conventional medial branch of the posterior ramus blockusing RF did. However, there is another report74) indicating that a medial branch of
the posterior ramus PRF provided longer analgesic effects than the medial branchof the posterior ramus block using a local anesthetic（and steroid drug）, and therefore it might be applicable for certain cases.
5）Idiopathic trigeminal neuralgia
According to a meta－analysis68) that compared and considered the efficacy andsafety of PRF, RF and a nerve block, used concomitantly to treat trigeminal neuralgia, there was no recognizable difference in analgesic effect between PRF and RF
but PRF had a higher level of safer. Researchers also indicated that rather than using RF alone, it was more effective and safe when RF was used in combination

RF：radiofrequency
thermocoagulation

390

D．Interventional Pain Treatment（Nerve Block）

with PRF. Therefore, if PRF is to be utilized as an analgesic method for trigeminal
neuralgia, then we recommend performing it in combination with RF.
PeriodDatabase
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P
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Limitations
Selection summary

2004～2019
PubMed,Cochrane CENTRAL,NPO Japan Medical Abstracts Society
pain, chronic pain, frozen shoulder, adhesive capsulitis,shoulder peroarthritis, radiculopathy,
osteoarthritis, postherpetic neuralgia
pulsed radiofrequency treatment, pulse－dose radiofrequency, pulsed radiofrequency ／ nothing
specified
Limited by publication type,PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, other（number of cases50＋）etc.
Of the 294 search hits, 11 were utilized that matched with PICO

CQ：D－9：Are intra－articular injections useful for chronic pain ?
Answer：Intra－articular steroid injections are useful over the short－and mid－term for adhesive shoulder capsulitis and hip osteoarthritis（hip OA）and their usefulness might increase when used concomitantly with physiotherapy. There is low
evidence regarding the possibility that hyaluronic acid injection might be effective
on adhesive shoulder capsulitis and hip OA. Its usefulness might possibly improvewhen using an ultrasound device.
Recommendation Grade & Summary of Overall Evidence1）Adhesive shoulder capsulitis
・Intra－articular steroid injectionR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 85.7%〕
Summary of overall evidence：C（low）
・Intra－articular hyaluronic acid injectionR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕
Summary of overall evidence：C（low）
2）Hip osteoarthritis（OA）
・Intra－articular steroid injectionR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 85.0%〕
Summary of overall evidence：C（low）
・Intra－articular hyaluronic acid injectionR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 95.2%〕
Summary of overall evidence：C（low）

391

D．Interventional Pain Treatment（Nerve Block）

Commentary：
This CQ will describe intra－articular injections on adhesive shoulder capsulitis
and hip osteoarthritis（hip OA）, and we will discuss knee osteoarthritis（knee OA） hip OA：hip osteoarat CQ K-3. There are many RCTs and systematic reviews on the efficacy of intra－
articular injections on adhesive capsulitis and OA.
1）Adhesive shoulder capsulitis
According to the clinical guidelines of the American Physical Therapy Association, using intra－articular steroid injection in combination with range of motion（ROM）exercises and stretching is more effective over the short term（4～6weeks）on pain and functional improvement in adhesive shoulder capsulitis thanperforming ROM exercises or stretching alone75).
In a systematic review of 9 RCTs regarding the efficacy of intra－articular steroid
injection on adhesive shoulder capsulitis and also the efficacy of a steroid injection
into the subacromial bursa, over the short－term, the group who were administeredwith an intra－articular steroid injection displayed significant improvement in pain
relief and improved ROM, compared with the group who were administered a steroid injection into the subacromial bursa. However, at 12 weeks, researchers
claimed there was no significant difference between the 2 groups76).
There is a systematic review of 5 RCTs that reported a comparison between an
intra－articular shoulder steroid injection with an intra－articular shoulder injectionof saline solution on adhesive shoulder capsulitis. 4 of these RCTs reported a single
injection, while in the other RCT, a total of 3 injections were administered at 1－
week intervals. Over the short term（0～8 weeks）, the intra－articular shoulder steroid injection showed to be significantly more effective in providing pain relief but
between 9～24 weeks after the procedure, there was no significant difference between the groups. Furthermore, over the short term, passive shoulder joint ROM
significantly improved in the intra－articular shoulder steroid injection group but
this significant difference was only temporary77). In addition, in a systematic review
of 8 research papers comparing the effects of intra－articular shoulder injection ofsaline solution on frozen shoulder with the effects of an intra－articular shoulder steroid injection, researchers indicated the possibility that intra－articular shoulder steroid injection was more effective over the short and mid term78). Because of small
sample size and methodological heterogeneity of the studies, the evidence on intra－
articular shoulder steroid injections is low.
In a systematic review of 3 RCTs examining intra－articular shoulder injections ofhyaluronic acid, researchers claimed that there was insufficient evidence due to alack of uniformity among the research reports.79)
In a systematic review of 7 RCTs comparing the efficacy of an intra－articularshoulder steroid injection under ultrasound guidance with one performed under thelandmark method, efficacy and accuracy improved under the ultrasound guidance

thritis392

D．Interventional Pain Treatment（Nerve Block）

method80).
The effects of both an intra－articular shoulder steroid injection and an intra－articular shoulder hyaluronic acid injection on adhesive shoulder capsulitis are limited
in either case and when performing these injections, their effects must be constantly evaluated and they should not be performed over the long term without a clear
aim in mind.
2）Hip OA
According to the guidelines of the Osteo Arthritis Research Society International（OARSI）, they compared the effects of an intra－articular hip steroid injection withthose of an intra－articular hip hyaluronic acid injection on hip OA and found thatthe intra－articular hip steroid injection had higher pain－relief effects and functional
improvement over the short－term compared with intra－articular hip hyaluronic
acid injection.
We need to consider the intra－articular hip steroid injection in cases where inflammation and severity of pain are strong. There is an RCT that claims that using
intra－articular hip steroid injection in combination with ROM exercises and stretching is more effective in improving pain and function than using ROM exercises andstretching alone81).
In a systematic review of 9 RCTs on the usefulness of intra－articular steroid injections on hip OA prior to total hip replacement,2 of these RCTs recommend an
intra－articular steroid injection before the replacement procedure while the other 7
RCTs claimed that they do not have an effect on post－surgical injections. On theother hand, in a research study comparing the frequency of incidence complications
on 40 patients who were administered an intra－articular hip steroid injection prior
to total hip replacement with 40 patients who did not under the operation, there
were injections in 3 of the joints（7.5%）among the group of subjects who did notundergo the procedure but there were 12 injections（30%）among the group who
were administered an intra－articular hip steroid injection, reporting a higher riskof post－surgical injection. Therefore, the procedure should not be performed overthe long－term without any clear aim in mind82).
We can expect short－term pain relief and functional improvement in subjects
with hip OA when administered with an intra－articular hip hyaluronic acid injection. In an RCT that considered the efficacy of intra－articular hip hyaluronic acidcompared with a placebo, when the injection was given 3 times under ultrasoundguidance fortnightly, researchers found that on the 14th day, the intra－articular hiphyaluronic acid injection had significantly improved pain at time of walking but after the 14th day, they claimed that there was no difference between the treatmentgroups83).
On the other hand, in an RCT that compared the usefulness of an intra－articular
hip hyaluronic acid injection on hip OA with an intra－articular hip local anesthetic

D．Interventional Pain Treatment（Nerve Block）

injection, both administered once a month, twice in total, researchers evaluated theintensity of pain after 3 months and after 6 months and reported that intensity ofpain had significantly improved in the intra－articular hip hyaluronic acid injectiongroup and that adverse events were insignificant at 6～23%84).
There are various RCTs on the usefulness of intra－articular hyaluronic acid injection but due to a lack of uniformity between the research studies, there is nohigh－quality evidence indicating its efficacy and level of safety. What is more, it is
not eligible to be covered under the Japanese health insurance system so caution isrequired when performing this procedure.
In a systematic review of intra－articular hip injections, researchers reported increased accuracy and efficacy if conducted under ultrasound guidance, just likewith intra－articular hip injections85).
PeriodDatabase
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Limitations
Selection summary

2005～2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
chronic pain, frozen shoulder Adhesive Capsulitis Hip Osteoarthritis
intra－articular injections
Limited by publication type,PubMed CER randomized controlled trial ／ systematic review
search filter,Cochrane RCT search filter, other（number of cases of50＋etc）
Of the 1,016 search hits, we utilized 27 of them that matched with the set PICO

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2）‌Manchikanti L, et al : Epidural injections for lumbar radiculopathy and spinal
stenosis : A comparative systematic review and meta－analysis. Pain Physician
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3）‌Kaye AD, et al : Efficacy of epidural injections in managing chronic spinal
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4）‌Manchikanti L, et al : Do cervical epidural injections provide long－term reliefin neck and upper extremity pain? : A systematic review. Pain Physician
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5）‌Zhai J, et al : Epidural injection with or without steroid in managing chronic
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6）‌Bicket MC, et al : Epidural injections in prevention of surgery for spinal
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PMID : 22430650
10）‌Manchikanti L, et al : Do the gaps in the ligamentum flavum in the cervicalspine translate into dural punctures? : An analysis of 4, 396 fluoroscopic interlaminar epidural injections. Pain Physician 2015 ; 18 : 259－266. PMID :26000669
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13）‌Lee JH, et al : Comparison of clinical efficacy between transforaminal and interlaminar epidural injections in lumbosacral disc herniation : A systematic
review and meta－analysis. Pain Physician 2018 ; 21 : 433－448. PMID : 30282389
14）‌Lee JH, et al : Comparison of clinical efficacy of transforaminal and caudal epidural steroid injection in lumbar and lumbosacral disc herniation : A systematic review and meta－analysis. Spine J 2018 ; 18 : 2343－2353. doi : 10.1016/j.
spinee.2018.06.720. PMID : 30030083
15）‌Feeley IH, et al : Particulate and non－particulate steroids in spinal epidurals : A systematic review and meta－analysis. Eur Spine J 2017 ; 26 : 336－344.
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17）‌Park KD, et al : Ultrasound－guided selective nerve root block versus fluoroscopy－guided interlaminar epidural block for the treatment of radicular painin the lower cervical spine : A retrospective comparative study. J Ultrasound2019 ; 22 : 167－177. doi : 10.1007/s40477－018－0344－z. PMID : 30519991
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19）‌Manchikanti L, et al : Comparative outcomes of a 2－year follow－up of cervical
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20）‌Manchikanti L, et al : The role of thoracic medial branch blocks in managing
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21）‌Civelek E, et al : Comparison of effectiveness of facet joint injection and radiofrequency denervation in chronic low back pain. Turk Neurosurg
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for interventional techniques in chronic spinal pain. Part II : guidance andrecommendations. Pain Physician 2013 ; 16（2 Suppl）: S49－S283. PMID :23615883
23）‌Carette S, et al : A controlled trial of corticosteroid injections into facet joints
for chronic low back pain. N Engl J Med 1991 ; 325 : 1002－1007. doi : 10.1056/

D．Interventional Pain Treatment（Nerve Block）

NEJM199110033251405. PMID : 1832209
24）‌Fuchs S, et al : Intraarticular hyaluronic acid versus glucocorticoid injections
for nonradicular pain in the lumbar spine. J Vasc Interv Radiol 2005 ; 16 : 1493－
1498. doi : 10.1097/01.RVI.0000175334.60638.3F. PMID : 16319156
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for myofascial pain disorders : A systematic review and meta－analysis. Clin J
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joint pain : A meta－analysis. Medicine（Baltimore）. 2019 ; 98 : e16230. doi : 10.
1097/MD.0000000000016230. PMID : 31261580
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patients with chronic low back pain : The mint randomized clinical trials.

D．Interventional Pain Treatment（Nerve Block）

JAMA 2017 ; 318 : 68－81. doi : 10.1001/jama.2017.7918. PMID : 28672319
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controlled clinical trials. Clin Drug Investig 2017 ; 37 : 819－831. doi : 10.
1007/s40261－017－0553－9. PMID : 28717987
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with 1, 600 patients. Neurosurgery 2001 ; 48 : 524－532. doi : 10.1097/
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for pain alleviation in chronic knee osteoarthritis : A single－blind randomized
controlled trial. Pain Physician 2018 ; 21 : 169－177. PMID : 29565947
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radicular pain : A meta－analysis. Medicine（Baltimore）2018 ; 97 : e11761.
doi : 10.1097/MD.0000000000011761. PMID : 30075599
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trials. Pain Pract 2016 ; 16 : 518－525. doi : 10.1111/papr.12310. PMID : 25990576
67）‌Shi Y, et al : Treatment of neuropathic pain using pulsed radiofrequency : A
meta－analysis. Pain Physician 2016 ; 19 : 429－444. PMID : 27676660
68）‌Wu H, et al : Therapeutic efficacy and safety of radiofrequency ablation for
the treatment of trigeminal neuralgia : A systematic review and meta－analysis. J Pain Res 2019 ; 12 : 423－441. doi : 10.2147/JPR.S176960. PMID : 30697063
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postherpetic neuralgia from the angulus costae : A randomized, double－blinded, controlled trial. Pain Physician 2013 ; 16 : 15－25. PMID : 23340530
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71）‌Yan J, et al : A randomized controlled trial of ultrasound－guided pulsed radiofrequency for patients with frozen shoulder. Medicine（Baltimore）
2019 ; 98 : e13917. doi : 10.1097/MD.0000000000013917. PMID : 30608419
72）‌Akbas M, et al : Efficacy of pulsed radiofrequency treatment on the saphenous nerve in patients with chronic knee pain. J Back Musculoskelet Rehabil

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2011 ; 24 : 77－82. doi : 10.3233/BMR－2011－0277. PMID : 21558611
73）‌De M, et al : Transforaminal epidural injection of local anesthetic and dorsal
root ganglion pulsed radiofrequency treatment in lumbar radicular pain : A
randomized, triple－blind, active－control trial. Pain Pract 2019 ; 20 : 154－167.
doi : 10.1111/papr.12840. PMID : 31538405
74）‌Hashemi M, et al : Effect of pulsed radiofrequency in treatment of facet－joint
origin back pain in patients with degenerative spondylolisthesis. Eur Spine J
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PMID : 23636125
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the treatment of adhesive capsulitis : A meta－analysis and systematic review.
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of shoulder : A meta－analysis. Medicine（Baltimore）2017 ; 96 : e7529.
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PMID : 25802845
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2015.05.011. PMID : 26590864‐
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Chapter E．Interventional Pain Treatment（Low-Invasive Surgery/Orthopedic
Treatments）：CQ E-1～CQ E-5
CQ E-1：Is spinal cord stimulation（SCS）useful for intractablechronic pain ?
CQ E-2：Are intradiscal therapies useful for chronic pain ?
CQ E-3： Are spring-guide catheters and epiduroscopy useful forchronic low back and leg pain ?
CQ E-4：Is spinal fusion useful for chronic pain associated withspinal diseases ?
CQ E-5：Is surgical therapy useful for chronic pain associated withstrangulated peripheral neuropathy ?

400

E．Interventional Pain Treatment（Low-Invasive Surgery/Orthopedic Treatments）

E．Interventional Pain Treatment（Low-Invasive Surgery/Orthopedic Treatments）
CQ E－1：Is spinal cord stimulation（SCS）useful for intractable chronic pain ?
Answer：SCS is something worth trying on chronic pain patients who did not
obtain sufficient analgesic effects from other forms of treatment. Its usefulness has
FBSS：failed backsurgery syndrome
PVD：peripheral
vascular disease
PDPN：painful
diabetic peripheral
neuropathy
PHN：postherpetic
neuralgia
CRPS：complex
regional pain
syndrome

been indicated especially for failed back surgery syndrome（FBSS）, peripheral vascular disease（PVD）, and painful diabetic peripheral neuropathy（PDPN）. Apartfrom this, there are reports of its efficacy on central post－stroke pain, pain following spinal cord injury, complex regional pain syndrome（CRPS）, phantom limb
pain, and postherpetic neuralgia（PHN）but there are no reports with high evidence.
Recommendation Grade & Summary of Overall Evidence
1）Lower limb pain of failed back surgery syndrome（FBSS）
R ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 90.5%〕
Summary of overall evidence：B（moderate）
2）Peripheral vascular disease（PVD）in the lower limbs
R ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 81.0%〕
Summary of overall evidence：C（low）
3）Painful diabetic peripheral neuropathy（PDPN）in the lower limbs
R ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 95.2%〕
Summary of overall evidence：B（moderate）
4）Central post－stroke pain, pain following spinal cord injury, phantom limb
pain, PHNR
 ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 90.5%〕
Summary of overall evidence：D（very low）
5）Complex regional pain syndrome（CRPS）
Recommendation grade：No recommendation〔Consensus 94.7%〕
Summary of overall evidence：C（low）
Commentary：1）Failed back surgery syndrome（FBSS）
In an RCT1) on lower limb pain in patients with FBSS, researchers compared an

E．Interventional Pain Treatment（Low-Invasive Surgery/Orthopedic Treatments）

SCS group with a group that underwent conservative treatment. There is also an
RCT2) that compared an SCS group with a group that underwent surgery again.
There was a significantly larger number of patients who experienced a reduction
in lower limb pain by 50% or more in the SCS group. In an RCT on low back pain3)
（LBP）
, that compared SCS using a paddle lead with SCS using cylindrical－type

leads, and an RCT4) that compared an optimal treatment group with a group that
had optimal treatment in addition to SCS, they found that SCS using the paddle
leads was more effective on LBP. In an RCT comparing an SCS group with a conservative treatment group1), researchers indicated that QOL and ADL had improved. In cost－benefit analysis1,2,5), researchers reported that SCS was superior toconservative forms of treatment and patients undergoing surgery for a secondtime.
In a systematic review6) that considered the differences in effect according tomethod of stimulation, such as high－frequency stimulation（10kHz）, burst stimulation, sub－perception simulation（1～5 kHz）
, researchers found these forms of stimulation superior in terms of absence of paresthesia, but they were unable to conclude whether the analgesic effects were high or not.
In a systematic review that investigated adverse events7), researchers found 184
complications out of 542 cases studied but it was possible to cope with the majorityof the complications and reported that the number of life－threatening events or severe adverse events that could cause dysfunction were extremely rare. FBSS has acomplex pathology, and there are patients with strong psychosocial factors. Whenperforming SCS, one needs to judge whether it is indicated for each individual patient or not so we assign it a weak recommendation for lower－limb pain. Researchers have indicated the utility of paddle－type leads for LBP but an even more cautious procedure is required.
2）Peripheral vascular disease（PVD）in the lower limbs
Several reviews of its efficacy on peripheral vascular disease（PVD）have beenreported8－10). Researchers have not yet established its efficacy in alleviating pain9,10),
but they indicated a rise in the limb salvage rate（decline in the amputation rate）.
However, they also indicated that it did not have an effect on the mortality rate or
ulcer healing rate8). In terms of its analgesic effect and limb salvage rate, researchers indicated increased efficacy with suitable patient selection, such as evaluating
percutaneous oxygen partial pressure8).
3）Painful diabetic peripheral neuropathy（PDPN）in the lower limbs
There are 2 RCTs on PDPN, which indicated not only an improvement 6 months
later in daytime pain, night－time pain and sleeping disorders, researchers also indicated that it was effective in improving ADL and QOL11,12). Furthermore, in termsof its long－term results, 55% of patients experienced reduced pain for a 5－year period13).

401

402

E．Interventional Pain Treatment（Low-Invasive Surgery/Orthopedic Treatments）

4）Other refractory pain diseases（central post－stroke pain, pain following spinal cord injury, phantom limb pain, PHN）
There have been reports of the efficacy of SCS on various forms of refractory
pain, such as central post－stroke pain14), pain following spinal cord injury15), phan17)
tom limb pain16), and postherpetic neuralgia（PHN）. However, the number of re-ports is low and the level of evidence is not high. Its applicability should be considered for each respective patient, in cases where there are no other means of effective treatment.
5）Complex regional pain syndrome（CRPS）
There have also been reports that SCS is effective on CRPS18), but there aresome patients with strong psychosocial factors, so one needs to make a cautious
judgment regarding their indication.
PeriodDatabase
Words
searched

P
I／C

Limitations
Selection summary

2005～2019
MEDLINE, Cochrane CENTRAL,NPO Japan Medical Abstracts Society
mainly chronic pain,words similar to thisspinal cord stimulation
Limited by publication type,PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, etc
Of the 59 search hits, we utilized 18 that matched with the set PICOCQ E－2：Are intradiscal therapies useful for chronic pain?
Answer：Researchers have indicated that intradiscal steroid injections have alimited effect on intradiscal low back pain（LBP）and that several intradiscal therapies are effective as a form of intradiscal treatment but their efficacy is limited.
Recommendation Grade & Summary of Overall Evidence1）Intradiscal steroid injection：R ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 80.0%〕S ummary of overall evidence：C（low）
2）Intradiscal treatmentR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 80.0%〕S ummary of overall evidence：C（low）
3）Intradiscal condoliase injection for lumbar disc herniationR ecommendation grade：2（weak）：No recommendation〔Consensus 89.5%〕S ummary of overall evidence：C（low）
Commentary：1）Lumbar intradiscal steroid injection

E．Interventional Pain Treatment（Low-Invasive Surgery/Orthopedic Treatments）

There is 1 RCT19) indicating its short term efficacy on intradiscal low back pain
（LBP）with Modic changes in the vertebral body on MRI and there is 1 RCT

20)

403

RCT：randomized
controlled trialthat showed no effect 3 months after the injection was performed. Administering
this injection should be limited to intradiscal LBP with an active period of inflammation in the endplate.
2）Intradiscal therapy
Intradiscal therapy is an intervention in which a percutaneous intra－discal puncture is performed using a cannula under X－ray fluoroscopy but there are few high－quality RCTs, and so its usefulness is limited.
① Percutaneous nucleotomy
A percutaneous nucleotomy is when the nucleus pulposus is excised, reducing
the intradiscal pressure, and its efficacy as a treatment has been indicated for thecontained type（swelling, protrusion, and subligamental prolapse）of intradiscal
lumbar hernia. Percutaneous disc decompression（PDD：Dekompressor®）, is a system of excising the nucleus pulposus using an Archimedes’ screw , and the procedure is simple using a cannula with an external diameter of 15 mm, compared withconventional types. In a review of 3 observational research studies, researchers
recognized its short－term and long－term effects but evidence was limited21).
② Percutaneous laser disc decompression（PLDD）
PLDD is a procedure which reduces intradiscal pressure by decreasing its volume by evaporating the water content of the nucleus pulposus using a laser. In an

PLDD：percutaneous
laser disc decompression

RCT that used a discectomy to treat sciatica as a control, researchers reported anequivalent short－term and long－term improvement in pain and QOL22).
③ Intradiscal electrothermal treatment（IDET）
IDET is performed on intradiscal LBP. A catheter is inserted cylindrically via acannula intradiscally, along the annulus fibrosus, and the coil part of the catheter is

IDET：intradiscal
electrothermal
treatment

placed dorsally to the site of lesion for the annulus fibrosus. Radiofrequency thermocoagulation（RF）is conducted on the coil, brining about a degeneration in theannulus fibrosus nerve and thereby reducing pain. In a recent review, there were 4
RCTs, 3 of them reporting its efficacy on pain, 1 reporting its efficacy on ADL, and
1 of them reported no significant difference in effect23). Overall, they confirmed its
efficacy with a high level of evidence.
④ Intradiscal pulsed radiofrequency（PRF）
Intradiscal PRF is a procedure in which the active tip is placed in the center ofthe disc, and creates an analgesic effect by adding a pulse radiofrequency. Its analgesic mechanism remains unclear but is believed to be highly safe as there is no
tissue damage or injury through heat, and a report has recognized that it provides
equivalent analgesic effect through an RCT on IDET24). Fukui et al.25) conducted
the procedure over 15 minutes on intradiscal LBP using intradiscal contrast and reported analgesic effect even 12 months after the procedure.

PRF：pulsed
radiofrequency

404

E．Interventional Pain Treatment（Low-Invasive Surgery/Orthopedic Treatments）⑤ Percutaneous radiofrequency intradiscal ablation／excision（Disc－Fx®）
Disc－Fx®treatment uses 1 cannula to excise the nucleus pulposus uses forceps,
RF uses a probe with a bended tip and modulation of the annulus fibrosus. In addition to the contained type（swelling, protrusion, and subligamentous extrusion）of
intradiscal hernia, it is believed to also be effective on LBP due to degenerative
disc, and there are observational research studies that have demonstrated its efficacy26,27) We recommend accumulating（more）evidence in future.
3）Intradiscal condoliase injection for lumbar disc hernia
There have been trials of new interventions as well. Condoliase that went on themarket in August 2018, is the first lumbar disc hernia drug to be used in Japanthat can be directly injected intradiscally. Condoliase specifically breaks down chondroitin sulfate and hyaluronic acid which are components of proteoglycan which isfound in the intradiscal nucleus pulposus, and reduces the intradiscal pressure bywater retention capacity in the marrow. As a result, it reduces the pressure in thenerve root that leads to a hernia in the parent nucleus pulposus, improving low
back and leg pain. It is believed to be effective on lumbar intra－discal hernia suchas bulging, protrusion and subligamentous extrusion, and there is 1 RCT that
demonstrated its efficacy in a dosage－controlled trial28) Furthermore, researchers
conducted condoliase treatment for lumbar intradiscal hernia on 47 patients andanalyzed the background details by dividing them into the 33 cases where it was
effective and 14 cases where it was not effective. There is also an observational research study29) on cases where it was ineffective, in which there were many complications such as discectomy, lumbar spondylolisthesis and a narrowing in the posterior intravertebral width（posterior intervertebral angle ≧ 5 degrees）. In bothresearch studies, there were no adverse events that became clinical problems. In
future, we recommend accumulating evidence on its long－term efficacy and safety.
PeriodDatabase
Words
searched

P
I／C

Limitations
Selection summary

2005～2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
chronic pain,lumbago, low back pain, disc hernia, discogenic pain, disc degeneration etc.
Intradiscal treatments such as intradiscal steroid injection, percutaneous disc decompression／conservative treatment／analgesic effect, QOL indicators, complications
Limited by publication type, PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, etc
From the searches of the above database, we utilized 9 search hits that matched with the set
PICO, as well as 2 important references which we found through manual search, for a total of
11 references

CQ E－3：Are spring－guide catheters and epiduroscopy useful for chronic
low back and leg pain ？
Answer：Treatment using a spring－guide catheter is effective on chronic lowback and leg pain. Epiduroscopy is effective for treating chronic lower back and leg
pain but there is insufficient evidence.

E．Interventional Pain Treatment（Low-Invasive Surgery/Orthopedic Treatments）

405

Recommendation Grade & Summary of Overall Evidence1）Spring－guide catheter：
Recommendation grade：2（weak）：Implementation is strongly recommended〔Consensus 85.0%〕
Summary of overall evidence：B（moderate）
2）Epiduroscopy
Recommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 80.0%〕
Summary of overall evidence：C（low）
Commentary：1）Spring－guide catheter
Epidural adhesiolysis is also called epidural neuroplasty and epidural nerve ablation using a spring－guide catheter is one type of intervention for treating refractory pain such as failed back surgery syndrome（FBSS）and spinal canal stenosis. In
2016, Helm et al.

30)

reported the results of a systematic review and meta－analysis oftreatments using spring－guide catheters. Patients’ pain status（level of improvement of pain was evaluated on a 5－point scale from 0～4, the higher the score thegreater the improvement）and functional improvement scores（evaluated in thesame way as pain status）improved significantly both 3 months later and 6 months
later in the group that underwent an epidural nerve ablation using a spring－guidecatheter, compared with groups that underwent other forms of treatment（mainly
epidural block）. In terms of pain that had improved by 50% or more, it was 55%
higher in the group that underwent the spring－guide catheter both 3 months laterand 6 months later. In a report by Manchikanti et al.31), researchers found that up
to 24 months later, the dosage of opioid analgesic had significantly decreased
through a spring－guide catheter treatment, compared with a caudal epidural block.
When performing percutaneous epidural adhesiolysis, in many cases hypertonic saline solution（10% [w／v] NaCl solution）is used. When using either 10% or 5% [w／v]
NaCl solution, there was no difference in analgesic effect and researchers reported
there was less pain in the group that was injected with 5% [w／v] NaCl solution32).
However, there have only been observational research studies and no RCTs so weare waiting for research to be conducted on this in future. With complications resulting from spring－guide catheters, there was a report of 47 cases, which included
dural puncture and arachnoid inflammation30). As of April 2018, epidural adhesiolysis using a spring－guide catheter became eligible to be covered under the healthinsurance system.
2）Epiduroscopy
Epiduroscopy is a procedure in which an endoscope is inserted into the lumbar
and sacral epidural space to observe the situation inside the epidural space and a

FBSS：failed backsurgery syndrome

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E．Interventional Pain Treatment（Low-Invasive Surgery/Orthopedic Treatments）

catheter is used for example with adhesions, and the procedure either separates orcleans it by injecting a saline solution. In 2005, Manchikanti et al.33) reported an
RCT in which they compared an epidural adhesiolysis using an epiduroscopy and a
VAS：visual analoguescale

caudal epidural block. Patients’ pain（VAS）and scores on the Oswestry Disability
Index had significantly improved in the group that underwent treatment using an
epiduroscopy at 3 months, 6 months, and 12 months following the procedure. Epiduroscopy is a relatively safe form of surgery but in terms of severe complications,
there have been cases of loss of eyesight due to excessive epidural hypostatic pressure, and Helm et al.30), reported 12 cases of this occurring. Other complications include dural puncture, epidural hematoma, and infection. There are no reports of
RCTs conducted on each type of illness such as failed back surgery syndrome（FBSS）and spinal canal stenosis and according to a systematic review and meta－
analysis that was published in 201630), they stated that at the current stage, the evidence supporting epidural adhesiolysis using epiduroscopy is limited. In Japan,
treatment using epiduroscopy had been recognized as a form of ‘advanced medical
treatment’ since 2004 but as of FY2015, it was withdrawn from this designation（asan ‘advanced medical treatment’）and can no longer be performed as such or as aform of treatment covered under insurance.
PeriodDatabase
Words
searched

P
I／C

Limitations
Selection Summary

2005～2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
Mainly chronic pain*, spinal stenosis, failed back surgery syndrome,low back pain etc.
epidural neuroplasty, epidural adhesiolysis, Racz catheter etc.／no limitations
Limited by publication type. Systematic reviews, Randomized controlled trial,Meta－analysisetc
Of the 81 PubMed search hits, 35 Cochrane CENTRAL search hits, 3 search hits from NPO
Japan Medical Abstracts Society, we used 2 search hits that matched with the set PICO aswell as 2 important references we had found through a manual search for a total of 4 references

CQ E－4：Is spinal fusion useful for chronic pain associated with spinal diseases ?
Answer：There are no high－level reports on the effects of spinal fusion for treating neck pain and back pain. The effects of spinal fusion on chronic low back pain
（LBP）without neuropathy are limited.
Recommendation Grade & Summary of Overall EvidenceR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕

Summary of overall evidence：C（low）
Commentary：
There are no high－level reports on the effects of spinal fusion for treating neck

E．Interventional Pain Treatment（Low-Invasive Surgery/Orthopedic Treatments）

407

pain and back pain. Therefore, in these guidelines we considered spinal fusion forchronic LBP. For LBP accompanied with neurological symptoms, generally decompression, fusion or corrective fusion is performed. Other forms of treatment arenecessary for these conditions and therefore we have excluded them from the purposes of this CQ. As a result, we considered the results of spinal fusion for treating
chronic LBP without any clear accompanying presence of stenosis or spondylolisthesis.
We utilized 3 recent systematic reviews34－36) which included spinal fusion and non－surgical forms of treatment for chronic LBP.
Results did not show any difference in a decrease in low back pain VAS scoresor decrease in ODI over the short term（1～2 years）among patients undergoing
spinal fusion compared with nonsurgical treatments. These 3 reviews included 6

VAS：visual analogue
scale
ODI：Oswestry
Disability Index

low～moderate level RCTs37－42). These reviews had different inclusion criteria andused different nonsurgical treatments as the control, and there is a diverse numberof fusion methods；ALIF, PLF, and PLIF among others.
In terms of nonsurgical forms of treatment that were used as a control, 4 of thestudies used a combination of physical therapy（PT）methods such as CBT, muscle－
strengthening exercises and stretches, whereas the other 2 studies conducted PT
alone so we divided them according to the control treatment used and conducted a
new meta－analysis. Furthermore, using the same references, we also considered
the incidence of complications and frequency of patients undergoing surgery a second time, following spinal fusion.
There are 4 RCTs that compared spinal fusion with CBT＋PT38－41), in which researchers compared the decrease in ODI one year later. Two of these studies39,41)
compared a decrease in VAS scores for LBP. In each respective meta－analysis, researchers did not recognize a significant difference in decline in LBP among eachof the treatment methods, and there was no difference in treatment effect between
spinal fusion and CBT＋PT one year later. Furthermore, in a follow－up report onthese RCTs, researchers reported that there was no difference between the 2 typesof treatment in terms of decline in LBP 9 years later43), or on average 11 years later44).
There are 2 RCTs that compared spinal fusion with physical therapy（PT）
alone37,42), and they found that ODI and VAS scores for LBP had significantly decreased 2 years later following spinal fusion, compared with the group that underwent PT alone. However, in 1 of these RCTs42), one of their inclusion criteria was“pain was triggered through an intradiscal contrast but reduced afterwards
through a block”, and so because they had rigorously conducted a diagnosis of intradiscal LBP, it is possible that the effects of spinal fusion were larger than otherreports.
In terms of complications resulting from treatment37,39－41), researchers reported

ALIF：anterior
intervertebral fusion
PLIF：posterior
lumbar intervertebral
fusion
CBT：cognitive-behavioral therapy
PT：physical therapy

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E．Interventional Pain Treatment（Low-Invasive Surgery/Orthopedic Treatments）

0% in the non－surgical treatment group, and an incidence of 19.0% complications
arising in the spinal fusion group, on average45). Furthermore, the % of those in thesurgical intervention group who underwent surgery a second time37,40) was 7.7％ ,on average.
All things considered, there are no RCTs with a high level of evidence and so infuture we expect researchers to report on RCTs containing little bias, and uniformity in terms of enrolled patients, surgical methods and non－surgical methods.
However, at the current stage, there is no difference in the effects of treatment between spinal fusion and CBT＋PT for patients with chronic LBP without any clear
signs of stenosis or spondylolisthesis. As there is a risk that complications may
arise after undergoing surgery or patients may need to undergo surgery a second
time, we believe it should only be conducted within the parameters of a well－thought－out treatment plan.
PeriodDatabase
Words
searched

P
I／C

Limitations
Selection summary

2005～2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
Mostly chronic pain and low back pain,similar words（back pain,neck pain etc.）
Spinal fusion, intervertebral fusion etc.／nothing specified
Limited by publication type, with PubMed we limited it to clinical trials, guidelines, meta－analysis etc., no limitations with Cochrane, with NPO Japan Medical Abstracts Society, we usedoriginal research papers, excluded meeting minutes
Of the 624 PubMed search hits, 139 Cochrane CENTRAL search hits, and 29 NPO Japan Medical Abstracts Society search hits, we utilized 8 search hits that matched with the set PICO,
and used 4 important references that were outside of the period through manual search togive us a total of 12 references in total that we utilized

CQ E－5：Is surgical therapy useful for chronic pain associated with strangulated peripheral neuropathy ?
Answer： Surgical treatment is more effective than conservative forms of treatment in achieving mid－ to long－term results with chronic pain due to carpal tunnel
syndrome. There is no evidence comparing its effect on pain related to cubital tunnel syndrome and tarsal tunnel syndrome with conservative methods of treating
pain and other surgical treatments.
Recommendation Grade & Summary of Overall Evidence1）Surgical therapy for carpal tunnel syndrome：R ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕
Summary of overall evidence：B（moderate）
2）Surgical therapy for cubital tunnel syndromeR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 85.0%〕
Summary of overall evidence：D（very low）

E．Interventional Pain Treatment（Low-Invasive Surgery/Orthopedic Treatments）

3）Surgical therapy for tarsal tunnel syndrome：Recommendation grade：No recommendation〔Consensus 95.0%〕
Summary of overall evidence：D（very low）
Commentary：
With strangulated peripheral neuropathies, carpal tunnel syndrome and cubital
tunnel syndrome are cited for the upper limbs as arising frequently and tarsal tunnel syndrome for the lower limbs. Conservative forms of treatment include drug
therapy, steroid injection, and orthotic treatment, and surgical procedures such as
decompression surgery and neurolysis are performed.
1）Carpal tunnel syndrome
There are 2 systematic reviews46,47) that compared the effect of conservative
forms of treatment（steroid injection, night orthosis）on carpal tunnel syndrome,with surgical forms of treatment, and there have been reports in 2 RCTs,48,49) as
well. Both conservative forms of treatment and surgical procedures were useful inmitigating pain；conservative forms of treatment were effective in reducing pain
over the short term, 3 months, whereas surgery was effective over the mid andlong term, from 6～12 months. Conservative forms of treatment were particularly
effective on mild to medium level pathologies, whereas on the other hand, there is
the risk of complications arising, such as postoperative wound pain and hematoma
with surgical treatments. However, researchers recognized an improvement insymptoms over the long term and improved nerve conduction studies.
Researchers recognized that conservative treatments were effective in mitigating
pain, and also reported cases in which a steroid injection was highly effective, cases
where the symptoms persisted for a short period of time, and cases of patients who
had been administered their initial steroid injection50). Researchers also reported
that 56 out of 68 patients, who had undergone conservative treatment for 6 months
since their initial consultation, either displayed no change in their condition andsymptoms or a deterioration so they ended up undergoing surgery and also there
were reports of inferior outcomes in patients who had undergone surgery without
undergoing any conservative form of treatment since their initial consultation51).
Therefore, around the time of choosing the form of surgical treatment, one needs tokeep in mind the degree of neuropathy, how long the symptoms have persisted
and the severity of the condition.
2）Cubital tunnel syndrome
There are reports of both conservative forms of treatment（drug therapy, orthotic treatment, steroid injections etc.）and surgical procedures（simple decompression, upper medial resection, forward transfers／translocations etc.）to treat cubital
tunnel syndrome. In our study, there were no research papers that compared thepain－mitigating effects from conservative forms of treatment and surgical proce-

409

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E．Interventional Pain Treatment（Low-Invasive Surgery/Orthopedic Treatments）

dures. In a review, conservative forms of treatment were effective on mild～moderate－level cases, and there were cases in which symptoms were aggravated, but insome cases, there was dysfunction such as impaired perception and decline in muscle strength, so timely surgical treatment is recommended52－54).
3）Tarsal tunnel syndrome
There were no research papers comparing the pain－mitigating effects of conservative forms of treatment with surgical procedures to treat tarsal tunnel syndrome.
Prior to treatment, an accurate diagnosis is required, and along with making a rigorous evaluation of the related clinical symptoms, neurological and neurophysiological findings, it is also important to carefully consider other possible differential diagnoses. Surgery is considered to be useful in cases where tumor mass lesions orpressure factors have been clearly identified55,56).
PeriodDatabase
Words
searched

P
I／C

Limitations
Selection summary

2005～2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
Mainly chronic pain*, similar terms（pain etc.）
carpal tunnel syndrome, cubital tunnel syndrome, tarsal tunnel syndrome, surgical treatment,
conservative treatment etc,／nothing specified
Limited by publication type, with PubMed, we searched for clinical trials, guidelines, meta－
analysis etc., no limitations with Cochrane, original research papers searched for on NPO Japan Medical Abstracts society, excluding meeting minutes
Of the 638 PubMed search hits, 389 Cochrane CENTRAL search hits, and 206 NPO Japan
Medical Abstracts Society search hits, we utilized 5 search hits that matched with the set
PICO, and also 6 important references outside of the period obtained by manual search to give
us a total of 11 search hits

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56）‌Ahmad M, et al : Tarsal tunnel syndrome : A literature review. Foot Ankle
Surg 2012 ; 18 : 149－152. doi : 10.1016/j.fas.2011.10.007. PMID : 22857954

Chapter F．Psychological Approach：CQ F-1～CQ F-8
CQ F-1：Is psychoeducation useful for chronic pain ?
CQ F-2：Is behavioral therapy（BT）useful for chronic pain ?
CQ F-3：Is cognitive-behavioral therapy（CBT）useful for chronic
pain ?
CQ F-4：Is mindfulness useful for chronic pain ?
CQ F-5：Is acceptance and commitment therapy（ACT）useful forchronic pain ?
CQ F-6：Is hypnotherapy useful for chronic pain ?
CQ F-7：Is autogenic training useful for chronic pain ?
CQ F-8：Is progressive muscle relaxation useful for chronic pain ?

416

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F．Psychological Approach
CQ F－1：Is psychoeducation useful for chronic pain ?
Answer：We are unable to acknowledge that psychoeducation（sharing information）alone is useful. However, it is a necessary part of a variety of psychological interventions to be introduced and so we recommend implementing it in combination
with other interventions.
Recommendation Grade & Summary of Overall EvidenceR ecommendation grade：2（weak）：Implementation is weakly recommended
under certain conditions〔Consensus 88.2%〕
Summary of overall evidence：C（low）
Commentary：
This is 1 systematic review1) that investigated whether psychoeducation（sharing information）, the use of which is limited to promoting the knowledge of chronic
pain, was effective or not when used alone. The review targeted patients sufferingfrom chronic pain aged 18 years or older, compared the target group with a waiting list or a treatment as usual, and they considered its effects on 4 outcomes（pain,
disability, depression, and catastrophizing）at 2 stages；post-treatment and3-month follow-up. There is a large variety of formats for implementing psychoeducation, including individual and group discussion, distributing paper materials, interacting with patients online and ways of implementing it without any direct interaction between the practitioner and patient. Because the number of researchstudies and sample sizes have been small, the quality of evidence is weak andtherefore there was no recognizable beneficial or harmful effect from it, irrespective of the stage or outcome. Therefore, we believe that psychoeducation alone is
not effective.
However, some researchers1,2) have indicated the efficacy of psychoeducation
when it is used in combination with other interventions. By fostering an understanding among patients, through psychoeducation, of the psychosocial factors that
relate to the onset, maintenance and deterioration of chronic pain, as well as how
the mechanism of their psychological intervention works, an intervention they willsoon undergo, as well as the procedures for implementing them, psychoeducation
may possibly have encouraging effects on the treatments that follow. Thus, we recommend implementing psychoeducation in combination with other interventions.

F．Psychological Approach

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Mainly chronic pain*, words regarded as synonyms（intractable pain, resistant pain, etc.）,
names of separate pathologies of which chronic pain is the main symptom（complex regional
pain syndromes, fibromyalgia, etc.）,etc
psychoeducat*, pain educat＊（education）,etc.／nothing specified
Limited by publication type（we targeted RCTs, systematic reviews, meta－analysis）, Limitedby target（on humans）,etc
Of the 796 MEDLINE search hits, 256 Cochrane CENTRAL search hits, and 59 NPO Japan
Medical Abstracts Society search hits, we utilized 1 systematic review that matched with
PICO and 1 other systematic review as a supplement

CQ F－2：Is behavioral therapy（BT）useful for chronic pain ?
Answer：Behavioral therapy（BT）alone（graded behavioral activation, operant（conditioning）therapy）is only partially effective and so we recommend that it be
implemented as part of multidisciplinary treatment and cognitive behavioral therapy（CBT）, as well as acceptance & commitment therapy（ACT）.
Recommendation Grade & Summary of Overall EvidenceRecommendation grade：2（weak）：Implementation is weakly recommended
under certain conditions〔Consensus 100.0%〕
Summary of overall evidence：C（low）
Commentary：
In a systematic review of psychological interventions on adult patients withchronic pain, excluding those with headache, researchers considered the effects of3)
behavioral therapy（BT）. We excluded an RCT related to relaxation from the sys-

tematic review（because in this guideline, new pages were created on autogenic
training and progressive muscle training）, and conducted a meta－analysis of theremaining 3 RCTs. As a result, there was a visible moderate effect on catastrophizing in the intervention group. A statistically－significant effect on intensity of painand disability was not observed. There was only 1 RCT which considered the effects on mood, which showed a high effect. However, overall we cannot say thatthe quality of the evidence is high and as there have been no RCTs since thenwhich meet the systematic review criteria（mention of ‘chronic’, 20 patients＋in a
group）, there has been insufficient consideration of the effects of behavioral therapy alone.
However, BT is often utilized as part of a multidisciplinary treatment, CBT or
ACT. For example, graded behavioral activation（a method in which activity is increased in stages）is often incorporated under occupational therapy（OT）or physical therapy（PT）4), whereas behavioral activation is often incorporated under CBT
and ACT5). Therefore, we recommend implementing BT for the purpose of improv-

CBT：cognitive
behavioral therapy
ACT：acceptance andcommitment therapy

418

F．Psychological Approaching catastrophizing and mood and also as part of a combined form of treatment forthe purposes of improving pain and disability.
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Mainly chronic pain*, words considered to be synonyms（intractable pain, resistant pain, etc.）,
names of separate pathologies of which chronic pain is the main symptom（complex regional
pain syndromes, fibromyalgia, etc.）, etc.
behavior therapy, behavior medicine, etc.／nothing specified
behavior therapy, behavior medicine, etc.／nothing specified
Limited by publication type（we targeted RCTs, systematic review, meta－analysis）, Limitedby target（on humans）, other（20 cases＋in one single group）, etc
Of the 104 MEDLINE search hits, 459 Cochrane CENTRAL search hits, 1,445 NPO Japan
Medical Abstracts Society 1,445 search hits, we utilized 1 systematic review that matchedwith PICO, and 2 systematic reviews（PubMed, Cochrane CENTRAL）that were found byhand search, as supplements

CQ F－3：Is cognitive－behavioral therapy（CBT）useful for chronic pain?
CBT：cognitive
behavioral therapy

Answer：Cognitive－behavioral therapy（CBT）has been recognized to be usefulfor chronic pain in multiple aspects, and is recommended as a psychological intervention for chronic pain. However, as the system in place of implementing CBT in
Japan is insufficient, we are hoping that it will undergo further development in theimmediate future.
Recommendation Grade & Summary of Overall EvidenceR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 93.8%〕

Summary of overall evidence：B（moderate）
Commentary：
There is 1 systematic review investigating the effects of CBT on chronic pain excluding headache3). They targeted adults aged 18 years and over with chronic pain
and conducted CBT face－to－face either in an individual or group format, assigninga waiting list or a treatment as usual as the control, and considered the effects of
CBT on 4 outcomes（pain, disability, mood, catastrophizing）at 2 stages, short－term
effects（post-treatment）and long－term effects（follow－up）. In terms of the short－term effects of CBT, it displayed a small effect on pain and disability and moderate－level effects on mood and catastrophizing. On the other hand, in terms of its long－term effects, researchers recognized only a small effect on mood. Considering theinsufficient number of research studies on this area and that the risk of bias is notnecessarily low, the strength of evidence was moderate but both in terms of its
short－term and long－term effects, we believe CBT is effective on chronic pain overRCT：randomized
controlled trial

all.
There are many systematic reviews and RCTs that have investigated its effects

F．Psychological Approachaccording to the site of treatment, and they have reported its effects on chronic
low－back pain6), and fibromyalgia7) among others. However, there was a recognizable difference in the size of the effect, how long the effects persist, and whether
CBT was effective or not, depending on the research study. As for the format under which it is implemented, researchers recognized that CBT was effective when
conducted online8,9). Furthermore, there are some research papers10) indicating theeffectiveness of CBT when it was incorporated under a form of multidisciplinary
treatment, and we expect CBT to also be useful when not implemented alone（butin combination）.
However, the system in place in Japan for implementing CBT has not yet been
sufficiently developed. In the field of chronic pain, in many cases there are no practitioners in medical departments who are able to implement CBT and there are issues about it being ineligible for health insurance coverage. In light of the above,
we recommend implementing CBT but on the premise that we expect that a system will quickly be put in place for its implementation.
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Mainly chronic pain*, words regarded as synonyms（intractable pain, resistant pain, etc.）,
names of separate pathologies of which chronic pain is the main symptom（complex regional
pain syndromes, fibromyalgia, etc.）,etc
cognitive behavior therapy, cognitive therapy, behavior medicine, etc.／nothing specified
Limited by publication type（we targeted RCTs, systematic reviews, meta－analysis）, Limitedby target（on humans）,other（20 cases＋in one single group）, etc
Of the 2,389 MEDLINE search hits, 1,993 Cochrane CENTRAL search hits, 1,004 NPO Japan
Medical Abstracts Society search hits, we utilized 1 systematic review that matched with
PICO, 3 systematic reviews as supplements, and 2 RCTs that were found by hand search（PubMed, Cochrane CENTRAL）

CQ F－4：Is mindfulness useful for chronic pain ?
Answer：Mindfulness-based intervention has been recognized to be useful forchronic pain in multiple aspects, and is recommended as a form of psychological intervention for chronic pain. However, the system in Japan for implementing mindfulness-based intervention is insufficient, so we expect that it will be quickly developed.
Recommendation Grade & Summary of Overall EvidenceRecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕

Summary of overall evidence：B（moderate）
Commentary：
Researchers reported on a systematic review comparing a group of patients who

419

420

F．Psychological Approach

underwent mindfulness-based intervention for managing chronic pain（mindfulness－
MBSR：mindfulness
based stress reduction

based stress reduction（MBSR）, mindfulness－based cognitive therapy（MBCT）,

MBCT：mindfulness
based cognitive
therapy

ment as usual, waiting list, or patient education/support group）11). Based on theand other types of mindfulness training）with a control group of patients（treatsynthesized results of the longest follow－up data in each RCT, it showed that mindfulness-based intervention has a significant small effect on pain intensity, depression, physical domains of QOL, and mental domains of QOL. There tended to be an
improvement in disability as well but a significant difference was not obtained. Subgroup analyses by the type of intervention, medical condition, or treatment duration showed that efficacy of mindfulness-based intervention on pain did not differ.
There is also some research which has compared mindfulness with other formsof psychotherapy. Compared against mindfulness－based stress reduction（MBSR）
and group-based cognitive-behavioral therapy（CBT）,it showed that there was no
significant difference in improvement for pain intensity, physical function, and depression at post-treatment12). A systematic review comparing mindfulness-based
intervention to acceptance & commitment therapy（ACT）showed that ACT hassignificantly greater effects on depression and anxiety than mindfulness-based intervention5). However, there is still only a small number of RCTs that have directlycompared mindfulness with CBT and ACT so we need to be cautious when interpreting the results. In recent years, they have been conducting mindfulness－based
interventions online. In an RCT comparing the effects of an online MBCT on patients with chronic pain against the effects of online psychoeducation, researchers
observed a moderate－level improvement in both groups in disability, at post-treatment and 6-month follow-up13). As interventions that are conducted online arehighly convenient, we expect them to be further developed in future.
However, in Japan there is no sufficient system in place for implementing mindfulness-based intervention. In the field of chronic pain, there are many cases inwhich there are no practitioners belonging to a medical department who are able
to implement mindfulness-based intervention, and there are issues with its healthinsurance coverage. In light of the above, we recommend implementing mindfulness-based intervention but under the premise that we soon expect that a system
will be put in place in Japan for its implementation.
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MEDLINE, Cochrane CENTRAL, NPO Japan Medical Abstracts Society, PubMed
Mainly chronic pain＊, words considered as synonyms（intractable pain, resistant pain, etc.）,
names of separate pathologies of which chronic pain is the main symptom（complex regional
pain syndromes, fibromyalgia, etc.）, etc
mindful＊, etc.／nothing specified
Limited by publication type（we targeted RCTs, systematic reviews, meta－analysis）, Limitedby target（on humans）, other（50 cases＋ in one single group）, etc
Of the 546 MEDLINE search hits, 480 Cochrane CENTRAL search hits, 100 NPO Japan Medical Abstracts Society search hits, we utilized 1 systematic review that matched with PICO, 2
systematic reviews as supplements, and 1 RCT that was found by hand search（PubMed, Cochrane CENTRAL）

F．Psychological Approach

421

CQ F－5：Is acceptance and commitment therapy（ACT）useful for chronic pain ?
Answer：Acceptance and commitment therapy（ACT）has been recognized tobe effective on chronic pain in multiple aspects and is recommended as a form of

ACT：acceptance andcommitment therapy

psychological intervention for chronic pain. However, there is an insufficient system
in place in Japan for implementing ACT and so we expect that this will be established soon.
Recommendation Grade & Summary of Overall EvidenceRecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕

Summary of overall evidence：B（moderate）
Commentary：
Researchers have reported on a systematic review14) that compared a group ofpatients with chronic pain（excluding pain due to headache or malignant diseases）
who underwent an ACT intervention with control groups（waiting list or treatment as usual）. At post-treatment, researchers found that compared with the control groups, there had been a small effect on disability and pain intensity, a moderate－level effect on anxiety, and a large effect on depression, pain acceptance andpsychological flexibility in the group that underwent ACT intervention. At 3-monthfollow-up, researchers indicated a small effect on disability and a moderate－level
effect on depression and psychological flexibility. There was a large variety in theformats in which the RCTs included in this review were conducted, including face－
to－face, self－help, online, individually and as a group.
In reports after this, researchers have proceeded to consider its effects on chron15)
ic headache（including migraine）, as well as consider the moderators and predict-able variables of the effects during web-based interventions16). Furthermore, researchers have focused on differences in the format of treatment；when they compared the effects of ACT conducted under interdisciplinary treatment with ACT
conducted under unidisciplinary treatment, they found that interdisciplinary ACT
had a larger effect on physical disabilities, psychosocial impacts and depression,
whereas there was no difference between the groups in terms of intensity of pain,
anxiety, and pain acceptance17).
Some have also compared ACT with other psychotherapy. Research has indicated5) that compared with mindfulness－based psychological interventions, ACT had alarger effect on anxiety and depression at post-treatment. In addition, other research has indicated that when comparing ACT and cognitive－behavioral therapy（CBT）, the response rate to each respective treatment varies according to the agegroup of the patients18). In recent years, some research19) has considered the effects

