Clinical Practice Guideline
for Chronic Pain

The Committee for Clinical Practice Guideline
for Chronic Pain

Publication Department, Shinko Trading Co. Ltd.

157

Preface
A little over a year after the 16th International Association of the Study of Pain (IASP)
Conference was held in Yokohama in 2016, it came to be recognized as a significant‘monument’ to Japanese pain research and treatment. For the development of pain
treatment, undoubtedly much research needs backing, including support for basic research, which pinpoints the pain mechanism, translational research, which leads to applications for future clinical practice, and also clinical research on new forms of treatment. There have been significant developments in pain research over the past 40～50
years. For example, the gate control theory of pain proposed by Melzack & Wall in
1965, Perl’s research on nociceptor sensitization in 1976, and Basbaum and Field’s (1979)
research into the descending pain (sensitization) inhibitory system are particularly famous, and in the 1980s, Woolf and his colleagues proposed the concept of increased excitability of spinal cord neurons (central nervous system sensitization). In the late 1980s,
Bennett et al., from the National Institutes of Health (‘NIH’), published their neuropathic
pain model, taking pain research into a new era. In addition, both the discovery of cloning opioid receptors and TRP channels in the 1990s were the results of molecular biology research methods and a massive number of papers and theories were spawned in
the 20 years or so that followed and research into drug discoveries was also very active. However, with these new forms of research into explicating the pain mechanism,
which led to the development of real drug discoveries and methods of treatment, someproblems also arose. With ‘pain’ as our target, for various reasons, there were several
difficulties with developing groundbreaking drug discoveries and new forms of treatment. Some of these issues, which we can cite here, include that：1) ‘pain’ is a subjective sensation and is therefore difficult to quantify；2) pain is susceptible to psychological and emotional modification；and 3) pain receptors often indicate plastic changes,
making it difficult to analyze and comprehend. Despite these difficulties, thanks to theefforts and awareness‒raising activities of a large number of pain clinicians and researchers around the world, we have seen significant changes and progress in pain
treatment and clinical practice over the past few decades. As a result of the efforts of
the IASP, WHO and a large number of other individuals and organizations, the current
situation has completely changed since the time when IASP founder, Bonica, indicatedthe lack of interest in and understanding of cancer pain at the time. At the same time
we have also been introducing multidisciplinary treatment by palliative care teams. In
Japan which has been decades behind the times, there has been definite progress in thetreatment of cancer pain and palliative care, meaning that a large number of patientsare now being saved, and there is no doubt that what needs to be tackled next in clinical settings is non‒cancer chronic pain, of which an immensely large number of people
suffer. An enormous amount of national wealth is lost due to chronic pain and therefore

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Prefacethis needs to be tackled effectively. What is more, unless we deal with chronic pain,
there is no way we can save individual patients. To date, the government has initiatedadministrative measures on a variety of diseases, including measures for cancer, lifestyle‒related diseases, infectious diseases, mental disorders and intractable diseases,
among others. However, a strategy for dealing with chronic pain diseases has been an
area of inquiry, which seems to have slipped through the cracks. However, thanks tothe efforts of a large number of people over the past 10 years, we are extremely delighted that countermeasures for dealing with chronic pain diseases have advanced to
become a national project.
Against this backdrop, work is being conducted by the ‘Research on Constructing a
System for the Treatment and Education of Chronic Pain Problems’ (Representative：
Takahiro Ushida) under the Health, Labour and Welfare (MHLW) Promotional Reseach
Grant. Furthermore, with the cooperation of the seven associations, which comprise thePain Consortium, who tackle the diagnosis and treatment of chronic pain (‘chronic pain’)
across the disciplines, we have been able to create the ‘Clinical Practice Guideline for
Chronic Pain’ in line with the current situation in Japan. The seven associations which
comprise the Pain Consortium are The Japanese Association for the Study of Musculoskeletal Pain, The Japanese Society of Orofacial Pain, The Japanese 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, and
The Japanese Society for the Study of Low Back Pain. The research team mentioned
above, along with these seven societies and associations, have formed the core of the‘The Committee for Clinical Practice Guideline for Chronic Pain’. In making these guidelines, we have paid particular care to ensure that the contents are consistent with pain
guidelines which have already been published in Japan (such as the ‘Guidelines for
Pharmacologic Management of Neuropathic Pain’ and ‘Guidelines for Prescribing Opioid
Analgesics for Chronic Non‒cancer Pain’) and to improve its function as a referencebook.
In closing, I wish to express my heartfelt gratitude to everyone from the promotional
research grant research team at MHLW, all members belonging to the seven societies
and associations, and in addition all members on the committee of the ‘The Committee
for Clinical Practice Guideline for Chronic Pain’.
March, 2018
President of the Japanese Society for the Study of Pain (JASP)
President of the Hyogo College of Medicine
Koichi Noguchi, MD, PhD

159

Introduction
Pain is a warning signal from the living body and has an important meaning but if itis prolonged and becomes chronic, then it is subject to being treated as a disease.
Chronic pain is a disease (pathological condition), which has an effect on the economy of
our country. In many cases, each medical society or association creates its own guidelines outlining their own forms of treatment for these types of diseases. However, inmany instances we fail to reach a consensus due to the different points of view of theseassociations and organizations. These guidelines, which have been compiled by a research team from the Japanese Ministry of Health, Labour and Welfare (MHLW), alongside seven pain‒related societies and associations (The Pain Consortium), represent
guidelines for the whole of Japan.
The purpose for making these guidelines for the management of chronic pain
These guidelines are a compilation of the opinions of medical practitioners, who aremainly involved in the examination and treatment of patients with chronic pain, on
what they consider are the most effective and most useful forms of treatment in current practice. In order to refer not only to the doctors who are mainly involved in examining patients with chronic pain, but also first‒line primary medical practitioners
who often interact with regional citizens, rehabilitation staff who perform physiotherapy
on patients suffering from pain, nursing staff who act as a liaison between the doctors
and patients, and psychotherapy staff who provide counseling to patients with pain,
among others, we prepare an extensive set of clinical questions (hereinafter ‘CQ’). It is
our hope that these guidelines will bring some light into the lives of patients sufferingfrom chronic pain.
Our basic philosophy behind the making these guidelines for the management ofchronic pain
Under the conduction of the research team from MHLW, we obtained the invaluable
opinions of the Pain Consortium (The Japanese Association for the Study of Musculoskeletal Pain, The Japanese Society of Orofacial Pain, The Japanese 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, and
The Japanese Society for the Study of Low Back Pain) and related societies and associations (the Japan College of Fibromyalgia Investigation, The Japan Neurosurgical Society,
The Japanese Headache Society, The Japanese Orthopaedic Association, the JapaneseSociety of Anesthesiologists the Japanese Society of Neurological Therapeutics, the Japanese Society of Psychosomatic Medicine [listed alphabetically]) in order to form a compilation of professional opinions from the whole of Japan. Furthermore, representatives

160

Introduction

from patient groups also participated in general meetings. These guidelines were created in accordance with the ‘2014 and 2017 Guidebook for the Creation of Clinical Practice
Guidelines’ by MINDS, a project to promote the spread of evidence‒based medicine(EBM) by the Japan Council for Quality Health Care (JCQHC), and the philosophy of
AGREE II. In the general remarks in Chapter Ⅰ , we have mentioned such topics as
the concept of chronic pain, its classification, diagnosis, and ways to evaluate treatment.
In addition, we also mention multidisciplinary treatment, which has recently been a topic of much discussion. Ensuring that the guidelines conform with actual clinical practice,from Chapter II onwards, we have established some chronic pain CQs regarding themain forms of treatment currently being performed within Japan. There is a commentary on these CQs, and for each item, the search methods and the words searched forhave been listed. As our top priority is on evidence, we have also decided to provide
commentary on drugs and methods of treatment, which are not covered under the Japanese health insurance system. In order for the guidelines to form a consensus of opinion representing the whole of Japan, we have integrated the various guidelines issued
by the seven associations of the Pain Consortium as well as the guidelines of related associations. However, as we have utilized the most recent evidence, some discrepancies
have also arisen in certain CQ sections.
Patients for whom these guidelines for the management of chronic pain have been
written and how to use these guidelines
These guidelines were written for adult patients suffering from chronic pain, not patients suffering from cancer pain or acute pain. However, it is our hope that cancer‒
bearing patients suffering from pain other than tumor‒or metastasis‒based pain will refer to these guidelines as well. As the main priority of these guidelines has been theprovision of evidence, some of the drugs and methods mentioned are currently (as ofMarch, 2018) ineligible for coverage under the Japanese health insurance system. However, with pharmacotherapy, we hope the readers will read the drug information thoroughly first, before undergoing treatment.
Acknowledgements
We wish to warmly thank Professor Kiyoshige Ohseto (specially‒appointed Professor
from the Department of Anesthesiology at Tokyo Medical University) for his invaluable
opinions as an outside expert, all of the observing members for all of their guidance andadvice, all of the various members from the seven member associations of the Pain Consortium, as well as all the members of the research team from the Ministry of Health,Labour and Welfare (MHLW) from the ‘The Committee for Clinical Practice Guideline for
Chronic pain’, in addition to all members from related associations and members of patientsgroups, without whose help these guidelines could not have been created. Finally, we
deeply thank Mr. Matthew James Mclaughlin for his excellent translation of the guidelines.

161

Introduction

March, 2018
Health, Labour and Welfare Policy Research Grants (Research on chronic pain)
Research on Constructing a System for the Treatment and Educationof Chronic Pain Problems
The Committee for Clinical Practice Guideline for Chronic pain
ChairmanResearch Representative

Hisashi Date, MD, PhD
Takahiro Ushida, MD, PhD

162

Preparative Method of these Guidelines
The Committee for Clinical Practice Guideline for Chronic Pain
These guidelines are different from the guidelines issued by each individual societyor association and were constructed by committee members selected from the Pain
Consortium (Japanese Association for the Study of Musculoskeletal Pain, The JapaneseSociety of Orofacial Pain, The Japanese 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, The Japanese Society for the Studyof Low Back Pain) which is a conglomerate of pain‒related societies and associations.
The research team on ‘Research on Constructing a System for the Treatment and Education of Chronic Pain Problems’, Research on Chronic Pain, were the supervising editors who oversaw the creation of this document.
Basic component of these guidelines
The component of these guidelines followed alongside the ‘Minds Handbook for Clinical Practice Guideline Development 2014 and 2017’ with the contents itemized and its
basic component consisting of CQs (clinical questions), answer, recommendation grades,
levels of evidence, commentary and precautions. In some CQs where we thought thelevel of recommendation and quality of evidence were not necessary, we only provided
an answer and commentary.
Preparation of clinical questions (CQs)
Members of the committee for preparing these guidelines composed drafts of CQs,
and then an answer and commentary was created for each CQ based on what wasagreed upon at the general meetings.
Levels of evidence
The ‘Minds Handbook for Clinical Practice Guideline Development 2014 and 2017’ wasused to prepare the quality of evidence for treatments. We devised the answer sectionof the Q&A in the CQs, by adding the following overall evaluation of the systematic reviews of treatment outcomes.
For our summary of the total evidence in each CQ (overall quality of evidence forgeneral outcomes), we made the following provisions based on the summary of the total
evidence for creating a recommendation grade as described in ‘Minds Handbook for
Clinical Practice Guideline Development 2014 and 2017’.
A (Strong)： The estimated value of an effect is strongly reliable.
B (Moderate)： The estimated value of an effect is moderately reliable.
C (Weak)： The estimated value of an effect is somewhat reliable but limited.
D (Very weak)：The estimated value of an effect is hardly reliable.

Preparative Method of these Guidelines

163

Recommendation grade
Using the ‘Minds Handbook for Clinical Practice Guideline Development 2014 and2017’, systematic reviews of the treatment outcomes were made for each CQ, after
which we generalized the quality of evidence of the outcomes and as outlined below weused this as a basis for determining a recommendation grade.
Two recommendation strengths were displayed,
1：intervention (non‒intervention) strongly recommended,
2：intervention (non‒intervention) weakly recommended (proposed).
In cases where a strength of recommendation could not be determined, in cases
where a clear recommendation could not be made, such as when members of the Committee failed to arrive at a consensus, then we displayed ‘no clear evidence for recommendation.’ At the end of the (CQ) answer, as mentioned above, we listed both thestrength of recommendation, either a ‘1’ or ‘2’, as well as the quality of evidence (A，B，C，D). When making decisions, we also took into consideration the fact that even if thequality of evidence is low, when there is a large difference between the balance of benefits and risks (harms), it is still possible for the treatment to receive a strong recommendation, and even if the quality of evidence is high, the treatment might receive a
weak recommendation, even when there is slight difference between the balance of
health benefits and risks. As a general principle, we gave consideration to those treatments, which are covered under the scope of the Japanese health insurance system.
However, even in instances where the treatment is not covered under our insurance
system, we did give those treatment methods, considered to be effective in overseas
settings and in terms of quality of evidence, a high recommendation grade. We utilized
the modified Delphi method to determine the levels of recommendation. The contents
created by each responsible party were peer‒reviewed and polished, through crosschecking by the Committee members for these guidelines (Round 1). Based on the results, further refinements were made at the general meeting, which included patient
representatives. These results were then reconsidered by each of the person in charge(Round 2) and then final decisions were ultimately made at the general meeting.
References searches and adoption
When running searches for references, as a general rule, we conducted searches byentering the key words, ‘chronic pain’ and ‘CQ.’ The scope of our search was in principle from 2005 up to October 2017. When searching for references, we used the searchmethods of PubMed, MEDLINE, Cochrane Database and Ichushi Web. We did also utilize some important reference materials from prior to 2005. Furthermore, references,which we judged to be important but not found through this search method, weresearched by hand and added to the list.

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Preparative Method of these Guidelines

Opinions from related societies & associations
Those concerned with the preparation of the guidelines；members of the Board of
Directors and Board of Trustees from the seven societies and associations of the Pain
Consortium (Japanese Association for the Study of Musculoskeletal Pain, The JapaneseSociety of Orofacial Pain, The Japanese 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, The Japanese Society for the Studyof Low Back Pain) as well as members of the research team on ‘Research for the Creation of a System Base for the Treatment and Education of Chronic Pain’, Chronic Pain
Research Project, solicited comments from The Japan College of Fibromyalgia Investigation, The Japan Neurosurgical Society, The Japanese Headache Society, The Japanese
Orthopaedic Association, the Japanese Society of Anesthesiologists, The Japanese Society of Neurological Therapeutics, The Japanese Society of Psychosomatic Medicine [listed alphabetically] and the Association for the Support of Patients with Intractable Pain(‘Goodbye‒pain’). At the core member meeting, they decided which of these solicited
opinions should be included herein or not and some revisions were made.
Conflict of interest
Our conflict of interest (COI) clause applies to all individuals involved in the preparation of these guidelines and in accordance with the COI regulations of the Japanese Association of Medical Sciences for those participating in the formulation of treatment
guidelines, in the event where an amount exceeds the standard required for disclosure,
we shall list the name of the committee member and the name of the corporation.
Indication for treatments
These guidelines were written for medical practitioners who are responsible for managing chronic pain, not for patients. However, we paid special attention to ensure thatthese guidelines would reflect the comments we receive from patients. When using
these guidelines, we ask medical practitioners not to just simply glance at recommendation grade on each page but to consider performing or prescribing treatment only after
thoroughly reading through the CQ text, summary and commentary. Another important point that we would like to make is that a large number of guidelines pertaining tochronic pain, created by the societies and associations specializing in each respective
field, already exist. It is our wish that we continue to learn from and comprehend theirlatest knowledge before applying it to actual clinical practice.
Finally, we wish to clearly state that these guidelines have been created as a useful
resource for managing chronic pain, and are not materials designed to be used for othersituations such as lawsuits or litigation.

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Preparative Method of these Guidelines

March, 2018
Health, Labour and Welfare Policy Research Grants (Research on chronic pain)
Research on Constructing a System for the Treatment and Educationof Chronic Pain Problems
The Committee for Clinical Practice Guideline for Chronic pain
ChairmanResearch Representative

Hisashi Date, MD, PhD
Takahiro Ushida, MD, PhD

166

Contents

Clinical Practice Guideline for Chronic Pain
Contents
Preface

157

Introduction

159

Preparative Method of these Guidelines

162

Contents

166

Ⅰ．Overview

171

CQ1：What kind of condition is chronic pain ?
CQ2：What kinds of classifications are there for chronic pain ?

172

172
CQ3：What are the characteristic symptoms and signs of patients
175with chronic pain ?
CQ4：What points need to be kept in mind when diagnosing
177
chronic pain ?
CQ5：What points should be kept in mind when evaluating
179
chronic pain patients ?
CQ6：What are the purposes and ultimate goals of chronic pain
182
management ?
CQ7：What kind of treatment is multidisciplinary treatment ? 184

Ⅱ．Phrmacotherapy

187

CQ8：Are nonsteroidal anti-inflammatory drugs effective in190
managing chronic pain ?
193
CQ9：Is acetaminophen effective in managing chronic pain ?
CQ10：Is an extract from inflamed cutaneous tissue of rabbits
inoculated with vaccinia virus effective in managing
196
chronic pain ?
200
CQ11：Is pregabalin effective in managing chronic pain ?
CQ12：Are antiepileptic drugs effective in managing
204
chronic pain ?
207
CQ13：Is duloxetine effective in managing chronic pain ?
211
CQ14：Is amitriptyline effective in managing chronic pain ?
CQ15：Are other types of antidepressants effective in managing
214
chronic pain ?

167

Contents

CQ16：Are NMDA receptor antagonists effective on
217
chronic pain ?
CQ17：Are antianxiety agents（benzodiazepine type drugs）
220
effective in managing chronic pain ?
224
CQ18：Is tramadol effective in managing chronic pain ?
CQ19：Are buprenorphine patches effective in managing
228
chronic pain ?
CQ20：Are opioid analgesics [strong] effective in managing
232
chronic pain ?
CQ21：Is Kampo medicine effective in managing chronic pain ?
236

Ⅲ．Interventional Management

241

CQ22：Are interlaminar epidural injections effective in managing
242
chronic pain ?
CQ23：Are nerve block/transforaminal epidural injections effective245
in managing chronic pain ?
CQ24：Are medial branch block and facet（zygapophyseal）joint248
injection effective in managing chronic pain ?
CQ25：Is stellate ganglion block effective in managing
251
chronic pain ?
CQ26：Is sympathetic ganglion block effective in managing
254
chronic pain ?
CQ27：Is a trigger point injection effective in managing
258
chronic pain ?
CQ28：Is radiofrequency denervation effective in managing chronic259
pain ?
CQ29：Is pulsed radiofrequency treatment effective in265
managing chronic pain ?
CQ30：Are spring-coil catheters, and epiduroscopy effective in268
managing chronic pain ?
CQ31：Is spinal cord stimulation effective in managing
272
chronic pain ?
CQ32：Are intradiscal therapies effective in managing
277
chronic pain ?
CQ33：Are intra-articular injections effective in managing
280
chronic pain ?

Ⅳ．Psychological Approach

287

CQ34：Is psychoeducation effective in managing chronic pain ? 288
CQ35：Is behavioral therapy effective in managing chronic pain ?
290

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Contents

CQ36：Is cognitive-behavioral therapy effective in managing
chronic pain ?
CQ37：Is mindfulness as proposed in the third wave ofcognitive-behavioral therapy effective in managing
chronic pain ?
CQ38：Is acceptance and commitment therapy under the third
wave of cognitive-behavioral therapy effective
in managing chronic pain ?
CQ39：Is hypnotherapy effective in managing chronic pain ?

Ⅴ．Rehabilitation
CQ40：Is general therapeutic exercise effective in managing
chronic pain ?
CQ41：Is exercise, other than general therapeutic exercise,effective in managing chronic pain ?
CQ42：Are physical modalities effective in managing
chronic pain ?
CQ43：Is manipulative therapy effective in managing
chronic pain ?
CQ44：Is the introduction of cognitive behavioral therapy andeducation into rehabilitation and its application totreatment effective in managing chronic pain ?
CQ45：Is orthotic therapy/taping effective in managing
chronic pain ?
CQ46：Is multidisciplinary rehabilitation effective in managing
chronic pain ?

Ⅵ．Multidisciplinary Treatment

292

297

300
302

305
306
308
312
315

318
322
324

327

CQ47：What does the multidisciplinary team for chronic pain
management consist of ? And what are the roles of its
328
staff members ?
CQ48：Is multidisciplinary treatment effective on chronic pain ?
330
CQ49：Is group cognitive behavioral therapy（teaching group331
education behavior）effective on chronic pain ?
CQ50：How should we begin multidisciplinary treatment in333
managing chronic pain ?
CQ51：What are the purposes and ultimate goals of334
multidisciplinary treatment for chronic pain ?

Index

339

169

Authors for the Clinical Practice Guideline for Chronic Pain
Academic advisors
Takahiro Ushida Multidisciplinary Pain Center / Physical Fitness Sports Medicine Rehabilitation
Center, Aichi Medical University, Professor ※Pfizer, Eli Lilly Japan
Kiyoshige Ohseto Department of Anesthesiology, Tokyo Medical University, Professor ※NoneToshihiko Taguchi Department of Orthopaedic Surgery, Yamaguchi University Graduate School of
Medicine, Professor and Chairman ※Pfizer, Ayumi‒pharma, Taisho Toyama Pharma, Hisamitsu,
Koichi Noguchi

Daiichi‒Sankyo, Chugai

Department of Anatomy and Neuroscience, Hyogo College of Medicine, President/
Professor ※ None
Toyoshi Hosokawa Department of Pain Management & Palliative Care Medicine, Kyoto Prefectural
University of Medicine, Professor ※Pfizer, Shionogi Pharma
Yoshizo Matsuka Department of Stomatognathic Function and Occlusal Reconstruction, Tokushima
University Graduate School of Biomedical Sciences, Professor ※None
The Committee for the Clinical Practice Guideline for Chronic Pain
Hisashi Date 〔Chairmnan〕Sendai Pain Clinic Center, Director ※None
Yoshiharu Kawaguchi 〔Sub‒chairmnan〕Department of Orthopaedic Surgery, University of Toyama, Associate professor ※Pfizer, Taisho Toyama Pharma, Eli Lilly Japan
Tetsuya Sakai 〔Sub‒chairmnan〕Department of Pain Clinic and Anesthesia, Sasebo Kyosai Hospital, Director ※ None
Sei Fukui 〔Sub‒chairmnan〕Pain Management Clinic, Interdisciplinary Pain Management Center,
Department of Anesthesiology, Shiga University of Medical Science Hospital, Clinical professor ※ Pfizer,
Kenichi Arai
Physical Fitness Sports Medicine Rehabilitation Center, Aichi Medical University,
Associate professor ※ None
Hiroshi Ueno
Department of Pain Management & Palliative Care Medicine, Kyoto Prefectural
University of Medicine, Associate professor ※None
Satoshi Kasahara Department of Anesthesiology and Pain Relief Center, The University of Tokyo
Hospital, Assistant professor ※None
Shinji Kimura
Department of Rehabilitation Medicine, Niigata University Medical and Dental
Hospital, Hospital professor ※Hisamitsu
Shizuko Kosugi Department of Anesthesiology, Keio University School of Medicine, Assistant professor ※ Pfizer, Medtronic Japan
Osamu Nishikido Department of Palliative Medicine, Showa University, Assistant professor
Makoto Nishihara
Keita Fukazawa※ NoneMultidisciplinary Pain Center, Aichi Medical University, Professor

Shionogi Pharma※Eli Lilly Japan,

Department of Pain Management & Palliative Care Medicine, Kyoto Prefectural
University of Medicine, Assistant professor ※None
Masako Hosoi
Department of Psychosomatic Medicine, Kyushu University Hospital, Clinical associate professor ※ None
Hiroki Hosogoshi Department of Modern Education, Faculty of Education, Kio University, Associate
professor ※ None
Takako Matsubara Department of Rehabilitation, Faculty of Health Sciences, Nihon Fukushi University, Professor ※ None
Shoji Yabuki
Department of Orthopaedic Surgery and Department of Pain Medicine, Fukushima Medical University School of Medicine, Professor ※None170

Toshihiko Yamashita Department of Orthopaedic Surgery, Sapporo Medical University School of
Medicine, Professor ※ Astellas, Taisho Toyama Pharma, Daiichi‒Sankyo, Eisai, Hitsujigaoka Hospital
Keisuke Watanabe Department of Pain Clinic, Nara Medical University Hospital, Clinical professor※ NoneContributors
Kozo Anno

Department of Psychosomatic Medicine, Kyushu University Hospital, Assistantprofessor ※ None
Yoshiki Imamura Department of Oral Diagnostic Sciences, Nihon University School of Dentistry,
Professor ※ None
Hironobu Uematsu Department of Anesthesiology and Intensive Care Medicine, Osaka University
Graduate School of Medicine, Assistant professor ※None
Masaki Kondo
Department of Psychiatry and Cognitive‒behavioral Medicine, Nagoya City University Graduate School of Medical Sciences, Research assistant professor ※None
Asako Sakano
Center for Development of Empirically Supported Treatment,Doshisha Universtiy,Resarch scholar ※ None
Junya Sakamoto Nagasaki University School of Health Scienses, Associate professor ※None
Yasushi Sakuma Department of Anesthesiology, Osaka Dental University, Associate professor
Yukiko Shiro※ NoneDepartment of Physical Therapy, Faculty of Rehabilitation Sciences, Nagoya Gakuin University, Associate professor ※None
Shunsuke Sugiyama Department of Psychiatry and Psychotherapy Gifu University Graduate Schoolof Medicine, Asssistant professor ※None
Noriyo Takahashi Department of Rehabilitation, Tokuyukai Rehabilitation Clinic, Director ※None
Masayuki Nakagawa Department of Pain Clinic, NTT Medical Center Tokyo, Head physician ※None
Tatsuya Nogami Department of Japanese Oriental Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Asssistant professor ※Tsumura, Japan
Kiyohiko Hatano
Yasuhiro Banno
Aki Fujiwara
Yoichi Matsuda

Kampo Medicine Education Foundation

Department of Pain Management & Palliative Care Medicine，Kyoto Prefectural
University of Medicine, Resident ※None
Department of Rehabilitation, Faculty of Health Sciences, Nihon Fukushi University, Associate professor ※None
Department of Anesthesiology, Nara Medical University, Asssistant professor※ NoneDepartment of Anesthesiology and Intensive Care Medicine, Osaka University
Graduate School of Medicine, Asssistant professor ※None
Miyuki Mizutani Multidisciplinary Pain Center, Aichi Medical University, Visiting resercher（Clinical
psychologist） ※ None
Takashi Muto
Faculty of Psychology, Doshisha Universtiy, Professor ※None
Wataru Muraoka Department of Dentistry and Oral Surgery, Kawasaki Municipal Ida Hospital, Division chief ※ None
Takanori Murakami Department of Rehabilitation Medicine, Sapporo Medical University, Associate
professor ※ Astellas
Yoshikazu Yanagisawa Department of Orthopedic Surgery, Hiroshima Red Cross Hospital & Atomic‒bomb Survivors Hospital, Assistant director ※Eli Lilly Japan
The Association for the Sopport of Patients with Intractable Pain (‘Good bye-pain’)※ disclosure of Conflicts of InterestChapter Ⅰ

Overview：CQ1～CQ7

Chapter Ⅱ

Pharmacotherapy：CQ8～CQ21

Chapter Ⅲ

Interventional Management：CQ22～CQ33

Chapter Ⅳ

Psychological Approach：CQ34～CQ39

Chapter Ⅴ

Rehabilitation：CQ40～CQ46

Chapter Ⅵ

Multidisciplinary Treatment：CQ47～CQ51

172

Ⅰ．Overview

CQ1：What kind of condition is chronic pain?
IASP：International
Association for the Study ofPain

Answer： International Association for the Study of Pain (IASP) defineschronic pain as, ‘pain that extends beyond the expected period of healing or
progressive pain due to non‒cancer diseases.’Commentary：
IASP defines chronic pain as ‘pain that extends beyond the expected periodof healing or progressive pain due to non‒cancer diseases.’ 1). However, in Japan, it still has not been clearly defined. Previously, it referred generally to apain condition persisting for more than six months since the time of onset but
currently it often refers to (pain persisting for) three months or more due tofactors such as improvement in pharmacotherapy. These guidelines do not define specifically designated illnesses as chronic pain illnesses and we have decided to consider it as a condition, based upon IASP’s definition.
Another thing is that pain that persists for a long time can also involve psychosocial issues and therefore it is considered to be an incredibly complex condition2).
References
1）Merskey H, et al : IASP Task force on Taxonomy Classification ofChronic pain, 2nd ed. IASP Press, Seattle, 1994 ; 209‒2142）Japanese Society of Neurological Therapeutics（Supervising Editors）: Treatment Guidelines Committee, ed : The standard neurologicaltherapeutics : Chronic pain. Neurological Therapeutics 2010 ; 27 : 595‒602

CQ2：What kinds of classifications are there for chronic pain?
Answer： Chronic pain is classified for example by pain syndrome and bymechanism. Searching for the pain syndrome or mechanism leads to not only
diagnosis but also treatment.
Commentary：
Chronic pain can be classified from a variety of different angles. When classifying by pain factors, there are nociceptive pain, neuropathic pain, psychosocial
pain and others1). Psychosocial pain used to be called psychogenic pain but
IASP：International
Association for the Study of
Pain

IASP does not call it psychogenic pain and because organic factors are involved, it has decided to call it psychosocial pain. When the pain becomeschronic, the cause is seldom due to one of these three and in many cases it is acomplex mixed pain condition involving several causing factors.
IASP recommends seven classifications of chronic pain2,3) to the ICD‒11

Ⅰ．Overview

Table 1‒1

173

IASP Chronic Pain Classifications（Cited from Reference #2 and #3）

1. Chronic primary pain
1.1. Widespread chronic primary pain（including fibromyalgia syndrome）
1.2. Localized chronic primary pain（including nonspecific 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 metastases Note 1
2.2. Chronic chemotherapy‒induced pain（primary parent : chronic neuropathic
pain）
2.3. Chronic pain due to cancer surgery（primary parent : chronic postsurgicaland posttraumatic pain）
2.4. Chronic pain due to radiotherapy
2.x. Other chronic pain related to cancer
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 specified
5. Chronic headache and orofacial pain
5.1. Chronic primary headaches＊
5.2. Chronic secondary headaches＊
5.3. Chronic orofacial pains†
5.z. Headache and orofacial pain not otherwise specified＊
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 mechanisms
6.6. Chronic visceral pain referred from other locations
6.7. Chronic visceral pain from cancer（primary parent : chronic cancer pain）
6.8. Functional or unexplained chronic visceral pain（primary parent : chronic
primary 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 disease of the nervous system（Allneuropathic pain will be classified under4. Chronic neuropathic pain.
Here, other chronic musculoskeletal pain originating from diseases of thenervous system, eg, spastic pain will be listed.）
7.4. Chronic nonspecific musculoskeletal pain（primary parent : chronic
primary pain）
7.x. Other chronic musculoskeletal pain syndromes
7.z. Chronic musculoskeletal pain not otherwise specified

Note 1：“2.1. Chronic pain
due to cancer and metastases”from the table refers tocancer pain but in Japan
does not apply as a type of‘chronic pain.’

174

Ⅰ．Overview(Table 1‒1). One of these items includes ‘cancer pain’ but the other items are
all non‒cancer pain and do not match with the classifications used in Japan Note 1.
multiple parenting：
When classifying a disease
with ICD-11, parenting
allows us to classify it boththe category of its primarylocation, and the category of
its origin.

These items sometimes cover two items and this is recognized as multiple parenting4)．
For the classification based on the mechanism causing chronic pain, we haveassumed the concepts in Table 1‒25)．The modality is also involved in theseclassifications and the stronger the psychosocial factors, the more frequently it
becomes hard to treat.
Table 1‒2

Acute Pain and Chronic Pain（Cited from Reference #5）
Chronic Pain
Acute Pain

Stimulation of
Cause of pain
nociceptors

Duration

Does not exceed
period for tissue
repairChronic pain which isa repetition of acute pain
Chronic pain which is
protracted acute pain

Intractable chronic pain

Stimulation of nociceptors

Functional changes in thecentral nervous system,
modulation due topsychosocial factors

Slightly exceeds period fortissue repair

Exceeds period fortissue repair（three months≦）

Hyperactive
Main
Insomnia，loss of appetite, Insomnia, loss of appetite,
sympathetic nerves
accompanying
constipation, Inhibition
constipation, Inhibition of（Hyperacute
symptomsof living activities
living activities
period）
Main
psychologicalsymptoms

Anxiety

Depression, anxiety,catastrophizing

Depression, anxiety,catastrophizing

References
1）Inoue M, et al : 痛 みの概念，定義．（Taguchi T, ed : 慢性疼痛疾患）．
Saishin Igakusha, Osaka, 2016 ; 8‒142）Treede RD, et al : A classification of chronic pain for ICD‒11. Pain 2015 ;
156 : 1003‒1007
3）Nishie H : 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 ; 8‒134）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 ; 17‒215）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

Ⅰ．Overview

175

CQ3：What are the characteristic symptoms and signs of patients withchronic pain?
Answer：Among patients with chronic pain, many display a variety of symptoms and signs apart from pain. As it is possible to reduce pain and expect an
improvement in ADL in order to cope, it is necessary to not only cope with the

ADL：activity of daily living

pain but with the various symptoms and signs.
Commentary：
Chronic pain patients exhibit a large number of symptoms and signs as theperiod of pain increases (Table 1‒3).
Table 1‒3Non‒pain Symptoms / Signs Exhibited by Patients with Chronic Pain

1. Cognitive / Emotional Factors
Depression, anxiety, loss of appetite, anger, catastrophzing, 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, economical stress
4. Spiritual Factors
Decline in feelings of self‒worth, decline in self‒efficacy
5. Other Factors
Litigation, excessive expectations in medical institutions, dependence on
treatment（medication）

Patients with chronic pain often display symptoms of depression but wehave yet to conclude whether the stress from pain is triggering feelings of depression or whether a state of depression is triggering the pain as a physicalsymptom1)．There has been some speculation that it may often be a depressive state as a reaction to the stress from the pain2). In actuality, it varies fromcase to case. It has been suggested that as the pain lingers, it becomes intractable and serious through a cyclical interaction with psychosocial factors. Furthermore, in cases where the pain becomes intractable, catastrophizing is often
involved3), and signs such as immobilization (disability) and disuse appear. As aresult, this triggers a decline in ADL (Fig. 1‒A)．Therefore, an improvement incatastrophizing may lead to an improvement in the symptoms and signs of
4)chronic pain patients ．
When the pain persists over a long period of time, it affects one’s work andacademic life. A high percentage of both men and women losing their jobs,
leaving school, having a break from their work or studies or changing jobs due

pain catastrophizing：
An exaggerated negative
perception of pain

176

Ⅰ．Overview

Neuropathy/tissue damage
・Disuse・Functional
disorder・Depression

Remission/
Recovery

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

Anxiety

Fear

Negative interpretation
Pain catastrophizing
Insomnia

Able to face pain
optimistically

ive
ns s
fe iorDe havbeOversensitive
response to pain

Pain

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…’)

Fig. 1‒A Pain Fear‒Avoidance Model（Cited from reference #3, partly paraphrased）
As pain persists over a long period of time, it has been indicated that it becomeschronic and serious through a cyclical interaction of psychosocial factors.

to chronic musculoskeletal pain were reported5). Factors such as loss of employment can also lead to a decline in the quality of social activity, a deterioration in one’s presence within the family and economical stress leads to a deterioration in perceptions of self‒worth. Along with this, there is a decline in self‒
efficacy and there have been reports6) that pain self‒efficacy is positively corQOL：quality of life
HRQL：health-related qualityof liferelated with health‒related quality of life (HRQL/HRQOL) and negatively correlated with the level of lifestyle disability. Therefore, we can expect an improvement in pain and ADL through a cognitive change.
References
1）Nishihara M : Psychiatric aspects of pain and pain behavior. Pain Clinic（JPN）2016 ; 37 : 741‒747
2）Maruta T : 痛みの心理学．疾患中心から患者中心へ．Chuokoron‒shinsha
Inc., Tokyo, 1989 ; 64‒883）Leeuw M, et al : The fear‒avoidance model of musculoskeletal pain : Current state of scientific evidence. J Behav Med 2007 ; 30 : 77‒944）Udo Y, et al : Predictive factors for degree of pain catastrophizing in patients with chronic lower back pain. JJSPC 2017 ; 24 : 12‒165）Masaya Nakamura, et al : Prevalence and characteristics of chronic musculoskeletal pain in Japan. J Orthop Sci 2011 ; 16 : 424‒4326）Adachi T, et al : Effects of pain self‒efficacy and other cognitive‒emo-

177

Ⅰ．Overview

tional factors on Health‒related Quality of Life, and Pain Interference inJapanese chronic pain patients. The Journal of the Japanese Society for
the Study of Chronic Pain 2015 ; 34 : 107‒111

CQ4：What points need to be kept in mind when diagnosing chronic
pain?
Answer：The most important thing when diagnosing chronic pain is having
an accurate understanding of the patient’s condition. Furthermore, diagnostic
criteria have been established for each condition under the guidelines for pain
diseases. Therefore, diagnosis should be made in accordance with these criteria.
Commentary：
Chronic pain not only involves organic factors but also often psychosocial
factors as well, and various factors such as these make the condition incredibly
complex1)．When diagnosing chronic pain, which occurs due to various conditions, the most important thing is having an accurate understanding of the patient’s condition. A method following what is called ‘diagnostics’ is used to do
this (Fig. 1‒B)2)．That is to say, first of all the patient’s condition can be inferred based on a detailed hearing of the patient’s medical history and a physical examination. Next, the patient’s condition can gradually be narrowed down

Questions：Cheif complaint, current history,
previous medical history, family medical history
Conclusions

Since when? How?
What was the cause?

Physical examination：
Inspection, palpation, auscultation

Therapeutics

Diagnostics

Conclusions

Examination：
Blood test, imaging
X-ray, CT, MRI,
PET, scintigraphy,
Establish patient’s condition etc.

＝Name of diagnosis

Fig. 1‒B

Method for Diagnosing Patients with Chronic Pain

178

Ⅰ．Overview

by making full use of a variety of examinations (such as a blood test) based
mainly around imaging (X‒ray, CT, MRI, contrast studies etc.)．Finally, judging whether the symptoms match with the examination findings is the basis ofdiagnostics；a method to have an accurate understanding of the patient’s condition. In this way, the reason why diagnostics is considered important is because the treatment should be based on an accurate understanding of the patient’s condition. Under this series of processes, there is a possibility that it
could be fatal if the condition is left unattended and it is therefore important
not to overlook as ‘red flag’ conditions (such as malignant tumors) and conditions which may trigger severe symptoms (such as infectious diseases andtraumatic illnesses).
In the guidelines on pain diseases published to date in Japan, diagnostic criteria have been established for each condition (Table 1‒4) and diagnosis should
Table 1‒4

Pain Diseases Indicated in the Guidelines According to the Japanese（October 2017（current）, as listed in ‘Minds’）〔Muscle/Bone/Joint〕
Guidelines for the Management of Rheumatoid Arthritis, Japan College of
Rheumatology 2014
Cervical Ossification of Posterior Longitudinal Ligament Diagnostic
Guidelines 2011
Cervical Spondylotic Myelopathy Diagnostic Guidelines 2015
Guidelines on the Prevention and Treatment of Osteoporosis 2011 Edition
Bone Metastasis
Lateral Epicondylitis of the Humerus Diagnostic Guidelines
Osteoarthritis of the Hip Diagnostic Guidelines
Lumbar Disc Herniation Diagnostic Guidelines
Low back Pain Diagnostic Guidelines 2012
Lumbar Spinal Canal Stenosis Diagnostic Guidelines 2011
〔Pain Clinic〕
Guidelines for the Interventional Pain Treatment
Guidelines for the Pharmacologic Management of Neuropathic Pain
Second Edition
Guidelines for Prescribing Opioid Analgesics for Chronic Non‒cancer Pain
Second Edition〔Brain/Nerves〕
Chronic Headache Diagnostic Guidelines 2013
Stereotactic and Functional Neurosurgery Treament Guidelines Second
Edition〔Dental/Oral〕
Initial Treatment Diagnostic Guidelines for Patients with
Temporomandibular ArthrosisNon‒odontogenic Toothache Diagnostic Guidelines〔Other〕
Fibromyalgia Diagnostic Guidelines 2013

Ⅰ．Overview

be conducted in accordance with these criteria.
When consulting patients with chronic pain, it is important not only to diagnose the pathology which causes chronic pain, but also to evaluate psychological factors such as anxiety, depression, and dissatisfaction which might modify
the pain condition, as well as the actual lifestyles of the patients. A careful interview is the most important, but on the occasion of an evaluation, we recommend using evaluation tools such as psychology tests for confirming their validity and reliability.
References
1）Japanese Society of Neurological Therapeutics（supervising editors）:
Treatment Guidelines Committee, ed : The standard neurological therapeutics : Chronic pain. Neurological Therapeutics, 2010 ; 27 : 591‒6222）Kawaguchi Y : Advance in the treatment for spinal diseases. Medication.
Drugs for pain and numbness. Orthopedics & Traumatology 2017 ; 60 :597‒6023）Kikuchi S : New concept of backache. Japanese Journal of Psychosomatic
Medicine 2003 ; 42 : 105‒110

CQ5：What points should be kept in mind when evaluating chronic pain
patients?
Answer：There are some factors involved with chronic pain：such as ‘nociceptive’；‘neuropathic’；‘psychosocial’, and others. In many cases, these factors
are intricately inter‒related. Using a biopsychosocial model for the purpose ofproviding a multifaceted evaluation of chronic pain patients, we can get an
overall (holistic) understanding of the patient’s pain and on top of this, selectthe treatment and care best suited to each individual patient.
Commentary：
Generally speaking, if acute pain can be promptly alleviated, the patient’s
concern can also be promptly eliminated. However, with chronic pain, the psychological background or social background can have a large effect on the patient’s pain. There are some factors related to chronic pain：such as ‘nociceptive’；‘neuropathic’；‘psychosocial’, and others,1) but in many cases these factors coexist and are intricately related (Fig. 1‒C)．The purpose of providing a
multifaceted evaluation of chronic pain patients using a biopsychosocial model
is to have an overall (holistic) understanding of the patient’s pain and on top ofthis, to select the treatment and care best suited to each individual patient.
In a multifaceted evaluation of chronic pain, the following points are important2)．
・Strength, site, quality, progression, changes throughout the day, enhanc-

179

180

Ⅰ．Overview

Neuropathic

Nociceptive
Psychosocial

Fig. 1‒C Pain Model Diagram
There are several factors involved in pain : ‘nociceptive’ ; ‘neuropathic’ ; ‘psychosocial’, and others.
Table 1‒5Main Questionnaires for Evaluating Psychological States suchas Depressive State, Anxiety, Catastrophizing and Degree ofLoss in ADL

Hospital Anxiety and Depression Scale（HADS）
Pain Catastrophizing Scale（PCS）
Beck Depression Inventory（BDI）
Center for Epidemiological Studies‒Depression scale（CES‒D）State Trait Anxiety Inventory（STAI）
Hamilton Depression Rating Scale（HAM‒D），
Hamilton Anxiety Rating Scale（HAM‒A）
Fear‒Avoidance Beliefs Questionnaire（FAB）
Pain Self‒Efficacy Questionnaire（PSEQ）
Pain Disability Assessment Scale（PDAS）
Athens Insomnia Scale（AIS）
Self‒rating Depression Scale（SDS）

ing factors and alleviating factors of pain：Understanding these points
will serve as clues for sounding out the pain’s pathology.
・Psychological state： There are many cases of patients suffering from a
combination of a depressive state, feelings of anxiety, a negative cognitive
pain catastrophizing：
An exaggerated negative
perception of pain

state called ‘catastrophizing’, feelings of fear, angry emotions, feelings oflow self‒efficacy, feeling dissatisfied and feeling distrust. There is a questionnaire used for screening the patient’s psychological state. (Table 1‒5)．
・How one spends the day, degree of loss in ADL：Due to a fear of exercise, patients with chronic pain spend the whole day sleeping, and it is frequently a cause of falling into a vicious cycle of immobilization and a cause
of insomnia. There is a need to assess what kind of treatment and care

Ⅰ．Overview

should be chosen, depending on the degree of loss in ADL.
・Family structure and situation：Among patients with chronic pain, there
are various family conflicts, tension between siblings, family pathologies
such as breakdowns in contact or communication within the family andthe level of satisfaction with one’s married life are sometimes involved in
the persistence or aggravation of the existing symptoms. In cases where
the living environment provides a low supporting function from the family,
self‒efficacy is low, and in some cases patients lapse into a state of alexithymia, in which one cannot convey one’s feelings to others. Early developmental history is considered to be one of the major factors in the onsetof chronic pain.
・Illnesses and clinical conditions in the field of psychiatry：Frequently‒cited illnesses and clinical conditions in the field of psychiatry, which are related to pain chronicity include somatization disorder, dysthymic (pain) disorder, depressive disorder, bipolar disorder, developmental disorder, dementia, and substance‒related disorder.
・Employment history, job details and conditions：If people change jobs
over and over again, it is suspected that they may be socially maladjusted.
In cases of patients who are having difficulty finding employment due totheir pain, the main goal of treatment is to improve their employment situation, on the assumption that information on the patient’s current conditionand progress is being shared between the patient and the medical practitioner. In patients with chronic pain, their relationships with others atwork, work‒related stress, physical burden, loss of employment, and levelof satisfaction with what they do at work often contribute towards thepersistence or aggravation of their existing symptoms. On top of the patient’s own predisposing factors, in cases where the patient is on leavefrom his/her job, it is also very important to consider the possibility thatsome type of social factors may also be involved, such as what is causing
mental stress at work or in the occupation, whether he/she is absent or on
leave from work, the type of employment, the the possibility of dismissalfrom the job, the current income situation and information related to his/her future prospects.
・Compensation and litigation：When the initial cause of the pain is a traffic
accident or work accident, we find out whether this person is receiving
compensation or not. If the patient is the victim of an accident, what iscalled the ‘victim’s awareness’ can make the pain become chronic.
・Changes in sleeping, eating, weight： Depressive states or conditions ofstress cause changes to one’s sleep and appetite. Therefore, it is importantto question patients on their sleeping and appetite history .