RCT：randomized
controlled trial422

F．Psychological Approachof ACT when a single session was conducted on breast－cancer patients in the early
postoperative stages, in terms of its effects in preventing persistent postoperative
pain. Other research20) has considered the effects of a 1－day workshop conductedprior to surgery on veterans for the purposes of preventing persistent postoperative pain and long－term usage of opioid analgesics.
However, there is an insufficient system in place in Japan for implementing ACT.
In the field of chronic pain, in many cases there are no practitioners in medical departments who are able to implement ACT and there are issues with health insurance coverage as well. In light of the above, we recommend implementing ACT but
on the premise that hopefully a system will soon be established for its implementation.
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MEDLINE, Cochrane CENTRAL, NPO Japan Medical Abstracts Society, PubMed
Mainly chronic pain*, words considered to be synonyms（intractable pain, resistant pain, etc.）,
names of separate pathologies of which chronic pain is the main symptom（complex regional
pain syndromes, fibromyalgia, etc.）, etc
acceptance and commitment therapy, acceptan＊, commit＊, etc.／nothing specified
Limited by publication type（we targeted RCTs, systematic review, meta－analysis）, Limitedby target（on humans）, etc
Of the 205 MEDLINE search hits, 151 Cochrane CENTRAL search hits, 43 NPO Japan Medical Abstracts Society search hits, we utilized 1 systematic review that matched with PICO, 1
systematic review as a supplement, 4 RCTs, 1 systematic review and 1 RCT that we found byhand search（PubMed, Cochrane CENTRAL）

CQ F－6：Is hypnotherapy useful for chronic pain ?
Answer：It is difficult to judge the effectiveness of hypnotherapy and therefore
we are unable to recommend its implementation apparently.
Recommendation Grade & Summary of Overall Evidence
Recommendation grade：2（weak）：No recommendation〔Consensus 100.0%〕
Summary of overall evidence：C（low）
Commentary：
Two systematic reviews21,22) have reported the effectiveness of hypnosis for managing chronic pain overall. We excluded 5 clinical trials that had been used in thesesystematic reviews（two studies with pre-post comparison design, one study that
tested the effect of hypnosis in combination with another psychotherapy, and two
studies that did not report the values required for conducting the meta-analysis）,
and then re-conducted a meta-analysis using 3 RCTs and 1 quasi-RCT. One newly
added RCT was identified by a hand search. Targeting chronic pain in general, we
HRQL：health-related
quality of life

used a waiting list or a treatment as usual as the control, to investigate the effectiveness of hypnosis on the outcomes including pain, disability, health－related quali-

F．Psychological Approach423

ty of life, depression, and anxiety. While a statistical significance was not observed,
we found pain reduction with large effect size in the hypnosis intervention group.
Concerning the other outcomes, we were unable to obtain sufficient evidence todiscuss the effectiveness of hypnosis. There was only 1 RCT that investigated theeffectiveness of hypnosis in outcomes other than pain. Also, the sample size of that
RCT was very small（only 18 participants）.
Hypnosis may have a large effect on reducing pain. Also, as another advantage,
hypnosis can be covered as a psychosomatic treatment within the current healthcare insurance in Japan. RCTs conducted abroad report that a short-term intervention23) consisting of 2 hypnosis sessions may be effective and that combining hypnosis with CBT and psychoeducation enhances its effectiveness24,25). However, evidence reported in the current stage is weak, and reporting on the effectiveness of
hypnosis on outcomes other than pain is lacking. In addition to them, there are several barriers to introduce hypnosis in Japanese medical settings. For example, inJapan, the training system for hypnosis is not well prepared. As a result, patients’
accessibility to hypnosis is poor. Also, the misunderstanding that patients would bemanipulated by a hypnotist and forced to act against their will is prevailing.
In light of the above, we are unable to indicate a apparent recommendation for
implementing hypnosis.
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Mainly chronic pain＊, words considered as synonyms（intractable pain, resistant pain, etc.）,
names of separate pathologies of which chronic pain is the main symptom（complex regional
pain syndromes, fibromyalgia, etc.）,etc
hypnosis, hypnotherapy, etc.／nothing specified
Limited by publication type（we targeted RCTs, systematic reviews, meta－analysis）, Limitedby target（on humans）,etc
Of the 600 MEDLINE search hits, 227 Cochrane CENTRAL search hits, 171 NPO Japan Medical Abstracts Society search hits, we utilized 2 systematic reviews that matched with PICO,
and 1 RCT that we found after conducting a hand search（PubMed, Cochrane CENTRAL）

CQ F－7：Is autogenic training useful for chronic pain ?
Answer：It is difficult to judge the usefulness of autogenic training alone so weare unable to recommend its implementation apparently.
Recommendation Grade & Summary of Overall EvidenceRecommendation grade：No recommendation〔Consensus 94.4%〕
Summary of overall evidence：Nothing
Commentary：
As there is only 1 small－scale randomized controlled trial（RCT）that has report-

RCT：randomized
controlled trial

424

F．Psychological Approached on the effects of autogenic training on chronic pain in general26), it is difficult toevaluate on the evidence level so we decided on a ‘no recommendation’ grade.
In the 1 RCT reported, there were 35 targeted adult patients with chronic pain
aged 20 years and over, researchers used a treatment as usual as a control, andconsidered its effects on pain, disability, depression and anxiety after the intervention. In this research study, patients undergoing treatment received individual
guidance for 20 minutes per session, fortnightly, for a total of 3 sessions, received
guidance from a recorded voice and pamphlet 3 times a day, as part of autogenic
training, and also some self－learning once for several minutes. Outcomes were measured 4 weeks later. As a result, researchers failed to recognize the effects of autogenic training alone in any of the 4 outcomes（pain, disability, depression, and anxiety）. However, in terms of heart rate variability which indicates autonomic nerve
activity, researchers did recognize a trend；high frequency components, which are
an indicator of parasympathetic activity, increased significantly in the intervention
group, compared with the control group. Some researchers reported27) that autogenic training was effective not on chronic pain in general but on specified pain
syndromes（migraine and somatoform disorders［somatic symptom disorder :DSM-5］）.
With autogenic training, although the person in charge needs to have special expertise and skills（for example a certified public psychologist）, its medical fee
points have been specified as a form of psychosomatic medicine, and therefore thefact that it can be implemented within the framework of medical treatments covered under health insurance is considered to be one of its benefits. As for contraindications for autogenic training, researchers have cited that at the time of implementation, caution needs to be exercised：1）when the practitioner suspects myocardial infarction, or immediately after myocardial infarction has occurred；2）withpatients with diabetes who would have trouble with glycemic control and those forwhom it is impossible to observe over the long term；3）with patients who experience hypoglycemia or patients with hypoglycemic－like symptoms；4）in cases ofacute psychosis and those with severe schizophrenic reactions；5）patients displaying degenerative psychosis, delusions of persecution, and delusions of grandeur；6）in cases of extreme anxiety and exacerbated feelings of frustration；and 7）active
periods for peptic ulcers28).
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MEDLINE, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
Mainly chronic pain＊, words regarded as synonyms（intractable pain, resistant pain, etc.）,
names of separate pathologies of which chronic pain is the main symptom（complex regional
pain syndromes, fibromyalgia, etc.）, etc
autogenic training, progressive muscle relaxat＊, etc.／nothing specified
Limited by publication type（we targeted RCTs, systematic reviews, meta－analysis）, Limitedby target（on humans）, etc
Of the 187 MEDLINE search hits, 151 Cochrane CENTRAL search hits, and 151 NPO Japan
Medical Abstracts Society search hits, we utilized 1 RCT that matched with PICO

F．Psychological Approach

CQ F－8：Is progressive muscle relaxation useful for chronic pain ?
Answer：It is difficult to judge the usefulness of progressive muscle relaxation
alone and so we are unable to recommend its implementation apparently.
Recommendation Grade & Summary of Overall Evidence
Recommendation grade：No recommendation〔Consensus 100.0%〕
Summary of overall evidence：Nothing
Commentary：
There have been reports of 2 RCTs that have investigated the effects of progressive muscle relaxation alone on chronic pain in general and for 1 research study,
we were unable to obtain the research data29) while for the other 1, we assessed
the quality of evidence as extremely low so we judge that it was difficult to assess
its evidence level, and decided on a ‘no recommendation’ grade.
For the 1 RCT study for which we were able to obtain the data30), researchers
targeted 89 patients with chronic pain, aged from 11～77 years, in which a treatment as usual was used as the control, and researchers considered the effects on
pain, disability and depression at 2 stages；post-treatment and 3-month follow-up.
With the progressive muscle relaxation used in this research study, patients followed the progressive muscle relaxation instructions which patients heard twice aweek and then measured the outcomes 5 weeks later. As a result, they were unable to recognize the efficacy of progressive muscle relaxation on all outcomes（pain, disability, depression）both at post-treatment and 3-month follow-up. Also,
massage, which was implemented as a treatment as usual, was significantly more
effective than progressive muscle relaxation for all outcomes（pain, disability, depression）at post-treatment but at 3-month follow-up, all outcomes deteriorated
significantly and were on par with those at the start of the treatment. On the other
hand, there was neither a significant improvement nor aggravation due to progressive muscle relaxation；the outcomes were around the same as those at the startof the treatment as compared with both post-treatment and 3-month follow-up.
Although progressive muscle relaxation requires that the person implementing it
has special expertise and skills（for example a certified public psychologist）, it is
widely used as a form of psychosomatic medicine for psychosomatic disorders andneurosis.

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Mainly chronic pain＊, words considered as synonyms（intractable pain, resistant pain, etc.）,
names of separate pathologies of which chronic pain is the main symptom（complex regional
pain syndromes, fibromyalgia, etc）
. etc
autogenic training, progressive muscle relaxat＊, etc.／nothing specified
Limitations by publication type／（we targeted RCTs, systematic reviews, meta－analysis）, Limited by target（on humans）, etc
Of the 187 MEDLINE search hits, 151 Cochrane CENTRAL search hits, 151 NPO Japan Medical Abstracts Society search hits, we utilized 2 RCTs that matched with PICO

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12）‌Khoo EL, et al : Comparative evaluation of group－based mindfulness－based
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management of chronic pain : A systematic review and network meta－analysis. Evid Based Ment Health 2019 ; 22 : 26－35. doi : 10.1136/ebmental－2018－
300062. PMID : 30705039
13）‌Dowd H, et al : Comparison of an online mindfulness－based cognitive therapy
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0201. PMID : 25565584
14）‌Hughes LS, et al : Acceptance and commitment therapy（ACT）for chronic
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doi : 10.1097/AJP.0000000000000425. PMID : 27479642
15）‌Khazraee H, et al : Effectiveness of acceptance and commitment therapy incognitive emotion regulation strategies, headache－related disability, andheadache intensity in patients with chronic daily headache. Iran Red Crescent Med J 2018 ; 20 : e57151. doi : 10.5812/ircmj.57151
16）‌Trompetter HR, et al : Positive psychological wellbeing is required for online
self－help acceptance and commitment therapy for chronic pain to be effective. Front Psychol 2016 ; 11 : 353. doi : 10.3389/fpsyg.2016.00353. PMID :27014159
17）‌Vowles KE, et al : A comparative meta－analysis of unidisciplinary psychology
and interdisciplinary treatment outcomes following acceptance and commitment therapy for adults with chronic pain. J Pain 2019 ; S1526－5900（19）30841－
7. doi : 10.1016/j.jpain.2019.10.004. PMID : 31683020
18）‌Wetherell JL, et al : Age moderates response to acceptance and commitment
therapy vs. cognitive behavioral therapy for chronic pain. Int J Geriatr Psychiatry 2016 ; 31 : 302－308. doi : 10.1002/gps.4330. PMID : 26216753
19）‌Hadlandsmyth K, et al : A single－session acceptance and commitment therapy intervention among women undergoing surgery for breast cancer : A randomized pilot trial to reduce persistent postsurgical pain. Psychooncology
2019 ; 28 : 2210－2217. doi : 10.1002/pon.5209. PMID : 31430830
20）‌Dindo L, et al : Acceptance and commitment therapy for prevention of chronic post－surgical pain and opioid use in at－risk veterans : A pilot randomized
controlled study. J Pain 2018 ; 19 : 1211－1221. doi : 10.1016/j.jpain.2018.04.016.
PMID : 29777950
21）‌Adachi T, et al : A meta－analysis of hypnosis for chronic pain problems : A
comparison between hypnosis, standard care, and other psychological interventions. Int J Clin Exp Hyp 2014 ; 62 : 1－28. doi : 10.1080/00207144.2013.841471.
PMID : 24256477
22）‌Bowker E, et al : Hypnotherapy for disability－related pain : A meta－analysis. J
Health Psychol 2016 ; 21 : 526－539. doi : 10.1177/1359105314530452. PMID :2478810423）‌Tan G, et al : A randomized controlled trial of hypnosis compared with biofeedback for adults with chronic low back pain. Euro J Pain 2015 ; 19 : 271－
280. doi : 10.1002/ejp.545. PMID : 24934738
24）‌Castel A, et al : Multicomponent cognitive－behavioral group therapy withhypnosis for the treatment of fibromyalgia : Long－term outcome. J Pain
2012 ; 13 : 255－265. doi : 10.1016/j.jpain.2011.11.005. PMID : 22285609
25）‌Rizzo RRN, et al : Hypnosis enhances the effects of pain education in patientswith chronic nonspecific low back pain : A randomized controlled trial. J Pain
2018 ; 19 : 1103. e1－. e9. doi : 10.1016/j.jpain.2018.03.013. PMID : 29654980
26）‌Kataoka T, et al : Effects of autogenic training for patients with chronic pain.
Medical Bulletin of Fukuoka University 2015 ; 42 : 69－79. Permalink : http : //

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F．Psychological Approachid.nii.ac.jp/1316/00003196/
27）‌Stetter F, et al : Autogenic training : A meta－analysis of clinical outcome studies. Appl Psychophysiol Biofeedback 2002 ; 27 : 45－98. doi : 10.1023/a : 10145765
05223. PMID : 12001885
28）‌Kubo C : Integrative Medicine and Psychosomatic Medicine. Biotherapy
2007 ; 21 : 387－393
29）‌Seers K : Maintaining people with chronic pain in the community : Teaching
relaxation as a coping skill : Department of Health Post－Doctoral Nursing Research Fellowship. Department of Health, London 199330）‌Hasson D, et al : A randomized clinical trial of the treatment effects of massage compared to relaxation tape recordings on diffuse long－term pain. Psychother Psychosom 200473 : 17－24. doi : 10.1159/000074436. PMID : 14665792

Chapter G．Rehabilitation：CQ G-1-1～CQ G-5-3
CQ G-1-1：Is general exercise therapy useful for chronic pain ?
CQ G-1-2：Is motor control exercise useful for chronic pain ?
CQ G-1-3：Is neuroscience-based rehabilitation（neurorehabilitation）useful for chronic pain ?
CQ G-1-4： Is exercise therapy used in combination with cognitivebehavioral therapy（CBT）, patient education, andoccupational therapy（OT）useful for chronic pain ?
CQ G-2： Is mind-body exercise（yoga, pilates, Tai chi etc.）usefulfor chronic pain ?
CQ G-3：Is physical therapy useful for chronic pain ?
CQ G-4：Is manual therapy useful for chronic pain ?
CQ G-5-1：Is cervical collars useful for chronic pain ?
CQ G-5-2：Are lumbar corsets（lumbar fixation belts）useful forchronic low back pain ?
CQ G-5-3：Are knee braces（knee corsets）useful for chronic knee
joint pain due to knee osteoarthritis（OA）?

430

G．Rehabilitation

G．Rehabilitation
CQ G－1－1：Is general exercise therapy useful for chronic pain ?
Answer：Exercise therapy is useful for improving pain and dysfunction in patients with chronic pain. However, there was not a large difference between disease-specific and general exercises in its effects. Furthermore, researchers did notrecognize that exercise therapy alone improved comprehensive quality of life
QOL：quality of life

（QOL）
, and therefore it needs to be used in combination with other forms of treatment.
Recommendation Grade & Summary of Overall EvidenceR ecommendation grade：1（strong）：Implementation is strongly recommended〔Consensus 87.5%〕
Summary of overall evidence：B（moderate）
Commentary：
We conducted a meta－analysis of 24 RCTs that investigated the effects of exercise therapy, such as aerobic exercise and muscle－strengthening exercises. The
target was adults aged 18 years and over with chronic low back pain（LBP）, chronic neck pain, and knee osteoarthritis（OA）, who were compared against a group
without exercise therapy（including waiting list group, and usual care group）,
physical therapy group, and other exercise therapy groups, as the control groups.
As a result, researchers acknowledge that compared with the group without exercise therapy, the exercise therapy group had analgesic effects and was effective in
improving dysfunction. However, there was not a large difference between like disease－specific exercise and general exercise therapies in terms of its effectiveness toimprove their condition. Neither did they recognize an improvement in comprehen-

Note G1：Please refer
to CQ L-5
Note G2：Please refer
to CQ Q-5

sive QOL due to exercise therapy. We did not include stiff shouldersNote G1, or fibromyalgiaNote G2 on this CQ.
In terms of non－pharmacological forms of treating patients with chronic pain, we
recommend incorporating exercise therapy under a treatment with the aim of improving lifestyle habits, such as obesity, and improving and maintaining physicalactivity1－3). Furthermore, researchers also claim it is advisable to utilize exercise
therapy in combination with pharmacotherapy and approaches to behavioral medicine1－3). Based on this, although the effects from exercise therapy are not that high,
it is useful for managing chronic pain.

G．Rehabilitation

PeriodDatabase
Words
searched

P
I／C

Limitations
Selection summary

431

2010～2019
MEDLINE, Cochrane Library, NPO Japan Medical Abstracts Society
chronic pain, chronic pain［mesh］,low back pain［TI］, neck pain［TI］, Osteoarthritis［TI］
exercise, aerobic exercise, Muscle Stretching Exercises, Resistance Training, walking, Exercise
Therapy
Review ; Systematic Reviews ; Meta－Analysis ; Randomized Controlled Trial ; published in thelast10 years ; English
Based on the search results of the database, we extracted 1,179 MEDLINE search hits, 1,167
Cochrane Library search hits, and 36 NPO Japan Medical Abstract Society search hits, collated the searches with PICO and confirmed the data etc., and conducted a meta－analysis using
24 RCTs. Furthermore, these did not apply to our search method but we utilized 3 reviews（References1）～ 3）, which we had found through a manual search, which we deemed to be
useful in providing supplementary information

CQ G－1－2：Is motor control exercise useful for chronic pain ?
Answer： Compared with a group without exercise therapy and exercise therapy
group, motor control exercise（MCE）is useful in improving chronic pain and dysfunction. Furthermore, compared with a group without exercise therapy, it is usefulin improving comprehensive quality of life（QOL）, but it is believed that there is
not a big difference when compared with exercise therapy.
Recommendation Grade & Summary of Overall EvidenceRecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 94.1%〕

Summary of overall evidence：C（weak）
Commentary：
Broadly speaking, MCE is training conducted with the aim of improving postureand motor control but generally speaking, its objective is to improve spinal stability
and control and frequently refers to training that fosters cooperative and efficient
activity of the superficial layer of muscles of the trunk such as the erector spinae
muscles and rectus abdominus muscle as well as the deep trunk muscles such as
the transverse abdominal muscles and the multifidus muscle. We conducted a meta－
analysis of 16 RCTs which investigated the effects of MCE. The target was adults
aged 18 years and over with chronic low back pain（LBP）and chronic neck pain.
A group without exercise therapy（including a waiting list group and standard－
treatment group）, a exercise therapy group, and manual－therapy group were usedas the control groups. As a result, researchers recognized that MCE was effective
in its analgesic effects and was effective in improving dysfunction compared with
non－treatment, exercise therapy and manual therapy. However, only 1 RCT was
utilized to compare it against manual therapy and so due to the low certainty ofevidence, careful attention is required. In addition, MCE is effective in improving
comprehensive QOL compared with non－treatment, but there was not a big differ-

MCE：motor control
exercise
QOL：quality of life

432

G．Rehabilitationence compared with exercise therapy.
The majority of RCTs on MCE targeted chronic LBP；there are few RCTs on
chronic neck pain. Therefore, careful attention is required to the fact that compared with chronic LBP, the certainty of evidence on the effects of MCE for chronic neck pain is low. Moreover, the analgesic effects and the effectiveness of MCE in
improving dysfunction are higher than those of exercise therapy, but there is a low
certainty of evidence. Therefore, when selecting and deciding on a type of exercise
for managing chronic pain, we recommend making a global judgment, consideringfactors such as patient preferences, costs and safety4,5).
PeriodDatabase
Words
searched

P
I／C

Limitations
Selection summary

2015～2020
MEDLINE, Cochrane Library, NPO Japan Medical Abstracts Society
chronic pain, chronic pain［mesh］, low back pain［TI］, neck pain［TI］, osteoarthritis［TI］
motor control exercise, core stabilization exercise, stabilization exercises, motor control
Review ; Systematic Reviews ; Meta－Analysis ; Randomized Controlled Trial ; published in thelast5 years ; English
Based on the search results of the database, we extracted 462 MEDLINE search hits, 590 Cochrane Library search hits, collated the searches with PICO and confirmed the data etc., andconducted a meta－analysis using 16 RCTs. Furthermore, we utilized 2 systematic reviews（References 4）5）,which we deemed to be useful in providing supplementary information.

CQ G－1－3：Is neuroscience－based rehabilitation（neurorehabilitation）usefulfor chronic pain ?
Answer：Using neurorehabilitation in combination with standard rehabilitationon the motor system is useful on patients with chronic pain but its effect in improving dysfunction has not been recognized. However, there is not a large differencein the effects obtained from using neurorehabilitation in combination with standard
rehabilitation on the somatosensory system compared with when using standard
rehabilitation alone. Its effects on comprehensive QOL and work remain unclear.
Recommendation Grade & Summary of Overall Evidence
1）Neurorehabilitation of the motor systemR ecommendation Grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕
Summary of overall evidence：B（moderate）
2）Neurorehabilitation of the somatosensory system：
Recommendation Grade：No recommendation〔Consensus 100.0%〕
Summary of overall evidence：B（moderate）
Commentary：
Neurorehabilitation is rehabilitation based on the knowledge of neuroscience. It
can be broadly divided into neurorehabilitation（such as exercise images, motor illusion）for processes related to motor expression（motor system）, from motor pro-

G．Rehabilitation

433

grams to motor output, and neurorehabilitation（such as identification of tactile
sites）for processes for somatosensory processing. In the former, visual feedbacksuch as using mirrors or the evocation of images that the affected painful limb ismoving even though it is not actually moving are used, which corresponds to mirror therapy which creates the illusion in the patient’s mind that the affected limb isactually moving. On the other hand, in the case of the latter, it corresponds to sensation identification tasks for identifying the site on the affected left which is
touched, without using any visual information. As the mechanisms that cause
chronic pain and make it persist are implicated in modulations occurring in thecentral nervous system6), neurorehabilitation has come to be implemented as one
form of rehabilitation treatment for chronic pain.
We conducted a meta－analysis using 12 RCTs that investigated the concomitanteffects when neurorehabilitation was used in combination with standard rehabilitation on the motor system. We targeted patients aged 18 years and over with chronic pain, excluding patients with cancer pain and visceral pain（such as phantom
limb pain, complex regional pain syndrome（CRPS）, pain after spinal cord injury（SCI）, post－stroke pain, low back pain（LBP）, and motor system pain）, and compared it with a standard rehabilitation group as the control. As a result, using neurorehabilitation in combination with standard rehabilitation on the motor system
displayed high analgesic effects. However, there was no difference between the 2groups in terms of its effects on improving dysfunction and in the RCT that wasused, comprehensive QOL was not used as an outcome, and therefore its effects oncomprehensive QOL are not clear. In terms of adverse events, there have been reports7) of aggravated pain or nausea arising when patients imagined exercising theaffected limb, and therefore one should advise a specialist（physical therapist, etc.）
at the time of implementation.
Furthermore, we conducted a meta－analysis using 4 RCTs that investigated theeffects of using neurorehabilitation and standard rehabilitation in combination on
the somatosensory system. The subjects and control group used for comparison
were the same as the above－mentioned neurorehabilitation analysis conducted on
the motor system. As a result, there was no difference in analgesic effect or its efficacy in improving dysfunction on the somatosensory system when neurorehabilitation was used in combination with standard rehabilitation. Once again, comprehensive QOL was not an outcome of the RCT we used, and so its effects were notclear. Based on this, we can say that at the current stage, neurorehabilitation is notuseful in managing chronic pain in the somatosensory system, when used in combination with standard rehabilitation.

QOL：quality of life

434

G．Rehabilitation

PeriodDatabase
Words
searched

P
I／C

Limitations
Selection summary

2005～2019
PubMed, Cochrane Libraryphantom limb pain, CRPS, low back pain, spinal cord injury, stroke, neuropathic pain, limb
pain, Musculoskeletal pain, Musculoskeletal disorders
motor imagery, graded motor imagery, movement representation, kinesthetic imagery techniques, illusion, virtual visual feedback, mirror visual feedback, mirror box, MVF, mirror therapy, sensory discrimination, tactile discrimination, sensory discrimination retraining, tactile
sensory discriminatory training, perceptive rehabilitation
Review ; Systematic Reviews ; Meta－Analysis ; Randomized Controlled Trial ; published in thelast 15 years ; English
Based on the search results of the database, we extracted 1,217 searches, collated the searchhits with PICO and confirmed the data etc, and conducted a meta－analysis using 16 RCTs

CQ G1－4：Is exercise therapy used in combination with cognitive－behavioral therapy（CBT）,
patient education, and occupational therapy（OT）useful for chronic pain ?
Answer：Exercise therapy used in combination with social approaches, cognitive－
CBT：cognitive
behavioral therapy
OT：occupational
therapy

behavioral therapy（CBT）, patient education, and occupational therapy（OT）isuseful for improving pain and dysfunction in patients with chronic pain as well ascomprehensive quality of life, and useful for social involvement and patients returning to work. However, the specific protocols for obtaining high effects remain unclear.
Recommendation Grade & Summary of Overall Evidence1）Exercise therapy using a combination of CBT and patient educationR ecommendation grade：1（strong）：Implementation is strongly recommended〔Consensus 94.4%〕
Summary of total evidence：B（moderate）
2）Occupational therapy, social approachesR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 89.5%〕
Summary of total evidence：C（low）
Commentary：
We conducted a meta－analysis using 26 RCTs that investigated the effects of exercise therapy in combination with CBT and patient education. The subjects were
adults aged 18 years and over with chronic pain（chronic low back pain（LBP）,
chronic neck pain, knee osteoarthritis（knee OA）, and other forms of chronic musculoskeletal pain）and the control groups were single interventions（CBT, patient
education, exercise therapy）, and standard rehabilitation. As a result, exercise therapy used in combination with CBT and patient education was recognized to havehigher analgesic effects, was more effective in improving dysfunction, and improved comprehensive QOL over the mid－ to long－term, compared with single in-

G．Rehabilitation

435

terventions. Furthermore, it was also recognized to provide analgesic effects overthe mid－ to long－term, was effective in improving dysfunction, and improved comprehensive QOL for patients with chronic neck pain and chronic pain, comparedwith standard rehabilitation.
In Europe and America, they recommend introducing CBT and patient education
for chronic pain management. Through these treatment methods, patients withchronic pain understand their pain and are encouraged to change their behaviors,
thereby contributing towards an improvement of and reduced risk of aggravating
various symptoms8－10). There is a large variety of protocols such as the contents ofa CBT and patient education program, the period of implementation, how frequently it is implemented, and the format（individual, group）and at the current stage, itremains unclear what kind of protocol yields high effects. In addition, we have notincluded fibromyalgia in this CQ.Note G3
Next, we conducted a meta－analysis, just like the one above, using 11 RCTs
which investigated the effects of exercise therapy when used in combination withoccupational therapy（OT）and social approaches. As a result, exercise therapy
used in combination with OT and social approaches proved to be effective in improving dysfunction over the short to long term, comprehensive QOL as well as social participation and a return－to－work, compared with standard rehabilitation.
OT not only targets physical dysfunction but also mental dysfunction such as depression, focusing on lifestyle actions（＝occupation）with objectives and values, forexample daily lifestyles, work and hobbies, and uses these as a mean for treatment
and guidance. To be more specific, it aims to improve activity, physical and psychological function through occupational activities such as self care and housework.
Therefore, OT has a wide target, and one of its treatment goals is securing social
roles beginning with a return－to－work. In addition, coordinating on the personallevel with people such as managers at the workplace or the patient’s family, towards the achievement of this aim, requires a social approach which is adjusting to
the environment at home and at work and in Japan ; an occupational therapist willoften attend to these matters as well.
Many patients with chronic pain have trouble participating in society and thisleads to the social problem of massive economic loss due to reduced productivity,
absence from work and taking time off work. By introducing for example activity
pacing and occupational counselling by an occupational therapist, and work－based
rehabilitation to tackle this problem, it is recognized to be effective in ways such as
reducing the number of days people are absent from work and encouraging people
to participate in society11,12). Therefore, there are still few RCTs at the current
stage, and the contents of an effective program, the period to implement it, andhow frequently it should be implemented remain unclear. In future, researchers are
required to accumulate much more evidence.

Note G3：refer to CQ
Q-3

436

G．Rehabilitation

Cognitive－behavioral therapy（CBT）, patient education
Period2015～2019
Database
PubMed, Cochrane Library, NPO Japan Medical Abstracts Society
Words
Pchronic pain, chronic pain［mesh］, chronic low back pain, chronic neck pain, knee osteoarthrisearchedtis, chronic musculoskeletal pain
I／C
cognitive behavioral therapy”, education, self－management, back school, pacing, pain coping
skills, brief education, behavioral approach, neuroscience education, neurophysiology education, cognitive behavioral treatment, general exercise, exercise, physical therapy, aerobic exercise, stretching exercise, resistance training, walking, physiotherapy
Limitations
Review ; Systematic Reviews ; Meta－Analysis ; Randomized Controlled Trial ; published in thelast5 years ; English
Selection summary
Based on the search results of the database, we extracted 488 PubMed search hits, 67 Cochrane Library search hits, and 7 NPO Japan Medical Abstract Society search hits, collated
the searches with PICO and confirmed the data etc, and conducted a meta－analysis of 26
RCTs. We also used 3 systematic reviews（References 8）～10）that were deemed useful as
supplementary information
Occupational therapy（OT）
Period
2005～2019
Database
Cochrane Library, PubMed, NPO Japan Medical Abstracts Society
Words
Pchronic pain, chronic pain［mesh］, upper limb conditions, chronic conditions, low back pain,
searched
neck pain
I／C
occupational therapy, pacing, chronic pain management, work strategies, counseling, work focused rehabilitation, workplace－based rehabilitation／nothing specified
Limitations
Meta－Analysis, Randomized Controlled Trial, Systematic Reviews, Reviews, guideline
Selection summary
Based on the search results of the database, we extract 94 Cochrane Library search hits, 748
PubMed search hits, 0 NPO Japan Medical Abstract searches, collated the search hits with
PICO and confirmed the data etc, and conducted a meta－analysis using 11 RCTs

CQ G－2：Is mind－body exercise（yoga, pilates, Tai chi etc.）useful for chronic
pain ?
Answer：Mind－body exercise is useful for improving pain and dysfunction in patients with chronic pain. On the other hand, researchers have not recognized thatmind－body exercise improves comprehensive quality of life（QOL）.
Recommendation Grade & Summary of Overall EvidenceR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 94.7%〕

Summary of overall evidence：B（moderate）
Commentary：
Mind－body exercise is a form of exercise that incorporates elements from meditation, such as deep rhythmical abdominal breathing, and making slow movements
and being conscious of the body’s movements and muscles. It includes yoga, pilates,
Tai Chi, and Qigong. Yoga and pilates cooperatively contract the superficial－layer
muscles and deep－layer muscles of the trunk and they have the same exercise
components in common with motor control exercise. Furthermore, mind－body exercise, which will be discussed here, is an exercise performed under medical management by a specialist such as a mind－body exercise therapist.

G．Rehabilitation

We conducted a meta－analysis using 26 RCTs that investigated the effects ofmind－body exercise. The subjects were adults aged 18 years and over with chronic
low back pain（LBP）, chronic neck pain, and knee osteoarthritis（knee OA）andthe control groups were groups without exercise therapy（including a waiting－list
group, standard－treatment group）, a exercise therapy group, a manual therapy
group, and patient－education group. As a result, mind－body exercise displayed
higher analgesic effects and effect on improving dysfunction than the waiting－list
groups, exercise therapy group and patient－education group. On the other hand,analgesic effects were higher in the manual therapy group but there was only 1
RCT so the certainty of evidence was low. As for improvement in comprehensive
QOL, there was no difference between mind－body exercise and the exercise therapy group and no－treatment groups. In addition, we did not include stiff shouldersNote 4, or fibromyalgiaNote 5 on this page.
There have been few reports of adverse events but some reports13－15) that there
is a higher risk of mild aggravated pain compared with non－treatment and patient
education. However, compared with exercise therapy, the risk of aggravated pain is
about the same and so mind－body exercise could be considered as an option for exercise therapy.
PeriodDatabase
Words
searched

P
I／C

Limitations
Selection summary

2015～2020
MEDLINE,Cochrane Library,NPO Japan Medical Abstracts Society
chronic pain, chronic pain［mesh］,low back pain［TI］, neck pain［TI］, osteoarthritis［TI］
mindful exercises, Tai Chi, yoga, pilates, Qigong
Review ; Systematic Reviews ; Meta－Analysis ; Randomized Controlled Trial ; published in thelast5 years ; English
Based on the search results of the database,we extracted 463 MEDLINE search hits, 895 Cochrane Library search hits, collated the searches with PICO and confirmed the data etc, andconducted a meta－analysis using 26 RCTs

CQ G－3：Is physical therapy useful for chronic pain ?
Answer：Physical therapy has been recognized to be effective in improving short－term pain and dysfunction compared with non－treatment but researchers have notrecognized that it improves QOL. Furthermore, the quality of evidence indicating
its effects is low so caution is required. Furthermore, the long－term effects underphysical therapy are still unclear. Furthermore, adverse events have been reported
such as strain and a feeling of tension at the site of treatment and exacerbatedpain. Therefore, when introducing physical therapy to manage chronic, it is important to sufficiently weigh up the pros and cons.
Recommendation Grade & Summary of Overall Evidence
Recommendation grade：2（weak）：No recommendation 〔Consensus 89.5%〕
Summary of overall evidence：C（low）

437

438

G．Rehabilitation

Commentary：
RCT：randomized
controlled trial

We conducted a meta－analysis using 26 RCTs that investigated the effects ofphysical therapy（including therapeutic ultrasound, transcutaneous electrical nerve
stimulation（TENS）, interferential current stimulation（IFC）, microwave therapy,

LLLT：Low level laser
treatment

low level laser treatment（LLLT）, cryotherapy, balneotherapy, indirect traction
therapy）. Subjects were patients aged 18 years or older with chronic low back pain
（LBP）
, chronic neck pain, and knee osteoarthritis（OA）.Control groups underwent
sham treatments, other forms of physical therapy, pharmacotherapy, and exercise
therapy. As a result, researchers found that while therapeutic ultrasound, TENS,LLLT had greater short－term analgesic effects and an effect on improving dysfunction than non－treatments（including sham treatments）, researchers did not recog-

QOL：quality of life

nize that it had an effect in improving comprehensive QOL. Furthermore, compared with other treatments such as exercise therapy, there was no difference inits effects. When we look at its concomitant effects when used together with another form of treatment, researchers recognized that therapeutic ultrasound used in
combination with exercise therapy had a greater effect in improving short－term
dysfunction than when exercise therapy alone was used. However, the sample usedin many of the RCTs for analysis was small and so the results of the meta－analysis
showed high heterogeneity and imprecision；meaning the certainty of the evidence
is low. Furthermore, its mid－to long－term effects have not been considered. Therefore, caution needs to be exercised when interpreting the above results. Also, we
have not included in this CQ stiff shoulders, painful diabetic neuropathy, and fibromyalgia.
In terms of RCTs that have investigated the effects of physical therapy on chronic pain, it has been pointed out that there has been an inadequate blinding andsmall sample sizes3), therefore the quality of the evidence is low, and we do not recommend it as a form of non－pharmacological therapy for chronic pain1,3). In addition, as physical therapy is a passive（inactive ／ hands－on）form of treatment, researchers fear that it may encourage inactivity in patients with chronic pain or
their（over）
dependence upon treatment1). Therefore, if introducing physical therapy as a treatment for chronic pain, it is advisable to implement it as an auxiliary
form of treatment alongside exercise therapy.

G．Rehabilitation

PeriodDatabase
Words
searched

P
I／C

Limitations
Selection summary

439

1999～2020
MEDLINE, Cochrane Librarychronic pain, chronic pain［mesh］,low back pain［TI］, neck pain［TI］, osteoarthritis［TI］
physical modalities, therapeutic ultrasound, transcutaneous electrical nerve stimulation, TENS,
low level laser therapy, LLLT, interferential therapy, superficial heat, thermotherapy, balneotherapy, diathermy, superficial cold, cryotherapy, cold therapy, electro－muscular stimulation,
traction
Review ; Systematic Reviews ; Meta－Analysis ; Randomized Controlled Trial ; published in thelast 22 years ; English
Based on the search results of the database, we extracted 401 MEDLINE search hits, and 348
Cochrane Library search hits, collated the searches with PICO and confirmed the data etc,
and conducted a meta－analysis using 26 RCTs. Furthermore, we used 2 reviews（References 1）3））that did not apply to our search method but through a manual search were deemed useful as supplementary information

CQ G－4：Is manual therapy useful for chronic pain ?
Answer：Compared with non－treatment, it is believed that manual therapy isuseful for improving pain and dysfunction. However, there is no difference in its effects compared with exercise therapy. Furthermore, researchers have not recognized that manual therapy alone leads to a comprehensive improvement in qualityof life（QOL）.
The certainty of the evidence indicating these effects is low and so when introducing manual therapy alone for managing chronic pain, one needs to sufficiently
weigh up the pros and cons.
Recommendation Grade & Summary of Overall EvidenceRecommendation grade：2（weak）：No recommendation 〔Consensus 100.0%〕
Summary of overall evidence：C（low）
Commentary：
We conducted a meta－analysis of 18 RCTs that investigated the effect of manual
therapy. Subjects were adults aged 18 years and over with chronic low back pain
（LBP）
, chronic neck pain, and knee osteoarthritis（OA）. The control groups weregroups without exercise therapy（waiting－list group, and standard－treatmentgroup）, a physical therapy group, and an exercise therapy group. As a result, there
was low analgesic effect and an improvement in dysfunction in the manual therapy
group, compared with the waiting－list groups and physical therapy group. On theother hand, compared with the exercise therapy group, there was not a big difference in its improvement effect. Furthermore, researchers did not recognize a comprehensive improvement in QOL through using manual therapy alone, in patientswith chronic LBP and chronic neck pain. Of the research papers that were used foranalysis, many of them did not handle data sufficiently and there was a lack ofblind studies, so caution needs to be exercised when interpreting these results. In

QOL：quality of life

440

Note 6：Refer to CQ
L-5
Note 7：Refer to CQ
Q-６

G．Rehabilitation

addition, we have not included stiff shouldersNote 6, and fibromyalgiaNote 7 in this CQ.
Researchers3) have pointed out the high bias risk and low－quality evidence of
RCTs to date that have investigated the effects of manual therapy on chronic pain.
Furthermore, as manual therapy is a passive（inactive ／ hands－on）form of treatment, there are fears that it may encourage inactivity in patients with chronic pain1)
and（over）dependence on treatment（medicalizing）. Therefore, we do not recom-

mend implementing manual therapy alone as a form of non－pharmacological therapy for chronic pain1,3). However, recently, some have asserted that manual therapy
is useful in improving pain when it is used in combination with exercise therapy
for a short period of time, rather than when exercise therapy alone is implemented16). Therefore, if introducing manual therapy for managing chronic pain, it is important to first have a clear purpose and timeframe and implement it in combination with exercise therapy.
PeriodDatabase
Words
searched

P
I／C

Limitations
Selection summary

2010～2019
MEDLINE, Cochrane Library, NPO Japan Medical Abstracts Society
chronic pain, chronic pain［mesh］, low back pain［TI］, neck pain［TI］, osteoarthritis［TI］
manual therapy, massage［Mesh］, muscle energy techniques, shiatsu, Acupressure, Musculoskeletal Manipulations［Mesh］, myofascial release
Review ; Systematic Reviews ; Meta－Analysis ; Randomized Controlled Trial ; published in thelast 10 years ; English
Based on the search results of the database, we extracted 278 MEDLINE search hits, 290 Cochrane Library search hits, and 11 NPO Japan Medical Abstract Society searches, collated thesearch hits with PICO and confirmed the data etc,and conducted a meta－analysis using 18
RCTs. Furthermore, we used 3 reviews（References 1）3）, 16））that did not apply to oursearch method but through a manual search were deemed useful as supplementary information

CQ G－5－1：Is cervical collars useful for chronic pain ?
Ans：Irrespective of whether neurological symptoms of chronic neck pain or a
related disease are present or not, we do not recommend cervical collar, more fromthe perspective of its harmful effects rather than in terms of its benefits.
Recommendation Grade & Summary of Overall EvidenceRecommendation grade：2（weak）No implementation is weakly recommended〔Consensus 100.0%〕
Summary of overall evidence：C（low）
Commentary：
According to the ‘Guidelines for Neck Pain and Related Diseases（2016）, ’ in theabsence of neurological symptoms within 3 months of onset, and furthermore, even
if neurological symptoms are present, in addition to within 3 months, we did notrecommend cervical collar even for follow－up cases beyond 3 months. This is due
to an ethical viewpoint that rather than its benefits, it has high harmful effects,

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441

such as inactivity, poor physical condition, and a decline in self－efficacy17). Furthermore, even though the amount of research and sample sizes were insufficient uponmeta－analysis, in terms of its response rate to cervical radiculopathy pain, as an
outcome, there was no difference between the group which used a cervical collar,
and the waiting list group, physical therapy group, and traction group18). According
to the guidelines on non－invasive treatment for non－specific low back pain（LBP）
and neck pain for low－ to medium－income families in Germany, researchers concluded that a cervical collar should not be used in the acute stage to treat non－specific neck pain or neck pain accompanying radiculopathy. However, they do notmention anything about its use for chronic－stage patients19). In an RCT conductedon patients with cervical radiculopathy, researchers compared 3 groups：a cervicalcollar group, a physical therapy group, and a control group；and reported that that
there was no significant difference for the cervical collar group compared with theother groups, in terms of alleviation of neck pain at 6 months, nor at 6 weeks wasthere any significant difference in level of satisfaction, the dosage of NSAIDs andopioid analgesics administered, or amount of sick leave taken20).
PeriodDatabase
Words
searched

2005～2019
MEDLINE, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
chronic neck pain, cervical radiculopathy
neck collar/nothing fixed（stand－by control group, physical therapy, traction etc.）
Limited by publication type. PubMed CER randomized controlled trial/systematic review
search filter, Cochrane RCT search filter, etc
Of the 198 MEDLINE 198 search hits, we used 4 which matched with the set PICOP
I/C

Limitations
Selection summary

CQ G－5－2：Are lumbar corsets（lumbar fixation belts）useful for chronic low
back pain ?
Answer：There is no significant difference in using a lumbar corset comparedwith other active treatment methods for LBP and functional improvement. Furthermore, lumbar corsets, used as an apparatus to prevent LBP among laborers and at
the workplace, are not effective compared to for example training, and also interms of LBP episodes（short－term and long－term）and short－term prevention ofsick leave, researchers did not observe that a lumbar corset was effective compared with controls.
Recommendation Grade & Summary of Overall Evidence
Recommendation grade：No recommendation〔Consensus 82.4%〕
Summary of overall evidence：C（low）
Commentary：
According to the US guidelines（2017）, although evidence is low, at 8 weeks or 6

RCT：randomized
controlled trial

442

G．Rehabilitation

months, comparing a lumbar corset＋exercise group with an exercise only group（muscle strengthening exercises）, researchers reported that there was no difference in pain or function and compared with other active treatment therapies（traction, spinal manipulation, exercise, physical therapy or TENS）, there was no clear
difference in pain or function from the use of a lumbar corset21). They did not report on ADL or QOL. As an apparatus for preventing LBP among laborers and at
the workplace, compared with training, the lumbar corset was not effective and so
we do not recommend its use as a form of protective equipment22). In a systematic
review on preventing LBP, researchers reported moderate－level evidence that it
does not reduce LBP episodes over the long－term and low－level evidence in which
they did not observe any effects in preventing short－term absence from work due
to sick leave23). In a report on the dosage of analgesics used, the pharmacologicalconsumption amount decreased in patients with sub－acute LBP but there were nolong－term reports on chronic LBP24). In a single report from Japan that a lumbar
corset was effective, LBP improved over the short term, increasing muscular endurance, and they reported that they did not observe a decrease in paraspinal muscular fatigue or reduced muscular strength through wearing the lumbar corset fora long period of 6 months24). Researchers suggested that wearing a lumbar corset
might possibly be useful for elderly patients with complications and as a form of
adjuvant therapy or alternative therapy to pharmacotherapy. However, there areissues such as the small total number of cases examined：40 patients24).
PeriodDatabase
Words
searched

P
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Limitations
Selection summary

2005～2019
MEDLINE, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
chronic low back pain
lumbar corset/not fixed（exercise therapy and surgery etc.）
Limited by publication type. PubMed CER randomized controlled trial/systematic review
search filter, Cochrane RCT search filter, etc
Of the 78 MEDLINE search hits, we used 4 which matched with the set PICOCQ G－5－3：Are knee braces（knee corsets）useful for chronic knee joint pain
due to knee osteoarthritis（OA）?
Ans：When pain, knee joint function, walking distance and QOL were assessed
after 12 months in a knee brace group, there was no significant difference compared with patients without a knee brace and therefore we are unable to judge
whether it is recommendable.
Recommendation Grade & Summary of Overall Evidence
Recommendation grade：No recommendation〔Consensus 94.4%〕
Summary of overall evidence：C（low）

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443

Commentary：
In a 2015 Cochrane review, at 12 months follow－up, through using VAS painscores, researchers did not recognize a statistically significant difference in analgesic effect in the knee brace group compared with a group that did not undergo thetreatment. At 12 months follow－up, there was no statistically significant differencein knee joint function between the knee brace group and the group which did notuse a knee brace. Furthermore, researchers reported that there was no evidence of
its effect on HSS knee function25). As for QOL, at 12 months follow－up, irrespectiveof whether patients were wearing a knee brace or not, researchers did not observea statistically significant difference in the EuroQol Scores among participants.
There is a low－level evidence report indicating the possibility that wearing a kneebrace might reduce the prevalence rate through prevention26). There were no reports of complications either in a group that wore a knee brace or in the non－treatment group but due to skin irritation and ill－fitting braces, a very small number ofpatients enrolled in the study discontinued wearing it25). There are no reports on
the effects of a knee brace on absence from work due to knee joint pain, workers
going back to work, dosage of analgesic administered or pain relapse. On the other
hand, according to guidelines published by the American College of Rheumatology／
Arthritis Foundation（2020）, pain experienced by patients when walking up anddown stairs and during the 6－minute walk test（6MWT）significantly improved in
the knee brace group compared with the standard－treatment group, and therefore
they recommend wearing a knee brace27).
PeriodDatabase
Words
searched

P
I/C

Limitations
Selection summary

2005～2020
MEDLINE, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
Osteoarthritis of the knee, chronic knee pain
knee brace/no equipment（non－treatment, footplate etc.）
Limited by publication type. PubMed CER randomized controlled trial/systematic review
search filter, Cochrane RCT search filter, etc
Of the 53 MEDLINE search hits, collating the searches with PICO, we used 2 reviews

References
1）‌Malfliet A, et al : Best evidence rehabilitation for chronic pain : Part 3 : Low
back pain. J Clin Med 2019 ; 8 : 1063. doi : 10.3390/jcm8071063. PMID : 31331087
2）‌Sterling M, et al : Best evidence rehabilitation for chronic pain : Part 4 : Neckpain. J Clin Med 2019 ; 8 : 1219. doi : 10.3390/jcm8081219. PMID : 31443149
3）‌Rice D, et al : Best evidence rehabilitation for chronic pain : Part 5 : Osteoarthritis. J Clin Med 2019 ; 8 : 1769. doi : 10.3390/jcm8111769. PMID : 31652929
4）‌Saragiotto BT, et al : Motor control exercise for chronic non－specific low－back pain. Cochrane Database Syst Rev 2016 ; Jan 8 （1）;: CD012004. doi : 10.
1002/14651858. CD012004. PMID : 26742533
5）‌Saragiotto BT, et al : Motor control exercise for nonspecific low back pain : A
Cochrane Review. Spine（Phila Pa 1976）2016 ; 41 : 1284－1295. doi : 10.1097/
BRS.0000000000001645. PMID : 27128390
6）‌Baliki MN, et al : Nociception, pain, negative moods, and behavior selection.
Neuron 2015 ; 87 : 474－491. doi : 10.1016/j.neuron.2015.06.005. PMID : 26247858

HSS：Hospital for Special Surgery
QOL：quality of life

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7）‌Hagenberg A, et al : Mirror visual feedback for phantom pain : International
experience on modalities and adverse effects discussed by an expert panel : A
delphi study. PM R 2014 ; 6 : 708－715. doi : 10.1016/j.pmrj.2014.01.005. PMID :244122648）‌Elbers S, et al : The effectiveness of generic self－management interventions
for patients with chronic musculoskeletal pain on physical function, self－efficacy, pain intensity and physical activity : A systematic review and meta－
analysis. Eur J Pain 2018 ; 22 : 1577－1596. doi : 10.1002/ejp.1253. PMID :29845678
9）‌Wood L, et al : A systematic review and meta－analysis of pain neuroscienceeducation for chronic low back pain : Short－and long－term outcomes of painand disability. Eur J Pain 2019 ; 23 : 234－249. doi : 10.1002/ejp.1314. PMID :30178503
10）‌Marris D, et al : The impact of combining pain education strategies withphysical therapy interventions for patients with chronic pain : A systematic
review and meta－analysis of randomized controlled trials. Physiother Theory
Pract 2019 ; Jun 28 : 1－12. doi : 10.1080/09593985.2019.1633714. PMID : 31250682
11）‌Jensen LD, et al : Counselling low－back－pain patients in secondary healthcare : A randomised trial addressing experienced workplace barriers andphysical activity. Occup Environ Med 2011 ; 69 : 21－28. doi : 10.1136/oem.2010.
064055. PMID : 21597108
12）‌Cheng AS, et al : Randomized controlled trial of workplace－based rehabilitation for work－related rotator cuff disorder. J Occup Rehabil 2007 ; 17 : 487－
503. doi : 10.1007/s10926－007－9085－0. PMID : 17520356
13）‌Tilbrook HE, et al : Yoga for chronic low back pain : a randomized trial. Ann
Intern Med 2011 ; 155 : 569－578. doi : 10.7326/0003－4819－155－9－201111010－
00003. PMID : 22041945
14）‌Sherman KJ, et al : A randomized trial comparing yoga, stretching, and a self－care book for chronic low back pain. Arch Intern Med 2011 ; 171 : 2019－2026.
doi : 10.1001/archinternmed.2011.524. PMID : 22025101
15）‌Saper RB, et al : Yoga, physical therapy, or education for chronic low backpain : A randomized noninferiority trial. Ann Intern Med 2017 ; 167 : 85－94.
doi : 10.7326/M16－2579. PMID : 28631003
16）‌Royal Australian College of General Practitioners : Guideline for the Management of Knee and Hip Osteoarthritis, 2nd ed ; Royal Australian College ofGeneral Practitioners, Melbourne, Australia, 201817）‌Côté P, et al : Management of neck pain and associated disorders : A clinicalpractice guideline from the Ontario Protocol for Traffic Injury Management（OPTIMa）Collaboration. Eur Spine J 2016 ; 25 : 2000－2022. doi : 10.1007/
s00586－016－4467－7. PMID : 26984876
18）‌Zhang X, et al : The effectiveness of therapeutic strategies for patients withradiculopathy : A network meta－analysis. Molecular Pain 2018 ; 14 : 174480691
8768972. doi : 10.1177/1744806918768972. PMID : 29651898
19）‌Chou R, et al : The Global spine care initiative : Applying evidence－based
guidelines on the non－invasive management of back and neck pain to low－
and middle－income communities. Eur Spine J 2018 ; 27（Suppl 6）: 851－860.
doi : 10.1007/s00586－017－5433－8. PMID : 29460009
20）‌Kuijper B, et al : Cervical collar or physiotherapy versus wait and see policy
for recent onset cervical radiculopathy : Randomised trial. BMJ 2009 ; 339 :b3883. doi : 10.1136/bmj.b3883. PMID : 19812130
21）‌Qaseem A, et al : Clinical Guidelines Committee of the American College of

G．Rehabilitation

Physicians : Noninvasive treatments for acute, subacute, and chronic low backpain : A clinical practice guideline from the American college of physicians.
Annals of Internal Medicine. 2017 ; 166 : 514－530. doi : 10.7326/m16－2367.
PMID : 28192789
22）‌Kuijer P, et al : An evidence－based multidisciplinary practice guideline to reduce the workload due to lifting for preventing work－related low back pain.
Ann Occup Environ Med 2014 ; 26 : 16. doi : 10.1186/2052－4374－26－16. PMID :24999432
23）‌Steffens D, et al : Prevention of low back pain : A systematic review and meta－
analysis. JAMA Intern Med 2016 ; 176 : 199－208. doi : 10.1001/jamainternmed.
2015. 7431. PMID : 26752509
24）‌Sato N, et al : Effects of long－term corset wearing on chronic low back pain.
Fukushima J Med Sci 2012 ; 58 : 60－65. doi : 10.5387/fms.58.60. PMID : 22790893
25）‌Duivenvoorden T, et al : Braces and orthoses for treating osteoarthritis of theknee. Cochrane Database Syst Rev 2015 ; 2015（3）: CD004020. doi : 10.1002/
14651858.CD004020.pub3. PMID : 25773267
26）‌Raja K, et al : Efficacy of knee braces and foot orthoses in conservative management of knee osteoarthritis : A systematic review. Am J Phys Med Rehabil 2011 ; 90 : 247－262. doi : 10.1097/PHM.0b013e318206386b. PMID : 21273902

445

Chapter H．Integrative Medicine：CQ H-1～CQ H-2
CQ H-1：Are acupuncture and moxibustion useful for chronic pain ?
CQ H-2：Is massage useful for chronic pain ?