181

182

Ⅰ．Overview

References
1）Kitahara M : Definition of pain：Overview 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 ; 17‒212）Iseki M : Assessment of Pain.（Japanese Association for the Study ofPain, 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 ; 75‒78

CQ6：What are the purposes and ultimate goals of chronic pain management ?
Answer： As non‒organic factors are larger components of chronic pain thanorganic factors, it is difficult to establish a pain‒free condition. Reducing pain is
one of the purposes and ultimate goals of chronic pain management but not
the leading goal. Medical practitioners should manage chronic pain while trying to minimize adverse events induced by the treatment and it is important
QOL：quality of life
ADL：activity of daily living

to improve the patient’s QOL and ADL actions.
Commentary：
Acute pain is a warning, notifying the body of injury and often reacts to thethe short‒term administration of analgesics and conservative treatment. On
the other hand, with chronic pain, non‒organic factors such as central sensitization and cognition of the nervous system are larger components of this pain
than organic factors. With chronic pain, even though injury as organic factor isrepaired, the body is unnecessarily releasing this warning1).
The treatment purpose and ultimate goals vary depending on the fundamen-

IASP：International
Association for the Study ofPaintal illness at its onset and the components of the pain. IASP defines chronic
pain as ‘pain that persists beyond normal tissue healing time, and progressive
non cancer pain’ and is generally a pain which persists for three months or
more2). However, even if the pain persists for longer than three months, a protracted pain disease also exists (for example trigeminal neuralgia, headache illnesses such as migraine and cluster headache, and rheumatoid arthritis) in order for the cause of this pain to persist. A larger number of these illnesses are
due to organic factors rather than non‒organic factors so pharmacotherapy
tends to have a rapid effect on them. Therefore, as the treatment purpose andultimate goals are different from other forms of chronic pain, they are excluded
from the eligible illnesses under the chronic pain treatment guidelines in every
country1,3)．
As mentioned above, a larger number of components of chronic pain are non‒

Ⅰ．Overview

183

organic factors rather than organic factors and therefore there is much distress with treatment. The Guidelines for the Treatment of Chronic Pain4) by
ASA and ASRA, cite the following four items as their treatment purposes objectives and ultimate goals.
① Optimize pain control, recognizing that a pain‒free state may not be attainable ;② Enhance functional abilities and physical and psychologic well‒being ;③ Enhance the quality of life of patients ;④ Minimize adverse outcomes.
In this way, we must manage pain while minimizing adverse outcome (sideeffects) induced by treatment and improving the patient’s QOL and ADL are
the purposes and ultimate goals of chronic pain management.
As chronic pain patients have been suffering from pain for a long time, theytend to expect that their medical practitioner can help completely remove
their pain. Of course, reducing pain is one of the goals but it should not be theleading goal. Before commencing pain treatment, the medical practitioner
should explain and convince the patient that the goal of pain treatment is ‘atbest to reduce strong pain to around a moderate level’ 1). In the managementof chronic pain, going against patient’s expectations, generally functional improvement comes first rather than a reduction in pain. Therefore, it is important to educate patients on this distinction, to avoid persistent and unrealistic
expectations for an elusive cure, where none exists 1)．
There are various methods to treat chronic pain such as pharmacotherapy,
interventional therapy, psychotherapy, and therapeutic exercise but these are
more effective when integrated, not implemented individually. All methods ofmanagement should focus on functional recovery as the leading goal, rather
than simply reducing pain, and evaluations of the treatment’s efficacy areachieved through reports on functional improvement1). The management goalof chronic pain should not be vague but directly associated with the problematic symptoms (such as insomnia and hypoactivity) identified in each patientand preferably these should be realistic and achievable to the patient (such asa reduced number of times the patient wakes up during the night, and managing household chores by oneself)5)．
The medical practitioner should set the treatment goal and determine thetreatment strategy with the patients, and it can be considered a success if
there is functional improvement and some degree of reduced pain after commencing treatment. However, in cases where there is no response to treatment
or the condition deteriorates, the medical practitioner needs to re‒assess thecomponents of the patient’s pain and needs to change the treatment policy.
Pain is ultimately subjective and with chronic pain in particular, it will be influ-

ASA：American Society ofAnesthesiologists
ASRA：American Society ofRegional Anesthesia and Pain
Medicine

184

Ⅰ．Overview

enced by the patient’s cognition, emotions and environmental factors. Furthermore, as time progresses and as a result of changes in the environment surrounding the patient, complaints about pain also change frequently. A patient’s
complaint about pain is one form of pain behavior but is not the pain itself. External gain such as money and compensation are large factors affecting pain
behavior. Therefore, the medical practitioner must carefully observe whether
these kinds of factors are involved or not 1)．
References
1）http : //www.dir.ca.gov/dwc/DWCPropRegs/MTUS_Regulations/
MTUS_ ChronicPainMedicalTreatmentGuidelines.pdf
2）Merskey H, Bogduk N : Classification of chronic pain : Descriptions ofchronic pain syndromes and definitions of pain terms. International Association for the Study of Pain, Seattle, 1994
3）http : //www.sign.ac.uk/pdf/SIGN136.pdf
4）American Society of Anesthesiologists Task Force on Chronic PainManagement : American Society of Regional Anesthesia and Pain Medicine : Practice guidelines 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 : 810‒8335）Marcus DA : Chronic pain : A primary care guide to practical management 2nd ed, Humana Press, New York, 2009 ; 15‒34

CQ7：What kind of treatment is multidisciplinary treatment?
Answer：Multidisciplinary treatment is an integrated and multifaceted formof treatment, in which specialists from a large number of fields and occupations
collaborate with a common goal in mind：to treat patients.
Commentary：
In multidisciplinary treatment, a multidisciplinary case conference is held
and a liaison case council is launched by different types of professionals, suchas physicians, nurses, mental health professionals, and physiotherapists in order to develop a comprehensive understanding of a patient’s pain and associated problems, and decide on recommendations for treatment. After the conference, all staff work together to provide treatment1)，and the multidisciplinary
treatment consists of the following five components：2‒7)
1．Intervening to weaken the effect that pain is having on the functional aspects of their daily life；
2．Training based on cognitive‒behavioral therapy (CBT), in which patientsare educated and provided guidance on acquiring ways to change their

Ⅰ．Overview

patterns of thought, which can have a negative effect on their reactions
to pain；
3．Step‒by‒step physical exercise (exercise therapy)；
4．Pharmacotherapy；
5．Interventional treatment.
Multidisciplinary treatment is when specialists from various fields and occupations exchange their opinions openly, from a diverse number of viewpoints,
sharing background information on patients, their pain conditions, as well as
their goals for treatment and providing treatment in accordance with the fivecomponents mentioned above.
References
1）Interdisciplinary Chronic Pain Management : International Perspectives.
https : //www.iasp‒pain.org/files/Content/ContentFolders/Publications2/
PainClinicalUpdates/Archives/PCU_20‒7_web.pdf2）Turk DC, et al : Interdisciplinary pain management. American Pain Society, Glenview, http : //americanpainsociety. org/uploads/about/position‒statements/interdisciplinary‒white‒paper.pdf
3）Jeffery MM, et al : Multidisciplinary pain programs for chronic noncancer pain. Agency for Healthcare Research and Quality, Rockville, 20114）Wickson‒Griffiths A, et al : Interdisciplinary approaches to managing
pain in older adults. Clin Geriatr Med 2016 ; 32 : 693‒704
5）Arai YC, et al : The review of innovative integration of Kampo medicine
and Western medicine as personalized medicine at the first multidisciplinary pain center in Japan. EPMA J 2014 ; 5 : 10
6）Arai K, et al : Problems and prospects in multidisciplinary pain center inJAPAN.Pain Clinic 2013 ; 34 : 753‒7597）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 Company
Ltd. , Publication Department of Medical Books, Tokyo, 2016

185

Chapter Ⅰ

Overview：CQ1～CQ7

Chapter Ⅱ

Pharmacotherapy：CQ8～CQ21

Chapter Ⅲ

Interventional Management：CQ22～CQ33

Chapter Ⅳ

Psychological Approach：CQ34～CQ39

Chapter Ⅴ

Rehabilitation：CQ40～CQ46

Chapter Ⅵ

Multidisciplinary Treatment：CQ47～CQ51

188

Ⅱ．Pharmacotherapy

Table 2
Drug nameMethod ofadministration

Drugs Used in Chronic Pain Treatment

Dosage/Directions for usage

Applicable diseases

Adverse events/
Precautions for usage

osteoarthritis, low back pain,
cervicobrachial syndrome,
periarthritis scapulohumeralis, other general pain

gastrointestinal tract
disturbance, renal dysfunction, edema, cardiovascular
event, asthma

CQ8（p.190）

general pain

digestive symptoms,
liver/renal dysfunction

CQ9（p.193）

Ref.

NSAIDs (only characteristic drugs have been listed)
Diclofenac

oral, suppository 25～100 mg/day

Ibuprofenoral

600 mg/day

Loxoprofenoral

60～180 mg/day

Celecoxib

oral

200 mg/day

oral

600～4,000 mg/day

Acetaminophine
Acetaminophine

An extract from inflamed cutaneous tissue of rabbits inoculated with Vaccinia virus
An extract fromoral
inflamed cutaneous tissue of
rabbits inoculatedwith Vaccinia virus injection

4 tablets（16 unit）/day

postherpetic neuralgia, low back nausea, eruption
pain, ervicobrachial syndrome,
periarthritis scapulohumeralis,
osteoarthritis

3.6 Unit intravenous injection, intramus- low back pain, cervicobrachial
cular injection, subcutaneous injection
syndrome, symptomatic neuralgia,
Itch with the skin disease

drowsiness, eruption

initial dose：10～25 mg/day
maintenance dose：10～100 mg/day

drowsiness, dizziness,fatigue, nausea, dipsia

CQ10（p.196）

Antidepressants
Tricyclic antidepressants
Amitriptyline

oral

Imipramine

oral

depression, enuresis

Nortriptyline

oraldepression

Clomipramine

oral

depression, enuresis,
emotional cataplexy
accompanying narcolepsy

injection

depression, enuresis,
peripheral neuropathic pain

CQ14
（p.211）
CQ15（p.214）

initial dose：25 mg/day
maintenance dose：25～75 mg/day

depression

initial dose：10 mg/day
maintenance dose：30～75 mg/day

depression

unknown

CQ15（p.214）CQ15（p.214）

Tetracyclic antidepressantsMaprotiline

oral

Selective serotonin re-uptake inhibitors（SSRI）
Paroxetine

oral

initial dose：10～20 mg/day
maintenance dose：10～40 mg/day

depression, panic disorder,
obsessive-compulsive
disorder (OC), social anxiety
disorder (SAD)

drowsiness, dizziness,fatigue, nausea, dipsia

Escitalopram

oral

initial dose：10 mg/day
maintenance dose：10～20 mg/day

depression, social anxiety
disorder (SAD)

drowsiness, dizziness,fatigue, nausea, dipsia

Sertraline

oral

initial dose：25 mg/day
maintenance dose：25～100 mg/day

depression, panic disorder，
posttraumatic stress disorder(PTSD)

unknown

Fluvoxamine

oral

initial dose：25～50 mg/day
maintenance dose：50～150 mg/day

depression, social anxiety
disorder (SAD), obsession

nausea, dipsia, constipation，Serotonin-noradrenaline re-uptake inhibitors (SNRI)
Duloxetine

oral

initial dose：20 mg/day
maintenance dose：40～60 mg/day

depression, fibromyalgia,
diabetic neuropathy, chronic
low back pain, osteoarthritisof the knee

nausea, drowsiness, dipsia,
headache, fatigue

CQ13（p.207）

Milnacipran

oral

initial dose：25 mg/day
maintenance dose：25～60 mg/day

depression

dipsia, nausea, vomiting,drowsiness

CQ15（p.214）Venlafaxine

oralinitial dose：37.5 mg

depression

nausea, abdominal discomfort, somnolence

Other antidepressantsMirtazapine

oralinitial dose：15 mg/day
maintenance dose：15～30 mg/day

depression

drowsiness, fatigue, dipsia,
constipation

Trazodone

oral

initial dose：25 mg/day
maintenance dose：25～50 mg/day

depression

drowsiness, fatigue, dipsia,
constipation

CQ15（p.214）

189

Ⅱ．Pharmacotherapy

Drug nameMethod ofadministration

Dosage/Directions for usage

Applicable diseases

Adverse events/
Precautions for usage

Ref.

Antiepileptic drugs
Pregabalin

oralinitial dose：50～150 mg/day
maintenance dose：300～600 mg/day

Gabapentin

oral

initial dose：400～600 mg/day
intractable epileptic seizure
maintenance dose：600～1,800 mg/day

drowsiness, dizziness

Carbamazepine

oral

initial dose：200～400 mg/day
trigeminal neuralgia
maintenance dose：600～1,200 mg/day epileptic seizure, bipolar
disorderdrowsiness, dizziness, rash,cytopenia

Sodium valproateoral

400～1,200 mg/day

prevention of migraine,
epileptic seizure, bipolar
disorderdrowsiness, dizziness, liverdisease, pancreatitis

Lamotrigine

oral

initial dose：25 mg/day
maintenance dose：50～200 mg/day

epileptic seizure, bipolar
disordertoxic epidermal necrolysis，Stevens-Jonson syndrome

Topiramate

oral

initial dose：50 mg/day
maintenance dose：50～200 mg/day

epileptic seizure

drowsiness, weight gain,
closed-angle glaucoma

Anticonvulsant
Baclofen ※ 1

oral

initial dose：5～15 mg/day
maintenance dose：15～30 mg/day

spastic paralysis

drowsiness, dizziness, weak- CQ12
ness, nausea, vomiting（p.204）NMDA receptor antagonists
Ketamine
injectionneuropathic pain,
fibromyalgia

drowsiness, dizziness, weight CQ11
gain, edema（p.200）CQ12（p.204）

single dose 0.5 mg/kg
general anaesthesia at time
（gradually administered over 30 minutes） of surgery, investigation,※2
procedure
maintenance dose：5～20 mg/hr

CQ16nightmares, excitement,
nausea, vomiting, respiratory （p.217）
and circular depression,abuse, misuse

Dextromethorphan

oral formula

maintenance dose：30～45 mg/day

coughdrowsiness, dizziness,
nausea, vomiting

Memantineoral formulainitial dose：5 mg/day
maintenance dose：10～20 mg/day

Alzheimer-type dementia

dizziness, nausea, vomiting

Antianxiety agents
Etizolamoral

initial dose：0.5～1.5 mg/day
maintenance dose：0.5～3.0 mg/day

drowsiness, dizziness,
neuropathy, depression,
relaxes the muscles,
anxiety/strain/depression/
dependency
sleep disorder in psychophysiologic disorder, cervicalspondylosis, low back pain,
muscle contraction headache

Clonazepam

oral

initial dose：0.5～1 mg/day
maintenance dose：0.5～3/day

epilepsy

drowsiness, dizziness,closed-angle glaucoma,
relaxes the muscles

Alprazolam

oral

initial dose：0.4～1.2 mg/day
maintenance dose：0.4～2.4 mg/day（not use over 1.2 mg/day in elderly
person）

anxiety/strain/depression/
sleep disorder in psychophysiologic disorder

drowsiness, dizziness,closed-angle glaucoma,
relaxes the muscles

Diazepamoral

initial dose：2～10 mg/day
maintenance dose：4～15 mg/day

anxiety/strain/depression in
psychophysiologic disorder,
muscle cramps in the
cerebrospinal disease

drowsiness, dizziness,closed-angle glaucoma,
relaxes the muscles

Opioid analgesics
Tramadoloral formulainitial dose：50～100 mg/day
maintenance dose：50～300 mg/day

chronic pain, cancer pain

Tramadol/oral formula
Acetaminophen pill
(T/A pill)

initial dose：75～150 mg/day
maintenance dose：150～300 mg/day※3

chronic pain, post-dental
treatment pain

drowsiness, dizziness, nausea, CQ18
vomiting, constipation（p.224）

Buprenorphine
patch

patch
(for 7 days)

initial dose：0.12 mg/day
maintenance dose：0.12～0.48 mg/day

osteoarthritis
chronic low back pain

drowsiness, dizziness,
nausea, vomiting

CQ19（p.228）Morphine

initial dose：10～30 mg/day
oral formula※4（quick-release maintenance dose：30～90 mg/day
formula）

chronic pain, cancer pain

nausea, vomiting, constipation, respiratory depression,
psychological dependence,
abuse, misuse

CQ20（p.232）

Fentanyl patch

patch(for 1 dayor 3 days)

initial dose：12.5～25 μg/hr
maintenance dose： 5～37.5 μg/hr

chronic pain, cancer pain

nausea, vomiting, constipation, respiratory depression,
psychological dependence,
abuse, misuse※ 1 Consider the usage for trigeminal neuralgia when carbamazepine can not be used.
※ 2 Caution that the risk of neuropsychiatric symptoms increases in dose-dependent manner.
※ 3 Initial dosage and maintenance dosage indicate amounts including tramadol.
※ 4 The upper limit is 90 mg/day but it is better to use a dosage of up to 60 mg/day.

CQ17（p.220）drowsiness, dizziness,
nausea, vomiting, constipation

190

Ⅱ．Pharmacotherapy

CQ8：Are nonsteroidal anti‒inflammatory drugs effective in managing
chronic pain?
NSAIDs：nonsteroidal
anti-inflammatory drugs

Answer：Nonsteroidal anti‒inflammatory drugs (NSAIDs) have an analgesic
effect and improve motor function in musculoskeletal pain, and can also be effective when applied topically to relieve pain caused by osteoarthritis (OA).
There has been no high‒quality research conducted on its analgesic effects onneuropathic pain and therefore the use of NSAIDs is not recommended. It has
been recognized as effective in preventing and improving headache, orofacial
pain and migraine and therefore NSAIDs should be considered. We do not recommend NSAIDs for fibromyalgia. When administering NSAIDs, careful attention must be paid to any adverse events and long‒term use without any clear
purpose in mind should be avoided.
Summary of recommendation grades and overall evidence：
Musculoskeletal pain：1A (Use is strongly recommended)
Neuropathic pain：2D (Non‒use is weakly recommended)
Headache/Orofacial pain：2B (Use is weakly recommended)
Fibromyalgia：2C (Non‒use is weakly recommended)
Commentary：
Musculoskeletal pain
In systematic reviews verifying the efficacy of NSAIDs on chronic low backpain1), there was a minor improvement in motor function and analgesic effect,in comparison with a placebo but no difference in efficacy according to thetype of NSAIDs has been found. Furthermore, as the period of observation is

RCT：randomized controlled
trial

short in randomized control trials (RCT) which are the object of analysis, thelong-term safety of administering NSAIDs is unknown.
In ‘Noninvasive treatments for acute, subacute and chronic low back pain：
A clinical practice guideline’ published in 2017 by the American College ofPhysicians2), it was first recommended to conduct non-pharmacotherapy on
chronic pain such as rehabilitation and therapeutic exercise. Pharmacotherapy
is then recommended and the first‒line drug is NSAIDs, if non-pharmacotherapy does not have a sufficient effect.
According to a systematic review verifying the efficacy of the analgesic effect of NSAIDs on OA3), the efficacy of NSAIDS was confirmed in 76 RCTs incomparison with a placebo. When these data were analyzed, at the current
stage, it appears that 150mg of diclofenac, taken orally, is the most effective
improving motor function and pain.
In addition, in a systematic review verifying the efficacy of celecoxib4), when
36 RCTs were analyzed, it appeared that celecoxib was slightly effective in im-

191

Ⅱ．Pharmacotherapy

proving motor function and pain, in comparison to a placebo and conventional
NSAIDs.
According to a systematic review verifying the efficacy of applying topical
NSAIDs5), both diclofenac and ketoprofen were found to be significantly superior in terms of analgesic effect, compared with a placebo, with a number needed to treat (NNT) of 9.8 and 6.9, respectively. However, apart for this, there
has been no other evidence indicating its efficacy on chronic pain.
According to the ‘OARSI Guidelines’ on OA, announced by the Osteoarthritis
Research Society International (OARSI) in 20146), based on the assumption thatpharmacotherapy and non-pharmacological therapy are used concomitantly inthe management of OA, oral NSAIDs under pharmacotherapy are recommended but OA has also been recognized outside of the knee, and in the case where

NNT：number needed totreat（the number of patients whoneed to be treated for one ofthem to benefit comparedwith a control）
OARSI：
Osteoarthritis ResearchSociety International
OA：Osteoarthritis

moderate complications are also present, it is recommended that highly selective NSAIDs, in particular cyclooxygenase‒2 (COX‒2) be used. When severe

COX-2：cyclooxygenase-2

complications have been recognized, we strongly urge that NSAIDs not be
used. We recommend topical use of NSAIDs only in cases of knee OA, irrespective of whether complications are present or not.
Neuropathic Pain
In a systematic review verifying the efficacy of NSAIDs on neuropathic
pain7), two RCTs were subjected to analysis but quality of the evidence waslow, and so they were unable to draw any conclusions about the efficacy of
NSAIDs. For each of the patients’ conditions, there was one RCT8) on postherpetic neuralgia (PHN) but this study is unsuitable for considering efficacy because it was conducted on COX-2 selective inhibitor which is not used in clinical settings. At the current stage, no high‒quality evidence indicating the efficacy of NSAIDs on neuropathic pain exists.
Headache/Orofacial Pain
American Academy of Neurology (AAN) and the Quality Standards Subcommittee of American Headache Society (AHS) state that fenoprofen, ibuprofen,
ketoprofen and naproxen are effective as treatments in early phases of migraine. Flurbiprofen is probably effective but aspirin and indomethacin are notreally effective9). In recent reviews, amongst patients with migraine from eight
RCTs who took between 50～650mg of oral aspirin, they reported a decreasein the frequency of migraines when 325mg of oral aspirin or more was administered10). Based on these facts, we recommend the use of NSAIDs for migraine. However, we advise caution because continuous and excessive use of
NSAIDs over a long period of time sometimes induce medication overuse
headache (MOH).
Fibromyalgia
In a systematic review verifying the efficacy of NSAIDs on fibromyalgia,11)

AHS：the American
Headache Society

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Ⅱ．Pharmacotherapy

upon analysis of six RCTs, no significant difference in analgesic effect was recognized between four types of NSAIDs (etoricoxib, ibuprofen, naproxen, tenoxicam) and the placebo and as there was a wide variation in the results, the evidence level is low. Therefore, under our guidelines we do not recommend theadministration of NSAIDs for fibromyalgia.
Precautions：
The typical side effects of NSAIDs are gastrointestinal ulcer, renal dysfunction, cardiovascular events and asthma. For elderly or high‒risk patients, wewould consider administering COX‒2 highly selective celecoxib, and to prevent
gastrointestinal ulcer, we would consider administering proton pump inhibitor
PPI：proton pump inhibitor(PPI) and misoprostol. When administering NSAIDs, careful attention must be
made to a risk assessment of the patient and side effects，and it is important
to avoid long-term use without any clear aim in mind and to limit its use to
the short term.

Note 2：refer to p.188

Dosage and directions for usage are shown in Table 2 Note 2.
References
1）Enthoven WT, et al : Non‒steroidal anti‒inflammatory drugs for chronic
low back pain. Cochrane Database Syst Rev, 2016 ; 2 : CD012087
2）Qaseem A, et al : Clinical Guidelines Committee of the American Collegeof Physicians : Noninvasive treatments for acute, subacute, and chronic
low back pain : A clinical practice guideline from the American Collegeof Physicians. Ann Intern Med 2017 ; 166 : 514‒5303）da Costa BR, et al : Effectiveness of non‒steroidal anti‒inflammatory
drugs for the treatment of pain in knee and hip osteoarthritis : A network meta‒analysis. Lancet 2017 ; 390（10090）: e21‒e334）Puljak L, et al : Celecoxib for osteoarthritis. Cochrane Database Syst Rev
2017 ; 5 : CD009865
5）Derry S, et al : Topical NSAIDs for chronic musculoskeletal pain in
adults. Cochrane Database Syst Rev 2016 ; 4 : CD007400
6）McAlindon TE, et al : OARSI guidelines for the non‒surgical management of knee osteoarthritis. Osteoarthritis Cartilage 2014 ; 22 : 363‒3887）Moore RA, et al : Oral nonsteroidalanti‒inflammatory drugs for neuropathic pain. Cochrane Database Syst Rev 2015 ; 10 : CD010902
8）Shackelford S, et al : A randomized, double‒blind, placebo‒controlled trial of a selective COX‒2 inhibitor, GW406381, in patients with postherpetic neuralgia. J Pain 2009 ; 10 : 654‒660
9）Baena CP, et al : The effectiveness of aspirin for migraine prophylaxis : A
systematic review. Sao Paulo Med J 2017 ; 135 : 42‒4910）Derry S, et al : Oral nonsteroidal anti‒inflammatory drugs for fibromyalgia in adults. Cochrane Database Syst Rev 2017 ; 27 : CD012332
11）Holland S, et al : Evidence‒based guideline update : NSAIDs and othercomplementary treatments for episodic migraine prevention in adults :Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 2012 ;78 : 1346‒1353

Ⅱ．Pharmacotherapy

Database
PeriodWords searchedby the combination
with ‘chronic pain’
＊
Notes

193

Cochrane library, PubMed2005‒2017
NSAIDs, low back pain, osteoarthritis, neuropathic pain, postherpetic neuralgia, diabetic neuropathy, trigeminal neuralgia, orofacial pain, migraine, chronic headache, fibromyalgia
Out of these, we mainly searched for systematic review, RCT and
selected the references by considering its contents and avoiding
any overlap.

CQ9：Is acetaminophen effective in managing chronic pain?
Answer：In terms of musculoskeletal pain, acetaminophen for managing
chronic low back pain is eligible for coverage under the Japanese health insurance system, and due to its high level of safety as well, we recommend the administration. There is no high‒quality study, which has investigated its analgesic effects on neuropathic pain and so we do not recommend the administration. However, in headache and orofacial pain, it has been recognized as effective in improving infrequent episodic tension‒type headache (IETTH) and migraine and therefore we recommend that it be administered. Its effects on fibromyalgia remain unclear.
Close attention must be paid however, as there is a higher possibility of thepatient developing liver disorders when administered high dosages.
Summary of recommendation grades and overall evidence：
Musculoskeletal pain：1A (Use is strongly recommended)
Neuropathic pain：2D (Use is weakly recommended)
Headache/Orofacial pain：1A (Use is strongly recommended)
Fibromyalgia：2C (Use is weakly recommended)
Commentary：
Musculoskeletal pain
According to a systematic review verifying the efficacy of acetaminophen on
low back pain1), it is not recognized as effective in improving the quality of life
(QOL) in acute low back pain, and no high‒quality RCTs indicating the efficacyof acetaminophen on sub‒acute pain and chronic pain exist. Furthermore, according to recent RCTs on non‒specific chronic low back pain2), celecoxib hadsignificantly higher analgesic effect than acetaminophen.
Results of the efficacy of acetaminophen on osteoarthritis (OA) vary depending on the RCTs. There have been reports that slow‒release acetaminophen(1,950～3,900 mg/day)3), and a combination of 3,000mg/day of acetaminophen
and therapeutic exercise4), significantly improved pain and joint function, compared with the placebo. On the other hand, there have also been reports that
3,000～4,000 mg/day of acetaminophen did not have a significant effect, com-

RCT：randomized controlled
trial

194

Ⅱ．Pharmacotherapy

pared with the placebo5,6). According to systematic reviews analyzing placebo‒
controlled RCTs including these7,8), the efficacy of acetaminophen was very
low and was limited to a short period of time. Furthermore, it found that comNSAIDs：nonsteroidal
anti-inflammatory drugs

pared with nonsteroidal anti‒inflammatory drugs (NSAIDs), acetaminophen
had significantly lower analgesic effect and there was no difference in levels ofsafety.
In this way, recently the efficacy of acetaminophen on musculoskeletal pain
has been questioned, mainly in Western countries. In light of the results ofthese systematic reviews, some physicians are of the opinion that the positioning of acetaminophen under the treatment guidelines for musculoskeletal pain
needs to be revised7). In actual fact9), under the ‘Noninvasive treatments for
acute, subacute, and chronic low back pain：A clinical practice guideline’9)released by the American College of Physicians in 2017, Acetaminophen is notrecommended under pharmacotherapy irrespective of whether it is for acuteor chronic pain.
However, as acetaminophen has a high level of safety and is administeredwith high frequency for managing chronic musculoskeletal pain in Japan, under the ‘guidelines for low back pain’10) its efficacy is considered, and is a first‒
line drug, along with NSAIDs, for chronic low back pain. In addition, as it iscovered under the Japanese health insurance system for managing chronic low
back pain, we also recommend that it be administered under these guidelines.
Neuropathic pain
There are no RCTs which meet the set criteria related to the efficacy of acetaminophen and therefore we have no grounds on which to indicate a recommendation grade11).
Headache/Orofacial pain
Depending on the frequency of headache, tension-type headaches are classified into infrequent episodic (less than once a month), frequent episodic (1～14
times a month) and chronic (more than fifteen times a month). Among thesetypes, in a systematic review related to the analgesic effects of acetaminophen
on infrequent episodic tension-type headache (IETTH)12), when 1,000 mg of acetaminophen was administered per dosage, it was more effective than the placebo but there was no significant difference when 500 mg was administeredper dosage. There are few RCTs related to the analgesic effects of acetaminophen on frequent episodic and chronic tension‒type headache (TTH). In a systematic review related to migraine13), a single dosage of 1,000 mg of acetaminophen had a significant analgesic effect, compared with the placebo and whena single dosage of 1,000 mg of acetaminophen was used in combination withmetoclopramide, it provided an analgesic effect equivalent to that of 100 mg ofsumatriptan.

Ⅱ．Pharmacotherapy

195

Fibromyalgia
No RCTs indicating the efficacy of acetaminophen alone on fibromyalgia exist. A placebo‒controlled RCT study on patients with fibromyalgia complainingof moderate pain or worse, reported a significant decrease in the degree andpressure points of pain after taking a tramadol‒acetaminophen tablet (T/A
tablet)14), However, these are unreliable grounds to indicate the efficacy of acetaminophen.
Precautions：
Dosage and directions for usage are shown in Table 2 Note 3.
Under many of the guidelines to date, acetaminophen has been a first‒line
drug for general pain diseases, for the reasons that it has few side effects andis highly safe. However, in high dosages, patients are at increased risk of liver
damage. In many cases of hepatic failure, the cause was an overdose of acetaminophen5,16). As an unexpected overdose may occur through the concomitant
use of drugs contained within acetaminophen (such as common cold remedies
and opioid analgesic compounds), we advise caution when increasing the dosage or in cases of long-term administration.
References
1）Saragiotto BT, et al : Paracetamol for low back pain. Cochrane Database
Syst Rev 2016 ; 6 : CD012230
2）Bedaiwi MK, et al : Clinical efficacy of celecoxib compared to acetaminophen in chronic nonspecific low back pain : Results of a randomized controlled trial. Arthritis Care Res（Hoboken）2016 ; 68 : 845‒8523）Altman RD, et al : Three‒month efficacy and safety of acetaminophen
extended‒release for osteoarthritis pain of the hip or knee : A randomized, double‒blind, placebo‒controlled study. Osteoarthritis Cartilage
2007 ; 15 : 454‒461
4）Casale R, et al : Efficacy of a comprehensive rehabilitation programme
combined with pharmacological treatment in reducing pain in a group of
OA patients on a waiting list for total joint replacement. Clin Exp Rheumatol 2012 ; 30 : 233‒239
5）Herrero‒Beaumont G, et al : Glucosamine sulfate in the treatment ofknee osteoarthritis symptoms : A randomized, double‒blind, placebo‒
controlled study using acetaminophen as a side comparator. Arthritis
Rheum 2007 ; 56 : 555‒5676）Miceli‒Richard C, et al : Paracetamol in osteoarthritis of the knee. Ann
Rheum Dis 2004 ; 63 : 923‒930
7）Machado GC, et al : Efficacy and safety of paracetamol for spinal pain
and osteoarthritis : Systematic review and meta‒analysis of randomised
placebo controlled trials. BMJ 2015 ; 350 : h1225
8）Ennis ZN, et al : Acetaminophen for chronic pain : A systematic review
on efficacy. Basic Clin Pharmacol Toxicol 2016 ; 118 : 184‒1899）Qaseem A, et al : Clinical Guidelines Committee of the American College

Note 3：refer to p.188

196

Ⅱ．Pharmacotherapyof Physicians : Noninvasive treatments for acute, subacute, and chronic
low back pain : A clinical practice guideline from the American Collegeof Physicians. Ann Intern Med 2017 ; 166 : 514‒53010）The Clinical Guidelines Committee, The Japanese Orthopaedic Association, eds : Clinical Practice Guidelines for Low‒back Pain 2012. Nankodo,
Tokyo, 201211）Wiffen PJ, et al : Paracetamol（acetaminophen）with or without codeineor dihydrocodeine for neuropathic pain in adults. Cochrane Database
Syst Rev, 2016 ; 12 : CD012227
12）Stephens G, et al : Paracetamol（acetaminophen）for acute treatment of
episodic tension‒type headache in adults. Cochrane Database Syst Rev
2016 ; 6 : CD011889
13）Derry S, et al : Paracetamol（acetaminophen）with or without an antiemetic for acute migraine headaches in adults. Cochrane Database Syst
Rev 2013 ; 4 : CD008040
14）Bennett RM, et al : Tramadol and acetaminophen combination tablets inthe treatment of fibromyalgia pain : A double‒blind, randomized, placebo‒
controlled study. Am J Med 2003 ; 114 : 537‒545
15）O’Neil CK, et al : Adverse effects of analgesics commonly used by older
adults with osteoarthritis : Focus on non‒opioid and opioid analgesics.
Am J Geriatr Pharmacother 2012 ; 10 : 331‒34216）Larson AM, et al : Acute Liver Failure Study Group : Acetaminophen‒induced acute liver failure : Results of a United States multicenter, prospective study. Hepatology 2005 ; 42 : 1364‒1372
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

Cochrane Library, PubMed2005‒2017
acetaminophen, paracetamol, low back pain, osteoarthritis, neuropathic pain, postherpetic neuralgia, diabetic neuropathy, trigeminal
neuralgia, orofacial pain, migraine, chronic headache, fibromyalgia
Out of the words searched, we searched mainly for systematic
review, RCT, and selected references by considering their details
and tried to avoid any overlap. As for those with few search results, we used references prior to 2004 which were considered
important (References 6, 14)

CQ10：Is an extract from inflamed cutaneous tissue of rabbits inoculatedwith vaccinia virus effective in managing chronic pain?
An extract from inflamed
cutaneous tissue of rabbits.
inoculated with vaccinia virus

Answer：There is some evidence indicating that an extract from inflamed
cutaneous tissue of rabbits inoculated with vaccinia virus is effective on chronic musculoskeletal pain and neuropathic pain, and therefore we recommendthat it be administrated. Evidence indicating that it be recommended to manage headache, orofacial pain and fibromyalgia is scarce but because there are
no severe adverse events and it is highly safe, it should be considered as an alternative option in cases where patients fail to react to standard treatment.
Summary of recommendation grades and overall evidence：
Musculoskeletal Pain：2B (Use is weakly recommended)
Neuropathic pain：Postherpetic neuralgia：1B (Use is strongly recommended)

Ⅱ．Pharmacotherapy

197

Neuropathic pain other than above：2C (Use is weakly recommended)
Headache/Orofacial pain：2D (Use is weakly recommended)
Fibromyalgia：2D (Use is weakly recommended)
Commentary：
An extract from inflamed cutaneous tissue of rabbits inoculated with vaccinia virus is a type of drug containing non‒protein type biologically active substances extracted from the inflamed cutaneous tissue of rabbits, which havebeen inoculated with the vaccinia virus. It exhibits analgesic effects throughactivation of the descending pain inhibitory system, anti‒inflammatory action,
inhibiting the release of excitatory neuropeptides, inhibiting the excitation of
sympathetic nerves, improving blood flow, and neuroprotective action, and inother ways1). It is a highly safe formulation and researchers have not found
any severe adverse events such as disturbance of the gastrointestinal tract,kidney damage, cardiovascular events or asthmatic attacks.
Musculoskeletal pain
Clinical trials conducted in Japan indicate that an extract from inflamed cutaneous tissue of rabbits inoculated with vaccinia virus is effective on chronic
pain due to various musculoskeletal pain diseases. In a randomized controlled
trial (RCT) conducted on 121 patients suffering from low back pain, this drug
was shown to be effective on subjects who were orally administered four tablets a day (administered twice/day), compared with a placebo group2). It wasalso shown to be effective in another placebo‒controlled RCT study on patientswith cervico‒omo‒brachial syndrome3). However, in another RCT study inwhich they compared the effects of the extract with indomethacin on patientswith periarthritis scapulohumeralis and osteoarthritis (OA) of the knee, they
did not find any significant difference in analgesic effect between the twogroups, and no difference in their levels of safety4). However, in both RCTs, patients’ symptoms were not caused by the same disease and therefore the methods for evaluating improvement of symptoms and drug utility are vague, andso the level of evidence is slightly weak.
Neuropathic Pain
As for its effect on neuropathic pain, a placebo-controlled RCT conducted inJapan on 228 subjects suffering from postherpetic neuralgia (PHN) indicatedthe efficacy of the extract from inflamed cutaneous tissue of rabbits inoculatedwith vaccinia virus. Compared with the placebo-controlled group, there was asignificant improvement in pain in the group which continued to take four tablets/day (taken twice/day) continuously over four weeks5). In addition, a smallscale preliminary study indicated that administering the extract from inflamed
cutaneous tissue of rabbits inoculated with vaccinia virus reduced peripheral

RCT：randomized controlled
trial

198

Ⅱ．Pharmacotherapy

neuropathy due to oxaliplatin in 80 patients undergoing chemotherapy for colorectal cancer6). Furthermore, in a case series study on 36 patients with painful
diabetic neuropathy (PDN) who were orally administered with the extract frominflamed cutaneous tissue of rabbits inoculated with vaccinia virus continuously for eight weeks, spontaneous pain and numbness improved in 65% of thesubjects7).
As seen above, as the usefulness of the extract from inflamed cutaneous tissue of rabbits inoculated with vaccinia virus for managing postherpetic pain
has been firmly established, it is a second-line drug under the ‘Guidelines forthe pharmacologic management of neuropathic pain, second edition’ 8) releasedby the Japan Society of Pain Clinicians．As there are few adverse events andit has high tolerability, we recommend its use for neuropathic pain.
Headache/Orofacial pain
There are no RCTs, either in Japan or abroad, which have investigated theefficacy of an extract from inflamed cutaneous tissue of rabbits inoculated withvaccinia virus on headache and orofacial pain. There are several case studies
which have shown its efficacy on headache and orofacial pain and in Japan,
there are some case series indicating its efficacy on tension‒type headache(TTH) and migraine9,10), but the evidence indicating its efficacy is weak. However, as an extract from inflamed cutaneous tissue of rabbits inoculated withvaccinia virus displays almost no severe adverse events and is a highly safe
formulation, it is worth considering as an alternative in cases where patients
fail to react to standard treatment.
Fibromyalgia
No RCTs investigating the efficacy of extract from inflamed cutaneous tissueof rabbits inoculated with vaccinia virus on fibromyalgia exist either in Japanor abroad. There are some instances of case reports here and there, whichclaimed that it was effective on fibromyalgia pain but the evidence indicating
its efficacy is weak. However, as there are almost no severe adverse eventsand it is highly safe, one could consider using these extracts as an alternativein cases where a highly recommended drug has poor effects on patients withfibromyalgia.
Precautions：
In RCTs and cases series on an extract from inflamed cutaneous tissue of
rabbits inoculated with vaccinia virus in the past, results have shown that
there are extremely few adverse events and it is highly safe. However, eventhough it is unclear how frequently this occurred, there have been reports ofsevere adverse events such as shock, anaphylactic-type symptoms, liver dys-

Ⅱ．Pharmacotherapy

199

function and jaundice and therefore caution is advised when using this agent.
Furthermore, in cases where it has proven to be ineffective on patients, evenafter administering it for four weeks, one needs to be careful not to administer
it without any clear purpose in mind11).
Dosage and directions for usage are shown in Table 2 Note 4.
References
1）Suzuki T, et al : New aspects of drugs and pharmacotherapy in pain clinic practice : New developments in mechanism of analgesic action of Neurotropin®. Pain Clinic 2010 ; 31（Suppl）: S441‒S445
2）Ono K, et al : 腰痛症に対する Neurotropin®tablet（NT）の臨床評価二重盲検比較試験．Japanese Pharmacology & Therapeutics（JPT）1981 ; 9 :2017‒2025
3）Nakagawa K, et al : 頸肩腕症候群に対する Neurotropin®tablet（NT）の臨 床 効 果 二 重 盲 検 比 較 試 験．Japanese Pharmacology & Therapeutics（JPT）1982 ; 10 : 5833‒5856
4）Miura T, et al : Clinical evaluation of effects of Neurotropin®tablets（NT）
on gonarthrosis and periarthritis scapulohumeralis : Multi‒institutional
double‒blind study in comparison with indometacin. The Clinical Report1986 ; 20 : 9089‒9118
5）Yamamura H，他 : Neurotropin®tablet の帯状疱疹後神経痛に対する効
果 : プラセボ錠を対照薬とした多施設二重盲検試験．Igaku no Ayumi
1988 ; 147 : 651‒6646）Zhang RX, et al : Neuroprotective effect of Neurotropin®on chronic oxaliplatin‒induced neurotoxicity in stage II and stage III colorectal cancer
patients : Results from a prospective, randomised, single‒centre, pilot
clinical trial. Int J Colorectal Dis 2012 ; 27 : 1645‒1650
7）Orishige H, et al : Therapeutic effect of Neurotropin®tablets on diabetic
neuropathy. Prog Med 1989 ; 9 : 1153‒1160
8）The Committee for the Guidelines for the Pharmacologic Managementof Neuropathic Pain of Japan Society of Pain Clinicians, eds. : Guidelines
for the pharmacologic management of neuropathic pain. Tokyo, Shinko
Trading Co. Ltd., 20169）Izumiyama H, et al : 筋緊張型頭痛に対する Neurotropin®錠の有用性．日
本頭痛学会誌 2002 ; 29 : 105‒10710）Shimomura T, et al : 片頭痛に対する Neurotropin®錠の効果 : 臨床効果と唾液中神経伝達物質の変動．The Journal of Therapy 2002 ; 84 : 1451‒145511）Neurotropin®Drug Infomation 2013

Note 4：refer to p.188

200

Ⅱ．Pharmacotherapy

Database
PeriodWords searchedby the combination
with ‘chronic pain’

＊

Notes

Cochrane Library, PubMed, Ichushi Web
1970 ‒ 2017neurotropin, low back pain, osteoarthritis, neuropathic pain, postherpetic neuralgia, diabetic neuropathy, trigeminal neuralgia,
orofacial pain, migraine, chronic headache, fibromyalgia (CochraneLibrary, PubMed)
an extract from inflamed cutaneous tissue of rabbits inoculatedwith vaccinia virus, neurotropin, pain, low back pain, cervico‒omo‒brachial syndrome, osteoarthritis (OA), neuropathic pain, postherpetic neuralgia (PHN), diabetic neuropathy, headache, orofacialpain, facial pain, fibromyalgia (Ichushi Web)
From these results, we searched mainly for systematic review,
RCT, clinical study, and clinical trial and selected the references.
In addition to this, we also referred to the Guidelines for the
Pharmacologic Management of Neuropathic Pain (Second Edition),published by the Japan Society of Pain Clinicians, and drug information of Neurotropin®.

CQ11：Is pregabalin effective in managing chronic pain?
Answer：Pregabalin is recommended as a first‒line drug for managing neuropathic pain as a whole. Analgesic efficacy of pregabalin on fibromyalgia has
been proven when administered at high doses. As there are few high-quality
RCTs on the efficacy of pregabalin on musculoskeletal pain (e.g. arthritic pain,
low back and lower extremity pain) and headache/orofacial pain, the recommendation grade for these diseases is low. However, for trigeminal neuralgia
patients allergic to carbamazepine and for neuropathic pain clearly derived
from trigeminal nerve disorder, use of pregabalin under the management of a
specialist is recommended. Adverse effects such as drowsiness and lightheadedness are common, therefore patients should start on a low dosage, according
to their age and gender, and the dosage should be titrated. Particular care isrequired with elderly patients.
Summary of recommendation grades and overall evidence：
Musculoskeletal pain：2C (Use is weakly recommended)
Neuropathic pain：1A (Use is strongly recommended)
Headache/Orofacial pain：2C (Use is weakly recommended)
Fibromyalgia：1A (Use is weakly recommended)
Commentary：
Musculoskeletal pain
In a non‒randomized controlled trial on lumbar and cervical radiculopathy
which had persisted for six months or more, the groups which had been administered pregabalin alone and pregabalin in combination showed significantly higher analgesic effects than the group which did not use pregabalin 1).
However, in a RCT study targeting patients with sciatic nerve pain, pregabalin

Ⅱ．Pharmacotherapy

201(starting dose of 150 mg/day, gradually increased to a maximum dose of 600
mg/day) did not have significantly greater analgesic effects, compared with theplacebo2). This study subjects included a large number of patients experiencing
sciatic nerve pain in the acute stage of less than three months since onset andtherefore it is hard to say that the results reflect the effects of pregabalin on
chronic radicular pain. Further high-quality RCTs about the effects of pregabalin on radicular pain are required. Out of the musculoskeletal pain in Japan,
low back pain is a common symptom with a high incidence rate. As low backpain has a mixture of nociceptive, neuropathic and psychosocial factors, it is assumed that using several types of drugs in combination with their different
acting mechanisms is effective. In a RCT targeting patients with low back andlower extremity pain, pregabalin administered in combination with celecoxib
displayed significantly higher analgesic effects than when pregabalin alone orcelacoxib alone was administered3). In another RCT on low back and lower extremity pain, buprenorphine patch used in combination with pregabalin
showed significantly higher analgesic effects than when buprenorphine patch
alone was administered4). In both RCTs，many of the subjects included patients with elements of neuropathic pain，and therefore we think the results
reflect the analgesic effects of pregabalin on neuropathic pain．At the current
stage, there are no significant reports indicating the efficacy of pregabalin on
back pain unaccompanied by lower extremity pain (i.e. back pain with few elements of neuropathic pain). Chronic arthritic pain due to osteoarthritis of theknee is a typical disease of nociceptive pain but in recent years, it has beensuggested that increased pain or protracted pain due to central sensitization is
involved and there are quite a few instances of patients who also display neuropathic pain-type symptoms5). In a RCT targeting chronic arthritic pain of
the knee, meloxicam administered in combination with pregabalin displayed
significantly higher analgesic effects than when meloxicam alone or pregabalinalone was used6). We need to compile even more data on the efficacy of pregabalin in managing chronic arthritic pain.
Neuropathic pain
There is much research indicating that pregabalin produces a higher analgesic effect than the placebo on neuropathic pain, including postherpetic neuralgia (PHN), painful diabetic neuropathy, painful polyneuropathy and post-spinal
cord injury pain. Therefore, pregabalin is highly effective on neuropathic pain7).
Regarding neuropathic pain as a whole, including the above diseases, when theoutcomes were a 50% reduction in pain or more compared with the baseline,
which was prior to treatment, the number needed to treat (NNT) and number
needed to harm (NNH) were 7.7 and 13.9, respectively, when subjects wereadministered 300～600 mg of pregabalin7).

NNT：number needed totreat（the number of patients whoneed to be treated for one ofthem to benefit comparedwith a control）
NNH：number needed toharm（the number of patients whoneed to be exposed to a risk
factor to cause harm to one
patient）

202

Ⅱ．Pharmacotherapy

Headache/Orofacial pain
There are no RCTs investigating the efficacy of pregabalin in preventing migraine. In non-odontogenic toothache, although there are few RCTs investigating the efficacy of pregabalin, when neuropathic pain elements are strong, pregabalin can be used as a first-line drug, in the same way as when other neuropathic pain is present in other parts of the body8). For trigeminal neuralgia
cases who are allergic to carbamazepine and for neuropathic pain clearly derived from trigeminal nerve disorder, use of pregabalin under the managementof a specialist is recommended9).
Fibromyalgia
In the several RCTs on fibromyalgia, pregabalin was not effective at doses of
150 mg/day10), but provided significant analgesic effects at dosages of 300 mg/
day or more, compared with the placebo11‒13). The NNT for outcomes in whichpain was reduced by 50% or more were 14 (300 mg/day), 9.7 (450 mg/day) and11 (600 mg/day), respectively14). The NNH for doses of 300～600 mg/day wastolerability：the degree towhich overt adverse effects
of a drug can be tolerated bya patient.

between 5.7～9.0, and the higher the dosage, the poorer the tolerability14). In a
RCT targeting Japanese patients with fibromyalgia, 450 mg/day of pregabalin
showed higher analgesic effect and improvement in sleep quality, comparedwith the placebo15). Considering the NNT and NNH, doses of 300～450 mg/dayof pregabalin for fibromyalgia are considered appropriate in terms of efficacy
and tolerability.
Precautions：

Note 5：refer to p.189

Dosage and directions for usage are shown in Table 2 Note 5.
A long‒term domestic study targeting patients with painful diabetic neuropathy who had participated in domestic Phase 3 clinical trials, investigated theoccurrence of adverse events when patients were administered between 150～
600 mg/day of pregabalin over 52 weeks. The overall side‒effect incidence rate
was 87%, which included drowsiness (28%), weight gain (27%), dizziness (26%),
and edema (19%). The level of severity of drowsiness and dizziness ranged
from light to moderate, but tended to appear at an early stage and would often
reduce over the course of the year. The incidence rate of severe complications
was extremely low16). The same results were obtained with the domestic long‒term study targeting patients with fibromyalgia17).
References1）Saldaña MT, et al : Patient‒reported‒outcomes in subjects with painful
lumbar or cervical radiculopathy treated with pregabalin : Evidence
from medical practice in primary care settings. Rheumatol Int 2010 ; 30 :1005‒1015
2）Mathieson S, et al : Trial of pregabalin for acute and chronic sciatica. N

Ⅱ．Pharmacotherapy

Engl J Med 2017 ; 376 : 1111‒1120
3）Romanò CL, et al : Pregabalin, celecoxib, and their combination for treatment of chronic low‒back pain. J Orthop Traumatol 2009 ; 10 : 185‒1914）Pota V, et al : Combination therapy with transdermal buprenorphine andpregabalin for chronic low back pain. Pain Manag 2012 ; 2 : 23‒315）Arendt‒Nielsen L, et al : Altered central sensitization and pain modulation in the CNS in chronic joint pain. Curr Osteoporos Rep 2015 ; 13 : 225‒
2346）Ohtori S, et al : Efficacy of combination of meloxicam and pregabalin for
pain in knee osteoarthritis. Yonsei Med J 2013 ; 54 : 1253‒1258
7）Finnerup NB, et al : Pharmacotherapy for neuropathic pain in adults : A
systematic review and meta‒analysis. Lancet Neurol 14 : 162‒73, 20158）Clark GT, et al : Medication treatment efficacy and chronic orofacialpain. Oral Maxillofac Surg Clin North Am 2016 ; 28 : 409‒421
9）Pérez C, et al : Patient‒reported outcomes in subjects with painful trigeminal neuralgia receiving pregabalin : Evidence from medical practicein primary care settings. Cephalalgia 2009 ; 29 : 781‒79010）Moore RA, et al : Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev 2009 ; 3 : CD007076
11）Arnold LM, et al : A 14‒week, randomized, double‒blinded, placebo‒controlled monotherapy trial of pregabalin in patients with fibromyalgia. J
Pain 2008 ; 9 : 792‒80512）Crofford LJ, et al : Pregabalin for the treatment of fibromyalgia syndrome : Results of a randomized, double‒blind, placebo‒controlled trial.
Arthritis Rheum 2005 ; 52 : 1264‒1273
13）Crofford LJ, et al : Fibromyalgia relapse evaluation and efficacy for durability of meaningful relief（FREEDOM）: A 6‒month, double‒blind, placebo‒controlled trial with pregabalin. Pain 2006 ; 136 : 419‒43114）Derry S, et al : Pregabalin for pain in fibromyalgia in adults. Cochrane
Database Syst Rev 2016 ; 9 : CD011790
15）Ohta H, et al : A randomized, double‒blind, multicenter, placebo‒controlled phase III trial to evaluate the efficacy and safety of pregabalin in
Japanese patients with fibromyalgia. Arthritis Res Ther 2012 ; 14 : R217
16）Satoh J, et al : Efficacy and safety evaluation of pregabalin treatment
over 52 weeks in patients with diabetic neuropathic pain extended after
a double‒blind placebo‒controlled trial. J Diabetes Investig 2011 ; 2 : 457‒
46317）Ohta H, et al : An open‒label long‒term phase III extension trial to evaluate the safety and efficacy of pregabalin in Japanese patients with fibromyalgia. Mod Rheumatol 2013 ; 23 : 1108‒1115
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

Cochrane Library, PubMed
2005～2017pregabalin, low back pain, osteoarthritis, neuropathic pain, postherpetic neuralgia, diabetic neuropathy, trigeminal neuralgia, orofacial pain, migraine, chronic headache, fibromyalgia
Out of these words, we searched mainly for systematic review,
RCT, and selected references by considering their details and by
trying to avoid any overlap.

203

204

Ⅱ．Pharmacotherapy

CQ12：Are antiepileptic drugs effective in managing chronic pain?
Answer：Similar to pregabalin，gabapentin is recommended as a first-line
drug for neuropathic pain, but at the current stage, from the perspective of
health insurance coverage, gabapentin is off label for neuropathic pain in Japan.
RCT：randomized controlled
trial

There are few high‒quality RCTs about the efficacy of other antiepileptics (e.g.
carbamazepine, lamotrigine, lacosamide, topiramate, sodium valproate) on
chronic pain diseases (e.g. neuropathic pain, fibromyalgia, musculoskeletal pain,
orofacial pain). Although antiepileptics can be used as an alternative when adrug with a high recommendation grade was not effective, great caution isneeded when using them, as there can be some severe adverse effects. Regarding the preventive effect of sodium valproate and topiramate on migraine, acertain evaluation has been obtained and the recommendation grade is high.
Summary of recommendation grades and overall evidence：
1) Gabapentin
Musculoskeletal pain：No clear evidence for recommendation
Neuropathic pain：1A (Use is strongly recommended)
Headache/Orofacial pain：No clear evidence for recommendation
Fibromyalgia：No clear evidence for recommendation
2) Carbamazepine
Musculoskeletal pain：No clear evidence for recommendation
Neuropathic pain：2C(Use is weakly recommended)(excluding trigeminal neuralgia)

Headache/Orofacial pain：trigeminal neuralgia：1A(Use is strongly recommended)

Other headache/orofacial pain：No clear evidence for recommendation
Fibromyalgia：No clear evidence for recommendation
3) Sodium valproate
Musculoskeletal pain：No clear evidence for recommendation
Neuropathic pain：2B (Use is weakly recommended)
Headache/Orofacial pain：1A(Use is strongly recommended)(as a preventative medicine for migraine)

Fibromyalgia：No clear evidence for recommendation
4) Lamotrigine
Musculoskeletal pain：No clear evidence for recommendation
Neuropathic pain：2B (Use is weakly recommended)
Headache/Orofacial pain：Trigeminal neuralgia: 2D(Use is weakly recommended)

Other headache/orofacial pain：No clear evidence for recommendation
Fibromyalgia：No clear evidence for recommendation

Ⅱ．Pharmacotherapy

2055) Topiramate
Musculoskeletal pain：No clear evidence for recommendation
Neuropathic pain：2C (Use is weakly recommended)
Headachie/Orofacial pain：1A(Use is strongly recommended) (as a preventative medicine for migraine)

Fibromyalgia：No clear evidence for recommendation
Commentary：1) Gabapentin
There are many RCTs indicating gabapentin’s higher analgesic effect, compared with the placebo, on neuropathic pain such as postherpetic neuralgia(PHN), painful diabetic neuropathy, painful polyneuropathy and post-spinal
cord injury pain1). Regarding neuropathic pain as a whole, including the above
diseases, the NNT and NNH of 1,800～3,600 mg/day of gabapentin were 6.2
and 25.9, respectively, for outcomes in which pain was reduced by 50% ormore compared with the baseline, which was prior to the commencement oftreatment. It has both a high efficacy and high tolerability1). There are no high‒quality RCTs on fibromyalgia2). In a RCT on low back pain with accompanying
radicular pain, significantly higher analgesic effect was obtained in the groupwhich used a combination of gabapentin (2,400 mg/day) and standard treatments such as physiotherapy and the oral administration of NSAIDs, than in

NNT：number needed totreat（the number of patients whoneed to be treated for one ofthem to benefit comparedwith a control）
NNH：number needed toharm（the number of patients whoneed to be exposed to a risk
factor to cause harm to one
patient）

the group which only used these standard treatments3). There are no RCTs
targeting low back pain without radicular pain. Regarding the efficacy of gabapentin on orofacial pain, there is only one RCT on patients with chronic painin the masticatory muscle. In this RCT, gabapentin (300 mg/day) displayed significantly higher analgesic effects4). Further studies are required to clarify theefficacy of gabapentin on fibromyalgia, low back and lower-extremity pain as
well as orofacial pain.
2) Carbamazepine
It has been established that carbamazepine is effective on trigeminal neuralgia5). On the other hand, there are few reports on its efficacy on other forms ofneuropathic pain, apart from trigeminal neuralgia. In addition, it has an NNH of
5.5 and low tolerability, therefore, its recommendation grade against neuropathic pain other than trigeminal neuralgia is low1). Some of the side effects
from carbamazepine include dizziness, lightheadedness, aplastic anaemia, granulocytopenia, toxic epidermal necrolysis (TEN), and Stevens‒Jonson syndrome.
When managing trigeminal neuralgia, in cases where carbamazepine alone is

TEN：toxic epidermal
necrolysis

unable to provide sufficient analgesic effect, or when carbamazepine cannot be
used due to old age or side effects, the use of baclofen should be considered Note 6.

Note 6：refer to p.189

206

Ⅱ．Pharmacotherapy3) Sodium valproate
The results of RCTs on the efficacy of 1,000～2,400 mg/day of sodium valproate on neuropathic pain vary from one study to the next6‒8). There are no
RCTs on fibromyalgia, low back and lower‒extremity pain or arthritic pain.
There are some severe side effects such as hepatic dysfunction, drug‒induced
pancreatitis (aggravated when used in combination with topiramate), and teratogenesis, and therefore its recommendation grade is low. In several RCTs on
its efficacy in preventing migraine, the consistent results were obtained and it
has been evaluated as a preventative drug which reduces the frequency ofheadache9).
4) Lamotrigine
In the results of several RCTs on neuropathic pain, the efficacy of lamotrigine varies from one study to the next1). There are no high‒quality RCTs onother chronic pain diseases (e.g. fibromyalgia, low back and lower‒extremity
pain, arthritic pain) and so there is no evidence for which we can recommend
it. In trigeminal neuralgia, although its analgesic effect is low, it can be used, although weakly recommended, as an analgesic option under the management ofa specialist in patients who are resistant to or allergic to carbamazepine10‒12).
Side effects of lamotrigine include some severe skin problems such as toxic
epidermal necrolysis (TEN) and Stevens-Jonson syndrome.
5) Topiramate
There are few RCTs on chronic pain diseases and the results of the efficacy
of topiramate vary from one study to the next1). In a RCT study on radiculopathy, there was no significant difference in analgesic effect between 400 mg/dayof topiramate and the placebo13). It has an NNH of 6.3, with a low tolerability.
Therefore, it has a low recommendation grade for chronic pain diseases. On
the other hand, there are several RCTs on migraine, which showed that when
patients were administered 50～200 mg/day of topiramate reduced the numbers of headache attacks and painkiller use, and improved QOL14). Therefore,
in the same way as with sodium valproate, it is recommended as a first‒line
drug to prevent migraine. Adverse events include drowsiness, weight loss andclosed‒angle glaucoma.
Precautions：
Dosages, precautions for usage and adverse events for each drug are shown
Note 7：refer to p.189

in Table 2 Note 7.
References
1）Finnerup NB, et al : Pharmacotherapy for neuropathic pain in adults : A
systematic review and meta‒analysis. Lancet Neurol 2015 ; 14 : 162‒173

Ⅱ．Pharmacotherapy2）Cooper TE, et al : Gabapentin for fibromyalgia pain in adults. Cochrane
Database Syst Rev 2017 ; 1 : CD012188
3）Yaksi A, et al : The efficiency of gabapentin therapy in patients withlumbar spinal stenosis. Spine（Phila Pa 1976）2007 ; 32 : 939‒9424）Kimos P, et al : Analgesic action of gabapentin on chronic pain in themasticatory muscles : A randomized controlled trial. Pain 2007 ; 127 : 151‒1605）Sindrup SH, et al : Pharmacotherapy of trigeminal neuralgia. Clin J Pain
2002 ; 18 : 22‒276）Kochar DK, et al : Sodium valproate in the management of painful neuropathy in type 2 diabetes : A randomized placebo controlled study.
Acta Neurol Scand 2002 ; 106 : 248‒2527）Kochar DK, et al : Sodium valproate for painful diabetic neuropathy : A
randomized double‒blind placebo‒controlled study. QJM 2004 ; 97 : 33‒388）Kochar DK, et al : Divalproex sodium in the management of post‒herpetic neuralgia : A randomized. QJM 2006 ; 98 : 29‒349）Linde M, et al : Valproate（valproic acid or sodium valproate or a combination of the two）for the prophylaxis of episodic migraine in adults. Cochrane Database Syst Rev 2013 ; 6 : CD010611
10）Zakrzewska JM, et al : Lamotrigine（lamictal）in refractory trigeminal
neuralgia : Results from a double‒blind placebo controlled crossover trial.
Pain 1997 ; 73 : 223‒23011）Dosenovic S, et al : Interventions for neuropathic pain : An overview ofsystematic reviews. Anesth Analg 2017 ; 125 : 643‒65212）Oomens MA, et al : Pharmaceutical management of trigeminal neuralgia
in the elderly. Drugs Aging 2015 ; 32 : 717‒72613）Khoromi S, et al : Topiramate in chronic lumbar radicular pain. J Pain
2005 ; 6 : 829‒83614）Silberstein SD : Topiramate in migraine prevention : A 2016 perspective.
Headache 2017 ; 57 : 165‒178
Database
PeriodWords searchedby the combination
with ‘chronic pain’
＊

Notes

Cochrane Library, PubMed2005‒2017
anticonvulsant, valproate, lamotrigine, topiramate, low back pain,
osteoarthritis, neuropathic pain, postherpetic neuralgia, diabetic
neuropathy, trigeminal neuralgia, orofacial pain, migraine, chronicheadache, fibromyalgia
Out of these words, we mainly searched for systematic review,
RCT, and selected references by considering their details and by
trying to avoid any overlap. As for those words with few search
results, we selected references prior to 2004 which were considered important (References 5, 6, 7)

CQ13：Is duloxetine effective in managing chronic pain?
Answer：There is much evidence that duloxetine is effective on neuropathic
pain, chronic low back pain, osteoarthritis, and fibromyalgia, and is therefore
recommended. One thing to be careful of when using duloxetine is that weshould cautiously judge whether to administer the drug or not after considering the possibility that it may cause mental states such as suicidal thoughts,
suicidal attempts，hostility and aggressiveness.

207

208

Ⅱ．Pharmacotherapy

Summary of recommendation grades and overall evidence：
Musculoskeletal pain：1A (Use is strongly recommended)
Neuropathic pain：1A (Use is strongly recommended)
Headache/Orofacial pain：2C (Use is weakly recommended)
Fibromyalgia：1A (Use is strongly recommended)
Commentary：
SNRI：serotonin-noradrenaline re-uptake inhibitor

Duloxetine is one of the serotonin‒noradrenaline re‒uptake inhibitors (SNRI),is safer and easier to use than amitriptyline, and is a better option for patientswith heart disease. It is believed that the analgesic mechanism of duloxetine
induces an activation of the descending pain inhibitory system (DPIS).
Musculoskeletal pain

RCT：randomized controlled
trial
ACP：The American Collegeof Physicians

There are some RCT studies on duloxetine and chronic low back pain1‒3),and even in the systematic reviews, it is strongly recommended. According to
the guidelines of the American College of Physicians (ACP), in three RCTs inwhich patients were administered 60 mg/day of duloxetine over the short period of 12 ～ 13 weeks, there was a mild improvement in pain, and only in one
RCT was there a large number of patients whose pain was reduced by 50%. In
three RCTs, there was an improvement in functional disorders but in one RCT
the quality of life (QOL) did not improve. It is reported that duloxetine increases the possibility of nausea as a side effect. However, in reports on pharmacotherapy for low back pain, in many of the reports the period of observation
was short and the effects of treatment ranged from moderate to low. Therefore, further investigation is required.
There are some RCTs on osteoarthritis of the knee and osteoarthritis of thehip7‒9), and in some systematic reviews10‒11) and it was strongly recommended.
According to the analysis of two RCTs on osteoarthritis of the hip in which patients were administered 60～120 mg/day of duloxetine over thirteen weeks10),

NNT：number needed totreat（the number of patients whoneed to be treated for one ofthem to benefit comparedwith a control）
NNH：number needed toharm（the number of patients whoneed to be exposed to a risk
factor to cause harm to one
patient）

the NNT was seven patients, when the study was set to have a therapeutic effect of reducing pain by 30% or more or by 50% or more as well as an improvement in physical function. The adverse events were nausea, fatigue andconstipation and the NNH was 16, 17, and 18, respectively.
Neuropathic pain
According to systematic reviews, the NNT is 6.4 when SNRIs are used,which mainly includes duloxetine, and therefore it is considered a first‒line
drug for treating neuropathic pain.12)
There are also some RCTs indicating the analgesic effects of duloxetine forpain and numbness due to diabetic neuropathy13‒18), and chemotherapy‒induced
peripheral neuropathy (CIPN) from cancer19). Furthermore, it has also shown tohave analgesic effects on peripheral neuropathy accompanying multiple sclero-

Ⅱ．Pharmacotherapy

209

sis (MS)20) and central post‒stroke pain (CPSP)21), but they are case‒series
study reports, so it needs to be evaluated in future.
Headache/Orofacial pain
There are only case studies on chronic pain (migraine, tension‒type headache)22‒23), so its efficacy is limited.
Fibromyalgia
There are some RCTs on duloxetine and fibromyalgia24‒27), and also somesystematic reviews28‒29), which have confirmed the effectiveness of the treatment and an improvement in QOL. When patients were administered 60～120
mg/day of duloxetine, the therapeutic effects on fibromyalgia were reported to
be a further improvement in psychological symptoms rather than analgesic effect28).
Precautions：
Dosage and directions for usage are shown in Table 2 Note 8.
In clinical tests conducted in our country, in order to inhibit the onset of side
effects in the early stages of administration, treatment should begin at 20 mg/
day, and 1 ～ 2 weeks later, the dosage should be increased to the ideal dose
(maintenance dose) of up to 40～60 mg/day. By administering a dosage of 40～
60 mg / day, the patient will receive analgesic effects in the first week after
commencing a course of duloxetine11). According to systematic reviews in the
Cochrane Database，within the twelve weeks of the observation period, thedegree of pain improved by 50% or more in patients administered with 40 mg,
60 mg and 120 mg of duloxetine, compared with the placebo. However, there
was no recognizable correlation between the level of dosage and the level of
improvement. Furthermore, physical function items evaluated on the SF‒36
significantly improved as well, compared with the placebo. The frequency ofside effects was not significant compared with the placebo (duloxetine：12.6%,
placebo：5.8%) but 12.6％ of the patients had discontinued oral administrationof the drug due to side effects27). The adverse events, which stopped the oral
administration of duloxetine were nausea, dipsia, diarrhea, headache, drowsiness, dizziness and insomnia. Infrequent symptoms also included attemptedsuicide, severe liver damage, metrorrhagia, a rise in blood pressure and difficulty urinating8).
References
1）Vlandimir S, et al : Duloxetine placebo in patients with chronic low backpain : A 12‒week, fixed‒dose, randomized, double‒blind trial. J Pain
2010 ; 11 : 1282‒1290
2）Shinichi K, et al : Randomized, double‒blind, placebo‒controlled phase Ⅲ
trial of duloxetine mantherapy in Japanese patients with chronic low

Note 8：refer to p.188

210

Ⅱ．Pharmacotherapy

back pain. Spine 2016 ; 41 : 1709‒17173）Regina PS, et al : Efficacy of duloxetine in chronic low back pain with aneuropathic component. Anesthesiology 2016 ; 124 : 150‒1584）Roger C, et al : Systemic pharmacological therapies for low back pain : A
systematic review for an American College of Physicians clinical practice guideline. Ann Intern Med 2017 ; 166 : 480‒4925）Urquhart DM, et al : Antidepressants for non‒specific low back pain. Cochrane Database Syst Rev 2008 ; CD001703
6）Owen DW, et al : Low back pain : Questioning the validity of meta‒analyses. Pain Practice 2013 ; 14 : E33‒E417）Wang G, et al : Efficacy and safety of duloxetine in Chinese patients withchronic pain due to osteoarthritis : A randomized, double‒blind, placebo‒
controlled study. Osteoarthritis Cartilage 2017 ; 25 : 832‒8388）Abou‒Raya S, et al : Duloxetine for the management of pain in older
adults with knee osteoarthritis : Randomised placebo‒controlled trial.
Age Ageing 2012 ; 41 : 646‒652
9）Chappell AS, et al : A double‒blind, randomized, placebo‒controlled
study of the efficacy and safety of duloxetine for the treatment of chronic pain due to osteoarthritis of the knee. Pain Pract 2011 ; 11 : 33‒4110）Citrome L, et al : A systematic review of duloxetine for osteoarthritic
pain : What is the number needed to treat, number needed to harm, andlikelihood to be helped or harmed? Postgrad Med 2012 ; 124 : 83‒9311）Wang ZY, et al : Efficacy and Safety of duloxetine on osteoarthritis knee
pain : A meta‒analysis of randomized controlled trials. Pain Med
2015 ; 16 : 1373‒1385
12）Finnerup NB, et al : Pharmacotherapy for neuropathic pain in adults : A
systematic review and meta‒analysis. Lancet Neurol 2015 ; 14 : 162‒17313）Wernicke JF, et al : A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology 2006 ; 67 : 1411‒1420
14）Raskin J, et al : A double‒blind, randomized multicenter trial comparing
duloxetine with placebo in the management to diabetic peripheral neuropathic pain. Pain Med 2005 ; 6 : 346‒35615）Wernicke JF, et al : An open‒label 52‒week clinical extension comparing
duloxetine with placebo in the management of diabetic peripheral neuropathic pain. Pain Med 2007 ; 8 : 503‒51316）Yasuda H, et al : Superiority of duloxetine to placebo in imaproving diabetic neuropahic pain : Results of randomized controlled trial in Japan. J
Diabetes Investig 2001 ; 2 : 132‒13917）Raskin J, et al : Duloxetine versus routine care in the long‒term management of diabetic peripheral neuropathic pain. J Pallial Med 2006 ; 9 : 29‒4018）Gao Y, et al : Duloxetine versus placebo in the treatment of patients withdiabetic neuropathic pain in China. Chin Med J 2010 ; 123 : 3184‒3192
19）Smith EML, et al : Effect of duloxetine on pain, function and quality oflife among patients with chemotherapy‒induced painful peripheral neuropathy. JAMA 2013 ; 309 : 1359‒1367
20）Vollmer TL, et al : A randomized, double‒blind, placebo‒controlled trialof duloxetine for the treatment of pain in patients with multiple sclerosis. Pain Pract 2014 ; 14 : 732‒74421）Brown TR, et al : A randomized placebo‒controlled trial of duloxetine forcentral pain in multiple sclerosis. Int J MS Care 2015 ; 17 : 83‒8922）Volpe FM : An 8‒week, open‒label trial of duloxetine for comorbid major

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211

depressive disorder and chronic headache. J Clin Psychiatry 2008 ; 69 :1449‒1454
23）Young WB, et al : Duloxetine prophylaxis for episodic migraine in persons without depression : A prospective study. Headache 2013 ; 53 : 1430‒
143724）Taylor AP, et al : Efficacy of duloxetine as a migraine preventive medication : Possible predictors of response in a retrospective chart review.
Headache 2007 ; 47 : 1200‒1203
25）Chappell AS, et al : A six‒month double‒blind, placebo‒controlled, randomized clinical trial of duloxetine for the treatment of fibromyalgia. Int
J Gen Med 2008 ; 1 : 91‒10226）Murakami M, et al : A randomized, double‒blind, placebo‒controlled
phase Ⅲ trial of duloxetine in Japanese fibromyalgia patients. Arthritis
Res Ther 2015 ; 17 : 22427）Murakami M, et al : An open‒label, long‒term, phase Ⅲ extention trial of
duloxetine Japanese patients with fibromyalgia. Mod Rheumatol
2016 ; 27 : 688‒69528）Lunn MP, et al : Duloxetine for treating painful neuropathy, chronic painor fibromyalgia. Cochrane Database Syst Rev 2014 ; 1 : CD007115
29）Hauser W, et al : Serotonin and noradrenaline reuptake inhibitors（SNRIs）
for fibromyalgia syndrome. Cochrane Database Syst Rev, 2013 ; CD010292
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

Cochrane Library, PubMed
2005～2017
duloxetine, low back pain, osteoarthritis, neuropathic pain, postherpetic neuralgia, diabetic neuropathy, trigeminal neuralgia, orofacial pain, migraine, chronic headache, fibromyalgia
Out of these words, we mainly searched for systematic review,
RCT, and selected references by considering their details and by
trying to avoid any overlap. As for those words with few search
results, we selected references prior to 2004 which were considered important. (Reference 16).

CQ14：Is amitriptyline effective in managing chronic pain?
Answer：In musculoskeletal pain, amitriptyline is not effective with chronic
pain but it can be effective on upper extremity pain. It is effective and is themost effective drug for neuropathic pain．With chronic headaches, it also acts
to prevent tension-type headache (TTH) and migraine. Amitriptyline is also effective in helping to treat idiopathic odontalgia (atypical odontalgia) and burning mouth syndrome (BMS). It has analgesic effects on fibromyalgia.
Summary of recommendation grades and overall evidence：
Musculoskeletal pain：2B (Use is weakly recommended)
Neuropathic pain：1A (Use is strongly recommended)
Headache/Orofacial pain：2A(Use is weakly recommended)(tension‒type headache (TTH) and migraine)

Fibromyalgia：2B (Use is weakly recommended)

BMS：burning mouth
syndrome

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Ⅱ．Pharmacotherapy

Commentary：
Amitriptyline has significant analgesic effects on chronic pain, comparedwith the placebo. It has been revealed that the analgesic properties of amitriptyline act through a different mechanism from that of antidepressants. Amitriptyline can also be used in lower dosages than the dosage indicated for antidepressants to act and it has also been revealed that it shows analgesic effects
within a short period of time. The main analgesic‒acting mechanism is the activation of the descending pain inhibitory system (DPIS) via the action of seroNMDA：N-methyl-D- aspartic acidtonin‒noradrenaline reuptake inhibitors, and NMDA receptor antagonists andNa＋ channel blockers are also involved1).
Musculoskeletal pain
In a systematic review of musculoskeletal pain2), the American College ofPhysicians (ACP)3) said that amitriptyline has little analgesic effect on chronic
low back pain. In a review in 2017, it claimed that it does have analgesic effects
on musculoskeletal diseases including low back pain and upper extremity

RCT：randomized controlled
trial

pain4). There has been one RCT each on low back pain and upper extremity
pain and as there are few cases on upper extremity pain, there is limited evidence.
Neuropathic pain
Amitriptyline is effective in providing analgesic effect on neuropathic pain,
regardless of the variety of diseases and pathologies such as postherpetic neuralgia5‒6), post‒traumatic nerve injury pain 7), pain and numbness due to diabetic neuropathy 8‒9), and central poststroke pain 10). In a systematic review pub-

NNT：number needed totreat（the number of patients whoneed to be treated for one ofthem to benefit comparedwith a control）

lished in 2005, the number needed to treat (NNT) neuropathic pain with amitriptyline was the lowest at 3.6 11). In the ‘Guidelines for the Pharmacologic
Management of Neuropathic Pain, Revised 2nd Edition’ by the Japan Society ofPain Clinicians12), they claimed it is effective, as it is one of the most effective
drugs for neuropathic pain. However, in a systematic review, amitriptyline wassaid to have limited efficacy on neuropathic pain even though amitriptyline has
been used for many years clinically to treat neuropathic pain. Therefore, one
needs to give it some consideration when judging its efficacy13).
Headache/Orofacial pain
In order for amitriptyline to have a preventative effects on tension‒type
headache (TTH), it is recommended that a patient should orally take 10～100
mg before sleeping, and in order to reduce the onset of side effects, one should
start by orally taking 10～25 mg. One needs to consider any improvement insymptoms and the patient’s whole physical condition before increasing the dosage14). Amitriptyline decreases the frequency of migraines, compared with aplacebo but there is a high possibility that the patient will have to stop taking
it orally due to adverse events15). In addition, according to systematic reviews

Ⅱ．Pharmacotherapy

213

on its effects on idiopathic odontalgia (atypical odontalgia) and burning mouth
syndrome (BMS)16‒18), both amitriptyline and nortriptyline, another tricyclic antidepressant, are effective. However, the number of observations and diagnostic criteria differ greatly between reports, so future study is necessary.
Fibromyalgia
According to a systematic review on fibromyalgia, amitriptyline is effective
if the patient takes 25 mg/day over a short‒term period (less than 6～8 weeks)
but its efficacy at high dosages (50 mg/day) or over a long period of time exceeding 8 weeks is unknown19).
Precautions：
Dosage and directions for usage are shown in Table 2 Note 9.
The adverse events of amitriptyline are mainly anitcholinergic problems
such as dipsia and constipation．In elderly patients, there have been reports ofincreased cases of patients falling over with doses of 75 mg or more and increased cases of sudden cardiac death with doses of 300 mg or more．Amitriptyline should be started at low doses and used cautiously20,21).
References
1）Dick IE, et al : Sodium channel blockade may contribute to the analgesic
efficacy of antidepressants. J Pain 2007 ; 8 : 3152）Urquhart DM, et al : Antidepressants for non‒specific low back pain. Cochrane Database Syst Rev 2008 ; CD001703
3）Roger C, et al : Systemic pharmacological therapies for low back pain : A
systematic review for an American College of Physicians clinical practice guideline. Ann Intern Med 2017 ; 166 : 480‒4924）Driest JJ, et al : Amitriptyline for musculoskeletal complaints : A systematic review. Fam Pract 2017 ; 34 : 138‒1465）Graff‒Rand SB, et al : Amitriptyline and fluphenazine in the treatment of
postherpetic neuralgia. Clin J Pain 2000 ; 16 : 188‒192
6）Max MB, et al : Amitriptyline, but not lorazepam, relieves postherpetic
neuralgia. Neurology 1988 ; 38 : 1427‒1432
7）Rintala DH, et al : Comparison of the effectiveness of amitriptyline andgabapentin on chronic neuropathic neuropathic pain inpersons with spinal cord injury. Arch Phys Med Rehabil 2007 ; 88 : 1547‒1560
8）Vrethen M, et al : A comparison amitriptyline and maprotiline in thetreatment of painful polyneuropathy in diabetic and nondiabetics. Clin J
Pain 1997 ; 13 : 313‒323
9）Max MB, et al : Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology 2003 ; 37 : 589‒59610）Leijion G, et al : Central post‒stroke pain : A controlled trial of amitriptyline and carbamazepine. Pain 1989 ; 36 : 27‒3611）Finnerup NB, et al : Pharmacotherapy for neuropathic pain in adults : A
systematic review and meta‒analysis. Lancet Neurol 2015 ; 14 : 162‒17312）Japan Society for Pain Clinicians. The Committee for the Guidelines for
the Pharmacologic Management of Neuropathic Pain of JSPC（eds.）:

Note 9：refer to p.188

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Ⅱ．Pharmacotherapy

Guidelines for the Pharmacologic Management of Neuropathic Pain, Revised 2nd Edition. Shinko Trading Co. Ltd., 2016 ; 184‒18513）Moore RA, et al : Amitriptyline for neuropathic pain in adults. Cochrane
Database Syst Rev 2015 ; CD008242
14）Eulalia TC, et al : Use of amitriptyline for the treatment of chronic tension type headache : Review of the literature. Med Oral Patol Oral Cir
Bucal 2008 ; 13 : E567‒E572
15）Xiao‒min X, et al : Tricyclic antidepressants for preventing migraine inadult. Medicine（Baltimore）2017 ; 96 : e6989
16）Melis M, et al : Atypical odontalgia : A review of the literature. Headache
2003 ; 43 : 1060‒1074
17）Lino PA, et al : Use of antidepressants in dentistry : A systematic review.
Oral Dis. Epub 2017 ; Aug 24, doi : 10. 1111/odi. 12747
18）Liu YF, et al : Burning mouth syndrome : A systematic review of treatments. Oral Dis. Epub 2017 ; Mar 1, doi : 10. 1111/odi. 12660
19）Nishishinya B, et al : Amitriptyline in the treatment of fibromyalgia : A
systematic review of its efficacy. Rheumatology 2008 ; 47 : 1741‒174620）Finnerup NB, et al : Pharmacotherapy for neuripathic pain in adults : A
systematic review and meta‒analysis. Lancet Neurol 2015 ; 14 : 162‒17321）Ray WA, et al : Cyclic antidepressants and the risk of sudden cardiac
death. Clin Pharmacol Ther 2004 ; 75 : 234‒241
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

Cochrane Library, PubMed
2005～2017
amitriptyline, low back pain, osteoarthritis, neuropathic pain, postherpetic neuralgia, diabetic neuropathy, trigeminal neuralgia,
orofacial pain, migraine, chronic headache, fibromyalgia
Out of these words, we mainly searched for systematic review,
RCT, and selected references by considering their contents andby trying to avoid any overlap. As for those words with few
search results, we selected references prior to 2004 which wereconsidered important (References 5, 6, 8, 9, 10).