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H．Integrative Medicine
CQ H－1：Are acupuncture and moxibustion useful for chronic pain ?
Answer：We believe that acupuncture and moxibustion are useful on patientswith chronic pain but when selecting a form of treatment, we recommend prioritizing the values of the patient after taking into consideration the effects and costs.
An important element when opting for acupuncture and moxibustion treatment ishaving acupuncture and moxibustion practitioners who have an appropriate knowledge of chronic pain.
Recommendation Grade & Summary of Overall EvidenceR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 84.2%〕

Summary of overall evidence：C（low）
Commentary：
We investigated the efficacy of acupuncture and moxibustion treatment on patients with chronic pain but definitions of chronic pain vary widely depending on
the research paper so this time we targeted “patients with pain persisting for 3
months or more” and investigated without narrowing it down by specific disease.
Furthermore, there are many research studies that have used sham acupuncture
treatment as the control when investigating the efficacy of acupuncture and moxibustion. However, considering the definition of sham acupuncture and also the factthat there are reports for example which have recognized bioactivity due to shamacupuncture, we considered its efficacy by using pharmacotherapy or pharmacotherapy＋regular care as the control groups, in accordance with actual clinical settings.
RCT：randomized
controlled trial

As a result, in the end we found 4 RCTs on chronic neck pain1), chronic migraine2), fibromyalgia3), and chronic pelvic pain syndrome4). With pain, the meandifference between the indicators（the pain-related scores of VAS, SF-36, FIQU,
NIH-CPSI, respectively）of each research paper were －0.8 [－2.4～0.77]（no significant difference）, －5.6 [－8.7～－2.5]（significant in the intervention group）,0.5 [－1.6
3)～2.6]（no significant difference）, and －2.8 [－4.6～－1]（significant in the interven-tion group）4). Two of these research papers mentioned QOL1,4), and the results1)were－3.7 [－5.4～－2.0]（significant in the intervention group）, and －1.2 [－2.5～0.2]
4)（no significant difference）. There was 1 research paper that clearly mentioned ad-verse events2)；there were side effects among 6% of the patients in the intervention group, and 66% in the control group. Additionally, there were 2 research pa-

H．Integrative Medicine

449

pers that mentioned there were no adverse events in either of the groups1,4).
For our meta－analysis, we integrated 2 research studies on pain1,3). Essentially,
these conditions were not suitable for conducting a meta－analysis so we deliberately chose the large category of what patients encounter in actual clinical settings at
an acupuncture and moxibustion clinic in order to understand what kind of results
we would get, using “subjects whose pain has persisted for 3 months or more, internal medicine as the control group, and pain as the outcome.” As a result, we did
not recognize a significant difference；SMD －0.24 [－0.75 ～ 0.27]（P＝0.35）. In
terms of a balance of benefits and harmful effects, we believe it was more effectivein the intervention group but we believe the control group was useful when considering costs.
In this systematic review, diseases were limited and therefore as it does not represent chronic pain overall, we ended up investigating the efficacy of acupuncture
and moxibustion only on specific diseases and symptoms. As diseases and symptoms vary and there are few research studies on it, the quality of evidence is low
so we are unable to reach a fixed conclusion. However, depending on the relative
importance of values, such as treatment effects, costs and side effects, we believethat for patients it is an effective option for both groups.
Based on the results above, when the “patient has a chronic illness（disease inwhich the main symptom is chronic pain）and there are no means for them to undergo suitable treatment by a health insurance doctor,” which is the condition forpatients to be eligible for medical expenses from acupuncture and moxibustion, thismight be regarded as the ideal option for patients, both in terms of effects andcosts. However, in this case, this is provided that the acupuncturist performing thetreatment has adequate knowledge of chronic pain.
Moreover, this time pharmacotherapy was set as the control group, so there
were few research papers but we saw many papers which had used a sham treatment for the control and also had compared acupuncture combined with pharmacotherapy against pharmacotherapy.
In a meta－analysis of chronic pain patients overseas, researchers reported highly
reliable evidence that moxibustion therapy was effective in managing chronic
pain5). In overseas clinical guidelines, The National Institute for Health and Care
Excellence（NICE）recommends acupuncture treatment in comparison to shamtreatments or standard care for reducing pain and improving QOL over a short pe6)
riod of time（3 months）. Furthermore, the American College of Physicians（ACP）

recommends acupuncture treatment for chronic LBP.7)

SMD：standardized
mean difference

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PeriodDatabase
Words
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P
I／C

Limitations
Selection summary

2005～2019
MEDLINE, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
Mainly chronic pain＊, similar words to this（intractable pain,complex regional pain syndromes
etc.）
acupuncture, moxibust,moxa,needl etc.／nothing specified
Limited by publication type, PubMed CER randomized controlled trials ／ systematic review
search filter,Cochrane RCT search filter
Of the 502 MEDLINE search hits, 1,102 Cochrane CENTRAL search hits, and 53 NPO Japan
Medical Abstracts Society search hits, we utilized 4 that matched with the set PICOCQ H－2：Is massage useful for chronic pain ?
Answer：We believe that massage is useful for chronic pain but from our results
this time, we were unable to recommended it with certainty. When choosing a formof treatment, it is recommended that one prioritize the patient’s values after taking
into consideration its costs and effects. Furthermore, an important element ofchoosing massage is the purpose for performing a massage and the credentials of
the masseur or masseuse and whether they have adequate knowledge of chronic
pain or not.
Recommendation Grade & Summary of Overall Evidence
Recommendation grade：No recommendation〔Consensus 85.0%〕
Summary of overall evidence：C（weak）
Commentary：
We investigated the usefulness of massage on patients with chronic pain but definitions of chronic pain vary widely depending on the research paper so this time
we targeted “patients with pain persisting for 3 months or more” and investigatedwithout narrowing it down particularly by disease.
To define ‘massage,’ we referred to the “traditional Japanese massage（anma）,
RCT：randomized
controlled trial

massage and shiatsu evidence report 2011－18：RCT－（EAMS 2011）”8) in our searchmethod and Cochrane systematic review search9) and used general manual therapy
search hits. Therefore, in addition to “massage” and “shiatsu” we also included“Thai－style massage.”
Researchers have thought of a variety of forms of treatment as the control
groups when considering the efficacy of massage, but this time we consideredpharmacotherapy or pharmacotherapy＋regular care as the control groups, in accordance with actual clinical settings. As a result, in the end we found 4 RCTs that
had targeted primary headache10), chronic headache11), chronic tension－type head12)ache（TTH）, and chronic musculoskeletal pain13). Not only does each disease

vary, there is no uniformity to the treatment methods used in the intervention
groups, and so because there were various control groups as well, we did not con-

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H．Integrative Medicine

duct a meta－analysis. In each respective research paper, pain was －0.5 [－2.8～1.78]（no significant difference）10), －23.1 [－41～－5]（significant in the intervention
11)
12)group）, 0.44 [0.11～0.76]（significant in the intervention group）, and 2.77 [0.2213)～5.32]（significant in the intervention group）.

There were 2 papers that mentioned QOL, and in each respective one it was
10)－1.07（SD not mentioned, P＝0.02）（significant in the intervention group） , 9.7[－9.54～28.9]（no significant difference）13).
There was 1 paper that clearly specified adverse events；0 out of 13 patients
had adverse events in the intervention group, 4 out of 13 patients had adverse
events（3 cases of drowsiness, 1 case of tachycardia）in the control group8) .
As for a balance of benefits and harmful effects, we believe that it is useful in intervention groups but the control groups are thought to be useful when thinking
about costs.
Diseases were limited in this systematic review, and therefore as it does not represent chronic pain as a whole, we ended up considering the efficacy of massage on
specific diseases and symptoms. As the diseases and symptoms vary and there is asmall number of research studies, the quality of the evidence is low so we are unable to reach a fixed conclusion. However, depending on the relative importance ofvalues such as treatment effects, costs and side effects, we believe that massage isa useful option for patients in both groups.
However, even if we use the single expression of “massage,” it is necessary tochoose this option after distinguishing whether practitioners have or do not have anational licence to practice anma massage and shiatsu, and also for practitioners
and patients to distinguish the purposes for conducting massage. In addition, this isalso provided that the anma massage and shiatsu practitioner has adequate knowledge of chronic pain for treating patients.
We came up with these results but as there were few patients in each of the research studies, there were many parts in each research design which lacked transparency, so as it was difficult to obtain reliable results, we were not able to recommend it this time.
PeriodDatabase
Words
searched

P
I／C

Limitations
Selection summary

2005～2019
MEDLINE, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
Mainly chronic pain, words similar to this（intractable pain,complex regional pain syndromesetc.）
Massage（massage, anma）,shiatsu,acupressure etc.／nothing specified
Limited by publication type, PubMed CER randomized controlled trials ／ systematic review
search filter, Cochrane RCT search filter
Of the 180 MEDLINE search hits, 326 Cochrane CENTRAL search hits, and 13 NPO Japan
Medical Abstracts Society search hits, we utilized 3 that matched with the set PICO

References
1）‌Cho JH, et al : Acupuncture with non－steroidal anti－inflammatory drugs（NSAIDs）versus acupuncture or NSAIDs alone for the treatment of chronic

QOL：quality of life

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neck pain : An assessor－blinded randomised controlled pilot study. AcupunctMed 2014 ; 32 : 17－23. doi : 10.1136/acupmed－2013－010410. PMID : 24171895
2）‌Yang CP, et al : Acupuncture versus topiramate in chronic migraine prophylaxis : A randomized clinical trial. Cephalalgia 2011 ; 31 : 1510－1521. doi : 10.
1177/0333102411420585. PMID : 22019576
3）‌Hadianfard MJ, et al : A randomized clinical trial of fibromyalgia treatment
with acupuncture compared with fluoxetine. Iran Red Crescent Med J
2012 ; 14 : 631－640. PMID : 23285415
4）‌Küçük EV, et al : Effectiveness of acupuncture on chronic prostatitis－chronic
pelvic pain syndrome category IIIB patients : A prospective, randomized,
nonblinded, clinical trial. Urology 2015 ; 85 : 636－640. doi : 10.1016/j.urology.2014.11.004. PMID : 25582816
5）‌Vickers AJ, Vertosick EA, Lewith G, et al : Acupuncture for chronic pain :Update of an individual patient data meta－analysis. J Pain 2018 ; 19 : 455－474.
doi : 10.1016/j.jpain.2017.11.005. PMID : 29198932
6）Kosky N, et al : Chronic pain : assessment and management. NICD. https://www.nice.org.uk/guidance/indevelopment/gid-ng10069 April, 2021 （inprinting）
7）‌Qaseem A, Wilt TJ, McLean RM, et al : Noninvasive treatments for acute,subacute, and chronic low back pain : A clinical practice guideline from theAmerican College of Physicians. Ann Intern Med 2017 ; 166 : 514－530.
doi : 10.7326/M16－23675）
8）‌Fujii R, et al : Evidence Reports of Anma－Massage－Shiatsu : 18 Randomized
Controlled Trials of Japan（EAMS 2011）: 東アジア伝統医学の有効性・安全性・経済性のシステマティック・レビュー．あん摩・マッサージ・指圧エビデンスレポート・タスクフォース http : //jhes.umin.ac.jp/abstract/EAMS2011J.pdf
9）‌Furlan AD, et al : Massage for low－back pain. Cochrane Database Syst Rev
2015 （9）;: CD001929 : . doi : 10.1002/14651858.CD001929.pub3. PMID : 26329399
10）‌Villani V, et al : Single－blind, randomized, pilot study combining shiatsu andamitriptyline in refractory primary headaches. Neurol Sci 2017 ; 38 : 999－1007
doi : 10.1007/s10072－017－2888－7. PMID : 28283760
11）‌Hsieh LL, et al : Effect of acupressure and trigger points in treating headache : A randomized controlled trial. Am J Chin Med 2010 ; 38 : 1－14. doi : 10.
1142/S0192415X10007634. PMID : 20128040
12）‌Damapong P, et al : A randomized controlled trial on the effectiveness ofcourt－type traditional Thai massage versus amitriptyline in patients withchronic tension－type headache. Evid Based Complement Alternat Med2015 ; 2015 : 930175. doi : 10.1155/2015/930175. PMID : 26472986
13）‌Plews－Ogan M, et al : A pilot study evaluating mindfulness－based stress reduction and massage for the management of chronic pain. J Gen Intern Med
2005 ; 20 : 1136－1138. doi : 10.1111/j.1525－1497.2005.0247.x. PMID : 16423104

Chapter I．Multidisciplinary Treatment：CQ I-1～CQ I-5
CQ I-1：What is the definition of multidisciplinary treatment ?
CQ I-2：What are the individual approaches（therapeutic interventions）included under multidisciplinary treatment ?
CQ I-3：What kind of staff make up the multidisciplinary treatment
team for managing chronic pain ? And what roles do thestaff play ?
CQ I-4：Is multidisciplinary treatment useful for chronic pain?
CQ I-5：What is the cost-effectiveness of multidisciplinary
treatment for chronic pain ?

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I．Multidisciplinary Treatment
CQ I－1：What is the definition of multidisciplinary treatment ?
Answer： Multidisciplinary treatment is a form of treatment for patients withchronic pain in which they are treated not by a single medical practitioner but by
medical experts from a variety of professionals. There is no established differentiation between this term and the term ‘interdisciplinary treatment’ in Japan, which isused with the same meaning. According to the definition by the International AssoIASP：International
Association for the
Study of Pain

ciation for the Study of Pain（IASP）, in both cases, specialists from various fields
and occupations are engaged in treatment but with ‘interdisciplinary treatment,’
specialists from diverse fields and occupations work in close co－operation with eachother in the decision－making process regarding the treatment policies（goals）, differentiating it from multidisciplinary treatment.
Commentary：
In patients with chronic pain, as the cause of the pain and the regions it affects
are diverse, having not only a physical, but also a psychological and social aspect, it
is recommended that the medical practitioners’ areas of specialty and what theytreat in terms of chronic pain should be diverse, taking into consideration these elements（physical, psychological, social）and their interrelations1－3). Multidisciplinary
treatment refers to a treatment intervention conducted by professionals from diverse fields and occupations.
The term ‘interdisciplinary treatment’ is used with the same meaning as multidisciplinary treatment. In both cases, a diverse range of specialists from various
fields and occupations coordinate their efforts to treat and there is no clear line
drawn between them. They are often confused in both clinical and academic settings but according to the IASP’s definition, the words are differentiated according
to whether the decision－making process for treatment policies（goals）is conductedby a single specialist or through shared communication2) with other health care
professionals.
To be more specific, in both instances, experts from a diverse range of fields andoccupations treat patients. However, in multidisciplinary treatment, each respective
specialist has his／her own treatment policies（goals）and it is not necessarily thecase that each specialist directly consults other specialists face－to－face（or for ex2)
ample online）. On the other hand, in interdisciplinary treatment, the experts fromvarious fields and occupations together form a treatment team, communicate frequently with each other, for example face－to－face or online, and then coordinate
their decision－making process regarding treatment policies（goals）and diagnosis

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based on the test results2). Within this clinical team, they share their concepts andtreatment goals based on a biopsychosocial model for pain1,2).
With the items of multidisciplinary treatment in these guidelines, we will handle
both multidisciplinary and interdisciplinary treatment, taking into consideration the
differences between them. For the sake of convenience, when there is no particularexplanation, we will use the term ‘multidisciplinary treatment’ meaning that it includes the definition of interdisciplinary treatment.
With the multidisciplinary approaches to patients with pain, we also use namesthat use the term ‘rehabilitation’（such as multidisciplinary rehabilitation）. According to the structure of an approach based on various professionals, it is the same as
the definition for multidisciplinary treatment but it can be thought of as a namefrom the viewpoint of something that places more emphasis upon for example therecovery of disability4).
In multidisciplinary treatment, reducing symptoms including pain is not the main
objective；it is encouraging social activity and improving quality of life（QOL）. QOL：quality of life
Therefore, what is important is not leaving it up to the physician to control the patient’s pain, but things like encouraging patients’ self－management of pain by skillfully making the most of the effects of physical activity for example, policies to encourage social activity including work, and also reducing dependence on healthcare,including pharmaceuticals5).

CQ I－2：What are the individual approaches（therapeutic interventions）included under multidisciplinary treatment ?
Answer：Multidisciplinary treatment for patients with chronic pain comprises individual approaches that make the most of the respective expertise of specialists,
each from a diverse range of fields and occupations, based upon a biopsychosocial
model. The individual approaches implemented by each specialist vary widely suchas exercise therapy, psychotherapy and pharmacotherapy.
Commentary：
As mentioned above in the definition of multidisciplinary treatment, when managing chronic pain through multidisciplinary treatment, in order to address the diverse number of causes of pain and their effects that cover physical, and psychosocial aspects, it is recommended to implement treatment while making the most of
the expertise of the respective experts who hail from various professions1－3). Several therapeutic approaches are described below, which may be included within amultidisciplinary treatment to manage chronic pain5－7).
1）Physical approach

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Multidisciplinary treatment is suited for goal－oriented treatment plans. The obQOL：quality of life

jectives are to improve physical capacity, lifestyle habits, quality of life（QOL）and
overall health. Negative behavioral patterns accompanying pain should be changed.
For example, these include advice recommending patients to be active, pacing, andvarious physical exercises. In addition, manual therapy, transcutaneous electrical

TENS：transcutaneous electrical nerve
stimulation

nerve stimulation（TENS）, and low－level laser therapy are sometimes used concomitantly5－7).
2）Psychological approach
After identifying the psychological aspects that the patient has including undesirable thoughts and behaviors, a suitable intervention such as corrections targetingthese thoughts and behaviors is conducted. For example, this includes education todevelop a deeper understanding of the mechanisms giving rise to pain and various

CBT：cognitive-behavioral therapy

patterns that accompany pain, cognitive－behavioral therapy（CBT）, gradual relax-

ACT：acceptance andcommitment therapy

and acceptance and commitment therapy（ACT）, which are called third－genera-ation, electromyographic（EMG）feedback, graded exposure, and also mindfulness
tion forms of CBT. With CBT in particular, specialists identify and correct non－adaptive reactions in for example cognition and behavior among chronic pain patients, and foster adaptive reactions for raising lifestyle functions including physicalfunction. CBT is frequently used in multidisciplinary treatment for the action of
maximizing the effects of the pain management5－7).
3）Pharmacotherapy
We will leave it for another chapter to detail the drugs used in pharmacotherapy.
Doctors not only select the pharmaceuticals that should be newly prescribed to patients but also evaluate, from a biopsychosocial aspect, the proper use of OTC
drugs and pharmaceuticals that have already been prescribed. It is especially important to provide guidance on the suitable use of opioid analgesics. In addition, if
polypharmacy（the harm of taking multiple medications at once）is an issue, thepossibility of curtailing the drugs will be considered6,7).
In addition to what has been mentioned above, after close scrutiny of its indication, various nerve blocks, acupuncture and moxibustion therapy and surgical treatment may also be introduced6,7).

CQ I－3：What kind of staff make up the multidisciplinary treatment team for
managing chronic pain ?

And what roles do the staff play ?

Answer：As mentioned above, multidisciplinary treatment involves specialists
from a wide variety of fields and professionals, and assumes a variety of styles,
such as a style in which specialists make treatment strategies（goals）together forthe same patient, a style in which each independent specialist has his／her own re-I．Multidisciplinary Treatment

spective treatment strategy（goal）, and also a style in which specialists coordinate
their efforts through providing intrahospital referrals for the patient or referring
them to other facilities.
The following outlines the general members of a multidisciplinary treatment
team. However, you can make the team flexibly, according to the circumstances ineach respective facility.
1）The professionals that make up the team
A multidisciplinary team for managing chronic pain is comprised of various professionals, such as medical doctors, nurses, physical therapists, occupational therapists, certified public psychologists（clinical psychologists）, pharmacists, registereddietitians, and social workers（social welfare workers ／ psychiatric social work8－11)
ers）.

With the current situation in Japan, there are few facilities in which all of theabove－mentioned professionals can be found in the one location；in many cases theteam is comprised of medical doctors, nurses, physical therapists and psychologists.
2）The roles of the staff
In the multidisciplinary treatment of pain, specialized staff evaluate patients withpain from the interactional physical, psychological and social aspects, consider treatment strategies, and need to conduct a multidisciplinary and comprehensive approach in coordination with each of the specialty disciplines. The multidisciplinary
approach is based on the biopsychosocial model, listed in the commentary column,
and the professionals who comprise the multidisciplinary treatment team first needto understand the biopsychosocial factors in each respective patient with chronic
pain before attending to treatment. In indicating the roles of the staff, for the sakeof convenience, it is easier to understand if we broadly divide them into a ‘physicalapproach’ and ‘psychosocial approach.’
The specialties who are mainly in charge of the physical approach include doctors, physical therapists and occupational therapists. We recommend including doctors from as diverse a range of departments as possible, such as orthopedic surgeons, anesthesiologists, neurosurgeons, neurologists, physicians, rehabilitation doctors, and dentists. The specialties who are mainly in charge of the psychosocial approach include psychiatrists, psychosomatic physicians, nurses, and certified public
psychologists（clinical psychologists）. When necessary, staff members, especially
doctors, may also have the role of coordinating with other medical members, for example doctors such as a patient’s family doctor and occupational physicians, as wellas public health nurses, in cases where it is difficult to attend to the patient within
the same facility.
① The roles of doctors mainly in charge of the physical approach
As a specialist, they diagnose whether biological factors contribute to pain symptoms based on physical findings, neurological examination and imaging. They con-

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duct swift management, conducting necessary tests to discern diseases requiringurgent attention, such as fractures and undiagnosed cancer i.e. ‘red flag signs’.
Based on their evaluations of the pathologies, they perform treatments such as patient education, pharmacotherapy, and nerve blocks. When conducting pharmacotherapy, careful attention needs to be given to improper use of drugs, such as polypharmacy（harm caused by taking multiple medications）, keeping in mind the peculiar pain behaviors of patients with chronic pain. Furthermore, surgical therapy
may be selected in some cases, after first carefully considering its applicability9).
② The roles of psychiatrists and psychosomatic physicians mainly in charge ofthe psychosocial approach
They diagnose psychiatric diseases as a specialist and they implement for example a suitable pharmacotherapy to treat mental diseases that coexist with chronic
pain. Furthermore, they cooperate with a psychologist to evaluate the psychosocial
problems of patients with chronic pain, manage the approach and conduct treatments.
③ Nurses
Nurses manage patients for example by taking patient history and conducting
self－reported questionnaires. When taking history, nurses inquire about patient’s
clinical history, past history of illnesses, family history and general lifestyle information, as well as information that patients are convinced is unrelated to their pain.
They also collect information on basic physical findings such as patient height,
weight and vital signs. When a patient receives a treatment intervention, they also
provide medical assistance, such as help with examination and treatment.
They carefully observe patient behavior, consult them on the various pain－related anxieties, concerns and worries that patients have, and while listening attentively to patients’ complaints, they also provide the necessary support at the sametime. They also serve as a bridge or channel between the multidisciplinary teammembers. When necessary, they may also be in charge of educating, not only theactual patient, but also educating people accompanying the patient, such as family,on things like lifestyle habits.
④ Physical therapists/Occupational therapists
They conduct evaluations of things like physical function, and in particular musculoskeletal flexibility, muscle endurance, muscular strength and physical capacity.
Subsequently, they provide guidance on stretching and muscular strengthening exercises, for the purposes of improving blood flow and muscular tone. They implement aerobic exercise such as walking and aquatic exercises, and provide guidanceon how patients can practice on their own. It is important to assign the pace of activity, in other words, understand the proper amount of physical activity for eachindividual patient, ensuring that it does not result in strong pain and an accompanying cessation of activity for a long period of time, and provide guidance so that

I．Multidisciplinary Treatment

the patient can continue to be active within the range for which it is comfortable
for that patient and gradually increase the amount of activity. Physical therapists
and occupational therapists analyze the patients’ actual activities of daily living（ADL）and contents of their activities, and conduct pragmatic training with theaim of improving their social adaptability.
⑤ Certified public psychologist／Clinical psychologist
After evaluating patients’ psychosocial problems through an intake interview,
they share information with members of the multidisciplinary team. Furthermore,they select the suitable form of psychotherapy, such as from various forms of CBTand psychoeducation, including suitable knowledge about pain and coping methods,
and they provide support to the patient and their family.
⑥ Pharmacists
They collect comprehensive information on pharmacotherapy, not just information related to pharmaceuticals, but information based on assessments by nurses,
and treatment strategies by doctors, as well as the patient’s physical and mental
condition. And through liaising with the actual patient and people accompanying
the patient, such as family, they manage the proper use of pharmaceuticals in thepharmacotherapy used for each individual patient. To be more specific, they explain the importance of maintaining strict adherence based on the prescription intentions of the physician and a correct knowledge of analgesics and occasionally
may also for example assist in explanations of the time of onset for the pharmaceutical product and any pharmacological actions of the drug.
As for matters that specifically apply to patients with chronic pain, they focus on
explaining the types of analgesics, especially the side effects of opioid analgesics, toensure they are used safely. Furthermore, in cases where their pain is not eligible
for pharmacotherapy, the explanations for this will be properly given, and they will
avoid any unnecessary oral administration of drugs. In addition, regarding the polypharmacy problem（harm caused by taking multiple medications）, information will
be provided to the prescribing physician. Pharmacists listen carefully to patients’complaints, and especially in terms of pharmaceuticals, in cases where patients
have not successfully conveyed information to their doctors, they will provide themwith the adequate information.
⑦ Registered dietitians
In addition to support on nutrients and calories to consume, they take into consideration their circadian rhythms（chrono nutrition）, provide nutritional support
and basic meals for their lifestyle, and nutritional guidance for chronic pain comorbidity, such as obesity, diabetes, osteoporosis and sarcopenia. Also in cases of loss ofappetite and oral hypofunction, they provide guidance to the actual patient and tofamily members accompanying them. Through coordinating with physical therapists, they can also calculate the necessary amount of energy the patients need to

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perform exercises（physical activity）.
⑧ Social worker（certified social worker／psychiatric social workers）
In cases where patients with chronic pain either are suspended from their job orlose their job and in cases where they do not receive any lifestyle support, they
provide or coordinate information on the social security system. For example, they
consult patients about matters relating to the social security system that they are
currently receiving, including whether intractable diseases or physical／mental disabilities apply, towards assisting a transition to work（return to work）, and they
provide comprehensive support towards helping them return to society.
Commentary：
When managing patients with chronic pain, a ‘biological model’ that understands
their pain as an organic disease is insufficient；it will be difficult to achieve an imQOL：quality of life

provement in the patient’s pathological condition and quality of life（QOL）.In otherwords, it is difficult to improve the pain by an etiology that simply believes it is a（single）cause for pain and just by getting rid of that（single）cause. In the multidisciplinary treatment of chronic pain, what is needed is comprehensive care, usinga ‘biopsychosocial model’ as its foundation, which includes psychosocial factors
along with organic abnormalities in the patient（biological factors）. This is notabout one single specialist managing the pain but specialists from various fields andmembers cooperating and if possible, what is needed is to regularly hold joint conferences and coordinate their efforts with treatment.8,10,11)
What is important is to make the most of the expertise, that is the knowledge
and skills for example of each individual specialist and also launch a cooperative approach.8－11)
When discussing the recommendations at I－4 and I－5, as a definition for ‘multidisciplinary treatment’ for these CQs, we assume in principle at least 2 or more different specialists performing the treatment. Moreover, we have targeted research that
has investigated the treatment effects of combining at least 2 or more types oftreatment（for example CBT and exercise therapy）.In other words, this means wehave excluded research which has investigated the effects of single treatments,
such as CBT（alone）or exercise therapy（alone）.Furthermore, in cases where it isunclear to mention who is performing the treatment, we have included under themultidisciplinary treatments in I－4 and I－5, the pain programs, back schools, andmultidisciplinary ／ interdisciplinary rehabilitation, which were planned to provide
multidimentional and comprehensive pain treatment, in which generally speaking
several medical practitioners are involved in performing the treatment.

I．Multidisciplinary Treatment

CQ I－4：Is multidisciplinary treatment useful for chronic pain ?
Answer：The effects of multidisciplinary treatment on chronic pain in generaland its adherence（the patients’ active stance of positively undergoing treatment）
depend upon their pain－related beliefs, such as catastrophizing, fear－avoidance beliefs, and self－efficacy. And there is a lack of consistency regarding the treatment
effects as an outcome, such as improvement in pain intensity and improvements indisability. In other words, there is room to give further consideration regarding pathologies, within chronic pain overall, which are applicable for undergoing multidisciplinary treatment. Therefore, we will limit ourselves to making weak recommendations regarding the implementation of multidisciplinary treatment for chronic
pain overall.
On the other hand, some evidence has been accumulated on some of the diseases
within chronic pain. In particular, much evidence has been gathered on chronic low
back pain（LBP）so we strongly recommend implementation. In addition, if further
research is conducted in future on osteoarthritis, fibromyalgia, and chronic pelvic
pain including chronic prostatitis, although it is possible that the certainty of theestimated effects might change, we weakly recommend conducting multidisciplinary treatment based on the grounds of the evidence available at the current
stage. However, this does not mean, in the case of these diseases, that multidisciplinary treatment applies across the board for all pathologies. As the symptoms
and pathologies of patients with chronic pain vary, it is essential to conduct a biopsychosocial evaluation prior to introducing treatment.
Recommendation Grade & Summary of Overall Evidence（However,
it is essential to conduct a biopsychosocial evaluation and consider
whether treatment applies, before introducing treatment）
1）Chronic pain overall
Recommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 81.3%〕
Summary of overall evidence：B（moderate）
2）Chronic low back pain
Recommendation grade：1（strong）：Implementation is strongly recommended〔Consensus 100.0%〕
Summary of total evidence：A（high）
3）Osteoarthritis
Recommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 88.2%〕
Summary of overall evidence：B（moderate）
4）Fibromyalgia

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I．Multidisciplinary TreatmentR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕
Summary of overall evidence：B（moderate）
5）Chronic pelvic pain including chronic prostatitisR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 94.1%〕
Summary of overall evidence：B（moderate）
Commentary：
This is something we can say about research in general which has investigatedthe effects of non－pharmacological treatments on chronic pain but when planningresearch to consider the effects of multidisciplinary treatment on chronic pain, insome cases researchers set respondent criteria for the individual disease category
for those displaying chronic low back pain（LBP）and fibromyalgia. And in manycases research has elected to target ‘chronic pain’ comprehensively defined as pain
persisting for 3 months or longer or a recurrent pain. According to a systematic reRCT：randomized
controlled trial

view by Thompson et al. based on 10 RCTs, the adherence to multidisciplinary rehabilitation for general chronic pain（the patients’ active stance of positively undergoing treatment）and the effects of the treatment depended upon their pain－related beliefs such as catastrophizing, fear－avoidance beliefs, and self－efficacy, affecting
our ability to recommend the treatment12).
There are many reports of multidisciplinary treatment of chronic LBP, from theperspective of not only patients’ subjective symptoms, such as pain, but also rehabilitation which placed emphasis on an improvement in functional aspects. According to a systematic review13) conducted in 2018, based on 13 RCTs, where the outcomes were an improvement in the intensity of pain and degree of daily lifestyledysfunction 1 year after intervention, the effects of a multidisciplinary rehabilitation
effect on chronic LBP were significant, along with having a moderate level of effect.
When the outcome was return to work, 3 of the reports indicated that 1 year after
multidisciplinary rehabilitation, there was a significant positive correlation with return to work as an outcome. When sick leave due to pain was the outcome, the results were the same, and in terms of the number of days absent due to sickness
during the follow－up period, 3 reports13) gave a moderate to high amount of effectdue to multidisciplinary rehabilitation. Furthermore, according to a 2014 Cochranereview, multidisciplinary rehabilitation was found to be superior in terms of improvement in analgesic effect and daily life dysfunction for patients with chronic
LBP, as compared to standard treatment. However, as the size of the effect was
small, researchers stated that a balance should be obtained between the amount oftime required for conducting the treatment and the costs of the equipment and facilities. Furthermore, the researchers were unable to assertively conclude how ef-

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fective it will be in improving symptoms but at the same time, concluded that multidisciplinary treatment is recommended for patients with chronic LBP exhibiting
psychosocial factors14). Furthermore, in terms of exercise－related fear, which canbecome a problem when conducting exercise, a systematic review conducted in
201915) reported a significant improvement in patient’s fear of falling over（compared with a group who underwent physical therapy alone）and patient kinesiophobia（compared with a group of patients undergoing regular treatment or exercise）, through multidisciplinary intervention.
In a systematic review conducted in 2016 regarding the effects of multidisciplinary treatment on osteoarthritis, RCTs on osteoarthritis in a large number of

OA：osteoarthritis

joints were considered, and although they concluded that multidisciplinary treatment was suitable for primary care, only 4 RCTs were eligible for consideration16).
In the recommendations for treating hip and knee osteoarthritis（OA）through non－pharmacological treatment, published in 2013 by the European League against
Rheumatism（EULAR）, they recommended a multidisciplinary biopsychosocial approach from the initial stage evaluation, and recommended providing individualized
medical treatment after taking into consideration the risk factors of OA. They recommended providing education on OA, pacing for the amount of activity, providing
a daily exercise program tailored to the individual patient and a multidisciplinary
treatment with weight control17).
In the 2016 EULAR recommendations for fibromyalgia treatment, they described
the recommendation grades based on a detailed review they undertook on 107 citations that were selected from a total of 2,979 references18). In the recommendations,they concluded that exercise therapy is the only treatment they can strongly recommend on the grounds of their meta－analysis as a guideline. Furthermore, in thesame recommendations, Häuser et al. determined the recommendation grades
based on a meta－analysis conducted on 9 RCTs and including a total of 1,119 patients19). The results of the meta－analysis showed that compared with a waiting list
group, multidisciplinary treatment had a mild effect on pain and fatigue and compared with regular treatment and education, multidisciplinary treatment also
showed to have a relaxation effect. However, these effects were limited to short periods of time and because they were not effective over the long term, they gave aweak recommendation to multidisciplinary treatment used alone. On top of this, inthe same recommendations, as an expert opinion, they stated that focus should be
put on education, exercise, and other non－pharmacological treatments（CBT, mindfulness, acupuncture and moxibustion therapy, manual therapy etc.）for the initialstages of treatment. In addition, if there is no improvement through these forms oftreatment and individualized treatment is considered as the next stage, they mention psychotherapy for cases of mood disorder or cases for whom training about
coping proved to be ineffective, and pharmacotherapy for strong pain or sleep dis-

EULAR：European
League against
Rheumatic Diseases

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I．Multidisciplinary Treatment

order. Moreover, they mention considering the implementation of a multimodal rehabilitation program alone or in combination “for severe disability.”18) Regarding fibromyalgia, we also wish to refer you to CQ Q－7.
According to a meta－analysis of the effects of treatment for chronic pelvic pain
including chronic prostatitis without any accompanying bacterial infection, sample
size was small in individual research studies and treatment protocols varied but researchers found that exercise therapy in the pelvic floor muscles alone or used in
combination with CBT was significantly effective20). In this meta－analysis, the NaCPSI：the National
Institutes of Health
Chronic Prostatitis
Symptom Index

tional Institutes of Health Chronic Prostatitis Symptom Index（CPSI）score, which
is an international evaluation scale for chronic prostatitis／chronic pelvic pain syndrome, was used and improvement by 6 points was regarded as a clinically－significant improvement. After an analysis based on the data from 8 reports, including a
total number of 280 patients who met the eligibility criteria, the CPSI score had improved by 8.8 points（95% CI 7.5－10.1, p＜0.001）20). There has been little research
conducted for the purpose of investigating the effects of multidisciplinary treatment on chronic pain patients in Japan. Therefore, in summarizing the recommendation grades and total evidence for these current guidelines, as mentioned above,
we have no choice but to make a judgment based on the research results that havebeen mainly conducted in foreign countries. If additional further research is conducted in future on Japanese patients, there is a possibility that our degree of certainty regarding its estimated effect may also change.

CQ I－5：What is the cost－effectiveness of multidisciplinary treatment forchronic pain ?
Answer：As mentioned above in CQ I－4, we recommend conducting multidisciplinary treatment for chronic pain but as of 2020, it is not covered under the healthinsurance system in Japan. There is increasing interest in its cost－effectiveness andthe costs of implementation when treatment is introduced. In terms of the cost－effectiveness of multidisciplinary treatment for chronic pain, there are few diseasecategories of chronic pain that are being considered for research. There is a certain
level of evidence that has been accumulated on the cost－effectiveness of multidisciplinary treatment for chronic low back pain（LBP）, traumatic cervical syndrome
and non－specific neck pain, but it is still insufficient.
Commentary：
From an analysis of cost－effectiveness, in cases where the costs of a new treatment increase compared with a conventional treatment, an incremental cost－effectiveness ratio（ICER）is used to evaluate whether the effect is worthwhile or not.

I．Multidisciplinary Treatment

To be more specific, ICER is additional costs required to extend 1QALY, and if thisis below the ceiling value（willingness－to－pay）, it is concluded to be cost－effective.
The ICER ceiling value varies from one country and study to the next；in the US,a figure of USD50,000～USD10,000 can be used, in the UK, it is £ 20,000～£ 30,000
and in Japan, is 5～6 million yen. For more details, we wish to refer you to the explanation of the terms later on.
In a systematic review that considered multidisciplinary treatment for chronic
LBP, they included 3 RCTs with cost－effectiveness as an outcome, and although
the cost－effectiveness of multidisciplinary treatment for chronic LBP was superior,
they claimed that evidence was insufficient13). In a systematic review21) that targeted 26 RCTs on the cost－effectiveness of LBP that complied with US LBP guidelines, they considered the individual effects of treatments such as multidisciplinary
rehabilitation, exercise therapy, and cognitive－behavioral therapy, and when usedin combination, on acute or chronic LBP. These 26 RCTs included 3 RCTs from theUK which compared treatments provided by general practitioners（GPs）and treatments that conformed with the definition of multidisciplinary treatment in theabove－mentioned CQ I－5. Compared with the single treatments performed by GPs
over a period of 18 months, the ICER when exercise therapy and behavior therapy（BT）counselling were added to the treatments provided by GPs came to £ 2,847
per 1 QALY22). Compared with the GP treatments conducted over 15 months, theICER for education using CBT and exercise therapy came to £ 5,000 per 1
QALY23). Furthermore, in an RCT conducted in the Netherlands, compared withphysical therapy conducted alone, the ICER for a back school combination based on
exercise therapy and CBT principles came to £ 5,141 per 1 QALY24).
In a systematic review conducted by a research team from Ontario, Canada, considering the cost－effectiveness of a treatment intervention method for traumatic
cervical syndrome and cervical pain disorder, they considered 6 research papers
that matched the eligibility criteria. They claimed that for the grades I－III ‘whiplash－associated disorder’, categories for the severity of traumatic cervical syndrome, education was more cost－effective, and for cervical pain disorder, multidisciplinary treatment that included a combination of advice and exercise therapy aswell as manual therapy was superior in terms of their cost－effectiveness25). In thissystematic review, interventions conducted solely by a physical therapist, which included advice, exercise therapy and manual therapy, were called ‘multimodal care.’In these research studies, there is a possibility that treatment was not conductedby 2 or more people from 2 or more different occupations, which is our definition ofmultidisciplinary treatment in these guidelines, but in Japan, interventions by aphysical therapist are conventionally conducted according to a physician’s guidance
so these research papers were also included as ones relating to multidisciplinary
treatment in Japan.

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In an RCT on traumatic cervical syndrome in an emergency department in theUK, the results did not support the cost－effectiveness of multidisciplinary treatment；they implemented a 2－stage intervention targeting patients with acute pain
within 6 weeks of injury, and of these patients who displayed symptoms 3 weeks
or more after receiving treatment. Standard advice given orally by expert practitioners, such as emergency department physicians, and also advice based on pamphlets for the acute stage was found to have superior cost－effectiveness than guidance on activating their behaviors（a special textbook was used, they were encouraged to lead a regular life and exercise, and take analgesics not only when needed
but regularly, and they were advised not to use a neck ／ cervical collar）. After 3
weeks, single evaluation and advice given by a physical therapist was found to be
more cost－effective than multidisciplinary treatment that introduced physical therapy for 8 weeks, but they did not calculate its ICER26). However, in Japan, in thecase of patients with traumatic cervical syndrome who are being treated in theacute state by a physician from an emergency department, assuming that it is notcommon to provide advice using pamphlets and consulting them on how to prevent
protracted pain, we cannot say that the results of this RCT negate the cost－effectiveness of multidisciplinary treatment for cases of traumatic cervical syndrome inJapan.
In a 2006 RCT conducted in Germany on patients with chronic neck pain, adding
acupuncture to a standard treatment was found to be more cost－effective, andcompared with a standard treatment, the ICER was CAD 23,443 per 1QALY27). In
a 2007 RCT conducted in the UK, targeting patients aged 18 years and over with
non－specific neck pain（pain duration was not defined）, multidisciplinary treatments（combination of advice and exercise therapy）was found to be more cost－effective from the healthcare beneficiary’s point of view than the one in which passive hyperthermic treatment or manual therapy was added to the above28).
＊Explanation of Terminology
QALY：quality－adjusted life year
This is a common method for measuring disease burden；a method in which the 2 aspects of survival, quantity andquality, are evaluated. It is used as a method for economically evaluating the cost－effectiveness of a medical practice.
It is an indicator that considers the number of years of survival and the quality of life（QOL）. It represents one’s QOL
with the pathology as a ‘utility value,’ in which a perfectly healthy condition is represented as ‘1’, and death as ‘0’ andthen it is calculated by multiplying this figure by the number of years of survival. The higher the value, the more effective it is considered to be.
ICER：incremental cost－effectiveness ratio
For the treatment in question, this is the additional cost required in order to extend it by 1 QALY through introducing the treatment. It is calculated by dividing the increase in cost by the amount of improvement（increase in effect）
as an outcome. The lower the ICER figure, the ‘more cost－effective’ the treatment is deemed to be.

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2）‌International Association for the Study of Pain（2020, February 12）: IASP
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3）‌Turk DC, et al : Psychological factors in chronic pain : Evolution and revolution. J Consult Clin Psychol 2002 ; 70 : 678－690. doi : 10.1037//0022－006x.70.3.
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treatment services. 2009 ; May 2. https : //www.iasp－pain.org/Education/
Content.aspx?ItemNumber＝1381
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back pain : A systematic review. Global Spine J 2018 ; 8 : 872－886. doi : 10.
1177/2192568218765483. PMID : 30560041
14）‌Kamper SJ, et al : Multidisciplinary biopsychosocial rehabilitation for chronic
low back pain. Cochrane Database Syst Rev 2014 （9）;: CD000963. doi : 10.
1002/14651858.CD000963. pub3. PMID : 25180773
15）‌Martinez－Calderon J, et al : Conservative interventions reduce fear in individuals with chronic low back pain : A systematic review. Arch Phys Med Rehabil 2020 ; 101 : 329－358. doi : 10.1016/j.apmr.2019.08.470. PMID : 31473206
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2016 ; 17 : 266. doi : 10.1186/s12891－016－1125－5. PMID : 27391036
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Chapter J．Chronic Low Back Pain
：CQ J-1～CQ J-9
CQ J-1：How to define low back pain（LBP）?
CQ J-2：What is the pathology of low back pain（LBP）?
CQ J-3：Is chronic low back pain（LBP）related to lifestyle habits ?
CQ J-4：Is there any relation between chronic low back pain（LBP）
and one’s occupation ?
CQ J-5：Are psychosocial factors related to chronic low back pain
（LBP）?
CQ J-6：Which elements are important when evaluating chronic
low back pain（LBP）?
CQ J-7-1：Are serotonin-noradrenaline reuptake inhibitors（SNRI）
useful for chronic low back pain（LBP）?
CQ J-7-2：Is tramadol useful for chronic low back pain（LBP）?
CQ J-7-3：Are nonsteroidal anti-inflammatory drugs（NSAIDs）
useful for chronic low back pain（LBP）?
CQ J-8：Is exercise therapy useful for chronic low back pain（LBP）?
CQ J-9：Are patient education and behavioral psychology
approaches useful for chronic low back pain（LBP）?

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J．Chronic Low Back Pain
CQ J－1：How to define low back pain（LBP）?
Answer：The site of the low back is defined as ‘located on the rear side of thetrunk, situated between the 12th rib and the lower end of the gluteal sulcus, andpain must persist for at least 1 day or more. This pain may or may not entail pain
diffusing to either one or both of the lower limbs.’
Commentary：
The term ‘low back pain’ is a medical term represent the ‘symptoms’, and so because it does not refer to ‘the name of the disease’, there are many vague parts tothis definition. It is difficult to define unambiguously, so the definition describes the
3 viewpoints of site of pain, period of illness and pathology according to the ‘Guidelines for Managing Low Back Pain（2019）’1).
1）Site of pain
It is located on the rear side of the trunk, is situated between the 12th rib andthe lower end of the gluteal sulcus, and pain must persist for at least 1 day ormore. This pain may or may not entail pain diffusing to either one or both of thelower limbs2). What is called ‘buttock pain’ may possibly include pain derived fromthe nerve root. Low－back pain sometimes entails nerve root or cauda equina typelower－limb symptoms（pain and numbness）, and lower－limb pain which is called‘referred pain.’2）Period of illness from onset
There is a respective definition for each period from time of onset：acute LBP,
subacute LBP, and chronic LBP. The definition that chronic LBP is ‘LBP that persists for 3 months or longer’ has basically been established3). On the other hand,
LBP less than 1 month old since time of onset should be classified as acute or subacute but there is no consistent viewpoint on this. However, acute LBP is generally
defined as pain less than 4 weeks old since onset4). Between acute LBP and chronic
LBP we have what is called subacute pain. This corresponds to LBP persisting forsome where between 4 weeks and less than 3 months since onset.
3）Pathology
LBP is caused by an impairment of anatomical tissue, which mostly makes up
the spine. In other words, this includes intervertebral discs, the facet joints, thenerve root, muscles, fascia and ligaments. These kinds of tissue are impaired byvarious disorders and trauma, leading to the onset of LBP. To be more specific, it
can be classified into spinal－derived, neuropathic, viscerogenic, angiogenic, psychosocial, and other classifications.

J．Chronic Low Back Pain

The following four differentiations regarding the origin of LBP are especially necessary：1）tumor（primary, metastatic spinal／spinal cord tumor etc.）；2）infection（pyogenic spondylodiscitis, spinal caries etc.）；3）fracture（vertebral fractureetc.）；4）lumbar disease with severe neurological symptoms（lower－limb paralysis,
lumbar disc herniation and lumbar spinal stenosis with neurogenic bladder and rectal dysfunction）.
When differentiating the underlying cause, it is also important to consider whether the LPB arises from one of these tissues that make up the spine. In other words,
this includes LBP derived from the intervertebral discs, the facet joints, muscles,
fascia, nerve root or ligaments. Many of them are affected by regressive changes
caused by aging.

CQ J－2：What is the pathology of low back pain（LBP）?
Answer：There are various causes of LBP：spinal－derived, neuropathic, viscerogenic, angiogenic, psychosocial, and other classifications. In terms of the anatomical
origins of the pain, LBP originates from for example the facet joints, muscles, fascia,
intervertebral discs, sacroiliac joints, hip joints, and spinal alignment.
Commentary：
The origins of low back pain（LBP）can be classified into spinal－derived, neuropathic, viscerogenic, angiogenic, deriving from psychosocial factors and other causes. LBP derived from the spine includes spinal tumor, spinal infection, spinal trauma, lumbar disc herniation, lumbar spinal stenosis, lumbar spondylolysis/isthmic
spondylolisthesis, lumbar degenerative spondylolisthesis, osteoporosis, ankylosing
spondylitis, among others. The origin of the anatomical pain includes the facet
joints, muscle, fascia, intervertebral discs, sacroiliac joints, and hip joints. Furthermore, there is LBP caused by spinal alignment such as adult spinal deformities（kyphosis, scoliosis）with a large variety of pathologies. In particular, LBP that accompanies regressive changes is not limited to one single origin of pain；it is not infrequent for several causes to be present. These diverse causes can be broadly categorized into two groups from a different perspective. One group consists of pathologies for which diagnostic methods and treatment have already been establishedand this applies to for example spinal tumor, spinal infection, spinal trauma, lumbar
disc herniation, and urinary tract stones. The other group consists of pathologies
for which diagnostic methods and treatment have not yet been sufficiently established. This applies to LBP caused by muscles, fascia, intervertebral discs and psychosocial factors. In order to further clarify the pathology, in addition to approaches
to the lumbar spine, extensive research is also required on other surrounding tissue

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and upper tissue, or in other words pain from the lumbar spine to the brain. With
the lumbar spine, the search for the mechanisms that develop pain is underway, as
well as evaluations of motor system function such as the intervertebral discs, thevertebrae, and trunk muscles. As for the pain itself, research is being conducted on
the posterior horn of the spinal cord, dorsal root ganglion, nociceptors and pain fibers. In addition, in the brain researchers are also analyzing cerebral functions inrelation to pain.

CQ J－3：Is chronic low back pain（LBP）related to lifestyle habits ?
Answer：Researchers have observed that low weight and obesity are related to
the risk of onset of LBP. Maintaining a healthy weight is recommended. Researchers have indicated a relationship between smoking and drinking alcohol and therisk of LBP onset and its prevalence rate. In order to prevent LBP, we recommend
leading a healthy lifestyle which incorporate a moderate amount of exercise.
Commentary：
There is little research with high－level evidence on the relationship between lifestyle habits and LBP. In a meta－analysis on weight control, they observed a low relationship between low weight and the prevalence rate of LBP, compared withstandard weight. As for being overweight or obese, researchers also recognized alow relationship between being overweight and the prevalence rate of LBP（OR1.37 [95%CI 1.09 ～ 1.71]）. In addition, they recognized a low relationship between a BMI of 30 or above and the prevalence rate of LBP, compared with thosewith a BMI under 30. There is also a meta－analysis on being overweight and obese
as a risk factor for LBP. That is to say, maintaining a regular weight is related tothe prevention of LBP and its prevalence rate5－10). Researchers recognized a low
risk of onset of LBP if either the patient has a lower weight than standard（BMI
18.5 ～ 25.0）or is not obese. Therefore, we recommend maintaining a healthy
weight.
We identified 6 research studies related to the prevalence rate of LBP and smoking. Researchers considered and compared categories by classifying subjects basedon the number of days smoked ／ week, targeting non－smokers, smokers, and ex－
smokers. In a meta－analysis of smokers and non－smokers, few non－smokers tended
to have LBP（OR1.10 [95%CI 0.78～1.57]）, and they did not notice a relationshipbetween whether patients had a history of smoking or not. Moreover, they showedthat there was a relatively higher complaint rate of LBP among smokers, thanamong non－smokers and they indicated that this trend was strong among young
people5,8,9,11,12).

J．Chronic Low Back Pain

Researchers also indicated a relationship between alcohol intake and LBP. Theyobserved a weak relationship between the frequency of alcohol intake and the
5,13,14)prevalence rate of LBP（OR2.62 [95%CI 1.65～4.16]）. However, to date there

is a limit to the number of research studies reported and the number of patientstargeted（in each study）, and therefore one must be careful when interpreting theresults.
Researchers have also demonstrated a weak relationship between the effects ofdaily exercise and LBP. In a research study comparing a group of patients who do
not exercise with an exercise group, there was an elevated risk of LBP in thegroup who did not do exercise5) but as it was a small－size research study, they did
not find a relationship between the two15). In all this research, there is a limit to thenumber of research studies included and the quality of the research so one should
consider them carefully. In terms of improving LBP and physical dysfunctions related to LBP, there is a connection between exercise and prevention and improvement of LBP. Therefore, we recommend healthy lifestyle habits which incorporatea moderate amount of exercise in order to prevent LBP5,7,15).

CQ J－4：Is there any relationship between chronic low back pain（LBP）and
one’s occupation ?
Answer：Although there is moderate－level evidence suggesting a relation between occupations with a high physical burden（physically－demanding jobs）and
LBP, we cannot necessarily identify any poor posture or jobs while working as independent factors for LBP. Work and psychosocial factors at the workplace are related to the onset and prevention of LBP.
Commentary：
Regarding LBP and occupation, there are many reports about the burden on thelower back from specific occupations and its relationship to the onset of LBP. According to epidemiological surveys in Japan on LBP and occupation, researchers reported for example 71～74% in the transport industry,69% in cleaning, 46～65% in
nursing, and 63% in aged care16－18), therefore heavy labor which has a high physicalburden is a risk factor in the onset of LBP. Furthermore, in a report on the prevalence rate of LBP in 4 types of industry in the Tokyo Metropolitan Area（deskwork, nursing, sales, transportation）, the prevalence rate（of LBP）was higher innursing and transportation, occupations with a higher workload, compared withdeskwork and sales.
In a systematic review of LBP and occupation in relation to physical activity,
there was a recognizable correlation between labor involving carrying heavy items

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and lifting and the onset of LBP. Researchers observed a strong correlation between movements involving lumbar flexion, rotation, and forward movements andthe onset of LBP19). In a meta－analysis on LBP and occupation, researchers also observed a correlation between farm work and nurses lifting patients and LBP20,21). Ina longitudinal research meta－analysis study on work involving the lifting of heavy
objects and LBP, they reported that the weight of the heavy objects and the frequency of lifting significantly increased the onset of LBP22). As seen above, although
we recognize a medium－level of evidence, there are many reports where researchers were not necessarily able to identify poor posture or labor while working as anindependent factor of LBP23－29). Some papers have also reported on the difficulty ofevaluating the relationship between physical burden due to occupation and LBP30).
There have been reports on the psychosocial factors in the workplace relating tothe onset of LBP. Level of satisfaction with work, the monotony of work, relationships with others at work, size of workload, mental stress, self－evaluations of one’s
ability at work, each of them has a strong relationship to the future onset of LBP31).
Poor levels of satisfaction with work, a depressive state, low sociability, fear－avoidance beliefs（a destructive mindset in which the person is convinced the situation
will get worse and worse without any particular reason）have been cited as psychosocial poor prognostic factors for LBP32).
In research that has focused on “non－specific LBP that is an impediment towork,” risk factors for new incidences of LBP are a history of LBP, and lifting
heavy objects with a weight of 25 kg or more, frequent lifting（more than half of
one’s daily work）, and additionally, working for more than 60 hours／week and highstress from human relationships in the workplace33,34). Furthermore, researchers
have cited that risk factors for prolonged or chronic LBP are dissatisfaction withwork or lifestyle, low social support, depression, anxiety the psychosocial factors ofsomatization, low expectations that LBP will improve and working for more than
60 hours／week35,37).
In a Cochrane review, only about half the research papers in question had investigated in detail the prognostic factors for LBP. As information about patient’s overall health, social support, and work－related conditions were often lacking, accurate
and forward－looking RCTs will need to be conducted in future38).

CQ J－5：Are psychosocial factors related to chronic low back pain（LBP）?
Answer：Psychosocial factors are related to the intensity of pain, dysfunction andprognosis.

J．Chronic Low Back Pain

Commentary：
In the field of primary care, there is a systematic review which has analyzed thepsychosocial factors related to the transition from acute LBP to chronic pain fromthe 3 domains of social／occupational factors, psychological factors and cognitive／behavioral factors. Researchers cited that risk factors included the existence of compensation issues, depression, psychological distress, passive coping and fear－avoidance beliefs as individual factors. On the other hand, occupation, education level, social status, level of job satisfaction, and social／occupational factors did not show aneffect on the prognosis of LBP39).
In a systematic review on the effects of catastrophizing on the treatment of non－
specific LBP, catastrophizing did have an effect on treatment, on the intensity of
LBP, its persistence, and dysfunction40). In each of the respective stages, the acutestage, the subacute stage and chronic stage, catastrophizing affected intensity of
LBP and dysfunction41).
In a systematic review on how fear－avoidance beliefs affect the prognosis of non－specific LBP, fear－avoidance beliefs elevated the risk of people taking sick leaveor people being unable to return to work in the subacute stage（4 weeks ～ 3months after onset）, and was a prognostic factor in poor clinical outcomes. Therefore, early－stage treatment interventions to reduce fear－avoidance beliefs prevent
delays to improvements in LBP and prevent it from becoming chronic. However, inchronic LBP, we cannot say that it is a prognostic factor that regulates the outcome of LBP42).
In a systematic review of forward－looking cohort research studies on the psychological predictive factors on the transition from acute or subacute LPB to chronic
LBP, distress, depression and somatization were found to be involved in the transition to chronic LBP42). In addition, there have been reports that depression is a risk
factor for LBP43－45).
There is a wide variety of psychosocial factors：there are social factors such as
work, education level, and social status, social factors such as compensation issues,
psychological factors of which depression is a typical example and also distinctive
thoughts on pain such as catastrophizing and fear－avoidance beliefs and factors related to cognition and behavior such as passive coping. It is believed that these factors act either independently or mutually. We must also bear in mind how psychosocial factors may vary depending on patients’ outcomes such as intensity of LBP,
period of illness, history of surgery, dysfunction due to LBP, quality of life（QOL）
and activities of daily living（ADL）, among others.

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CQ J－6：Which factors are important when evaluating chronic low back pain
（LBP）?
Answer：We need to be careful of red flags, in which severe spinal diseases（tumors, infections, fractures etc.）are also suspected to be present. When red flags
and neurological symptoms are present, physicians actively conduct imaging studies such as X－ray photography and MRI, and blood biochemistry, striving to identify the underlying disease. Evaluations are made from a variety of aspects such as
intensity of pain, quality of pain, QOL, ADL and psychosocial factors. Images arelooked at from the point of view of whether they can address the functional abnormality that can explain the patient’s complaint.
Commentary：
1）LBP triage1)
What is necessary during the first consultation with an LBP patient is that bycarefully taking patient history and conducting a physical examination, the following 3 diagnostic triage can be performed accurately.
① LBP with red flags（Table J－1）present, severe spinal diseases（tumors, inflammation, fractures etc.）are suspected to be also present；② LBP with neurological symptoms；③ LBP other than 1 or 2 above.
2）Confirmation of neurological symptoms1)
When patients do not have a clear awareness of their lower－limb symptoms, it isimportant to conduct tests of their lower limb deep tendon reflexes, perceptions
and muscular strength to prevent any pathologies from being overlooked. In termsof neurological symptoms, physicians should evaluate the presence or absence ofsevere nerve deficiency symptoms accompanied by rapidly progressive or a clear
weakness in muscular strength, and bladder and rectal dysfunction. Researchers
have indicated that urinary retention in particular accompanies cauda equina syndrome. Symptoms of radiculopathy complications are indicated if the following
points are present：
・Single lower－limb pain is stronger than LBP・Pain diffusing to the feet and toes・Numbness at the same site and sensory paralysis
・When they test positive to a straight leg raising（SLR）test
When the above－mentioned red flags or neurological symptoms are present, physicians actively conduct imaging studies such as X－ray photography or MRI andblood biochemistry, striving to identify the underlying disease.
Note J1：Refer to
Chapter B Table B-3

3）Evaluation methods of specific QOL for LBP Note J1
The RDQ（Roland－Morris Disability Questionnaire）47), the ODI（Oswestry Low

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477

48)
Back Pain Disability Questionnaire）, and JOABPEQ（JOA Back Pain Evaluation

Questionnaire）49) are used as specific QOL scales for LBP diseases.
4）Evaluation of psychosocial factors
Chronic pain and psychosocial factors are closely related, and so when evaluating

ADL：activity of dailylivingpsychosocial factor

the pathology, physicians needs to evaluate the psychological factors and social（environmental）factors at the same time. As for social factors related to LBP, researchers have cited culture, family and social support, social status, education, employment management and labor relations, the unemployment situation, early retirement, and lawsuits／litigation. One needs to be careful in cases of LBP involving
compensation issues such as traffic accidents and work－related injuries.
When evaluating psychosocial factors, one must not depend upon the subjective

MMPI：Minnesota
Multiphasic Personality Inventory

evaluations of a medical practitioner but must evaluate them objectively. Useful
50,51)
tools for evaluating include the Hospital Anxiety and Depression Scale（HADS）
52,53)and the Pain Catastrophizing Scale（PCS）, the Fear－Avoidance Beliefs Ques-

tionnaire（FABQ）54,55) Subgrouping for Targeted Treatment Screening Tool
56,57)（STarT Back）

and the Brief Scale for Psychiatric Problems in Orthopedic Pa-

58,59)
tients（BS－POP）.

5）Physical findings
On a physical examination, physicians can further differentiate pathologies assumed from taking patient history；it is a means of confirmation. In order to avoid
anything being overlooked on the examination, it is important to make standard
protocols.
a．Palpation
Physicians check the presence or absence of knock pain on spinous process andtenderness on paraspinal muscles. If there is knock pain on spinous processes, onemust bear in mind the possibility of inflammation such as infection or vertebral
fracture at this level.
b．Spinal findings
Physicians also check motion limitations such as when the lumbar spine is bending forward or backwards. They confirm what kinds of symptoms manifest withwhat particular postures or actions. When patients are restricted in bending forward, and the posterior or lateral side of the lower leg induces radiating pain, thena herniated disc of the lower lumbar spine is suspected. If a patient has restrictions
in bending backwards with reappearing lower－limb pain and numbness, then one
suspects spinal stenosis and a herniated disc of the upper lumbar spine due tospondylosis and spondylolisthesis. When patients test positive to the Kemp test,
then one suspects radiculopathy due to lateral recess stenosis of the spinal canal. In
other words, researchers often observe positive findings with nerve root type lumbar spinal stenosis and lumbar disc herniation.
c．Differentiating between the pelvic region and hip joint disorders

HADS：Hospital
Anxiety and Depression Scale
PCS：Pain Catastrophizing Scale
SDS：Self-rating
Depression Scale
BS-POP：Brief Scalefor PsychiatricProblems in Orthopaedic Patients

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When pain is evoked on the Patrick test, then one suspects hip joint disease. In
addition, when pain is evoked on the Newton test, and Gaenslen test, then one suspects sacroiliac joint－derived LBP. In the one－finger test, the patient him／herself
points to the site exhibiting the strongest pain and when they point to the posterior superior iliac spine and in the vicinity of the ilium side, one suspects pain derived from the sacroiliac joints.
d．Evaluating motor function
For conducting a global evaluation of motor function such as walking ability andbalance, useful tests are the Timed－Up－and－Go test（TUG）60), and for evaluating
61)
exercise tolerance, there is the 6－minute walking test（6MWT）. Furthermore, as

there is the risk of overlooking the pathology just from examining a patient at rest
for LBP which mainly occurs while moving, the tester should walk together withthe person taking the test, the walking load test is useful for evaluating subjective
symptoms when they manifest and neurological findings62).
6）Diagnostic imaging
Diagnostic imaging such as X－ray imaging, myelography, MRI, CT, CT myelography, discography, CT discography, radiculography and facetgraphy are conducted to clarify the morphological causes. According to the Guidelines for Managing
Low Back Pain（2019）, X－ray image is claimed to be meaningful for the initial diagnosis of LBP in patients with this condition1). However, imaging is not essential
during the first consultation for non－specific LBP patients without radiculopathy.
With patients with red flags and neurological symptoms, after X－ray imaging, we
recommend conducting an MRI. The images are needed just from the viewpoint ofdeciding whether they are attending to the functional abnormality which can explain the patient’s complaint. And where necessary, we recommend using several
diagnostic imaging in combination.

CQ J－7－1：Are serotonin－noradrenaline reuptake inhibitors（SNRI）useful forchronic low back pain（LBP）?
SNRI：serotonin-noradrenaline reuptake
inhibitor

Answer：SNRI is effective on pain, QOL and dysfunction in patients with chronic
LBP. On the other hand, there tend to be many adverse events.
Recommendation Grade & Summary of Overall EvidenceR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 81.0%〕

Summary of overall evidence：B（moderate）

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479

Commentary：
The results of a systematic review found 9 references that met the eligibility criteria, and 4 of them were used for meta－analysis63－66). The indicators used for themeta－analysis include the Roland－Morris Disability Questionnaire（RMDQ）[lumbar
function], EQ－5D [QOL], Brief Pain Inventory（BPI－S）[degree of severity of pain],

QOL：quality of life

BPI－I [degree of impairment due to pain]. In each of the outcomes, SNRI showed asignificant improvement in these outcomes, as compared with the placebo. However, even though it was statistically significant, degree of improvement was small, so
we are unable to say that the effect exceeded a difference that was clinically important difference and the certainty of the synthesized evidence is weak.
Adverse events include nausea, dipsia, and loss of appetite and the degree ofthese adverse events ranged from mild to medium. In a meta－analysis in the‘Guidelines for Managing Low Back Pain（2019）’ on the adverse events due to
SNRI compared with a placebo, researchers did not observe a significant difference
between the two gorups but adverse events were frequent in the SNRI group1).
In a calculation of the quality－adjusted life year（QALY）, which included the

QALY：quality-adjusted life yearside effects and cost of treatment, and incremental cost－effectiveness ratio（ICER）, ICER：Incremental
comparing duloxetine and an existing drug, researchers reported that duloxetine
67,68)

was more cost－effective.

SNRI received a recommendation grade of 1 for chronic pain in general but（refer to Chapter C）, as it has a small effect only on chronic LBP, its recommendation
grade only came to a 2. However, in research that is used for analysis, we must pay
attention to the fact that there are diverse pathologies for chronic LBP which aretargeted. For local primary chronic pain according to the chronic pain categories of
the International Association for the Study of Pain（IASP）, there is a possibility ofgetting a stronger effect so physicians should consider actively using SNRI according to the patient’s condition.
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P
I／C

Limitations
Selection summary

2005～2019
MEDLINE, Cochrane CENTRAL,NPO Japan Medical Abstracts Society
Mainly chronic low back pain, similar words to this（back pain, not acute, refractor, intractable, resistan, etc.）
SNRI, serotonin, duloxetine, milnacipran, venlafaxine etc.／nothing specified
We limited the test design to randomized controlled trial, meta－analysis, systematic review including chronic low back pain, and SNRI in the title
Of the 11 MEDLINE search hits, and 34 Cochrane CENTRAL search hits, we used 4 of themthat matched with the set PICO.

CQ J－7－2：Is tramadol useful for chronic low back pain（LBP）?
Answer：Tramadol is effective for the pain and dysfunction due to chronic LBP.
On the hand, there are many adverse events.

cost-effectiveness
ratio

480

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Recommendation Grade & Summary of Overall EvidenceRecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕

Summary of overall evidence：B（moderate）
Commentary：
The results of a systematic review were 6 references met the eligibility criteria
and 4 of the references were used for meta－analysis69－72). The items used for themeta－analysis were the Roland－Morris Disability Questionnaire（RMDQ）〔lumbarfunction〕, and the Short－Form McGill Pain Questionnaire（SF－MPQ）〔pain evaluation scale 〕, and in each of the outcomes, researchers indicated that tramadol usedalone（or tramadol ／ acetaminophen used in combination）significantly improved
these outcomes compared with the placebo. On the other hand, the degree of improvement was small so we are unable to say whether the effect exceeded clinicallyimportant difference and judged that the certainty of the synthesized evidence waslow.
Adverse events included nausea, vomiting, dizziness, drowsiness, constipation,
headache and insomnia, with adverse events significantly more frequent when tramadol was used alone（or tramadol／acetaminophen were used in combination）. Ina meta－analysis from the ‘Guidelines for Managing Low Back Pain（2019）’ on adverse events from tramadol, they found that the frequency of adverse events was
significantly more frequent from tramadol as compared with the placebo1).
PeriodDatabase
Words
searched

P
I／C

Limitations
Selection summary

2005～2019
MEDLINE, Cochrane CENTRAL,NPO Japan Medical Abstracts Society
Mainly chronic low back pain, similar words to this（back pain, not acute, refractor, intractable, resistan, etc.）
Tramadol etc.／nothing specified
We limited the test design to randomized controlled trial, meta－analysis, systematic review including chronic low back pain, and tramadol in the title
Of the 5 MEDLINE search hits, and 24 Cochrane CENTRAL 24 search hits, we used 4 ofthem that matched with the set PICO.

CQ J－7－3：Are nonsteroidal anti－inflammatory drugs（NSAIDs）useful forchronic low back pain（LBP）?
NSAIDs：nonsteroidal
anti-inflammatory
drugs

Answer：NSAIDs are effective on the pain intensity of chronic LBP and also dysfunction due to chronic LBP. However, they have a small effect.
Recommendation Grade & Summary of Overall EvidenceR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 95.0%〕

Summary of overall evidence：B（moderate）

J．Chronic Low Back Pain

481

Commentary：
In the results of a 2016 Cochrane systematic review73), researchers found 6 placebo－controlled study references（1,354 patients）that met the eligibility criteria andused them for a meta－analysis. The items used in the meta－analysis were VAS[pain indicator], RMDQ [function indicator], and adverse events. Research indicatedthat NSAIDs significantly improved the outcomes of pain and function as comparedwith the placebo, but the degree of improvement was small so we are unable tosay whether the effects exceeded a difference that was statistically significant andassessed that the certainty of the evidence was low. According to the IASP’s classifications of chronic pain, they do not recommend the use of NSAIDs for localized
chronic primary pain Note J2.
With adverse events, there was no statistical difference in the incidence rate ofNote J2：refer to
Chapter A. table A-1

events as compared with the placebo.
In the ‘Guidelines for Managing Low Back Pain（2019）’1), they utilized 4 references74－77). In terms of improved pain, they observed a tendency for reduced pain according to the meta－analysis of 2 research studies76,77), and in the other 2 researchstudies74,75)pain had significantly improved. There were 3 research studies which
considered its efficacy in improving function but as their evaluations methods weredifferent, it was not possible to perform a meta－analysis. In 2 of these researchstudies,75,76) researchers observed that it was effective in improving function but in
1 of the research studies they did not observe that it was effective.77). In a meta－
analysis on adverse events, they did not recognize a significant difference fromNSAIDs as compared with the placebo. However, we need to consider how only
subjective symptoms are detected when it comes to adverse events. With selective
COX－2 inhibitors, as there is the risk of side effects such as the upper gastrointestinal tract, and the cardiovascular system, one must pay attention to avoid any long－term administration without any clear aim in mindNote J3
PeriodDatabase
Search
words

P
I／C

Limitations
Selection summary

2005～2019
MEDLINE, Cochrane CENTRAL,NPO Japan Medical Abstracts Society
Mainly chronic low back pain, similar words（back pain, not acute, refractor, intractable, resistan, etc.）
NSAIDs, non－steroid etc.／placebo
We limited our test design to randomized controlled trial, meta－analysis, systematic review,
including chronic low back pain, tramadol in the title.
Of the 18 MEDLINE search hits, and 87 Cochrane CENTRAL search hits, we used 3 thatmatched with the set PICO but they were not suitable for meta－analysis. Therefore, we usedthe 2016 Cochrane systematic review.

CQ J－8：Is exercise therapy useful for chronic low back pain（LBP）?
Answer：Exercise therapy for chronic LBP is effective in improving pain, function and LBP－related QOL.

Note J3：refer to
Chapter C

482

J．Chronic Low Back Pain

Recommendation Grade & Summary of Overall EvidenceRecommendation grade：1（strong）：Implementation is strongly recommended〔Consensus 95.0%〕
Summary of total evidence：B（moderate）
Commentary：
There are many reports on the efficacy of exercise therapy on chronic LBP. In a2017 systematic review of non－drug therapies for treating chronic LBP by theAmerican College of Physicians（ACP）, researchers found that in addition to being
effective on chronic LBP, exercise therapy was also effective in improving dysfunction78). In particular, they found that in terms of reducing pain and physical disability in patients with chronic CBP, multidisciplinary biopsychosocial rehabilitation
MBR：multidisciplinary biopsychosocial rehabilitation（MBR）was more effective on pain and dysfunction than regular treatment or non－multidisciplinary biopsychosocial rehabilitation78). In a Cochrane systematic review
as well, researchers claimed that MBR was effective in reducing pain and dysfunc-

RCT：randomized
controlled trial

tion in patients with chronic LBP79). In RCTs conducted in Japan, although researchers did not observe a difference in intensity of LBP when they compared an
exercise group（strengthening of trunk muscles and stretching conducted 10 times,
with at least 2 sets／day）with a control group（NSAIDs taken orally）, LBP－related
QOL improved significantly in the exercise group80). However, at the current stage,
the types of effective therapeutic exercise and their long－term effects remain unclear1).
There has not been a rigorous investigation into the adverse events from exercise therapy but there have been many reports that adverse events are rare1).
In terms of cost－effectiveness, in an RCT on 3 different types of exercise therapy, the research described their effects in improving QOL and their QALY. However, there were no high－quality reports about the cost－effectiveness of these exercise therapies1).
PeriodDatabase
Words
searched

P
I／C

Limitations
Selection summary

2005～2019
MEDLINE, Cochrane CENTRAL,NPO Japan Medical Abstracts Society
Mainly chronic low back pain, similar words to this（back pain, not acute, refractor, intractable, resistan, etc.）
exercise, rehabil, physiotherp etc.／nothing specified
We limited our test design to randomized controlled trial, meta－analysis, systematic review including either chronic low back pain, exercise, rehabil, physiotherp in the title.
Of the 120 MEDLINE search hits, 139 Cochrane CENTRAL search hits, and 15 NPO Japan
Medical Abstracts Society search hits, we used 7 key papers that matched with the set PICO.

CQ J－9：Are patient education and behavioral psychological approaches
useful for chronic low back pain（LBP）?
Answer：Patient education and behavioral psychological approaches are effective

J．Chronic Low Back Pain

in improving pain cognition in patients with chronic LBP.
Recommendation Grade & Summary of Overall EvidenceRecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 95.2%〕

Summary of overall evidence：B（moderate）
Commentary：
The results of a systematic review found that 11 references met the eligibility
criteria, and were used for a meta－analysis81－91). As the contents of many of the research studies on patient education and behavioral psychological approaches weredifferent and also as there was a large number of research studies that used different interventions as the control for comparison, we were unable to secure a sufficient number of patients and research studies. The items used for the meta－analysis were the Roland－Morris Disability Questionnaire（RMDQ）[lumbar function] 81,82), and NRS [intensity of pain]82－84), and because the evaluation scales used foreach outcome, QOL, pain cognition and medical costs varied from one reference tothe next, we decided on a qualitative systematic review85－90).
For the 3 outcomes of function, intensity of pain and QOL, we did not observe adesirable affect from the intervention used. On the other hand, it indicated that it
might possibly improve pain cognition. The intervention group was on pair withthe control group for medical costs. In each of the outcomes, there was a high riskof performance bias and detection bias related to making the study blind, and inconsistencies were also found, therefore we assessed that the certainty of the synthesized evidence was low.
There were no reports of adverse events.
In terms of the cost－effectiveness of patient education and behavioral psychological approaches, there are RCTs that have reported on the cost－effectiveness ofgroup cognitive－behavioral therapy（GCBT）and face－to－face patient education
but, some opinions were positive whereas others were not, so it was not uniform.82,91). In patient education, with treatment that is included in the category of
informed consent for example, we believe the costs are at a level where they canbe basically ignored. On the other hand, in implementing a more specialized behavioral psychological approach, what is necessary are the costs to cover the humanresources who possess a set level of knowledge and the time required for the person in charge to implement patient education. In particular, we also assume thatnew persons in charge must be obtained for general hospitals. Another problem isthat in Japan, behavioral psychological approaches for chronic LBP are not covered
under the health insurance system at the moment.

483

484

J．Chronic Low Back Pain

PeriodDatabase
Words
searched

P
I／C

Limitations
Selection summary

2005～2019
MEDLINE, Cochrane CENTRAL,NPO Japan Medical Abstracts Society
Mainly chronic low back pain, words similar to this（back pain, not acute, refractor, intractable, resistan, etc.）
patient education, behavior therapy, psycho therapy etc.／nothing specified
We limited our test design to randomized controlled trial, meta－analysis, systematic review,
including either chronic low back pain, patient education, behavior therapy, or psychotherapy
in the title.
Of the 38 MEDLINE search hits, 78 Cochrane CENTRAL search hits, and 9 NPO Japan Medical Abstracts Society search hits, we used 11 that matched with the set PICO.

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combination tablets（Ultracet）in treatment of chronic low back pain : A
multicenter, outpatient, randomized, double blind, placebo controlled trial. J
Rheumatol 2004 ; 12 : 2454－2463. PMID : 15570651
73）‌Enthoven WT, et al : Non－steroidal anti－inflammatory drugs for chronic low
back pain. Cochrane Database Syst Rev, 2016 Feb 10 ; 2 ; 2 : CD012087. doi : 10.
1002/14651858.CD012087. PMID : 26863524
74）‌Berry H, et al : Naproxen sodium, diflunisal, and placebo in the treatment ofchronic back pain. Ann Rheum Dis 1982 ; 41 : 129－132. doi : 10.1136/ard.41.2.
129. PMID : 6462116
75）‌Birbara CA, et al : Treatment of chronic low back pain with etoricoxib, a new
cyclo－oxygenase－2 selective inhibitor : Improvement in pain and disability : A
randomized, placebo－controlled, 3－month trial. J Pain 2003 ; 4 : 307－315.
doi : 10.1016/s1526－5900（03）00633－3. PMID : 14622687
76）‌Kivitz AJ, et al : Efficacy and safety of tanezumab versus naproxen in thetreatment of chronic low back pain. Pain 2013 ; 154 : 1009－1021. doi : 10.1016/
j.pain.2013.03.006. PMID : 23628600
77）‌Katz N, et al : Efficacy and safety of tanezumab in the treatment of chronic
low back pain. Pain 2011 ; 152 : 2248－2258. doi : 10.1016/j.pain.2011.05.003.
PMID : 21696889
78）‌Chou R, et al : Nonpharmacologic therapies for low back pain : A systematic
review for an American College of Physicians Clinical Practice Guideline.
Ann Intern Med 2017 ; 166 : 493－505. doi : 10.7326/M16－2459. PMID : 28192793
79）‌Kamper SJ, et al : Multidisciplinary biopsychosocial rehabilitation for chronic
low back pain : Cochrane systematic review and meta－analysis. BMJ
2015 ; 350 : h444. doi : 10.1136/bmj.h444. PMID : 25694111
80）‌Shirado O, et al : Multicenter randomized controlled trial to evaluate the effect of home－based exercise on patients with chronic low back pain : The Ja-

J．Chronic Low Back Pain

pan low back pain exercise therapy study. Spine（Phila Pa 1976）,2010 ; 35 : E811－E819. doi : 10.1097/BRS.0b013e3181d7a4d2. PMID : 20628332
81）‌Pincus T, et al : Delivering an optimised behavioural intervention（OBI）topeople with low back pain with high psychological risk : Results and lessons
learnt from a feasibility randomised controlled trial of contextual cognitive
behavioural therapy（CCBT）vs. physiotherapy. Musculoskelet Disord 2015 ;16 : 147. doi : 10.1186/s12891－015－0594－2. PMID : 26076755
82）‌Werner EL, et al : Cognitive Patient Education for Low Back Pain in Primary
Care : A Cluster Randomized Controlled Trial and Cost－Effectiveness Analysis. Spine（Phila Pa 1976）2016 ; 41 : 455－462. doi : 10.1097/BRS.000000000000
1268. PMID : 26966970
83）‌Glombiewski JA, et al : Two psychological interventions are effective in severely disabled, chronic back pain patients : A randomised controlled trial. J
Behav Med 2010 ; 17 : 97－107. doi : 10.1007/s12529－009－9070－4. PMID : 19967572
84）‌Christiansen S, et al : A short goal－pursuit intervention to improve physicalcapacity : A randomized clinical trial in chronic back pain patients. Pain
2010 ; 149 : 444－452. doi : 10.1016/j.pain.2009.12.015. PMID : 20199846
85）‌Paolucci T, et al : Psychological features and outcomes of the Back School
treatment in patients with chronic non－specific low back pain : A randomized
controlled study. Eur J Phys Rehabil Med 2012 ; 48 : 245－53. PMID : 22095057
86）‌Cherkin DC, et al : Effect of mindfulness－based stress reduction vs cognitive
behavioral therapy or usual care on back pain and functional limitations inadults with chronic low back pain : A randomized clinical trial. JAMA 2016 ;315 : 1240－1249. doi : 10.1001/jama.2016.2323. PMID : 27002445
87）‌Linden M, et al : Randomized controlled trial on the effectiveness of cognitive
behavior group therapy in chronic back pain patients. J Back Musculoskelet
Rehabil 2014 ; 27 : 563－568. doi : 10.3233/BMR－140518. PMID : 25096315
88）‌Carpenter KM, et al : An online self－help CBT intervention for chronic lower
back pain. Clin J Pain 2012 ; 28 : 14－22. doi : 10.1097/AJP.0b013e31822363db.
PMID : 21681084
89）‌Turner JA, et al : Mindfulness－based stress reduction and cognitive behavioral therapy for chronic low back pain : Similar effects on mindfulness, catastrophizing, self－efficacy, and acceptance in a randomized controlled trial. Pain
2016 ; 157 : 2434－2444. doi : 10.1097/j.pain.0000000000000635. PMID : 27257859
90）‌Herman PM, et al : Cost－effectiveness of mindfulness－based stress reduction
versus cognitive behavioral therapy or usual care among adults with chronic
low back pain. Spine（Phila Pa 1976）2017 ; 42 : 1511－1520. doi : 10.1097/BRS.
0000000000002344. PMID : 28742756
91）‌Lamb SE, et al : Group cognitive behavioural treatment for low－back pain inprimary care : A randomised controlled trial and cost－effectiveness analysis.
Lancet 2010 ; 375（9718）: 916－923. doi : 10.1016/S0140－6736（09）62164－4. PMID :20189241489

Chapter K．Knee Osteoarthritis（Knee OA）：CQ K-1～CQ K-4
CQ K-1：What kind of illness is knee osteoarthritis（knee OA）?
CQ K-2：Are chondroitin and glucosamine useful for knee
osteoarthritis（knee OA）?
CQ K-3：Is an intra-articular injection of hyaluronic acid useful forknee osteoarthritis（knee OA）?
CQ K-4：Is total knee arthroplasty（TKA）useful for knee osteoarthritis（knee OA）when conservative therapies are ineffective at a progressed stage of the illness ?

492

K．Knee Osteoarthritis（Knee OA）

K．Knee Osteoarthritis（Knee OA）
CQ K－1：What kind of illness is knee osteoarthritis（knee OA）?
Answer：Knee osteoarthritis（knee OA）is a regressive degenerative disease of
ADL：activities of dailyliving
QOL：quality of life

the knee joints causing pain restricting activities of daily living（ADL）. It has anextremely high prevalence rate and is a severe illness that threatens the quality oflife（QOL）of middle－aged and senior citizens. The goals of treatment are to improve physical function and alleviate the symptoms such as pain and stiffness.
Commentary：

OA：osteoarthritis

Osteoarthritis（OA）is a regressive degenerative disease which typically causes
proliferative changes that frequently occur in the joint structures such as bones
and synovium membrane, as well as changes and wear to articular cartilage. Thereis a high incidence of OA for example in the hands, hip and knees and the prevalence rate is especially high in knee OA. It inhibits ADL in middle－aged and seniorcitizens and causes a remarkable deterioration in the QOL. The number of people
suffering from knee OA in Japan is estimated to be approximately 25 million people
according to X－ray, of which 8 million people are estimated to have symptomaticknee OA, displaying pain symptoms1).
Diagnosis is made according to clinical symptoms and simple X－ray findings.
Typical symptoms include pain, stiffness, swelling, and restricted movement. Painmainly occurs while moving and as the condition progresses, it may also be accompanied by for example pain at rest and pain during the night. Symptoms are often
aggravated when going upstairs, rather than walking on level ground, and in Japanese lifestyles rather than Western ones. In a plain X－ray test, images are takenfrom 3 directions：standing anteroposterior, lateral and an axial images. With thestage classifications that are used for X－rays of knee OA, the Kellgren－Lawrenceclassifications is widely used；it is graded on a 5－point scale from Grade 0～4, focusing on things like osteophyte formation, joint space narrowing（JSN）, and subchondral bone sclerosis.
As no clear disease－modifying anti－OA drugs currently exist, the goal of treatment is to improve physical function and alleviate symptoms such as pain and stiffness. At the X－ray stage, many things are not related to the symptoms so it is recommended to assess, in addition to the imaging findings, the symptoms and degreeof dysfunction, the age and level of activity of the patient and also consider the patient’s lifestyle and values when making an overall assessment.
Treatment of knee OA can be broadly divided into conservative treatment andsurgical treatment and no matter what stage it is, we recommend conducting con-

K．Knee Osteoarthritis（Knee OA）

servative treatment first. Within conservative treatment, what should be conductedfirst is patient education, exercise therapy and reducing the weight for patients
who are overweight. Its usefulness is evaluated both from the aspects of efficacy
and safety, and has high cost－effectiveness and so it should be the first line of treatment for knee OA2) . Exercise therapy not only alleviates symptoms but also has
the effect of improving physical function and so it should be the central form oftreatment, and for the contents of the exercise therapy, researchers recommend
muscle training, aerobic exercise, and range of motion（ROM）training. For further
details about exercise therapy, we would like to refer you to the chapter G on ‘rehabilitation.’
In pharmacotherapy, oral and topical nonsteroidal anti－inflammatory drugs（NSAIDs）, acetaminophen, tramadol, opioid analgesics, and duloxetine for example
are used to treat OA. Furthermore, in terms of injection therapy, hyaluronic acidand steroids are injected into the joint. The recommendation grades for each drug
vary slightly depending on the guidelines. For more details, we wish to refer you tothe latest international guidelines2,3) that were published in 2019 by the Osteoarthritis Research Society International and American College of Rheumatology.
If conservative treatments are unsuccessful and pain and dysfunction persist,then surgical treatments should be considered. Surgery can be broadly divided into
joint－sparing surgery, which is typically represented by a high tibial osteotomy（HTO）and joint replacement. Generally, joint－sparing surgery applies in cases ofunicompartmental OA in relatively young patients who are highly active and withmild deformations, whereas joint replacement applies in elderly patients with ahigher degree of deformations. Knee OA is a disease that progresses into thechronic stage and therefore specialists should carefully consider the patient’s lifestyle and their values throughout their career and consider the applicability of thesurgical method and the best timing.

CQ K－2：Are chondroitin and glucosamine useful for knee osteoarthritis（knee OA）?
Answer：We are unable to say with clinical significance that chondroitin and glucosamine are effective in improving ADL and as an analgesic. The chondroitin andglucosamine that are used in high－quality clinical trials are not the same formulation as those commonly used in Japan.
Recommendation Grade & Summary of Overall Evidence
1）Chondroitin
Recommendation grade：No recommendation〔Consensus 94.4%〕

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K．Knee Osteoarthritis（Knee OA）

Summary of overall evidence：B（moderate）
2）Glucosamine
Recommendation grade：No recommendation〔Consensus 94.7%〕
Summary of overall evidence：B（moderate）
Commentary：1）Chondroitin
We used 5 randomized controlled trials（RCTs）which had investigated the effects of chondroitin on patients with pain due to knee OA4－8). The dosage of chondroitin used ranged from between 400～1,500mg, the period of administration was
wide and varied with chondroitin administered over a period of 6 months in 2 of
the RCTs, and 2 years in 3 RCTs, with a high risk of indirectness we conducted aqualitative review instead of a meta-analysis. In 2 of the reports4,7)researchers observed a significant difference in analgesic effect between chondroitin and the placebo but the improvement was not recognized to be clinically significant. In 1 report,7) researchers observed a significant difference in the effects of improved ADL
from chondroitin as compared with the placebo but the difference in the effect was
8)small. Limited to reports without conflict of interest（COI）, researchers did notobserve that chondroitin was effective. Researchers observed mild side effects（gastrointestinal disorders, stomachache, nausea）in 4.0～8.5％ of the patients but
did not observe any severe side effects and the there was no significant differencecompared with the placebo. Based on the above, chondroitin may be slightly effective on knee OA but its efficacy was not indicated in reports without COI, meaningthat chondroitin has low usefulness.
2）Glucosamine
We used 2 randomized controlled trials（RCTs）which had investigated the effects of glucosamine on patients with pain due to knee OA7,8). The dosages of glucosamine administered were 1,500 mg and 753 mg, and the administration periods
were not consistent either with 6 months and 2 years, with a high indirect risk, andno meta－analysis, we conducted a qualitative review. Neither report recognized asignificant difference in analgesic effect and improved ADL between the glucosamine group and placebo group. They observed mild side effects（gastrointestinal
disorders, rash）in 1.3～2.8％ of the patients but did not observe any severe side
effects and there was no significant difference when compared with the placebo.
Based on the above, glucosamine is not useful on knee OA.
If chondroitin and glucosamine are taken appropriately, they are probably safe
but there have been some case reports of side effects so some matters remain unclear. Furthermore, one also needs to consider the aspect of how it might encourage polypharmacy, which has become a problem among the elderly, as well as theburden of costs for the patient.

K．Knee Osteoarthritis（Knee OA）

PeriodDatabase
Words
searched

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Limitations
Selection Summary

2005～2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
knee osteoarthritis
chondroitin, glucosamine, placebo
Randomized controlled trials（RCTs）
Of the 35 Pubmed search hits and 7 Cochrane CENTRAL search hits, we used 5 that matchedwith the set PICOCQ K－3：Is an intra－articular injection of hyaluronic acid useful for knee
osteoarthritis（knee OA）?
Answer：An intra－articular injection of hyaluronic acid may possibly have aslightly effect on improving pain and ADL.
Recommendation Grade & Summary of Overall EvidenceRecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕

Summary of overall evidence：B（moderate）
Commentary：
Intra－articular hyaluronic acid（IAHA）is covered under the Japanese health insurance system as a treatment for knee OA and so it is a widely used form oftreatment. However, according to the international guidelines reported by theAmerican College of Rheumatology（2019）and Osteoarthritis Research Society International（2019）, there is not a consistent viewpoint regarding its usefulness. This
time we did a systematic review of an RCT on IAHA, in which an intra－articular
injection of saline solution was used as the control.
After the results of our citation search, we considered 5 RCTs that were applicable. We were unable to do a meta－analysis as the outcomes set varied from one research paper to the next so we conducted a qualitative systematic review. In 2 papers9,10) researchers recognized a statistically－significant difference in efficacy（analgesic effect, effect on improving ADL）in the IAHA group, compared with thecontrol group, whereas in the other 3 papers11－13), they did not recognize a difference and there was no consistency among the papers. Furthermore, in 1 of the 2
research studies that recognized that IAHA was effective, they acknowledged a9)conflict of interest（COI）. We were unable to conduct a meta－analysis on the 5 re-search papers we considered and the amount of research and sample size in each
one was small and as there were strong inconsistencies in the results, we cannot
say that the evidence is sufficiently strong. There were no severe side effects recognized from IAHA and therefore we can say that there are no major problems interms of its safety. Mild side effects were observed in both the IAHA group and

495

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K．Knee Osteoarthritis（Knee OA）

control group, such as pain at the site of puncture from the injection, bleeding, stiffness, joint pain, and allergic－type reactions9).
Considering the above results and the current situation with this form of treatment in Japan, there are no severe side effects from IAHA, it is a form of treatment which may have a slight effect and so we decided that “implementation is
weakly recommended.” However, there are many unclear aspects on the usefulnessof continuing to administer IAHA and so if it has a poor effect, then care should betaken to ensure that it is not administered for a long period of time without a clear
and specific aim in mind.
PeriodDatabase
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January 2005－December 2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
chronic pain, knee osteoarthritis
hyaluronic acid／placebo
Randomized controlled trial
Of the 11 PubMed search hits, 40 Cochrane CENTRAL search hits, and 1 NPO Japan Medical
Abstracts Society search, we used 5 search hits that matched with the set PICOCQ K－4：Is total knee arthroplasty（TKA）useful for knee osteoarthritis（knee OA）when
conservative therapies are ineffective at a progressed stage of the illness ?
TKA：total knee
arthroplasty

Answer：Total knee arthroplasty（TKA）for patients with knee OA at a progressed stage of the illness, and who have been resistant to conservative forms oftreatments and with deteriorated joint function, is useful for its effects in improving
pain and ADL over the mid and long term.
Recommendation Grade & Summary of Overall EvidenceR ecommendation grade：1（strong）：Implementation is strongly recommended〔Consensus 100.0%〕
Summary of overall evidence：C（low）
Commentary：
As total knee arthroplasty（TKA）is used as a final treatment for patients whereconservative treatments have proved to be ineffective, there are extremely few
clinical trials which have been conducted with the purpose of comparing it withother treatment methods. On this systematic review, we only targeted RCTs thatcompared TKA with conservative treatment and ran a search for citations. We selected 3 research papers but although what they had in common was the original

Note K1：ClinicalTrials.gov NCT01410409

clinical trialsNote K1, they differed in their follow－up periods, what they compared
TKA against, and which items they evaluated. In 2 research papers that evaluatedit 1 year after surgery and 2 years after surgery, researchers found that analgesic
pain and improved ADL were significantly superior in the group where TKA had

K．Knee Osteoarthritis（Knee OA）

been performed rather than in the conservative treatment group14,15). In 1 research
paper which evaluated pain at 3 months after surgery, researchers did not observea significant difference between the two groups in their analgesic effects16). However, 3 months later, there was lingering wound pain is commonly observed 3 months
after the procedure, and this may have affected the results. In 1 research study
which evaluated complications, they reported that in the group which had undergone TKA, there were complications such as stiffness that required joint mobilization, deep vein thrombosis that required anticoagulant therapy, periarticular infection, and supracondylar fracture of the femur16).
There was only 1 RCT and the group that underwent TKA was small at just 50
patients so the evidence was insufficient. However, in a report on the mid－and long－term effects that TKA had in analgesic effect and improving ADL, there is an incredibly large number of research papers in the past, which are observational studies and so there is almost no scope for discussion on its efficacy, we believe. On theother hand, surgery may possibly cause severe complications and so in principle itshould be applied when conservative treatments have proven ineffective and there
is end-stage knee OA with deterioration of joint function. In addition, even thoughknee pain may clearly decrease and ADL improve prior to the operation, it is recommended that physicians explain to the patients before surgery that one sees
persistent postoperative pain（PPP）in around 20% of the cases. The eligibility criteria for surgery, which we wish to refer you to, are “an Oxford knee score of 26 or
below or a varus or valgus deformity” according to the UK’s NHS（National HealthService）and “when there are moderate－level or high－level osteoarthritic changes
according to the X－ray”, when complications have been adequately controlled andthese have continued for 18 weeks or longer17). Finally, it is necessary to take into
consideration aspects such as the individual patient’s age, level of activity, illness
complications as well as his／her values and lifestyle when considering TKA.
PeriodDatabase
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2005～2019
PubMed, Cochrane CENTRAL, NPO Japan Medical Abstracts Society
knee osteoarthritis
TKA／non－surgicalRandomized controlled trial, other（guidelines, notifications）etc.
Of the 7 PubMed 7 search hits, 35 Cochrane CENTRAL search hits, we used 4 search hits
that matched with the set PICO

References
1）‌Muraki S, et al : Prevalence of radiographic knee osteoarthritis and its association with knee pain in the elderly of Japanese population－based cohorts :The ROAD study. Osteoarthritis Cartilage 2009 ; 17 : 1137－1143. doi : 10.1016/j.
joca.2009.04.005. PMID : 19410032
2）‌Bannuru RR, et al : OARSI guidelines for the non－surgical management ofknee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage 2019 ; 27 :
1578－1589. doi : 10.1016/j.joca.2019.06.011. PMID : 31278997

497

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3）‌Kolasinski SL, et al : 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, andKnee. Arthritis Rheumatol 2020 ; 72 : 220－233. doi : 10.1002/art.41142. PMID :31908163
4）‌Mazières B, et al : Effect of chondroitin sulphate in symptomatic knee osteoarthritis : A multicentre, randomised, double－blind, placebo－controlled study.
Ann Rheum Dis 2007 ; 66 : 639－645. doi : 10.1136/ard.2006.059899. PMID :17204566
5）‌Clegg DO, et al : Glucosamine, chondroitin sulfate, and the two in combination
for painful knee osteoarthritis. N Engl J Med 2006 ; 354 : 795－808. doi : 10.1056/
NEJMoa052771. PMID : 16495392
6）‌Fransen M, et al : Glucosamine and chondroitin for knee osteoarthritis : A
double－blind randomised placebo－controlled clinical trial evaluating single
and combination regimens. Ann Rheum Dis 2015 ; 74 : 851－858. doi : 10.1136/
annrheumdis－2013－203954. PMID : 24395557
7）‌Reginster JY, et al : Pharmaceutical－grade chondroitin sulfate is as effective
as celecoxib and superior to placebo in symptomatic knee osteoarthritis : The
ChONdroitin versus CElecoxib versus Placebo Trial（CONCEPT）. Ann
Rheum Dis 2017 ; 76 : 1537－1543. doi : 10.1136/annrheumdis－2016－210860.
PMID : 28533290
8）‌Michel BA, et al : Chondroitins 4 and 6 sulfate in osteoarthritis of the knee : A
randomized, controlled trial. Arthritis Rheum 2005 ; 52 : 779－786. doi : 10.1002/
art.20867. PMID : 15751094
9）‌Navarro－Sarabia F, et al : A 40－month multicentre, randomised placebo－controlled study to assess the efficacy and carry－over effect of repeated intra－
articular injections of hyaluronic acid in knee osteoarthritis : The AMELIAproject. Ann Rheum Dis 2011 ; 70 : 1957－1962. doi : 10.1136/ard.2011.152017.
PMID : 21852252
10）‌Huang T－L, et al : Intra－articular injections of sodium hyaluronate（Hyalgan®）in osteoarthritis of the knee : A randomized, controlled, double－blind, multicenter trial in the Asian population. BMC Musculoskelet Disord 2011 ; 12 : 221.
doi : 10.1186/1471－2474－12－221. PMID : 21978211
11）‌van der Weegen W, et al : No difference between intra－articular injection of
hyaluronic acid and placebo for mild to moderate knee osteoarthritis : a randomized, controlled, double－blind trial. J Arthroplasty 2015 ; 30 : 754－757.
doi : 10.1016/j.arth.2014.12.012. PMID : 25548079
12）‌Jørgensen A, et al : Intra－articular hyaluronan is without clinical effect inknee osteoarthritis : A multicentre, randomised, placebo－controlled, double－
blind study of 337 patients followed for 1 year. Ann Rheum Dis 2010 ; 69 : 1097－
1102. doi : 10.1136/ard.2009.118042. PMID : 20447955
13）‌Lundsgaard C, et al : Intra－articular sodium hyaluronate 2 mL versus physiological saline 20 mL versus physiological saline 2 mL for painful knee osteoarthritis : A randomized clinical trial. Scand J Rheumatol 2008 ; 37 : 142－150.
doi : 10.1080/03009740701813103. PMID : 18415773
14）‌Skou ST, et al : Total knee replacement and non－surgical treatment of knee
osteoarthritis : 2－year outcome from two parallel randomized controlled trials.
Osteoarthritis Cartilage 2018 ; 26 : 1170－1180. doi : 10.1016/j.joca.2018.04.014.
PMID : 29723634
15）‌Skou ST, et al : A randomized, controlled trial of total knee replacement. New
Eng J Med 2015 ; 373 : 1597－1606. doi : 10.1056/NEJMoa1505467. PMID : 26488691
16）‌Skou ST, et al : The effects of total knee replacement and non－surgical treat-

K．Knee Osteoarthritis（Knee OA）

ment on pain sensitization and clinical pain. Eur J Pain 2016 ; 20 : 1612－1621.
doi : 10.1002/ejp.878. PMID : 27029553
17）‌NHS Prior Approval Procedures. https : //www.neneccg.nhs.uk/document－library/trauma.Htm

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Chapter L．Chronic Neck and Shoulder Pain
（Katakori）：CQ L-1～CQ L-6
CQ L-1：What is the pathology of chronic neck and shoulder pain
（Katakori）?
CQ L-2：Which elements are useful for diagnosing and evaluating
chronic neck and shoulder pain（Katakori）?
CQ L-3：Is pharmacotherapy useful for chronic neck and shoulder
pain（Katakori）?
CQ L-4：Are interventional treatments useful for chronic neck andshoulder pain（Katakori）?
CQ L-5：Which elements of non-drug and non-invasive therapy areuseful for treating chronic neck and shoulder pain
（Katakori）?
CQ L-6：Is there a useful way to prevent chronic neck and shoulder
pain（Katakori）?

502

L．Chronic Neck and Shoulder Pain（Katakori）

L．Chronic Neck and Shoulder Pain（Katakori）
CQ L－1：What is the pathology of chronic neck and shoulder pain（Katakori）?
Answer：Chronic neck and shoulder pain（called “Katakori” in Japanese）is generally considered to be dull pain, discomfort, and muscle tension from the posterior
region of the neck spreading to the shoulders and researchers have indicated thatmany women have it, and is associated with sleep, build, work content, and psychological condition. However, this does not necessarily mean that we have clarified
everything on the pathology of chronic neck and shoulder pain（Katakori）.
Commentary：
The expression ‘chronic neck and shoulder pain（Katakori）’ is unique to Japan；
and is generally believed to be discomfort, dull pain, and a feeling of heaviness fromthe posterior neck region to the scapula and surrounding regions1). However, it ismainly assessed on subjective symptoms alone；there is no consensus on standardized diagnostic criteria or its symptom recognition site1). Chronic neck and shoulder
pain（Katakori）can be divided into one with an unclear underlying（primary）condition and a symptomatic type with a clear primary disease（secondary：orthopedic disease, a surgical disease, an internal medicine disease, otorhinolaryngologicaldisease, ophthalmic disease, psychiatric disorder, dental disease）. The category ofsymptomatic chronic neck and shoulder pain（Katakori）can also include severe illnesses such as tumor, infection and neurological disorders2). The complaint rate forchronic neck and shoulder pain（Katakori）is incredibly high, with approximately
6% of males, and 13% of females reported to suffer from this condition3), and the incidence rate of new cases of severe chronic neck and shoulder pain（Katakori）
among workers over 1 year was claimed to be approximately 3%2). Furthermore,
the amount of work estimated to be lost due to chronic neck and shoulder pain
（Katakori）is so large that it is regarded as a problem4). Furthermore, researchers
have cited that the risk factors for onset including being a woman, lack of sleep（sleeping for less than 5 hours a night）, work－related depressive mood, loss oftrunk muscle mass, and deskwork2,5). On the other hand, regarding morphologicalchanges to muscle tissue, with trapezius（muscle）myalgia, which displays similar
symptoms to chronic neck and shoulder pain（Katakori）, some researchers havereported that the trapezius muscle fibers change exclusively in women6). However,as the research study did not target Japanese patients, the evidence on this is limited.

L．Chronic Neck and Shoulder Pain（Katakori）

503

CQ L－2：Which elements are useful for diagnosing and evaluating chronic neckand shoulder pain（Katakori）?
Answer：Although researchers have indicated that the elements for diagnosing
and evaluating chronic neck and shoulder pain（Katakori）might possibly relate toupper－back pain and a reduction in the size of the cervical muscles, as well as a decline in blood flow and oxygen saturation in the trapezius muscles, there is limited
evidence to conclude that this is useful. Furthermore, level of satisfaction with one’s
workplace environment, position of the keyboard, repeating the same type of work,and subjective muscle tone are the elements related to the onset of work－related
neck pain.
Commentary：
Researchers have indicated a decrease in the volume of multifidus muscle, longus
colli muscle and the semispinalis capitis muscle in people with neck pain7). Furthermore, there have been reports that compared with healthy subjects, researchers
observed a decrease in blood flow in the trapezius muscle and a decrease in oxygenated hemoglobin in people with upper－back muscular pain when at rest, when
performing work involving the upper limbs（typing, hand grip）, and during coldpressor stimulation4).
The risk factors related to the onset of non－specific chronic neck pain from office
work that were extracted were：low level of satisfaction with one’s workplace environment（RR 1.28；CI 1.07～1.55）, the keyboard is positioned too close to thetrunk（RR 1.46；CI 1.07～1.99）, having monotonous work tasks（RR 1.27；CI 1.08
～1.50）, and high subjective muscle tension（RR 2.75／1.82；CI 1.60／1.14～4.72／
2.905).
These results are based on research studies conducted outside of Japan andtherefore they act as limited evidence on their usefulness in diagnosing and evaluating ‘chronic neck and shoulder pain（Katakori）’.