CQ15：Are other types of antidepressants effective in managing chronic
pain?
Answer：Apart from amitriptyline and duloxetine, there have been few high‒
RCT：randomized controlled
trial

quality RCTs on antidepressants, and their recommendation grades are low.
They can be used as an option for patients in which standard treatment was
not effective.
Summary of recommendation grades and overall evidence：
Musculoskeletal pain：2C (Use is weakly recommended)
Neuropathic pain：2C (Use is weakly recommended)
Headache/Orofacial pain：2C (Non‒use is weakly recommended)
Fibromyalgia：2B (Use is weakly recommended)
Commentary：
Musculoskeletal pain
In chronic pain, there are few RCTs on tricyclic antidepressants (imipramine,

Ⅱ．Pharmacotherapy

215

nortriptyline, clomipramine), tetracyclic antidepressants (maprotiline)，selective
serotonin reuptake inhibitors (SSRI) (paroxetine) and drugs such as trazodone.
Even if such reports exists, the scope of research is small and the level of evi-

SSRI：selective serotonin
reuptake inhibitor

dence is low1‒2). They report that apart from duloxetine, other antidepressantswere ineffective1). Furthermore, according to the guidelines of the American
College of Physicians (ACP)3), there have been few RCTs on escitalopram andonly one clinical research study in which no difference in analgesic effect wasreported between it and duloxetine, also a serotonin-noradrenaline reuptake
inhibitor (SNRI), meaning there is little evidence.
Neuropathic Pain
RCTs have indicated that the tricyclic antidepressants imipramine4), clomip5‒6)

ramine7‒8)

and nortriptyline

have an analgesic effect but both the number of

eligible patients and the period of observation were short so there is little on
the evidence level. How the tricyclic antidepressants are used differently is clomipramine is the only one of the tricyclic antidepressants which is administered intravenously and is used in cases where something fast‒acting is expected or oral administration is ineffective 6). On the other hand, nortriptyline
is the main metabolite of amitriptyline and has fewer adverse events than amitriptyline. There have been RCTs on its analgesic effects but with few eligible
patients and over a short period of observation so there is little on the evidence level. Nortriptyline is not used as a first‒line drug with neuropathic pain
but can be used in cases where the other tricyclic antidepressants are ineffective8).
In RCTs, venlafaxine has been described as having analgesic effects on neuropathic pain but there is little high‒quality research and according to the systematic reviews in the Cochrane Database9) it is poorly evaluated. In Japan,
there have been few instances of prescribing it for neuropathic pain so it is difficult to evaluate its efficacy.
With paroxetine which is an SSRI10), escitalopram11) and milnacipran which isan SNRI12), there have been RCTs on each that they are effective on neuropathic pain but the number of eligible patients used was small and therefore
the level of evidence is low.
Headache/Orofacial Pain
According to systematic reviews related to its preventive action on migraine13), SSRIs (sertraline) and SNRIs (venlaflaxine) do not act to prevent migraine．Even in systematic reviews on tension‒type headache (TTH)14), there
was no difference in strength or frequency of onset of TTH with SSRIs (citalopram, sertraline, paroxetine, fluvoxamine) and SNRIs (venlaflaxine), in comparison with the placebo.
With chronic pain, both SSRIs and SNRIs were ineffective in the prevention

SNRI：serotonin-noradrenaline re-uptake inhibitor
ACP：The American Collegeof Physicians

216

Ⅱ．Pharmacotherapyof migraine and TTH.
Fibromyalgia
The efficacy of mirtazapine15), and milnacipran which is an SNRI16) on fibromyalgia have been indicated but SSRIs (citalopram, paroxetine) have provenineffective17).
Precautions：
Dosages, precautions when using and adverse events for each drug areNote 10：refer to p.188

shown in Table 2 Note 10.
Caution is advised when administering large dosages of SSRIs or a multidrug regimen of SSRIs, or the concomitant use of tramadol drugs which run
the risk of causing serotonin syndrome.
References
1）Owen DW, et al : Low back pain : Questioning the validity of meta‒analyses. Pain Practice 2013 ; 14 : E33‒E412）Urquhart DM, et al : Antidepressants for non‒specific low back pain. Cochrane Database Syst Rev 2008 ; CD001703
3）Roger C, et al : Systemic pharmacological therapies for low back pain : A
systematic review for an American College of Physicians clinical practice guideline. Ann Intern Med 2017 ; 166 : 480‒4924）Hearn L, et al : Imipramine for neuropathic pain in adults. Cochran Databases Syst Rev 2014 ; CD010769
5）Sindrup SH, et al : Clomipramine vs desipramine vs placebo in treatment
of diabetic neuropathy symptoms : A double‒blind cross‒over study. Br
J Clin Pharmacol 1990 ; 30 : 683‒691
6）Fallon BA, et al : Intravenous clomipramine for obsessive‒compulsive
disorder refractory to oral clomipramine : A placebo‒controlled study.
Arch Gen Psychiatry 1998 ; 55 : 918‒9247）Khoromi S, et al : Nortriptyline and their combination vs. placebo in patients with chronic lumbar root pain. Pain 2007 ; 130 : 66‒758）Derry S, et al : Nortriptyline for neuropathic pain in adults. Cochrane
Databases Syst Rev 2015 ; CD011209
9）Gallagher HC, et al : Venlafaxine for neuropathic pain in adults. Cochrane
Database Syst Rev 2015 ; CD011091
10）Sindrop SH, et al : The selective serotonin reuptake inhibitor, paroxetine
is effective in the treatment of diabetic neuropathy symptom. Pain
1990 ; 42 : 135‒14411）Otto M, et al : Escitalopram in painful polyneuropathy : A randomized,
placebo‒controlled, cross‒over trial. Pain 2008 ; 139 : 275‒28312）Derry S, et al : Milnacipran fpr neuropathic pain in sdults. Cochrane Database Syst Rev 2015 ; CD011789
13）Benzi R, et al : Selective serotonin reuptake inhibitors（SSRIs）and serotonin‒norepinephrine reuptake inhibitors（SNRIs）for the prevention of
migraine in adults. Cochrone Database Syst Rev 2015 ; CD002919
14）Benzi R, et al : Selective serotonin reuptake inhibitors（SSRIs）and serotonin‒norepinephrine reuptake inhibitors（SNRIs）for the prevention of

Ⅱ．Pharmacotherapy

217

tension‒type headache in adults. Cochrane Database Syst Rev 2015 ;CD011681
15）Miki K, et al : Efficacy of mirtazapine for the treatment of fibromyalgia
without concomitant depressin : A randomized, double‒blind, placebo‒
contralled phase Ⅱ a study in Japan. Pain 2016 ; 157 : 2089‒2096
16）Hauser W, et al : Serotonin and noradrenaline reuptake inhibitors（SNRIs）for fibromyalgia syndrome. Cochrane Database Syst Rev 2013 ;CD010292
17）Walitt B, et al : Selective serotonin reuptake inhibitor for fibromyalgia
syndrome. Cochrane Database Syst Rev 2015 ; CD011735
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

Cochrane Library, PubMed2005‒2017
antidepressants, low back pain, osteoarthritis, neuropathic pain,
postherpetic neuralgia, diabetic neuropathy, trigeminal neuralgia,
orofacial pain, migraine, chronic headache, fibromyalgia
Out of the words searched, we focused mostly on systematic review, RCT and chose references in consideration of their contents
and to avoid any overlap. Regarding those with few search results, we adopted those references prior to 2004 which were considered important (References 5, 6, 10)

CQ16：Are NMDA receptor antagonists effective on chronic pain?
Answer：There have been few RCTs which indicate significantly higher analgesic effects of NMDA receptor antagonists (ketamine, dextromethorphan,memantine) on chronic pain compared to the placebo, and therefore the recommendation grade is low. Since NMDA receptor antagonists act on the central
nervous system and have psychotropic effects such as causing hallucinations,sufficient consideration is necessary for its use.
Summary of recommendation grades and overall evidence：
1) Ketamine
Musculoskeletal pain：2D (Use is weakly recommended)
Neuropathic pain：2C (Use is weakly recommended)
Headache/Orofacial pain：2D (Use is weakly recommended)
Fibromyalgia：1C (Non‒use is strongly recommended)
2) Dextromethorphan
Musculoskeletal pain：2D (Non‒use is weakly recommended)
Neuropathic pain：2C (Use is weakly recommended)
Headache/Orofacial pain：2D (Non‒use is weakly recommended)
Fibromyalgia：2D (Non‒use is weakly recommended)
3) Memantine
Musculoskeletal pain：2D (Non‒use is weakly recommended)
Neuropathic pain：2C (Non‒use is weakly recommended)
Headache/Orofacial pain：2C (Use is weakly recommended)
Fibromyalgia：2C (Use is weakly recommended)

NMDA：N-methyl-D-aspartic
acid
RCT：randomized controlled
trial

218

Ⅱ．Pharmacotherapy

Commentary：
Central sensitization of the spinal cord and brain play a major role in the intensification and protraction mechanism of chronic pain. As the activation of
NMDA receptors is considered to be involved in central sensitization, much attention has been given to NMDA receptor antagonists as an analgesic strategy
against chronic pain. However, contrary to this expectation, there have been
few clinical trials indicating its efficacy. Moreover，it has poor tolerability,
therefore its recommendation grade is low. There have been several RCTs examining the efficacy of NMDA receptor agonists on neuropathic pain, while
there have been few studies on musculoskeletal pain such as low back pain
and arthritis. As ketamine has not been manufactured as an oral formula, it isessential to be administered intravenously under medical supervision, andthere is also the heavy burden of hospitalization or visiting hospital as an outpatient. Furthermore, it carries the risk of illegal misuse or abuse, therefore
sufficient care is required to ensure that it is not used in these ways. The efficacy of memantine, which is indicated for Alzheimer’s disease, has been suggested in RCTs targeting migraine and fibromyalgia，but further clinical research needs to be made.
1) Ketamine
Ketamine is approved as a general anesthetic, and is only available throughintravenous or intramuscular administration. In 2007, ketamine was designatedas a narcotic under the ‘Narcotics and Psychotropics Control Law’. Comparedwith the dosage used for general anaesthesia, it displays analgesic effects atlower dosages when used for the purpose of alleviating pain. There are several
RCTs on various forms of chronic pain such as central pain, post‒spinal cord
injury pain, postherpatic neuralgia (PHN), migraine, complex regional pain synCRPS：complex regional
pain syndrome

drome (CRPS), fibromyalgia, and traumatic cervical syndrome1).
Although ketamine provides short‒term analgesic effects only while being
administered intravenously2,3), reports on its long‒term effects after discontinuation are limited．Some RCTs targeting CRPS and post‒spinal cord injury
pain showed that, when ketamine was administered continuously or intermittently (but daily) for 4～14 days, analgesic effects remained, even several weeks
after discontinuation4‒6). Based on these results，a single dose of ketamine cannot be expected to provide an analgesic effect longer than the period of its administration, while prolonged continuous or intermittent administration could
provide analgesic effects, for a moderate period of time, even after discontinuation. However, as it has a higher risk of affecting the central nervous system(psychotropic action), cardiovascular system (tachycardia, high blood pressure),
and causing hepatic disorder, it should be used as an alternative only in cases
where other analgesic treatments for chronic pain were ineffective.

Ⅱ．Pharmacotherapy

2192) Dextromethorphan
Dextromethorphan is approved as an antitussive drug. Out of the two RCT
studies which indicated the efficacy of dextromethorphan on painful diabetic
peripheral neuropathy7,8), one of the studies indicated the efficacy of dextromethorphan (with an average dosage of 381mg/day), although the sample size
was very small. In the other study, dextromethorphan (30～45 mg/day) administered concomitantly with quinidine (30 mg/day) displayed a significantly
higher analgesic effect, compared with the placebo. In a RCT study on postherpetic neuralgia (PHN), it was found to be ineffective.
3) Memantine
Memantine is approved as a drug to treat Alzheimer’s Disease. It has few
side‒effects such as psychotropic effect and the safety of long‒term administration of memantine has been established. The main adverse events are dizziness and nausea. Several RCTs targeting postherpetic neuralgia, painful diabetic peripheral neuropathy and phantom limb pain showed that the analgesic effect of memantine was not significant compared with the placebo9‒11). In RCTs
targeting fibromyalgia, memantine (20 mg/day) displayed significant analgesic
effects compared with the placebo, and also improved overall function, depression and quality of life (QOL)12). There are no RCTs on low back pain. In a RCT
on migraine, the number of migraines, the severity of the migraines and thenumber of days absent from work due to migraine significantly decreased in
the subjects who were administered with memantine (10 mg/day), comparedwith the placebo group13). In a RCT on tension‒type headache (TTH), memantine (40 mg/day) was found to be effective on female patients14).
Precautions：
Dosage and directions for usage for each drug, precautions for usage andside effects etc. are shown in Table 2 Note 11.
References
1）Niesters M, et al : Ketamine for chronic pain : Risks and benefits. Br J
Clin Pharmacol 2014 ; 77 : 357‒3672）Noppers I, et al : Absence of long‒term analgesic effect from a short‒term S‒ketamine infusion on fibromyalgia pain : A randomized, prospective, double blind, active placebo‒controlled trial. Eur J Pain 2011 ; 15 :942‒9493）Graven‒Nielsen T, et al : Ketamine reduces muscle pain, temporal summation, and referred pain in fibromyalgia patients. Pain 2000 ; 85 : 483‒491
4）Sigtermans MJ, et al : Ketamine produces effective and long‒term pain
relief in patients with complex regional pain syndrome Type 1. Pain
2009 ; 145 : 304‒311
5）Schwartzman RJ, et al : Outpatient intravenous ketamine for the treatment of complex regional pain syndrome : A double‒blind placebo con-Note 11：refer to p.188

220

Ⅱ．Pharmacotherapy

trolled study. Pain 2009 ; 147 : 107‒1156）Amr YM : Multi‒day low dose ketamine infusion as adjuvant to oral gabapentin in spinal cord injury related chronic pain : A prospective, randomized, double blind trial. Pain Physician 2010 ; 13 : 245‒2497）Nelson KA, et al : High‒dose oral dextromethorphan versus placebo in
painful diabetic neuropathy and postherpetic neuralgia. Neurology
1997 ; 48 : 1212‒12188）Shaibani AI, et al : Efficacy and safety of dextromethorphan/quinidine at
two dosage levels for diabetic neuropathic pain : A double‒blind, placebo‒
controlled, multicenter study. Pain Med 2012 ; 13 : 243‒254
9）Sang CN, et al : Dextromethorphan and memantine in painful diabetic
neuropathy and postherpetic neuralgia : Efficacy and dose‒response trials. Anesthesiology 2002 ; 96 : 1053‒1061
10）Nikolajsen L, et al : Memantine（a N‒methyl‒D-aspartate receptor antagonist）in the treatment of neuropathic pain after amputation or surgery : A randomized, double‒blinded, cross‒over study. Anesth Analg
2000 ; 91 : 960‒96611）Maier C, et al : Efficacy of the NMDA‒receptor antagonist memantine inpatients with chronic phantom limb pain : Results of a randomized double‒blinded, placebo‒controlled trial. Pain 2003 ; 103 : 277‒28312）Olivan‒Blázquez B, et al : Efficacy of memantine in the treatment of fibromyalgia : A double‒blind, randomised, controlled trial with 6‒monthfollow‒up. Pain 2014 ; 155 : 2517‒2525
13）Noruzzadeh R, et al : Memantine for prophylactic treatment of migraine
without aura : A randomized double‒blind placebo‒controlled study.
Headache 2016 ; 56 : 95‒10314）Lindelof K, et al : Memantine for prophylaxis of chronic tension‒type
headache : A double‒blind, randomized, crossover clinical trial. Cephalalgia 2009 ; 29 : 314‒321
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

Cochrane Library, PubMed2005‒2017
NMDA antagonist, low back pain, osteoarthritis, neuropathic pain,
postherpetic neuralgia, diabetic neuropathy, trigeminal neuralgia,
orofacial pain, migraine, chronic headache, fibromyalgia
Out of the words searched, we searched mainly for systematic
review, RCT and selected the references by considering theircontents and to avoid any overlapping. As for those with few
search results, we adopted references prior to 2004 which wereconsidered important (References 3, 7, 9, 10, 11)

CQ17：Are antianxiety agents (benzodiazepine type drugs) effective inmanaging chronic pain?
RCT：randomized controlled
trial

Answer： There are few high‒quality RCTs on the efficacy of antianxiety
agents (benzodiazepines) on chronic pain diseases (musculoskeletal pain, neuropathic pain, headache/orofacial orofacial pain, fibromyalgia), therefore the recommendation grade is low. The use of benzodiazepine is considered as an adjunctive option for chronic pain patients who are resistant to other medication.

Ⅱ．Pharmacotherapy

221

Summary of recommendation grades and overall evidence：
Musculoskeletal Pain：2C (Use is weakly recommended) (etizolam)
Neuropathic Pain：2C (Use is strongly recommended) (clonazepam)
Headache/Orofacial Pain：2B (Use is weakly recommended)(TTH：etizolam, alprazolam
Orofacial pain：diazepam, clonazepam)

Fibromyalgia：2C (Use is weakly recommended)
Commentary：Among drugs that can be classified as antianxiety agents, we will only explain the efficacy of benzodiazepine. It is assumed that the analgesic effect ofbenzodiazepine is mainly in mediating the activation of GABAA receptors. It is
often used to alleviate insomnia which accompanies chronic pain, to reduce
psychological stress, and to relax muscles. There are reports that concomitant
use of NSAIDs with benzodiazepine could provide higher analgesic effect thansingle use of NSAIDs. However, they are addictive, therefore there is much debate over their long‒term usage. In addition, using benzodiazepine concomitantly with opioid analgesics heightens the risk of dependence so this should
be avoided.
Musculoskeletal Pain
As benzodiazepines are effective as a muscle relaxant, they are used for low
back pain and stiff shoulders. There have been reports1,2) suggesting that etizolam, which was a benzodiazepine developed in Japan, might be effective on
cervical spondylosis and low back pain but there are no high‒quality RCTs. In
systematic reviews on pain associated with rheumatoid arthritis, there exist
several RCTs comparing benzodiazepine with a placebo, benzodiazepine with
NSAIDs, as well as the concomitant use of benzodiazepine/NSAIDs with
NSAIDs but in each case, benzodiazepine was not shown to be effective3).
Neuropathic Pain
In a RCT related to the analgesic effects of amitriptyline, lorazepam and aplacebo on postherpetic neuralgia (PHN)，there was a lower percentage of patients who felt significant analgesic effects in the lorazepam group (0.5～6 mg/day) than in the amitriptyline group (12.5～150 mg/day) but it was about thesame as the placebo group4). There have been reports suggesting an analgesic
effect of clonazepam, as an adjuvant therapy, on neuropathic pain due to cancer5). However, at the current stage, there are no RCTs on the efficacy of
clonazepam on neuropathic pain and therefore further clinical research is required6).
Headache/Orofacial pain
In a RCT study on tension‒type headache (TTH), in female subjects, the con-

GABA：γ (gamma)-aminobutyric acid reuptake
inhibitor

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Ⅱ．Pharmacotherapy

comitant use of etizolam and NSAIDs was more significantly effective in alleviating headache and its accompanying neck and shoulder pain than using
NSAIDs alone7). Similarly, in another RCT, alprazolam had a higher analgesic
effect on TTH compared with the placebo8). There are quite a few reports on
its efficacy on TTH but there is a need for even higher‒quality RCTs.
The results of the efficacy of benzodiazepine on orofacial pain vary fromstudy to study. In a RCT related to the efficacy of diazepam on chronic orofacial pain, diazepam administered in combination with ibuprofen and diazepam
administered alone had higher analgesic effects compared with administering
ibuprofen alone and the placebo9). In a RCT on stomatalgia, the oral local administration of clonazepam (1 mg) displayed significantly higher analgesic effects compared with the placebo．In this study, the patient does not swallow
the pill but it is placed for several minutes in the vicinity of the site of pain in
the mouth, after which the subject spits out the pill10). In another RCT on
BMS：burning mouth
syndrome

burning mouth syndrome (BMS), clonazepam (0.5 mg/day) displayed significantly
higher analgesic effect than the placebo11). In an RCT related to the efficacy ofdiazepam on temporomandibular joint syndrome, it did not have significantly
higher analgesic effects compared with the placebo12). Similarly, clonazepam
didn’t have significantly higher analgesic effects on temporomandibular joint
syndrome compared with the placebo13).
Fibromyalgia
In a RCT related to the analgesic effects of alprazolam on fibromyalgia, Ibuprofen used in combination with alprazolam displayed significantly higher analgesic effects compared with the placebo but this was not the case when alprazolam alone was administered14). In a different RCT, tenoxicam (discontinued inJapan) used in combination with bromazepam showed a recognizable significant improvement in overall symptoms, compared with when tenoxicam alone
was used15). However, in this research study, tenoxicam used in combination
with bromazepam and tenoxicam used alone showed no recognizable significant effect in improving the symptoms, when compared with the placebo.
Precautions：
Dosage, possible adverse events and precautions for usage are shown in

Note 12：refer to p.189

Table 2 Note 12.
References
1）Tsuji Y, et al : 腰痛性疾患を中心とした慢性疼痛性疾患に対するデパス®
の臨床的検討．新薬と臨床．Journal of New Remedies and Clinics, 1989 ;
38 : 80‒862）Okada T, et al : 脊椎疾患に対する Nifran®, Depas®併用効果の検討．新薬と臨床．Journal of New Remedies and Clinics, 1988 ; 37 : 122‒128

Ⅱ．Pharmacotherapy3）Richards BL, et al : Muscle relaxants for pain management in rheumatoid arthritis. Cochrane Database Syst Rev, 2012 ; CD008922
4）Max MB, et al : Amitriptyline, but not lorazepam, relieves postherpetic
neuralgia. Neurology 1988 ; 38 : 1427‒1432
5）Hugel H, et al : Clonazepam as an adjuvant analgesic in patients withcancer‒related neuropathic pain. J Pain Symptom Manage 2003 ; 26 :1073‒1074
6）Corrigan R, et al : Clonazepam for neuropathic pain and fibromyalgia in
adults. Cochrane Database Syst Rev, 2012 ; 16 : CD009486
7）Hirata K, et al : Multi‒center randomized control trial of etizolam plus
NSAID combination for tension‒type headache. Intern Med 2007 ; 46 :467‒4728）Shukla R, et al : Alprazolam in chronic tension type headache. J Assoc
Physicians India 1996 ; 44 : 641‒6449）Singer E, et al : A controlled evaluation of ibuprofen and diazepam forchronic orofacial muscle pain. J Orofac Pain 1997 ; 11 : 139‒14610）Gremeau‒Richard C, et al : Topical clonazepam in stomatodynia : A randomised placebo‒controlled study. Pain 2004 ; 108 : 51‒5711）Heckmann SM, et al : A double‒blind study on clonazepam in patientswith burning mouth syndrome. Laryngoscope 2012 ; 122 : 813‒81612）Pramod GV, et al : Analgesic efficacy of diazepam and placebo in patients with temporomandibular disorders : A double blind randomized
clinical trial. Indian J Dent Res 2011 ; 22 : 404‒40913）Herman CR, et al : The effectiveness of adding pharmacologic treatment
with clonazepam or cyclobenzaprine to patient education and self‒care
for the treatment of jaw pain upon awakening : A randomized clinical
trial. J Orofac Pain 2002 ; 16 : 64‒7014）Russell IJ, et al : Treatment of primary fibrositis/fibromyalgia syndrome
with ibuprofen and alprazolam : A double‒blind, placebo‒controlled
study. Arthritis Rheum 1991 ; 34 : 552‒56015）Quijada‒Carrera J, et al : Comparison of tenoxicam and bromazepan in
the treatment of fibromyalgia : A randomized, double‒blind, placebo‒controlled trial. Pain 1996 ; 65 : 221‒225
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

Cochrane Library, PubMed2005‒2017
benzodiazepine, low back pain, osteoarthritis, neuropathic pain,
postherpetic neuralgia, diabetic neuropathy, trigeminal neuralgia,
orofacial pain, migraine, chronic headache, fibromyalgia
Out of these words searched, we searched mainly for systematic
review, RCT and chose the references by considering their contents and to avoid any overlapping. For those which returned
few search results, we selected the references prior to 2004
which were considered important 2004 (References 4, 5, 8-10, 1315). Furthermore, with etizolam which was developed in ourcountry, On Ichushi Web (by the Japan Medical Abstracts Society) we searched for ‘etizolam’ and ‘chronic pain’ and selected
those references, which were considered important. (References 1, 2)

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CQ18：Is tramadol effective in managing chronic pain?
Note 13：Tramadol isclassified as opioid analgesics[weak]

Answer：TramadolNote 13 is recognized as having analgesic effects on musculoskeletal pain, and effective in improving motor function. It has also been confirmed to have analgesic effects on neuropathic pain, such as painful diabetic
neuropathy and postherpetic neuralgia (PHN) as well as effective in improving

QOL：quality of life

QOL. Furthermore, it is also possible that it might be useful on pain caused by
fibromyalgia. Its effect on headache/orofacial pain has not been confirmed.
However, the efficacy and safety of its long‒term administration remains unclear and therefore this should be avoided.
Summary of recommendation grades and overall evidence：
Musculoskeletal pain：1B (Use is strongly recommended)
Neuropathic pain：1B (Use is strongly recommended)
Headache/Orofacial pain：No clear evidence for recommendation
Fibromyalgia：2C (Use is weakly recommended)
Commentary：
Musculoskeletal pain
According to a systematic review of fifteen RCTs which considered the efficacy of opioid analgesics on chronic pain1), tramadol (150 ～ 300 mg / day) was
significantly superior in its analgesic effects and its effectiveness in improving
motor function than the placebo. Furthermore, tramadol (200 mg/day) and celecoxib (400 mg/day) displayed the same degree of analgesic effect. Tramadol
had the same analgesic effect and was as effective as a motility stimulant as
antidepressants. Furthermore, tramadol‒acetaminophen oral tablets (T/A tablets) have been indicated as effective on chronic low back pain, and significantly improved pain and QOL, compared with the placebo2). In another RCT, nu-

NRS：numerical rating scale
SDS：Self-Rating Depression
Scalemerical rating scale (NRS) and Self‒Rating Depression Scale (SDS) significantly
improved in patients with chronic low back pain and comorbid depression
when taking T/A tablets, compared with NSAIDs3).
In three RCT studies related to osteoarthritis4,5,6), on patients with knee osteoarthritis or hip osteoarthritis suffering from moderate pain or worse, theyreported that 8～12 weeks administration of sustained‒release tramadol
brought about a significant improvement in analgesic effects, physical function
and sleep, compared with the placebo. Furthermore, according to a systematic
review which summarized eleven RCTs of the administration of tramadol (including T/A tablets) on osteoarthritis7), tramadol (average dosage of 201.4 mg/day) significantly improved analgesic effects and motor function, comparedwith the placebo. However, as the patient drop‒out rate due to adverse eventswas 12.5%, and as the average period of observation for the RCTs was 35 days,

Ⅱ．Pharmacotherapy

225

three months at the most, the results only showed that it is effective over ashort period of time.
Neuropathic Pain
As for neuropathic pain, tramadol significantly improved the pain from painful diabetic neuropathy8), postherpetic neuralgia (PHN)9), and post‒spinal cord
injury10), compared with the placebo. According to a systematic review summarizing six RCTs (including cancer pain) which verified the efficacy of tramadol on neuropathic pain11), tramadol had a number needed to treat (NNT) of 4.4
and high analgesic effects compared with the placebo. However, overall, due tofactors such as a small sample population and diverse types of pain, it was concluded that the evidence of tramadol’s efficacy on neuropathic pain was low,
both in terms of quality and quantity.
Headache/Orofacial Pain
As for research into the efficacy of tramadol on headache and orofacial pain,
RCT studies on acute pain and postsurgical pain exist but there are some occasional case reports on chronic pain. No high‒quality RCTs exist.
Fibromyalgia
In a RCT investigating the efficacy of tramadol on fibromyalgia12), the degreeof pain and the number of points of tenderness significantly decreased in thegroup administered orally with a T/A tablet, compared with the placebogroup. However, while the drop‒out rate due to adverse events was 2% in theplacebo group, it was as high as 19% in the T/A tablet group. According to asystematic review announced in 2016 however13), while it recognizes the efficacy of tramadol to some degree, it is not for its effect as an opioid analgesic but
infers that it is effective as an SNRI. There is no clinical research evidence
supporting the efficacy and safety of opioid analgesics on fibromyalgia.
We are far from having a sufficient understanding of the causes and pathology of fibromyalgia and currently many also suffer from psychiatric disorders
concomitantly. Administering opioid analgesics in such patients, runs the highrisk of causing psychological dependence. Therefore, under our guidelines, if
one is considering the administration of opioid analgesics, we only propose theuse of tramadol, which has a low risk of patients forming a dependence on it,
while simultaneously consulting a pain specialist, and limiting administration toa short period of time.
Out of the opioid analgesics, tramadol is highly safe and there have beenvery few incidences of psychological dependence14). However, in many of the
RCTs, the period of observation was short (three months or less) and they described a patient drop‒out rate of around 10～20% due to adverse events suchas nausea and vomiting. In a placebo‒controlled open‒label trial, testing thecontinual administration of sustained‒release tramadol over one year on 1,052

NNT：number needed totreat（the number of patients whoneed to be treated for one ofthem to benefit comparedwith a control）

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Ⅱ．Pharmacotherapy

patients with chronic non-cancer pain, 795 patients (approximately 76%)dropped out due to reasons such as adverse events15). Due to this and otherreasons, the efficacy and safety of tramadol over the long‒term have not been
established and it is best to be discontinued after a relatively short period oftime16). Therefore, long-term administration should be conducted only while
consulting a pain specialist.
Precautions：
Currently in Japan, tramadol formulas, which can be administrated forchronic pain are orally disintegrating tablets (ODT) (25 mg, 50 mg), sustained-release tablets over a 24-hour period (100 mg) as well as tramadol (37.5mg)/acetaminophen (325 mg) tablets.
As mentioned in the drug information, administration of tramadol should begin with 100～150 mg per day but considering the patient’s age and build, thedosage should start small and then be gradually increased. In the same way aswith other opioid analgesics, when a course of tramadol is begun, adverse
events such as nausea, vomiting, drowsiness and constipation become severe
so appropriate treatments need to be taken in accordance with the symptoms
at the time. The clinical effective limit of tramadol is 300 mg/day and even if
the dosage is increased beyond this, an improvement in analgesic effect cannot
be expected.
Tramadol is metabolized into M1 by CYP2D6, a drug‒metabolizing enzymeof the liver, and M1 exhibits the main analgesic effect. Activity of the CYP2D
enzyme varies from person to person and the analgesic effect of tramadol isweaker in people where the enzyme has low activity. Therefore, when the expected analgesic effect is not obtained even after gradually increasing the dosage, we should consider changing to another drug on the assumption that thisis possibly due to low-enzyme activity. When switching over to an opioid analgesic, such as morphine, one should begin with a smaller dosage rather than anequivalent reduced dosage.
Furthermore, tramadol acts as a monoamine reuptake inhibitor and as it canalso act like an SNRI at the same time, it activates the descending pain inhibitory system and displays analgesic effects and is effective on neuropathic pain.
However, when administrated in combination with drugs which act to increase
serotonin, such as duloxetine, one needs to be careful that it does not lead tothe onset of serotonin syndrome.
If tramadol is reduced or discontinued suddenly, there is a risk that it may
cause withdrawal or serotonin syndrome, so it is best to gradually reduce thedosage to 1/4～1/2 of a daily dosage, administered every 2‒3 days.
Note 14：refer to p.189

Dosage and directions for usage are shown in Table 2 Note 14.

Ⅱ．Pharmacotherapy

References
1）Chaparro LE, et al : Opioids compared with placebo or other treatments
for chronic low back pain : An update of the Cochrane Review. Spine（Phila Pa 1976）2014 ; 39 : 556‒5632）Lee JH, et al : Ultracet ER Study Group : A randomized, double‒blind,placebo‒controlled, parallel‒group study to evaluate the efficacy andsafety of the extended‒release tramadol hydrochloride/acetaminophen
fixed‒dose combination tablet for the treatment of chronic low backpain. Clin Ther 2013 ; 35 : 1830‒1840
3）Tetsunaga T, et al : Efficacy of tramadol‒acetaminophen tablets in low
back pain patients with depression. J Orthop Sci 2015 ; 20 : 281‒2864）Thorne C, et al : A randomized, double‒blind, crossover comparison of
the efficacy and safety of oral controlled‒release tramadol and placeboin patients with painful osteoarthritis. Pain Res Manag 2008 ; 13 : 93‒1025）Gana TJ, et al : 023 Study Group : Extended‒release tramadol in thetreatment of osteoarthritis : A multicenter, randomized, double‒blind,placebo‒controlled clinical trial. Curr Med Res Opin 2006 ; 22 : 1391‒1401
6）DeLemos BP, et al : Tramadol hydrochloride extended‒release once‒daily in the treatment of osteoarthritis of the knee and/or hip : a double‒
blind, randomized, dose‒ranging trial. Am J Ther 2011 ; 18 : 216‒226
7）Cepeda MS, et al : Tramadol for osteoarthritis. Cochrane Database Syst
Rev 2006 ; 3 : CD005522
8）Harati Y, et al : Double‒blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology 1998 ; 50 : 1842‒1846
9）Boureau F, et al : Tramadol in post‒herpetic neuralgia : A randomized,
double‒blind, placebo‒controlled trial. Pain 2003 ; 104 : 323‒33110）Norrbrink C, et al : Tramadol in neuropathic pain after spinal cord injury : A randomized, double‒blind, placebo‒controlled trial. Clin J Pain
2009 ; 25 : 177‒18411）Duehmke RM, et al : Tramadol for neuropathic pain in adults. Cochrane
Database Syst Rev 2017 ; 6 : CD003726
12）Bennett RM, et al : Tramadol and acetaminophen combination tablets inthe treatment of fibromyalgia pain : A double‒blind, randomized, placebo‒
controlled study. Am J Med 2003 ; 114 : 537‒54513）Goldenberg DL, et al : Opioid use in fibromyalgia : A cautionary tale.
Mayo Clin Proc 2016 ; 91 : 640‒64814）Cicero TJ, et al : Rates of abuse of tramadol remain unchanged with theintroduction of new branded and generic products : Results of an abusemonitoring system, 1994‒2004. Pharmacoepidemiol Drug Saf 2005 ; 14 :851‒859
15）Pascual ML, et al : Open‒label study of the safety and effectiveness oflong‒term therapy with extended‒release tramadol in the managementof chronic nonmalignant pain. Curr Med Res Opin 2007 ; 23 : 2531‒2542
16）NICE Clinical Guideline 2013 : Neuropathic pain : The pharmacologicalmanagement of neuropathic pain in adults in non‒specialist settings.
2013

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Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

Cochrane Library, PubMed2005‒2017tramadol, low back pain, osteoarthritis, neuropathic pain, postherpetic neuralgia, diabetic neuropathy, trigeminal neuralgia, orofacial pain, migraine, chronic headache, fibromyalgia
Out of these words searched, we mainly searched for systematic
review, RCT, and selected references by considering their contents and by avoiding any overlap. As for those words with few
search results, we used references prior to 2004 which were considered important. (References 8, 9, 12, 14)

CQ19：Are buprenorphine patches effective in managing chronic pain?
Note 15：Buprenorphine isclassified as opioid analgesics[moderate]culoskeletal pain and are expected to bring about an improvement in quality of

QOL：quality of life

life (QOL). As for neuropathic pain, it has the possibility of being effective on

Answer： Buprenorphine Note 15 patches have a high analgesic effect on mus-conditions such as painful diabetic neuropathy. Furthermore, its effect on headache/orofacial pain and fibromyalgia has not been confirmed. Another point isthat at the current stage, buprenorphine patches are only eligible for coverage
under the Japanese health insurance system for chronic low back pain and osteoarthritis.
Even in senior patients, it has few severe adverse events such as respiratory
depression, has high tolerability and its efficacy and safety if administered overa long period of time has also been confirmed but it is relatively likely for patients to suffer from nausea and vomiting.
Summary of recommendation grades and overall evidence：
Musculoskeletal pain：1B (Use is strongly recommended)
Neuropathic pain：2C (Use is weakly recommended)
Headache/Orofacial pain：No clear evidence for recommendation
Fibromyalgia：1D (Non‒use is strongly recommended)
Commentary：
Musculoskeletal pain
There are many RCTs, which indicate the effectiveness of buprenorphine
patches on musculoskeletal pain and the level of evidence is also high.
RCT：randomized controlled
trial

In six RCTs on chronic low back pain1‒6) there was a significant improvement in analgesic effect, motor function, sleep and QOL in the group whichused buprenorphine patch (5～40 μg/hr), compared with the placebo group. The
period of observation was 4～12 weeks, and the drop‒out rate due to side‒effects was around 20%. In two of these RCTS，buprenorphine patch was continued up to six months after the end of the observation period, and an improvement in pain and motor function persisted3,4).

Ⅱ．Pharmacotherapy

There is one RCT on osteoarthritis and in the buprenorphine patch group (5～20 μg/hr), pain improved significantly at four weeks, compared with the placebo group7). In another RCT which compares one group administered with sustained-release tramadol (75～400 mg) and one group administered with buprenorphine patch (5～20 μg/hr), analgesic effects were recognized in both groups andthe percentage of subjects who terminated treatment due to adverse eventswas 29.2% in the sustained-release tramadol group, while it was low at 14.5%
in the buprenorphine patch group. The number of patients who wished to continue receiving treatment with the same agent was also higher in the buprenorphine patch group8).
With musculoskeletal pain, managing patients experiencing moderate orworse levels of pain due to the insufficient effects of non‒pharmacologic therapy or non‒opioid analgesic pharmacotherapy, one should prescribe this after
assessing certain factors such as the patient’s background.
Neuropathic Pain
Buprenorphine patch can be effective on neuropathic pain but there are almost no high‒quality RCTs and the level of evidence is low.
In a systematic review of the Cochrane Database，there have been reportson the effects of buprenorphine on neuropathic pain9), but in all eleven research studies which were candidates for inclusion, as the quality of the research was low, they were excluded from analysis and its efficacy was not discussed. In terms of a RCT which verifies the efficacy of buprenorphine patchon neuropathic pain, there exists only one on painful diabetic neuropathy andin this RCT, analgesic effect was significantly higher in the buprenorphine
patch group (5～40 μg/hr) than in the placebo group，and analgesic effect wasapproximately 30% above the baseline．However, approximately 40% of thepatients in the buprenorphine patch group dropped out of treatment due toadverse events such as nausea, vomiting and constipation, which is a low tolerability result10). Furthermore, in an open‒label trial on buprenorphine patch’s
effect on neuropathic pain, they reported a significant improvement in pain
due to sciatic neuralgia, protracted post‒surgical shoulder joint pain, and postherpetic neuralgia (PHN) eight weeks after the trial11).
Headache/Orofacial Pain
There are some sporadic cases of research investigating the efficacy of buprenorphine patch on headache and orofacial pain but no high-quality RCTs
exists.
Fibromyalgia
No RCT indicating the efficacy of buprenorphine patch on fibromyalgia exists. Furthermore, under the guidelines of various American societies and academies, the long‒term administration of opioid analgesics [strong] for fibromyal-

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gia is not recommended, as it is less effective than other forms of treatment in
improving QOL and analgesic effect. As a result of this and other factors, under our guidelines, just like with opioid analgesics [strong], we do not recommend using buprenorphine patch in cases of fibromyalgia.
There is little risk of respiratory depression with buprenorphine patch12),
and reports have not recognized a significant difference in efficacy or safety
when comparing patients 65 years or older with patients under 65 years ofage13), and so it is also safe to use with elderly patients. As for its long‒term
use, in long‒term open‒label trials conducted in Japan14,15) high‒frequency(10%+) adverse events included nausea, itchiness at the patch site, constipation,
vomiting and drowsiness but few adverse events were severe and therefore it
is considered to have a high level of safety.
Precautions：
Currently in Japan，buprenorphine patches are changed once a week and it
is a 5 mg, 10 mg, and 20 mg drug, releasing 0.12 mg, 0.24 mg, and 0.48 mg ofbuprenorphine per day, respectively. To secure its safety, only doctors who
have undergone an e‒learning course and have received permission are able toprescribe the drug. As mentioned on the drug information, it applies in casesof chronic pain associated with osteoarthritis and low back pain which are difficult to treat with non-opioid analgesics, and limited only to musculoskeletal
chronic pain. Dosages should start at 5 mg，and in cases where it provides insufficient analgesic effect, dosages can be increased by a minimum of 5 mg /week, up to a maximum of 20 mg/week. In cases where it becomes difficult tocontinue administration due to adverse events, either after commencing or after raising the dosage, administration should be terminated promptly or a lower dosage should be administered. When the analgesic effect obtained is insufficient, even after raising the dosage, one should consider changing to another
drug.
Clinically speaking, it is a full μ‒opioid receptor agonist, with no ceiling effect in its analgesic potential and it is not considered a problem if used in combination with other opioid analgesics. In addition, compared with other opioid
analgesics, it produces few severe adverse events such as respiratory depression and as it can be used even in patients with impaired renal function without reducing the dosage, it is also easy to use on elderly patients.
Note 16：refer to p.189

Dosage and directions for usage are shown in Table 2 Note 16.
Adverse events to be cautious of are nausea and vomiting and if necessary,antiemetics such as prochlorperazine and metoclopromide can be used in combination．In addition, caution is advised with the concomitant use of benzodiazepine type agents, muscle relaxants and alcohol as this may cause respirato-

Ⅱ．Pharmacotherapy

ry depression. Furthermore, as it is a patch, sometimes itchiness or rasharound the site where the patch is placed can become a problem.
Buprenorphine is metabolized by CYP3A4, a drug‒metabolizing enzyme of
the liver, so one should be careful of the drug having a stronger or weaker action, when used in combination with agents which cause drug interactions.
References
1）Steiner DJ, et al : Efficacy and safety of the seven‒day buprenorphinetransdermal system in opioid‒naïve patients with moderate to severe
chronic low back pain : An enriched, randomized, double‒blind, placebo‒
controlled study. J Pain Symptom Manage 2011 ; 42 : 903‒917
2）Yarlas A, et al : A randomized, placebo‒controlled study of the impact of
the 7‒day buprenorphine transdermal system on health‒related qualityof life in opioid‒naïve patients with moderate‒to‒severe chronic low
back pain. J Pain 2013 ; 14 : 14‒233）Gordon A, et al : Buprenorphine transdermal system for opioid therapy
in patients with chronic low back pain. Pain Res Manag 2010 ; 15 : 169‒1784）Gordon A, et al : Buprenorphine transdermal system in adults withchronic low back pain : A randomized, double‒blind, placebo‒controlled
crossover study, followed by an open‒label extension phase. Clin Ther
2010 ; 32 : 844‒860
5）Miller K, et al : The impact of buprenorphine transdermal delivery system on activities of daily living among patients with chronic low backpain : An application of the international classification of functioning, disability and health. Clin J Pain 2014 ; 30 : 1015‒1022
6）Yarlas A, et al : Buprenorphine transdermal system compared with placebo reduces interference in functioning for chronic low back pain. Postgrad Med 2015 ; 127 : 38‒457）Munera C, et al : A randomized, placebo‒controlled, double‒blinded, parallel‒group, 5‒week study of buprenorphine transdermal system inadults with osteoarthritis. J Opioid Manag 2010 ; 6 : 193‒2028）Karlsson M, et al : Efficacy and safety of low‒dose transdermal buprenorphine patches（5, 10, and 20 μg/h）versus prolonged‒release tramadol tablets（75, 100, 150, and 200 mg）in patients with chronic osteoarthritis pain : A 12‒week, randomized, open‒label, controlled, parallel‒
group noninferiority study. Clin Ther 2009 ; 31 : 503‒513
9）Wiffen PJ, et al : Buprenorphine for neuropathic pain in adults. Cochrane
Database Syst Rev 2015 ; 9 : CD011603
10）Simpson RW, et al : Transdermal buprenorphine relieves neuropathic
pain : A randomized, double‒blind, parallel‒group, placebo‒controlled trial in diabetic peripheral neuropathic pain. Diabetes Care 2016 ; 9 : 1493‒
1500
11）Rodriguez‒Lopez M : The opioid study Group of the Spanish Pain Society : Transdermal buprenorphine in the management of neuropathic
pain. Rev Soc Esp Dolor 2004 ; 11（Suppl Ⅴ）: 11‒2112）Dahan A, et al : Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humans and rats. Br J Anaesth 2005 ; 94 :825‒834
13）Mercadante S, et al : Safety and effectiveness of intravenous morphine

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Ⅱ．Pharmacotherapy

for episodic breakthrough pain in patients receiving transdermal buprenorphine. J Pain Symptom Manage 2006 ; 32 : 175‒17914）Ogawa S, et al : 変形性関節症患者に対するブプレノルフィン経皮吸収型
製剤における長期投与時の安全性と有効性．J New Rem Clin 2014 ; 63 :551‒56715）Kikuchi, S : 慢性腰痛患者に対するブプレノルフィン経皮吸収型製剤における長期投与時の安全性と有効性．J New Rem Clin 2014 ; 63 : 1420‒1435
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

Cochrane Library, PubMed2005‒2017buprenorphine, transdermal, low back pain, osteoarthritis, neuropathic pain, postherpetic neuralgia, diabetic neuropathy, trigeminal
neuralgia, orofacial pain, migraine, chronic headache, fibromyalgia
Out of these words searched, we searched mainly for systematic
review, RCT and selected references by considering their contents and to avoid any overlap. As for words with few search results, we selected references prior to 2004 which were considered
important (Reference 11). We also used 2 important references(References 14, 15) by searching ‘Buprenorphine, dermal’ on
Ichushi Web (Japan Medical Abstracts Society).

CQ20：Are opioid analgesics [strong] effective in managing chronic pain?
Answer：Opioid analgesics [strong] provide short‒term analgesic effect on
musculoskeletal pain and are effective in improving motor function but its long‒term effects and level of safety remain unclear. As for neuropathic pain, they
are effective over the short‒term on each type of patient condition but have a
low tolerability to adverse events and as psychological dependence is a concern if administered over the long term it is recommended that only those patients who have been specially selected by a pain specialist should be administered with opioid analgesics [strong]. Furthermore, there is no evidence indicating the efficacy and level of safety of opioid analgesics [strong] on headache/orofacial pain and fibromyalgia.
Summary of recommendation grades and overall evidence：
Musculoskeletal pain：2B (Use is weakly recommended)
Neuropathic pain：2B (Use is weakly recommended)
Headache/Orofacial pain：2D (Non‒use is weakly recommended)
Fibromyalgia：1D (Non‒use is strong recommended)
Commentary：
Note 17：morphine
formulations and fentanyl
formulations are classified as
opioid analgesics [strong]

At the current stage, the only opioid analgesics [strong] Note 17, which areavailable for chronic non‒cancer pain in Japan, are morphine formulations(morphine hydrochloride powder and morphine hydrochloride tablets) and fentanyl formulations (fentanyl 1‒day patch, 3‒day patch). We will now explain theefficacy of using morphine and fentanyl patches in managing chronic pain.