CQ L－3：Is pharmacotherapy useful for chronic neck and shoulder pain
（Katakori）?
Answer：Non－steroidal anti－inflammatory drugs（NSAIDs）may possibly improve cervical dysfunction due to chronic neck and shoulder pain（Katakori）in the
short term and in terms of its analgesic effect, it is believed to be more effective
when used in combination with other treatments, rather than when used alone.
However, the certainty of the evidence on its effects is very low and on top of this,researchers have not recognized the usefulness of pharmacotherapy using for ex-

NSAIDs：nonsteroidal
anti-inflammatory
drugs

504

L．Chronic Neck and Shoulder Pain（Katakori）

ample capsaicin.
Recommendation Grade & Summary of Overall EvidenceR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕
under certain conditions（limited to NSAIDs only）

Summary of overall evidence：C（low）
Commentary：
We conducted a meta－analysis using 8 RCTs that investigated the effects ofpharmacotherapy on chronic neck and shoulder pain（Katakori）. The only drugs
we extracted were NSAIDs, local anesthetics, and capsaicin；no other RCTs investigating the effects of other drugs on chronic neck and shoulder pain（Katakori）
exist.
As a result, researchers observed that patch NSAIDs may possibly improve cervical dysfunction due to chronic neck and shoulder pain（Katakori）over the shortterm, more than menthol patches9). Furthermore, other researchers indicated that
NSAIDs may possibly have a higher immediate analgesic effect when used in combination with physical therapy（hot packs and transcutaneous electrical nerve stimulation（TENS））or acupuncture, rather than when used alone10,11). However, ineach case, the amount of research conducted and sample size were very small andtherefore we need to take plenty of care when interpreting these results. In addition, there are no reports which have investigated its mid－to long－term effects andtherefore we do not recommend using NSAIDs without some clear purpose inmind. What is more, the effects of using a local anesthetic or capsaicin comparedwith a placebo were unclear12,13). In addition, the effects of these drugs on neck moQOL：quality of life

bility, the pressure pain threshold and QOL were around the same as those of other treatments and the placebo and therefore researchers did not acknowledge theusefulness of pharmacotherapy.
Furthermore, as there are no high－quality research papers targeting Japanesepatients, there is no conclusive evidence which can allow us to conclude that thetarget of these research studies was chronic neck and shoulder pain（Katakori）

Note L1：Please refer
to Chapter C forpharmacotherapy on
diseases and symptoms other thanchronic neck andshoulder pain（Katakori）.

and therefore we believe the certainty of the evidence is very lowNote L1.
PeriodDatabase
Words
searched

P
I／C

Limitations
Selection summary

2010～2019
PubMed, Cochrane Library, NPO Japan Medical Abstracts Society
neck shoulder pain, neck and shoulder pain, trapezius myalgia, work related neck shoulder
pain, work related trapezius myalgia, chronic neck pain, myofascial pain, neck pain
pharmacological, medication, NSAIDs, acetaminophen, kampo, muscle relaxant, antianxiety,benzodiazepine, eperisone, myonal, telnelin, baclofen, indometacin, patch, poultice, compress,
ointment, cream, liniment／nothing specified
Review ; Systematic Reviews ; Meta－Analysis ; Randomized Controlled Trial ; published in thelast10 years ; English
We extracted 501 PubMed search hits, 32 Cochrane Library search hits, and 11 NPO Japan
Medical Abstracts Society search hits, and compared them alongside PICO and confirmed thedata etc., and ultimately conducted a meta－analysis using 8 RCTs

L．Chronic Neck and Shoulder Pain（Katakori）

505

CQ L－4：Are interventional treatments useful for chronic neck and shoulder
pain（Katakori）?
Answer：Trigger－point injections（TPI）might possibly be effective on chronicneck and shoulder pain（Katakori）which have trigger point and muscle stiffness.
However, one must be careful about continuing to perform them without any clear
aim in mind and one must consider the period of treatment as well. There is a lackof evidence regarding other forms of interventional treatment and therefore its usefulness is unclear.
Recommendation Grade & Summary of Overall Evidence
Recommendation grade：No recommendation〔Consensus 100.0%〕
Summary of overall evidence：C（low）
Commentary：
We performed a meta－analysis using 14 RCTs which investigated the effects ofinterventional treatments on chronic neck and shoulder pain（Katakori）. The interventional treatments that we extracted were mainly TPI. TPI can be divided into
the procedures of dry needlingNote L2（a procedure in which only a puncture is madewithout injecting a liquid medicine）and a drug injection（local anesthetic, botulinum toxin）. TPI used for chronic neck and shoulder pain（Katakori）which havetrigger point and muscle stiffness
Researchers have observed that dry needling could possibly improve pain, dysfunction, neck mobility, muscle conditions（pressure pain threshold）, and QOL bothover the short－and mid－term, compared with other treatments（trigger－point man14－16)
ual pressure, stretching）. Local anesthetic may possibly have a higher analgesic

effect over the short－term than dry needling and placebo injections but its effects
on dysfunction, muscle condition and QOL was unclear17). On the other hand, a botulinum toxin injection had no significant difference18) when compared with a placebo injection and on top of this, one needs to consider its side－effects and the problem with it being ineligible to be covered under the health insurance system so we
do not recommend it.
Pain at the injection site and bleeding for example have been reported as adverse events from TPI but there have been few reports of severe adverse events.
However, as there have been a poor number of reports which have investigated its
long－term effects, one needs to be careful about continuing to perform TPI without
any clear aim in mind. As for other interventional treatments, there is a lack ofhigh－quality evidence and so we were unable to confirm their usefulness. Furthermore, there are no high－quality research studies which have targeted Japanese
subjects and we have no conclusive evidence which allow us to say with certainty

Note L2：Technique isdifferent fromacupuncture

506

L．Chronic Neck and Shoulder Pain（Katakori）

that these reports targeted chronic neck and shoulder pain（Katakori）so we believe the certainty of the evidence is low.
PeriodDatabase
Words
searched

P
I／C

Limitations
Selection summary

2010～2019
PubMed, Cochrane Library, NPO Japan Medical Abstracts Society
neck shoulder pain, neck and shoulder pain, trapezius myalgia, work related neck shoulder
pain, work related trapezius myalgia, chronic neck pain, myofascial pain, neck pain
trigger points, myofascial trigger points, injections, needlesdry needling, hydrodissection, hydrorelease, myofacial release, nerve root block, stellate ganglion block, botulinum type A toxin,
invasive techniques, saline, ozone, lidocaine, hyaluronidase, steroid, corticosteroid, wet needling,
local anesthetic／Nothing specified
meta－analysis, randomized controlled trial, systematic review, review, guideline filters : published in the last10 years
We extracted 1,038 PubMed search hits, 8 Cochrane Library search hits, and 37 NPO Japan
Medical Abstracts Society search hits, compared them with PICO and confirmed the data etc.,
and ultimately performed a meta－analysis using 14 RCTs. We also used 2 systematic reviews
that we had deemed useful as supplementary information

CQ L－5：Which elements of non－drug and non－invasive therapy are useful fortreating chronic neck and shoulder pain（Katakori）?
Answer：With non－drug and non－invasive treatments for chronic neck andshoulder pain（Katakori）（exercise therapy, physical therapy, patient education／behavioral psychology approaches, manual therapy, and complementary and alternative medicine）, researchers have indicated that exercise therapy（using several exercise programs in combination）, physical therapy（low－level laser therapy）andcomplementary and alternative medicine（acupuncture）are effective in improving
pain and dysfunction over the short－term. However, it remains unclear what the
mid－term～long－term effects are for each of these interventional methods.
Commentary：
In a systematic review19) which investigated the efficacy of non－drug and non－invasive treatments for chronic neck and shoulder pain（Katakori）（exercise therapy,
physical therapy, patient education ／ behavioral psychology approaches, manual
therapy, and complementary and alternative medicine）, researchers reported that
although each respective exercise therapy（such as muscle－strengthening exercises, flexibility ／ stretching exercises, aerobic exercise, yoga and pilates）performed
alone, had a poor effect on improving pain and dysfunction and although there wasno difference between the exercise programs20) , when used in combination, theyNote L3：Refer to CQ
G-1 for exercise
therapy and CQ G-3
for physical therapy on
diseases and symptoms other thanchronic neck andshoulder pain（Katakori）.

reported that it showed an improvement in dysfunction and reduced pain over the
short－term. With dysfunction, researchers observed a short－term improvement in
pain and physical function through low－level laser therapy but did not acknowledge the usefulness of other forms of physical therapy such as transcutaneous electrical nerve stimulation（TENS）and cervical tractionNote L3. Furthermore, in termsof complementary and alternative medicine, researchers recognized that acupunc-

L．Chronic Neck and Shoulder Pain（Katakori）

ture was effective in improving dysfunction over the short term but its effects in
reducing pain were unclear. With behavioral psychology approaches such as cognitive－behavioral therapy（CBT）and（patient）education, although they had poor efficacy when used alone, when used in combination with for example exercise therapy, researchers reported that it was effective in improving physical function andreducing pain over the short－term21). However, none of these interventional methods were recognized to be useful on pain and physical function over the mid－to
long－term.
As the conditions such as control group settings and interventional amount andperiod were not consistent in these reports, it was difficult for use to compare theusefulness of each interventional method and therefore the certainty of the evidence is low.

CQ L－6：Is there a useful way to prevent chronic neck and shoulder pain
（Katakori）?
Answer：Although exercise intervention may possibly be useful in preventing
chronic neck and shoulder pain（Katakori）, there is insufficient evidence on this.
Commentary：
In a systematic review which targeted office workers and investigated the methods of preventing the onset of “neck pain” , researchers reported a moderate levelof evidence indicating that an exercise program was useful22). To be more specific,
through exercise intervention, the risk of incidence of “neck pain” declined by 53%（RR 0.47, 95%CI 0.32～0.68）22). However, there were only 2 RCTs relating to theexercise that were used in the meta－analysis and the contents of these interventions varied so it did not lead to a standard conclusion.
On the other hand, researchers did not recognize that ergonomic interventions（work environment guidance, posture guidance, and the use of arm supports etc.）
were effective in preventing chronic neck and shoulder pain（Katakori）22). Furthermore, in a Cochrane systematic review, even though the results of a meta－analysis partially acknowledged the preventive effects of using arm supports, researchers were able to conclude that the effects were unclear23).
What is more, these research results were based on studies conducted outside ofJapan and therefore, strictly speaking, we think we are unable to interpret them astargeting ‘chronic neck and shoulder pain（Katakori）’.
References
1）‌Takagishi K, et al : Project study on katakori（2004－2006）. J Jpn Orthop As-

507

508

L．Chronic Neck and Shoulder Pain（Katakori）

soc 2008 ; 82 : 901－911（in Japanese）
2）‌Sawada T, et al : Potential risk factors for onset of severe neck and shoulder
discomfort（Katakori）in urban Japanese workers. Ind Health 2016 ; 54 : 230－
236. doi : 10.2486/indhealth.2015－0143. PMID : 26829974
3）‌Japan Ministry of Health, Labour and Welfare. Comprehensive Survey of Living Conditions 2016. https : //www.mhlw.go.jp/toukei/saikin/hw/k－tyosa/k－tyosa16/dl/04.pdf（Accessed July 31, 2020）
4）‌Wada K, et al : The economic impact of loss of performance due to absenteeism and presenteeism caused by depressive symptoms and comorbid healthconditions among Japanese workers. Ind Health 2013 ; 51 : 482－489.
doi : 10.2486/indhealth.2013－0016. PMID : 23892900
5）‌Kato G, et al : Analysis of factors related to neck and shoulder discomfort inJapanese workers. JJOMT 2019 ; 67 : 87－94
6）‌De Meulemeester K, et al : Morphological differences in the upper trapezius
muscle between female office workers with and without trapezius myalgia : Facts or fiction? Am J Phys Med Rehabil 2019 ; 98 : 117－124. doi : 10.1097/
PHM.0000000000001029. PMID : 30153122
7）‌Gold JE, et al : Systematic review of quantitative imaging biomarkers forneck and shoulder musculoskeletal disorders. BMC Musculoskelet Disord
2017 ; 18 : 395. doi : 10.1186/s12891－017－1694－y. PMID : 28899384
8）‌Jun D, et al : Physical risk factors for developing non－specific neck pain in office workers : A systematic review and meta－analysis. Int Arch Occup Environ
Health 2017 ; 90 : 373－410. doi : 10.1007/s00420－017－1205－3. PMID : 28224291
9）‌Hsieh LF, et al : Efficacy and side effects of diclofenac patch in treatment ofpatients with myofascial pain syndrome of the upper trapezius. J Pain Symptom Manage 2010 ; 39 : 116－125. doi : 10.1016/j.jpainsymman.2009.05.016.
PMID : 19822404
10）‌Cho JH, et al : Acupuncture with non－steroidal anti－inflammatory drugs（NSAIDs）versus acupuncture or NSAIDs alone for the treatment of chronicneck pain : An assessor－blinded randomised controlled pilot study. AcupunctMed 2014 ; 32 : 17－23. doi : 10.1136/acupmed－2013－010410. PMID : 24171895
11）‌Kim DH, et al : Comparison of NSAID patch given as monotherapy and
NSAID patch in combination with transcutaneous electric nerve stimulation,a heating pad, or topical capsaicin in the treatment of patients with myofascial pain syndrome of the upper trapezius : A pilot study. Pain Med 2014 ; 15 :
2128－2138. doi : 10.1111/pme.12611. PMID : 25371275
12）‌Lin YC, et al : Therapeutic effects of lidocaine patch on myofascial pain syndrome of the upper trapezius : A randomized, double－blind, placebo－controlled study. Am J Phys Med Rehabil 2012 ; 91 : 871－882. doi : 10.1097/PHM.
0b013e3182645d30. PMID : 22854911
13）‌Cho JH, et al : Efficacy of a 0. 1％ capsaicin hydrogel patch for myofascial
neck pain : A double－blinded randomized trial. Pain Med 2012 ; 13 : 965－970.
doi : 10.1111/j.1526－4637.2012.01413. x. PMID : 22681259
14）‌Liu L, et al : Effectiveness of dry needling for myofascial trigger points associated with neck and shoulder pain : A systematic review and meta－analysis.
Arch Phys Med Rehabil 2015 ; 96 : 944－955. doi : 10.1016/j.apmr.2014.12.015.
PMID : 25576642
15）‌Cerezo－Téllez E, et al : Effectiveness of dry needling for chronic nonspecificneck pain : a randomized, single－blinded, clinical trial. Pain 2016 ; 157 : 1905－
1917. doi : 10.1097/j.pain.0000000000000591. PMID : 27537209
16）‌Cerezo－Téllez E, et al : Health related quality of life improvement in chronic

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non－specific neck pain : Secondary analysis from a single blinded, randomized
clinical trial. Health Qual Life Outcomes 2018 ; 16 : 207. doi : 10.1186/s12955－
018－1032－6. PMID : 30400984
17）‌Ay S, et al : Comparison of injection methods in myofascial pain syndrome : A
randomized controlled trial. Clin Rheumatol 2010 ; 29 : 19－23. doi : 10.1007/
s10067－009－1307－8. PMID : 19838864
18）‌Ahmed S, et al : Effect of local anesthetic versus botulinum toxin－A injections
for myofascial pain disorders : A systematic review and meta－analysis. Clin J
Pain 2019 ; 35 : 353－367. doi : 10.1097/AJP.0000000000000681. PMID : 30589660
19）‌Skelly AC, et al : Noninvasive nonpharmacological treatment for chronic
pain : A systematic review. Agency for Healthcare Research and Quality（US）; 2018 Jun. Report No. : 18－EHC013－EF. PMID : 30179389
20）‌Gross A, et al : Exercises for mechanical neck disorders. Cochrane Database
Syst Rev 2015 ; 1 : CD004250. doi : 10.1002/14651858.CD004250.pub5. PMID :25629215
21）‌Thompson DP, et al : Does adding cognitive－behavioural physiotherapy to exercise improve outcome in patients with chronic neck pain? : A randomised
controlled trial. Physiotherapy 2016 ; 102 : 170－177. doi : 10.1016/j.physio.2015.
04.008. PMID : 26383695
22）‌de Campos TF, et al : Exercise programs may be effective in preventing a
new episode of neck pain : A systematic review and meta－analysis. J Physiother 2018 ; 64 : 159－165. doi : 10.1016/j.jphys.2018.05.003. PMID : 29908853
23）‌Hoe VC, et al : Ergonomic interventions for preventing work－related musculoskeletal disorders of the upper limb and neck among office workers. Cochrane Database Syst Rev 2018 ; 10 : CD008570. doi : 10.1002/14651858.
CD008570.pub3. PMID : 30350850

509

Chapter M．Orofacial Pain：CQ M-1～CQ M-4-4
CQ M-1：How is chronic orofacial pain classified ?
CQ M-2-1：What is the pathology of trigeminal neuralgia ?
CQ M-2-2：What is the algorithm for diagnosing trigeminal
neuralgia ?
CQ M-2-3：What kind of pharmacotherapy is useful for trigeminal
neuralgia ?
CQ M-2-4：What other treatments, apart from pharmacotherapy,
are useful for treating trigeminal neuralgia ?
CQ M-3-1：What kind of disease is burning mouth syndrome（BMS）?
CQ M-3-2：What is the algorithm for diagnosing burning mouth
syndrome（BMS）?
CQ M-3-3：What kinds of pharmacotherapy are useful for burning
mouth syndrome（BMS）?
CQ M-3-4：What other forms of treatment, apart from pharmacotherapy,
are useful for treating burning mouth syndrome（BMS）?
CQ M-4-1：What is the pathology of persistent idiopathic
dentoalveolar pain ?
CQ M-4-2：What is the algorithm for diagnosing persistentidiopathic dentoalveolar pain ?
CQ M-4-3：What kinds of treatment are there for burning mouth
syndrome（BMS）apart from pharmacotherapy ?
CQ M-4-4：What are other ways to treat persistent idiopathic dentoalveolar pain, apart from pharmacotherapy ?

512

M．Orofacial Pain

M．Orofacial Pain
CQ M－1：How is chronic orofacial pain classified ?
Answer：It is classified into primary chronic orofacial pain when the cause of thepain is unknown, and secondary chronic orofacial pain when it involves dental disease－derived chronic pain and when the disease causing the pain is clearly known.
Chronic primary orofacial pain is characterized as persistent spontaneous pain, thatappears to be from the mucous membrane of the oral cavity（burning mouth syndrome）, the teeth and alveolar part（persistent idiopathic dentoalveolar pain）, andthe face（persistent idiopathic facial pain）. It cannot be explained by known diseases of the orofacial area；it is indicated by modulations to the central pain control
mechanism. On the other hand, what is included under chronic secondary orofacial
pain is chronic pain derived from dental diseases, temporomandibular disorders ofwhich the origin is clearly known, trigeminal neuralgia, neuropathic pain derived
from trigeminal neuralgia／the glossopharyngeal nerve and orofacial pain with accompanying functional headache.
Commentary：
Orofacial function is controlled by several sensation－related and exercise－related
cranial nerves, and the pain is involved with several cranial nerves and these
symptoms are incredibly complex and diverse1).
The prevalence rate of orofacial pain, which includes toothache such as pulpitis
and periodontitis and the prevalence rate of chronic orofacial pain is reported to beapproximately 10%1). Furthermore, 5% of adults have jaw／facial pain persisting for
3 months or longer, and it is relatively high among women, and tends to increase
with age.
Orofacial pain is classified as a secondary headache in Part Two of the InternaICHD：International
Classification of
Headache Disorders

tional Classification of Headache Disorders（ICHD－3）, and in Part Three, among

ICOP：The international classification of
orofacial pain

In the International Classification of Orofacial Pain（ICOP）, 1st edition, it was re-painful cranial nerve neuropathy, other orofacial pain and other types of headache2).

Table M－1

International Classifications of Orofacial Pain

1．Orofacial pain attributed to disorders of dentoalveolar and anatomically related structures
2．Myofascial orofacial pain
3．Temporomandibular joint（TMJ）pain
4．Orofacial pain attributed to lesion or disease of the cranial nerves
5．Orofacial pains resembling presentations of primary headaches
6．Idiopathic orofacial pain

M．Orofacial Pain

513

classified by following the international chronic pain categories, with orofacial pain
3)
being classified into 6 categories（Table M－1）.

CQ M－2－1：What is the pathology of trigeminal neuralgia ?
Answer：Trigeminal neuralgia is pain from the trigeminal nerve affected unilaterally, or paroxysmal sudden shooting unilateral pain, restricted to the adjacent regions dominated by several branches. In particular, a recognizable constriction andexclusion of the blood vessels of the trigeminal nerve root is called typical trigeminal neuralgia.
Commentary：
Trigeminal neuralgia is strong pain in the orofacial region. It is sharp paroxysmal
pain appearing in regions dominated by 1 or several branches of the trigeminal
nerve root, and is stabbing pain which recurs in a short period of time. This pain ischaracteristically triggered when for example washing one’s face, shaving, brushing
one’s teeth, chewing or engaging in conversation. As an intense pain arises in theteeth and periodondal tissue when moving the mouth, such as for brushing theteeth, chewing or engaging in conversation, on many occasions people sufferingfrom it visit a dentist. It is also not rare for people to undergo tooth extraction, an
irreversible and invasive treatment. It becomes necessary for departments involvedin the treatment of dentistry, oral surgery, pain clinics, neurosurgery, neurology,
radiology and diagnostic imaging to coordinate their efforts4).
In the past, trigeminal neuralgia was classified into idiopathic trigeminal neuralgia（ITN）and symptomatic trigeminal neuralgia（STN）but now the International
Classification of Headache Disorders, 3rd Edition（ICHD－3）2), and the International
Classification of Orofacial Pain（ICOP）1st Edition3), have organized the pathologies
in a clearer manner.
When the cause is pressure on root entry zone（REZ）of the trigeminal nerve
due to microvessels, frequently occurring in the superior cerebellar artery, this iscurrently classified as typical trigeminal neuralgia and through improvements
made to diagnostic imaging technology, it has become possible to evaluate this byperforming an MRI test. Pathologies that had been previously summarized undersymptomatic trigeminal neuralgia, have been classified into 2 different diseases：
secondary trigeminal neuralgia not derived from the microvessels, such as cerebellopontine angle lesion and multiple sclerosis（MS）, and trigeminal neuropathic pain
arising due to damage to the peripheral trigeminal nerve. The nature of the pain isdifferent for secondary trigeminal neuralgia and trigeminal neuropathic pain. While
there is paroxysmal pain with typical trigeminal neuralgia and secondary trigemi-

ICOP：The international classification of
orofacial pain
REZ：root entry zone

514

M．Orofacial Pain

nal neuralgia, trigeminal neuropathic pain is generally persistent, deriving from impaired tissue／nerves. Therefore, as a result, it is accompanied by for example hypoesthesia in the trigeminal nerve region（negative symptoms）, as well as allodynia
and hyperalgesia（positive symptoms）. This meets the IASP’s diagnostic criteria
for neuropathic pain.
On the other hand, with pressure on the root entry zone of the trigeminal nerve
due to microvessels and when physicians are unable to acknowledge that the pain
might be caused by another disease, it is diagnosed as idiopathic trigeminal neuralgia. The majority of ‘idiopathic trigeminal neuralgia’ that was formerly used currently refers to typical trigeminal neuralgia, and therefore one must be careful because pathologies that are shown to be idiopathic are different. Trigeminal neuralgia has been clearly categorized in this way according to the IASP algorithm, ICHD－
3, and ICOP categories.

CQ M－2－2：What is the algorithm for diagnosing trigeminal neuralgia ?
Answer：The algorithm for diagnosing trigeminal neuralgia is thought out over
the two stages of a medical interview and a test. In the medical interview, physicians need to confirm through taking patient history whether the patient has a current history of paroxysmal pain occurring on one side of the face due to exercise of
the face or when lightly stimulated through touch. In the physical examination,
physicians test to see whether there are any sensation abnormalities, whether theparoxysmal pain recurs on one side of the face when touched with something like a
cotton swab. Diagnostic imaging by MRI is an essential test to perform in order todifferentiate between typical trigeminal neuralgia and secondary trigeminal neuralgia.
Commentary：
When diagnosing trigeminal neuralgia, physicians first confirm whether paroxysmal pain is recurring unilaterally in the region dominated by the trigeminal nerve,
whether it is sharp pain that disappears within 2 minutes from the onset of the attack, and whether it is like an electric shock, with a shooting, stabbing, or sharp
pain. If these criteria are met, then through taking patient history and actual medical tests, if the physician can confirm through a brushing test using a cotton swab
or a non－invasive form of stimulation of their daily activities such as washing theface, shaving and brushing the teeth, or that an attack of pain is triggered throughstimulation when exercising or moving such as chewing or engaging in conversation, then the condition is clinically diagnosed as trigeminal neuralgia. In addition,
an MRI and electrophysiological examination are performed if the MRI confirms

515

M．Orofacial Pain

Table M－2

Differentiating Trigeminal Neuralgia

ICHD－3（2018） Classical trigeminal
ICOP（2010）
neuralgia

Cause

Constriction of theblood vessels（mainly the superior
cerebellar artery（SCA））

Former disease
nameIdiopathic trigeminal
neuralgia
Primary trigeminal
neuralgia

Secondarytrigeminal neuralgia

Trigeminal neuropathic
pain

Tumor, multiple
sclerosis（MS）,
arteriovenous
malformation

Trauma, Herpes zoster
etc.

Symptomatic trigeminal neuralgia（STN）

Symptoms

Paroxysmal pain
（several seconds ～ 2 mins.）

Persistent pain，Induced pain, Allodynia,
Hyperalgesia

Refractory
periodYes

No

Sensation

NormalHypoesthesia（＋／－）

Hypoesthesia（＋）

Diagnosed through QST

compression and exclusion of the blood vessels of the root entry zone（REZ）of thetrigeminal nerve, then the condition is diagnosed as typical trigeminal neuralgia.
On the other hand, if the physician confirms the characteristic findings of a neurological disorder such as multiple sclerosis（MS）or brain tumor on the MRI test or
an electrophysiological test, then the condition is diagnosed as secondary trigeminal
neuralgia. Finally, if there is no clear abnormality observed on the MRI or electrophysiological test, then it is diagnosed as idiopathic trigeminal neuralgia5).
Furthermore, when abnormal findings are confirmed on an MRI or electrophysiological test, trigeminal neuropathic pain is the disease required in order for it to bedifferentiated from secondary trigeminal neuralgia. Quantitative sensory testing（QST）is useful for a differential diagnosis. With differentiating between secondary
trigeminal neuralgia and trigeminal neuropathic pain, they are differentiated byparoxysmal pain, which is mainly for trigeminal neuralgia, whereas persistent pain
is mainly for trigeminal neuropathic pain2,3,6)（Table M－2）.

CQ M－2－3：What kind of pharmacotherapy is useful for trigeminal neuralgia ?
Answer：In terms of pharmacotherapy for trigeminal neuralgia, carbamazepine,
an antiepileptic drug, is recommended as a first－line drug. However, when continuing a patient on carbamazepine becomes difficult, researchers have cited gabapen-

QST：quantitative
sensory testing516

M．Orofacial Paintin and pregabalin as alternatives. In addition, researchers have recognized the effects of oxycarbazepine, baclofen and lamotrigine, which are not covered under thehealth insurance system in Japan. However, there is scant medical grounds that using these second－line drugs either alone or in combination with carbamazepine provide satisfying analgesic effect and therefore often non－drug therapy is necessary.
Recommendation Grade & Summary of Overall Evidence
1) CarbamazepineR ecommendation grade：1（strong）：Implementation is strongly recommended〔Consensus 100.0%〕
Summary of overall evidence：A（high）
2）GabapentinR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 94.4%〕
Summary of overall evidence：B（moderate）
3）PregabalinR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 94.4%〕
Summary of overall evidence：B（moderate）
4）OxcarbazepineR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 84.2%〕
Summary of overall evidence：B（moderate）
5）BaclofenR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 84.2%〕
Summary of overall evidence：B（moderate）
6）Lamotrigine
Recommendation grade：No recommendation〔Consensus 89.5%〕
Summary of overall evidence：B（moderate）
Commentary：
In terms of pharmacotherapy for trigeminal neuralgia, the antiepileptic drug, carbamazepine, is recommended as a first－line drug by western guidelines in theAmerican Academy of Neurology（AAN）and the European Federation of NeuroAAN：American Academy of Neurology
EFN：The European
Federation of
Neurological Societies
NNT：number needed
to treat

7,8)
logical Societies（EFN）. The ‘Pharmacotherapy Guidelines for Neuropathic Pain,

Revised 2nd Edition’ by the Japan Society of Pain Clinicians（JSPC）is used as theexisting guidelines for Japan, and they recommend carbamazepine as a first－line
drug9). The number needed to treat（NNT）trigeminal neuralgia with carbamazepine is between 1.7～1.8（95%CI 1.3～2.2）, indicating that it is highly effective.

M．Orofacial Pain

517

However, in a report on the long－term efficacy of Carbamazepine, although the initial response rate was 60%, this dropped to 22% 5－16 years later, 44% of patientsneeded additional or alternative treatment10). In a systematic review by Zakrzewska et al.11), they reported that the response rate had fallen by over 50% over a long－term observation of 5～10 years.
Along with its declining effect, side effects also made it difficult for patients tocontinue on carbamazepine. A wide variety of side effects manifest, from mild side
effects such as drowsiness and lightheadedness to more severe ones such as immunoreactions like drug rash, bone marrow suppression, and liver disorder. In a Cochrane review by Wiffen et al.12), 66% of patients who had used carbamazepine had
experienced some form of side effects（27% for the placebo group）, and the number needed to harm（NNH）was 2.6（95% CI 2.1～3.5）. In most cases, their condition improves if administration is discontinued but in the event of severe casessuch as Stevens－Johnson syndrome（SJS）, toxic epidermal necrolysis（TEN）, anddrug－induced hypersensitivity syndrome（DIHS）, treatment interventions by anexpert are required. With DIHS in particular, it may manifest after several months～several years have passed and therefore caution is required. As it is difficult toforesee these side effects, it is important to start patients on a small dosage and not

NNH：number
needed to harm
SJS：Stevens-Johnson
syndrome
TEN：toxic epidermal
necrosis
DIHS：drug-induced
hypersensitivity
syndrome

neglect monitoring and observing their condition.
When it is difficult for patients to continue taking carbamazepine, then alternative drugs researchers cite for example gabapentin, pregabalin, baclofen, and lamotrigine. In addition, the effects of oxcarbazepine and type－A botulinum toxin havebeen recognized, although they are not covered under the Japanese health insurance system.
In a systematic review of gabapentin on trigeminal neuralgia13), researchers reported its effects on the disease. In a meta-analysis on the use of gabapentin to
manage trigeminal neuralgia14), gabapentin’s OR＝1.6（95%CI 1.185 ～ 2.161）, was
not inferior to that of carbamazepine, and the results for its side effects were low
at OR＝0.312（95%CI 0.240～0.407）. According to the guidelines for the European
Headache Federation, both Gabapentin and Pregabalin are second-line drugs for
managing trigeminal neuralgia15). In the European Federation Headache Congress
guidelines, it was a second－line drug, along with gabapentin, for treating trigeminal
neuralgia.
In a network meta－analysis of the effects and tolerance of antiepileptic drugs fortrigeminal neuralgia, what researchers recommended first and foremost as an alternative for carbamazepine was oxcarbazepine16). There was no significant difference
from its effects and those of carbamazepine17), and researchers also confirmed its
high tolerance9), and therefore in western guidelines, they strongly recommend
long－term administration of oxcarbazepine for treating trigeminal neuralgia18). However, in Japan, its use has been approved only as a limited epileptic drug and its

NMA：network
meta-analysis

518

M．Orofacial Painuse in treating trigeminal neuralgia is not covered under the health insurance system. We expect that its use will be expanded to be covered under health insurance
for trigeminal neuralgia.
RCT：randomized
controlled trial

Baclofen can be an alternative drug for carbamazepine but in a 4－armed RCT（carbamazepine, baclofen, phenytoin, and a placebo）conducted on 10 patients withtrigeminal neuralgia, researchers observed that it was effective in alleviating pain
over a 2－week treatment period. In addition, in a 3－armed RCT（carbamazepine,
baclofen＋carbamazepine, baclofen）RCT on 30 patients with trigeminal neuralgia,
researchers found good outcomes in the group that had been administered a mix ofbaclofen and carbamazepine but due to a dropout rate of over 30% and its unclear
randomization, it had a low level of evidence. In Japan, baclofen is evaluated as 2 C（implementation is weakly recommended）and in overseas guidelines, it has received a Level C evaluation19).
Compared with a placebo, lamotrigine had a significantly high combined effectiveness score（p＜0.01）, and its NNT was 2.119). When administering lamotrigine,
one must be careful of side effects such as lightheadedness, constipation, nausea
and drowsiness. Furthermore, one must be careful of increasing the dosage all of asudden as it might cause allergic reactions or severe skin redness.
One can say that type－A botulinum toxin is superior in terms of side effects but
its coverage under the Japanese health insurance system is strictly determined so
it is difficult to use.
PeriodDatabase
Search word P

I／C
Limitations
Selection Summary

MVD：microvasculardecompression
RF：radiofrequency
thermocoagulation
LLLT：low level laser
therapy
PRF：pulsed
radiofrequency
GKS：gamma knife
surgery
Note 14：Please refer
to CQ D-7, CQ D-8

2005～2019
MEDLINE, Cochrane CENTRAL,NPO Japan Medical Abstracts Society（Trigeminal neuralgia）AND（randomized controlled trial OR controlled clinical trial OR random allocation OR double－blind method OR single－blind method OR clinical trial OR placebo
OR random OR evaluation studies OR follow－up studies OR prospective studies OR cross－over studies OR control OR prospective OR systematic review OR meta analysis）
carbamazepine, gabapentine,pregabaline, oxcarbazepine,baclofen, lamotrigine, type-A
botulinum toxin
Limited by publication type, PubMed CER randomized controlled trials ／ systematic review
search filter, Cochrane RCT search filter, the conditions of an RCT with SR, N＝100＋, and observational research studies with N＝500＋. etc.
We extracted 1,343 references from PubMed, Cochrane, and NPO Japan Medical Abstracts
Society, we used 7 searches that matched with the set PICOCQ M－2－4：What other treatments, apart from pharmacotherapy, are usefulfor treating trigeminal neuralgia ?
Answer：Forms of treatment other than pharmacotherapy can be divided into
surgical treatment and non－invasive treatment. In terms of surgical treatment,
there is microvascular decompression（MVD）, percutaneous radiofrequency rhizotNote 14
omy of the trigeminal nerve〔radiofrequency thermocoagulation（RF）, pulsedradiofrequencyNote 14, trigeminal ganglion balloon compression, glycerol rhizotomy〕,
radiation stereotactic surgery〔gamma knife surgery（GKS）, cyber knife, linac〕.

M．Orofacial Pain

Moxibustion, low－level laser therapy（LLLT）are examples of non－invasive treatment methods that are performed. The level of evidence for each treatment method is low but there are almost no reports of adverse events.
Recommendation Grade & Summary of Overall Evidence1）Surgical treatmenta．Microvascular decompression（MVD）
Recommendation grade：1（strong）：Implementation is strongly recommended〔Consensus 95.0%〕
Summary of overall evidence：B（moderate）
b．Radiation stereotactic surgery（gamma knife surgery, cyber knife, linac）
Recommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕
Summary of overall evidence：B（moderate）
c．Radiofrequency thermocoagulation（RF）
Recommendation grade：1（strong）：Implementation is strongly recommended〔Consensus 95.0%〕
Summary of overall evidence：C（low）
d．Pulsed radiofrequency（PRF）
Recommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕
Summary of overall evidence：C（low）
2）Non－invasive treatments
a．Low－level laser therapy（LLLT）
Recommendation grade：No recommendation〔Consensus 85.0%〕
Summary of overall evidence：C（low）
b．Moxibustion
Recommendation grade：No recommendation〔Consensus 100.0%〕
Summary of overall evidence：C（low）
Commentary：Forms of treatment other than pharmacotherapy can be divided into surgicaltreatment and non－invasive treatment, and according to overseas guidelines, whenpharmacotherapy cannot be used or when it fails to provide insufficient effect, thensurgical treatment is recommended as a second－stage treatment7). There havebeen no reports of RCTs conducted on each type of surgical treatment using asham treatment as the control and therefore the level of evidence is low for eachtreatment. At the current stage, our considerations are based upon case control research and research which has evaluated treatment effect and complications bycomparing the forms of surgical treatment with each other.

519

520

M．Orofacial Pain

Surgical treatments such as percutaneous trigeminal nerve surgery, typically
represented by microvascular decompression（MVD）and radiofrequency thermoSR：stereotactic radiosurgery

coagulation（RF）, and stereotactic radiosurgery（SR）typically represented by
gamma knife surgery（GKS）, were all shown to be effective in improving intractable trigeminal neuralgia in patients resistant to carbamazepine 21－25). In terms of
their analgesic effects right after surgery was performed, the % of patients who did
not need to be administered with medicine post－operatively was about the samefor MVD and RF21), while MVD was superior to SR23). Compared with SR, MVD
has a higher pain removal rate 5 years later23). In addition, MVD led to a higher
QOL than SR24). The pain recurrence rate post－surgery was 11% for MVD, and
25% for SR, but there was no difference in the amount of time up to recurrence25).
There were more cases of secondary procedure required due to a recurrence of
pain post－surgery in RF patients than MVD patients21). An issue with these RCTs
is that MVD targeted young patients while RF and RS targeted elderly patients.
Gamma knife surgery is problematic in terms of immediate analgesic effect and recurrence rate but it is a first－line surgical treatment that should be performed on
patients who receive anticoagulation therapy. With RF, there is sustained method
and intermittent method but if patients are treated through the sustained method
at a high temperature, patients have strong post－operative sensory impairment but
if they are treated at a low temperature, then the analgesic effects are weakened.
There are accidental symptoms post－surgery such as facial sensory disorders anddecline in muscular strength such as the muscles of mastication. There are almost
no reports of severe complications.
Non－invasive therapy on the other hand, is often used as an alternative treatment method instead of pharmacotherapy or as a supplementary treatment methodin addition to pharmacotherapy. There are reports which have compared it withcarbamazepine but the level of evidence is low26). However, compared with carbamazepine, there are almost no adverse events so it may be okay to try using it in
combination with carbamazepine. There exists 1 systematic review on the use oflower－level laser therapy（LLLT）to treat trigeminal neuralgia but in each of the
RCTs used, there are major problems with the control group settings, the level ofevidence is low and therefore, it does not help us reach a fixed conclusion27).
PeriodDatabase
Search word P

I／C
Limitations
Selection Summary

2005～2019
MEDLINE, Cochrane CENTRAL,NPO Japan Medical Abstracts Society（Trigeminal neuralgia）AND（randomized controlled trial OR controlled clinical trial OR random allocation OR double－blind method OR single－blind method OR clinical trial OR placebo
OR random OR evaluation studies OR follow－up studies OR prospective studies OR cross－over studies OR control OR prospective OR systematic review OR meta－analysis）
microvascular decompression, radiofrequency thermocoagulation, puled radiofrequency, gamma knife surgery, CyberKnife, LINAC, lower－level laser therapy, acupuncture
Limited by publication type, PubMed CER randomized controlled trial ／ systematic review
search filter,, Cochrane RCT search filter, the conditions of an RCT with SR, N＝100＋, andobservational research studies with N＝500＋, etc.
We extracted 1,343 references from PubMed, Cochrane, and NPO Japan Medical Abstracts
Society, we used 7 searches that matched with the set PICO

M．Orofacial Pain

521

CQ M－3－1：What kind of disease is burning mouth syndrome（BMS）?
Answer：Burning mouth syndrome（BMS）is a typical disease causing chronic
primary pain in the oral region and a characteristic of this syndrome is persistent
pain of the oral mucosa. The pain is bilateral and it frequently occurs on the edgeof the tongue, with glossitis, and on the palate. There have been reports on its relationship to mood disorder and menopause, but it is unclear which mechanism causes it. Physicians diagnose BMS only after they have excluded all local and systemic
causes.
Commentary：
As global diagnostic criteria have not yet been established regarding whether toinclude secondary BMS symptoms as BMS or not, there is a lack of uniformity
from one research study to the next regarding how rigorously each study has excluded secondary BMS from the target of its research. Therefore, there is a riskthat past research studies may have included patients exhibiting various BMS
symptoms and therefore it is difficult to collect accurate epidemiological data fromthese research studies. In fact, we observed a large variance in the prevalence rate
among the whole population, depending on the report, from 0.7～15%. On the other
hand, BMS occurs more frequently in women than in men, and in particular, many
researchers have reported that cases perimenopause or post－menopause are frequent28), and as this is a widely shared finding, the tendency of this condition to appear frequently in post－menopausal women we believe reflects the pathology of thedisease.
Many of the causes of BMS have not been explained but with many BMS patients, we believe that it involves the mutual interaction of local, systemic and mental factors. Much recent research has indicated grounds that it derives from neuropathies involving central and peripheral nerves. According to the 2020 ‘International Classification of Orofacial Pain 1st, edition’3)（ICOP）, when conducting a quantitative sensory test（QST）, we recommend classifying it into one of 2 sub－categories：the ‘6.1.1 BMS without somatosensory changes’ or ‘6.1.2 BMS with somatosensory changes’.
BMS is a pain which usually occurs bilaterally；it is rarely seen to be unilateral.
The severity of pain fluctuates. The most frequently occurring site is the tip of the
tongue. There have been reports that in 2／3 of the cases, there was subjective drymouth（xerostomia）, dysesthesia and an alteration to taste. We could say that persistent BMS is a symptom which causes a severe impediment to one’s daily lifestyle. Furthermore, just like with other chronic pain illnesses such as anxiety, hypersensitivity, depression and reduced sociability, there are findings that are often
observed among BMS patients. However, it still remains unclear what kind of sig-

BMS：burning mouth
syndrome（also known
as glossodynia,
glossopyrosis, oral
dysesyhesia, stomatodynia）

522

M．Orofacial Pain

nificance these factors play in the underlying cause of BMS. Furthermore, it ischaracteristic to often see BMS patients’ fear of oral cancer29).

CQ M－3－2：What is the algorithm for diagnosing burning mouth syndrome（BMS）?
Answer：When patients complain of persistent pain on both sides of the oral mucosa, first of all, the physician will examine and test whether there are local lesions
exhibiting a burning sensation inside the mouth, which will be touched upon later,
and a systemic disease present or not. When some type of underlying disease issuspected, the necessary treatment is conducted and in cases where both local andsystemic involvement have been negated, then the physician will pronounce a diagBMS：burning mouth
syndrome

nosis of burning mouth syndrome（BMS）if the following diagnostic criteria aremet.
Commentary：
3)
The International Classification of Orofacial Pain（ICOP）
define this disease as,“a burning sensation inside of the mouth or dysesthesia, which recurs repetitively
for over 2 hours a day, and persisting for more than 3 months, and for which thephysician fails to identify a clear underlying disease after conducting clinical examinations and tests”. What is very important when diagnosing BMS is differentiating
between cases in which there is an underlying cause of the disease where theburning sensation arises secondarily, or in which cases it is BMS. When the burning sensation arises secondarily, researchers believe it is due to one of the local
causes（oral candidiasis, oral lichen planus, decreased saliva volume, metal allergy）
or systemic causes（drug－induced, anemia, vitamin B12 and folic acid deficiency,
zinc deficiency, Sjogren’s syndrome, diabetes, hypothyroidism）（in such cases, thedisease is identified and the burning sensation must disappear through the treat29)
ment）. A diagnosis by exclusion is made by considering these factors.

According to the ICOP, after a diagnosis of BMS is pronounced, we recommend
conducting a sensory test of the affected site using a quantitative sensory test
（QST）and in the event that neither positive nor negative symptoms can be seen,
it is sub－classified as BMS without accompanying somatosensory changes, and if either positive symptoms or negative symptoms are recognized, then it is sub－classified into BMS with accompanying somatosensory changes.

M．Orofacial Pain

523

CQ M－3－3：What kinds of pharmacotherapy are useful for burning mouth
syndrome（BMS）?
Answer：The only RCT reports on BMS have been on clonazepam, capsaicin,
and α－lipoic acid（ALA）. Like with other forms of chronic pain, antidepressants
are used experimentally but there are not reports which have considered the evidence. Research has recognized the analgesic effects of local administration of
clonazepam, on BMS over the short－term（3 months）and over the long－term（6months＋）. Administering clonazepam orally may possibly be useful but we recommend avoiding long－term administration from the perspective of side effects anddependence. Researchers have confirmed the efficacy of administering capsaicin locally but there are few high－quality RCTs and its usefulness when administeringover the long－term remains unclear.
Recommendation Grade & Summary of Overall Evidence
1) Local administration of clonazepam
Recommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 95.0%〕
Summary of overall evidence：C（low）
2) Local administration of capsaicin
Recommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕
Summary of overall evidence：C（low）
Commentary：
Methods for treating BMS have not yet been established. The first line for treating BMS is pharmacotherapy. In a recent meta－analysis, in accordance with thetreatment for neuropathic pain, local and oral administration of clonazepam is thefirst line that is used clinically to treat BMS30). Local administration of clonazepam（1.0 mg）inside the mouth（clonazepam is placed on the top of the tongue and dissolved in the saliva, and placed near the site of pain inside the mouth for 3 minutes,
and after that, spat out with the saliva；this action is conducted 3 times a day）had
a reduced（intensity of pain）outcome, compared with the placebo and displayed
analgesic effects both over the short－term（3 months）and the long－term（6months＋）. After administering clonazepam（1.0mg）both over the short－term andlong－term, there are no side effects（dysgeusia, dryness in the mouth）, and therefore we think clonazepam is useful but it has a weak recommendation grade31).
In a research study which considered the usefulness of ALA32), a publication bias
has been pointed out as a problem so it is not listed in these guidelines.
There are few research studies which have investigated the effects of adminis-

ALA：α-lipoic acid524

M．Orofacial Pain

tering capsaicin locally and the sample sizes of the studies are small as well. Capsaicin for gargling（0.02%[w／v]）or 0.01% [w／v] of capsaicin or 0.025% [w／v] of a gel
application, showed beneficial effects on improving pain over the short－term, after
intervention31).
Other drugs that have been reported on include drugs that act on the serotonin
nervous system, such as amitriptyline, nortriptyline, duloxetine, paroxetine, but although their analgesic effects on BMS were reported, there were no high－quality
research reports and therefore its evaluation in a Cochrane systematic review was
low31).
PeriodDatabase
Search word P

2005～2019
MEDLINE, Cochrane CENTRAL,NPO Japan Medical Abstracts Society（Burning mouth syndrome）AND（randomized controlled trial OR controlled clinical trial OR
random allocation OR double－blind method OR single－blind method OR clinical trial OR placebo OR random OR evaluation studies OR follow－up studies OR prospective studies OR cross－over studies OR control OR prospective OR systematic review OR meta－analysis）
Clonazepam, capsaicin,
Limited by publication type, PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, the conditions of an RCT with SR, N＝100＋, and observational research studies with N＝500＋, etc.
We extracted 1,343 searches from PubMed, Cochrane, and NPO Japan Medical Abstracts Society, we used 3 searches that matched with the set PICO

I／C
Limitations
Selection summary

CQ M－3－4：What other forms of treatment, apart from pharmacotherapy, areuseful for treating burning mouth syndrome（BMS）?
CBT：cognitive
behavioral therapy
PCS：pain catastrophizing scale
HRQL：health-ralated
quality of life

Answer：Researchers have confirmed that cognitive－behavioral therapy（CBT）
intervention, improves the pain catastrophizing scale, which is related to pain andanalgesic effect for BMS, as well as facial health－related quality of life（QOL）. Researchers observed that a long－term CBT intervention was effective over the short－to mid－term. However, its effects after 6 months remain unclear. They have confirmed the efficacy of other forms of psychotherapy but there are no RCTs on
BMS, and therefore no high－quality research reports exist. There is little research

LLLT：low level laser
therapy
TMS：transcranial
magnetic stimulationthat has been conducted on low level laser therapy（LLLT）, and transcranial magnetic stimulation（TMS）but these treatments were not recognized as providing
sufficient effect.
Recommendation Grade & Summary of Overall Evidence
1) Cognitive－behavioral therapy（CBT）
R
 ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕
Summary of overall evidence：C（low）
2）Low level laser therapy
Recommendation grade：No recommendation〔Consensus 100.0%〕

M．Orofacial Pain

525

Summary of overall evidence：D（very low）
3）Transcranial magnetic stimulation（TMS）
Recommendation grade：No recommendation〔Consensus 100.0%〕
Summary of overall evidence：D（very low）
Commentary：
There are few research reports on CBT for treating BMS；there is 1 Cochranesystematic review that has been reported31). The outcomes（VAS）of a CBT intervention（once ／ week）were evaluated after 6 months, and researchers observed

VAS：visual analogue
scale

that it was effective with a reduction in long－term pain（after 6 months）.
As for other forms of non－pharmacological treatment, there have been 4 RCTs
which have reported on LLLT but 2 of these RCTs showed the same level of analgesic effect as that from the pseudo－irradiation；in the other 2 RCTs, there was alarge indirect bias. In 1 RCT, researchers conducted transcutaneous electricalnerve stimulation（TENS）, running a current of 10 Hz on the left temporo－frontal
area of patients with BMS, and reported that pain had significantly reduced ascompared with the control group. However, in each of these reports, the number ofcases was small, and therefore we need to wait for further research to be conducted in future in order to discuss its efficacy.
PeriodDatabase
Search word P

I／C
Limitations
Selection summary

2005～2019
MEDLINE, Cochrane CENTRAL, NPO Japan Medical Abstracts Society（Burning mouth syndrome）AND（randomized controlled trial OR controlled clinical trial OR
random allocation OR double－blind method OR single－blind method OR clinical trial OR placebo OR random OR evaluation studies OR follow－up studies OR prospective studies OR cross－over studies OR control OR prospective OR systematic review OR meta－analysis）
cognitive behavior therapy, low reactive－level laser therapy, transcranial magnetic stimulation
Limited by publication type, PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, the conditions of an RCT with SR, N＝100＋, and observational research studies with N＝500＋, etc.
We extracted 1,343 searches from PubMed, Cochrane, and NPO Japan Medical Abstracts Society, we used 2 searches that matched with the set PICOCQ M－4－1：What is the pathology of persistent idiopathic dentoalveolar pain ?
Answer：Persistent idiopathic dentoalveolar pain（PIDAP）is a chronic primarypain which along with burning mouth syndrome（BMS）is characteristic of the orofacial region. While BMS is superficial pain of the oral mucosa, PIDAP is pain of the
tooth and alveolar part, equivalent to deep pain. It tends to be understood as a typeof neuropathic pain, as pain after tooth extraction, after a root canal treatment.
However, the International Classification of Orofacial Pain（ICOP）, recommends diagnosing it as post－traumatic trigeminal neuropathic pain if it is clearly related totrauma, whereas PIDAP is considered to be an idiopathic form of pain with an unclear cause.

PIDAP：persistentidiopathic dentoalveolar pain

526

M．Orofacial Pain

Commentary：
The term ‘persistent idiopathic dentoalveolar pain’（PIDAP）, is a persistent pain
arising in the（alveolar）site in 1 tooth or after the loss of a tooth and is used whenno dental cause for the pain exists whatsoever4,34).
It was first reported in 1778, and the pathologies of idiopathic periodontalgia
were named in 1974, phantom tooth pain was named in 1978, and atypical odontalAO：atypicalodontalgia

gia（AO）was named in 1979, and it has been called ‘AO’ for the past 40 years up
until the present. Because they have not clarified its pathophysiology, various
names have been used for this disease, and in 1992 they proposed idiopathic toothache, in 2012 painful post－traumatic trigeminal neuropathy（PTTN）,and persistent
dentoalveolar pain disorder3,34).
In the 2018 International Classification of Headache Disorders 3rd Edition（ICHD－PIFP：persistentidiopathic facial pain32), in classification 13.12 for persistent idiopathic facial pain（PIFP）, the viewpoint
they indicate is that “AO is a sub－type of PIPF.” Experts define PIPF as a persistent pain of the face or mouth（or both）with various accompanying symptoms.
And they indicated that its characteristics are that it is not clearly localized andthe majority of the patients are women, whereas with AO, the localization is clear,
the age of onset is relatively young／low, and there is little difference in gender（ofthe patients）.
On the other hand, in the 2020 International Classification of Orofacial Pain 1st
3)
Edition（ICOP）, they bring up PIFP in category 6.2 but they list PIDAP in cate-gory 6.3, which had up until then been called AO, and so both have been classified
as a separate disease.
There have been 2 mainstream theories regarding the pathophysiology of PIDAP：it has been conventionally considered to be a form of neuropathic pain or assumed to arise due to mental and psychological factors. However, recently, someresearchers have also proposed the theory that it arises due to central sensitizationand modulations to the pain processing process in the brain.
In 70～83% of PIDAP cases, it is triggered by dental treatment, and as many ofthe patients who have this disease are seen to have for example a peculiar feelingof distrust in healthcare, anger and anxiety, an existing history of mental diseases
such as anxiety disorder, stress－related disorder, and somatoform disorders（somatic symptom disorder : DSM-5）,or several of these coexist, one needs to evaluate patients both on their mental state and on their psychosocial condition. In other words, the key to obtaining an accurate diagnosis of PIDAP is to exclude organic diseases including of the brain, and the physician needs to try diverse approaches, such as confirm that it is not some other non－odontogenic disease and conduct a
psychosocial evaluation4).