Ⅱ．Pharmacotherapy

233

Musculoskeletal pain
In ‘Noninvasive treatments for acute, subacute, and chronic low back pain: A
clinical practice guideline from the American College of Physicians’ released by
the American College of Physicians (ACP) in 20171), they first recommend non‒pharmacological therapy for chronic low back pain, such as therapeutic exer-

ACP：The American Collegeof Physicians

cise and rehabilitation, and if the effects proved to be insufficient, pharmacotherapy is recommended. In pharmacotherapy, nonsteroidal anti‒inflammatory
drugs (NSAIDs) are the first‒line drug, tramadol and duloxetine are second‒line drugs and opioid analgesics [strong] are third‒line drugs. In cases where

NSAIDs：nonsteroidal
anti-inflammatory drugs

the first‒line and second‒line drugs are ineffective, opioid analgesics [strong]
can be used after considering the patient’s condition and if the benefits outweigh the risks.
In RCTs regarding each individual opioid analgesic [strong] on chronic low
back pain, one showed that fentanyl patches were effective in providing anal-

RCT：randomized controlled
trial

gesic effect compared with the placebo2) and in another study3), researchers
showed that fentanyl patches had similar analgesic effects to morphine．In addition, according to a systematic review of fifteen RCTs verifying the efficacy
of opioid analgesics on chronic low back pain, opioid analgesics [strong] produced a stronger improvement in pain and motor function than the placebo.
However, considering that with many of the drugs, 20% of the patients or more
dropped out of treatment due to adverse events and the period of observation
was short at under fifteen weeks, its long-term efficacy remains unclear4).
Both morphine5) and fentanyl patches6) displayed significant analgesic effects
on osteoarthritis in placebo‒controlled studies. In a systematic review whichbroadly verified the efficacy of opioid analgesics on osteoarthritis7), the analgesic effects of opioid analgesics drop at the cut-off point of one month, and there
is no discernible interrelation between the dosage administered and analgesic
effects and its effect in improving motor function and there is little evidence of
its long‒term efficacy and levels of safety. In addition, as fentanyl patches aresuperior in terms of analgesic effect, there have also been reports that thesymptoms of osteoarthritis can progress in a short period of time so caution isadvised8).
Neuropathic Pain
There are many RCTs indicating the efficacy of opioid analgesics [strong] onneuropathic pain. They show that morphine is effective on postherpetic neuralgia (PHN)9,10), painful diabetic neuropathy10), post-traumatic peripheral neuropathic pain 11,12), and lumbar radiculopathy13), while fentanyl patches are effective on postherpetic neuralgia (PHN), CRPS and persistent postsurgical pain14).
However, in systematic reviews of these agents, their tolerability to adverse
events and their long‒term effects and level of safety remain unclear, so the

CRPS：complex regional
pain syndrome

234

Ⅱ．Pharmacotherapy

level of evidence is said to be low15,16,17).
There is a risk of dependence on, or abuse of opioid analgesics [strong], so
considering that that its long‒term effects and level of safety have not been
firmly established, as a first‒line drug for neuropathic pain, administration of
SNRI：serotonin/ noradrenaline reuptake inhibitors

drugs such as Ca2＋ channel α2δ ligands, serotonin/noradrenaline reuptake inhibitors (SNRI), tricyclic antidepressants and pregabalin should be prioritized18).
Headache/Orofacial Pain
There is no evidence from clinical research supporting the efficacy and levelof safety of opioid analgesics [strong] on headache and orofacial pain.
Fibromyalgia
Overseas, a large number of patients with fibromyalgia are currently prescribed with opioid analgesics [strong] but there are many cases in which prescription was terminated as a result of side effects, dependence or abuse. In
large‒scale studies, the administration of opioid analgesics [strong] over thelong term is shown to lead to poor outcomes19,20). There is no evidence fromclinical research supporting the efficacy and level of safety of opioid analgesics[strong] on fibromyalgia. Therefore, the use of opioid analgesics [strong] for fibromyalgia is not recommended.
Precautions：
The way of thinking when it comes to administering opioid analgesics tomanage chronic non‒cancer pain differs largely from when it involves cancer
pain (pain which is directly caused by cancer).
As The Japan Pain Society of Clinicians (JPSC) has outlined a detailed explanation of this in its ‘Guidelines for Prescribing Opioid Analgesics for ChronicNon‒cancer Pain, Second Edition’21), we would like to refer to it. In the guidelines listed above, some of the important points mentioned are：
① The purpose of treatment with opioid analgesics is to alleviate pain andimprove quality of life (QOL)② Opioid analgesic treatment shall be limited to only those patients who areat a low risk of things such as dependence and abuse③ Treatments of some kind should be considered for typical side‒effects of
opioid analgesics such as nausea, vomiting, constipation and drowsiness.
④ The dosage of opioid analgesics shall be kept to the bare minimum required amount, with no more than 60 mg/day of oral morphine hydrochloride at a reduced quantity and a limit of 90 mg/day.
⑤ The standard period of treatment for opioid analgesics [strong] is threemonths and at the maximum period of six months, one should consider

CDC: Centers for Disease
Control and Prevention

discontinuing administration of the drug or reducing its dosage.
In the ‘CDC Guideline for Prescribing Opioids for Chronic Pain’ released inⅡ．Pharmacotherapy

235

2016’ 22), weighing up the balance of risks and benefits as well as the suitabilityof the method of treatment should be reassessed at least every three months,
while patients are undergoing treatment with opioid analgesics. We also sharethe same basic way of thinking, which includes that the dosage upper limit fora reduced quantity of oral morphine hydrochloride should be 90 mg/day.
Dosage and directions for usage are shown in Table 2 Note 18.
References
1）Qaseem A, et al : Clinical Guidelines Committee of the American Collegeof Physicians : Noninvasive treatments for acute, subacute, and chronic
low back pain : A clinical practice guideline from the American Collegeof Physicians. Ann Intern Med 2017 ; 166 : 514‒5302）Arai T, et al : Two placebo‒controlled, randomized withdrawal studies toevaluate the fentanyl 1 day patch in opioid‒naïve patients with chronic
pain. Curr Med Res Opin 2015 ; 31 : 2207‒2218
3）Allan L, et al : Transdermal fentanyl versus sustained release oral morphine in strong‒opioid naïve patients with chronic low back pain. Spine（Phila Pa 1976）2005 ; 30 : 2484‒2490
4）Chaparro LE, et al : Opioids compared with placebo or other treatments
for chronic low back pain : an update of the Cochrane Review. Spine（Phila Pa 1976）2014 ; 39 : 556‒563
5）Caldwell JR, et al : Efficacy and safety of a once‒daily morphine formulation in chronic, moderate‒to‒severe osteoarthritis pain : Results from arandomized, placebo‒controlled, double‒blind trial and an open‒label extension trial. J Pain Symptom Manage 2002 ; 23 : 278‒2916）Langford R, et al : Transdermal fentanyl for improvement of pain andfunctioning in osteoarthritis : A randomized, placebo‒controlled trial. Arthritis Rheum 2006 ; 54 : 1829‒1837
7）da Costa BR, et al : Oral or transdermal opioids for osteoarthritis of theknee or hip. Cochrane Database Syst Rev 2014 ; 9 : CD003115
8）Fujii T, et al : Progressive change in joint degeneration in patients withknee or hip osteoarthritis treated with fentanyl in a randomized trial.
Yonsei Med J 2014 ; 55 : 1379‒13859）Raja SN, et al : Opioids versus antidepressants in postherpetic neuralgia :A randomized, placebo‒controlled trial. Neurology 2002 ; 59 : 1015‒1021
10）Gilron I, et al : Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med 2005 ; 352 : 1324‒1334
11）Wu CL, et al : Morphine versus mexiletine for treatment of postamputation pain : A randomized, placebo‒controlled, crossover trial. Anesthesiology 2008 ; 109 : 289‒29612）Huse E, et al : The effect of opioids on phantom limb pain and corticalreorganization. Pain 2001 ; 90 : 47‒5513）Khoromi S, et al : Morphine, nortriptyline and their combination vs. placebo in patients with chronic lumbar root pain. Pain 2007 ; 130 : 66‒7514）Arai T, et al : Two placebo‒controlled, randomized withdrawal studies toevaluate the fentanyl 1 day patch in opioid‒naïve patients with chronic
pain. Curr Med Res Opin 2015 ; 31 : 2207‒2218
15）Cooper TE, et al : Morphine for chronic neuropathic pain in adults. Cochrane Database Syst Rev 2017 ; 5 : CD011669

Note 18：refer to p.189

236

Ⅱ．Pharmacotherapy16）Derry S, et al : Fentanyl for neuropathic pain in adults. Cochrane Database Syst Rev 2016 ; 10 : CD011605
17）Gaskell H, et al : Oxycodone for neuropathic pain in adults. Cochrane Database Syst Rev 2016 ; 7 : CD010692
18）Japan Society of Pain Clinicians. The Committee for the Guidelines for
the Pharmacologic Treatment of Neuropathic Pain（Second edition）of
JSPC（eds.）: Guidelines for the pharmacologic management of neuropathic pain, second eidtion. Shinko Trading Company Ltd. Publication
Department of Medical Books, Tokyo, 201619）Goldenberg DL, et al : Opioid use in fibromyalgia : A cautionary tale.
Mayo Clin Proc 2016 ; 91 : 640‒64820）Ngian GS, et al : The use of opioids in fibromyalgia. Int J Rheum Dis
2011 ; 14 : 6‒1121）Japan Society of Pain Clinicians. The Committee for the Guidelines for
Prescribing Opioid Analgesics for Chronic Non‒cancer Pain of JSPC
（eds.）. Guidelines for prescribing opioid analgesics for chronic non‒cancer pain, second edition. Shinko Trading Co. Ltd., Tokyo, 201722）Dowell D, et al : CDC Guideline for Prescribing Opioids for Chronic Pain‒
United States, 2016. MMWR Recomm Rep 2016 ; 65 : 1‒49
Database
PeriodWords searchedby the combination
with ‘chronic pain’
＊

Notes

Cochrane Library, PubMed2005‒2017
opioids, morphine, fentanyl, transdermal, low back pain, osteoarthritis, neuropathic pain, postherpetic neuralgia, diabetic neuropathy, trigeminal neuralgia, orofacial pain, migraine, chronic headache, fibromyalgia
Out of these words searched, we mainly searched for systematic
review, RCT and selected references by considering their contents and to avoid any overlap. Regarding those which returned
few results, we used those references prior to 2004 which wereconsidered important (References 5, 9, 12). In addition, we referred to the guidelines published by the Japan Society of Pain
Clinicians, regarding the current usage of opioids for chronic non‒cancer pain in Japan (References, 18, 21)

CQ21：Is Kampo medicine effective in managing chronic pain?
Answer： At present there is little evidence regarding the effect and safetylevel of Kampo medicine in managing chronic pain, and therefore this issue remains unclear.
Summary of recommendation grades and overall evidence：
Musculoskeletal pain：2D (Use is weakly recommended)
Neuropathic pain：2D (Use is weakly recommended)
Headache/Orofacial pain：2C (Use is weakly recommended)
Fibromyalgia：2D (Use is weakly recommended)
Commentary：
Kampo medicine is a traditional form of medicine in Japan that originated in
China, and it is based on the accumulation of numerous experiences from long

Ⅱ．Pharmacotherapy

ago. It is a system of treatment based upon a unique theory, and Kampo medicine is what is used for this treatment. In principle, the use of Kampo medicines are based on eligible patient conditions according to the Kampo diagnosis, or what is called‘proof’. This is also described in the package inserts ofthese extract preparations for medical treatment as “important basic precautions”. Under the health care services covered by the health insurance system
of Japan, not only can doctors use high‒quality extract formulations for medical treatment, but it is also possible for them to use natural remedies in powder or pill form, as well as decoctions consisting of natural remedies.
The administration of Kampo medicines for chronic pain is widely seen indaily consultations, and there are quite a few reports on its efficacy. Some typical examples include goshajinkigan for chronic low back pain1), yokukansan forneuropathic pain2), shakuyakuzanzoto for algospasm of the leg3,4), kamishoyosan for glossalgia5), and keishikajutsubuto and bushi powder for postherpetic
neuralgia (PHN)6). However, up to the present there has been almost no high‒quality clinical research conducted on the efficacy of kampo formulas targetinga large number of cases of chronic pain, meaning that at the current stage weare unable to clearly demonstrate their effects or levels of safety.
There have only been a few reports on patients suffering from chronic headache for whom ‘goshuyuto’ was effective. In one such study, patients were randomly allocated into a ‘goshuyuto’ group and a placebo group, and it was reported that the number of days on which they suffered from a headache decreased in the ‘goshuyuto’ group7). The design of this study was slightly unusual, considering the ‘goshuyuto proof’, but it can be said that it showed the preventive effects of goshuyuto on chronic headache. Furthermore, there havebeen some forward‒looking randomized blind comparison tests, which positively investigated the therapeutic value of boiogito with shuchi‒bushi powder andloxoprofen sodium over a ten‒year period of osteoarthritis. While it wasclaimed that boiogito with shuchi‒bushi powder provided a better level of improvement in ADL (pain from passive exercise, spontaneous pain, oppressive
pain, ballottement of the patellae, soft‒tissue swelling, local heat, chronic painscores and health‒related QOL scores)8), many details still remain unclear, andtherefore further investigation is required. In addition, although reports haveindicated the analgesic effects of ‘tsumura’ powdered aconite root, the tests
were not blinded and were not conducted against control drugs, and therefore
serious evaluations are still necessary9).
Pseudoaldosteronism from glycyrrhizae radix, drug‒induced interstitial pneumonia and drug‒induced liver injury from scutellariae radix, excessive β stimulus action from ephedrae herba, aconitine poisoning from aconiti tuber, andmesenteric phlebosclerosis from gardeniae fructus are some of the known side‒

237

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Ⅱ．Pharmacotherapy

effects from Kampo medicine. When administering Kampo medicines, weshould also have an interest in the natural remedies from which they are
made. Furthermore, there are some combinations which raise the risk of causing adverse events, similar to when steroidal drugs, loop diuretics and glycyrrhizae radix are used in combination, so caution is advised concerning the interactions between drugs used in combination.
In addition, in recent years, there have been reports that the administrationof goshajinkigan aggravated chemotherapy‒induced peripheral neuropathy(CIPN)10), and therefore careful attention needs to be paid to the possibility that
Kampo medicine might worsen the targeted symptoms.
As the effects and safety levels of Kampo medicines on chronic pain have
not yet been established, it is important to judge their efficacy in each individual case in fine detail and continue this evaluation in terms of whether it hascaused adverse events or not. In addition, Kampo medicines should not be administered for a long time without a clear purpose in mind.
References
1）Hamaguchi T, Yoshino T, Horiba Y, et al : Goshajinkigan for low backpain : An observational study. J Altern Complement Med 2007 ; 23 : 208‒
213
2）Nakamura Y, Tajima K, Kawagoe I, et al : Efficacy of traditional herbal
medicine, Yokukansan on patients with neuropathic pain. Masui
2009 ; 58 : 1248‒12553）Hyodo T, Taira T, Takemura T, et al : Immediate effect of Shakuyaku‒
kanzo‒to on muscle cramp in hemodialysis patients. Nephron Clin Pract2006 ; 104 : c28‒c324）Takao Y, Takaoka Y, Sugano A, et al : Shakuyaku‒kanzo‒to（Shao‒Yao‒
Gan‒Cao‒Tang）as treatment of painful muscle cramps in patients withlumbar spinal stenosis and its minimum effective dose. Kobe J Med Sci
2016 ; 61 : E132‒E137
5）Shinno E, et al : The use of traditional Chinese medicine（Kampo medicines）for glossodynia. Pain and Kampo Medicine 2005 ; 15 : 77‒816）Nakanishi M, Arimitsu J, Kageyama M, et al : Efficacy of traditional Japanese herbal medicines‒Keishikajutsubuto（TJ‒18）and Bushi‒matsu（TJ‒3022）-against postherpetic neuralgia aggravated by self‒reported
cold stimulation : A case series. J Altern Complement Med 2012 ; 18 : 686‒
6927）Odaguchi H, Wakasugi A, Ito H, et al : The efficacy of goshuyuto, a typical Kampo（Japanese herbal medicine）formula, in preventing episodesof headache. Curr Med Res Opin 2006 ; 22 : 1587‒1597
8）Nishizawa Y, et al. : エビデンスに基づいた漢方医療 : 各種疾患に対しての処方（2）: 変形性膝関節症に対する防已黄耆湯加修治附子末の治療効果 :Evidence への試み Loxoprofen sodium との 10 年間前向き無作為比較試
験．Pharma Medica 2007 ; 25 : 15‒219）Fukuda Y : The study of the bushi‒matsu（Tsumura processed bushi
powder for ethical dispensing : TJ‒3023）on the safety and the dosage inⅡ．Pharmacotherapy

patients treated with Kampo medicines. Pain and Kampo Medicine
2008 ; 18 : 25‒3010）Oki E, Emi Y, Kojima H, et al : Preventive effect of Goshajinkigan on peripheral neurotoxicity of FOLFOX therapy（GENIUS trial）: A placebo‒
controlled, double‒blind, randomized phase III study. Int J Clin Oncol
2015 ; 20 : 767‒775
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

Cochrane Library, PubMed, Ichushi Web
2005‒2017herbal medicine, traditional Japanese medicine, traditional Chinese medicine, kampo medicine (Cochrane Library, PubMed,)
Kampo medicine (Ichushi Web)Out of these words searched, we mainly searched for RCT andcase series, and in addition we conducted hand research for themost recent academic papers, and from research which used
Kampo extraction formulas which can be used under the scope ofwhat is covered by the health system in Japan, we selected references by considering the quality of the research details.

239

Chapter Ⅰ

Overview：CQ1～CQ7

Chapter Ⅱ

Pharmacotherapy：CQ8～CQ21

Chapter Ⅲ

Interventional Management：CQ22～CQ33

Chapter Ⅳ

Psychological Approach：CQ34～CQ39

Chapter Ⅴ

Rehabilitation：CQ40～CQ46

Chapter Ⅵ

Multidisciplinary Treatment：CQ47～CQ51

242

Ⅲ．Interventional Management

CQ22：Are interlaminar epidural injections effective in managing chronic
pain?
Answer：Interlaminar epidural injections are mainly useful for spinal diseases and in particular it is useful to administer steroids for radiculopathy due tolumbar or cervical disc herniation.
Summary of recommendation grades and overall evidence：
1) Lumbar spine disease
Steroid injection for radiculopathy due to lumbar disc herniation：1A (Execution is strongly recommended)

Interlaminar epidural injections and caudal epidural injections for lumbar
spinal canal stenosis, discogenic pain：1B (Execution is strongly recommended)
Caudal epidural injections for failed back surgery syndrome (FBSS)：2C(Execution is weakly recommended)

2) Cervical/thoracic spine disease
Steroid injection for radiculopathy due to cervical disc herniation：1A (Execution is strongly recommended)

Interlaminar epidural injections for cervical spinal canal stenosis, discogenic pain：1B (Execution is strongly recommended)
Interlaminar epidural injections for failed back surgery syndrome (FBSS)：
2C (Execution is weakly recommended)
3) Prevents the transition to postherpetic neuralgia (PHN) in patients withherpes zoster：2C (Execution is weakly recommended)
4) Execution using fluoroscopy, ultrasound guide：1C (Execution is strongly recommended)

Commentary：
Epidural injections are an interventional therapy frequently used to manage
pain. Here we will discuss interlaminar epidural injections and caudal epidural
injections, while transforaminal epidural injections will be described as a nerve
root block on the following CQ.
Furthermore, it is important to constantly judge the effects of treatment andnot administer these injections repetitively without a set intention.
1) Lumbar spine disease
RCT：randomized controlled
trial

In a systematic review of the seventeen randomized controlled trials (RCTs)
related to the efficacy of lumbar interlaminar epidural injections on lumbar diseases, and fourteen RCTs related to caudal epidural injections, there is evidence indicating efficacy1). However, the majority of these RCTs are not placebo‒controlled, and instead they compare the drugs patients were injected with(whether a steroidal drug had been added or not) and the method of approach.

Ⅲ．Interventional Management

243

Regarding lumbar spine diseases, there are two RCTs on the use of caudal
epidural injections for treating radiculopathy due to lumbar disc herniation andfive RCTs on interlaminar epidural injections have been described and in bothcases, they have strong evidence of its long‒term efficacy. There are high‒quality RCTs on both caudal epidural injections2) and epidural injectons3) for lumbar
spinal canal stenosis indicating their long‒term efficacy and there have also
been reports of the long‒term effects of caudal epidural injections4) and epidural injections5) on discogenic pain. Caudal epidural injections are also effective
on failed back surgery syndrome6). Differences in efficacy as a result of the different approaches used in caudal and interlaminar epidural injections have notbeen shown7).
There is much debate over which drug should be administered to the patient. There is strong evidence suggesting that the use of steroid with local anaesthetic for treating lumbar disc herniation is more effective than using local
anaesthetic alone8), but there was also a meta‒analysis indicating that there
was no advantage of administering steroid drugs to treat other diseases9). In
clinical settings, if the cause of pain is suspected to be inflammation around thenerve root/spine, steroid can be added to local anesthetic but we recommendthat it not be used without a set purpose.
2) Cervical/thoracic spine disease
Similarly, in cervical spine diseases, the efficacy of cervical interlaminar epidural injections were displayed in a systematic review of eight RCTs1), and inparticular, in a systematic review of five studies on radiculopathy as a result of
cervical disc herniation, there is evidence indicating its long‒term efficacy10).
Even though the evidence is weak, it has also been indicated that it can be usefulfor treating spinal canal stenosis, discogenic pain, and cervical post‒surgery
pain 11). There are few reports on thoracic diseases but it is believed to havethe same kind of efficacy12).
3) Prevents the transition to postherpetic neuralgia (PHN) in patients withherpes zoster
There have been indications of its efficacy as a treatment for clearly reducing the pain from herpes zoster. However, in terms of its effects for preventing
its transition to PHN, a form of chronic pain, while there is a RCT on the efficacy of a continuous epidural block13), there has also been a RCT that a single
dose of epidural steroid injections was not effective in its prevention14). Epidural injections have a limited effect on PHN.
There are no other reports with high-quality evidence on other forms ofchronic pain, and therefore its efficacy remains unknown.
4) Execution using fluoroscopy, ultrasound guide
In investigations using fluoroscopy, intravascular entry was detected in 0.5%

PHN：postherpetic neuralgia

244

Ⅲ．Interventional Managementof lumbar and 4.1% of cervical epidural injections, and dural puncture was observed in a total of 0.5% of the procedures15). It can have greater efficacy andsafety if confirmed on epidurogram, and although a lumbar one is not essential,
it should be done under fluoroscopy as much as possible. When performing
cervical interlaminar epidural injections, as there have been reports of fatal
complications with transforaminal epidural injections through the intravascular
injections of particulate steroid, it is essential to make a caudal puncture between the C6/7 laminae, and conduct a fluoroscopy in real time1). There havealso been reports of ultrasound-guided procedures. There is a RCT whichclaims that ultrasound-guided caudal epidural injections had approximately
the same efficacy as a block performed under fluoroscopy 2), and there is also a
RCT which states that by confirming the laminae to be punctured and theirdepth by conducting a scan before performing epidural injections, it had approximately the same efficacy as a block performed under fluoroscopy16).
There is no risk of radiation exposure and to raise safety and efficacy, we recommend that it be performed under the guidance of ultrasound rather thanprocedures based only on landmarks.
References
1）Kaye AD, et al : Efficacy of epidural injections in managing chronic spinal
pain : A best evidence synthesis. Pain Physician 2015 ; 18 : E939‒E1004
2）Park Y, et al : Ultrasound‒guided vs. fluoroscopy‒guided caudal epiduralsteroid injection for the treatment of unilateral lower lumbar radicular
pain : A prospective, randomized, single‒blind clinical study. Am J Phys
Med Rehabil 2013 ; 92 : 575‒5863）Manchikanti L, et al : A randomized, double‒blind controlled trial of lumbar interlaminar epidural injections in central spinal stenosis : 2‒year follow‒up. Pain Physician 2015 ; 18 : 79‒924）Manchikanti L, et al : Fluoroscopic caudal epidural injections in managing chronic axial low back pain without disc herniation, radiculitis, or
facet joint pain. J Pain Res 2012 ; 5 : 381‒3905）Manchikanti L, et al : A randomized, double‒blind, active‒controlled trialof fluoroscopic lumbar interlaminar epidural injections in chronic axial
or discogenic low back pain : Results of 2‒year follow‒up. Pain Physician2013 ; 16 : E491‒E504
6）Manchikanti L, et al : Fluoroscopic caudal epidural injections in managing post lumbar surgery syndrome : Two‒year results of a randomized,
double‒blind, active‒control trial. Int J Med Sci 2012 ; 9 : 582‒591
7）Ackerman WE 3rd, et al : The efficacy of lumbar epidural steroid injections in patients with lumbar disc herniations. Anesth Analg 2007 ; 104 :
1217‒1222
8）Manchikanti L, et al : The role of fluoroscopicinter laminar epidural injections in managing chronic pain of lumbar disc herniation or radiculitis : A randomized, double‒blind trial. Pain Pract 2013 ; 13 : 547‒558
9）Manchikanti L, et al : Epidural injections for lumbar radiculopathy andspinal stenosis : A comparative systematic review and meta‒analysis.

Ⅲ．Interventional Management

Pain Physician 2016 ; 19 : E365‒E410
10）Manchikanti L, et al : Cervical radicular pain : The role of interlaminarand transforaminal epidural injections. Curr Pain Headache Rep 2014 ;18 : 389
11）Manchikanti L, et al : Two‒year follow‒up results of fluoroscopic cervicalepidural injections in chronic axial or discogenic neck pain : A randomized, double‒blind, controlled trial. Int J Med Sci 2014 ; 11 : 309‒32012）Manchikanti L, et al : Thoracic interlaminar epidural injections in managing chronic thoracic pain : A randomized, double‒blind, controlled trial
with a 2‒year follow‒up. Pain Physician 2014 ; 17 : E327‒E338
13）Pasqualucci A, et al : Prevention of post‒herpetic neuralgia : Acyclovir
and prednisolone versus epidural local anesthetic and methylprednisolone. Acta Anaesthesiol Scand 2000 ; 44 : 910‒91814）van Wijck AJM, et al : The PINE study of epidural steroids and local anaesthetics to prevent postherpetic neuralgia : A randomized controlled
trial. Lancet 2006 ; 367 : 219‒22415）Manchikanti L, et al : A prospective evaluation of complications of 10,000
fluoroscopically directed epidural injections. Pain Physician 2012 ; 15 : 131‒14016）Evansa I, et al : Ultrasound versus fluoroscopic‒guided epidural steroid
injections in patients with degenerative spinal diseases : A randomised
study. Eur J Anaesthesiol 2015 ; 32 : 262‒268
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

PubMed, MEDLINE, Cochrane Library2010‒2017
epidural injection
We searched for ‘chornic pain’ and ‘epidural block’ on Ichushi. We
narrowed down our search by guidelines, RCT, maintenance andsystematic review, and focused on the most recent academic papers. References 13 and 14 were not from our search method but
have been added because of their importance.

CQ23：Are nerve root block/transforaminal epidural injections effective inmanaging chronic pain?
Answer：Nerve root blocks are mainly effective on lumbar diseases, and inparticular steroid injections are effective on radiculopathy due to disc herniation.
Summary of recommendation grades and overall evidence：
1) Nerve root block for the purpose of diagnosis：2B (Execution is weakly recommended)

2) Lumbar spine disease
Nerve root block using steroid on lumbar disc herniation：1A (Execution isstrongly recommended)

Nerve root block on lumbar spinal canal stenosis：1B (Execution is strongly
recommended)

3) Cervical spine disease：2C (Execution is weakly recommended)
4) Herpes zoster pain：2D (Execution is weakly recommended)

245

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Ⅲ．Interventional Management

Commentary：
In Japan, nerve root block is a technique of puncturing into the nerve sheathand some think that it is different from transforaminal epidural injections but
this concept is not consistently agreed upon. Under the scope of our search forthese guidelines, nerve root block is used in some papers as a diagnostic blockand in most of the research where treatment was the objective, they discussed
transforaminal epidural injections but as they have been unable to clearly distinguish between the two，we will treat them as the same technique.
1) Nerve root block for the purpose of diagnosis
In a systematic review1) of fifteen academic papers investigating the efficacy
of diagnostic nerve root block performed for the purpose of identifying the impaired nerve root, they found that it had limited effects. Considering its adverse events, we recommend it only under limited conditions such as high‒grade diagnosis prior to operation, in cases where disc herniation is present inseveral sites.
2) Lumbar spine diseases
In a systematic review2) of eighteen RCTs on transforaminal epidural injections, they indicated its efficacy on lumbar spine diseases. There is strong evidence indicating its long‒term efficacy on radiculopathy due to disc herniation,and there are some small-scale RCTs indicating the superiority of transforaminal epidural injections over caudal epidural injections and interlaminar epidural injections3,4). Long‒term effects have also been described for lumbar spinal
canal stenosis but there have been no high‒quality RCTs on discogenic pain in
the low back and failed back surgery syndrome (FBSS)．Regarding the agent
patients are injected with, administration of steroid for radiculopathy due tolumbar disc herniation is effective but there is some debate over whether the
addition of steroid for other patient conditions has a superior effect or not.
Careful consideration needs to be given to whether administration of steroid isapplicable or not, taking into account the adverse events.
3) Cervical spine diseases
Although rare, there have been reports of severe complications with cervicaltransforaminal epidural injections 5). The mechanism is apparently a brain
stem and spinal cord infarction mainly through the intravascular injection ofparticulate steroid. Other possibilities include vasospasm due to the punctureneedle. As a result, there have been few high‒quality RCTs in recent years．
In a review of cervical radiculopathy, in five papers its efficacy (analgesic effectand avoidance of surgery) was indicated but the evidence was limited and werecommend performing the interlaminar approach for which there is evenstronger evidence6). When performing cervical transforaminal epidural injections, particulate steroid is not used, and one needs to confirm the images of

Ⅲ．Interventional Management

the injected contrast media in real time on fluoroscopy.
In reports comparing the ultrasound guide method with the fluoroscopy
method for cervical radiculopathy, in one RCT they reported similar efficacy
up to twelve weeks later7) and although conducted retrospectively, there is areport8) that it had similar long‒term effects one year later.
It remains unclear whether attempts to increase the safety of fluoroscopy
conducted in real time, ultrasound guide and injection of nonparticulate steroid would reduce the risk of severe complications or not. On the one hand,
there are some severe complications due to the interlaminar approach such asaccidental dural puncture, spinal cord damage，and epidural hematoma/abscess and there is no evidence indicating that it is superior to the transforaminal approach which takes safety into consideration. As it is predicted thattransforaminal epidural injections will show specifically more analgesic effects
than interlaminar epidural injections, we need to continue to consider its usage
by examining cautiously its applicability when performing this technique.
4) Herpes zoster pain
There are no high‒quality RCTs related to herpes zoster pain but in termsof thoracolumbar, it is predicted to have similar or better effects to interlaminar epidural injections, and therefore is recommended to the same degree.
References
1）Datta S, et al : Diagnostic utility of selective nerve root blocks in the diagnosis of lumbosacral radicular pain : Systematic review and update ofcurrent evidence. Pain Physician 2013 ; 16 : SE145‒SE172
2）Kaye AD, et al : Efficacy of epidural injections in managing chronic spinal pain : A best evidence synthesis. Pain Physician 2015 ; 18 : E939‒
E1004
3）Ackerman WE 3rd, et al : The efficacy of lumbar epidural steroid injections in patients with lumbar disc herniations. Anesth Analg 2007 ; 104 :
1217‒1222
4）Lee JH, et al : Comparison of the effectiveness of interlaminar and bilateral transforaminal epidural steroid injections in treatment of patientswith lumbosacral disc herniation and spinal stenosis. Clin J Pain 2009 ;25 : 206‒2105）Manchikanti L, et al : Safeguards to prevent neurologic complications after epidural steroid injections : Analysis of evidence and lack of applicability of controversial policies. Pain Physician 2015 ; 18 : E129‒E138
6）Manchikanti L, et al : Cervical radicular pain : The role of interlaminarand transforaminal epidural injections. Curr Pain Headache Rep 2014 ;18 : 389
7）Jee H, et al : Ultrasound‒guided selective nerve root block versus fluoroscopy‒guided transforaminal block for the treatment of radicular painin the lower cervical spine : A randomized, blinded, controlled study.
Skeletal Radiol 2013 ; 42 : 69‒788）Yongbum P, et al : Treatment effects of ultrasound guide selective nerve

247

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Ⅲ．Interventional Management

root block for lower cervical radicular pain : A retrospective study of 1‒
year follow‒up. Ann Rehabil Med 2013 ; 37 : 658‒667
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

PubMed, MEDLINE, Cochrane Library
2005‒2017transforaminal epidural injection, nerve root block
We searched for ‘chronic pain’ and ‘root block’ on Ichushi. We
narrowed down our search by guidelines, RCT, meta‒analysis
and systematic reviews, and focused on the most recent academic papers. Reference 8 was not through our search method but
we added it due to its importance.

CQ24：Are medial branch block and facet (zygapophyseal) joint injection
effective in managing chronic pain?
Answer：Medial branch block is an essential procedure for diagnosing chronic neck pain, back pain and low back pain originating from the facet (zygapophyseal) joints. Furthermore, if performed under an accurate diagnosis, medial branch block has short-term and long-term effectiveness for treating
chronic neck pain, back pain and low back pain originating from the facet (zygapophyseal) joints. Facet (zygapophyseal) joint injection is widely performed
in order to diagnose and treat chronic neck pain, back pain and low back pain
originating from the facet (zygapophyseal) joints but evidence indicating its
utility is limited.
Summary of recommendation grade and overall evidence：
1) Medial branch block
Diagnosis of chronic neck pain, back pain, low back pain originating fromfacet (zygapophyseal) joints：1B (Execution is strongly recommended)
Treatment of chronic neck pain, back pain, low back pain originating fromfacet (zygapophyseal) joints：1B (Execution is strongly recommended)
2) Facet (zygapophyseal) joint injection
Diagnosis of chronic neck pain, back pain, low back pain originating fromfacet (zygapophyseal) joints：2D (Execution is weakly recommended)
Treatment of chronic neck pain, back pain, low back pain originating fromfacet (zygapophyseal) joints：2C (Execution is weakly recommended)
Commentary：1) Medial branch block
Previous guidelines1,2) describe that the prevalence of chronic facet pain is
36～67% in chronic neck pain, 34～48% in chronic back pain and 15～45% inchronic low back pain (often classified as non-specific low back pain). The
mechanism of pain originating from the facet (zygapophyseal) joints has not

Ⅲ．Interventional Management249

been completely clarified. Although there are various opinions about the diagnostic criteria, the diagnostic medial branch block to confirm pain relief is currently positioned as the gold standard procedure for the diagnosis of facet pain.
The facet (zygapophyseal) joints are innervated by medial branches of dorsal
rami. There are many studies which have investigated medial branch block forthe diagnosis of chronic pain originating from the facet joints. Guidelines basedon systematic review2), have recommended that facet pain be diagnosed withthe criterion standard of 75% or greater pain relief, and also recommended
confirming reproducibility of the efficacy of the diagnostic medial branch blockby performing it twice.
There were five non‒placebo‒controlled RCTs (1 cervical, 1 thoracic, 3 lumbar spine) which investigated the effectiveness of medial branch block fortreating chronic facet pain3‒7). The study on lumbar spine7), showed that repeated medial branch block with corticosteroid and local anesthetic has equivalent long-term effects in comparison with medial branch radiofrequency thermocoagulation which is supported by much evidence. Other studies also reported similar effects of medial branch block regardless of whether corticosteroids were used or not．There were some two-year follow-up studies on neckpain, thoracic pain and low back pain 3,4,6). The authors described that the patients in the studies experienced significant pain relief for two years, requiring
approximately five to six treatments with an average relief of 14 ～ 19 weeks
per episode of treatment. Furthermore, in these studies, diagnostic medial
branch block was performed strictly for adequate patient enrollment in thestudies. Therefore, we concluded that medial branch block, based on an accurate diagnosis, was an effective way to manage chronic neck pain, back pain
and low back pain originating from facet (zygapophyseal) joints, both over the
short-term and long-term.
2) Facet (zygapophyseal) joint injection
Facet (zygapophyseal) joint injection (intraarticular injection) has also been
performed as a diagnostic procedure for chronic pain originating from the facet
joints, but there are no high‒quality studies investigating its usefulness in the
diagnosis of facet pain.
There are seven non‒placebo‒controlled RCTs (2 cervical, 5 lumbar spine)
investigating the effectiveness of facet joint injection for treating chronic facet
pain8‒14). Studies on the cervical spine have shown conflicting results; in a study
where the procedure was found to be ineffective8), the only subjects investigated were whiplash-injury patients, while in a study in which the procedure was
effective9), there were some problems with how subjects were assigned into
treatment and control groups and with evaluation．Studies on lumbar spine
have also shown conflicting results. Results on the effectiveness of facet joint

RCT：randomized controlled
trial

250

Ⅲ．Interventional Management

injection were inconclusive because the injected agents or the subjects varied
from one study to the next. In a systematic review15) and a set of guidelines2),
authors evaluated that the evidence of facet joint injection for treating chronic
facet pain was limited for both cervical and lumbar spine. In general, facet joint
injection is often performed for acute pain or acute exacerbation of chronic
pain originating from facet joints. Therefore, we need further studies evaluating the effectiveness of facet (zygapophyseal) joint injection for acute exacerbation of chronic facet pain.
References
1）Tanabe Y : Medial branch block and facet（zygapophyseal injection）.
（The Team for the Guidelines for the Interventional Pain Treatment of
JSPC, eds.）: Guidelines for the Interventional Pain Treatment）. Shinko
Trading Co Ltd., 2014, 18‒212）Manchikanti L, et al : An update of comprehensive evidence‒based
guidelines for interventional techniques in chronic spinal pain. Part
II : guidance and recommendations. Pain Physician 2013 ; 16 : S49‒S283
3）Manchikanti L, et al : Comparative outcomes of a 2‒year follow‒up of
cervical medial branch blocks in management of chronic neck pain : A
randomized, double‒blind controlled trial. Pain Physician 2010 ; 13 : 437‒4504）Manchikanti L, et al : The role of thoracic medial branch blocks in managing chronic mid and upper back pain : A randomized, double‒blind, active control trial with a 2‒year follow‒up. Anesthesiol Res Pract 2012 ;2012 : 585806
5）Manchikanti L, et al : Effectiveness of lumbar facet joint nerve blocks inchronic low back pain : A randomized clinical trial. Pain Physician 2001 ;4 : 101‒1176）Manchikanti L, et al : Evaluation of lumbar facet joint nerve blocks inmanaging chronic low back pain : A randomized, double‒blind, controlled
trial with a 2‒year follow‒up. Int J Med Sci 2010 ; 7 : 124‒1357）Civelek E, et al : Comparison of effectiveness of facet joint injection andradiofrequency denervation in chronic low back pain. Turk Neurosurg
2012 ; 22 : 200‒2068）Barnsley L, et al : Lack of effect of intra‒articular corticosteroids forchronic pain in the cervical zygapophyseal joints. N Engl J Med 1994 ;
330 : 1047‒1050
9）Park SC, et al : Effect of adding cervical facet joint injections in a multimodal treatment program for long‒standing cervical myofascial pain
syndrome with referral pain patterns of cervical facet joint syndrome. J
Anesth 2012 ; 26 : 738‒74510）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
11）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
12）Yun DH, et al : Efficacy of ultrasonography‒guided injections in patientswith facet syndrome of the low lumbar spine. Ann Rehabil Med
2012 ; 36 : 66‒71

Ⅲ．Interventional Management

25113）Ribeiro LH, et al : Natour J. Effect of facet joint injection versus systemic
steroids in low back pain : A randomized controlled trial. Spine（Phila
Pa 1976）2013 ; 38 : 1995‒2002
14）Lakemeier S, et al : A comparison of intraarticular lumbar facet joint steroid injections and lumbar facet joint radiofrequency denervation in thetreatment of low back pain : A randomized, controlled, double‒blind trial.
Anesth Analg 2013 ; 117 : 228‒23515）Manchikanti L, et al : A systematic review and best evidence synthesisof the effectiveness of therapeutic facet joint interventions in managing
chronic spinal pain. Pain Physician 2015 ; 18 : E535‒E582
Database
PeriodWords searchedby the combination
with ‘chronic pain’

＊

Notes

PubMed, MEDLINE, Cochrane Library
2005‒2017
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
We searched for ‘chronic pain’ (‘facet joint injection’ or ‘medial
branch block’) on Ichushi. We narrowed it down by RCT, meta‒
analysis and systematic review and focused on the most recent
academic papers. We searched for References 1, 3-5, 8, 10-15 byhand search and as they are important they were added.

CQ25：Is stellate ganglion block effective in managing chronic pain?
Answer： Stellate ganglion block (SGB) is often used, in clinical settings, forthe purpose of alleviating pain for example in the head and neck area and upper extremities and there are many reports indicating its efficacy. However,there is no high‒quality evidence except with complex regional pain syndrome(CRPS).
Summary of recommendation grades and overall evidence：
1) CRPS in the upper extremities：2B (Execution is weakly recommended)
2) Preventing the transition to postherpetic neuralgia (PHN) in patients withherpes zoster：2C (Execution is weakly recommended)
3) Pain due to peripheral vascular disease in the upper extremities, sympathetically maintained pain (SMP) following cervical spine surgery,cluster headache, various pains in the head and neck area：2D(Execution is weakly recommended)

Commentary：
SGB is a type of nerve block widely used in other diseases apart from chronic pain such as in the head and neck area and in the upper extremities as wellas vascular disorders in the upper extremities and facial paralysis.

SGB：stellate ganglion block252

Ⅲ．Interventional Management

1) CRPS in the upper extremities
There are several reports indicating the efficacy of CRPS in the upper extremities. A placebo‒controlled double‒blind study on a small number of subjects1) indicated the utility of SGB. In a report targeting 22 patients with CRPS
type Ⅰ in the upper extremities2), a significant improvement in pain and range
ROM：range of movementof movement (ROM) of the wrist due to SGB was recognized and the improvement was more significant in the group with a shorter period of time (28weeks or less, average 17.0±6.3 weeks), between onset of pain until treatment by
SGB began, than in the group with a longer period of time (29 weeks or more, average 49.8±17.6 weeks). Furthermore, in cases where 16 weeks or more had passed
since onset or skin blood flow had decreased by over 22% in comparison withnormal subjects, there have been reports that SGB had low effects and there isa correlation between the effects of treatment and how early on treatment by
SGB begins. Furthermore, in a comparison of a case series claiming that continual SGB is effective on patients with CRPS4), a landmark method5) and amethod under fluoroscopy6), there have been reports of a case series indicating
the superiority of a method under ultrasound guidance, a case series indicating
the efficacy of radiofrequency thermocoagulation7) and reports on cases indicating
the effects of the pulsed radiofrequency method8). In a review announced in
20119), the effects of SGB on CRPS was evaluated as 2B＋(One or more RCTs,
while methodologically flawed, demonstrated effectiveness. Benefits closely balanced with risk and burdens : Positive recommendation). Furthermore, there
have also been several case reports indicating its efficacy on facial CRPS10‒12).
2) Preventing the transition to postherpetic neuralgia (PHN) in patients withherpes zoster
There are reports indicating the efficacy of SGB on postherpetic neuralgia

PHN：postherpetic neuralgia(PHN)13) and, negative reports14) as well. In a double‒blinded RCT on the possibility of preventing the transition from acute‒stage herpes zoster to postherpetic neuralgia15), they targeted 64 patients (50 years old or more) with acute‒stage herpes zoster and found that the frequency of transitions to PHN was
significantly lower.
3) Pain due to peripheral vascular disease in the upper extremities, sympathetically maintained pain (SMP) following cervical spine surgery, cluster
headache, various pains in the head and neck area
There have been reports elsewhere indicating its efficacy on pain due to peripheral vascular disease in the upper extremities16), sympathetically maintained pain (SMP) following cervical spine surgery17), There have also been reports indicating its efficacy on cluster headache18), and reports indicating the

RCT：randomized controlled
trial

efficacy of radiofrequency thermocoagulation19) on various types of pain, for example in the head and neck area but no high‒quality RCTs exist.

Ⅲ．Interventional Management

References
1）Price DD, et al : Analysis of peak magnitude and duration of analgesia
produced by local anesthetics injected into sympathetic ganglia of complex regional pain syndrome patients. Clin J Pain 1998 ; 14 : 216‒2262）Yucel I, et al : Complex regional pain syndrome type I : Efficacy of stellate ganglion blockade. J Orthop Traumatol 2009 ; 10 : 179‒1833）Ackerman WE, et al : Efficacy of stellate ganglion blockade for the management of type Ⅰ complex regional pain syndrome. South Med J 2006 ;99 : 1084‒10884）Toshniwal G, et al : Management of complex regional pain syndrome
type Ⅰ in upper extremity : Evaluation of continuous stellate ganglion
block and continuous infraclavicular brachial plexus block : A pilot
study. Pain Med 2012 ; 13 : 96‒1065）Imani F, et al : Effectiveness of stellate ganglion block under fuoroscopy
or ultrasound guidance in upper extremity CRPS. J Clin Diagn Res
2016 ; 10 : UC9‒126）Yoo SD, et al : Efficacy of ultrasonography guided stellate ganglion
blockade in the stroke patients with complex regional pain syndrome.
Ann Rehabil Med 2012 ; 36 : 633‒6397）Kastler B, et al : Stellate ganglion radiofrequency neurolysis under CT
guidance. Preliminary study. JBR‒BTR 2001 ; 84 : 191‒1948）Singh Rana SP, et al : Stellate ganglion pulsed radiofrequency ablation
for stretch induced complex regional pain syndrome type II. Saudi J Anaesth 2015 ; 9 : 470‒4739）van Eijs F, et al : Evidence‒based interventional pain medicine according
to clinical diagnoses : 16. Complex regional pain syndrome. Pain Pract2011 ; 11 : 70‒8710）Khoury R, et al : Facial causalgia : Report of case. J Oral Surg 1980 ; 38 :782‒78311）Jaeger B, et al : Reflex sympathetic dystrophy of the face : Report of twocases and a review of the literature. Arch Neurol 1986 ; 43 : 693‒69512）Arden RL, et al : Reflex sympathetic dystrophy of the face : Current
treatment recommendations. Laryngoscope 1998 ; 108 : 437‒44213）Milligan NS, et al : Treatment of postherpetic neuralgia. A review of 77
consecutive cases. Pain 1985 ; 23 : 381‒38614）Nurmikko T, et al : Pain and allodynia in postherpetic neuralgia : Role ofsomatic and sympathetic nervous system. Acta Neurol Scand 1991 ; 84 :146‒152
15）Makharita MY, et al : Effect of early stellate ganglion blockade for facial
pain from acute herpes zoster and incidence of postherpetic neuralgia.
Pain Physician 2012 ; 15 : 467‒47416）Woo JH, et al : Successful treatment of severe sympathetically maintained pain following anterior spine surgery. J Korean Neurosurg Soc
2014 ; 56 : 66‒7017）Kulkarni KR, et al : Efficacy of stellate ganglion block with an adjuvant
ketamine for peripheral vascular disease of the upper limbs. Indian J
Anaesth 2010 ; 54 : 546‒55118）Albertyn J, et al : Cluster headache and the sympathetic nerve. Headache 2004 ; 44 : 183‒185

253

254

Ⅲ．Interventional Management19）Forouzanfar T, et al : Radiofrequency lesions of the stellate ganglion inchronic pain syndromes : Retrospective analysis of clinical efficacy in 86
patients. Clin J Pain 2000 ; 16 : 164‒168
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

PubMed, MEDLINE, Cochrane Library
2005‒2017
stellate ganglion block, cervical sympathetic block
We searched for ‘chronic pain’ and ‘stellate ganglion block’ on
Ichushi. We narrowed down our search by RCT, meta‒analysis
and systematic review and focused on the most recent academic
papers. References 1‒17 and 19 were not a result of our searchmethod but were added due to their importance.

CQ26：Is sympathetic ganglion block effective in managing chronic pain?
Answer：Thoracic sympathetic ganglion block and lumbar sympathetic ganglion block have often been used in clinical settings for the purpose of alleviatCRPS：complex regional
pain syndrome
SMP：sympatheticallymaintained pain

ing pain from impaired blood flow, complex regional pain syndrome (CRPS),
and pain due to sympathetically maintained pain (SMP), and there are also
many reports indicating its efficacy. However, there is little high‒quality evidence.
Summary of recommendation grades and overall evidence：
1) Thoracic sympathetic ganglion block
CRPS in the upper extremities：2B (Execution is weakly recommended)
Pain due to vascular disorders of the upper extremities, post‒traumatic
syndrome, postherpetic neuralgia, failed spinal surgery syndrome：2D(Execution is weakly recommended)

2) Lumbar sympathetic ganglion block
Pain due to vascular disorders in the lower extremities：1B (Execution isstrongly recommended)

Lower extremity CRPS, failed spinal surgery syndrome, sympatheticallymaintained pain (SMP), diabetic neuropathy, lumbar spinal stenosis：
2D (Execution is weakly recommended)
Commentary：
In the management of chronic pain，sympathetic ganglion block is often usedin clinical settings for the purpose of alleviating pain due to vascular disorders
and pain involved in the sympathetic afferent pathways. We have established aseparate CQ about stellate ganglion block, and in this CQ, we will discuss thoracic sympathetic ganglion block and lumbar sympathetic ganglion block.

Ⅲ．Interventional Management

2551) Thoracic sympathetic ganglion blockThoracic sympathetic ganglion block is used for example to treat CRPS, postherpic neuralgia (PHN), phantom breast pain and pain due to vascular disor-

PHN：postherpetic neuralgia

ders in the upper extremities. They have experienced cases where it was effective in clinical settings in the past but evidence on its efficacy is limited. In
a RCT investigating the effects of thoracic sympathetic ganglion block on 36

video associated endoscopic
thoracic sympathectomy

subjects with CRPS1), in the group of patients who had undergone thoracic
sympathetic ganglion block, the strength of pain twelve months later, the McGill Pain Questionnaire scores, the Neuropathic Pain Symptom Inventory values and the Hospital Anxiety and Depression Scale (HADS) were significantly
lower. Furthermore, in a study targeting 51 patients with chronic pain of theupper extremities (CRPS, post‒traumatic syndrome, PHN, failed spinal surgery
syndrome) they reported that the thoracic sympathetic ganglion block had
shown to be highly effective, especially in patients in which onset had occurred
within the last year2). In a controlled study on the effects of percutaneous thoracic sympathetic ganglion high‒frequency thermocoagulation on vascular disorders of the upper extremities3), they compared 50 subjects with Raynaud’s
disease who had been classified into two groups；those who underwent conventional T2 and T3 high‒frequency thermocoagulation and those who only underwent T2 thermocoagulation as well being administered with an injection of
6% phenol. In both groups, they recognized a significant reduction in pain, arise in skin temperature in the upper extremities and an improvement in QOL
but outside of the duration of the procedure, there was no recognizable significant difference. There have been reports indicating the efficacy of thoracic
sympathectomy by open thoracotomy4), but no high‒quality RCTs exist．
There have also been reports on thoracoscopic sympathectomy 5,6) but wereunable to conclude that it was sufficiently effective over the long term. As seen
above, evidence is insufficient and even in a systematic review conducted in
20117), they have not reached any definite conclusions on its efficacy.
2) Lumbar sympathetic ganglion block
In clinical settings，lumbar sympathetic ganglion block is often used for the
purpose of alleviating pain due to blood flow disorders of the lower extremities
and pain from SMP but there is little high‒quality evidence．In terms of managing pain, there have been reports indicating its efficacy in diagnosing SMP
as a diagnostic block8). There is a RCT indicating the efficacy of lumbar sympathetic block for pain due to vascular disorders of the lower extremities9).
Studying 41 ischemic limbs, they compared a group undergoing chemical lumbar sympathetic block from phenol with a placebo‒controlled group administered with a local anaesthetic, and found that pain six months later had significantly improved in the phenol block group. There are several other reports in-

SMP : sympatheticallymaintained pain

256

Ⅲ．Interventional Management

dicating the efficacy of chemical lumbar sympathetic block10,11). As for diabetes,
there have been reports that blocks using phenol were useful on diabetic lower‒
limb ischemia12), several reports that they had reduced pain and promoted thehealing of ulcers13,14), and in recent years, it has alleviated intractable pain accompanying diabetic neuropathy and improved QOL15). There are no RCTs
which have investigated the effects of lumbar sympathetic block on lumbar
spinal canal stenosis. As for reports which have shown its efficacy, there is one
report indicating the possibility of its effectiveness on cases of cauda equina lesion of short‒term duration16) and it had an effective rate of 48.4% in 62 casesof lumbar spinal canal stenosis, had a high effective rate in cases who also felt
cold in their lower limbs，and there are also reports of a recognizable improvement in intermittent claudication17). There are no RCTs which have investigated the effects of a lumbar sympathetic ganglion block on CRPS but
there are several reports indicating its efficacy18‒19). In a review released in
201620), on the effect of lumbar sympathetic ganglion block using a local anaesthetic on CRPS, they were unable to conclude that it was effective. Apart from
this, there have also been reports indicating its efficacy on neuropathic pain21),
SMP21‒23), lower‒limb pain24), and pain due to rectal tenesmus.
References
1）Rocha Rde O, et al : Thoracic sympathetic block for the treatment ofcomplex regional pain syndrome type I : A double‒blind randomized
controlled study. Pain 2014 ; 155 : 2274‒2281
2）Yoo HS, et al : Early thoracic sympathetic block improves the treatment
effect for upper extremity neuropathic pain. Anesth Analg 2011 ; 113 :
605‒6093）Gabrhelik T, et al : Percutaneous upper thoracic radiofrequency sympathectomy in Raynaud phenomenon : A comparison of T2/T3 procedureversus T2 lesion with phenol application. Reg Anesth Pain Med 2009 ;34 : 425‒4294）Khan MI, et al : Efficacy of cervicothoracic sympathectomy versus conservative management in patients suffering from incapacitating Raynaud’s syndrome after frost bite. J Ayub Med Coll Abbottabad 2008 ; 20 :21‒245）Maga P, et al : Long‒term effects of thoracic sympathectomy on microcirculation in the hands of patients with primary Raynaud disease. J
Thorac Cardiovasc Surg 2007 ; 133 : 1428‒1433
6）El Samadoni A, et al : Thoracoscopic sympathectomy is a valuable addition on the management of recreational intra‒arterial drug injection : Pilot study. Int J Surg 2010 ; 8 : 229‒2327）Huisstede BM, et al : Effectiveness of interventions for secondary Raynaud’s phenomenon : A systematic review. Arch Phys Med Rehabil
2011 ; 92 : 1166‒1180
8）Krumova EK, et al : Are sympathetic blocks useful for diagnostic purposes? Reg Anesth Pain Med 2011 ; 36 : 560‒567

Ⅲ．Interventional Management

9）Cross FW, et al : Chemical lumbar sympathectomy for ischemic rest
pain : A randomized, prospective controlled clinical trial. Am J Surg
1985 ; 150 : 341‒345, 1985
10）Tomlinson L : Case study to illustrate a multidisciplinary approach to acase of critical limb ischemia and the role of chemical lumbar sympathectomy. J Tissue Viability 2000 ; 10 : 140‒14311）Alexander JP : Chemical lumbar sympathectomy in patients with severe
lower limb ischemia. Ulster Med J 1994 ; 63 : 137‒143
12）Mashiah A, et al : Phenol lumbar sympathetic block in diabetic lower
limb ischemia. J Cardiovasc Risk 1995 ; 2 : 467‒46913）Wetland A, et al : Neurolytic block of the lumbar sympathetic trunk inadvanced stages of peripheral arterial occlusive disease. Anashesiol Intensivmed Notfallmed Schmerzther 1993 ; 28 : 420‒42614）Boas RA : Sympathetic nerve blocks : In search of a role. Reg Anesth
Pain Med 1998 ; 23 : 292‒30515）Cheng J, et al : Sympathetic blocks provided sustained pain relief in apatient with refractory painful diabetic neuropathy. Case Rep Anesthesiol 2012 ; 285328
16）Yabuki S, et al : Therapeutic effect of lumbar sympathetic ganglion
block‒adaptation to cauda equina injury due to lumbosacral degenerative disease. Clinical Orthopaedic Surgery 2002 ; 37 : 1397‒1400
17）Yamagami H, et al : Effect of lumbar sympathetic ganglion block on spinal diseases. Pain Clinic 1999 ; 20 : 1009‒1014
18）Plancarte R, et al : Complex regional pain syndrome type Ⅱ（causalgia）
after automated laser discectomy : A case report. Spine 1997 ; 22 : 459‒461
19）Manjunath PS, et al : Management of lower limb complex regional pain
syndrome type Ⅰ : An evaluation of percutaneous radiofrequency thermal lumbar sympathectomy versus phenol lumbar sympathetic neurolysis : A pilot study. Anesth Analg 2008 ; 106 : 647‒64920）Stanton TR, et al : Local anaesthetic sympathetic blockade for complex
regional pain syndrome. Cochrane Database Syst Rev 2016 ; 19 :CD00459821）Furlan AD, et al : Chemical sympathectomy for neuropathic pain : Does
it work? : Case report and systematic literature review. Clin J Pain
2001 ; 17 : 327‒33622）Tran KM, et al : Lumbar sympathetic block for sympathetically maintained pain : Changes in cutaneous temperatures and pain perception.
Anesth Analg 2000 ; 90 : 1396‒1401
23）Rocco AG : Radiofrequency lumbar sympatholysis : The evolution of atechnique for managing sympathetically maintained pain. Reg Anesth
1995 ; 20 : 3‒1224）Ohno K, et al : Transdiscal lumbar sympathetic block : A new techniquefor a chemical sympathectomy. Anesth Analg 1997 ; 85 : 1312‒131625）Bristow A, et al : Lumbar sympathectomy in the management of rectal
tenesmoid pain. Ann R Coll Surg Engl 1988 ; 70 : 38‒39

257

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Ⅲ．Interventional Management

Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

PubMed, MEDLINE, Cochrane Library
2005‒2017
sympathetic nerve block
We searched for ‘chronic pain’ and ‘sympathetic block’ on Ichushi.
We then narrowed down by guidelines, RCT, meta‒analysis, andsystematic review and focused on the most recent academic papers. References 1 and 3‒25 were not through our search method
but were added because of their importance.

CQ27：Is a trigger point injection effective in managing chronic pain?
Answer：There is not enough evidence to conclude that a trigger point injection is effective but there is evidence of its efficacy over the short‒term. As
long as experienced specialists perform the procedure, it is relatively safe andeasy. Thus it can be used to help treat chronic pain．When used, it is necessary to consider which drug to use and how frequently it should be administered.
Summary of recommendation grades and overall evidence：2C (Execution is
weakly recommended)

Commentary：
A systematic review of fifteen RCTs investigating the utility of a trigger point
TPI：trigger point injection

injection (TPI) in treating chronic pain, including various diseases, was unable
to reach a conclusion due to the small sample sizes used and lack of methodological uniformity (such as eligibility, site of injection, type and dosage of drug
used, volume and number of injections etc.)1). A systematic review of RCTs
with placebo drugs showed no difference in effectiveness by injected drug (local anaesthetic, steroid, botulinus toxin) and dry needling (procedure in which
patient is punctured, not injected with the drug)2). Use of a local anaesthetic is
expected to have alleviative effects on pain at the injection site. As there is nostrong evidence recommending the use of a steroid or botulinus toxin, we needto consider issues such as their side effects and patients being ineligible for insurance coverage. A systematic review of nineteen RCTs showed the efficacy

MPS：myofascial pain
syndromeof TPI on the trigger point for myofascial pain syndrome (MPS)3), but they reported that it was mostly short‒term effects. There are also reviews of casesof MPS in which TPI had displayed short‒term effects but who also had received long‒term effects through the injection of botulinus toxin4), but this usage is not covered under the Japanese insurance system and therefore we cannot recommend it. A review of three RCTs on chronic pain, including tension‒
type headache (TTH)5), showed that it was effective over the short-term．According to a systematic review of eighteen RCTs on chronic low back pain6),

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Ⅲ．Interventional Management

they indicated no difference in reduction in pain or improvement in function
compared with a placebo injection and so there is insufficient evidence to draw
a conclusion7). There is a systematic review in which TPI through local anaesthetic (local steroid injection) was useful not only for the diagnosis of acute cutaneous nerve entrapment syndrome (ACNES) but also helped reduce pain
8)

over the long‒term . However, with only one RCT to date, the evidence is low.

ACNES：anterior cutaneous
nerve entrapment syndrome

It is a widely‒performed procedure in clinical settings and is believed to behighly safe but when performed, we must constantly be evaluating its effects
and we should not continue to aimlessly administer it over the long‒term.
References
1）Scott NA, et al : Trigger point injections for chronic non‒malignant musculoskeletal pain : A systematic review. Pain Med 2009 ; 10 : 54‒692）Singh V, et al : Injections for chronic pain. Phys Med Rehabil Clin N Am
2015 ; 26 : 249‒2613）Boyles R, et al : Effectiveness of trigger point dry needling for multiple
body regions : A systematic review. J Man Manip Ther 2015 ; 23 : 276‒2934）Ho KY, et al : Botulinum toxin A for myofascial trigger point injection : A
qualitative systematic review. Eur J Pain 2007 ; 11 : 519‒5275）Robbins MS, et al : Trigger point injections for headache disorders : Expert consensus methodology and narrative review. Headache 2014 ; 54 :1441‒1459
6）Watters WC 3rd, et al : Guideline update for the performance of fusion
procedures for degenerative disease of the lumbar spine : Part 13 : injection therapies, low‒back pain, and lumbar fusion. J Neurosurg Spine2014 ; 21 : 79‒907）Staal JB, et al : Injection therapy for subacute and chronic low backpain : An updated Cochrane review. Spine（Phila Pa 1976）2009 ; 34 : 49‒598）Oor JE, et al : A systematic review of the treatment for abdominal cutaneous nerve entrapment syndrome. Am J Surg 2016 ; 212 : 165‒174
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

PubMed, MEDLINE, Cochrane Library
2005‒2017
trigger point injection
We searched for ‘chronic pain’ and ‘trigger point block’ on
Ichushi. We narrowed our search down by guidelines, RCT, meta
‒analysis and systematic review and focused on the most recent
academic papers.

CQ28：Is radiofrequency denervation effective in managing chronic pain?
Answer：Radiofrequency denervation (RF), is an effective treatment onchronic neck and low back pain originating from facet (zygapophyseal) joints,
chronic hip, low back and buttock pain originating from sacroiliac joint, and trigeminal neuralgia. It is possibly also effective on ischemic pain in the extremi-

RF：radiofrequency
thermocoagulation/
denervation

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Ⅲ．Interventional Management

ties, complex regional pain syndrome (CRPS), and chronic knee pain due toknee osteoarthritis, however there is limited evidence on its effectiveness.
Summary of recommendation grades and overall evidence：
1) Chronic neck and low back pain originating from facet (zygapophyseal)
joints：1A (Execution is strongly recommended)
2) Chronic hip, low back and buttock pain originating from sacroiliac joint：
2B (Execution is weakly recommended)
3) Trigeminal neuralgia：1B (Execution is strongly recommended)
4) Ischemic pain in the extremities, complex regional pain syndrome(CRPS), and chronic knee pain due to knee osteoarthritis：2C (Execution
is weakly recommended)

Commentary：
1) Chronic neck and low back pain originating from facet (zygapophyseal)
jointsFacet (zygapophyseal) joints are innervated by the medial branches of the
RCT：randomized controlled
trial

dorsal rami．There were four RCTs comparing the effectiveness of radiofrequency denervation (RF) of medial branches of the dorsal rami with sham therapy (needle insertion without RF) for chronic low back pain originating fromfacet joints, three studies1,3,4) describing its short‒term and long‒term effectiveness, and one study2) reporting that it was ineffective．Furthermore, eleven systematic reviews and one set of guidelines16), which were reported after
2005, supported the short-term and the long-term effectiveness of the medial
branch RF for chronic low back pain originating from facet joints5-15). There is
one RCT comparing the effectiveness of medial branch RF with sham therapy
for chronic cervical pain originating from facet joints, which indicated theshort-term and the long-term effectiveness of the medial branch RF17). Moreover, six systematic reviews6,8,9,13,18,19) and one set of guidelines16), which werereported after 2005, supported the short-term and the long-term effectivenessof the medial branch RF for chronic cervical pain originating from facet joints.
2) Chronic hip, low back and buttock pain originating from the sacroiliac
joint
There were two RCTs which compared the effectiveness of RF of S1‒3 lateralbranches of the sacral nerves and L5 (＋L4) medial branches of the dorsal ramiwith sham therapy for chronic hip, low back and buttock pain originating fromthe sacroiliac joint (sacroiliac joint complex). They described the short-term
and the long-term effectiveness of the sacroiliac joint RF20,21). In these studies,
they used cooled radiofrequency system which is not currently approved in Japan. A study comparing the effectiveness of conventional RF with cooled RF22),
showed similar effects for both treatments. Furthermore, since 2005, there

Ⅲ．Interventional Management

have been six systematic reviews11,23‒27) and one set of guidelines16), on chronic
hip, low back and buttock pain originating from the sacroiliac joint (sacroiliac
joint complex), and although they supported the effectiveness of cooled RF on
the medial branch of the dorsal ramus and the posterior branches of the sacral
nerves, they mentioned that further research was required.
3) Trigeminal neuralgia
In the treatment of trigeminal neuralgia，RF is performed on the Gasserian
ganglion (trigeminal ganglion) and the trigeminal nerves (supraorbital nerve，
supratrochlear nerve，maxillary nerve，infraorbital nerve, mandibular nerve，and mental nerve). In the studies regarding Gasserian ganglion RF for trigeminal neuralgia, there was no RCT comparing the effectiveness of it with shamtherapy. In four relevant RCTs without sham therapy, they compared the effects of different methods of needle guidance28), different approaches of radiofrequency treatment (vs Gasserian ganglion pulsed radiofrequency (PRF)29), vssupraorbital nerve RF30)), and different treatment time of combined PRF31).
These studies showed that despite a high incidence of dysesthesia, Gasserian
ganglion RF was an effective treatment with a high success rate. In studies ontrigeminal nerve peripheral branch RF for trigeminal neuralgia, there was no
RCT comparing the effectiveness of it with sham therapy. In one relevant
RCT, they compared its effects with Gasserian ganglion RF. This study
showed that supraorbital nerve RF displayed similar effects to the Gasserian
ganglion RF for first division trigeminal neuralgia30). Furthermore, since 2005,
there has been one systematic review32) and four sets of guidelines33‒36) on theeffects of RF on trigeminal neuralgia. In the systematic review32), as there waspoor evidence to compare the effectiveness of interventional treatments for trigeminal neuralgia, they stated that they were unable to conclude whether interventional treatments including RF were effective or not. In the guidelines
on trigeminal neuralgia management33), they concluded that Gasserian ganglion
RF was an effective treatment, the effectiveness of trigeminal nerve peripheral
branch RF on trigeminal neuralgia has been evaluated as insufficient, and theearly application of interventional treatments including RF might be recommended in pharmacotherapy-resistant patients．In the guidelines for interventional treatment of neuropathic pain34), they were unable to draw conclusions
about the effectiveness of interventional treatments including RF for trigeminal neuralgia because of the small amount of high‒quality evidence. However,they mentioned that it should be considered for pharmacotherapy-resistantcases. Even in the guidelines on pharmacotherapy for neuropathic pain including trigeminal neuralgia35), they recommend considering interventional treatments including RF in cases where first‒line drugs such as carbamazepine
prove to be ineffective.

261

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Ⅲ．Interventional Management

4) Ischemic pain in the extremities, complex regional pain syndrome (CRPS),
and chronic knee pain due to knee osteoarthritis
Other reported indications of RF for chronic pain, apart from those alreadymentioned above, are thoracic and lumbar sympathetic RF for CRPS and ischemic pain in the extremities, and genicular nerve RF for chronic knee pain due
to knee osteoarthritis. We have excluded intradiscal radiofrequency thermocoagulation for discogenic low back pain from this CQ, as strictly speaking it
does not qualify as a nerve block. In RCTs verifying the effects of a thoracic
and lumbar sympathetic RF for ischemic pain in the extremities and CRPS,
there was no study compared with sham therapy. With thoracic sympathetic
RF for Raynaud’s syndrome of the upper extremities, there was a study comparing the effect of RF monotherapy with RF＋phenol injection treatments36)，
and with lumbar sympathetic RF for lower-limb CRPS, there was a study comparing the effect of RF with phenol block37)；both studies showing the longterm analgesic effects of RF. There was also one RCT comparing the effectiveness of genicular nerve RF with sham therapy for chronic knee pain due toknee osteoarthritis. This study described that genicular nerve RF improved
pain and activities of daily living (ADL) over the long-term compared withsham therapy38). These RF treatments have been insufficiently evaluated insystematic reviews and guidelines, and while it is possible that RF treatments
are effective, it is supported by limited evidence．
References
1）van Kleef M, et al : Randomized trial of radiofrequency lumbar facet denervation for chronic low back pain. Spine（Phila Pa 1976）1999 ; 24 :1937‒19422）van Wijk RM, et al : Radiofrequency denervation of lumbar facet joints
in the treatment of chronic low back pain : A randomized, double‒blind,sham lesion‒controlled trial. Clin J Pain 2005 ; 21 : 335‒344
3）Tekin I, et al : A comparison of conventional and pulsed radiofrequency
denervation in the treatment of chronic facet joint pain. Clin J Pain
2007 ; 23 : 524‒5294）Nath S, et al : Percutaneous lumbar zygapophysial（facet）joint neurotomy using radiofrequency current, in the management of chronic low
back pain : A randomized doubleblind trial. Spine（Phila Pa 1976）
2008 ; 33 : 1291‒12975）Boswell MV, et al : Therapeutic facet joint interventions in chronic spinal
pain : A systematic review of effectiveness and complications. Pain Physician 2005 ; 8 : 101‒1146）Boswell MV, et al : A systematic review of therapeutic facet joint interventions in chronic spinal pain. Pain Physician 2007 ; 10 : 229‒2537）Datta S, et al : Systematic assessment of diagnostic accuracy and therapeutic utility of lumbar facet joint interventions. Pain Physician
2009 ; 12 : 437‒4608）Falco FJ, et al : An update of the effectiveness of therapeutic lumbar fac-

Ⅲ．Interventional Management

et joint interventions. Pain Physician 2012 ; 15 : E909‒E953
9）Smuck M, et al : Success of initial and repeated medial branch neurotomy for zygapophysial joint pain : A systematic review. PM R 2012 ; 4 :686‒692
10）Poetscher AW, et al : Radiofrequency denervation for facet joint low
back pain : A systematic review. Spine（Phila Pa 1976）2014 ; 39 : E842‒
E84911）Leggett LE, et al : Radiofrequency ablation for chronic low back pain : A
systematic review of randomized controlled trials. Pain Res Manag2014 ; 19 : e146‒e15312）Maas ET, et al : Radiofrequency denervation for chronic low back pain.
Cochrane Database Syst Rev 2015 ; 10 : CD008572
13）Manchikanti L, et al : A systematic review and best evidence synthesisof the effectiveness of therapeutic facet joint interventions in managing
chronic spinal pain. Pain Physician 2015 ; 18 : E535‒E582
14）Manchikanti L, et al : Management of lumbar zygapophysial（facet）
joint pain. World J Orthop 2016 ; 7 : 315‒33715）Lee CH, et al : The efficacy of conventional radiofrequency denervationin patients with chronic low back pain originating from the facet
joints : A meta‒analysis of randomized controlled trials. Spine J
2017 ; 17 : 1770‒1780
16）Manchikanti L, et al : An update of comprehensive evidence‒based
guidelines for interventional techniques in chronic spinal pain : Part
II : guidance and recommendations. Pain Physician 2013 ; 16 : S49‒S283
17）Lord SM, et al : Percutaneous radio‒frequency neurotomy for chronic
cervical zygapophyseal‒joint pain. N Engl J Med 1996 ; 335 : 1721‒1726
18）Falco FJ, et al : Systematic review of diagnostic utility and therapeutic
effectiveness of cervical facet joint interventions. Pain Physician 2009 ;12 : 323‒34419）Engel A, et al : The Effectiveness and risks of fluoroscopically‒guided
cervical medial branch thermal radiofrequency neurotomy : A systematic review with comprehensive analysis of the published data. Pain Med
2016 ; 17 : 658‒66920）Cohen SP, et al : Randomized placebo‒controlled study evaluating lateralbranch radiofrequency denervation for sacroiliac joint pain. Anesthesiology 2008 ; 109 : 279‒28821）Patel N, et al : A randomized, placebo‒controlled study to assess the efficacy of lateral branch neurotomy for chronic sacroiliac joint pain. Pain
Med 2012 ; 13 : 383‒39822）Cheng J, et al : Comparative outcomes of cooled versus traditional radiofrequency ablation of the lateral branches for sacroiliac joint pain. Clin J
Pain 2013 ; 29 : 132‒13723）Hansen H, et al : A systematic evaluation of the therapeutic effectivenessof sacroiliac joint interventions. Pain Physician 2012 ; 15 : E247‒E27824）Rupert MP, et al : Evaluation of sacroiliac joint interventions : A systematic appraisal of the literature. Pain Physician 2009 ; 12 : 399‒41825）King W, et al : Diagnosis and treatment of posterior sacroiliac complex
pain : A systematic review with comprehensive analysis of the publisheddata. Pain Med 2015 ; 16 : 257‒26526）Simopoulos TT, et al : Systematic review of the diagnostic accuracy andtherapeutic effectiveness of sacroiliac joint interventions. Pain Physician

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2015 ; 18 : E713‒E756
27）Aydin SM, et al : The role of radiofrequency ablation for sacroiliac joint
pain : A meta‒analysis. PM R 2010 ; 2 : 842‒85128）Xu SJ, et al : Neuronavigator‒guided percutaneous radiofrequency thermocoagulation in the treatment of intractable trigeminal neuralgia. Chin
Med J 2006 ; 119 : 1528‒153529）Erdine S, et al : Comparison of pulsed radiofrequency with conventional
radiofrequency in the treatment of idiopathic trigeminal neuralgia. Eur J
Pain 2007 ; 11 : 309‒31330）Huibin Q, et al : The treatment of first division idiopathic trigeminal neuralgia with radiofrequency thermocoagulation of the peripheral branches
compared to conventional radiofrequency. J Clin Neurosci 2009 ; 16 : 1425‒
142931）Li X, et al : A prospective study of Gasserian ganglion pulsed radiofrequency combined with continuous radiofrequency for the treatment oftrigeminal neuralgia. J Clin Neurosci 2012 ; 19 : 824‒82832）Zakrzewska JM, et al : Neurosurgical interventions for the treatment ofclassical trigeminal neuralgia. Cochrane Database Syst Rev 2011 ; 9 :CD007312
33）Cruccu G, et al : AAN‒EFNS guidelines on trigeminal neuralgia management. Eur J Neurol 2008 ; 15 : 1013‒1028
34）Dworkin RH, et al : Interventional management of neuropathic pain : NeuPSIG recommendations. Pain 2013 ; 154 : 2249‒2261
35）Attal N, et al : EFNS guidelines on the pharmacological treatment ofneuropathic pain : 2010 revision. Eur J Neurol 2010 ; 17 : 1113‒e8836）Gabrhelik T, et al : Percutaneous upper thoracic radiofrequency sympathectomy in Raynaud phenomenon : A comparison of T2/T3 procedureversus T2 lesion with phenol application. Reg Anesth Pain Med 2009 ; 34 :425‒42937）Manjunath PS, et al : Management of lower limb complex regional pain
syndrome type Ⅰ : An evaluation of percutaneous radiofrequency thermal lumbar sympathectomy versus phenol lumbar sympathetic neurolysis : A pilot study. Anesth Analg 2008 ; 106 : 647‒64938）Choi WJ, et al : Radiofrequency treatment relieves chronic knee osteoarthritis pain : A double‒blind randomized controlled trial. Pain 2011 ; 152 :481‒487
Database
TimingWords searchedby the combination
with ‘chronic pain’＊
Notes

PubMed, MEDLINE, Cochrane Library
2005‒2017
radiofrequency
We searched for ‘chronic pain’ and ‘radiofrequency denervation’on Ichushi. We narrowed down our search by RCT, meta‒analysis, and systematic review, and focused on the most recent academic papers. References 1-7, 9, 10, 13-15, 17-31, 33-37 weresearched by hand and were added due to their importance.

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Ⅲ．Interventional Management

CQ29：Is pulsed radiofrequency treatment effective in managing chronic
pain?
Answer：Pulsed radiofrequency (PRF) treatment has been reported as a

PRF：puled radiofrequency

highly safe and effective tool to manage chronic cervical radiculopathy, postherpetic neuralgia (PHN) and chronic shoulder joint pain in the short and long

PHN：postherpetic neuralgia

term (at least for three months), and therefore PRF should be selected to manage these pain conditions. Radiofrequency thermocoagulation (RF) is also
thought to be the prioritized form of treatment for managing pain deriving

RF：radiofrequency
thermocoagulation/
denervationfrom the lumbar facet joints and idiopathic trigeminal neuralgia. Further investigation is needed to indicate its efficacy for other pain conditions (such as lumbar radiculopathy and occipital neuralgia, cervicogenic headache, and chronic
knee joint pain), optimal duration of application, and parameters.
Summary of recommendation grades and overall evidence：
1) Radiculopathy
Cervical radiculopathy：1A (Execution is strongly recommended)
Lumbar radiculopathy：2C (Execution is weakly recommended)
2) Herpes zoster‒associated pain

ZAP：zoster-associated pain

PHN：1A (Execution is strongly recommended)
Preventing transition to PHN (herpes zoster pain)：2C (Execution is weakly
recommended)

3) Chronic shoulder joint pain：1B (Execution is strongly recommended)
4) Patient conditions in which RF is prioritized (pain deriving from the lumbar facet joints, idiopathic trigeminal neuralgia)：2B (Execution is weakly
recommended)5) Occipital neuralgia, cervicogenic headache, chronic knee joint pain]：2C(Execution is weakly recommended)

Commentary：
There are several randomized controlled trials (RCTs) and prospective comparative studies demonstrating the efficacy of PRF for chronic pain. In particular, recent meta‒analysis and systematic reviews revealed that performing
PRF once for patients with cervical radiculopathy, PHN, and chronic shoulder
joint pain, was a highly safe way to provide pain relief for at least twelve
weeks. Therefore, we propose that PRF should be selected mainly for management of the chronic pain conditions listed above. However, there is no evidence
for the optimal duration, target and parameters of PRF, so it warrants further
investigation in future.
1) Radiculopathy
In a double‒blinded RCT1) on PRF for cervical radiculopathy, the PRF group

RCT：randomized controlled
trial

266

Ⅲ．Interventional Management(eleven cases), in which subjects underwent PRF on the dorsal root ganglion
DRG：dorsal root ganglion
VAS：visual analogue scale(DRG), showed significantly better outcomes with regard to the global perceived effect and pain intensity (visual analogue scale, VAS) than the shamgroup (twelve cases) over a six-month period. In contrast, a placebo-controlled
double-blinded RCT on PRF for lumbar radiculopathy2) compared the DRGPRF group (sixteen cases) and the placebo group (fifteen cases) over a threemonth period, and reported no significant difference. Furthermore, a systematic review in 20163) investigating the efficacy of PRF for the management ofpain associated with different spinal conditions, concluded that while the use of
PRF on the DRG is effective in cases of cervical radiculopathy, further investigation into its efficacy on lumbar radiculopathy is required. Moreover, in a meta-analysis conducted in 2015 on the efficacy of PRF for neuropathic pain4), as
they had analyzed the efficacy of PRF for neuropathic pain without classifying
cases into cervical or lumbosacral radiculopathy, they were unable to showwhether PRF was effective for the management of radiculopathy or not. As
seen above, performing PRF once on the DRG could be effective for cervical
radiculopathy over the long-term (for at least three months). However, further
investigation into its efficacy for lumbosacral radiculopathy is required.
2) Herpes zoster‒associated pain
There is one placebo‒controlled double‒blinded RCT on thoracic PHN. In
this study of PHN5), they compared the group (48 cases) who underwent PRF
on the peripheral nerve (intercostal nerve) with the group who underwent a
sham treatment (48 cases) over a six‒month period5), and demonstrated a significant improvement in pain intensity (VAS), physical function and QOL (SF‒36). Furthermore, a meta‒analysis of twelve RCTs on the efficacy of PRF forneuropathic pain4), showed PRF to be effective on PHN and a safe form oftreatment. In a retrospective study6) targeting 58 patients with ZAP who underwent PRF on DRG, they reported a significantly lower intensity of pain (nu-

NRS：numerical rating scalemerical rating scale, NRS) in the group of subjects (29 cases) who underwent
PRF in an acute phase (90 days or less) than those subjects (29 cases) who underwent PRF in a chronic phase (90 days or more). Overall, we could say PRF
is a recommended treatment for PHN. Further investigation is required on differences in its effects according to the site where PRF is performed, and in its
efficacy on herpes zoster-associated pain from the acute phase to the subacute phase.
3) Chronic shoulder joint pain
According to a systematic review7) discussing five RCTs which investigatedthe effects of PRF on chronic shoulder joint pain, PRF on the suprascapularnerve was effective on chronic shoulder joint pain for at least twelve weeks,
and showed high safety because no complications were reported. In a RCT on

Ⅲ．Interventional Management

adhesive capsulitis8), a group (21 cases) who underwent twelve weeks of rehabilitation as well as PRF on suprascapular nerve reported a significantly higher
improvement in VAS and restricted range of motion (ROM) of the shoulder
joint, compared with a group (21 cases) who only underwent rehabilitation. In asingle-blinded RCT on patients with shoulder joint pain persisting for threemonths or more, they compared a group who underwent PRF on the suprascapular nerve (25 cases) with a group who were administered with an intra-articular steroid (20 mg of triamcinolone) injection (25 cases) and reported almost
the same results for VAS and shoulder joint function between the two groups
up to 12 weeks later9).
4) Patient conditions in which RF is prioritized (pain deriving from the lumbar facet joints, idiopathic trigeminal neuralgia)
Regarding pain deriving from the lumbar facet joints and idiopathic trigeminal neuralgia，they reported less effects with PRF, than with a conventional
nerve block using RF3,10). On the other hand, by using PRF in combination
with RF, they also reported a lower frequency of complications due to nerve
damage and shorter time until recovery11). Therefore, using PRF is suitable insome cases.
5) Occipital neuralgia, cervicogenic headache, chronic knee joint pain
There are a large number of studies12) indicating the efficacy of PRF for pain
conditions such as occipital neuralgia, cervicogenic headache and chronic knee
joint pain. However, there are few studies of high-quality and because the existing evidence remains unclear, PRF has only been given a weak recommendation. On the other hand, because the temperature at the needle tip under
PRF is maintained below 42℃, there is a low possibility of nerve damage, andthere have been no reports of complications to date. Therefore, overall we cansay that PRF is a highly safe tool for chronic pain management12) and in clinical settings, nothing has prevented the use of PRF for the conditions mentioned above but further research is also desirable.
References
1）Van Zundert J, et al : Pulsed radiofrequency adjacent to the cervical dorsal root ganglion in chronic cervical radicular pain : A double blind shamcontrolled randomized clinical trial. Pain 2007 ; 127 : 173‒1822）Shanthanna H, et al : Pulsed radiofrequency treatment of the lumbar
dorsal root ganglion in patients with chronic lumbar radicular pain : A
randomized, placebo‒controlled pilot study. J Pain Res 2014 ; 7 : 47‒553）Facchini G, et al : A comprehensive review of pulsed radiofrequency inthe treatment of pain associated with different spinal conditions. Br J
Radiol 2017 ; 90 : 20150406
4）Shi Y, et al : Treatment of Neuropathic Pain Using Pulsed Radiofrequency : A Meta‒analysis. Pain Physician 2016 ; 19 : 429‒444

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Ⅲ．Interventional Management5）Ke M, et al : Efficacy of pulsed radiofrequency in the treatment of thoracic postherpetic neuralgia from the angulus costae : A randomized,
double‒blinded, controlled trial. Pain Physician 2013 ; 16 : 15‒256）Kim K, et al : Pulsed radiofrequency to the dorsal root ganglion in acuteherpes zoster and postherpetic neuralgia. Pain Physician 2017 ; 20 : E411‒
E4187）Liu A, et al : Evidence‒based status of pulsed radiofrequency treatment
for patients with shoulder pain : A systematic review of randomized controlled trials. Pain Pract 2016 ; 16 : 518‒5258）Wu YT, et al : Ultrasound‒guided pulsed radiofrequency stimulation of
the suprascapular nerve for adhesive capsulitis : A prospective, randomized, controlled trial. Anesth Analg 2014 ; 119 : 686‒6929）Eyigor C, et al : Intra‒articular corticosteroid injections versus pulsed radiofrequency in painful shoulder : A prospective, randomized, single‒
blinded study. Clin J Pain 2010 ; 26 : 386‒392
10）Sridharan K, et al : Interventions for refractory trigeminal neuralgia : A
bayesian mixed treatment comparison network meta‒analysis of randomized controlled clinical trials. Clin Drug Investig 2017 ; 37 : 819‒831
11）Yao P, et al : Efficacy and safety of continuous radiofrequency thermocoagulation plus pulsed radiofrequency for treatment of V1 trigeminal
neuralgia : A prospective cohort study. Medicine（Baltimore）2016 ; 95 :e5247
12）Vanneste T, et al : Pulsed radiofrequency in chronic pain. Curr Opin Anaesthesiol 2017 ; 30 : 577‒582
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

PubMed, MEDLINE, Cochrane Library
2005‒2017
pulsed radiofrequency
We searched for ‘pulsed radiofrequency’ on Ichushi. We then narrowed our search down by RCT, meta‒analysis and systematic
review, and focused on the most recent academic papers and uncovered 42 references on chronic pain. Reference 6 is a report on
pain between the acute and sub‒acute stages but we have added
it because we judged that it was important.

CQ30：Are spring‒coil catheters, and epiduroscopy effective in managing
chronic pain?
Answer：Treatment using spring‒coil catheter is effective on chronic low
back and lower‒limb pain. The only reports of its efficacy on chronic cervicobrachial pain are observational studies and so as its level of safety has not been
established, careful judgment about its applicability is necessary. Treatmentusing epiduroscopy is highly useful on the adhesion of the epidural space as acause of chronic low back and lower‒limb pain and useful in diagnosing thesite which is highly responsible for the pain. It is highly effective in treating
lumbar failed back surgery syndrome (FBSS) but there is insufficient evidenceof its effects on lumbar spinal canal stenosis, and lumbar disc herniation.