M．Orofacial Pain

527

CQ M－4－2：What is the algorithm for diagnosing persistent idiopathic dentoalveolar pain ?
Answer： Diagnosing persistent idiopathic dentoalveolar pain（PIDAP）is basically a diagnosis by exclusion, and so it is necessary to confirm that diseases or lesions
that could be the cause of the pain at the site in question（the tooth or alveolarpart）are not present. When physicians are unable to find any abnormalities to thetooth or surrounding tissue（periodontal membrane, the jawbone）, then they
search for pathologies which may give rise to referred pain at the same site. With
the results of a diagnosis by exclusion, if one cannot see a pathology which could
be thought of as another cause of the pain, then it is compared against the diagnostic criteria of PIDAP, and if it meets those diagnostic criteria, then a diagnosis of
PIDAP is pronounced.
Commentary：
2)
In the International Classification of Headache Disorders 3rd Edition（ICHD－3）
itis assumed to be PIFP, and in the International Classifications of Orofacial Pain
（ICOP）3), they classify PIDAP as pain of the tooth and alveolar part whereas painof the face is classified as PIFP. In these guidelines we will follow the classificationsof the ICOP.
In the ICOP, when there is no event that could be thought of as a preceding
cause, and the pain has persisted for more than 2 hours a day and for more than 3months, and recurs every day, it is considered to be a persistent pain of the mouthwith various accompanying symptoms. It is rare for it to manifest in several places；in many cases it manifests unilaterally3). It is rare for the pain to appear at several sites and over time, it might possibly spread to a wider region of the head andneck.
Several words are used to explain the characteristics and nature of this pain. It issometimes expressed as a pain in a deep part of the face, and is sometimes expressed as being on the surface. In order to explain the sensations and complexitiesof this disorder, sometimes one opts to explain the supplementary symptoms. It
displays relatively stable symptoms but sometimes the pain worsens and may possibly be exacerbated due to stress.
In a clinical somatosensory evaluation such as pinprick or light exposure to thetouch, it is almost never the case that paresthesia becomes apparent. A nociceptive
pain which reflects the processes of a changed somatosensory system is present
and this may possibly be related to changes in a descending pain inhibitory system.
On the other hand, in cases of an existing history of clear trauma to the trigeminal
nerve（disorders which are mechanical, chemical, temperature-based or due to radiation）, and when it has been less than 6 months since receiving the trauma, dis-

PIDAP：persistentidiopathic dentoalveolar pain

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M．Orofacial Pain

playing either negative symptoms indicating dysfunction in the area served by thenerve that has received trauma（hypaesthesia/hypoesthesia, hypoalgesia）or positive symptoms（hyperalgesia, allodynia）, or when both symptom types are present,
then according to the ICOP classification, it is classified as ‘4.1.2.3 post－traumatic
trigeminal neuropathic pain.
Furthermore, in the ICOP classification, they define ‘6.2 persistent idiopathic fa3)
cial pain’（PIFP）, as “symptoms of neurological deficit are absent, pain persists formore than 2 hours a day and for more than 3 months, recurs every day, and is persistent pain in the face with various accompanying symptoms.” Patients sufferingfrom PIFP sometimes also suffer from other pain diseases such as chronic widespread pain and irritable bowel syndrome（IBS）, and mental illness or psychosocial
problems are frequently concomitant. PIFP is sometimes triggered by minor operations or trauma to the face, maxillary sinus, teeth or periodontal tissue, and after
the wounds have healed, the situation might be prolonged without a clear identification of the local cause. However, a psychophysical and a neurophysiological examination may sometimes indicate a sensory disorder.

CQ M－4－3：What kinds of treatment are there for burning mouth syndrome（BMS）apart from pharmacotherapy ?
Answer： Amitriptyline, gabapentin, pregabalin, venlafaxine, duloxetine are used
experimentally, but at the present stage, there is no scientifically－proven pharmacological method.
Commentary：
In 2020, primary chronic orofacial pain of the orofacial region was sorted andclassified by the ICOP, and this led to the establishment of the disease concept, PIDAP. As mentioned previously, with chronic pain which does not clearly originate
from the orofacial region, just like with chronic pain in other regions, antidepressants have come to be used experimentally. There are some research studies whichhave considered the effects of antidepressants, including its effects on chronic painof the orofacial region of which the cause is unknown, but with this, it is difficult toevaluate their effects in treating PIDAP. At the current stage. no high－quality evidence reports exist which could allow us to judge the efficacy of specific drugs on
PIDAP. As for case reports and case control studies on pathologies which apply to
PIDAP, there are scattered research papers here and there which have reported
on the utility of TCA, SNRI and Gabapentinoid. Therefore, using analgesics and antidepressants for treating PIDAP is not at this stage supported by evidence35), andtherefore there will be a need for materials allowing us to judge its effects based

M．Orofacial Pain529

on the ICOP3) in an objective manner through future RCT studies.

CQ M－4－4：What are other ways to treat persistent idiopathic dentoalveolar
pain, apart from pharmacotherapy ?
Answer： Researchers have considered cognitive－behavioral therapy（CBT）,
transcranial magnetic stimulation（TMS）, and lower－level laser therapy（LLLT） TMS：transcranial
for treating primary chronic pain of the orofacial region. However, just like withpharmacotherapy, they have yet to establish a specific form of treatment for PIDAP.
Commentary：
PIDAP was established as a disease concept by the ICOP in 20203), and its neuropathic mechanism is not required as part of its diagnostic criteria. Pathologies that
had traditionally been covered and treated as orofacial pain without a known cause,
no longer need to have elements of neuropathic pain. Regarding the effects of themethods to treat primary chronic orofacial pain mentioned above, revision is now
required on which pathology was targeted. As for non－pharmacological ways oftreating primary chronic orofacial pain, including PIDAP, there are reports whichhave considered the effects for example from CBT, hypnotherapy, TMS, and LLLT
but nothing has yet been reported on research specifically on the effects of treating
PIDAP. We hope researchers will consider the effects of treatments targeting patients with PIDAP based on the ICOP diagnostic criteria3).
References
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5）‌IASP : 7. Persistent Idiopathic Facial Pain Fact Sheets in English revised in2016 for the 2013－2014 Global Year Against Orofacial Pain. https : //www.
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magnetic stimulation

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1091. doi : 10.1111/papr.12406. PMID : 26891784
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Burden : The Global Campaign against Headache. J Headache Pain 2019 ; 20 :57. doi : 10.1186/s10194－018－0899－2. PMID : 31113373
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25）‌Gubian A, et al : Meta－analysis on safety and efficacy of microsurgical and radiosurgical treatment of trigeminal neuralgia. World Neurosurg 2017 ; 103 :
757－767. doi : 10.1016/j.wneu.2017.04.085. PMID : 28435111
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27）‌de Pedro M, et al : Efficacy of low－level laser therapy for the therapeutic
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28）‌Imamura Y, et al : An updated review on pathophysiology and managementof burning mouth syndrome with endocrinological, psychological and neuropathic perspectives. J Oral Rehabil 2019 ; 46 : 574－587. doi : 10.1111/joor.12795.
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29）‌IASP : 5. Burning Mouth Syndrome Fact Sheets in English revised in 2016 forthe 2013－2014 Global Year Against Orofacial Pain. https : //www.iasp－pain.
org/Advocacy/Content.aspx?Item Number＝107830）‌Cui Y, et al : Efficacy evaluation of clonazepam for symptom remission inburning mouth syndrome : A meta－analysis. Oral Dis 2016 ; 22 : 503－511. doi :10.1111/odi.12422. PMID : 26680638
31）‌McMillan R, et al : Interventions for treating burning mouth syndrome. Cochrane Database Syst Rev 2016 ; 11（11）: CD002779. doi : 10.1002/14651858.
CD002779.pub3. PMID : 27855478
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33）‌de Souza IF, et al : Treatment modalities for burning mouth syndrome : A
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018－2454－6. PMID : 29696421
34）‌Malacarne A, et al : Persistent dentoalveolar pain disorder : A comprehensive
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the evidence－based principles of dentistry. Cranio 2011 ; 29 : 219－226. doi :10.1179. PMID : 22586831

531

Chapter N．Headache：CQ N-1～CQ N-5-3
CQ N-1：How is headache classified ?
CQ N-2：How do we differentiate dangerous headaches ?
CQ N-3：How can we treat medication-overuse headache ?
CQ N-4-1：Are anti-CGRP antibodies and anti-CGRP receptor
antibodies useful for preventing chronic migraine ?
CQ N-4-2：Are oral drugs useful for preventing chronic migraine ?
CQ N-5-1：Is non-invasive（percutaneous）vagus nerve stimulation
useful for chronic cluster headache ?
CQ N-5-2：Is transcranial magnetic stimulation（TMS）useful forchronic migraine and chronic tensions-type headache ?
CQ N-5-3：Is acupuncture useful for chronic migraine／chronic
tension-type headache ?

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N．Headache

N．Headache
CQ N－1：How is headache classified ?
Answer：We recommend using the ‘International Classification of Headache DisICHD：International
Classification of
Headache Disorders

orders 3rd Edition’（ICHD－3）published by the International Headache Society forclassification and diagnosis, in order to advance headache treatment based upon
scientific research.
Commentary：
Epidemiological research into headaches is lagging behind other fields. The reason for this is, although there were no problems with diagnosis secondary headache, diagnosis of primary headache, which accounts for the majority of headache
disorders, is not consistent among reports and investigators. Therefore, one is unable to compare findings with other reports and it has been difficult to conduct epidemiological research. In this context, in 1988, the International Headache Society
announced the classification of headaches according to clinical findings as well as
diagnostic criteria in its ‘International Classification of Headache Disorders’（ICHD）,
thereby swiftly bringing about a worldwide standardization to the treatment ofheadaches. Upon this occasion, there was the first consensus regarding migraine asa disease concept. A 2nd Edition was published in 2004, and then in agreement withformulation ICD－11 by the World Health Organization（WHO）, they published the
3rd Edition（beta edition）in 2013. They published the Official 3rd Edition（ICHD－3）
in January 2018, and a Japanese version was published in November of the sameyear1－3).
In ICHD－3, they have made significant changes mainly to migraine and what had
been previously categorized as a complication of migraine. ‘Chronic migraine’ wasclassified in the same level headache category as “migraine without aura” and “migraine with aura”, making it even more important to differentiate it from ‘tension－
type headache（TTH）’. Furthermore, ‘basilar migraine’ was reclassified under “migraine with aura” as “migraine with brainstem aura”. As mentioned above, researchers have pointed out the relationship between dizziness and migraine, butthey have added the new category of “vestibular migraine” to the Appendix.
The current ICHD－3 is comprised of Part 1：The primary headache, Part 2：
The secondary headache, and Part 3：Painful cranial neuropathies, other facial pain
and other headaches. It has classified over 300 types of headache categories andeach one is diagnosed in stages according to first to fifth-digit levels. In cases
where patients exhibit several headache diagnoses, they will be enumerated in theorder of importance to the patient（Table N－1）.

N．Headache

Table N－1

Headache Classifications according to the International Classification of
Headache Disorders 3rd Ed（Cited from References #3）

Part 1 : The primary headache
1．Migraine
2．Tension－type headache（TTH）
3．Trigeminal/autonomic cephalalgias（TACs）
4．Other primary headache disorders
Part 2 : The secondary headache
5．Headache attributed to trauma or injury to the head and/or neck
6．Headache attributed to cranial and/or cervical vascular disorder
7．Headache attributed to non-vascular intracranial disorder
8．Headache attributed to a substance or withdrawal disorder
9．Headache attributed to infection
10．Headache attributed to disorder of homeostasis disorder
11．Headache or facial pain attributed to disorder of the cranium, neck, eyes, ears,
nose, sinuses, teeth, mouth or other facial or cervical structure
12．Headache attributed to psychiatric disorderPart 3 : Painful cranial neuropathies, other facial and other headaches
13．Painful lesions in the cranial nerves and other facial pain
14．Other headache disorders
Appendix

CQ N－2：How do we differentiate dangerous headaches ?
Answer：There is an overwhelmingly high percentage of people with primaryheadache in which no abnormalities can be found on tests, and if it progresses tochronic headache and new symptoms arise, it is important to discern dangerous
secondary headache at an early stage, especially possibility of subarachnoid haemorrhage. In the following cases, the physicians actively investigates when secondary headache is suspected. ① Systemic symptoms including fever；② Neoplasm inhistory；③ Neurologic deficit or dysfunction（including decreased consciousness）；④ Onset of headache is sudden or abrupt；⑤ Older age（after 50 years）；⑥ Pattern change or recent onset of headache；⑦ Positional headache；⑧ Precipitatedby sneezing, coughing, or exercise；⑨ papilledema；⑩ Progressive headache andatypical presentations；⑪ Pregnancy or puerperium；⑫ Painful eye with autonomic features；⑬ Posttraumatic onset of headache；⑭ Pathology of the immune
system such as HIV；⑮ Painkiller overuse or new drug at onset of headache.
Commentary：
Headache is divided into two types：primary headache where the headache itself
is a disease and secondary headache which manifests due to some underlying
cause. The ‘SNNOOP10 List’ introduces the red－flag symptoms of secondary head-

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N．Headacheache as clinical clues allowing us to differentiating between the two（primary andsecondary）（Table N－2）
.4) . It is hard to diagnose secondary headache in patients
who complain just of a mild headache and who are able to walk without assistanceto the hospital, in particular even upon their first consultation or if they are a patient with a previous history of chronic pain, if patients are aware that their headache is different from usual, such as the site of pain and how long it persists, thenit is important to make a differential diagnosis of secondary headache.
Dangerous secondary headache is one that occurs frequently and unexpectedly
and which within 1 minute the intensity of the pain reaches a peak and becomes athunderclap headache. With this kind of sudden headache, it is difficult to differentiate it as primary headache just on consultation alone, especially in cases where
there are no other symptoms other than headache., In the ‘Clinical Practice Guidelines for Chronic Headache 2013’ they recommend actively conducting imaging
tests5). The cause of a thunderclap headache is often due to cerebrovascular diseasRCVS：reversible cerebral vasoconstriction
syndrome

es such as subarachnoid haemorrhage, reversible cerebral vasoconstriction syndrome（RCVS）, cerebral artery dissection, cerebral venous sinus thrombosis, andpituitary apoplexy. Other causes of sudden headache include hydrocephalus, meningitis, encephalitis, glaucoma, acute sinusitis, systemic infection, brain tumor, drug－
induced headache, and trauma. One should proceed with treatment after underTable N－2

Secondary headache warning signs（red flags）：SNNOOP 10 List
（Cited from Reference #1）
Signs & Symptoms

Flag color

1

Systemic symptoms including fever

Red（orange if only
fever is present）

2

Neoplasm in history

Red

3

Neurologic deficit or dysfunction（including decreased
consciousness）

Red

4

Onset of headache is sudden or abrupt

Red

5

Older age（after 50 years）

Red

6

Pattern change or recent onset of headache

Red

7

Positional headache

Red

8

Precipitated by sneezing, coughing, or exercise

Red

9

Papilledema

Red

10

Progressive headache and atypical presentations

Red

11

Pregnancy or puerperium

Red

12

Painful eye with autonomic features

Red

13

Posttraumatic onset of headache

Red

14

Pathology of the immune system such as HIV

Red

15

Painkiller overuse or new drug at onset of headacheRed

N．Headache

Table N－3

Ottawa Subarachnoid Haemorrhage Rule（Ottawa SAH Rule）（based on Reference #5）  
Headache in which pain reaches its peak within 1 hour, in adult patients without any
recognizable neuropathy, and when the following items do not apply, then generally
subarachnoid haemorrhage（SAH）can be ruled out. If one of them is present,
sensitivity 100％（97.2～100.00）；specificity 15.3％（13.8～16.9）, then one needs
to consider the possibility of subarachnoid haemorrhage.
Ⅳ・Age
40 years old
・Neck pain or stiffness
・Witnessed loss of consciousness
・Onset during exertion
・Thunderclap headache（instantly peaking pain）
・Limited neck flexion on examination

standing the characteristics of each respective disease, such as the mode of onset
and physical findings of the headache and if necessary, conduct additional tests
such as on imaging test findings.
With subarachnoid haemorrhage（SAH）, the most important disease to differentiate is thunderclap headache but in cases were only mild pain manifests and a diagnosis is delayed and the condition is not properly attended to, then it can lead to
medical litigation6). A frequent characteristic of this pain is thunderclap headachein 80% of the cases, and symptoms are throbbing pain and stabbing pain7). According to a report which considered whether subarachnoid haemorrhage（SAH）could
be diagnosed or not on clinical characteristics alone, the Ottawa SAH rule says that
it is not subarachnoid haemorrhage when none of these 6 items apply：patientⅣaged

40 years old, neck pain or stiffness, witnessed loss of consciousness, onset

during exertion, thunderclap headache (instantly peaking pain), limited neck flexion
8)
on examination（Table N－3）
. However, in actual clinical settings, it is difficult togive a definitive diagnosis of subarachnoid haemorrhage（SAH）just on headache
symptoms and taking patient history alone, and therefore imaging test is essential.
CT and MRI are the typical imaging tests but sometimes a CT is unable to detect
small amounts of bleeding or a hematoma at the posterior fossa or vertex side andthe rate of diagnosis declines over time：98% within the first 12 hours；86～93%
within the first 24 hours, 76% within the first 48 hours, 50% within the first week,and 30% within two weeks9). On the other hand, with Fluid Attenuated Inversion
Recovery（FLAIR）images on MRI, the false negative rate within 24 hours of onset
is 2%, which is relatively low at 14% on CT. In cases where a subarachnoid haemorrhage（SAH）cannot be ruled out, an MRI including FLAIR images and T2＊
weighted images（T2＊WI）can be useful10). When doing this, an MR angiography（MRA）should be performed at the same time, and it is important to confirm thepresence or absence of cerebrovascular lesions, which are often a cause of thunder-

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N．Headacheclap headache, such as cerebral aneurysm and arterial dissection and reversible cerebral vasoconstriction syndrome（RCVS）.

CQ N－3：How can we treat medication－overuse headache ?
Answer：Patients who have had recurrent headache before and whose condition
has deteriorated due to an excessive amount of analgesics and for example triptan,
MOH：medicationoveruse headache

experience medication－overuse headache（MOH）. This condition is diagnosed
based on the International Classifications of Headache Disorders 3 rd Edition（ICHD-3）and the basic principles of treatment are① discontinue the overused

medication；② treatment of headache after discontinuation of the overused medication；and ③ administer preventive medicine.
Commentary：1）Diagnosis
MOH is a condition in which patients with a previous history of primary headache overuse in the acute phase symptomatic headache medicine or a new type ofheadache manifests. Alternatively the primary headache that was already present
becomes markedly worse and the person suffers from the headaches for more than3)
15 days a month in total（Table N－4）
. In the International Classification of Head-ache Disorders 3rd Edition（ICHD－3）, it is classified as a sub－type 8.2 under “medication-overuse headache（MOH）”（Table N－5）which is then sub－divided into each
respective sub－category depending on the underlying drug that the patient was
overusing. Overuse is defined as taking medication for more than 15 days in amonth in total for over 3 months for non－opioid analgesics, and for other types of
medication, it refers to taking medication for more than 10 days a month.
The prevalence rate has been reported to be about 1～2% of the entire population, chronic pain is 25～50％, and 30～50% of headache outpatients and headache
center patients11－13). Often the original headache is a migraine14). It tends to occur
Table N－4

Diagnostic criteria for headaches due to medication－overuse headache（MOH）（Cited from Reference #1）

A．Headache occurring on 15 days/month in a patient with a pre-existing headache
disorderB．Regular overuse* for ＞ 3 months of one or more drugs that can be taken for acuteand/or symptomatic treatment of headache
C．Not better accounted for by another ICHD-3 diagnosis
Abuse ／ overuse＊ is defined as taking non－opioid analgesics for 15 days or more permonth and for other medication, 10 days or more per month

N．Headache

Table N－5
8.2

Classifications of headache due to medication－overuse headache（MOH）（Cited from Reference #1）

Medication－overuse headache（MOH）
8.2.1 Ergotamine－overuse headache
8.2.2 Triptan－overuse headache
8.2.3 Non－opioid analgesic overuse headache
8.2.3.1 Paracetamol（Acetaminophen）overuse headache
8.2.3.2 Non－steroidal anti－inflammatory drugs（NSAIDs）overuse headache
8.2.3.2.1 Acetylsalicylic acid overuse headache
8.2.3.3 Other non－opioid analgesic overuse headache
8.2.4 Opioid overuse headache
8.2.5 Combination-analgesic overuse headache
8.2.6 Medication-overuse headache attributed to multiple drug classes notindividually overused
8.2.7 Medication-overuse headache attributed to unspecified or unverified
overuse of multiple drug classes
8.2.8 Medication-overuse headache attributed to other medication

often in women, and if the person is a habitual smoker and lacks exercise, the prevalence rate of MOH doubles and low－income families and those with a poor educational background are at risk of MOH15－17). Researchers claims that compared withtriptan and ergotamine, there is a higher risk from combined analgesics as they area medication that causes MOH18).
2）Treatment
When treatment begins, the most important thing is to provide advice and education on MOH to patients and then discontinue the medicine causing the problem
and provide preventive treatment19). It is also important to encourage patients that
there is a reasonable possibility for their condition to improve through a treatment
intervention, explain to them that overusing analgesics can in fact make their headache worse and first make them withdraw through the thought that, “the headache
they are aware of＝taking analgesics orally.” In some cases, their condition improved just through advice on how to use analgesics. Many cases do not improve
immediately after commencing treatment and one should explain to patients a long－term treatment plan, such as how treatment will last for more than several
months, including how the effects of headache preventive medicine would be expressed. In particular, physicians should explain properly the rebound symptoms
once the medicine causing the headache has been discontinued, and by making
them aware beforehand of the treatment process, in which temporarily the symptoms may worsen but after that, before a steady improvement in symptoms, one
may continue the treatment smoothly without terminating it. Furthermore, one
should let patients know beforehand of the high possibility that treatment might be
prolonged, that in terms of intractable cases, there are intractable complications,mental disease complications such as mood disorder and eating disorder, and cases

539

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N．Headacheof patients using several symptomatic drugs, and relapse cases of MOH20).
The basic principles for treatment according to the ‘Clinical Practice Guideline
for Chronic Headache 2013’ are：① discontinuing the overused medication；② attend to headaches that occur after medication has been discontinued；and ③ administer preventive medicine5). During treatment, a ‘headache diary’ is used, and it
is important to proceed by objectively evaluating the frequency and intensity ofheadache, and how frequently medication is being used.
① Discontinuing the overused medication
There is no evidence on methods for discontinuing the drug of cause but someresearchers have claimed there is a higher relapse rate when dosage is gradually
decreased compared with when suddenly stopped21). Furthermore, as there was nodifference in the prevalence rate when the drug was discontinued during hospitalization or for outpatients, one should first of all consider immediately discontinuing
the drug for outpatients22). However, withdrawal is recommended during hospitalization for overuse of more complex analgesics（barbiturates, benzodiazepines, andopioid analgesics etc.）, long－term overuse of acute－stage treatment drugs, for patients with a failed history of withdrawal as outpatients, and for patients with coexisting mental disease2).
② Treatment of the headache after discontinuing the overused medication
Between 24～72 hours after discontinuing the drug of cause, withdrawal symptoms occur such as aggravated headache, nausea, vomiting, low blood pressure,tachycardia, and sleeping disorders23). These typically continue for 2～10 days butvary depending on the drug of cause；researchers claim an average of 4.1 days
with triptan, an average of 6.7 days with ergotamine, and an average of 9.5 days
with NSAIDs24).
What is used as a rescue for post－withdrawal headache is long－lasting naproxen
and COX－2 inhibitors for example used in combination with tizanadine. In patientswhere there is a strong migraine attack, one could consider using triptan but it isnecessary to limit the number of days they can use it25). Furthermore, for withdrawal symptoms other than headache, physicians should provide symptomatic
treatment such as through rehydration, antiemetics, sedatives and steroid drugs26).
③ Administering preventive medicine
It is recommended to start patients on preventive medicine either while theoveruse medication has been discontinued or before it is discontinued27). The choiceof preventive medicine varies depending on what triggered the onset of MOH but
often it is migraine so for example sodium valproate, lomeridine, proplanol, and amitriptyline are frequently used. Although they are not eligible to be covered under
the Japanese health insurance system, there are many overseas reports that topiramate and botulinum toxin are effective too19). Furthermore, in cases where mooddisorder is also present, one can proceed with a more efficient treatment by choos-

N．Headache

ing a drug taking into consideration any coexisting conditions. In future, one ofthese possible choices is a new type of drug for treating migraine which is alreadyon the market overseas（anti－CGRP antibodies and anti－CGRP receptor antibod28)
ies）.

3）Prognosis
Many cases respond well to treatment, with an improvement in episodic migraine in 57% in the 1st year, and 66% in the 2nd year. On the other hand, researchers have reported a recurrence of episodic migraine in 28－31％ of cases at 6
months, in 41% of cases at 1 year, and 45% of cases at 4 years29). Reports of poor
prognosis factors include a long period of duration for migraine, frequent migraine
attacks after withdrawal, frequent taking of combination medicine, or frequent intake of medication after withdrawal, alcohol, smoking, or taking previous drugs
once again11,30).
The most important thing with MOH is to take precautions and even after remission due to treatment, it is important to prevent a relapse by providing patient
education while confirming at the same time the frequency of headaches and frequency with which medication is taken through using a headache diary.

CQ N－4－1：Are anti－CGRP antibodies and anti－CGRP receptor antibodies
useful for preventing chronic migraine ?
Answer：Anti－CGRP antibodies and anti－CGRP receptor antibodies are useful for
preventing chronic migraine.
Recommendation Grade & Summary of Overall EvidenceRecommendation grade：1（strong）：Implementation is strongly recommended〔Consensus 95.0%〕
Summary of overall evidence：B（moderate）
Commentary：
Anti－CGRP receptor antibodies are useful for preventing chronic migraine but
considering their cost－effectiveness, one must consider administering them or notin cases where for example 2 types of oral medications can either be ineffective or
produce side－effects.
There have been 6 RCT reports which considered and compared the usefulnessof anti－CGRP antibodies on chronic migraine（eptinezumab：not approved in Japan, galcanezub：approved in Japan, fremanezumab：currently under application
for approval）and anti－CGRP receptor antibodies（erenumab：currently under application for approval）. These studies targeted adult patients aged 18 years old＋

541

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N．Headachewith chronic migraine, and researchers investigated whether there was an improvement in chronic migraine or not, and whether it was safe or not, in a placebo－
RCT：randomized
controlled trial

controlled RCT in which patients were administered the treatment drug once amonth through a subcutaneous injection. In all of the research studies, the results
consistently showed that the antibody medicine for CGRP or CGRP receptors was
effective in reducing symptoms of chronic migraine and also that there were few
adverse events. However, in some parts of the research, they identified some slightrisk of bias, for example the reporting of selected outcomes and therefore thestrength of the evidence was around the medium level.
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Selection Summary

2001～2019
Cochrane Library, PubMed, NPO Japan Medical Abstracts Society
chronic migraine
eptinezumab, galcanezumab, fremanezumab, erenumab,preventive therapy, prevention,cgrp
Limited by publication type, PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, other（cases of50＋）etc
Of the 142 MEDLINE 142 search hits, 237 Cochrane search hits, a NPO Japan Medical Abstracts Society search hits, we used 9 of them which matched with the set PICOCQ N－4－2：Are oral drugs useful for preventing chronic migraine ?
Answer：Oral drugs are useful for preventing chronic migraine.
Recommendation Grade & Summary of Overall EvidenceRecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 94.7 %〕Summary of overall evidence：B（moderate）
Commentary：
There have been reports from 3 placebo－controlled RCTs which investigated andcompared the efficacy of oral drugs on chronic migraine；2 of the RCTs were on
topiramate（not eligible for health insurance coverage）and 1 was on sodium valproate. The number of days which adult patients aged 18 years old＋suffered fromchronic migraine significantly decreased at around 4 weeks in the group who wereorally administered with topiramate compared with the placebo. Researchers havenot proven the preventive effects of valproic acid on reducing the number of days
patients suffer from a migraine but compared with the placebo, the frequency of
pain significantly decreased on the visual analogue scale（VAS）, maximum VAS
level and pain frequency. There were no problems with safety in any of the research studies but in the preventive effects of oral drugs for chronic migraine, researchers did notice a slight risk of bias, for example a different oral drug was usedor different outcomes and therefore, the strength of the evidence was medium.
In actual clinical settings when topiramate and valproic acid are not successful,

N．Headachean RCT targeting patients with chronic daily headache used amitriptyline which
was recognized to have preventive effects, and propranolol and romeridine wereused to prevent ‘migraines without warning signs’ and ‘migraines with warning
signs.
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chronic migraine
preventive therapy, prevention
Limited by publication type, PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, other（cases of50＋）etc
Of the 172 MEDLINE search hits, and 1 Cochrane search hit, we used 3 search hits whichmatched with the set PICOP
I／C

Limitations
Selection Summary

CQ N－5－1：Is non－invasive（percutaneous）vagus nerve stimulation useful forchronic cluster headache ?
Answer：Non－invasive（percutaneous）vagus nerve stimulation（nVNS）is usefulfor chronic cluster headache.
Recommendation Grade & Summary of Overall EvidenceRecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕

Summary of overall evidence：C（low）
Commentary：
There was 1 RCT which considered and compared the usefulness of nVNS for
chronic cluster headache. This study targeted adults aged 18 years old＋with
chronic cluster headache and used a standard－treatment group for the control, andperformed non－invasive vagus nerve stimulation（nVNS）6 times a day, and foundthat the number of headache attacks and the actual attacks had significantly decreased by over 50%. There was 1 RCT which considered and compared the usefulness of nVNS on chronic migraine, and researchers confirmed its safety but although it was effective in reducing the number of days when patients had a migraine 2 months later in the nVNS group compared with a sham treatment group,
the difference was not significant.
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2001～2019
Cochrane Library, PubMed, NPO Japan Medical Abstracts Society
chronic migraine, chronic headache
nerve stimulation, brain stimulation, preventive therapy, prevention
Limited by publication type, PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, other（cases of 50＋）etc
Of the 172 MEDLINE search hits, 1 Cochrane search hit, we used 2 of them which matchedwith the set PICO

543

544

N．Headache

CQ N－5－2：Is transcranial magnetic stimulation（TMS）useful for chronic
migraine and chronic tension－type headache ?
Answer：Transcranial magnetic stimulation（TMS）is believed to be useful in reducing chronic migraine pain and reducing the usage of analgesics but there is insufficient evidence on this. There is insufficient evidence allowing us to believe that
it is useful in reducing the intensity of pain from chronic tension－type headache（TTH）. The equipment used for the research which would serve as evidence is different from the equipment used in Japan so we do not have certain grounds on
TMS：transcranial
magnetic stimulation

which we can recommend TMS.
Recommendation Grade & Summary of Overall EvidenceR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 90.0%〕

Summary of overall evidence：C（low）
Commentary：
There are only 4 RCTs which have considered and compared the usefulness of
TMS for chronic migraine. Three of them used repetitive magnetic stimulation, andthe other one used deep transcranial magnetic stimulation. The transcranial magnetic stimulation study did not observe that it was effective in reducing the number of attacks and the number of days patients had a headache. In 2 of the studies,
they observed that it was effective in reducing intensity of pain, and in 3 of thestudies, it was effective in reducing the number of times analgesics were used.
Overall, there were few cases, and some of the research poorly explained their
methods regarding how they made the test blind, and the methods of treatment
were different as well so the level of the evidence was low. There was only 1 RCT
in which researchers observed a decrease in the intensity of pain from chronic tension－type headache and a rise in the pain threshold so the level of evidence waslow.
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2001～2019
Cochrane Library, PubMed, NPO Japan Medical Abstracts Society
chronic migraine, chronic headachetranscranial magnetic stimulation
Limited by publication type, PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, other（cases50＋）etc
Of the 172 MEDLINE search hits etc, we used 6 of them which matched with the set PICON．Headache

CQ N－5－3：Is acupuncture useful for chronic migraine／chronic tension－type
headache ?
Answer：An acupuncture may be useful for preventing chronic migraine. Its effects for preventing chronic tension－type headache are not superior to those ofphysical therapy and relaxation.
Recommendation Grade & Summary of Overall EvidenceRecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 83.3%〕

Summary of overall evidence：C（low）
Commentary：
There are 2 studies which considered the effects of acupuncture on chronic migraine by comparing it against taking oral medication and both of these studies
found that it was significantly more effective in preventing it. However, comparedwith the oral medication, the placebo effect from acupuncture was fairly high andtherefore one must consider the possibility that the significant difference may havebeen caused by the placebo effect. The effects from acupuncture in preventing
chronic tension－type headache, as well as from sham treatments or physical therapy and relaxation, showed that it had reduced the intensity of pain compared withprior to treatment but there was no significant difference in the mitigating effects
from acupuncture, sham treatments or physical therapy and relaxation. In terms ofsafety, there have been no reports mentioning severe adverse events and therefore
it is believed to be generally safe.
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2001～2019
Cochrane Library, PubMed, NPO Japan Medical Abstracts Society
chronic migraine, chronic tension－type headacheacupuncture
Limited by publication type, PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, other（cases of50＋）etc
Of the 54 MEDLINE search hits and 1 Cochrane search hit, we used 6 of them which matchedwith the set PICO

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53）‌Linde K, et al : Acupuncture for the prevention of tension－type headache. Cochrane Database Syst Rev 2016 ; 4 : CD007587. doi : 10.1002/14651858.
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55）‌Söderberg E, et al : Chronic tension－type headache treated with acupuncture,physical training and relaxation training : Between－group differences. Cephalalgia 2006 ; 26 : 1320－1329. doi : 10.1111/j.1468－2982.2006.01209.x. PMID :17059439
56）‌Kwak B－M, et al : Persisting effects of acupuncture method for chronic tension－type headache : A randomized controlled trial. J Acupunct Res 2008 ; 25（2）: 165－177［Korean］

549

Chapter O．Herpes Zoster-Related Pain
：CQ O-1～CQ O-8
CQ O-1：What kind of pathology is herpes zoster ?
CQ O-2：How is herpes zoster-related pain categorized ?
CQ O-3：Is vaccine useful for preventing herpes zoster andpostherpetic neuralgia（PHN）?
CQ O-4：Is the administration of antiviral drugs, after onset of herpes
zoster, useful for preventing postherpetic neuralgia ?
CQ O-5-1：Is pregabalin useful for postherpetic neuralgia（PHN）?
CQ O-5-2：Is gabapentin useful for postherpetic neuralgia（PHN）?
CQ O-5-3：Is mirogabalin useful for postherpetic neuralgia（PHN）?
CQ O-5-4：Is amitriptyline useful for postherpetic neuralgia（PHN）?
CQ O-5-5：Is nortriptyline useful for postherpetic neuralgia（PHN）?
CQ O-5-6：Is tramadol useful for postherpetic neuralgia（PHN）?
CQ O-6：Is performing nerve block therapy soon after onset ofherpes zoster, useful for preventing postherpetic neuralgia（PHN）?
CQ O-7-1：Is pulsed radiofrequency of the dorsal root ganglion（DRG-PRF）useful for herpes zoster-related pain ?
CQ O-7-2：Is applying pulsed radiofrequency to the peripheral
nerves useful for postherpetic neuralgia（PHN）?
CQ O-8：Is spinal cord stimulation useful for postherpetic neuralgia（PHN）?

552

O．Herpes Zoster-Related Pain

O．Herpes Zoster-Related Pain
CQ O－1：What kind of pathology is herpes zoster ?
Answer：Herpes zoster is a painful small rash that occurs when a latent infection
VZV：varicella-zostervirus

of the sensory ganglion by the varicella－zoster virus（VZV）,after someone has hadchickenpox, is reactivated. Normally, the rash is treated in a few weeks but sometimes there are various complications that arise afterwards.
Commentary：
Varicella－zoster virus（VZV）is a neurotropic virus which invades the sensory
ganglion at the onset of chickenpox. However, even after the chickenpox is cured,
there is a latent infection in the cranial ganglion and dorsal root ganglion. Due to avariety of factors, when the patient’s specific cellular immunity is weakened, the latent infection of VZV is reactivated, causing herpes zoster1－3). Normally, this gives
onset to acute painful herpes at one dermatome. Frequently, several days before
the rash appears, premonitory symptoms manifest such as fever, headache, feelingof discomfort, and pain. Several weeks after onset, the skin lesions heal and may
leave scars and pigmentation. The main risk factor is ageing, and in patients aged
50 years old and over, onset clearly increases. Various complications have been reported but the most frequently occurring complication is postherpetic neuralgia

PHN：postherpetic
neuralgia（PHN）.

CQ O－2：How is herpes zoster－related pain categorized ?
Answer：Herpes zoster－related pain includes acute mainly inflammatory pain
and chronic neuropathic pain.
Commentary：
Herpes zoster－related pain can range from acute to chronic pain4,5). The acutepain is a precursor pain and arises when a patient has herpes zoster and as the virus multiplies, patients mainly suffer from an inflammatory pain that arises whennerve cell tissue is damaged as a result of the body’s immune response. As a resultof chronic impairment of the peripheral nerves and central nerves and secondary
sensation, it develops into postherpetic neuralgia（PHN）, which is an intractableform of neuropathic pain. There is no standard definition of PHN but it is often defined as pain that persists after 90 days have passed since manifestation of therash. Allodynia and hyperalgesia are frequent characteristics of PHN. Risk factors

O．Herpes Zoster-Related Pain553

of PHN include aging, precursor pain, severe rash, severe pain, and ocular complications6).

CQ O－3：Is vaccine useful for preventing herpes zoster and postherpetic
neuralgia（PHN）?
Answer：Either a live－virus vaccine or sub－unit vaccine works on the chickenpox／varicella－zoster virus（VZV）and prevents the onset of herpes zoster, and prevents the transition to postherpetic neuralgia（PHN）. There are no severe side effects. The usefulness of the live－virus vaccine deteriorates over time. We are expecting that future research will investigate how long the sub－unit vaccine is effective.
The sub－unit vaccine is more useful than the live－virus vaccine and although it
is possible to vaccinate immunodeficient patients, there are often side reactions.
Recommendation Grade & Summary of Overall Evidence1）Live－virus vaccine
Recommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕

Summary of overall evidence：B（moderate）
2）Sub－unit vaccine
Recommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 80.0%〕

Summary of overall evidence：B（moderate）
Commentary：
In Japan, the use of the live－virus vaccine for the prevention of herpes zoster
was approved in 2016 and the use of the sub－unit vaccine was approved in 2018.
The live－virus vaccine is administered once subcutaneously and the sub－unit vaccine is administered intramuscularly twice with a two－month interval between thefirst and second shot. The sub－unit virus has an adjuvant（AS01B）added to theglycoprotein components of the varicella zoster virus.
Patients with immune function abnormalities and patients undergoing treatment
for immunosuppression cannot be vaccinated with the live－virus vaccine. On theother hand, such patients can be vaccinated with the sub－unit virus. The Centers
for Disease Control and Prevention（CDC）in the US, stated in 2017 that they recommend the sub－unit vaccine more for preventing herpes zoster and related complications7).
The sub－unit vaccine may be beneficial for patients who are at high risk of se-

PHN：postherpetic
neuralgia

554

O．Herpes Zoster-Related Painvere herpes zoster. As there is a possibility that systemic side reactions may manifest, it is necessary for the patients to understand this properly when administeringit.
1）Live－virus vaccine
RCT：randomized
controlled trial

According to 2 RCTs8,9), during the observation period which is approximately 6months～3 years, the live－virus vaccine reduced the onset of herpes zoster by 53%,
thereby reducing PHN by 67%. There have been no severe adverse events fromthe live－virus vaccine. The efficacy of the live－virus vaccine deteriorates over timebut, there have been reports that it inhibits the onset rate of herpes zoster up to 8
years after the vaccination10).
2）Sub－unit vaccine
According to 2 RCTs11,12), in an observation period of approximately 3～4 years,
the sub－unite vaccine reduced the onset of herpes zoster by 93%, thereby reducing
PHN by 89%. There were no severe adverse events from the sub－unit vaccine. Local reactions at the site of injection（pain, redness, swelling）and systemic side reactions（fatigue, gastrointestinal symptoms, headache, muscle pain, and the chills）,
a few days after the vaccine, were significantly higher than the placebo. At follow－
up approximately 3 years later, researchers confirmed cellular immunity and humoral immunity had been maintained by the vaccine13).
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2005～2019
MEDLINE, Cochrane Central,NPO Japan Medical Abstracts Society
adult
herpes zoster vaccine, chickenpox vaccine／nothing specified
Limited by publication type, Pubmed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, etc
Of the 279 MEDLINE search hits, 315 Cochrane Central search hits, and 12 NPO Japan Medical Abstracts Society search hits, we used 7 references that matched with the set PICOCQ O－4：Is the administration of antiviral drugs, after onset of herpes zoster,useful for preventing postherpetic neuralgia ?
Answer：By administering a patient with an anti－viral drug within 72 hours of
onset of herpes zoster, it helps cure the rash and reduce acute pain. Acyclovir does
not prevent herpes zoster transitioning into PHN. Famciclovir, valaciclovir,
amenamevir may possibly prevent the transition to PHN but we are unable to saythat the evidence on this is sufficient.
Recommendation Grade & Summary of Overall EvidenceRecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 95.0%〕

Summary of overall evidence：C（low）

O．Herpes Zoster-Related Pain

555

Commentary：
Antiviral drugs that are used against herpes zoster are acyclovir, famciclovir, valaciclovir, and amenamevir. Famciclovir is a penciclovir prodrug, and valaciclovir isan acyclovir prodrug, with a higher bioavailability rate than acyclovir. One should
be careful about usage and dosage when it comes to acyclovir, famciclovir, and valaciclovir as side effects can easily arise in elderly patients and those with impaired
kidney function. Amenamevir is a relatively new drug, approved for use in 2017,
which by inhibiting the activation of helicase and primase in the chickenpox／varicella－zoster virus（VZV）, blocks the duplication of its DNA. It is metabolized in theliver and excreted in the feces, so there is no need to regulate the dosage due todecreased renal function. Furthermore, administering patients once a day is fine.
Amenamevir is believed to be easy to use in patients with impaired renal function
and those with medication non－compliance. As it is a new drug, there are still few
reports on its usefulness.
There are several placebo－controlled RCTs on the usefulness of acyclovir14－17). If
administration is begun within 72 hours after the rash manifests, it reduces thetime until the skin lesions are healed and reduces acute pain. The number of patients who had pain 4 months after onset did not decrease14,15).
There is an RCT on the usefulness of famciclovir18) which used a group administered with acyclovir for the control19－21). It has the same effect as acyclovir on rash
and acute pain. Among patients who commenced treatment within 48 hours, there
were fewer patients with pain at between 1～6 months than with acyclovir19).
There is also an RCT on the usefulness of valaciclovir which used a group administered with acyclovir for the control22), and an RCT which used a group administered with famciclovir for the control23). It had the same effect on patients’ rash as
acyclovir and famciclovir22,23). The period in which pain disappeared in the acute to
sub－acute phase was shorter in the group administered with valaciclovir than it
was for the group administered with acyclovir. Furthermore, patients had less pain
after 24 weeks in the group that were administered with valaciclovir for 14 days22).
There is an RCT which investigated the usefulness of amenamevir using a group
administered with valaciclovir for the control24). There was a higher number of patients in whom the formation of new lesions no longer manifested on the 4th day oftreatment in the group administered with amenamevir. There was no difference
between the groups in the amount of time that it took for the rash to turn into ascab, no difference in the amount of time it took for the pain to improve and at 91
days, there was no difference in the number of patients suffering from pain.
We are unable to say that there is sufficient evidence on the preventive effects
of antiviral drugs for postherpetic neuralgia（PHN）and therefore further investigation is required in future25). However, it is clearly useful in the acute phase andtherefore antiviral drugs should be administered early for herpes zoster.

RCT：randomized
controlled trial

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O．Herpes Zoster-Related Pain

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2005～2019
MEDLINE, Cochrane Central, NPO Japan Medical Abstracts Society
herpes zoster, postherpetic neuralgia, zoster associated pain
antiviral agent, acyclovir, valacyclovir, famciclovir, Amenamevir／nothing specified
Limited by publication type, Pubmed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, etc
Of the 47 MEDLINE search hits, 163 Cochrane Central search hits, and 54 NPO Japan Medical
Abstracts Society search hits, we utilized references that matched with the set PICO. We
used references from before 2005 that we searched for and which were important as papers
for reference purposes. From the above, we used 12 search hits

CQ O－5－1：Is pregabalin useful for postherpetic neuralgia（PHN）?
Answer：Pregabalin is useful for postherpetic neuralgia. Research indicates that
it is effective in terms of dosage dependency but it does have a high incidence rateof side effects（sleepiness and drowsiness etc.）.One needs to be careful with its usage and dosage in patients with renal dysfunction.
Recommendation Grade & Summary of Overall EvidenceR ecommendation grade：1（strong）：Implementation is strongly recommended〔Consensus 100.0%〕
Summary of overall evidence：A（high）
Commentary：
There are several RCTs on the effects of pregabalin on PHN26－32). According to asystematic review which summarizes these studies33), when the outcome was set at
a 50%＋reduction in pain, the number needed to treat（NNT）when patients wereadministered with 150 mg, 300 mg, and 600 mg, was 8.3,5.1, and 3.9, respectively.
There were no severe side effects from pregabalin but drowsiness and dizzinessdid increase with dosage dependence.
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Selection summary

2005～2019
MEDLINE, Cochrane Central,NPO Japan Medical Abstracts Society
postherpetic neuralgia, zoster associated pain
pregabalin／nothing specified
Limited by publication type, Pubmed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, etc
Of the 55 MEDLINE search hits, 139 Cochrane Central search hits, and 9 NPO Japan Medical
Abstracts Society search hits, we used 6 references that matched with the set PICO. We usedsome references from before 2005 which we searched for and were important. From theabove, we used 8 references

CQ O－5－2：Is gabapentin useful for postherpetic neuralgia（PHN）?
Answer：Gabapentin is useful on postherpetic neuralgia（PHN）. One must be
careful of side effects such as drowsiness and dizziness and be careful of its usage
and dosage in patients with renal dysfunction.

O．Herpes Zoster-Related Pain

Recommendation Grade & Summary of Overall EvidenceRecommendation grade：1（strong）：Implementation is strongly recommended〔Consensus 94.7%〕
Summary of overall evidence：A（high）
Commentary：
Since 2018, gabapentin has been approved for use on neuropathic pain but is not
eligible to be covered under the Japanese health insurance system. There are several RCTs on the effects of gabapentin on PHN. According to a systematic review
which summarizes these studies34), when the outcome was a 50％＋reduction inpain, the number needed to treat（NNT）when patients were administered with
between 1,200～3,600 mg, was 6.9. There were no severe side effects from gabapentin but there were side effects such as drowsiness and dizziness.
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Selection summary

2005～2019
MEDLINE, Cochrane Central, NPO Japan Medical Abstracts Society
postherpetic neuralgia, zoster associated pain
gabapentin／nothing specified
Limited by publication type,Pubmed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, etc
Of the 55 MEDLINE search hits, 147 Cochrane Central search hits, and 1 NPO Japan Medical
Abstracts Society search hits, we used 6 references which matched with the set PICO. We
used some citations from references prior to 2005 that were important. From the above, weused 1 review

CQ O－5－3：Is mirogabalin useful for postherpetic neuralgia（PHN）?
Answer：Mirogabalin is useful for postherpetic neuralgia（PHN）. The incidence
rate of side effects such as drowsiness and dizziness increase as the dosage increases and therefore physicians need to be careful of this. One must also be careful
about its usage and dosage when administering it to patients with renal dysfunction.
Recommendation Grade & Summary of Overall EvidenceRecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 90.0%〕

Summary of overall evidence：B（moderate）
Commentary：
Mirogabalin is a new drug, which became available for clinical use for treating
peripheral neuropathic pain as of 2019. According to an RCT which investigated its
effects on PHN35), in groups who had been administered with 15 mg／day, 20 mg／
day, and 30 mg／day of mirogabalin, after 14 weeks of treatment, there was a significantly higher number of patients from the mirogabalin groups who had experi-

557

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enced a reduction in pain of 30% or more, compared with the placebo group.（group
administered 15mg ／ day：risk ratio 1.30；group administered with 20 mg ／ day：risk ratio 1.29；group administered with 30 mg／day：risk ratio 1.42）. The number of patients who had experienced a reduction in pain of 50% or more was significantly higher in the group administered with 30 mg／day than in the placebo group（risk ratio 1.47）. It was unclear whether there were any severe side effects related
to mirogabalin. The frequency of incidence of side effects such as drowsiness, dizziness and edema tended to increase with a higher dosage. There are few reports
yet on the usefulness of mirogabalin；further accumulation of clinical research is
required.
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Selection summary

2005～2019
MEDLINE, Cochrane Central, NPO Japan Medical Abstracts Society
postherpetic neuralgia, zoster associated pain
mirogabalin／nothing specified
Limited by publication type, Pubmed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, etc.
Of the 3 MEDLINE search hits, 15 Cochrane Central search hits, and 0 NPO Japan Medical
Abstracts Society search hits, we used 1 search hit which matched with the set PICO.

CQ O－5－4：Is amitriptyline useful for postherpetic neuralgia（PHN）?
Answer：We believe that amitriptyline is useful for postherpetic neuralgia（PHN）but we cannot say that there is sufficient evidence and therefore cannot
evaluated the size of its effect.
Recommendation Grade & Summary of Overall EvidenceRecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕

Summary of overall evidence：C（low）
Commentary：
Amitriptyline is a tricyclic antidepressant which was approved in Japan in 2015as a drug for treating peripheral neuropathic pain. There are placebo－controlled
RCTs which have investigated the effects of amitriptyline for PHN36,37), and researchers observed its analgesic effects after administering patients with the drugfor 6～8 weeks. There was a large number of side effects such as drowsiness anddry mouth in the group administered with amitriptyline. However, there was asmall number of patients the study targeted and therefore we cannot say that
there was a high level of evidence on its analgesic effects. According to a systematic review which summarized the effects of amitriptyline on neuropathic pain38), it
was unclear whether there were severe side effects caused by amitriptyline. There
was at least 1 or more patients in the amitriptyline group who more frequently had

O．Herpes Zoster-Related Pain

adverse events than in the placebo group（risk ratio 1.5, NNH 5.2）.
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Selection summary

2005～2019
MEDLINE, Cochrane Central, NPO Japan Medical Abstracts Society
postherpetic neuralgia, zoster associated pain
amitriptyline／nothing specified
Limited by publication type, Pubmed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, etc
Of the 10 MEDLINE search hits, 29 Cochrane Central search hits, and 3 NPO Japan Medical
Abstracts Society search hits, we used 1 search which matched with the set PICO. We usedsome citations from prior to 2005 that were important for reference purposes. From the above,
we used 3 references

CQ O－5－5：Is nortriptyline useful for postherpetic neuralgia（PHN）?
Answer：Nortriptyline may possibly be useful for postherpetic neuralgia（PHN）
but we cannot say that there is sufficient evidence.
Recommendation Grade & Summary of Overall EvidenceRecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕

Summary of overall evidence：C（low）
Commentary：
Nortriptyline is a tricyclic antidepressant which is the main metabolite of amitriptyline. In Japan, it is not applied for the treatment of pain. There are some
RCTs which have reported that nortriptyline has equivalent effects on PHN as gabapentin and amitriptyline39,40). However, these studies targeted a small number ofpatients and did not use a placebo for the control, and therefore we are unable tosay that there is sufficient evidence on the analgesic effects of nortriptyline. It is
unclear whether there are severe side effects from nortriptyline but there are side
effects such as dry mouth, constipation and drowsiness.
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Selection summary

2005～019
MEDLINE, Cochrane Central, NPO Japan Medical Abstracts Society
postherpetic neuralgia, zoster associated pain
nortriptyline／nothing specified
Limited by publication type, Pubmed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, etc.
Of the 6 MEDLINE search hits, 9 Cochrane Central search hits, 1 NPO Japan Medical Abstracts Society search hit, we used 1 search that matched with the set PICO. We used somecitations from prior to 2005 which were important for reference purposes. From the above, weused 2 references.

CQ O－5－6：Is tramadol useful for postherpetic neuralgia（PHN）?
Answer：Tramadol might possibly be useful for postherpetic neuralgia（PHN）.
The amount of evidence is insufficient but this does not mean that we should dis-

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miss its usefulness.
Recommendation Grade & Summary of Overall EvidenceR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕

Summary of overall evidence：C（low）
Commentary：
41)
There is 1 RCT on the effects of tramadol on postherpetic neuralgia（PHN）. By

administering patients with the drug for 6 weeks, there was a larger number of patients in the tramadol group who experienced a 50%＋reduction in pain comparedwith the placebo group（risk ratio 1.37, NNT 4.8）. However, the number of patients they targeted was small, so the amount of evidence is insufficient. According
to a systematic review which summarized the usefulness of tramadol for neuropathic pain42), it was unclear whether there were any severe side effects from administering patients with tramadol. There was at least 1 more patient who more
frequently experienced adverse events in the tramadol group than the placebogroup（risk ratio 1.6, NNH 4.2）. Adverse events that were particularly common
were nausea, constipation, a feeling of fatigue, and dizziness.
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2005～2019
MEDLINE, Cochrane Central, NPO Japan Medical Abstracts Society
postherpetic neuralgia, zoster associated pain
tramadol／nothing specified
Limited by publication type,Pubmed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, etc.
Of the 7 MEDLINE search hits, 35 Cochrane Central search hits, and 4 NPO Japan Medical
Abstracts Society search hits, we used 1 search hit that matched with the set PICO. We usedcitations from prior to 2005 that were important for reference purposes. From the above, weused 2 references.

CQ O－6：Is performing nerve block therapy soon after onset of herpes zoster,useful for preventing postherpetic neuralgia（PHN）?
Answer：There are many reports on preventing postherpetic neuralgia（PHN）
using various types of nerve blocks. There is also a report by a systematic review
which globally scrutinized this therapy. However, there were problems such as alack of uniformity between the trials and with the control group settings. However,rather than performing a nerve block just once, performing a nerve block continuously or several times has been shown to prevent acute－stage pain after 6 months
and after 12 months, and therefore we think that it does prevent PHN.
Recommendation Grade & Summary of Overall EvidenceR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕

561

O．Herpes Zoster-Related Pain

Summary of overall evidence：C（low）
Commentary：
There is a systematic review based on 9 research studies related to stellate ganglion block, epidural block, paraspinal nerve block and PHN. At 6 months, the incidence rate of PHN was 13.3 ～ 33.9% in the control group, and 0 ～ 26.7% in theblock groups；at 12 months it was 16～34.4% in the control group, and 2～5.9% in
the block group, indicating a significant difference. However, taking into consideration the lack of uniformity between the research studies, researchers concluded
that for each type of nerve block, it was more effective when performed continuously or repetitively. Furthermore, they claimed that there were no reports of serious adverse events due to nerve block43).
PeriodDatabase
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2005～2019
MEDLINE, Cochrane Central, NPO Japan Medical Abstracts Society
mainly postherpetic neuralgia, words similar to this（herpes zoster, postherpetic neuralgia*
etc）
nerve block／nothing specified
Nothing
Of the 53 MREDLINE search hits, 46 Cochrane CENTRAL search hits, and 57 NPO Japan
Medical Abstracts Society search hits, we used 1 search hit that matched with the set PICO＊
Searches were conducted in English and in Japanese

P

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Selection summary

CQ O－7－1：Is pulsed radiofrequency of the dorsal root ganglion（DRG－PRF）
useful for herpes zoster－related pain ?
Answer：In a randomized controlled trial（RCT）which compared the usefulness
before and after a block, researchers indicated in each case that pulsed radiofrequency of the dorsal root ganglion（DRG－PRF）was useful on herpes zoster－related pain. However, the longest period of observation was relatively short at 3

PRF:：pulsed
radiofrequency
DRG：dorsal root
ganglionmonths, so it is unclear whether it is useful over the long－term. They did not mention anything about adverse events but caution is advised.
Recommendation Grade & Summary of Overall EvidenceRecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕

Summary of overall evidence：C（low）
Commentary：
There is an RCT which investigated the effects of pulsed radiofrequency of thedorsal root ganglion（DRG－PRF）on 160 patients with PHN currently being administered gabapentin. Researchers reported that the visual analogue scale（VAS） VAS：visual analoguescores were significantly lower in the group which underwent DRG－PRF at 1

scale

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week, 2 weeks and 4 weeks after the procedure44). In a retrospective study whichtargeted 59 patients with herpes zoster who underwent DRG－PRF, researchers reported that intensity of pain was significantly lower at 12 weeks, in the acute－stage（within 90 days）group of patients who underwent PRF－DRG（29 patients）than
the chronic－phase（90 days＋）patients who underwent the procedure（29 pa45)
tients）. In a retrospective controlled trial on continuous epidural block and DRG－

NRS：numerical rating
scale

PRF, researchers considered 42 cases. In each case, NRS decreased over time butin the DRG－PRF group, researchers reported that the dosage of the drug decreased and there were fewer patients who transitioned to PHN46). Ninety patients
who were diagnosed with PHN and had symptoms for 3 months or more underwent DRG－PRF, and researchers reported that 1 week, 4 weeks, 8 weeks, and 12
weeks later, their VAS scores had significantly decreased and their SF－36 scores
had improved47). In 49 of the patients with PHN who underwent DRG－PRF, researchers reported that the treatment had been effective in alleviating pain at 4
weeks, 8 weeks, and 12 weeks after treatment48). There are many reports from one
single institution that PRF is useful for herpes zoster－related pain and PHN. In future, researchers will need to consider unified conditions such as method of performing DRG－PRF, time since onset and the site of procedure.
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Selection summary

2005～2019
MEDLINE, Cochrane Central, NPO Japan Medical Abstracts Society
mainly postherpetic neuralgia, words similar to this（herpes zoster, postherpetic neuralgia*
etc.）pulsed radiofrequency／nothing specified
Limited by publication type,PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, other（cases of50＋）etc
Of the 17 MREDLINE search hits, 30 Cochrane CENTRAL search hits, 5 NPO Japan Medical
Abstracts Society search hits, We used 5 search hits that matched with the set PICO＊
Searches were conducted in English and in Japanese

CQ O－7－2：Is applying pulsed radiofrequency to the peripheral nerves usefulfor herpes zoster－related pain ?
Answer：There are several double－blind RCTs on applying pulsed radiofrequency（PRF）to the peripheral nerves to treat PHN. These studies indicated that itwas effective in each case in providing analgesic effect, had an effect on the dosageof the drug used and on QOL. Furthermore, they indicated that there was no significant difference in severe complications as compared with the control group.
Recommendation Grade & Summary of Overall EvidenceR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕

Summary of overall evidence：B（moderate）

O．Herpes Zoster-Related Pain

563

Commentary：
There are placebo－controlled double－blind RCTs which have investigated the application of pulsed radiofrequency to the peripheral nerves（intercostal nerve）and
performing a nerve block for patients with chest PHN. In one of the controlled trials, one group of patients（30 patients）was administered pregabalin and underwent PRF while the other group（30 patients）was administered pregabalin andgiven a sham treatment. Researchers reported that pain significantly decreased 4
weeks and 8 weeks later in the PRF group, QOL improved, and patients tended to

PRF：pulsed
radiofrequency
QOL：quality of life

49)

have a reduced dosage of analgesics . Furthermore, there is a controlled trial
which targeted patients with chest PHN, in which one group（48 patients）underwent PRF to the peripheral nerves（intercostal nerves）and one group（48 patients）underwent a sham treatment for 6 months. This study reported that were
no severe complications in the PRF group, patients’ dosage of analgesics（tramadol）
decreased and there was a significant difference in improved physical function
50)
QOL（SF－36）. Furthermore, there is a placebo－controlled double－blind RCT in

which PRF was applied to the intercostal nerve under ultrasound guidance andwhile patients were observed over a period of 12 months, researchers reported seeing a significant decrease in VAS scores and a decreased dosage of the patients’51)
drug（pregabalin and acetaminophen）.

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Selection summary

2005～2019
MEDLINE, Cochrane Central, NPO Japan Medical Abstracts Society
mainly postherpetic neuralgia, words similar to this（herpes zoster, postherpetic neuralgia＊）etc
pulsed radiofrequency／nothing specified
Limited by publication type, PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, Other（50 cases＋）etc
OF the 17 MREDLINE search hits, 30 Cochrane CENTRAL search hits, and 5 NPO Japan
Medical Abstracts Society search hits, we used 3 search hits that matched with the set PICO＊
Searches were conducted in English and in Japanese

CQ O－8：Is spinal cord stimulation useful for postherpetic neuralgia（PHN）?
Answer：There are few reports on the usefulness of spinal cord stimulations（SCS）to treat postherpetic neuralgia（PHN）and few cases used in the reports.
Furthermore, there were no research studies which were compared against a placebo. However, we saw reports indicating an improvement in analgesic effect andactivities of daily living（ADL）due to SCS. We also saw several reports on temporary SCS reducing long－term pain in the acute and sub－acute phase.
Recommendation Grade & Summary of Overall Evidence
Recommendation grade：No recommendation〔Consensus 100.0%〕
Summary of overall evidence：D（very low）

SCS：spinal cord
stimulation

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Commentary：
There is some researchs which has looked at the analgesic effects of spinal－cord
stimulation（SCS）on patients with PHN. Researchers reported performing SCS on
28 patients, in which it had a long－term effect on 23 of them. At the same time,they performed SCS on 4 patients with acute－phase herpes zoster, and in each caseit had a long－term effect on the patients52).
There is one report in which PHN patients with kidney failure underwent SCS
and did not have to increase their dosage of the drug and it raised their quality of53)
life（QOL）. In addition, some other reporters performed temporary SCS on pa-

tients from the acute phase to around 6 months, and reported that patients had
passed through this period without a recurrence of pain54).
PeriodDatabase
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Selection summary

2005～2019
MEDLINE, Cochrane Central, NPO Japan Medical Abstracts Society
Mainly chronic pain, postherpetic neuralgia, words similar to this（Herpes zoster,Postherpetic
neuralgia* etc.）
Spinal cord stimulation etc.／nothing specified
Limited by publication type, PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, other（50 cases＋）etc.
Of the 24 MREDLINE search hits, 21 Cochrane CENTRAL search hits, 29 NPO Japan Medical
Abstracts Society search hits, we used 3 references that matched with the set PICO. Reference # 52 is outside of our targeted period but it was used in previous guidelines and wasconsidered to be important so we used it this time as well.
＊
Searches were conducted in English and in Japanese.

References
1）‌Cohen JI : Clinical practice : Herpes Zoster. N Engl J Med 2013 ; 369 : 255－263.
doi : 10. 1056/NEJMcp1302674. PMID : 23863052
2）‌Johnson RW, et al : Clinical practice : Postherpetic neuralgia. N Engl J Med
2014 ; 371 : 1526－1533. doi : 10.1056/NEJMcp1403062. PMID : 25317872
3）‌Saguil A, et al : Herpes zoster and postherpetic neuralgia : Prevention andmanagement. Am Fam Physician 2017 ; 96 : 656－663. PMID : 29431387
4）‌Johnson RW, et al : The impact of herpes zoster and post－herpetic neuralgia
on quality－of－life. BMC Med 2010 ; 8 : 37. doi : 10.1186/1741－7015－8－37. PMID :205659465）‌Johnson RW, et al : Herpes zoster epidemiology, management, and disease
and economic burden in Europe : A multidisciplinary perspective. Ther Adv
Vaccines 2015 ; 3 : 109－120. doi : 10.1177/2051013615599151. PMID : 26478818
6）‌Forbes HJ, et al : A systematic review and meta－analysis of risk factors forpostherpetic neuralgia. Pain 2016 ; 157 : 30－54. doi : 10.1097/j.pain.000000000000
0307. PMID : 26218719
7）‌Dooling KL, et al : Recommendations of the Advisory Committee on Immunization Practices for Use of Herpes Zoster Vaccines. MMWR Morb Mortal
Wkly Rep 2018 ; 67 : 103－108. doi : 10.15585/mmwr.mm6703a5. PMID : 29370152
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O．Herpes Zoster-Related Pain

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18）‌Tyring S, et al : Famciclovir for the treatment of acute herpes zoster : Effects
on acute disease and postherpetic neuralgia : A randomized, double－blind,placebo－controlled trial : Collaborative Famciclovir Herpes Zoster Study
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adults : A randomized, multicenter, double－blind clinical trial. J Clin Virol
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21）‌Shen M－C, et al : Double－blind, randomized, acyclovir－controlled, parallel－
group trial comparing the safety and efficacy of famciclovir and acyclovir inpatients with uncomplicated herpes zoster. J Microbiol Immunol Infect2004 ; 37 : 75－81. PMID : 15181487
22）‌Beutner KR, et al : Valaciclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother 1995 ; 39 : 1546－1553. doi : 10.1128/aac.39.7.1546. PMID : 7492102
23）‌Tyring SK, et al : Antiviral therapy for herpes zoster : Randomized, controlled
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24）‌Kawashima M, et al : Amenamevir, a novel helicase－primase inhibitor, fortreatment of herpes zoster : A randomized, double－blind, valaciclovir－controlled phase 3 study. J Dermatol 2017 ; 44 : 1219－1227. doi : 10.1111/1346－
8138.13948. PMID : 28681394
25）‌Chen N, et al : Antiviral treatment for preventing postherpetic neuralgia. Cochrane Database Syst Rev 2014 ;（2）: CD006866. doi : 10.1002/14651858.

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CD006866.pub3. PMID : 24500927
26）‌Dworkin RH, et al : Pregabalin for the treatment of postherpetic neuralgia : A
randomized, placebo－controlled trial. Neurology 2003 ; 60 : 1274－1283.
doi : 10.1212/01.wnl.0000055433.55136.55. PMID : 12707429
27）‌Sabatowski R, et al : Pregabalin reduces pain and improves sleep and mood
disturbances in patients with post－herpetic neuralgia : Results of a randomised, placebo－controlled clinical trial. Pain 2004 ; 109 : 26－35. doi : 10.1016/
j.pain.2004.01.001. PMID : 15082123
28）‌van Seventer R, et al : Efficacy and tolerability of twice－daily pregabalin fortreating pain and related sleep interference in postherpetic neuralgia : A 13－
week, randomized trial. Curr Med Res Opin 2006 ; 22 : 375－384. doi : 10.1185/
030079906x80404. PMID : 16466610
29）‌Stacey BR, et al : Pregabalin for postherpetic neuralgia : Placebo－controlled
trial of fixed and flexible dosing regimens on allodynia and time to onset ofpain relief. J Pain 2008 ; 9 : 1006－1017. doi : 10.1016/j.jpain.2008.05.014. PMID :1864007430）‌Ogawa S, et al : Efficacy and tolerability of pregabalin for postherpetic neuralgia : A multicenter, randomized, double－blind, placebo－controlled clinical trial.
J Japan Society of Pain Clinicians 2010 ; 17 : 141－152
31）‌Huffman CL, et al : Efficacy and safety of once－daily controlled－release pregabalin for the treatment of patients with postherpetic neuralgia : A double－
blind, enriched enrollment randomized withdrawal, placebo－controlled trial.
Clin J Pain 2017 ; 33 : 569－578. doi : 10.1097/AJP.0000000000000445. PMID :27753650
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the efficacy and safety of pregabalin for postherpetic neuralgia in a population of chinese patients. Pain Pract 2017 ; 17 : 62－69. doi : 10.1111/papr.12413.
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33）‌Derry S, et al : Pregabalin for neuropathic pain in adults : Meta－analysis. Cochrane Database Syst Rev 2019 ; 1（ 1）: CD007076. doi : 10.1002/14651858.
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34）‌Wiffen PJ, et al : Gabapentin for chronic neuropathic pain in adults : Review.
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CD007938.pub4. PMID : 28597471
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randomized, double－blind, placebo－controlled phase 3 study in Asian patients.
Pain 2019 ; 160 : 1175－1185. doi : 10.1097/j.pain.0000000000001501. PMID :3091316436）‌Max MB, et al : Amitriptyline, but not lorazepam, relieves postherpetic neuralgia. Neurology 1988 ; 38 : 1427－1432. doi : 10.1212/wnl.38.9.1427. PMID :341259137）‌Graff－Radford SB, et al : Amitriptyline and fluphenazine in the treatment of
postherpetic neuralgia. Clin J Pain 2000 ; 16 : 188－192. doi : 10.1097/00002508－
200009000－00002. PMID : 11014390
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1166. PMID : 9781549
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O．Herpes Zoster-Related Painpatients : A randomized, double－blind clinical trial : The GONIP trial. Int J
Clin Pharmacol Ther 2006 ; 44 : 358－363. doi : 10.5414/cpp44358. PMID : 16961166
41）‌Boureau F, et al : Tramadol in post－herpetic neuralgia : A randomized, double－
blind, placebo－controlled trial. Pain 2003 ; 104 : 323－331. doi : 10.1016/s0304－
3959（03）00020－4. PMID : 12855342
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00629. PMID : 29757758
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567

Chapter P．Painful Diabetic Peripheral
Neuropathy：CQ P-1～CQ P-7
CQ P-1：What kind of pathology is painful diabetic peripheral neuropathy（PDPN）?
CQ P-2：What are the symptoms of painful diabetic peripheral neuropathy（PDPN）?
CQ P-3：How is painful diabetic peripheral neuropathy（PDPN）diagnosed ?
CQ P-4-1：Is blood-sugar control useful for alleviating symptoms of painful
diabetic peripheral neuropathy（PDPN）?
CQ P-4-2：Is blood-sugar control useful for preventing the onset of painful
diabetic peripheral neuropathy（PDPN）?
CQ P-5-1：Are Ca2＋ channels and α2δ ligands useful for painful diabetic
peripheral neuropathy（PDPN）?
CQ P-5-2：Are serotonin-noradrenaline reuptake inhibitors useful for painful
diabetic peripheral neuropathy（PDPN）?
CQ P-5-3：Are tricyclic antidepressants useful for painful diabetic peripheral
neuropathy（PDPN）?
CQ P-5-4：Are antiepileptic drugs useful for painful diabetic peripheral
neuropathy（PDPN）?
CQ P-5-5：Is tramadol useful for painful diabetic peripheral neuropathy（PDPN）?
CQ P-5-6：Are opioid analgesics〔strong〕useful for painful diabetic
peripheral neuropathy（PDPN）?
CQ P-5-7：Is Kampo medicine useful for painful diabetic peripheral
neuropathy（PDPN）?
CQ P-6-1：Is nerve block useful for painful diabetic peripheral neuropathy（PDPN）?
CQ P-6-2：Is transcutaneous electrical nerve stimulations（TENS）useful for
painful diabetic peripheral neuropathy（PDPN）?
CQ P-6-3：Is low level laser therapy（LLLT）useful for painful diabetic
peripheral neuropathy（PDPN）?
CQ P-7：Is spinal cord stimulation（SCS）useful on intractable painful
diabetic peripheral neuropathy（PDPN）?

570

P．Painful Diabetic Peripheral Neuropathy

P．Painful Diabetic Peripheral Neuropathy
CQ P－1：What kind of pathology is painful diabetic peripheral neuropathy（PDPN）?
PDPN：painful
diabetic peripheral
neuropathy

Answer：Painful diabetic peripheral neuropathy（PDPN）, is a form of symmetricsensorimotor polyneuropathy, dependent upon nerve length, which arises whenhigh blood sugar persists in diabetic patients, and it is estimated that over 1 million
patients are affected by the disease in Japan. Researchers have indicated that advanced glycation end products（AGEs）are involved in the mechanism of onset.
Commentary：
PDPN occurs when high blood sugar persists in diabetic patients, and is a formof symmetric sensorimotor polyneuropathy which is dependent upon nerve length,
based upon diabetic neuropathy1,2).
According to the National Health and Nutrition Survey published by the Ministry of Health, Labor and Welfare（MHLW）in 20163), the number of people who are
estimated to have diabetes or who are in danger of developing diabetes is approximately 10 million people in each case. On the other hand, the European EURODIAB study and a survey conducted by Japan’s ‘Society for Thinking about Diabetic
Neuropathy’, reported that approximately 30% of patients with diabetes suffer fromneuropathy, and the prevalence rate of patients with pain which was diagnosed as
DN was 40～50%4－6), and as 75% of these cases are PDPN7), we roughly calculated
that there exists more than 1 million people in Japan with PDPN, and therefore theprevention and treatment of PDPN is a matter that should be tackled to improve
the health of the Japanese people.
The incidence rate of people who have suffered from PDPN throughout theirwhole life consists of 54～59% of patients with type 1 diabetes, and 45% with type 2
diabetes, indicating a higher incidence rate of type 1 diabetes8). The prevalence
rate of PDPN is known to increase both with a low age of onset of diabetes andlength of sickness and also there is a statistically－significant correlation with people
with a high BMI, women, and smokers8). Researchers have indicated that factors
such as increased polyol metabolism, increased oxidative stress, abnormal protein
kinase C activity, an accumulation of advanced glycation end products（AGEs）,elevated inflammatory cytokines, a decrease in neurotrophic factors, and abnormalities
in Na＋ and Ca2＋ channels are involved. In particular, it is claimed that reactive dicarbonyl and α－oxoaldehyde, which are precursors of advanced glycation end
products（AGEs）, are factors involved in the onset and development of PDPN.
Methylglyoxal is known for its depolarization of sensory nerves, hyperalgesia via

P．Painful Diabetic Peripheral Neuropathy

571

voltage－gated Na＋ channels（NaV 1.8）
, promoting neurosecretions of CGRP, andprovoking heat and mechanical hyperalgesia via activation of TRPA19).
We should also point out that in these guidelines we have not touched uponacute transient PDPN, which may arise at any stage of the disease, and treatment－
induced neuropathy of diabetes（TIND）, which arises in a short period of time due
to blood－sugar control.

CQ P－2：What are the symptoms of painful diabetic peripheral neuropathy ?
Answer：Typical painful diabetic peripheral neuropathy（PDPN）exhibits glove－
and－stocking type dysesthesia, and its pain symptoms match with the characteristics of neuropathic pain. As time passes, hypalgesia, hypanakinesis, and autonomic
dysfunction become salient, and diabetic foot ulcers are formed. As for the local
form of neuropathy, one sees single nerve dysfunction as well as multifocal neuropathy.
Commentary：
Pain due to PDPN is often the initial symptom for patients who undergo treatment at a healthcare facility10). With diabetic neuropathy（DN）, which is the basisof PDPN, as small－diameter neuropathy comes first, PDPN begins with bilateraland symmetrical numbness, pain, and dysesthesia in distal sites of the lower limbs
and over time, exhibits the glove－and－stocking type symptoms11,12). Patients complain of for example a ‘pins and needles’ like pricking pain, a ‘stinging’ pain, a burning－hot like pain, a shooting pain like an electric shock, an unpleasant sensationthat is accompanied by pain from a stimulus, hyperalgesia, and allodynia. While
walking, some patients have described the pain as “a pain like one is walking barefoot over marbles” and “a pain like one is walking barefoot over hot sand”.13) These
symptoms match with the characteristics of neuropathic pain. The pain increases
at night, and patients may also complain of insomnia, lack of sleep and a feeling of
fatigue5). Furthermore, some researchers have also observed paresthesia like muscle cramps in the lower limbs14). In the initial stage, motor function does not deteriorate, but gradually hypalgesia, hypanakinesis and autonomic dysfunction becomesalient and there is an elevated risk of the patient falling over15). In the final stage,
sufferers experience a lack of sensation in the lower limbs and leg ulcers areformed.
With local symptoms, patients may exhibit single nerve or multifocal nerve
symptoms11), and impaired blood flow of a single nerve, due to for example theblockage of a neurotrophic blood vessel, can be the cause of mononeuropathy. On
the other hand, multifocal nerve dysfunction, which is seen in the nerve plexus of

PDPN：painful
diabetic peripheral
neuropathy

572

P．Painful Diabetic Peripheral Neuropathy

the lumbosacral spinal cord, exhibits for example pain and muscular atrophy of thefemur as well as unilateral or bilateral hip pain.

CQ P－3：How is painful diabetic peripheral neuropathy（PDPN）diagnosed ?
PDPN：painful
diabetic peripheral
neuropathy

Answer：Painful diabetic peripheral neuropathy（PDPN）is diagnosed if the patient’s underlying disease is diabetes and also through for example a questionnaireon the patient’s pain symptoms and neuropathic pain. Each diagnostic criteria forneuropathic pain is useful for diagnosing PDPN as well.
Commentary：
When diagnosing painful diabetic peripheral neuropathy（PDPN）, the basic assumption is that diabetic neuropathy exists as an underlying condition, physiciansneed to hear the patient’s history and clinical conditions, and confirm on the blood
test whether the patient’s fasting blood glucose is 126mg／dl or higher and whether
their HbA1C is 6.5% or higher15). Pain is generally observed bilaterally and symmetrically and at distal sites, and patients complain of pain symptoms mentioned in
the previous CQ16). Their condition often deteriorates at night, and as it progresses,
symmetrical loss of sensation becomes salient, and this sensory loss may extend tothe calf muscles and upper limbs. For example, a Neuropathic Pain Screening Questionnaire, Neuropathic Pain Questionnaire（NPQ）, and the McGill Pain Question-

Note P1：Refer to CQ
B-8，B-9
VAS：visual analogue
scale
NRS：numerical rating
scale

naire may be used to confirm that the pain is neuropathic pain17,18) Note P1. Neuro－
13)
QoL is used to evaluate a decline in quality of life（QOL）, while VAS and NRS

are used to evaluate intensity of pain. A tactile test using a Semmes－Weinstein filament is widely used for screening, in many cross－sectional studies, the monofilament is known as a useful tool for identifying patients with foot ulcers19). Normally,
patients experience a reduction or loss of their Achilles tendon reflex, and in somecases a reduction in the kneecap reflex. An abnormality on a nerve conduction
study（NCS）and a microfiber nerve function test are required in order to confirm
a neurological disorder20,21). A skin biopsy to evaluate a patient’s intraepidermal
nerve fiber density can also be beneficial for diagnosis but such occasions are limited and can be useful in cases where small fiber neuropathy is suspected in patients
whose condition has followed an atypical course.
Simple tools used for diagnosing diabetic neuropathy（DN）include the ‘Simple
Diagnostic Criteria for Diabetic Polyneuropathy’ by the ‘Society for Thinking About
22)
Diabetic Neuropathy’（Table P－1）
, the ‘Toronto Consensus’ by the Toronto Dia-

betic Neuropathy Expert Group（Table P－2）23), as well as the ‘Michigan Neuropathy Screening Instrument（MNSI）’ and the Italian Society of Diabetology questionnaire（on neuropathy syndromes）. In clinical conditions in Japan, the ‘Simple Diag-

P．Painful Diabetic Peripheral Neuropathy

nostic Criteria for Diabetic Polyneuropathy’ is frequently used.
Table P－1

 imple Diagnostic Criteria for Diabetic Polyneuropathy（distal symmetricS
polyneuropathy）（Cited from Reference #22）

Essential Criteria
Patient meets the following 2 criteria
1．Diabetes is present
2．Peripheral neuropathy other than diabetic polyneuropathy can be ruled out
Conditional Criteria
Patient has‘neuropathy’ if he ／ she meets 2 or more of the 3 criteria below
1．Exhibits subjective symptoms believed to be based on diabetic polyneuropathy
2．Bilateral reduction of loss of Achilles tendon reflex
3．Bilateral hypopallesthesia of the inner ankles
Precautions
1．Subjective symptoms believed to be based on diabetic polyneuropathy are1）Bilateral symptoms
2）Patient complains of one of these symptoms：‘numbness’‘pain’ or‘dysesthesia’in the toes or sole of the footWhen the above 2 criteria are met
This does not include when only the above symptoms are present or when only‘psychroesthesia’ is present
2．The Achilles tendon reflex test confirms knee standing position
3．Hypopallesthesia is under 10 seconds on a C－128 tuning fork used as a guideline
4．Carefully consider effects due to ageing in elderly patients
Referential Criteria
If any of the following referential criteria are met, patients are considered to‘haveneuropathy’ even if conditional criteria are not met：
1．Clear abnormality is recognized for one of the test criteria（conduction velocity,
amplitude, latency）at 2 or more nerves, for 1 criteria or more at each nerve, on a
nerve conduction study
2．From the clinical symptoms, there is clear diabetic autonomic dysfunction.
However, it is recommended that an abnormality is confirmed on an autonomic（nerve）function test

Table P－2

The Toronto Consensus by the Toronto Diabetic Neuropathy Expert Group（Cited from Reference #23）

Defined as ‘may possibly have diabetic neuropathy’ if patient meets 2 or more of thefollowing criteria
1．Symptoms of neuropathic pain
2．Reduced distal sensation in all 4 limbs
3．Reduction or lack of Achilles tendon reflex
Precautions
In some cases, patients have a normal reduction or loss of Achilles tendon reflex.
Sometimes patients will have a reduced kneecap reflex as well.

573

574

P．Painful Diabetic Peripheral Neuropathy

CQ P－4－1：Is blood－sugar control useful for alleviating symptoms of painful
diabetic peripheral neuropathy（PDPN）?
Answer：There is no evidence on the effects of blood－sugar control in alleviating
PDPN：painful
diabetic peripheral
neuropathy

pain from painful diabetic peripheral neuropathy（PDPN）. There is no correlation
between the indicators of blood－sugar management, blood－sugar levels and HbA1C,
and the severity of diabetic neuropathy（DN）. There is also a small－scale researchstudy which indicated that treatments which introduced insulin therapy did not alleviate pain due to PDPN.
Commentary：
Blood－sugar control and administering for example aldose reductase inhibitor
drugs are recommended to alleviate symptoms of DN, and there is much evidence
indicating a correlation between poor blood－sugar control and aggravated DN.
However, there is no research which has investigated the relationship between
blood－sugar control and the alleviation of PDPN symptoms.
In the Diabetes Control and Complications Trial（DCCT）, a research study whichinvestigated the relationship between blood－sugar levels and DN, researchers indicated that there was no correlation between fluctuations in blood－sugar levels andseverity of neuropathy25). Furthermore, in the secondary outcome of a research
26)
study which targeted diabetic patients with coronary artery disease（BARI－2D）,

researchers investigated the relationship between HbA1C and neuropathy but they
indicated that there was no relationship between a reduction in HbA1c and alleviated neuropathy. Furthermore, other researchers indicated that compared with a
non－insulin treatment group, the incidence rate of DN was 30%＋higher in the insulin treatment group（OR＝1.34（95% CI 1.08 ～ 1.67））, in which patients who
were being treated with a hypoglycemic drug were then transitioned to an insulin
treatment and without using an oral hypoglycemic drug, even when they performed reinforced insulin therapy through administering insulin subcutaneously, it
did not reduce PDPN－related pain27). Therefore, after onset of PDPN, even if blood－
sugar control is performed, using blood－sugar levels and HbA1C as indicators,
there is a low possibility that pain will be reduced.

CQ P－4－2：Is blood－sugar control useful for preventing the onset of painful
diabetic peripheral neuropathy（PDPN）?
Answer：There is no direct evidence that prevents the onset of painful diabetic
peripheral neuropathy（PDPN）. Due to the epidemiological fact that onset of PDPN
has diabetic neuropathy as an underlying condition and the fact that blood sugar

P．Painful Diabetic Peripheral Neuropathy

575

regulation prevents the onset of DN, we can indirectly recommend that reinforced
blood－sugar control prevents the onset of PDPN.
Commentary：
There are no research studies which have investigated the relationship between
blood－sugar control and preventing the onset of PDPN27). It has been known thatblood－sugar control could prevent the onset of DN in the past, and in a 2012 systematic review28), reinforced blood－sugar control significantly prevented the onset
of DN in type 1 diabetic patients（annual RD 1.84%（95% CI －1.11～－2.56）, highrecommendation）, and reinforced blood－sugar control indicated that it tended toprevent the onset of DN in type 2 diabetic patients as well（annual RD －0.58%（95% CI 0.01－1.17）, moderate recommendation）. Furthermore, researchers observed that these preventive effects continued for 3～6 years29). Therefore, basedon the epidemiological fact that 75% of DN patients will develop PDPN and also thefact that blood－sugar regulation prevents the onset of DN, we can verify, albeit indirectly, that reinforced blood－sugar control probably prevents the onset of PDPN.
However, as the risk of developing hypoglycemia is elevated while patients are undergoing reinforced blood－sugar control30), patients need to be treated carefully bya specialist and monitored closely. In recent years, there was a report on the relationship between PDPN and abnormal glucose tolerance, not blood－sugar levels31),
and therefore we expect future research to be conducted on the prevention of
PDPN using abnormal glucose tolerance as an indicator.
PeriodDatabase
Words searched
P
I／C
Limitations
Selection summary

2004～2019
PubMed, Cochrane Central,NPO Japan Medical Abstracts Society
chronic pain,chronic pain treatment,painful diabetic neuropathy, diabetic neuropathic pain, glucose control, hyperglycemia, insulin
chronic pain＊／painful diabetic peripheral neuropathy
Treatment／placebo or standard treatment
Limited by publication type,PubMed randomized controlled trial／systematic review search filter, Cochrane RCT search filter, other（cases of50＋）etc
Of the 23,620 search hits（painful diabetic neuropathy）and 164,742 search hits（glucose control）, we took 19 from our search history, and used 5 of them from a second screening. In addition we used 1 supplementary reference for the commentary

CQ P－5－1：Are Ca2＋ channels and α2δ ligands useful for painful diabetic
peripheral neuropathy（PDPN）?
Answer：Ca2＋ channels and α2δ ligands（gabapentinoids）are recommended as
first－line drug therapies for neuropathic pain in general and gabapentin and pregabalin are useful for alleviating pain from painful diabetic peripheral neuropathy（PDPN）. Furthermore, researchers have indicated that a novel Ca2＋ channel andα2δ ligand, mirogabalin, may possibly be useful for alleviating pain due to PDPN.

PDPN：painful
diabetic peripheral
neuropathy

576

P．Painful Diabetic Peripheral Neuropathy

Recommendation Grade & Summary of Overall Evidence
1）Gabapentin
Recommendation grade：1（strong）：Implementation is strongly recommended〔Consensus 100.0%〕
Summary of overall evidence：A（high）
2）PregabalinR ecommendation grade：1（strong）：Implementation is strongly recommended〔Consensus 100.0%〕
Summary of overall evidence：A（high）
3）MirogabalinR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕

Summary of overall evidence：B（moderate）
Commentary：
In a 2017 systematic review of the effects of gabapentin on PDPN31), researchers
observed that by administering patients with 1,200 mg of gabapentin ／ day, there
was a significant analgesic effect（pain was reduced by 30% or more）in 52% of patients who were administered the drug, and there was an improvement in the Patient Global Impression of Change（PGIC）（RR 1.4（95% CI 1.3～1.6））. Furthermore, researchers observed a 50% or more reduction in pain in 38% of cases and an
improved PGIC（RR 1.7（95%CI 1.4～2.0））, indicating a high level of evidence on
the usefulness of gabapentin for PDPN. However, as they are unable to make a proportion of the dosage for the Cmax（maximum serum concentration）for administrating gabapentin, researchers claim that fine adjustments need to be made to thedosage32).
A 2019 systematic review33) indicated that 47% of patients who were administered 300 mg of pregabalin／day experienced a 30% or more reduction in pain（RR
1.1（95% CI 1.01～1.2））, and 31% of cases experienced a 50% or more reduction
in pain（RR 1.3（95% CI 1.2～1.5））. Furthermore, PGIC improved in 51% of thepatients（RR 1.8（95% CI 1.5～2.0））. In addition,63% of patients who were administered 600 mg of pregabalin／day experienced a 30% or more analgesic effect（RR
1.2（95% CI 1.04～1.4））, and 41% of cases experienced a 50% or more analgesic
effect（RR 1.4（95% CI 1.2～1.7））. As for side effects, although there was a low
incidence of severe complications, researchers observed many cases of drowsiness（11% of patients administered 300 mg／day,15% of patients administered 600 mg／day）and dizziness（13% of patients administered 300 mg／day, and 22% of patientsadministered 600 mg／day）. In a domestic long－term administration study on PDPN
patients34), the incidence rate of side effects was high at 87%（28% had drowsiness,
27% gained weight, 26% had dizziness, and 19% edema）. Therefore, the dosage of

P．Painful Diabetic Peripheral Neuropathy

577

pregabalin needs to be set carefully.
In 2019, there was 1 RCT which studied the newly－available Ca2＋ channel andα2δ ligand, mirogabalin, in a study targeting Asian patients with PDPN35). Administering 15 mg of mirogabalin／day, 20 mg／day, and 30 mg／day randomly to subjects, resulted in an average daily reduction in pain scores by －1.34, －1.47 and－1.81, respectively, with the group administered 30 mg of mirogabalin／day experiencing a significant reduction in pain compared with the control group.（RR ?0.5
（95%CI －0.82～－0.17））. However, the amount of research was small so it did notindicate a high level of evidence. Furthermore, researchers observed mild to moderate side effects in each of the groups administered with 15 mg of mirogabalin／day, 20 mg／day, and 30 mg／day, including sleepiness, dizziness, peripheral edema,
and weight gain.
Based on the above, by setting and administering the optimal dosage for a Ca2＋
channel and α 2 δ ligand（gabapentinoids）, PDPN－related pain is significantly reduced and the benefits of using mirogabalin may possibly increase through the accumulation of research studies conducted in future.

CQ P－5－2：Are serotonin－noradrenaline reuptake inhibitors useful for painful
diabetic peripheral neuropathy ?
Answer：There is a high amount of evidence on the serotonin－noradrenaline re－uptake inhibitor, duloxetine, and painful diabetic peripheral neuropathy（PDPN）.
Researchers have indicated that administering 60 mg of duloxetine ／ day is usefulfor alleviating PDPN－related pain.
Recommendation Grade & Summary of Overall Evidence
Duloxetine
Recommendation grade：1（strong）：Implementation is strongly recommended〔Consensus 100.0%〕
Summary of overall evidence：A（high）
Commentary：Compared with the tricyclic antidepressant, amitriptyline, SNRIs are safe andeasy to use and a good choice for patients with heart disease.
In a research study which evaluated the analgesic effects of SNRI, duloxetine, on
PDPN36), researchers confirmed that pain had decreased by 30% or more in thegroup administered with 40 mg of duloxetine／day（RR 1.57（95% CI 1.18～2.07））,and 60 mg／day（RR 1.53（95% CI 1.3～1.75））. Furthermore, the number of patients who experienced a 50% or more reduction in pain was 20.4% higher in the

SNRI：serotonin-noradrenaline
re-uptake inhibitor
PDPN：painful
diabetic peripheral
neuropathy

578

P．Painful Diabetic Peripheral Neuropathygroup administered 60 mg of duloxetine／day compared with the placebo（RR 1.73,（95%CI 1.44～2.08））, and those who had changed from baseline according to the
SF－36 was 2.65 physically speaking（95% CI 1.38 ～ 3.92）, thereby confirming asignificant improvement（mentally speaking, there was a significant improvement
in some of the patients, but the difference was not significant at 1.08（95%CI－0.32～2.48））. In addition, the average change from baseline in the level of patient satisfaction according to the Patient Reported Global Impression（PGI）was －0.6（95%CI －0.07 ～－0.44）, indicating a significant improvement. Side effects manifest
from duloxetine depending on the dosage used but severe side effects are rare andthere was no significant difference compared with the placebo. However, caution isrequired with using antidepressants, including SNRIs, in cases of serotonin syndrome.（It should also be pointed out that researchers considered a 120 mg of duloxetine／day group but as the maximum dosage for duloxetine in Japan is set at 60
mg／day, an evaluation was not conducted）.
Other SNRI in Japan are venlafaxine and milnacipran. In a Cochrane systematic
review, they indicated that 150～225 mg of venlafaxine／day significantly reduced
pain compared with the control group or a 75 mg of venlafaxine／day group.（painreduced by 50% in the 150～225 mg／day group, by 32% in the 75 mg／day group,and 27% in the control group37). However, the sample size in the selected researchstudies was small and the period of observation was also short. Furthermore, there
was no meta－analysis so the quality of evidence was not high.

CQ P－5－3：Are tricyclic antidepressants useful for painful diabetic peripheral
neuropathy（PDPN）?
TCA：tricyclic
antidepressant

Answer：Tricyclic antidepressants（TCAs）have the effect of alleviating neuropathic pain, and so are useful for alleviating pain due to painful diabetic peripheral
neuropathy（PDPN）. However, there are a small number of research studies whichhave targeted PDPN, and so the quality of evidence is not high and as there is alarge number of side effects, one needs to approach this treatment cautiously.
Recommendation Grade & Summary of Overall EvidenceR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕

Summary of overall evidence：B（moderate）
Commentary：
It is widely known that the tricyclic antidepressants（TCAs）, amitriptyline andnortriptyline have an analgesic effect on neuropathic pain. However, nortriptyline is

P．Painful Diabetic Peripheral Neuropathy

not eligible to be used in Japan for neuropathic pain.
In a Cochrane systematic review38), it was apparent from the analysis of 2 cross－over studies that amitriptyline was useful compared with the placebo, and there isalso a report of a meta－analysis which concluded that TCAs are useful for treating
PDPN39). However, the number of these research reports and the number of patients in them were both small so the accuracy is low. In terms of the side effects,
it is known that TCAs tend to cause for example narrow－angle glaucoma, prostatic
hypertrophy and orthostatic hypotension as they have an anticholinergic effect40).
Furthermore, there is a risk of Torsade de Pointes due to extended QT, and therefore it is contraindicated in patients with cardiac circulatory disorders, including
heart failure, arrythmia, and recent myocardial infarction.
Based on the above, TCAs have the effect of alleviating neuropathic pain but as
the number of research studies which have targeted PDPN is small, the quality ofevidence is not high, and also there was much harm caused in cases where thedrug was not chosen suitably. However, as the price of TCA drugs is reasonable,
we expect further research to be conducted in future focusing on its cost－effectiveness from a healthcare economical point of view.

CQ P－5－4：Are antiepileptic drugs useful for painful diabetic peripheral
neuropathy（PDPN）?
Answer：Administering 400 mg of lacosamide, an antiepileptic drug, to patients a
day reduces pain from painful diabetic peripheral neuropathy（PDPN）by 50% ormore. However, there are few high－quality RCTs on the effects of other antiepileptic drugs（carbamazepine, lamotrigine, topiramate, oxycarbazepine）on PDPN.
Therefore, it can be considered as an option in cases where other drugs prove to
be ineffective. However, there are no drugs in Japan which have an indication for
PDPN and one must pay plenty of attention to the fact that they are many side effects.
Recommendation Grade & Summary of Overall Evidence
Recommendation grade：No recommendation〔Consensus 100.0%〕
Summary of overall evidence：B（moderate）
Commentary：
Antiepileptics such as carbamazepine, phenytoin, sodium valproate, clonazepam
have long been used for treating neuropathic pain and other neurological disorders.
Out of these drugs, there have only been high－quality research studies conductedon carbamazepine；there is no research on phenytoin and clonazepam.

579

580

P．Painful Diabetic Peripheral Neuropathy

In a Cochrane systematic review, there was a report indicating that administering 200～600 mg of carbamazepine／day had a significant analgesic effect on neuropathic pain, including PDPN, compared with the placebo. However, as the study
targeted a small number of patients, there was no obtainable evidence limited to
PDPN41). On the other hand, there are many side effects from administering carbamazepine such as drowsiness, dizziness, constipation, nausea, and ataxia, and as
there is a risk of developing toxic epidermal necrolysis and Steven－Johnson syndrome, and the risk of incidence is 10 times more frequent in patients with humanleukocyte antigen B*1502, which is common among Asians42), it can be used for trigeminal neuralgia in Japan but one needs to administer it carefully.
In the 2 RCTs on lamotrigine43), PDPN－related pain had decreased by 50% ormore within 12 weeks of being administered between 200 ～ 400 mg/day of lamotrigine. However, an assessment of its comprehensive effects were that it was not
significant compared with the placebo（RR 1.1（95% CI －0.8～1.4））. In addition,
there was a relatively high number of side effects due to lamotrigine comparedwith the placebo（RR 1.1（95%CI 1.01～1.2））,and one should especially pay attention to how common rashes appear（RR 1.4（95% CI 1.01～2.0））.
In a Cochrane systematic review, research on the usefulness of administering 200～400 mg of tramadol／day was not limited to PDPN, and the sample size was small
as well so we were unable to conduct an effective analysis44). On the other hand,
there was a significantly higher number of occasions when administration of topiramate was discontinued due to side effects, compared with the placebo（RR 3.4（95%CI 2.4～4.7））, and therefore it was evaluated as not being of high usefulness.
A small－scale research study indicated that administering 300～2,400 mg/day ofoxycarbazepine was useful for treating PDPN, but in a systematic review, researchers did not recognize a significant difference compared with the placebo45). On theother hand, adverse events were seen to be slightly higher in the group who had
been administered oxycarbazepine.
In a systematic review, administering 400 mg/day of lacosamide contributed to a
50%＋decrease in pain（RR 1.4（95% CI 1.01～1.9））and improved symptoms with
PGIC（RR 1.5（95% CI 1.2～1.9））. However when 600 mg of the drug were administered per day, researchers did not observe a significant analgesic effect or improved symptoms with PGIC46,47).
Based on the above, administering 400 mg/day of lacosamide reduced PDPN－related pain by 50% or more but as there are few high－quality RCTs on other antiepileptics, we decided assign a ‘no recommendation’ grade, and so this drug should
be considered as an option in cases where other highly－recommended drugs prove
to be ineffective, while at the same time paying attention to preventing and avoiding side effects. Furthermore, one must also pay attention to the fact that there are
no antiepileptic drugs which have an indication for PDPN in Japan.

P．Painful Diabetic Peripheral Neuropathy581

CQ P－5－5：Is tramadol useful for painful diabetic peripheral neuropathy（PDPN）?
Answer：Researchers have reported that opioid analgesics are effective in alleviating neuropathic pain, and tramadol is useful for alleviating pain from painful diabetic peripheral neuropathy（PDPN）. However, long－term administration of opioid
analgesics does not improve physical function in patients and as it leads to an elevated risk of drug dependence and overdose, its disadvantages increase. While being aware that the risk of dependence or overdose on tramadol is low, we do notrecommend that anyone other than a pain management specialist treat the patient,someone who can screen the patient prior to administration and conduct rigorous
monitoring of the patient once administration of the drug commences.
Recommendation Grade & Summary of Overall EvidenceRecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus100.0%〕

Summary of overall evidence：B（moderate）
Commentary：
Some researchers have reported that opioid analgesics were effective in alleviating neuropathic pain compared with the placebo40) but there have only been small－scale research studies which have investigated the efficacy of opioid analgesics limited to their effects on PDPN alone48).
In a systematic review49), researchers indicated that administering 100～400 mg／
day of tramadol, which overseas applies as an opioid analgesic〔mild〕,reduced neuropathic pain, including PDPN, by 50% or more（RR 2.2（95%CI 1.02～4.6））.However, considering things like the research was a small size study and there was ahigh amount of latent bias, the quality of the evidence was low. In other small－scale
research studies, researchers reported that the odds of achieving 50% analgesic effect from administering 210 mg of tramadol per day were 3.8（95% CI 1.8～8.0）.
In an RCT on administering 4～8 tablets of tramadol－acetaminophen to treat
PDPN, pain due to PDPN decreased significantly in those who took the tramadol－acetaminophen tablets compared with the placebo, and contributed to improved
sleep, quality of life（QOL）and mood50). However, the sample size was small andthe quality of evidence was low and nausea was a frequently observed side effectand therefore one cannot ignore the amount of harm it causes.
Research has indicated that opioid analgesics are effective in treating neuropathic pain over the short－period but according to a systematic review51) conducted by
the US Centers for Disease Control and Prevention（CDC）,researchers did not recognize that long－term administration of opioid analgesics improved physical func-

CDC：Centers for
Disease Control andPrevention

582

P．Painful Diabetic Peripheral Neuropathy

tion in patients and indicated a strong correlation with the risk of opioid analgesic
dependence and an elevated risk of overdose. Furthermore, in a report on prescribing opioid analgesics to patients with neuropathic pain52), 66% of patients were prescribed with at least 1 type of opioid analgesic, and they reported that 9% of thesepatients were undergoing long－term administration and only a mere 26% of thesepatients had used a drug recommended by guidelines prior to being administeredwith an opioid analgesic. While being conscious of the fact that there is a low riskof dependence and abuse from tramadol, these drugs and psychotropic drugs are
not indicated in Japan53), and we do not recommend that patients be treated byanyone other than a pain management specialist who can conduct rigorous patient
screening prior to administration of opioid analgesics and also conduct rigorous
monitoring of the patient once administration commences.

CQ P－5－6：Are opioid analgesics〔strong〕useful for painful diabetic peripheral neuropathy（PDPN）?
Answer：In the treatment of painful diabetic peripheral neuropathy（PDPN）
with opioid analgesics〔strong〕, some research on the usefulness of oxycodone has
been reported. However, as mentioned above, researchers did not observe an improvement in physical function through long－term administration of opioid analgesics〔strong〕and this leads to an elevated risk of dependence on opioid analgesics
and overdose, we do not recommend that patients be treated by anyone other thana pain management specialist.
Recommendation Grade & Summary of Overall Evidence
Recommendation grade：No recommendation〔Consensus 100.0%〕
Summary of overall evidence：B（moderate）
Commentary：
Just like with opioid analgesics〔weak〕, researchers have not proven that opioid
analgesics〔strong〕are effective in alleviating neuropathic pain41), and there are
few research studies which have investigated the usefulness of opioid analgesics〔strong〕limited to its effects on PDPN alone49).
According to 3 research studies which targeted 537 patients with PDPN54), results indicated that oxycodone controlled－release（CR）tablet reduced moderate
pain due to PDPN（RR 1.7（1.3～2.1）, NNT 5.7（4.0～9.9）. Furthermore, according to 2 research studies which targeted 259 patients with PDPN55), results indicated that oxycodone controlled－release（CR）tablet alleviated pain by 30% or more in
45% of the patients in the studies and the RR of alleviating PDPN－related pain by

583

P．Painful Diabetic Peripheral Neuropathy

30% or more from oxycodone controlled－release tablet was 2.1（95% CI 1.4～3.1）.
Researchers indicated that the effective dosage from oxycodone was between 10～
120 mg／day, with the average being between 40～60 mg／day.
However, as mentioned above, researchers did not recognize an improvement inphysical function through long－term administration of opioid analgesics and as itleads to an elevated risk of dependence and overdose, we do not recommend thatpatients be treated by anyone other than a pain management specialist.

CQ P－5－7：Is Kampo medicine useful for painful diabetic peripheral neuropathy（PDPN）?
Answer：There are no clear grounds to suggest that Kampo medicine is usefulfor alleviating pain due to painful diabetic peripheral neuropathy（PDPN）.

PDPN：painful
diabetic peripheral
neuropathy

Recommendation Grade & Summary of Overall EvidenceRecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 95.0%〕

Summary of overall evidence：C（weak）
Commentary：
In a Cochrane systematic review on the effects of pharmacology on PDPN56),
there were 2 research studies which investigated the effects of treatment throughKampo medicine. In 1 of the research studies used, researchers evaluated aspects
such as reduced pain, improvement in PGIC, and side effects but as the results
were inconsistent and as the scale of the research study was small, there was ahigh amount of bias, meaning the quality of the evidence was not high. In 10 research studies that were used in another Cochrane systematic review, researchersreported on the usefulness of Kampo medicine but the quality of the evidence usedin these research reports was low57), and researchers had not set objective outcome
indicators when conducting the RCT. Therefore, the quality of evidence on the usefulness of Kampo medicine for PDPN is extremely low, and therefore we decided toassign a recommendation grade of ‘ 2（weak）’.
In Japan, there have been reports on the usefulness of gosha－jinki－gan58,59), a kidney－supporting medicine, for pain and numbness due to PDPN, and the usefulnessof shakuya－kukanzo－to60) on painful muscle cramps（leg cramps）resulting from diabetic neuropathy（DN）and recommend that Kampo（Chinese herbal）medicine
treatments be conducted according to the characteristics of each patient’s ‘individual constitution’（known as ‘sho’ in this field）.

DN：diabetic
neuropathy

584

P．Painful Diabetic Peripheral Neuropathy

PeriodDatabase
Words searched

P
I／C
Limitations
Selection summary

2004～2019
PubMed, Cochrane Central,NPO Japan Medical Abstracts Society
chronic pain,chronic pain treatment,painful diabetic neuropathy, drug therapy, pharmacological treatment, alpha2－delta ligands, gabapentinoids, gabapentin, pregabalin, mirogabalin, antidepressants, serotonin－noradrenaline reuptake inhibitors, duloxetine, venlafaxine, tricyclic antidepressants, anticonvulsants, antiepileptic agents, carbamazepine, lamotrigine, topiramate,
oxcarbazepine, lacosamide, opioid analgesics, tramadol, tramadol－acetaminophen, oxycodone,
herbal medicine, Kampo medicine
chronic pain*／painful diabetic peripheral neuropathy
Pharmacotherapy／placebo
Limited by publication type,PubMed randomized controlled trial／systematic review search filter, Cochrane RCT search filter, other（cases of50＋）etc.
Of the 23,620 search hits on painful diabetic neuropathy, 3,266,997 search hits on pharmacological treatment, we used 15,000 from our search history, and used 15 search hits as a resultof our secondary screening process. In addition to this, we used 9 references to supplement
the Commentary.

CQ P－6－1：Is nerve block useful for painful diabetic peripheral neuropathy（PDPN）?
Answer：Lumbar sympathetic ganglion block is often used clinically, for the purPDPN：painful
diabetic peripheral
neuropathy

pose of alleviating pain due to painful diabetic peripheral neuropathy（PDPN）.
However, there are no high－quality research studies on this. There are some small－scale research studies which have indicated the usefulness of using radiofrequency thermocoagulation（RF）and pulsed radiofrequency（PRF）in combination witha neurolytic agent.
Recommendation Grade & Summary of Overall Evidence
1）Lumbar sympathetic nerve block
Recommendation grade：No recommendation〔Consensus 95.0%〕
Summary of overall evidence：C（low）
2）Pulsed radiofrequency（PRF）
Recommendation grade：No recommendation〔Consensus 95.0%〕
Summary of overall evidence：C（low）
Commentary：
There is no high－quality evidence on the usefulness of nerve block for treating
PDPN61). In a retrospective－controlled trial, the findings indicated that the group

RF：radiofrequency
thermocoagulation

which underwent a combination of radiofrequency thermocoagulation（RF）of thelumbar sympathetic nerve as well as a neurolytic agent experienced a significant
decrease in pain compared with the sympathetic nerve block groups which either

TENS：transcutaneous electrical nerve
stimulation
PRF：pulsed
radiofrequency

had only a neurolytic agent or only RF treatment62). Furthermore, in a researchstudy which compared the efficacy of transcutaneous electrical nerve stimulation
63)（TENS）and pulsed radiofrequency（PRF）, both groups experienced a significant

decrease in pain as a result of the treatments but reported that the PRF group ex-

P．Painful Diabetic Peripheral Neuropathy

585

perienced a longer period of reduced pain than the TENS group. In addition to this,we have seen examples of scattered case reports64) reporting that a lumbar sympathetic nerve block reduced intractable PDPN pain and improved QOL. Therefore,
as the quality of evidence on the usefulness of nerve block for treating PDPN is nothigh, we decided to assign a “no recommendation” grade.

CQ P－6－2：Is transcutaneous electrical nerve stimulations（TENS）useful for
painful diabetic peripheral neuropathy（PDPN）?
Answer：The research studies on using transcutaneous electrical nerve stimulation（TENS）to manage painful diabetic peripheral neuropathy（PDPN）targeted asmall number of cases, and so there is no high－quality evidence. However, as there

TENS：transcutaneous electrical nerve
stimulation

have been few severe adverse events from using TENS, it is useful for PDPN patients as a form of adjuvant treatment.
Recommendation Grade & Summary of Overall Evidence
Recommendation grade：No recommendation〔Consensus 100.0%〕
Summary of overall evidence：B（moderate）
Commentary：
A Cochrane systematic review which evaluated the usefulness of transcutaneouselectrical nerve stimulation（TENS）for PDPN used 2 research studies65), but the
number of cases was small and the control was not set so the quality of evidence is
not high. According to the guidelines of the European Federation of NeurologicalSocieties（EFN）66), ultra－high frequency TENS has more analgesic effect on the leg
muscles in PDPN patients than low frequency TENS, and while they propose thatlow frequency TENS has a higher analgesic effect than sham stimulation treatments, the number of patients used in each of the research studies cited was small
and the bias was high so the quality of evidence is low. Therefore, we decided toassign a “no recommendation” grade. However, as there are few severe adverse
events from TENS, excluding the possibility of a cardiac pacemaker intervention, it
is useful as a form of adjuvant therapy as it indicates that it provides temporary
analgesic effects for PDPN pain.