Ⅲ．Interventional Management269

Summary of recommendation grades and overall evidence：1) Spring‒coil catheter
Chronic low back and lower‒limb pain：1B (Execution is strongly recommended)
Chronic cervicobrachial pain：2C (Execution is weakly recommended)
2) Epiduroscopy
Lumbar FBSS：2B (Execution is weakly recommended)
Lumbar spinal canal stenosis, other, intractable low back and inferior‒limb
pain：2C (Execution is weakly recommended)
Commentary：1) Spring‒coil catheter
Epidural neuroplasty and epidural adhesiolysis by spring-coil catheter, andepidural adhesiolysis by epiduroscopy, are forms of interventional therapy for
pain such as low back and inferior-limb pain and cervicobrachial pain as accompanying pain which is not responding to conservative medical treatment.
In a systematic review and meta‒analysis released in 2016 on spring‒coil
catheters1), they reported strong evidence of the effect of epidural neuroplasty
and epidural adhesiolysis on chronic intractable low back and inferior‒limb
pain. Patients with chronic radiculopathy, improved significantly at threemonths, six months, and twelve months in terms of their Oswestry Disability
Index (ODI) scores and VAS scores, compared with the placebo treatment (anVAS：visual analogue scaleindwelling catheter was placed under the skin, and patients were injected withnormal saline solution)2). In a report on patients with chronic low back and inferior‒limb pain, the VAS scores as well as the ODI scores significantly decreased after three months in the epidural neuroplasty group in contrast to thegroup that underwent physiotherapy, and at twelve months after the procedure, these results persisted3). In patients with lumbar FBSS, compared withpatients who received caudal epidural injection (steroid)，VAS had improved
significantly at one week, one month and six months4). There is a report inwhich NRS and ODI had significantly improved at three months, six months,
and twelve months, in comparison with caudal epidural injection (a local anaesthetic and steroid and 0.9%[w/v] sodium chloride solution [saline])5), and a report showing a significant improvement in NRS up to two years later and asignificant improvement in ODI up to one year later6). In a study on patientswith spinal canal stenosis, NRS and ODI significantly improved at threemonths, six months and twelve months, in comparison with caudal epidural injection (a local anaesthetic and steroid and 0.9%[w/v] sodium chloride solution[saline])7). In this way, we can see strong evidence regarding low back and inferior‒limb pain but due to differences in what is covered under the insurance
system overseas and in Japan, we need to consider that there are differences

NRS：numerical rating scale

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Ⅲ．Interventional Managementin the drugs used．There is an observation study reporting its efficacy on cervicobrachial pain8) and another report on its efficacy on sub-acute stage cervicobrachial pain9). However, these are only observation studies and as there are
no RCT reports, its effects and level of safety remain unclear. Therefore, we
are waiting for further research to be conducted.
2) Epiduroscopy
Epiduroscopy has high diagnostic value，and compared with lumbar MRI, it
allows us to make a diagnosis of adhesion to the epidural space as a cause of
intractable chronic low back and lower‒extremity pain and also the site which
is highly responsible for the pain. In a report on 78 cases of patients with lumbar FBSS, while they reported diagnosis of approximately 16% of cases of adhesion to the same site by MRI, in approximately 90% of the cases, adhesion
was recognized on epiduroscopy, and additionally, they reported that they
could diagnose the site which was responsible for the pain10). According to areport in 2005 on the effects on patients with intractable chronic low back andlower‒extremity pain (many of which were FBSS patients), in a RCT comparing adhesiolysis by epiduroscopy with caudal block11), by epiduroscopy they
were able to diagnose with certainty the site responsible for the pain, and byadministering patients with local anaesthetic and steroid after adhesiolysis of
the site, patients experienced a significant alleviation of pain for over six months
or more. In another observational study released in 2014 on 114 patients withFBSS12), in which they compared the effects of an epiduroscopy and a transforaminal epidural injection, six months later12), there was a significant recognizable improvement in low back NRS and lower‒extremity NRS and ODI in theepiduroscopy group, compared with prior to the procedure and its rate of efficacy was higher than in the group administered with a transforaminal epidural
injection. Furthermore, epiduroscopy was more effective in patients who had
undergone decompression surgery than in spinal fusion surgery.
Also, there are several reports which have shown the efficacy of epiduroscopy on lumbar FBSS13‒15), and a report indicating its efficacy on chronic sciatic
nerve pain16). In an observational study17) released in 2004 on the effects of adhesiolysis by epiduroscopy in patients with lumbar spinal canal stenosis, adhesiolysis by epiduroscopy was performed on patients with lumbar spinal canalstenosis who failed to respond to conservative medical treatment, and they reported a significant improvement in pain within one year for those with low
back pain, within one year for those with lower‒extremity pain of the nerve‒root type and within three months for those of the cauda‒equina type. At thecurrent stage, there are no reports on the evidence of effects of epiduroscopy
on lumbar disc hernia. In a systematic review and meta‒analysis released in
20161), they said that the amount of evidence supporting adhesiolysis by epi-

Ⅲ．Interventional Management

duroscopy is currently limited, and therefore mentioned the need to accumulate high‒quality data on its technical issues and applicability.
References1）Helm S 2nd, et al : Percutaneous and endoscopic adhesiolysis in managing low back and lower extremity pain : A systematic review and meta‒
analysis. Pain Physician 2016 ; 19 : E245‒E282
2）Gerdesmeyer L, et al : Percutaneous epidural lysis of adhesions in chronic lumbar radicular pain : A randomized, double‒blind, placebo‒controlled trial. Pain Physician 2013 ; 16 : 185‒1963）Veihelmann A, et al : Epidural neuroplasty versus physiotherapy to relieve pain in patients with sciatica : A prospective randomized blindedclinical trial. J Orthop Sci 2006 ; 11 : 365‒3694）Chun‒jing H, et al : The application of percutaneous lysis of epidural adhesions in patients with failed back surgery syndrome. Acta Cirurgica
Brasileira 2012 ; 27 : 357‒362
5）Manchikanti L, et al : A comparative effectiveness evaluation of percutaneous adhesiolysis and epidural steroid injections in managing lumbar
post surgery syndrome : A randomized, equivalence controlled trial. Pain
Physician 2009 ; 12 : E355‒E368
6）Manchikanti L, et al : Assessment of effectiveness of percutaneous adhesiolysis and caudal epidural injections in managing post lumbar surgery
syndrome : 2‒year follow‒up of a randomized, controlled trial. J Pain Res
2012 ; 5 : 597‒608
7）Manchikanti L, et al : The preliminary results of a comparative effectiveness evaluation of adhesiolysis and caudal epidural injections in managing chronic low back pain secondary to spinal stenosis : A randomized,
equivalence controlled trial. Pain Physician 2009 ; 12 : E341‒E354
8）Moon DE, et al : Assessment of clinical outcomes of cervical epidural
neuroplasty using a Racz‒catheter and predictive factors of efficacy inpatients with cervical spinal pain. Pain Physician 2015 ; 18 : E163‒E1709）Ji GY, et al : Randomized controlled study of percutaneous epidural neuroplasty using Racz catheter and epidural steroid injection in cervicaldisc disease. Pain Physician 2016 ; 19 : 39‒48
10）Bosscher HA, et al : Incidence and severity of epidural fibrosis after
back surgery : An endoscopic study. Pain Pract 2010 ; 10 : 18‒2411）Manchikanti L, et al : A randomized, controlled trial of spinal endoscopic
adhesiolysis in chronic refractory low back and lower extremity pain.
BMC Anesthesiol 2005 ; 5 : 10
12）Lee JH, et al : Clinical effectiveness of percutaneous adhesiolysis versus
transforaminal epidural steroid injection in patients with postlumbar
surgery syndrome. Reg Anesth Pain Med 2014 ; 39 : 214‒21813）Avellanal M, et al : Interlaminar approach for epidurascopy in patientswith failed back surgery syndrome. Br J Anaesth 2008 ; 101 : 244‒249
14）Richardson J, et al : Spinal endoscopy in chronic low back pain with radiculopathy : A prospective case series. Anaesthesia 2001 ; 56 : 454‒46015）Geurts JW, et al : Targeted methylprednisolone acetate/hyaluronidase/clonidine injection after diagnostic epiduroscopy for chronic sciatica : A
prospective, 1‒year follow‒up study. Reg Anesth Pain Med 2002 ; 27 : 343‒
352

271

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Ⅲ．Interventional Management16）Sakai T, et al : Adhesiolysis and targeted steroid/local anesthetic injection during epiduroscopy alleviates pain and reduces sensory nerve dysfunction in patients with chronic sciatica. J Anesth 2008 ; 22 : 242‒24717）Igarashi T, et al : Lysis of adhesions and epidural injection of steroid/local anaesthetic during epidurascopy potentially alleviate low back andleg pain in elderly patients with lumbar spinal stenosis. Br J Anaesth
2004 ; 93 : 181‒187
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

PubMed, MEDLINE, Cochrane Library
2005‒2017
Racz catheter, epidural neuroplasty, epidural adhesiolysis, epiduroscopy, endoscopic adhesiolysis
We searched for ‘chronic pain’ and ‘Racz catheter’ on Ichushi. We
narrowed down our search by RCT, meta‒analysis, systematic
review and review but there were no references which applied.
References 1‒9 were not based on our search method but wereadded due to their importance.
We searched for ‘chronic pain’ and ‘epiduroscopy’ on Ichushi. We
narrowed our search down by guidelines, RCT, meta‒analysis
and systematic review, and focused on the most recent academic
papers. References 2017 were not based on our search method
were added due to their importance.

CQ31：Is spinal cord stimulation effective in managing chronic pain?
SCS：spinal cord stimulation

Answer：Spinal cord stimulation (SCS) has a unique analgesic mechanism,based on neuromodulation, which has the value of being trialed on patientswith chronic pain in which other forms of treatment proved to be insufficient．

FBSS：failed back surgery
syndrome

In particular, its utility on patients with failed back surgery syndrome (FBSS),

PDPN：painful diabetic
peripheral neuropathy(PDPN) has been indicated. It is different from other forms of interventional

peripheral vascular disorders，and painful diabetic peripheral neuropathy
therapy in that it is not directly invasive on the site of pain and in that it is areversible form of treatment. These are the advantages of spinal cord stimulation.
Summary of recommendation grades and overall evidence：
1) Failed back surgery syndrome (FBSS)：1B (Execution is strongly recommended)
2) Peripheral vascular disorders：1B (Execution is strongly recommended)
3) Painful diabetic peripheral neuropathy (PDPN)：2B (Execution is weakly recommended)

CPSP：central post-stroke
pain4) Central post‒stroke pain (CPSP)：2C (Execution is weakly recommended)
5) Pain in the extremities due to multiple sclerosis：2C (Execution is weakly
recommended)

6) Post‒spinal cord injury pain：2C (Execution is weakly recommended)
CRPS：complex regional
pain syndrome7) Complex regional pain syndrome (CRPS) type Ⅰ：2C (Execution is weakly
recommended)

CRPS type Ⅱ：2D (Execution is weakly recommended)

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Ⅲ．Interventional Management

8) Phantom limb pain：2C (Execution is weakly recommended)
9) Postcervical spine surgery cervico‒omo‒brachial pain：2D (Execution is
weakly recommended)

10) Brachial plexus avulsion injury：2D (Execution is weakly recommended)
11) Postherpetic neuralgia：2D (Execution is weakly recommended)

PHN：postherpetic neuralgia

12) Angina pectoris：2D (Execution is weakly recommended)
Commentary：
1) Failed back surgery syndrome (FBSS)
There are six RCTs on FBSS，which have reported on the efficacy of tonic
stimulation

1,2)

3)

, the efficacy of burst stimulation , the efficacy of 10kHz high‒frequency stimulation4,5), and the efficacy of adaptive stimulation6). In a reportcomparing a group of patients who had undergone surgery again with a group
who had undergone SCS，they claimed that it was more effective in the SCS
group than in the group who had undergone surgery again1). In a RCT on a

RCT：randomized controlled
trial
adaptive stimulation：
When the patient change
positions, the stimulationlevel is automaticallyadjusted.

large number of facilities, they compared SCS with conservative forms of medical treatment，and reported a greater amount of pain relief, a larger improvement in quality of life (QOL) and a higher level of satisfaction in the SCS group2)

than in the conservative medical treatment group . With conventional tonic
stimulation, they reported a sufficient level of efficacy but expect that the newer stimulation methods, which are burst stimulation and high‒frequency stimulation, will have an even greater efficacy.
2) Peripheral vascular disorders
There is a systematic review on a total of 444 patients from six reports on
pain of the extremities due to peripheral vascular disorders7). The limb salvage
rate one year after SCS was 83%, they recognized that pain had been alleviated and the dosages of analgesics had been significantly decreased. They reported that conservative medical treatments were ineffective, could not be applied
for revascularization，that it could be applied in cases of ulcers which were
3cm in size or less, and that a transcutaneous partial pressure of oxygen (TcPO2)of 10～30 mmHg was a selecting indicator for patients.
3) Painful diabetic peripheral neuropathy (PDPN)

There are two RCTs on pain of the extremities due to painful diabetic peripheral neuropathy (PDPN). In one study, 60 patients were enrolled and wererandomly allocated into either a SCS group or a control group. After six
months, the VAS scores in the SCS group had decreased from 73 to 31 but inthe control group, there was no recognizable change from 67 to 678). In the other RCT, 22 patients underwent test stimulation of SCS, and seventeen patients
received an implant. Eleven out of these seventeen subjects (65%) reported a
reduction in pain of 50% or more, which persisted for up to two years later9).

QOL：quality of life

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Ⅲ．Interventional Management

4) Central post‒stroke pain (CPSP)
There was a retrospective study on central post‒stroke pain, which reported
that it had been effective in seven subjects out of 3010), and also another which
report that it had been effective in three subjects out of 45 (7%)11). Although
the efficacy rate is not high, before conducting invasive treatments such as
DBS：deep brain stimulation
MCS：motor cortex
stimulation
SCS：spinal cord stimulation

deep brain stimulation (DBS) and motor cortex stimulation (MCS), it could begiven some consideration as a form of treatment.
5) Pain in the extremities due to multiple sclerosis (MS)In a retrospective research study, out of 410 subjects who underwent SCS，
seventeen subjects suffered from lower‒extremity pain due to multiple sclerosis (MS), and fifteen of these subjects experienced a 50% or greater relief in
pain over the long‒term12). There is not a high level of evidence but it could begiven some consideration when no other analgesic methods are available.
6) Post‒spinal cord injury
In a retrospective research study on post‒spinal cord injury, twelve subjects
with incomplete spinal cord injury underwent SCS，and they reported that

NRS：numerical rating scale

their NRS scores decreased from 9.9 to 3.613). There is not a high level of evidence but it could be given some consideration when no other analgesic methods are available.
7) Complex regional pain syndrome (CRPS)
There are retrospective studies and RCTs on CRPS type Ⅰ. One group underwent a combination of SCS and physiotherapy while the other group only
underwent physiotherapy. Six months later, while the level of pain in the SCS
group had decreased in NRS by 2.4, it had increased in the physiotherapy
group by 0.2. Therefore they reported14) that it had significantly decreased in
the SCS group. Two years later they had the same kind of results15), but three
years later, four years later, and five years later, there was no recognizable difference between the two groups16). There are only several case series on CRPS
type Ⅱ suggesting the efficacy of SCS, so the level of evidence is not high．
We can expect SCS to be effective on CRPS type I but it is possible that it
does not provide long-term effects．Currently studies are being conducted onwhether burst stimulation and high-frequency stimulation improve efficacy or
not17). We need to exercise careful judgment when it comes to its applicability
for CRPS type Ⅱ.
8) Phantom limb pain
A systematic review has reported on its efficacy on phantom limb pain18) but
in each of these reports, the number of subjects is small and therefore thequality of evidence is not high.
9) Post‒cervical spine surgery cervico‒omo‒brachial pain
There is a case series on post‒cervical spine surgery cervico‒omo‒brachial

Ⅲ．Interventional Management

275

pain. Five subjects suffering from cervico‒omo‒brachial pain after cervical fusion according to a previous approach, underwent SCS, and four of these subjects reported pain relief of up to 70～90%19). It is possible that SCS might beeffective on cervical pain and upper‒limb pain following cervical spine surgery
but there is no high quality evidence.
10) Brachial plexus avulsion injury
There are some retrospective research studies on brachial plexus avulsion
injury20,21). Four subjects suffering from brachial plexus avulsion injury underwent a SCS trial and in all cases experienced alleviation of pain and therefore
they underwent an implant procedure. Up to nine months following the procedure, their pain gradually became lighter and they reported a reduction in
NRS scores, from a score of 9 prior to the procedure to 5.9 in the ninth-monthfollowing the procedure20). There is little high-quality evidence but it is possible that it is effective on upper‒limb pain due to brachial plexus avulsion injury，and it should be given some consideration before patients undergo invasive treatments such as dorsal root entry zone lesion (DREZ).
11) Postherpetic neuralgia
There is prospective study on postherpetic neuralgia (PHN)．28 patientswith PHN underwent SCS, and 23 subjects (82%) reported a significant improvement in pain22). The efficacy rate is not high but SCS could be given
some consideration when no other analgesic methods are available.
12) Angina pectoris
Although this treatment is not eligible for coverage under the Japanese
health insurance system, there have been reports on the efficacy of SCS in
treating angina pectoris．In a review on treating patients with intractable angina pectoris, SCS decreased the number of angina pectoris attacks and wasreported as a useful method for improving patient’s QOL23).
References
1）North RB, et al : Spinal cord stimulation versus repeated lumbosacral
spine surgery for chronic pain : A randomized, controlled trial. Neurosurgery 2005 ; 56 : 98‒106, discussion 106‒1072）Kumar K, et al : Spinal cord stimulation versus conventional medical
management for neuropathic pain : A multicentre randomised controlled
trial in patients with failed back surgery syndrome. Pain 2007 ; 132 : 179‒
1883）Schu S, et al : A prospective, randomised, double‒blind, placebo‒controlled study to examine the effectiveness of burst spinal cord stimulation patterns for the treatment of failed back surgery syndrome. Neuromodulation 2014 ; 17 : 443‒4504）Perruchoud C, et al : Analgesic efficacy of high‒frequency spinal cord
stimulation : A randomized double‒blind placebo‒controlled study. Neuromodulation 2013 ; 16 : 363‒369, discussion 369

DREZ：dorsal root entry
zone lesion

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Ⅲ．Interventional Management

5）Kapural L, et al : Novel 10‒kHz high‒frequency therapy（HF10 therapy）
is superior to traditional low‒frequency spinal cord stimulation for thetreatment of chronic back and leg pain : The SENZA‒RCT randomized
controlled trial. Anesthesiology 2015 ; 123 : 851‒8606）Schultz DM, et al : Sensor‒driven position‒adaptive spinal cord stimulation for chronic pain. Pain Physician 2012 ; 15 : 1‒127）Ubbink DT, et al : Spinal cord stimulation for critical leg ischemia : A review of effectiveness and optimal patient selection. J Pain Symptom
Manage 2006 ; 31 : S30‒S358）de Vos CC, et al : Spinal cord stimulation in patients with painful diabetic
neuropathy : A multicentre randomized clinical trial. Pain 2014 ; 155 :
2426‒2431
9）van Beek M, et al : Sustained treatment effect of spinal cord stimulationin painful diabetic peripheral neuropathy : 24‒Month follow‒up of a prospective two‒center randomized controlled trial. Diabetes Care2015 ; 38 : e132‒e13410）Aly MM, et al : Spinal cord stimulation for central poststroke pain. Neurosurgery 2010 ; 67 : ons206‒212 ; discussion ons212
11）Katayama Y, et al : Motor cortex stimulation for post‒stroke pain : comparison of spinal cord and thalamic stimulation. Stereotact Funct Neurosurg 2001 ; 77 : 183‒18612）Kumar K, et al : Spinal cord stimulation in treatment of chronic benign
pain : Challenges in treatment planning and present status, a 22‒year experience. Neurosurgery 2006 ; 58 : 481‒496, discussion 481‒49613）Rogano L, et al : Chronic pain after spinal cord injury : Clinical characteristics. Stereotact Funct Neurosurg 2003 ; 81 : 65‒6914）Kemler MA, et al : Spinal cord stimulation in patients with chronic reflex
sympathetic dystrophy. N Engl J Med 2000 ; 343 : 618‒62415）Kemler MA, et al : The effect of spinal cord stimulation in patients withchronic reflex sympathetic dystrophy : Two years’ follow‒up of the randomized controlled trial. Ann Neurol 2004 ; 55 : 13‒1816）Kemler MA, et al : Effect of spinal cord stimulation for chronic complex
regional pain syndrome type I : Five‒year final follow‒up of patients in arandomized controlled trial. J Neurosurg 2008 ; 108 : 292‒29817）Kriek N, et al : Comparison of tonic spinal cord stimulation, high‒frequency and burst stimulation in patients with complex regional pain
syndrome : A double‒blind, randomised placebo controlled trial. BMC
musculoskeletal disorders 2015 ; 16 : 222
18）Aiyer R, et al : A systematic review on the treatment of phantom limb
pain with spinal cord stimulation. Pain Manag 2017 ; 7 : 59‒6919）Vallejo R, et al : Neuromodulation of the cervical spinal cord in the treatment of chronic intractable neck and upper extremity pain : A case series and review of the literature. Pain Physician 2007 ; 10 : 305‒31120）Piva B, et al : Spinal cord stimulation in the management of pain frombrachial plexus avulsion. Neuromodulation 2003 ; 6 : 27‒3121）Garcia‒March G, et al : Dorsal root entry zone lesion versus spinal cord
stimulation in the management of pain from brachial plexus avulsion.
Acta Neurochir Suppl 1987 ; 39 : 155‒15822）Harke H, et al : Spinal cord stimulation in postherpetic neuralgia and inacute herpes zoster pain. Anesth Analg 94 : 694‒700 ; table of contents23）Borjesson M, et al : Spinal cord stimulation for long‒term treatment of

Ⅲ．Interventional Management277

severe angina pectoris : What does the evidence say? Future Cardiol
2011 ; 7 : 825‒833
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

PubMed, MEDLINE, Cochrane Library
2005‒2017spinal cord stimulation
We searched for ‘chronic pain’ and ‘spinal cord stimulation’ on
Ichushi. We narrowed our search down by RCT, meta‒analysis,
systematic review and review and focused on the most recent academic papers. References 2, 4, 7-17, 19-23 were not from oursearch method but were added due to their importance.

CQ32：Are intradiscal therapies effective in managing chronic pain?
Answer：An intradiscal steroid injection has limited efficacy on discogenic
low back pain. There are several forms of intradiscal therapies, which are limited, but have been shown to be effective.
Summary of recommendation grades and overall evidence：
1) Diagnostic discography：2C (Execution is weakly recommended)
2) Lumbar intradiscal steroid injection：2C (Execution is weakly recommended)
3) Intradiscal therapies：2C (Execution is weakly recommended)
Commentary：1) Diagnostic discography
Injection into the lumbar intervertebral disc is used to diagnose discogenic
low back pain and assumes that at the time of injection, inducement of pain ispositive. According to the diagnostic standards1) of the International Association for the Society of Pain (IASP), it is useful with analgesic effects by using a
local anesthetic, can be continued for a suitable amount of time, and as long as

IASP：International
Association for the Study ofPain

it induces no pain by injection into adjoining intervertebral discs, it has highdiagnostic value2). It can also be useful as a pre-surgical test3). There is somedebate over its accuracy for diagnosis and furthermore, as it has been suggested that it may possibly help advance degenerative changes in the disc4), its applicability needs to be given careful scrutiny. There have been almost no reports on thoracic intervertebral disc injections5) but there is a review of 41
studies related to cervical intervertebral disc injections6) and each one indicates its limited diagnostic effects.
2) Lumbar intradiscal steroid injection
As a form of treatment, there is a review7) denying the efficacy of injecting
steroid into the lumbar intervertebral disc with strong supporting evidence.
On the other hand, there is also a RCT8) indicating its short‒term efficacy on
discogenic low back pain accompanying modic changes in the vertebral body

RCT：randomized controlled
trial

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Ⅲ．Interventional Management

on MRI. It has limited applicability for the period of activity of discogenic low
back pain accompanying inflammation of the endplate.
3) Intradiscal therapy
Intradiscal therapy is an intervention, in which a cannula is punctured into
the intervertebral disc percutaneously, under fluoroscopy, but is shown to beof limited efficacy as there are few high-quality RCTs.
Percutaneous discectomy reduces intradiscal pressure by removing the nucleus pulposus. It has been shown to have therapeutic effects especially on thecontained type of disc herniation which means herniated disc material remains
below the posterior longitudinal ligament without leaking into epidural space (adisc protrusion and subligamentous extrusion). Automated percutaneous lumbar discectomy (APLD) is a system developed in 1985 with an automated suction‒cutting device using pistons which removes the nucleus pulposus. There
are no RCTs about it but there are many observational studies. In a review ofnineteen studies9), they showed that it was effective in 80% of cases out of a total of 5,515 patients one year later. Percutaneous disc decompression (PDD) isa system which uses an “Archimedian screw” to remove the nucleus pulposus,
and uses a cannula with an outside diameter of 15mm, making it easy to perform with precision. In a review of three observational studies, which does notinclude any RCTs, they recognize its short‒term and long‒term effects, but evidence is limited10).
PLDD：percutaneous laser
disc decompression

Percutaneous laser disc decompression (PLDD) is a procedure for reducing
intradiscal pressure. It reduces the volume of the area by vaporizing the nucleus pulposus watery material through laser irradiation. In a review of fifteen
observational studies, they indicated its short‒term and long‒term efficacy onintervertebral disc hernia but there are no RCTs on it so evidence is limited11).

IDET：intradiscal electrothermal treatment

Intradiscal electrothermal treatment (IDET) is performed on lumbar discogenic pain. A flexible heating element is inserted through a cannula and in acircular fashion alongside the annulus of the disc and the catheter’s coil isplaced on the site of lesion of the posterior annulus. Radiofrequency denervation (RF) is performed via the coil, causing changes in the nerves of the annulus and thereby reducing pain. In a recent review, there were two RCTs. In
one of these studies, it was effective over the short‒term in 40% of cases but inthe other study, it did not prove to be effective, even though the level of evidence was low. In addition, there have been six observational studies, in whichfour of them it was found to be effective, one in which it was found to be negative and in the remaining study, the results were inconclusive. To sum up
these studies, it is weakly recommended12).
New interventions are also being trialed. There is a procedure, which has
been named annulo‒nucleoplasty, using radio waves. It uses one cannula toⅢ．Interventional Management

surgically remove the nucleus pulposus with the aid of forceps and using aprobe with a bent tip it performs nucleus ablation and annular modulation. In
addition to the contained type of disc herniation, it is considerd to have shown
its efficacy on low back pain due to degenerative intervertebral disc and there
is an observational study in which it proved to be effective up to one year later13). Intradiscal pulsed radiofrequency (PRF), is a procedure, which brings pain
relief by placing an active tip in the middle of the intervertebral disc and supplying RF. Its analgesic mechanism is unknown, but it is considered to be highly safe as it does not cause damage due to heat or tissue damage and there
are several observational studies, which have reported on it. Fukui et al.14), exposed exposed subjects, diagnosed with intervertebral lumbar disc pain, with
PRF under discography, for 15 minutes and reported that it showed analgesic
effects up to twelve months later. In future, we would like to see an accumulation of evidence on these types of procedures.
It is hard to conduct controlled studies on intradiscal therapies and although
there is insufficient evidence, in cases in which conservative medical treatment
proved to be ineffective, we might consider performing this treatment after
careful deliberating its applicability. Regarding radiculopathy due to intervertebral disc herniation, contained type of disc herniation has good applicability but
prior to procedure, as the quality of evidence is low, we recommend performing diagnostic blocks such as nerve root block and discography. As discogenic
low back pain is hard to diagnose, through conducting discography in addition
to the MRI findings on intervertebral disc degeneration, we need to clarify thelesions responsible and also properly differentiate other causing factors as well.
References
1）https : //www. iasp‒pain. org/files/Content/ContentFolders/Publications2/ClassificationofChronicPain/Part_II‒G. pdf2）Manchikanti L, et al : An update of the systematic appraisal of the accuracy and utility of lumbar discography in chronic low back pain. Pain
Physician 2013 ; 16 : SE55‒SE95
3）Eck JC, et al : Guideline update for the performance of fusion proceduresfor degenerative disease of the lumbar spine. : Part 6 Discography forpatient selection. J Neurosurg Spine 2014 ; 21 : 37‒414）Carragee EJ, et al : 2009 ISSLS Prize Winner : Does discography cause
accelerated progression of degeneration changes in the lumbar disc : Aten‒year matched cohort study. Spine（Phila Pa 1976）2009 ; 34 : 2338‒
2345
5）Singh V, et al : An update of the appraisal of the accuracy of thoracic
discography as a diagnostic test for chronic spinal pain. Pain Physician
2012 ; 15 : E757‒E775
6）Onyewu O, et al : An update of the appraisal of the accuracy and utilityof cervical discography in chronic neck pain. Pain Physician 2012 ; 15 :E777‒E806

279

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7）Chou R, et al : Nonsurgical interventional therapies for low back pain : A
review of the evidence for an American Pain Society clinical practiceguideline. Spine 2009 ; 34 : 1078‒1093
8）Cao P, et al : Intradiscal injection therapy for degenerative chronic discogenic low back pain with end plate modic changes. Spine J 2011 ; 11 :100‒106
9）Manchikanti L, et al ; An updated review of automated percutaneous
mechanical lumbar discectomy for the contained herniated lumbar disc.
Pain Physician 2013 ; 16 : SE151‒SE18410）Helm Ii S, et al ; Effectiveness of thermal annular procedures in treating
discogenic low back pain. Pain Physician 2012 ; 15 : E279‒E304
11）Manchikanti L, et al : Percutaneous lumbar mechanical disc decompression utilizing Dekompressor®: An update of current evidence. Pain Physician 2013 ; 16 : SE1‒SE2412）Singh V, et al : Percutaneous lumbar laser disc decompression : An update of current evidence. Pain Physician 2013 ; 16 : SE229‒SE260, 201313）Kumar N, et al : Annulo‒nucleoplasty using Disc‒FX in the managementof lumbar disc pathology : early results. Int J Spine Surg 2014 ; 1 ; 814）Fukui S, et al : Intradiscal pulsed radiofrequency for chronic lumbar discogenic low back pain : A one year prospective outcome study using discoblock for diagnosis. Pain Physician 2013 ; 16 : E435‒E442
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

PubMed, MEDLINE, Cochrane Library
2005‒2017
lumbar discography
We narrowed our search down by guidelines, RCT, meta‒analysis
and systematic review, and focused on the most recent academic
papers. There are various procedures for intervertebral disctreatment so we ran a search for these one‒by‒one on PubMed.

CQ33：Are intra‒articular injections effective in managing chronic pain?
Answer： Evaluations of the effects of intra‒articular steroid injection on osteoarthritis of the knee (knee OA) are uneven. It is effective over the short‒term and long‒term on adhesive capsulitis (periarthritis scapulohumeralis) andusing steroid injection in combination with physiotherapy may possibly improve its efficacy. Its effects should be constantly evaluated and it is important
not to continue injections over the long‒term, without a particular purpose in
RCT：randomized controlled
trial

mind. There are some RCTs showing that an intra‒articular hyaluronic acid injection is effective on knee OA and adhesive capsulitis. However we cannot
say that there is high‒quality evidence and therefore more evidence needs tobe compiled in future in order to draw conclusions. It is also useful to use an
ultrasound device.

Ⅲ．Interventional Management

Summary of recommendation grades and overall evidence：
1) Knee OA
Intra‒articular steroid injection：2C (Execution is weakly recommended)
Intra‒articular hyaluronic acid injection：2C (Execution is weakly recommended)
2) Adhesive capsulitis
Intra‒articular steroid injection：2C (Execution is weakly recommended)
Intra‒articular hyaluronic acid injection：2C (Execution is weakly recommended)
Subacromial bursa steroid injection：2C (Execution is weakly recommended)
Commentary：
In this CQ, we will discuss intra‒articular injections on knee OA and adhesive capsulitis. There are many RCTs and meta‒analyses on the efficacy of
intra‒articular injection on knee OA and adhesive capsulitis.
1) Knee OA
In the ‘Osteoarthritis Research Society International (OARSI) guidelines’1),
they compared the effects of intra‒articular steroid injection into the knee withintra‒articular hyaluronic acid injection into the knee in patients with knee
OA, and concluded that the early‒stage pain‒suppressing effects of the intra‒
articular steroid injection into the knee were higher than those from the intra‒
articular hyaluronic acid injection into the knee. In contrast, in a meta‒analysis
comparing the longer‒term effects of both, they reported that from twelve
weeks onwards, intra‒articular hyaluronic acid injection into the knee displayed more significant pain‒suppressing effects than an intra‒articular steroid
injection into the knee2). In a meta‒analysis of twelve studies on OA, in which
they compared both injections 3), they concluded that over the short‒term(within one month), an intra‒articular steroid injection into the knee showed
more significant analgesic effects than an intra‒articular hyaluronic acid injection into the knee, but, on the contrary, over the longer term of six months or
more, an intra‒articular hyaluronic acid injection into the knee showed moresignificant effects. There was no significant difference between the two groups
in terms of the number of times analgesics were used on an as‒needed basis orin terms of range of motion (ROM) of the joint. This indicates that an intra‒articular steroid injection may be effective over the short‒term while an intra‒
articular hyaluronic acid injection may be effective over the long‒term. On theother hand, there is a systematic review4) which showed no significant difference over the short‒term in pain‒suppressing effects with an intra‒articular
steroid injection into the knee4), and so there is an uneven perception of its effects.
The ‘OARSI guidelines’1) have also discussed the safety of intra‒articular steroid injection into the knee and there is a RCT5) which showed a recognizable
reduction in cartilage due to regular intra‒articular steroid injection into the

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knee, and therefore steroid injections should be limited to single doses in cases
where symptoms are strong and should not be administered regularly.
In a meta‒analysis6) investigating the effects of intra‒articular hyaluronic
acid injection into the knee, compared with the placebo, the degree of effectfrom the intra‒articular injection into the knee was small but from 4 ～ 24
weeks, it showed significant pain‒suppressing effects. In a single‒blinded RCTon the effects of intra‒articular hyaluronic acid injection into the knee andintra‒articular steroid injection into the knee on patients with OA, there was a
VAS：visual analogue scalesignificant improvement in VAS scores in the hyaluronic acid group and arecognizable improvement in knee function scores as well7). In addition, there
are dozens of RCTs investigating the efficacy of intra‒articular hyaluronic acidinjection into the knee but due to a lack of uniformity among the researchstudies (drug dosage used, molecular weight of the agent, period of administration, outcomes), we cannot say that there is high‒quality evidence indicating its
efficacy and safety. Furthermore, in Japan, there are many instances in which
intra‒articular hyaluronic acid injection is administered, starting with mild cases, for the purposes of joint protection, whereas overseas it is recommended insevere cases and therefore the treatment environment varies to a large degree.
We need to accumulate evidence unique to Japan. When administering an intra‒
articular knee injection, we need to constantly assess its effects and it should
not be continuously administered over the long‒term without a particular purpose in mind.
2) Adhesive capsulitis
According to the Guidelines of the American Physical Therapy Association(APTA)8), they found that a combination of intra‒articular steroid injection into
the shoulder along with range of motion (ROM) exercises on the joint andstretching was more effective over the short‒term (4 ～ 6 weeks) in terms ofpain and functional improvement of adhesive capsulitis, than just ROM exercises of the joint and stretching alone. In a systematic review9) of five RCTs related to the efficacy of intra‒articular shoulder steroid injection on adhesive capsulitis, they compared the effects of an intra‒articular shoulder steroid injection
with an intra‒articular shoulder 0.9%[w/v] sodium chloride solution [saline]) injection. In four out of the five papers, they administered a single dose and in
the other 1 study they administered a total of three doses every other week.
They showed that over the short‒term (0～8 weeks), an intra‒articular shoulder steroid injection had more significant pain‒suppressing effects but there
was no difference at 9～24 weeks after administration. Furthermore, intra‒articular shoulder steroid injection showed a more significant improvement inpassive shoulder range of motion (ROM) but this significant difference wasonly temporary. Due to the small number of subjects used and the lack of uni-

Ⅲ．Interventional Management

formity between the research studies, we need more high‒quality RCT studies
in order to show its efficacy. In a systematic review10) of 9 RCTs regarding theeffects of intra‒articular shoulder steroid injection＋physiotherapy, and either
at‒home exercises or physiotherapy alone, there was a recognizable improvement in reduction of pain and improved movement at 6 weeks and at 6 months
in the group which was also administered with an intra‒articular shoulder steroid injection. In addition, in a systematic review of eight studies comparing
the effects of an intra‒articular shoulder steroid injection with an intra‒articular shoulder saline injection solution on frozen shoulder, they showed that intra‒
articular shoulder steroid injection may possibly be more effective over the
short‒term and medium‒term11). However, in each of these reports, subjects
were often administered with a single dose and so there is a need for high‒quality RCTs related to the frequency of injections. As we saw with knee OA,
single doses should be limited to only when symptoms are strong and it should
not be administered regularly.
In a forward‒looking study which compared the efficacy of a subacromial
bursa steroid injection with an intra‒articular shoulder steroid injection on frozen shoulder, they reported a significant improvement in pain over the short‒term in the group administered with an intra‒articular shoulder steroid injection but over the long‒term there was no recognizable significant difference
and there was no difference with range of motion (ROM) of the joint12). In a
RCT which compared the efficacy of intra‒articular shoulder steroid injection,
subacromial bursa steroid injection and intra‒articular shoulder saline injection
on frozen shoulder, there was a significant improvement in range of motion(ROM) of the joint and pain in the group administered with an intra‒articularshoulder saline injection one month later but they reported no significant difference at three months and six months after administration13). We might possibly recognize the short‒term effects of subacromial bursa steroid injection
but there is no high‒quality evidence. Just like with knee OA, administration
should be limited to single doses in cases where symptoms are strong andshould not be administered regularly.
In a systematic review14) of intra‒articular shoulder hyaluronic acid injection,
they investigated three RCTs but due to a lack of uniformity between the research studies, the evidence is insufficient.
Furthermore, in a systematic review of intra‒articular joint injections performed under ultrasound guidance, they reported an improvement in accuracy
and efficacy15).
As with knee OA, we need to constantly assess the effects when it is performed and it should not be continuously administered over the long‒term
without a particular purpose in mind.

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References
1）McAlindon, et al : OARSI guidelines for the non‒surgical management ofknee osteoarthritis. Osteoarthritis Cartilage 2014 ; 22 : 363‒3882）Bannuru RR, et al : Therapeutic trajectory of hyaluronic acid versus corticosteroids in the treatment of knee osteoarthritis ; A systematic review
and meta‒analysis. Arthritis Rheum 2009 ; 61 : 1704‒1711
3）He WW, et al : Efficacy and safety of intraarticular hyaluronic acid andcorticosteroid for knee osteoarthritis : A meta‒analysis. Intl J Surg2017 ; 39 : 95‒1034）Jüni P, et al : Intra‒articular corticosteroid for knee osteoarthritis. Cochrane Database Syst Rev 2015 ; 10 : CD005328
5）McAlindon TE, et al : Effect of intra‒articular triamcinolone vs saline on
knee cartilage volume and pain in patient with knee osteoarthritis : A
randomized clinical trial. JAMA 2017 ; 317 : 1967‒1975
6）Bannuru RR, et al : Therapeutic trajectory following intra‒articular hyaluronic acid injection in knee osteoarthritis : Meta‒analysis. Osteoarthritis
Cartilage 2011 ; 19 : 611‒6197）Bisicchia S, et al : HYADD 4 versus methylprednisolone acetate in symptomatic knee osteoarthritis : A single‒centre single blind prospective
randomised controlled clinical study with 1‒year follow‒up. Clin Exp
Rheumatol 2016 ; 34 : 857‒8638）Kelley MJ, et al : Shoulder pain and mobility deficits : Adhesive capsulitis. J Orthop Sports Phys Ther 2013 ; 43 : A1‒A319）Wang W, et al : Effectiveness of corticosteroid injection in adhesive capsulitis of shoulder : A systematic review and Meta‒analysis. Medicine
2017 ; 96 : e7529
10）Sun Y, et al : Steroid injection versus physiotherapy for patients withadhesive capsulitis of the shoulder : A PRIMSA systematic review andmeta‒analysis of randomized controlled trials. Medicine 2016 ; 95 : e3469
11）Sun Y , et al : Intra‒articular steroid injection for frozen shoulder : A
systematic review and meta‒analysis of randomized controlled trials
with trial sequential analysis. Am J Sports Med 2017 ; 45 : 2171‒2179
12）Oh JH, et al : Comparison of glenohumeral and subacromial steroid injection in primary frozen shoulder : A prospective, randomized short‒term
comparison study. J Shoulder Elbow Surg 2011 ; 20 : 1034‒1040
13）Yoon JP, et al : Intra‒articular injection, subacromial injection, and hydrodilatation for primary frozen shoulder : A randomized clinical trial. J
Shoulder Elbow Surg 2016 ; 25 : 376‒38314）Lee LC, et al : Effectiveness of hyaluronic acid administration in treating
adhesive capsulitis of the shoulder : A systematic review of randomized
controlled trials. Biomed Res Int 2015 ; 2015 : 314120
15）Aly AR, et al : Ultrasound‒guided shoulder girdle injections are more accurate and more effective than landmark‒guided injections : A systematic review and meta‒analysis. Br J Sports Med 2015 ; 49 : 1042‒1049

Ⅲ．Interventional Management

Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

PubMed, MEDLINE, Cochrane Library
2005‒2017
osteoarthritis, intra‒articular corticosteroid, frozen shoulder,shoulderWe narrowed our search down by guidelines, RCT, meta‒analysis
and systematic review and focused on the most recent academic
papers. References 1-3, 5-8, 10-15 which were not found using
our search method, we searched for by hand and were added dueto their importance.

285

Chapter Ⅰ

Overview：CQ1～CQ7

Chapter Ⅱ

Pharmacotherapy：CQ8～CQ21

Chapter Ⅲ

Interventional Management：CQ22～CQ33

Chapter Ⅳ

Psychological Approach：CQ34～CQ39

Chapter Ⅴ

Rehabilitation：CQ40～CQ46

Chapter Ⅵ

Multidisciplinary Treatment：CQ47～CQ51

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Ⅳ．Psychological Approach

CQ34：Is psychoeducation effective in managing chronic pain?
Answer：There is low‒quality evidence that the execution of psychoeducation alone is effective on chronic pain but we do recommend the basics of psychoeducation as a psychological approach.
Summary of recommendation grades and overall evidence：1C (Execution isstrongly recommended)

Commentary：
Within a psychological approach to chronic pain, the most fundamental principle is psychoeducation. This psychoeducation is defined as “conveying thecorrect knowledge and information about diseases which are hard for the patient to accept, considering the psychological aspects, and educating them andassisting them with coping methods for their issues.” In other words, psychoeducation is already included with various types of psychological treatments,
and it would be safe to say that there is no psychological approach which does
not include psychoeducation. For this reason, unfortunately, there is almost no
research which has assessed the effects of psychoeducation alone. On the other
hand, there are cases in which psychoeducation has been used as an active
control group for actual treatment when investigating the effects of other psychological approaches. For example, the Cochrane Review on chronic pain patients includes research which used educational programs as a control group inorder to see the effects of cognitive behavioral therapy (CBT)1). However, there
are few high quality research studies which have clearly showed the effects ofpsychoeducation.
In a Cochrane Review on cervical pain, irrespective of whether symptoms ofradiculopathy were present or not, they evaluated psychoeducation, including
what is so‒called the ‘Neck School’, in which subjects were educated on instress coping：
ストレス対処行動

creasing the amount of physical activity and were educated on pain and stresscoping, but in each case the effects were refuted2). However, there was only asmall number of applicable research papers, and therefore they mentioned thefuture need for research on specified educational programs. Furthermore, evenin other Cochrane Reviews on cervical pain, the educational effects of the levelof daily activity, stress coping, the ergonomical approach, and self‒care ap-

RCT：randomized controlled
trial

proach, did not prove to be effective3). However, in a RCT on a 12‒minute video education on patients with traumatic cervical syndrome, they reported thatthe pain had reduced by the time of six months follow‒up, and physical dysfunction had been prevented and in the Cochrane Review, they evaluated thisas a high‒quality study4). In addition, in a RCT on a short‒term educational
program of primary care on low back pain, they reported that although it had

Ⅳ．Psychological Approach

had a small effect on pain, physical dysfunction and catastrophizing, the effects
did persist for a six-month period5). Furthermore, some have also presented aunique form of treatment in which an educational textbook on pain is read out
for patients with low back pain6). Although we cannot call it general psychoeducation, there was also a systematic review of neuroscience educational programs on pain7). In this review, they assessed that this program had effects on
pain and physical dysfunctions.
As mentioned above, although there is evidence of no considerable effects ofconducting psychoeducation alone for managing chronic pain, we must also
consider the fact that there is a lack of uniformity, for example in terms ofwhich diseases are targeted and their educational procedures, but realisticallybecause they clearly act as the foundations for other types of psychotherapy(the psychological approach), we have decided that they be recommended.
References
1）Williams AC, et al : Psychological therapies for the management ofchronic pain（excluding headache）in adults. Cochrane Database Syst
Rev 2012 ; 11 : CD007407
2）Haines T, et al : Patient education for neck pain with or without radiculopathy. Cochrane Database Syst Rev 2009 ; 1 : CD005106
3）Gross A, et al : Patient education for neck pain. Cochrane Database Syst
Rev 2012 ; 3 : CD005106
4）Oliveira A, et al : A psycho‒educational video used in the emergency department provides effective treatment for whiplash injuries. Spine（Phila Pa 1976）2006 ; 31 : 1652‒1657
5）Albaladejo C, et al : The efficacy of a short education program and ashort physiotherapy program for treating low back pain in primarycare : A cluster randomized trial. Spine（Phila Pa 1976）2010 ; 35 : 483‒4966）Udermann BE, et al : Can a patient educational book change behavior
and reduce pain in chronic low back pain patients? Spine J 2004 ; 4 : 425‒
4357）Louw A, et al : The effect of neuroscience education on pain, disability,
anxiety, and stress in chronic musculoskeletal pain. Arch Phys Med Rehabil 2011 ; 92 : 2041‒2056
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

Cochrane Library, PubMed
2004‒2017
psychoeducation, pain education
From these results, we selected references by focusing mainly on
systematic reviews, and RCTs.