CQ P－6－3：Is low level laser therapy（LLLT）useful for painful diabetic
peripheral neuropathy（PDPN）?
Answer：There are no high－quality research studies on using low level laser

EFN：The European
Federation of
Neurological Societies

586

LLLT：low level laser
therapy

P．Painful Diabetic Peripheral Neuropathy

therapy（LLLT）to manage painful diabetic peripheral neuropathy（PDPN）. However, there have been few severe adverse events from LLLT, so it is useful as aform of adjuvant therapy for treating PDPN pain.
Recommendation Grade & Summary of Overall Evidence
Recommendation grade：No recommendation〔Consensus 100.0%〕
Summary of overall evidence：C（low）
Commentary：
According to a systematic review which evaluated the effects of LLLT on
PDPN67), 5 out of the 6 research studies which used VAS and screening scores as
indicators, indicated that LLLT reduced pain due to PDPN. However, the lightwavelength and average output used in these 6 studies varied so in the systematic
review, they did not provide adequate analysis and as it had a high amount of research bias, we judged that there was no high－quality evidence available, so we decided to assign a “no recommendation” grade. However there are few severe adverse events from LLLT, and therefore it is useful as a form of adjuvant therapy
which indicates that it provides temporary analgesic effects on PDPN pain.
In Japan, there is 1 review article on the efficacy of LLLT for treating diabetic
neuropathy（DN）, including PDPN68), which describes an example of their own teston the usefulness of LLLT based on the analgesic mechanism.
PeriodDatabase
Words searched
P
I／C
Limitations
Selection summary

2005～2019
PubMed, Cochrane Central,NPO Japan Medical Abstracts Society
chronic pain, pain treatment, painful diabetic neuropathy, neural blockade, nerve block, sympathetic nerve block, radiofrequency, pulsed radiofrequency, transcutaneous electrical nerve
stimulation, TENS, low level laser therapy, LLLT
chronic pain
Interventional treatment（nerve block, pulsed radiofrequency, transcutaneous electrical nerve
stimulation, low reactive－level laser therapy）／nothing specified
Limited by publication type,PubMed randomized controlled trial／systematic review search filter, Cochrane RCT search filter, other（cases of 50＋）etc.
Nerve block : We used one NeuPSIG recommendation which was found through a manual
search, and 2 controlled trials which had different controls.
TENS : Of the 14 search hits, we used 4 after a secondary screening, and in addition used 1
other guideline.
LLLT : Of the 9 search hits, we used one after secondary screening.

CQ P－7：Is spinal cord stimulation（SCS）useful on intractable painful diabetic peripheral neuropathy（PDPN）?
Answer：In cases where no analgesic effect is obtained from other forms of treatment for intractable pain, it is worth trying the surgical treatment of spinal cord
SCS：spinal cord
stimulation

stimulation（SCS）, but there is a risk that severe complications may arise.

P．Painful Diabetic Peripheral Neuropathy

587

Recommendation Grade & Summary of Overall EvidenceRecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 90.0%〕

Summary of overall evidence：B（moderate）
Commentary：
Spinal cord stimulation（SCS）, which had a peculiar analgesic mechanism called‘neuromodulation’, is a surgical treatment which is worth trying in cases of intractable pain and when analgesic effect was not obtained from other forms of treatmentNote P2, and its usefulness for PDPN has been reported on. There are 2 RCTs
69,70)

which have considered the usefulness of SCS for treating PDPN

, and research-ers found that pain significantly decreased and QOL improved in the group that
underwent SCS compared with the control group. Furthermore, in a researchstudy which observed the long－term results over a 2－year period, researchers reported obtaining an analgesic effect of 50% or higher through using SCS in 65% of
patients with PDPN.71). Moreover, in a 5－year observational study which investigated 48 patients72), 80% of patients who underwent implant surgery continued to use
SCS, and researchers indicated that the weakened effects of treatment were related to an increase in their Michigan Diabetic Neuropathy Score（MDNS）（RR 3.9（95% CI 1.3～11.6））. However,3 of these research studies had been conducted under the initiative of one single institution, and therefore there was a high risk ofbias, and there was a higher number of dropout cases, and therefore the quality ofevidence was not high. In addition, we believe it can be harmful for patients as inthese RCTs, there was a report of a death（details are unknown）for example, due
to the complication of an epidural hematoma. Therefore, we assigned a recommendation grade of ‘2B’ but physicians should exercise plenty of caution when deciding
whether to apply SCS and when performing this procedure.
PeriodDatabase
Words searched
P
I／C
Limitations
Selection summary

2005～2019
PubMed, Cochrane Central,NPO Japan Medical Abstracts Society
chronic pain, painful diabetic neuropathy, spinal cord stimulation
chronic pain＊
Surgical treatment（spinal cord stimulation） ／nothing specified
Limited by publication type, PubMed randomized controlled trial ／ systematic review searchfilter, Cochrane RCT search filter, other（cases of50＋）etc.
Of the 21 search hits, we used 4 of them which matched with the set PICO.

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Chapter Q．Fibromyalgia：CQ Q-1～CQ Q-7
CQ Q-1：What kind of pathology is fibromyalgia ?
CQ Q-2：What are the clinical symptoms of fibromyalgia in Japan ?
CQ Q-3：What kinds of pathology coexist with fibromyalgia ?
CQ Q-4：Is pharmacotherapy useful for fibromyalgia ?
CQ Q-5：Is exercise therapy useful for fibromyalgia ?
CQ Q-6：Are alternative therapies useful for fibromyalgia ?
CQ Q-7：Is multidisciplinary treatment useful for fibromyalgia ?

594

Q．Fibromyalgia

Q．Fibromyalgia
CQ Q－1：What kind of pathology is fibromyalgia ?
FM：fibromyalgia,

FMS：fibromyalgia
syndrome

Answer：Fibromyalgia（FM）is a form of chronic pain of unknown cause which
manifests at a wide number of sites on the body. The cardinal sign is a systemic
stiffness, and its accompanying symptoms are diverse physical symptoms and men­tal symptoms. With each of these symptoms, just like with chronic pain, clinicaltests including a physical examination and general image testing will not detect
any abnormalities which can explain the symptoms. Symptomatically, it is a form of

FSS：functional
somatic syndromesrheumatoid arthritis which belongs to the functional somatic syndromes（FSS）,fre­quently occurs in middle－aged women, and although there are no problems with
their vital prognosis, apart from suicide, their quality of life（QOL）and activities ofdaily living（ADL）are remarkably impaired. Similar to reports in the West to date,
it is a disease with a relatively high incidence rate with 1.7～2.1% of the popula­tion suffering from this condition. Through future advances into the causes of thisdisease and research into its pathology, there is the possibility that our concept of
FM as a disease may undergo a significant transformation. For ICD－11, we haveused the chronic pain categories that were issued by the International Association
for the Study of Pain (IASP) in 2015, in which fibromyalgia is classified into chronic
primary pain and chronic widespread pain.
Commentary：
In terms of fibromyalgia（FM）as a disease concept, we came up with 231 searchhits on PubMed for “concept,” and 177 of these reports were in English. There
were 114 search hits related to its “definition”, and 101 of these reports were in En­
glish. Of these, 7 reports were related to either the disease concept of FM or a defi­
nition of the disease1－7). On the other hand, we came up with 45 search hits for“definition” and “concept” on NPO Japan Medical Abstracts Society. Of these, 12were either about disease concept or gave a definition of the disease, and we used
11 of these search hits8－18). Considering these points, we decided on the following
disease concept at this present stage in Japan.
FM is not a new and emerging disease；it has been known for a while under thesame pathology, and is called various names such as non－articular rheumatism,
psychogenic rheumatism, soft tissue rheumatism, fibrositis, fibrositis syndrome, fi­bromyalgia（FM）, fibromyalgia syndrome（FMS）. Fibrositis gives us the picture ofa pathological inflammation in the connective tissue but as the existence of a classi­
cal image of inflammation cannot be confirmed with FM and in clinical tests, as it
does not detect findings which would suggest the existence of inflammation, in 1990

595

Q．Fibromyalgia

the American College of Rheumatology proposed a definition of the disease andproposed highly useful classification criteria so FM／FMS became commonly used.

ACR：American
College of Rheumatology

Furthermore, pathologies which resemble FM include chronic fatigue syndrome（CFS）, irritable bowel syndrome（IBS）, temporomandibular joint disorder, young
children skipping school, panic disorder, Gulf War syndrome, sick building syn­

CFS：chronic fatigue
syndromedrome, chemical sensitivity, interstitial cystitis. There is also functional somatic syn­dromes（FSS）, and mental illnesses such as depression and somatoform disorders（somatic symptom disorders : DSM－5）, and differentiating them from FM is a con­stant problem but at the present stage, no clear difference between them has beenshown. Furthermore, there have been some cases of young（child）cases, although
the number of such cases is small, and unlike in adult cases, these cases share thesame psychosocial background prior to onset, and non－drug treatments are more
important than pharmacotherapy.
At the present stage, the concept and definition for FM is, “a form of chronic
pain of unknown origin which covers a wide area of the body and its cardinal sign
is a systemic stiffness, with various physical symptoms and nerve ／ mental symp­
toms as its accompanying symptoms, and with each of its symptoms, just like withchronic pain, clinical tests including a physical examination and general image test­
ing will not detect any abnormalities which can explain the symptoms.” FM is an
isolated form of rheumatoid arthritis belonging to FSS, occurs frequently among
middle－aged women, and although there are no problems with its vital prognosis,
apart from suicide, their quality of life（QOL）and activities of daily living（ADL）
are remarkably impaired. Similar to reports in the west to date, it is a disease witha relatively high incidence rate with 1.7 ～ 2.1% of the population suffering fromthis condition. On the other hand, FM pain is not nociceptive pain；it is a neuro­pathic central pain with lesions that cannot be pinpointed, which established what
is called ‘central sensitization,’ one type of central nervous system syndrome（CSS）. CSS：central
Another common characteristic is that these pathologies tend to mutually coexist.
It is also sometimes called for example “central dysfunctional pain” and “psychoso­
cial pain”.

CQ Q－2：What are the clinical symptoms of fibromyalgia in Japan ?
Answer：The clinical symptoms of fibromyalgia in Japan are basically the same
clinical symptoms exhibited as in cases in the Western countries（clinical signs ／clinical images）（Table Q－1, Table Q－2）
. However, there is a large number of stud­ies that have reported differences in how frequently clinical symptoms have mani­
fested depending on the patient’s ethnicity and region. Moreever, in cases of juve­
nile fibromyalgia, although basically they exhibit the same symptoms as adult pa­

sensitization syndrome

596

Q．Fibromyalgia

Table Q－1

Positive rate of clinical symptoms among Japanese fibromyalgia patients（Cited from reference #28）

Clinical symptoms ＋Rate〔％〕Pain
Systemic pain
91.7
Arthritic pain
82.0
Muscular pain
70.9
Other soft tissue pain
47.2
Rheumatoid arthritis－like symptoms
Stiffness
63.7
Dry symptoms
49.3
Hand swelling
23.8
Mouth ulcer
22.4
Fever
17.6
Itchy skin
17.5
Raynaud’s phenomenon
12.9
Rash
10.9
Photosensitivity
9.8
Physical symptoms
Fatigue
90.9
Abdominal symptoms
44.2
Abnormal BM
43.1
Cold sensation
32.5
Palpitations
30.1
Burning sensation
26.8
Difficulty breathing
24.3
Weight fluctuations
23.7
Snoring
19.1
Allergic symptoms
17.1
Table Q－2
Clinical symptoms

Clinical symptoms ＋Rate〔％〕Neurological symptoms（Dull）headache
72.9
Numbness
64.8
Dizziness
44.6
Anacatesthesia
25.4
Photophobia
15.8
Hand root canal syndrome
5.5
Mental symptoms
Sleep disorder
73.1
Anxiety
64.3
Depressive mood
60.5
Feeling frustrated
41.1
Reduced concentration
38.7
Forgetfulness
18.5
Sleep apnea
7.8
Disturbance of consciousness
2.0（Dull）headache
Headache
66.2
Tension－type headache
37.0
Vascular headache
6.0
Migraine
57.0
Dull headache
33.8
Cystitis symptoms
Pollakiuria
15.0
Residual urine
15.0
Painful urination
10.3

Positive rate of clinical symptoms among American fibromyalgia patients（Cited from reference #31）
＋Rate〔％〕Clinical symptoms＋Rate〔％〕Sleep disorder
Fatigue ／ lethargy

89.1
88.6

Irritable bowel syndrome（IBS）
Heartburn

46.3
44.4

Myalgia
Muscle weakness
Numbness

85.2
70.2
67.6

Itch
Dizziness
Constipation

44.3
42.1
41.9

Cognitive impairment
HeadacheXerostomia
Insomnia

66.3
64.7
53.3
51.8

Abdominal colic
Upper abdominal pain
Tinnitus
Neurotic

41.5
40.3
41.4
39.7

Sensitive
Dry eyes
Depressive mood
Impaired eyesight

49.1
47.5
47.5
47.0

NauseaDiarrhea
Difficulty breathing
Difficulty hearing

37.7
33.6
32.3
29.8

n＝2,784

Clinical symptoms ＋Rate〔％〕Systemic pain
Upper－right of body
89.9
Upper－left of body
81.9
Right half of body
91.4
Left half of body
79.1
Dull headache
59.7
Arthritic pain
Knee
64.4
Shoulder
63.5
Elbow
49.5
Fingers
45.2
Feet
44.7
Crotch
44.2
Toes
29.8
Sternoclavicular
19.2
Jaw
16.3
Cough
16.3
Odynophagia
12.2
Wheeze11.0
Menstrual pain
13.0
Dysmenorrhea
22.3

Clinical symptoms＋Rate〔％〕Hair loss

23.6

Stomatitis（mouth ulcer）
WheezeReduced appetite

22.4
21.4
21.1

Raynaud’s phenomenon
Chest pain
Rash
Photosensitivity

20.1
29.2
17.1
16.7

Loss of taste ／ dysgeusia
Fever
Allergy
Vomiting
Epileptic fit

14.4
13.4
9.3
9.1
1.7

Q．Fibromyalgia

597

tients, it is unclear whether there is any difference in the positive rate of symp­
toms.
Commentary：
We cited 12 cases in total, including reports with analytical data on a large num­
ber of cases, and reports which targeted patients with juvenile fibromyalgia. How­ever, there were zero reports on Japanese patients. We had 13 search hits for “clin­
ical symptoms” “clinical pictures” and “clinical signs” on the NPO Japan Medical
Abstracts Society site5,19－33), and we cited 1 report which had a relatively high num­
ber of cases analyzed. Furthermore, there was 1 survey report by a research team31)
from the Ministry of Health, Labour and Welfare（MHLW）, and we cited 1 study

on juvenile fibromyalgia33).
The frequency of incidence of clinical symptoms, clinical signs or clinical pictures
was reported on based on observation studies of various patient groups. At thecurrent stage, there are almost no clear reports on whether there are any differ­ences in symptoms according to the patient’s country, region, ethnicity, gender, agegroup, religion, culture or economic situation. As these guidelines are for Japanese
residents of Japan, we collected data on Japanese people residing in this country. In
other words, there are analytical data based on an analysis of adult patients under­
going treatment at 1 facility30) and studies from a large number of facilities obtained
from a nationwide epidemiological survey31), whereas for children, we only have theanalytical results from 1 facility cases33).

CQ Q－3：What kinds of pathology coexist with fibromyalgia ?
Answer：There is no common consensus on what comorbidities exists but myal­
gic encephalomyelitis（ME）and chronic fatigue syndrome（CFS）very frequently
coexist with fibromyalgia. Other（comorbid）diseases we can cite include various
types of rheumatoid arthritis, self－immune disorders, autoimmune endocrine disor­ders, functional somatic syndromes（FSS）, and mental diseases and disorders.
Commentary：
In an analysis of 1.7 million American fibromyalgia（FM）patients who were dis­charged from hospital（a retrospective study）, the most common comorbidities forprimary FM were non－specific chest pain, mood disorder, and spondylosis／disc dis­order／other low－back pain（LBP）. The most frequent underlying disease of second­ary FM were essential hypertension, dyslipidemia, coronary atherosclerosis／otherheart disease and mental disorder34). In a review by Giacomelli et al.35), their analy­
sis focused particularly upon patients with FM and autoimmune rheumatoid arthri­

ME：myalgic
encephalomyelitis
CFS：chronic fatigue
syndrome syndrome
FSS：functional
somatic syndromes

598

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tis and non－rheumatic disease as comorbidities and found that among the FM cas­es, the prevalence rates were systemic lupus erythematosus（SLE）in 32% of cases,
Sjogren’s syndrome in 18% of cases, primary antiphospholipid syndrome in 16.7%
of cases, rheumatoid arthritis in 15 ～ 43% of cases, psoriatic arthritis in 53.3% ofcases, Behcet’s disease in 18% of cases, Hashimoto’s disease in 31% of cases, autoim­
mune thyroiditis in 19% of cases, and diabetes in 17% of cases.
Furthermore, in a retrospective study into the medical records of 1,100 adult pa­
tients with FM, they found that more than 50% of the patients had 7 or more exist­
ing comorbidities. The most common comorbidities were chronic joint pain and os­
teoarthritis（OA）（88.7%）, followed by depression（75.1%）, migraine and headache
36)（62.4%）and anxiety（56.5%）. Often diseases with the same pathophysiology asFM（for example, irritable bowel syndrome, interstitial cystitis, tension－type head­ache）coexist, and there are reports also of coexisting peripheral disorders and in­37)
flammation（for example, self－immune disorders, osteoarthritis）.

The results of a US study of the prevalence rate of FM adults among 8,446 pa­tients have been described below. We have estimated the prevalence rate among
the general population（prevalence rate of fibromyalgia）, and the odds of the FMprevalence rate among the general population（corrected by age, gender, ethnicity,
education, obesity, smoking history, region）. The following were reported as signifi­
cant：myocardial infarction（2.9／95% CI 1.31～3.64）, heart disease（2.47／1.43～
4.28）, stroke（2.37／1.09～5.15）,liver disease（5.07／2.11～12.21）,kidney disorder（4.16／1.97～8.81）high blood pressure（2.32／1.44～3.75）, diabetes（2.73／1.74～
4.30）, chronic obstructive pulmonary disease（2.64 ／ 1.47 ～ 4.75）, asthma（2.88 ／1.88～4.04）, stomach ulcer（4.15／2.59～6.66）, rheumatoid arthritis（5.76／3.25～
10.12）, systemic lupus erythematosus（SLE）（1.65／0.46～5.86）, migraine（7.68／
4.70 ～ 12.53）, hepatitis（1.15 ／ 0.39 ～ 3.37）, influence ／ pneumonia（3.38 ／ 2.26 ～5.07）, depression（7.9／4.94～12.65）, anxiety（7.62／4.84～11.99）, bipolar disorder（7.03／3.21～15.39）, other mental diseases（9.40／5.39～16.41）, colorectal cancer（0.4／1.1～5.09）, liver cancer（41.25／2.99～569）, pancreatic cancer（32.86／2.69～
401）38). The prevalence rate of mental comorbidities for fibromyalgia（FM）andwidespread chronic pain among Japanese patients was 96.9% in the case of FM
and 93.5% in the case of widespread chronic pain39). Although widespread chronic
pain does not meet the diagnostic criteria for FM, it is a disease in which patientscomplain of pain throughout the whole body and its pathology and method of treat­ment are believed to be the same. Somatoform disorder（somatic symptom
disorders : DSM-5）, dysthymic disorder, major depressive disorder, personality dis­order, pervasive developmental disorder（PDD）, dissociative disorder, and schizo­
phrenia are highly frequent comorbidities. For a diagnosis of fibromyalgia（FM）,
the medical practitioner needs to be an expert on psychiatric disorders.

Q．Fibromyalgia

599

CQ Q－4：Is pharmacotherapy useful for fibromyalgia ?
Answer：Administering between 300～600 mg／day of pregabalin and 60 mg／dayof duloxetine has been shown to provide analgesic effects. Generally, considering
how adverse events and severe side－effects manifest with pharmacotherapy, one
should confirm improvement in analgesic effect and QOL before administering
medication.
Recommendation Grade & Summary of Overall EvidenceRecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕

Summary of overall evidence：QOL：C（low）, Adverse events：B（moderate）
Commentary：
Administering between 300～600 mg／day of pregabalin continuously over a peri­
od of 12 ～ 26 weeks reduces medium to strong pain40). Furthermore, other condi­
tions, QOL and ADL improved in the same way. Although administering 60 mg／
day of duloxetine has analgesic effects, the NNT for indicating an analgesic effect41)

of 50% or more is 8 .
The results of a systematic review were that 7 reports met the eligibility criteria,
and 3 of these reports42－44) were used for meta－analysis. As the drugs that wereused in the research papers that were eligible for meta－analysis were limited tomirtazapine, nonsteroidal anti－inflammatory drugs（NSAIDs）and oxycodone, thevalidity of other forms of pharmacotherapy is low. The indicators used for meta－
analysis were NRS（an indicator of analgesic effect）, improvement in the pain scaleof 30%＋, and the SF－36（QOL）. The 3 reference papers which were eligible formeta－analysis were mirtazapine, NSAIDs, and oxycodone and the drugs used ineach respective one were different so there was a high amount of inconsistency.
Researchers indicated that in terms of both analgesic effect and QOL, there waspossibly no significant difference in analgesic effect that was clinically significant
between the pharmacotherapy group and placebo group, and considering factors
such as the small size of the sample and the lack of consistency, the evidence waslow. It was possible that there were more adverse events in the pharmacotherapy
group but the strength of the evidence was moderate.
With standard fibromyalgia（FM）, 10 ～ 50 mg ／ day of amitriptyline is recom­
mended but when depression is also present or for FM patients with general anxi­
ety, they recommend 60 mg／day of duloxetine. When depression is not a comorbid­
ity, one should consider administering 50～450 mg／day of duloxetine and pregaba­lin. There are some guidelines which do not recommend opioid analgesics
45－48)〔strong〕. In a Cochrane review, researchers evaluated intensity of pain, physi­

NNT：number needed
to treat

600

Q．Fibromyalgia

cal function, mental function, and level of patient satisfaction after administering 60
mg／day of duloxetine over a period of 8～12 week for patients with FM. The % ofpatients who experienced a 50% reduction in pain or more, compared with the pla­cebo, was high for FM at 13.1%（RR：1.57, 95% CI：1.2 ～ 2.06）. Physical andmental function were evaluated using the SF－36, and the difference in the averagechange from the baseline was 1.28 for physical aspects（95% CI：－0.33～－2.89）,
and 3.11 for mental aspects（95% CI：0.59～6.02）；in both cases it had improved
significantly. The level of patient satisfaction was evaluated using the Patient Re­
ported Global Impression（PGI）, and the difference in the average change frombaseline was －0.45（95% CI：－0.37～－0.18）,in any case it had improved signifi­
cantly. Mirtazapine significantly and greatly reduced patients’ average NRS scores（pain scores）compared with the placebo（difference：0.44,95% CI：－0.72 ～－0.17）. Compared with the placebo, from 6 weeks onwards, there was a larger
number of patients in the group who were administered mirtazapine whose NRSscores decreased by 30% from the baseline.（45.5% vs. 30.8%）. Furthermore, withmirtazapine, both the pain－related QOL , which is evaluated on the survey of the
impact of FM（Japanese version）and the SF－36, had improved. There were more
adverse events from mirtazapine than the placebo（68.8% vs. 56.7%）, which in­cluded drowsiness（32.1% vs. 7.4%）, weight gain（17.7% vs. 0.9%）, and increased
48)
appetite（11.6% vs. 3.3%）. In a systematic review of 3 RCTs on fibromyalgia（FM）, researchers evaluated changes in intensity of pain and QOL in a group thatwas only administered tramadol, a group that was administered a combination oftramadol／acetaminophen and a group that was administered a combination of tra­madol／amitriptyline. The differences in the average changes in pain intensity fromthe baseline were －13（95%：CI：－25.37 ～－0.63）, －12（95% CI：－18.77 ～－5.23）, and －13（95% CI：－19.08～－6.92）, respectively；showing a significant
improvement. QOL was evaluated using the Fibromyalgia Impact Questionnaire（FIQ）and the average change in FIQ from baseline in the tramadol ／ acetamino­
phen group was －6.00（95% CI：－9.55～－2.45）, indicating an improvement but
in the Tramadol alone group it was －2.9（95% CI：－10.86～5.06）；a significant
effect was not observed. In light of the above, tramadol is not useful enough when
implemented alone.
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Fibromyalgia
Pharmacotherapies etc.／placebo etc
Limited by publication type,PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, etc
Of the 14 MEDLINE search hits, and 1 Cochrane Central search hit, we used 9 of them whichmatched with the set PICOQ．Fibromyalgia

601

CQ Q－5：Is exercise therapy useful for fibromyalgia ?
Answer：Exercise therapy improves the severity of fibromyalgia（FM）, qualityof life（QOL）, pain, fatigue, physical function, and muscle stiffness so we believe it

QOL：quality of life

is useful.
Recommendation Grade & Summary of Overall EvidenceRecommendation grade：1（strong）：Implementation is strongly recommend­ed〔Consensus 100.0%〕
Summary of overall evidence：B（moderate）
Commentary：
There have been 4 reports of Cochrane systematic reviews which investigatedthe effects of exercise therapy（aerobic exercise, aquatic exercises, muscle－streng­thening exercises etc.）on chronic pain49－52). These studies targeted adults aged 18
years old＋with chronic pain and used a waiting-list group or regular－treatmentgroup for the control. There were problems with the bias risk and sample size inthese research studies but researchers indicated that with each outcome（QOL,
pain, fatigue, physical function, muscle stiffness）, there was a high possibility thatexercise therapy was effective on fibromyalgia（FM）both 3 months after and 4
months after intervention. Furthermore, in the EULAR（European League Against
53)
Rheumatism）guidelines（2016）, they recommend aerobics and stretching exer­

cises. Therefore, we believe we can recommend implementing exercise therapy.
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Exercise／nothing in particular
Limited by publication type,PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, etc
Of the 20 MEDLINE search hits,and 19 Cochrane Central search hits, we used 5 of themwhich matched with the set PICOCQ Q－6：Are alternative therapies useful for fibromyalgia ?
Answer：Although cognitive－behavioral therapy（CBT）alone improves depres­sion, it is unable to improve pain and quality of life（QOL）.CBT which uses hypno­

CBT：cognitive-behavioral therapy

therapy and guided imagery（image therapy）do improve pain and QOL. Althoughmind－body exercise therapy（Qigong, Tai chi, Yoga）does not improve pain, it doessignificantly improve depression and QOL. Balneotherapy（hot－spring therapy）
and hydrotherapy do improve pain and QOL. We do not recommend transcranial

TMS：transcranial

magnetic stimulation（TMS）or massage therapy（including myofascial release）. magnetic stimulation
No particular adverse events or severe side effects have been reported.

myofascial release602

Q．Fibromyalgia

Recommendation Grade & Summary of Overall Evidence1）Transcranial magnetic stimulation（TMS）
Recommendation grade：No recommendation〔Consensus 100.0%〕
Summary of overall evidence：B（moderate）
2）Cognitive－behavioral therapy（CBT）
R
 ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 94.7%〕

Summary of overall evidence：C（low）
3）Cognitive－behavioral therapy（CBT）using hypnotherapy, guided imagery（image therapy）
R ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 86.4%〕

Summary of overall evidence：B（moderate）
4）Balneotherapy, hydrotherapyR ecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 85.7%〕

Summary of overall evidence：C（low）
5）Massage therapyR ecommendation grade：2（weak）：No implementation is weakly recom­
mended〔Consensus 100.0%〕
Summary of overall evidence：C（low）
Commentary：
Even though cognitive－behavioral therapy（CBT）improved depression, it did
not improve pain or QOL. Patient’s self－efficacy for their own pain improved signifi­
cantly. In CBT performed for around 6～12 weeks（for a total of 6～72 hours）, re­searchers found that its effects still persisted from 2 months later to 4 years later54).
CBT using hypnotherapy significantly improved pain and QOL. When CBT wasused in combination with hypnotherapy over a period of 12 ～ 14 weeks, in which
patients underwent training for about 90～120 minutes every week, effects persist­ed up to 6 months later. When training was used with a combination of hypnother­apy and physical therapy（conducted 8 times over a 12－week period ／ 1 hour per
session）, researchers recognized its effects up to 3 months later and 6 months later.
CBT which used guided imagery（image therapy）significantly improved pain andimproved QOL. With training using image therapy（over a period of 4～6 weeks,with patients undergoing around 1～1.5 hour sessions each time／day for 4 consec­
utive days／week）, researchers observed its effects up to 6～10 weeks later55－60).
Although exercise therapy which used mind－body exercise therapy（Qigong, Taichi, Yoga）did not improve pain, depression and QOL significantly improved61).
Through undergoing a total of 6～24 hours of training over a 4～12 week period,

Q．Fibromyalgia

603

researchers observed that it was effective up to 3～6 months later62,63). There is areport that repetitive transcranial magnetic stimulation（rTMS）did improve fibro­
myalgia（FM）pain and depression, as well as QOL but there was some reporting
bias, and some inconsistencies in the results64). Subjects underwent 10～14 sessionsof rTMS from between 2 weeks up to 3 months, and researchers observed its ef­
fects 30 days later. Balneotherapy（hot－spring therapy）and hydrotherapy improvepain and QOL. A total of 200－300 minutes of balneotherapy and hydrotherapy overa period of 2～5 weeks had significantly improved pain and QOL 14 weeks later65).
Massage therapy（including Swedish style massage, connective tissue massage,
lymph drainage, myofascial release, acupressure, Chinese style massage, tui na,
etc.）did not have a clear effect on pain or depression66－71). In EULAR, no implemen­tation is weakly recommended53).
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alternative medicine etc.
Limited by publication type,PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, etc
Of the 19 MEDLINE search hits, and 7 Cochrane CENTRAL search hits, we used 20 thatmatched with the set PICOCQ Q－7 Is multidisciplinary treatment useful for fibromyalgia ?
Answer：Compared with pharmacotherapy, multidisciplinary treatment improves
Fibromyalgia Impact Questionnaire（FIQ）results and pain. However, its effects onother parameters such as physical capabilities and mental aspects remain unclear.
Recommendation Grade & Summary of Overall EvidenceRecommendation grade：2（weak）：Implementation is weakly recommended〔Consensus 100.0%〕

Summary of overall evidence：B（moderate）
Commentary：
In many cases single forms of treatment, such as conventional pharmacotherapy,
provide insufficient effects on fibromyalgia（FM）. Therefore, one considers the effi­cacy of providing multidisciplinary treatment from the start to patients, instead of
combining individual therapies together based on the individual patient. Research­ers have reported that multidisciplinary treatment has a tendency to improve QOL
and pain, rather than just using pharmacotherapy alone72－74). QOL and pain areclosely interrelated, and therefore multidisciplinary treatment is recommended as a
strategy for treating FM.
There are individual reports indicating the efficacy and harmlessness of multidis­

FIQ：Fibromyalgia
Impact Questionnaire

604

Q．Fibromyalgia

ciplinary treatment on many parameters including physical capabilities such as
ADL, as well as mental aspects such as depression. In Japan, it already has the ob­jective of establishing uniform accessibility to a chronic pain treatment system andthey are pushing ahead with the construction of multidisciplinary centers. We hopethat between these numerous facilities, widespread mutual research will progress,for example with reducing medication due to multidisciplinary treatment, facilitatea return－to－work for patients, and seek out ways to provide even better treatment
programs for them.
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Fibromyalgia*
Multidisciplinary treatment／pharmacotherapy
Limited by publication type,PubMed CER randomized controlled trial ／ systematic review
search filter, Cochrane RCT search filter, etc
Of the 46 MEDLINE search hits, and 11 Cochrane Central search hits, we used 3 of themwhich matched with the set PICO

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609

索
あ行
アクセプタンス＆コミットメント・セラ
ピー

117, 119, 149

アセトアミノフェン

γ アミノ酪酸

36, 57

管理栄養士

150, 152237
48, 60, 205, 208,

219, 220, 233, 234, 250, 268
依存・乱用49, 65, 67

社会福祉士

150, 152

集学的治療

117, 118, 148, 271

急性痛

痛みの破局化思考

24, 25

一次性慢性疼痛

24, 41

緊張型頭痛

23, 168, 170, 208
76, 102,190

51, 52, 61, 62, 86, 214,

221, 222, 267

運動療法

268

136

33, 35, 128, 131, 149, 152,

経皮的末梢神経電気刺激療法（TENS）
134, 137, 149, 191, 255

オピオイド27, 41, 49, 61, 64, 65, 67,

73, 106, 120, 136, 149, 151, 180,
218, 252
オピオイド鎮痛薬〔強度〕 67, 253,
268
温熱療法

48, 49, 58, 60, 204, 208,

交感神経依存性疼痛

82

交感神経節ブロック

83, 255

口腔顔面痛

23, 82, 83, 196

口腔灼熱痛症候群（以前は，口腔内灼熱症候群） 61, 62, 196, 202, 203, 204,
205

157

抗コリン作用後枝内側枝ブロック

外傷後症候群84

外傷性頚部症候群
顎関節症

高周波熱凝固155

合併症81, 85, 87, 91, 104, 201,

抗てんかん薬27, 53, 58, 60, 208

51, 65, 77, 78, 79, 83, 85, 86,

行動療法48, 55, 57, 198, 251

116, 117

公認心理師
抗不安薬

49, 61201, 218, 228, 249, 257

呼吸抑制49, 6631, 33, 82, 92, 93, 180

ガバペンチン48, 54, 198, 199, 200,

208, 232, 234, 236, 248
過敏性腸症候群

208, 264, 266, 267

カルバマゼピン48, 57, 198, 199, 202,

251
看護師

150, 151, 164

患者教育119, 131, 133, 150, 171,

180, 191, 219
がん性疼痛

22, 23, 49, 130

関節内ステロイド薬注射

90, 91, 93

関節内ヒアルロン酸注射

91, 9368, 25476, 78

神経障害性疼痛

22, 23, 37, 39, 40, 48,

196, 199, 204, 206, 228, 232, 233,
235, 244, 245, 246, 248, 250, 251,
心血管イベント
身体診察

身体表現性障害（身体症状症） 207,
264, 268
診断学39, 60, 68, 148, 168, 264
69, 25422

34, 188, 197, 202, 203, 207,

208, 209, 214, 217, 245, 246, 267
診断的神経ブロック
心理教育

87

116, 119, 121, 172
22, 24, 25, 26, 30, 41, 77,

83, 85, 103, 116, 120, 149, 150, 151,
152, 153, 154, 163, 164, 165, 166,
167, 207, 208, 264, 265
心理的アプローチ
心療内科医
心理療法
睡眠障害

国際疼痛学会（IASP） 22, 23, 26, 34,

混合性疼痛

30, 166

診断基準

頭痛

牛車腎気丸

48, 5130, 167, 264

116, 149

150
119, 120, 121, 149, 151,

155, 205

122, 150

87, 88, 93, 103, 105, 106, 108, 183,
可動域

80, 91

255

196, 264

下行性疼痛抑制系

神経根ブロック

心理社会的61, 251

後根神経節（DRG） 90, 163, 228

か行

漢方薬

92

233, 234, 250

105

22

48, 51, 55, 230, 231, 232

252, 253

134

抗うつ薬

侵害受容性疼痛
腎機能障害

148, 154

82, 8454, 55, 57, 60, 61, 62, 64, 66, 67, 90,

104

肩峰下滑液包内ステロイド薬注射

154, 170, 180, 191, 269
エピドラスコピー

128, 191

頚椎カラー

牽引療法

（大）うつ病性障害

上肢の CRPS

86

経皮的髄核摘出術

インターベンショナル治療

集学的リハビリテーション

24, 228, 230

筋力増強運動痛みの恐怖回避モデル

31, 33, 37, 39, 40, 41, 84, 151,

167, 245, 271

134

筋筋膜痛症候群

アミトリプチリン

質問票

133, 270

寒冷療法
気功

48, 51, 180, 218,

引24, 25, 49, 103, 155, 266

49, 59, 61, 82, 117, 169, 228,266
ステロイド薬投与76, 77, 78, 79, 80,

104, 109
ストレッチング

92, 151, 190, 270

星状神経節ブロック
精神科医

さ行

精神保健福祉士

最終目標

25, 40催眠療法

121, 209, 270

82, 235

150, 151
150, 152

生物心理社会的リハビリテーション
170

作業療法士

132, 150

生物心理社会モデル

三叉神経痛

48, 57, 87, 88, 89, 91, 196,

脊髄刺激療法（SCS） 102, 237, 257

197, 198, 201, 251
シクロオキシゲナーゼ
持続性特発性歯痛

50

196, 206, 207

31, 149, 150, 152

脊髄損傷後の痛み

102, 130

脊椎手術後症候群102, 106

脊椎マニピュレーション

137

610

索

セロトニン・ノルアドレナリン再取り込
み阻害薬

49, 58, 168, 208, 249

セロトニン症候群59, 250

線維筋痛症（FM） 23, 34, 48, 49, 50,
51, 55, 58, 60, 62, 64, 65, 118, 142,
線維筋痛症質問票
仙骨ブロック271

漸進的筋弛緩法
装具療法

ま行

認知行動療法（CBT） 107, 108, 117,

117, 123

267

マッサージ

156, 172, 191, 205, 208, 270

マネジメント56, 58, 200

150, 152

24, 25, 41, 116, 117, 118,
88, 89, 104, 201, 236,
48, 57, 219,

膝 OA（変形性膝関節症） 33, 35, 49,

133, 270

慢性頭痛

23, 120, 144, 215, 217, 267

慢性腰痛34, 38, 41, 49, 50, 51, 52, 55,

61, 62, 80, 87, 107, 118, 128, 129,
131, 133, 134, 135, 137, 143, 153,

237, 255
220, 251

太極拳

22128, 131, 133, 134, 135,

136, 142, 157

破局化思考

バルプロ酸ナトリウム

た行

32, 81, 150, 154

慢性頚部痛

パルス高周波法ソーシャルワーカー

118, 120, 149, 155123, 143, 270

マルチプルペアレンチング

153, 165, 166, 167, 205

108

マインドフルネス

120, 121, 131, 149, 151, 152, 155,

は行

76

双極性障害

な行

忍容性

153, 154, 264

引154, 155, 162
ミロガバリン48, 54, 56, 232, 248

むち打ち損傷156

50, 69, 87, 88, 89, 92, 128, 131, 133,

モーターコントロールエクササイズ

帯状疱疹後神経痛（PHN） 48, 53, 54,

134, 135, 138, 180（MCE） 128, 133

55, 60, 69, 82, 83, 89, 90, 102, 228,

非ステロイド性抗炎症薬

帯状疱疹関連痛228, 236

230, 231, 232, 233, 234, 235, 237

180, 189, 218, 268

63, 198

非特異的腰痛中枢性感作（中枢感作） 22, 26, 207,

ピラティス

多発性硬化症57, 251

治療的超音波療法

134

231, 232, 235, 253, 268
椎間関節ブロック
椎間板内治療80, 81

物理療法
不動化76, 78, 104, 162, 163,

49, 67

128, 134, 135, 189, 191
24, 25201, 202, 205, 209, 256
デュロキセチン49, 58, 168, 180, 205,

49, 6538, 48, 54, 69, 90, 198,

199, 208, 231, 237, 248, 268
229, 253
変形性関節症35, 48, 49, 50, 58, 64,

65, 67, 68, 153, 180, 267
変形性股関節症

208, 249, 268

91, 93変形性膝関節症（膝 OA） 33, 35, 49,26

糖尿病性神経障害

50, 69, 87, 88, 89, 92, 128, 131, 133,

49

129, 133, 135, 149, 155, 191

トピラマート219, 220, 251

トラマドール49, 59, 63, 64, 169, 180,

48, 51, 52, 57, 120, 122, 142,

214, 217, 219, 220, 221, 222, 266,
267

234, 237, 252, 269
トリガーポイント注射

134, 135, 138, 180
片頭痛35, 86, 190

150, 151

痛） 217
有酸素運動128, 151, 180, 191

有痛性糖尿病性末梢神経障害

ベンゾジアゼピン

腰部固定帯

91

137

腰部脊柱管狭窄症
ヨガ

76, 78, 84, 162, 163

133, 191, 270

ら行
ラモトリギン

199, 251

リウマチ性疾患

265, 267

理学療法士

130, 150, 151, 156

臨床心理士

150

レッドフラッグ（red flag） 150, 166

わ行
ワクシニアウィルス接種家兎炎症皮膚抽出液49, 61, 218

54, 57,

58, 60, 102, 103, 134, 244
癒着性肩関節包炎

ブプレノルフィン

米国疾病管理予防センター（CDC）

167
低出力レーザー治療（LLLT） 134,や行薬剤師

薬剤の使用過多による頭痛（薬物乱用頭複合性局所疼痛症候群（CRPS） 34, 35,

プレガバリン103, 104

椎間板ヘルニア

徒手療法

133, 191

82, 83, 102, 103, 130

治療必要数（NNT） 60, 68, 199, 200,

疼痛行動

23, 136, 165, 168

フェンタニル貼付剤

265
中毒性表皮壊死症

48, 50, 169,48, 53

611

Index
325, 328, 337, 338, 340, 345, 353,

A

354, 375, 384, 406, 419, 430, 431,

acceptance & commitment therapy

463, 464, 470

417, 420, 456
acetaminophen

336, 340, 493, 539,

administer steroids390

371, 372, 373,

amitriptyline

305, 479, 481,

529
clinical psychologist

457, 459

430, 458, 493, 506

407, 408, 417, 422, 424, 434, 456,
459, 460, 464, 465, 483, 507, 524,
529, 601

543, 558, 559, 577, 599
anticholinergic effectantidepressant353, 579

336, 337, 349, 350,

complex regional pain syndrome（CRPS） 320, 322, 378, 379, 400,
complication

339, 358, 371, 373, 375,

379, 382, 384, 385, 386, 392, 401,

579
337, 352

Bbenzodiazepine

biopsychosocial model
460

biopsychosocial rehabilitation

482

378, 380

438
338

D
337, 357, 359（major）depressive disorderdescending pain inhibitory systemcancer pain

598

310, 343, 349, 351, 527
diabetic neuropathy
diagnostic criteria

337
320, 502, 514, 521,

522, 527, 529, 534, 538, 572, 573,
305, 306, 337, 433

carbamazepine

336, 347, 515, 516,

cardiovascular event
catastrophizing

336, 340

307, 308, 328, 416,

417, 418, 461, 475, 477, 524
catastrophizing of pain
caudal block

308, 328

304, 308, 526,

595
certified public psychologist

424, 459

440

chronic headache

305, 421, 450, 535,

539, 598
chronic low back pain（LBP） 319,

Ggabapentin

336, 344, 516, 517, 528,

556, 559, 561, 575

diagnostic nerve block385

314, 476

disc herniation
477

337, 350, 352, 378, 417,
552, 561

hip osteoarthritis（hipOA） 390, 392
hyperthermic treatment
hypnotherapy

466

422, 529, 602

I
immobilization

307, 308

impaired kidney function

336, 340,

International Association for the Study
304, 305, 308, 320, 326,

351, 360, 454, 479, 594
interventional treatment

389, 472, 552

337, 348, 479, 493, 524,

epiduroscopy

370, 400,

504
intra-articular hyaluronic acid injection
390, 392
intra-articular steroid injection

E

389,

390, 392
404

exercise therapy

319, 322, 430, 434,

455, 460, 463, 481, 493, 506, 601
extract from inflamed cutaneous tissueof rabbits

36, 57, 323, 347

Hof Pain

370, 373, 402, 471,

dorsal root ganglion
duloxetine

362, 583

344, 555

528, 577, 599

370

central sensitization

cervical collar

599
diagnostics

520, 579

603

herpes zoster-related pain

dependence/abuse

598

C

419, 448, 461, 463, 594

480, 552, 596

337, 358
352, 353,

339, 344, 349, 350, 353, 356, 357,

headachebuprenorphine

512, 521, 522, 523, 524

337, 360

gosha-jinki-gan

bipolar disorderburning mouth syndrome

307,

305, 319, 336, 337, 338,

γ-aminobutyric acid

cyclooxygenase

315, 455, 457,

fibromyalgia

576, 587
cryotherapy

417, 418

337, 353, 540

fentanyl patch

404, 406, 408, 497, 519, 540, 552,
CRPS in the upper limbs

behavioral therapy

fear-avoidance model of pain

Fibromyalgia Impact Questionnaire

402, 433

523, 528, 558, 559, 577
antiepileptic drugs 336, 345, 347, 515,

400,

308

336, 350, 524, 528, 541,

aerobic exercise

failed back surgery syndrome405

cognitive behavioral therapy（CBT）

374, 402, 409

anxiolytics

430, 434, 437, 438,

chronic primary pain

306, 552, 554

adhesive shoulder capsulitis

F
facet（zygapophyseal）joint block 375,
376

chronic neck pain

439, 440, 448, 466

563
acute pain

434, 437, 438, 439, 441, 450, 462,

336, 342

Intradiscal treatment

402, 403

irritable bowel syndrome
596, 598

528, 595,

612

Index

nonsteroidal anti-inflammatory drugK

336, 338, 480, 493, 503, 539, 599

Kampo medicine

361, 583

number needed to treat

knee osteoarthritis（knee OA） 319,
322, 337, 339, 363, 385, 386, 387,
391, 430, 434, 437, 442, 492

opioid516, 579
438, 519,

lumbar corset/lumbar fixation belts
lumbar spinal（canal）stenosis

370,

435, 457

310, 328, 337, 352, 356, 357,

359, 366, 405, 422, 441, 456, 459,
359, 582,

317, 377, 457

manual therapy

431, 437, 439, 456,

463, 506
425, 450, 601

medial branch block

orofacial pain

305, 378, 379, 512409

322, 336, 337, 338, 340,

medication overuse headache

538

336, 339, 342, 347, 421,

424, 448, 534, 539, 540, 542, 544,
545, 596
419, 422, 456, 463

mirogabalin

336, 344, 347, 557, 575

mixed pain condition
motor control exercise

431, 436

462
multidisciplinary treatment

417, 419,

454, 603

painful diabetic peripheral neuropathy

renal dysfunction

344, 348, 351, 400, 401, 438, 570
patient education

420, 434, 437, 458,
403

512, 525, 527
314, 477, 594

physical therapist

433, 457, 458, 465

physical therapy

430, 437, 439, 504,

506

387, 388, 400, 552, 554, 556, 557,
558, 559, 560, 562
380

325, 336, 345, 363, 388,

516, 528, 556, 563, 576, 599

nerve root block

370, 373

progressive muscle training

neuropathic pain

304, 305, 321, 324,

psychiatric social worker

326, 336, 344, 345, 347, 350, 352,

psychiatrist

353, 356, 359, 388, 512, 516, 523,

psychoeducation

525, 552, 557, 558, 560, 571, 572,

psychological approach

573, 575, 578, 579, 581, 582

psychosocial

non-specific lower back pain
441, 474, 478

417, 425

457, 460

457, 458

337, 349, 478, 528, 577
306, 307, 337, 401,

464, 596
457, 460

457, 460

sodium valproate

336, 347, 541, 542,

579
somatoform disorders（somatic（DSM-5） 526, 595, 598
spinal cord injury

400, 433

spinal cord stimulation
spinal manipulation

400, 563, 586

442

stellate ganglion block

378, 561

steroid injection into the subacromial

416, 420, 423, 483
416, 456

304, 306, 307, 308, 315,

328, 371, 379, 381, 401, 416, 422,
305,

350, 578

symptoms and related disorders）

post-traumatic syndrome,pregabalin

304

inhibitor

sleeping disordersocial worker

342, 343, 345, 351, 362, 378, 379,

nociceptive painSsocial welfare worker
436, 506

postherpetic neuralgia（PHN） 336,N

337, 358

595, 598

serotonin-noradrenaline re-uptake

306

383

557
respiratory depression

serotonin syndrome

457, 459

355, 515

myofascial pain syndrome

457, 459
336, 340, 344, 556,

rheumatoid arthritis

482, 493, 506, 541

multiple sclerosis

430,

458, 476

registered dietitian

multiple parenting

506

376, 381, 384, 389, 403, 518, 584

309

pilates

muscular strengthening exercise

radiofrequency thermocoagulation

377, 391, 392, 493

physical examination

455,

R

red flagpharmacist

multidisciplinary rehabilitation

315, 318, 321, 326, 327,

P

persistent idiopathic dentoalveolar pain

304

436, 601

questionnaire

range of motion（ROM） 316, 318,

percutaneous nucelotomy

mindfulness

Q492, 588

pain behavior

375, 389

386, 387, 404,

329, 381, 458, 477, 572, 603

341, 349, 356, 358, 359, 361, 461,

management455, 459,

518, 561, 562, 584

Qigongopioid analgesics [strong]

osteoarthritisM

459, 464, 524

pulsed radiofrequency

orthotic treatment

371, 380, 471

420, 422, 423, 455,

464, 524

599

441

457

psychotherapy

psychological treatment

493, 539, 581

520, 524, 529, 586

migraine

457, 458, 473

occupational therapist

low level laser treatment

massage

517, 518, 556, 557, 560, 582, 599
nurse

O

L
lamotrigine

351, 360,595
psychotherapist

456, 457, 458, 460, 461, 463, 471,
474, 475, 476, 477, 526, 528, 594,

bursa
stretching

391
391, 458, 505, 601

sympathetic ganglion block

380, 585

sympathetic nerve-dependent pain
378

613

Index

T
Tai chi

436, 603

512, 595
tension-type headache

340, 341, 352,

353, 383, 535, 544, 545, 598
therapeutic ultrasoundtolerability/tolerance
topiramate

438
346, 348, 518

541, 543, 579

toxic epidermal necrolysis
traction therapy
tramadol

348, 580

438

337, 350, 355, 356, 479,transcutaneous electrical nerve stimula438, 442, 456, 506, 584

traumatic cervical syndrome
trigeminal neuralgia

436, 506, 601

略語

464

336, 347, 384,

385, 386, 389, 512, 514, 515, 518,
trigger point injection

322, 383, 505

U308, 327

Prevention（CDC） 553, 581

whiplash-associated disorder

465

NNH

199, 233, 235, 517, 559, 560

NNT60, 68, 199, 231, 232, 235, 253,

117, 119, 149, 417, 420, 456

AHS

51, 339

ASA

26, 308

OARSI

ASRA

26, 308

PDD

BMS

37, 61, 202, 203, 204, 205, 206,

PDPN

102, 244, 400, 570

PHN

54, 82, 84, 89, 102, 228, 343,

CBT

107, 117, 131, 149, 156, 205,

268, 351, 360, 516, 556, 557, 560,
582, 599

378, 380, 387, 400, 552
PLDD

524, 529, 601

PRF

CDC

253, 581

COX-2

50, 338

CRPS

34, 82, 83, 102, 320, 378, 380,400

93, 392

104, 403

208, 270, 407, 417, 434, 456, 465,

104, 403
88, 89, 104, 201, 236, 237, 255,

386, 387, 403, 519, 562, 563, 584
RF85, 87, 91, 201, 255, 382, 384,

389, 518, 584
RMDQ

37, 166, 170, 321, 476, 481

90, 389

SCS

102, 237, 257, 400, 563, 586

FBSS

76, 102, 106, 400, 405

SGB82, 378

FIQ

65, 269, 271, 357, 600, 603

SNRI

49, 58, 168, 208, 249, 337, 349,

57, 347

478, 528, 577

HRQL

121, 205, 423, 524

TEN57, 348

IASP

22, 26, 34, 39, 60, 68, 148, 168,

TENS

134, 137, 149, 191, 255, 438,

170, 197, 264, 304, 308, 320, 326,
351, 360, 454, 479, 481, 514, 594

W

86, 383

ACTGABA

US Centers for Disease Control and128, 431

MPS

61, 143, 353, 449

DRG

580

64, 356

MCE

ACP

321, 353, 521, 522, 523, 524, 525

493, 560, 563, 581, 600

ultimate goal

M1

yoga

temporomandibular joint disordertion519, 524, 529, 585

Y

ICD-11

22, 264, 306, 594

LLLT

134, 201, 205, 209, 256, 438,

442, 456, 506, 584
TPI

86, 383

WAD

156

まんせいとうつうしんりょう

慢性疼痛診療ガイドライン
2021 年 6 月 30 日

第 1 版第 1 刷発行©
編集・発行

慢
 性疼痛診療ガイドライン
作成ワーキンググループ

このガイドラインは「厚生労働行政推進調査事業費補助金（慢性の痛み政策研究事業）：慢性疼痛診療システムの均てん化と痛みセンター診療デー
タベースの活用による医療向上を目指す研究」で作成された．
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印刷・製本㈱リーブルテックClinical Practice Guideline for the Management
Chronic Pain
The Committee for Clinical Practice Guideline
for the Management of Chronic Pain

First edition first published in 2021
by Publication Department, Shinko Trading Co. Ltd.
Ⓒ ‌The Committee for Clinical Practice Guideline for theManagement of Chronic Pain
2021 All Right Reserved
These guidelines are prepaired by “Health, Labour and Welfare
Policy Research Grants (Research on chronic pain) in Japan :Research for the Uniform Accessibility to Chronic PainManagement Systems and Improved Healthcare Utilizing Pain
Center Treatment Databases”

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