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CQ35：Is behavioral therapy effective in managing chronic pain?
Answer：The various methods of behavioral therapy (relaxation method, self‒monitoring, communication skills, graded behavioral activation etc.) are generally recommendable as a basis for chronic pain management. However, researchers have found that behavioral therapy only has a small effect on moodin chronic pain, may possibly have short‒term effects on intensity of pain, but
in some cases there is no difference between its effects and those from grouptherapeutic exercise over the mid‒ to long‒term. It has been incorporated as
CBT：cognitive behavioral
therapy

an element within the utility of cognitive behavioral therapy (CBT) and is alsoutilized in clinical settings.
Summary of recommendation grades and overall evidence：1B (Execution isstrongly recommended)

Commentary：
In a Cochrane Review on psychological interventions on adult patients withchronic pain, excluding those with headache, they mainly investigated the effects of behavioral therapy and CBT, but there were few RCTs on behavioral
therapy for each outcome, with around 1～5 only, and generally they did not
find any significant difference1). In a study comparing behavioral therapy withregular treatment, investigating intensity of pain, lifestyle dysfunction, moodand catastrophizing, they found that it only had a small short‒term effect onmood.
In a Cochrane Review on the effects of behavioral therapy on chronic low
back pain, they investigated three therapies classified as behavioral therapy；
operant therapy, cognitive therapy, and respondent therapy (progressive muscle relaxation [PMR] and biofeedback therapy). Over the short‒term, operant
therapy was more effective in improving chronic low back pain, comparedwith a waiting‒list group of patients. General behavioral therapy was also more
effective than standard treatment (physiotherapy, in both low back pain classes
and medical treatment together or individually) over the short‒term in termsof its effects on reducing low back pain but over the long‒term, they did not
find any difference. With each combination of operant therapy, cognitive therapy or behavioral therapy, they found almost no difference in their effects on
improving pain over the short‒ to mid‒term. Over the long‒term, they foundalmost no difference between behavioral therapy and group therapeutic exercise in terms of improvement in pain and reduction in symptoms of depression.
Even when behavioral therapy was added for patients undergoing hospitalized
rehabilitation, they did not find that it had any increased effects as comparedwith when patients underwent hospitalized rehabilitation alone2).

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In a Cochrane Review on Internet‒based interventions offering behavioral
therapy or CBT to children, they found that, although the quantity and qualityof the research conducted was insufficient, over the short‒term it reduced
headache and the intensity of complex pain in young children and adolescents
but they did not find that it had an effect in improving physical function3).
In order to advance evidence‒based practice, Division 12 of the American
Psychological Association (APA) (clinical psychology) compiled a list of effective
interventions (limited to those which were supported by actual experimental

APA：American Psychological Association

studies) for specified diseases and disabilities；a list which they are continually
updating4). The items for chronic pain on this list included, ‘fibromyalgia’,‘chronic low back pain’, ‘rheumatic disease’, ‘headache’ and ‘general pain’ as low‒ranked items, and below is an outline of their recommendations5).
For fibromyalgia (FM), we strongly recommend multi‒component [components (1)～(3)] CBT, which is adapted to the varied symptom domains. These
multi‒components comprise：(1) education about FM including the nature of
the disorder and the role patients can play in its management；(2) symptom
self‒management skills targeting pain, fatigue, sleep, cognition, mood, and functional status；and (3) life style change promoting skills targeting barriers tochange, unhelpful thinking styles, and long‒term maintenance of change. This
includes the approaches of behavioral therapy, which are relaxation therapy,
graded behavioral activation, pleasant activity scheduling, sleep hygiene, communication skills, self‒monitoring, skill rehearsal, and social reinforcement.
Behavioral therapy and CBT are strongly recommended for chronic low
back pain. This includes behavioral therapy approaches such as time‒contingent pacing, spouse involvement and reinforcement of adaptive responding,use of quotas and goals for gradual return of functioning, relaxation approaches
such as progressive muscle relaxation (PMR) and biofeedback therapy, self‒monitoring, skill rehearsal, and social reinforcement.
Multi‒component [(1)～(3)] CBT is strongly recommended for rheumatic disease. These multi‒components comprise：(1) education about the nature ofpain, options for treatment, and the importance of patients playing an activerole in pain management；(2) symptom self‒management skills targeting pain,
affect, cognition, and functional status；(3) promotion of life style change andrelapse prevention. This encompasses the approaches of behavioral therapy,
which include relaxation therapy, graded behavioral activation, pleasant activity scheduling, communication skills, self‒monitoring, skill rehearsal and social
reinforcement.
Multi‒component CBT is strongly recommended for chronic headache. Researchers claim that through the addition of cognitive coping skills for pain torelaxation therapy, it alleviates headache more than just when relaxation ther-

FM：fibromyalgia

292

TTH：tension-type headache

Ⅳ．Psychological Approachapy alone is conducted, especially in the case of tension‒type headache (TTH).
As for vascular headaches, such as migraine, it remains unclear whether there
is any value in adding cognitive skills to relaxation, or not. This relaxation includes behavioral therapy approaches such as progressive muscle relaxation(PMR), visual imagery (visualization) method, biofeedback therapy and also
mindfulness.
References
1）Williams AC, et al : Psychological therapies for the management ofchronic pain（excluding headache）in adults. Cochrane Database Syst
Rev 2012 ; 11 : CD007407
2）Henschke N, et al : Behavioural treatment for chronic low‒back pain. Cochrane Database Syst Rev 2010 ; 7 : CD002014
3）Fisher E, et al : Psychological therapies（remotely delivered）for the
management of chronic and recurrent pain in children and adolescents.
Cochrane Database of Syst Rev 2014 ; 3 : CD011118
4）APA Presidential Task Force on Evidence‒Based Practice : Evidence‒
based practice in psychology. Am Psychol 2006 ; 61 : 271‒2855）Division 12 of the American Psychological Association : Resources‒psychological treatment. http : //www.div12.org/psychological‒treatments/
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

Cochrane Library, PubMed2005‒2017
behavioral therapy, operant therapy
Based on these search results, we focused mainly on systematic
review, RCT, and selected the references. We also referred to the
APA Presidential Task Force on Evidence‒Based Practice：Evidence‒based practice in psychology.

CQ36：Is cognitive‒behavioral therapy effective in managing chronic pain?
Answer：Based on a large amount of research, cognitive‒behavioral therapy
CBT：cognitive behavioral
therapy(CBT) is recognized as having small‒medium effects on chronic pain and we
can say that it is an intervention, which we can recommend overall. However,there are some cases where little research has been done or the effects were
not recognized, depending on the site of disease, how long the effects persist
and what it was being compared against.
Summary of recommendation grades and overall evidence：1A (Execution isstrongly recommended)

Commentary：1) Overall effects
RCT：randomized controlled
trial

Many RCTs have already been conducted on the overall effects of CBT on
chronic pain and systematic reviews have been made based on them. In a Co-

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chrane Review on face‒to‒face psychological interventions on patients withchronic pain, excluding headache, compared with standard treatment, CBT had
a small recognizable effect, over the short‒term, on improving the intensity ofpain and quality of life (QOL), and a moderate‒level effect on improving mood

QOL：quality of life1)

and catastrophizing . These effects are limited, compared with other active
forms of treatment but it did have a small recognizable effect on QOL and catastrophizing. Over the long‒term, they confirmed that it had a small effect inimproving QOL and mood. In a systematic review on adult patients withchronic migraine, they showed that CBT contributed to an improvement insymptoms2).
There is also a Cochrane Review on face‒to‒face psychotherapy on children3). CBT showed small short‒term and long‒term effects on improving theintensity of headache and QOL. However, it only displayed small short‒term
effects in improving anxiety and did not have any short‒term or long‒term effects in improving symptoms of depression. In patients with chronic pain otherthan headache, CBT showed medium‒level effects in improving intensity ofpain and QOL over the short‒term, but did not have long‒term effects.
Although they point out that the number and quality of research studies on
cases of CBT offered through the Internet is insufficient, at the present stage,
generally it has displayed similar results to face‒to‒face treatments.4,5).
In a research study on South‒East Asians, including Japanese people, although in terms of quantity and quality it has been pointed out as insufficientcompared with studies undertaken in the West, in a systematic review on
South‒East Asian patients suffering from chronic pain, CBT displayed low- tomoderate‒level effects in improving intensity of pain, QOL, symptoms of depression and anxiety6).
Therefore, CBT on chronic pain has low- to medium‒level effects over the
short‒term in various facets, and over the long‒term, even though its effective
aspects are limited, it does have a small recognizable effect and therefore, we
can say that it is an effective intervention for chronic pain overall.
2) By site of disease and name of disease
In a RCT comparing mindfulness‒based stress reduction (MBSR) and CBTwith standard multidisciplinary chronic pain management on patients withchronic low back pain, the percentage of patients who experienced an improvement in the level of irritation felt towards pain and their QOL after 26 weeks
was both statistically and clinically more significant in the CBT and MBSR
groups, which were around the same level7). In a different RCT, they foundthat the MBSR group showed a better short‒term improvement than the CBTgroup in catastrophizing and in avoiding their own pain. But in terms of self‒
efficacy towards their pain and accepting internal experiences for what they

MBSR：mindfulness based
stress reduction

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were, over the short‒term CBT and MBSR had similar effects and over thelong‒term, both were equally effective also in improving their tendencies toavoid pain and catastrophizing8). In a systematic review investigating the long‒term effects of CBT on chronic low back pain, there was a small improvement
ADL：activities of daily livingin activities of daily living (ADL) and pain intensity in the group which underwent CBT, compared with the group which didn’t undergo treatment and compared with the group which received active treatment in accordance with theguidelines, there was a large improvement in ADL and a medium‒level improvement in the intensity of pain in the CBT group9). There is a RCT whichshowed more of an improvement in pain intensity and catastrophizing in subjects where CBT was not provided face‒to‒face but in a group, compared withthose who received standard multidisciplinary chronic pain management10).
Based on the above, we can say that CBT is recommendable for chronic low
back pain. Under the ‘Clinical Practice Guidelines for the Management ofChronic Low back Pain’ in Japan, CBT is recommended11).
In a systematic review of CBT on fibromyalgia, while there was no short‒

HRQL/HRQOL：health-related QOL reduction

term or long‒term improvement in intensity of pain, fatigue, sleep and health‒related QOL, there was a small short‒term improvement in symptoms of depression, and a large short‒term and long‒term effect on improving patient’s
sense of self‒efficacy for their pain12). In a different systematic review, a meta‒
analysis investigated the effects of psychotherapy on fibromyalgia, and foundthat psychotherapy had a small but definite effect on sleep, symptoms of depression, QOL and catastrophizing. In addition, they reported that CBT wasparticularly effective in comparison with other forms of psychotherapy13). After
that, a Cochrane Review which investigated the short‒term and long‒term effects of CBT on patients with fibromyalgia, from children through to adults,
was released and they reported that over the short‒term it had a small effecton intensity of pain, negative mood, and QOL and over the long‒term, it had asmall- to medium‒size effect on intensity of pain, negative mood and ADL14).
In the ‘Guidelines on the Treatment of Fibromyalgia’15) in Japan, CBT was given a strong recommendation due to the long duration required to perform
CBT and also due to the small number of facilities where it is actually offered.
In a Cochrane Review of CBT’s effects on chronic neck pain, even though
the quality of evidence is low, they found that subjects who had undergone
CBT, compared with subjects who had currently not undergone treatment, experienced a medium‒level improvement in intensity of pain and ADL and alarge improvement in QOL over the short‒term16). However, compared withsubjects who underwent other forms of active treatment, although there wasonly a small effect on kinesiophobia over the long‒term, it was not effective in
improving intensity of pain or ADL over the short‒term and over the long‒

Ⅳ．Psychological Approachterm. There were no particular effects found on subjects who underwent CBTand another form of treatment concomitantly. Based on the above, it remains
uncertain whether conducting CBT on patients with chronic cervical pain has
clinical value or not.
In a Cochrane Review of the effects of psychotherapy on chronic neuropathic pain, only two research studies matched the eligibility criteria17). However,
one of these studies investigated the effects of CBT on patients with spinal
cord injury, by comparing its effects before and after treatment18)and theyfound a long‒term improvement in intensity of pain, ADL, anxiety and level ofactivity.
In a Cochrane Review of the effects of non‒pharmacological therapy on patients with somatoform disorders (somatic symptom disorder), fourteen out of
the 21 studies which matched the eligibility criteria were related to CBT, andcompared with subjects who did not undergo treatment, there was definitely
an effect, although the reduction in physical symptoms was small, and its long‒term effects were also confirmed19). However, there was no difference in comparison with other forms of active treatment.
As seen above, in terms of the efficacy of CBT according to the site of injury
or the name of the disease, there are differences in the quality and quantity of
research that has already been done and in some cases there were no visible
effects.
3) The concomitant use of other interventions
Researchers have also investigated the effects of other forms of treatment in
combination with CBT. In a research study on patients with chronic low backpain, they compared a group of patients who underwent general therapeutic
exercise with a group of patients who underwent general therapeutic exercise
in addition to CBT. In both groups, there was a visible improvement in intensity of pain and ADL, compared with the baseline but at twelve weeks after
treatment had been concluded, there was a greater improvement in intensityof pain and ADL in the group which had undergone CBT20).
A review showed that in the perioperative period of patients who had undergone spinal fusion surgery for chronic low back pain, they were able to obtain even better results, in many aspects, by dealing with psychological risk
factors using CBT21).
In an RCT study on patients with chronic low back pain currently being
treated with opioid analgesics, they implemented a composite group program,using meditation and CBT specially designed for chronic low back pain. Compared with the control group, intensity of pain and pain hypersensitivity to aheat stimulus improved in the group which underwent CBT22).
As seen above, not only when CBT is implemented alone, but also when it is

295

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used in combination with various existing interventions, we can say that it iseffective. However, as we saw with chronic cervical pain above, in some cases
CBT did not have any additive effects, when used in combination with otherforms of treatment16).
References
1）Williams AC, et al : Psychological therapies for the management ofchronic pain（excluding headache）in adults. Cochrane Database Syst
Rev 2012 ; 11 : CD007407
2）Cho SJ, et al : Treatment update of chronic migraine. Curr Pain Headache Rep 2017 ; 21 : 26
3）Eccleston C, et al : Psychological therapies for the management of chronic and recurrent pain in children and adolescents. Cochrane Database
Syst Rev 2014 ; 5 : CD003968
4）Eccleston C, et al : Psychological therapies（internet‒delivered）for the
management of chronic pain in adults. Cochrane Database Syst Rev
2014 ; 2 : CD010152
5）Fisher E, et al : Psychological therapies（remotely delivered）for the
management of chronic and recurrent pain in children and adolescents.
Cochrane Database Syst Rev 2015 ; 3 : CD011118
6）Yang SY, et al : Psychological treatments for chronic pain in East andSoutheast Asia : A systematic review. Int J Behav Med 2016 ; 23 : 473‒
4847）Cherkin DC, et al : Effect of mindfulness‒based stress reduction vs cognitive behavioral therapy or usual care on back pain and functional limitations in adults with chronic low back pain : A randomized clinical trial.
JAMA 2016 ; 315 : 1240‒1249
8）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
9）Richmond H, et al : The effectiveness of cognitive behavioural treatment
for non‒specific low back pain : A systematic review and meta‒analysis.
PLoS One 2015 ; 10 : e0134192
10）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 : 563‒56811）The Japanese Orthopaedic Association/The Japanese Society for the
Study of Low Back Pain（Supervising eds）: Clinical practice guidelines
for the management of low back pain. Nankodo, Tokyo 2012 ; 54‒5612）Bernardy K, et al : Efficacy of cognitive‒behavioral therapies in fibromyalgia syndrome : A systematic review and meta‒analysis of randomized
controlled trials. J Rheumatol 2010 ; 37 : 1991‒200513）Glombiewski JA, et al : Psychological treatments for fibromyalgia : A
meta‒analysis. Pain 2010 ; 151 : 280‒29514）Bernardy K, et al : Cognitive behavioural therapies for fibromyalgia. The
Cochrane database of systematic reviews, 2013 ; 9 : CD009796
15）Japan College of Fibromyalgia Investigation, eds : 線維筋痛症診療ガイド
ライン 2017. Japan Medical Journal, Tokyo, 2017 ; 173‒175

297

Ⅳ．Psychological Approach16）Monticone M, et al : Cognitive‒behavioral treatment for subacute andchronic neck pain : A Cochrane review. Spine（Phila Pa 1976）2015 ; 40 :1495‒1504
17）Eccleston C, et al : Psychological therapies for the management of chronic neuropathic pain in adults. Cochrane Database Syst Rev 2015 ; 10 :CD011259
18）Heutink M, et al : Long‒term outcomes of a multidisciplinary cognitive
behavioural programme for coping with chronic neuropathic spinal cord
injury pain. J Rehabil Med 2014 ; 46（6）: 540‒54519）van Dessel N, et al : Non‒pharmacological interventions for somatoform
disorders and medically unexplained physical symptoms（MUPS）in
adults. Cochrane Database Syst Rev 2014 ; 11 : CD011142
20）Khan M, et al : The effectiveness of cognitive behavioral therapy（CBT）
with general exercises versus general exercises alone in the management of chronic low back pain. Pak J Pharm Sci 2014 ; 27（4 Suppl）:
1113‒1116
21）Gaudin D, et al : Considerations in spinal fusion surgery for chronic lumbar pain : Psychosocial factors, rating scales, and perioperative patient
education : A review of the literature. World Neurosurg 2017 ; 98 : 21‒2722）Zgierska AE, et al : Mindfulness meditation and cognitive behavioral
therapy intervention reduces pain severity and sensitivity in opioid‒
treated chronic low back pain : Pilot findings from a randomized controlled trial. Pain Med 2016 ; 17 : 1865‒1881
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

Cochrane Library, PubMed2009‒2017
cognitive behavioral therapy, psychological intervention, CBT
From these results, we searched mainly for systematic review,
randomized controlled trial, and selected the references. Then,
we added 2 known guidelines related to domestic chronic pain.

CQ37：Is mindfulness as proposed in the third wave of cognitive‒behavioral therapy effective in managing chronic pain?
Answer：Mindfulness‒based intervention may be effective on chronic pain in
improving intensity of pain, the degree of depression symptoms, dysfunction,and quality of life (QOL).
Summary of recommendation grades and overall evidence：1A (Execution isstrongly recommended)

Commentary：
Mindfulness refers to ‘paying attention in a particular way：intentionally, inthe present moment, and non‒judgmentally.’ This state of mind is trained
through mindfulness meditation and, as a result, our ability to objectively andnon‒judgmentally notice our own sensations, thoughts and emotions, and otherthings improves. Through doing this, it has been suggested that one’s ability to

QOL：quality of life

298

Ⅳ．Psychological Approachendure physical and psychosocial stress improves. There are many reports
claiming that mindfulness based interventions are effective on chronic pain. A
systematic review1) of 38 RCTs was conducted comparing groups of subjects
who underwent a mindfulness‒based intervention for chronic pain (mindfulness‒
MBSR：mindfulness based
stress reduction
MBCT：mindfulness based
cognitive therapy

based stress reduction [MBSR], mindfulness‒based cognitive therapy [MBCT],
and other programs based on mindfulness) with a control group (waiting‒list
group, group only undergoing usual treatment, patient education/support
group). According to this review, within 4～60 weeks follow‒up, although thedegree of effect was small, the intensity of pain and the degree of depression
symptoms as well as physical and mental QOL had significantly improved in
the group undergoing mindfulness‒based intervention compared with the control group. The evidence of improvement of depression symptoms was evaluated as high, and improvement of mental QOL was evaluated as medium. They
reported some disparity in the results on improvement of pain intensity andphysical QOL and so the evidence was low. Although investigations on dysfunction tend to show improvement, no significant difference was obtained

RCT：randomized controlled
trial

when compared with the control group. Only four RCTs were used for the investigation, far too few to generalize the results. In an investigation into thedifferent effects that each of the three above mentioned types of mindfulness‒based interventions had on pain intensity, no significant difference between themethods was found. Seven RCTs investigated adverse events arising due tothe implementation of mindfulness, but no severe events were reported. However, at the current stage of research into mindfulness, findings on adverse
events are insufficient and therefore further investigation is needed.
A systematic review of RCTs was conducted, investigating the effects ofmindfulness‒based intervention on several specific forms of pain diseases. In
systematic reviews of the effects of MBSR on chronic low back pain2,3) compared with standard treatment/patient education, a significant short‒term improvement in the MBSR group was found in terms of pain intensity and dysfunction, even though the degree of effect was small. In a review4) of the effects of MBSR on headache, it was claimed that there was a moderate‒level effect in the group that underwent mindfulness‒based intervention and that it
significantly reduced the intensity of pain, compared with a group undergoingstandard treatment. A review5) of a group of subjects with irritable bowel syndrome (IBS) reported that a moderate‒level effect was seen in a group that underwent mindfulness‒based intervention and that there was a significant improvement in intensity of pain, symptom severity, and symptom‒related QOL
compared with a waiting‒list/support only group. Systematic reviews of its effects on fibromyalgia have been reported by a German group6) and by the Cochrane Musculoskeletal Group7). According to the German group, in six RCTs

Ⅳ．Psychological Approachthat compared standard treatment and patient education, MBSR was effective
in providing a short‒term improvement in pain intensity and QOL, but theyclaimed that there was no difference over the long‒term. The Cochrane Musculoskeletal group reported that mindfulness‒based intervention did not significantly improve intensity of pain, depression symptoms, or physical function incomparison with standard treatment. Thus, the findings of the studies conducted on fibromyalgia are too unclear for generalization and therefore we are unable to draw any conclusions at this stage. However, researchers have implied
its effectiveness on chronic low back pain, headache, and irritable bowel syndrome (IBS).
To compare the second wave of CBT, which has the largest amount of evidence among the psychological approaches to chronic pain, with MBSR, there
is a high‒quality RCT8) that compared the effects of MBSR, CBT, and standard
treatment on chronic low back pain. At 26 weeks follow‒up, subjects in both
the MBSR and CBT groups showed a significant improvement in pain intensity and disability compared with the standard‒treatment group. However, nosignificant difference was found suggesting that MBSR is as useful as CBT.
In light of the above, it is possible that mindfulness‒based intervention could
be a useful alternative to conventional CBT.
References
1）Hilton L, et al : Mindfulness meditation for chronic pain : Systematic review and meta‒analysis. Ann Behav Med 2017 ; 51 : 199‒2132）Chou R, et al : Nonpharmacologic therapies for low back pain : A systematic review for an American College of Physicians clinical practiceguideline. Ann Intern Med 2017 ; 166 : 493‒5053）Anheyer D, et al : Mindfulness‒based stress reduction for treating low
back pain : A systematic review and meta‒analysis. Ann Intern Med
2017 ; 166 : 799‒8074）Probyn K, et al : Non‒pharmacological self‒management for people livingwith migraine or tension‒type headache : A systematic review including
analysis of intervention components. BMJ Open 2017 ; 7 : e016670
5）Lakhan SE, et al : Mindfulness‒based therapy in the treatment of somatization disorders : A systematic review and meta‒analysis. PLoS One
2013 ; 8 : e71834
6）Lauche R, et al : A systematic review and meta‒analysis of mindfulness‒based stress reduction for the fibromyalgia syndrome. J Psychosom Res
2013 ; 75 : 500‒5107）Theadom A, et al : Mind and body therapy for fibromyalgia. Cochrane
Database Sys Rev 2015 4 : CD001980
8）Cherkin DC, et al : Effect of mindfulness‒based stress reduction vs cognitive behavioral therapy or usual care on back pain and functional limitation in adults with chronic low back pain : A randomized clinical trial.
JAMA 2016 ; 315 : 1240‒1249

299

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Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

Cochrane Library, PubMed2005‒2017
mindfulness, mindfulness‒based stress reduction, MBSR, mindfulness‒based cognitive therapy, MBCT, pain, headache, irritablebowel syndrome, fibromyalgia, arthritis
From these search results, we searched mainly for systematic review, randomized controlled trial and selected the references.

CQ38：Is acceptance and commitment therapy under the third wave ofcognitive‒behavioral therapy effective in managing chronic pain?
RCT：randomized controlled
trial
ACT：acceptance andcommitment therapy

Answer：A large number of RCTs have indicated that acceptance and commitment therapy (ACT) has small- to medium‒level efficacy, as an evaluation
item in the treatment of chronic pain. In particular, it may possibly have alarge effect on psychological flexibility and dysfunctions due to pain and therefore we can say that it is a recommendable form of intervention.
Summary of recommendation grades and overall evidence：1A (Execution isstrongly recommended)

Commentary：
Acceptance and commitment therapy (ACT) is a form of psychotherapy inwhich we do not spend the majority of our time and effort on removing painor unpleasant thoughts or emotions related to pain but realizing that existingwith this unpleasant phenomenon is a normal state for human beings, andACT will support patients live the life they wish.
There have been over 20 RCTs1) which have shown the efficacy of ACT on
chronic pain, and two meta‒analyses have been conducted2,3). According to oneof these meta‒analyses2), patients who had undergone ACT treatment showeda small improvement in intensity of pain, degree of depression symptoms, anddysfunction, immediately after treatment, compared with a group of subjects
who underwent standard treatment or a group of subjects on a waiting-list
and also it had a medium‒level effect in improving patients’ degree of pain interference and their degree of anxiety. In addition, in this research study, within 2～6 months follow‒up, they indicated that the level of improvement in intensity of pain, degree of depression symptoms, and quality of life (QOL) had
increased. Furthermore, they demonstrated that it had a large effect on improving the level of pain interference in particular. They also indicated thatthe level of improvement in anxiety and dysfunction had been maintained ataround the same level. In addition, in another meta‒analysis3), they found thatcompared with subjects who had undergone standard treatment and subjects
on a waiting list, ACT had a medium‒level effect directly after treatment on

Ⅳ．Psychological Approach301

patients’ acceptance of pain, a large effect on their psychological flexibility, amedium‒level effect on improving their anxiety and depression symptoms, anda small effect on dysfunction. Furthermore, within 3～6 months follow‒up, they
showed that it had had a small effect on intensity of pain and dysfunction.
CBT has the largest amount of strong evidence on chronic pain. The amountof effect by the second wave of CBT

4)

and the amount of effect by the third

CBT：cognitive behavioral
therapy

5)

wave of CBT (mindfulness) on chronic pain is almost the same but comparedwith the second wave of CBT, the third wave tends to show persistent effects
at the time of follow‒up (2 ～ 6 months after treatment). Furthermore, within
the third wave of CBT, ACT has tended to show a larger amount of effect2)
than interventions based on mindfulness meditation (mindfulness based stress
reduction [MBSR] and mindfulness based cognitive therapy [MBCT]). Therefore, ACT might possibly be the most effective psychological approach tochronic pain at the current stage. However, in a RCT directly comparing the

MBSR：mindfulness based
stress reduction
MBCT：mindfulness based
cognitive therapy

second wave of CBT and MBSR5), and in another RCT directly comparing thesecond wave of CBT with ACT6), they did not find any significant difference inpain or other outcomes and therefore it is unclear which of these three is better than the others.
In order to promote evidence‒based actual cases, Division 12 of the American Psychological Association (clinical psychology), has compiled a list of effective interventions (limited to those supporting experimental studies) against
specific diseases and disabilities, and is updating them consecutively7). As forchronic pain items on this list, ‘fibromyalgia’, ‘chronic low back pain’, ‘rheumatic
disease’, ‘headache’ and ‘chronic pain in general’ are low‒ranked items. For oneof these items；chronic pain in general, they only recommend ACT. For theother items, they recommend conventional behavioral therapy or CBT8).
Just like with ACT and mindfulness, dialectical behavior therapy (DBT) was
developed under the third wave of CBT, and is a comprehensive cognitive‒behavioral therapy developed as a form of intervention specifically for borderline
personality disorder (a personality disorder in which sufferers are accustomed
to harming themselves, and while within clinical psychology this requires thelargest amount of effort, it is also extremely hard to obtain therapeutic effects).
RCTs on the effects of DBT on chronic pain have not been conducted but incases of intractable fibromyalgia or protracted chronic pain, there is a tendency for some patients with personality disorders to also be suffering from a history of abuse or trauma. There is a neuroscience case study report9) on the effects of DBT on pain and we are waiting for further research to be conductedin future.

DBT：dialectical behavior
therapy

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Ⅳ．Psychological Approach

References
1）Association for Contextual Behavioral Science : ACT randomized controlled trials since 1986. https : //contextualscience. org/ACT_Randomized_Controlled_Trials2）Veehof MM, et al : Acceptance‒and mindfulness‒based interventions forthe treatment of chronic pain : A meta‒analytic review. Cogn Behav
Ther 2016 ; 45 : 5‒313）Hughes LS, et al : Acceptance and commitment Therapy（ACT）forchronic pain : A systematic review and meta‒analyses. Clin J Pain 2017 ;33 : 552‒5684）Hilton L, et al : Mindfulness meditation for chronic pain : Systematic review and meta‒analysis. Ann Behav Med 2017 ; 51 : 199‒2135）Cherkin DC, et al : Effect of mindfulness‒based stress reduction vs cognitive behavioral therapy or usual care on back pain and functional limitations in adults with chronic low back pain : A randomized clinical trial.
JAMA 2016 ; 315 : 1240‒1249
6）Wetherell JL, et al : A randomized, controlled trial of acceptance andcommitment therapy and cognitive‒behavioral therapy for chronic pain.
Pain 2011 ; 152 : 2098‒2107
7）APA Presidential Task Force on Evidence‒Based Practice : Evidence‒
based practice in psychology. Am Psychol 2006 ; 61 : 271‒2858）Division 12 of the American Psychological Association : Resources‒psychological treatment. http : //www.div12.org/psychological‒treatments/
9）Niedtfeld I, et al : Pain‒mediated affect regulation is reduced after dialectical behavior therapy in borderline personality disorder : A longitudinal
fMRI study. Soc Cogn Affect Neurosci 2017 ; 12 : 739‒747
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

Cochrane Library, Pubmed
2005‒2017
acceptance and commitment therapy, ACT
From these search results, we focused mainly on systematic review, RCT for our selection. Furthermore, we also referred to the
APA Presidential Task Force on Evidence‒Based Practice：Evidence‒based practice in psychology.

CQ39：Is hypnotherapy effective in managing chronic pain ?
Answer：There is evidence indicating that hypnotherapy is effective on
chronic pain. If patients are undergoing treatment from a therapist who hasreceived an education on hypnotherapy, it is recommended.
Summary of recommendation grades and overall evidence：2B (Execution is
weakly recommended)

Commentary：
Clinical hypnosis for chronic pain, is a method of treatment which uses
trance (state of modified consciousness). Its mode of action is known to be related to the several neurophysiological mechanisms in the experience of pain1).

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Ⅳ．Psychological Approach

A meta‒analysis2) concluded that hypnosis has medium‒level effects on chronic
pain.
Below we will cite some hypnosis‒related RCTs on various diseases. Compared with a control group which just underwent relaxation, hypnosis signifi-

RCT：randomized controlled
trialcantly improved pain in patients with temporomandibular arthritis and reduced the number of times patients were awakened by their pain during
night3). Furthermore, hypnosis also significant improved pain in patients withpersistent orofacial pain, compared with a control group which only underwent
relaxation, and the area of the pain site also decreased4). In a research study on
fibromyalgia, they compared a group undergoing pharmacotherapy alone witha group undergoing cognitive‒behavioral therapy (CBT), and a group undergoing a combination of CBT and hypnotherapy. In this research study, sensory

CBT：cognitive behavioral
therapyand emotional aspect of pain improved more significantly in the CBT groupand the CBT and hypnotherapy combined group than the pharmacotherapy
alone group, but there was no difference between the two former groups5). In
another research study on osteoarthritis (OA) of the knee and osteoarthritis(OA) of the hip, pain had improved by standardized hypnosis, compared with agroup of patient on a waiting list, by three months follow‒up, and hypnosis had
helped reduce the number of times patients had to use analgesics6). Next, in a
research study on patients with chronic pain due to spinal cord injury, they reported a significant reduction in pain due to hypnosis, compared with biofeedback thrapy7). However, a Cochrane Review claims that there is no evidence
indicating that self‒hypnosis is effective on post‒spinal cord injury chronic
pain8). In addition, the effects of hypnosis on non‒cardiogenic chest pain were
found to be significantly higher in terms of the overall level of improvement ofpain, compared with supportive psychotherapy9). None of the other reports are
RCTs and although there is a low level of sufficient evidence, they are investigating the clinical effects of hypnosis on chronic headache and chronic low
back pain. In a systematic review on its effects on irritable bowel syndrome(IBS) in children, although hypnotherapy was more effective than standard
treatment, they mentioned that it is difficult to verify the effect size of hypnotherapy10).
As mentioned above, hypnotherapy is effective on chronic pain overall andwe conclude that, if conducted properly, it is recommended for patients who
are undergoing treatment by a therapist who has received an education on
hypnosis. However, this therapy is not standardly performed yet in Japan, andso we hope that it will spread as an important treatment methodology forchronic pain.

IBS：irritable bowel
syndrome

304

Ⅳ．Psychological Approach

References
1）Jensen MP, et al : Neuromodulatory treatments for chronic pain : Efficacy and mechanisms. Nat Rev Neurol 2014 ; 10 : 167‒1782）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 Hypn 2014 ; 62 : 1‒283）Abrahamsen R, et al : Effect of hypnosis on oral function and psychological factors in temporomandibular disorders patients. J Oral Rehabil
2009 ; 36 : 556‒570
4）Abrahamsen R, et al : Hypnosis in the management of persistent idiopathic orofacial pain : Clinical and psychosocial findings. Pain 2008 ; 136 :44‒525）Castel A, et al : Cognitive‒behavioural group treatment with hypnosis : A
randomized pilot trial in fibromyalgia. Contemporary Hypnosis 2009 ; 26 :48‒596）Gay MC, et al : Differential effectiveness of psychological interventions
for reducing osteoarthritis pain : A comparison of Erickson（correctionof Erickson）hypnosis and Jacobson relaxation. Eur J Pain 2002 ; 6 : 1‒167）Jensen MP, et al : Effects of self‒hypnosis training and EMG biofeedback
relaxation training on chronic pain in persons with spinal‒cord injury.
Int J Clin Exp Hypn 2009 ; 57 : 239‒268
8）Boldt I, et al : Non‒pharmacological interventions for chronic pain in people with spinal cord injury. Cochrane Database Syst Rev 2014 ; 11 :CD009177
9）Jones H, et al : Treatment of non‒cardiac chest pain : A controlled trialof hypnotherapy. Gut 2006 ; 55 : 1403‒1408
10）Rutten JM, et al : Gut‒directed hypnotherapy for functional abdominal
pain or irritable bowel syndrome in children : A systematic review. ArchDis Child 2013 ; 98 : 252‒257
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

Cochrane Library, PubMed
2004‒2017
hypnosis, hypnotic state
Based on these search results, we focused mainly on systematic
reviews, and RCTs and selected the references. We also selected
some academic papers conducted before our period which we believed to be important (Reference 6.)

Chapter Ⅰ

Overview：CQ1～CQ7

Chapter Ⅱ

Pharmacotherapy：CQ8～CQ21

Chapter Ⅲ

Interventional Management：CQ22～CQ33

Chapter Ⅳ

Psychological Approach：CQ34～CQ39

Chapter Ⅴ

Rehabilitation：CQ40～CQ46

Chapter Ⅵ

Multidisciplinary Treatment：CQ47～CQ51

306

Ⅴ．Rehabilitation

CQ40：Is general therapeutic exercise effective in managing chronic pain?
Answer：Compared with rest and guidance on daily living, therapeutic exercise alone is effective on chronic pain and dysfunction. On the other hand, it is
not clear if there are any differences in effect depending on the type of exercise.
Summary of recommendation grades and overall evidence：
1) Chronic low back pain：1A (Execution is strongly recommended)
2) Osteoarthritis (OA) of the knee：1A (Execution is strongly recommended)
3) Chronic cervical pain：1B (Execution is strongly recommended)
Commentary：
1) Chronic low back pain
RCT：randomized controlled
trial

In a quantitative systematic review of RCTs investigating the effects of general therapeutic exercise, such as stretching, aerobic exercise and muscle‒
strengthening exercise on chronic low back pain1,2), they reported1) that it wasmore effective in terms of reducing pain, and improving dysfunction and quali-

QOL：quality of life

ty of life (QOL), compared with a waiting‒list group of patients and a group notundergoing treatment1). On the other hand, there are also some reports2) claiming that it has no recognizable effect. However, comparing a group which underwent general therapeutic exercise with a group which did not undergo
treatment, researchers recognized that in the group which underwent therapeutic exercise, it had been effective in reducing pain and improving dysfunction. Furthermore, they also reported2) its effects on improving pain and dysfunction at follow‒up, twelve months post‒treatment2). One thing that should
be pointed out is that depending on the type of exercise implemented, there
have been reports of adverse events such as low back pain.
2) Osteoarthritis (OA) of the knee
As for its effects on osteoarthritis (OA) of the knee3), they have found thatgeneral therapeutic exercise is effective in reducing pain and improving dysfunction. Furthermore, researchers have also shown that an individually‒formulated exercise program was more effective in reducing pain over the long‒term than a group exercise program3).
As for the differences in efficacy depending on the method of exercise used,
they found that land‒based muscle strengthening exercise and aerobic exercise were effective in reducing pain and improving physical function4‒6). There
have also been claims that aquatic muscle‒strengthening and aerobic exercises
slightly reduced pain7). However, differences in therapeutic effect depending on
the type of exercise used remain unclear7). It should also be pointed out thatwith some forms of exercise, there have been reports of adverse events, such

Ⅴ．Rehabilitation

as aggravated knee pain3).
3) Chronic cervical pain
Compared with a waiting‒list group, supervised multimodal exercises (rangeof motion [ROM] exercises and muscle‒strengthening exercises) have shown tobe effective in reducing pain for patients suffering from chronic cervical pain8).
Furthermore, they found that a combination of strengthening the muscles
around the neck region and stretching had a large effect over the short‒term
and a slight effect over the long‒term in reducing pain, and reported that muscle‒strengthening exercises and stabilization exercises for the muscles aroundthe neck region were effective in improving pain and dysfunction9). On the other hand, some reports have also shown that high‒frequency muscle‒strengthening exercise had no effect on reducing pain and improving dysfunction,
when compared with non‒supervised stretching10,11).
References
1）Chou R, et al : Nonpharmacologic therapies for low back pain : A systematic review for an American College of Physicians clinical practiceguideline. Ann Intern Med 2017 ; 166 : 493‒5052）van Middelkoop M, et al : Exercise therapy for chronic nonspecific low‒back pain. Best Pract Res Clin Rheumatol 2010 ; 24 : 193‒2043）Fransen M, et al : Exercise for osteoarthritis of the knee. Cochrane Database Syst Rev 2015 ; 1 : CD004376
4）Jansen MJ, et al : Strength training alone, exercise therapy alone, andexercise therapy with passive manual mobilisation each reduce pain anddisability in people with knee osteoarthritis : A systematic review. J
Physiother 2011 ; 57 : 11‒205）Iversen MD : Rehabilitation interventions for pain and disability in osteoarthritis : A review of interventions including exercise, manual techniques, and assistive devices. Orthop Nurs 2012 ; 31 : 103‒1086）Fransen M, et al : Does land‒based exercise reduce pain and disability
associated with hip osteoarthritis ? : A meta‒analysis of randomized controlled trials. Osteoarthritis Cartilage 2010 ; 18 : 613‒6207）Bartels EM, et al : Aquatic exercise for the treatment of knee and hip
osteoarthritis. Cochrane Database Syst Rev 2016 ; 3 : CD005523
8）Côté P, et al : Management of neck pain and associated disorders : A
clinical practice guideline from the Ontario Protocol for Traffic Injury
Management（OPTIMa）Collaboration. Eur Spine J 2016 ; 25 : 2000‒2022
9）Gross A, et al : Exercises for mechanical neck disorders. Cochrane Database Syst Rev 2015 ; 1 : CD004250
10）Salo P, et al : Effects of long‒term home‒based exercise on health‒related
quality of life in patients with chronic neck pain : A randomized study
with a 1‒year follow‒up. Disability & Rehabilitation 2012 ; 34 : 1971‒1977
11）Häkkinen A, et al : Strength training and stretching versus stretching
only in the treatment of patients with chronic neck pain : A randomizedone‒year follow‒up study. Clin Rehabil 2008 ; 22 : 592‒600

307

308

Ⅴ．Rehabilitation

Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

MEDLINE, CINAHL, PEDro2010‒2017
guideline, meta‒analysis, RCT, randomized controlled, chronic
pain treatment, exercise, aerobic, resistance, isometric, stabilization, tai chi, yoga, Pilates, qigong
From these search results, we focused mainly on searching forsystematic reviews, RCT and selected the references.

CQ41：Is exercise, other than general therapeutic exercise, effective inmanaging chronic pain ?
MCE：motor control exercise

Answer：Motor control exercise (MCE) is effective on chronic pain and dysfunction, compared with general therapeutic exercise. Yoga, Tai Chi, Qigong(breathing exercises), and the Pilates method are also effective on chronic pain
compared with general therapeutic exercise, such as aerobic exercise and muscle‒strengthening exercise. However, the difference in their effects comparedwith other forms of exercise is unknown.
Summary of recommendation grades and overall evidence：
1) Motor control exercises：1B (Execution is strongly recommended)
2) Yoga：2B (Execution is weakly recommended)
3) Tai Chi：2B (Execution is weakly recommended)4) Qigong (breathing exercises)：2C (Execution is weakly recommended)
5) Pilates Method：2C (Execution is weakly recommended)
6) Radio calisthenics (TV calisthenics)：2D (Execution is weakly recommended)
Commentary：
1) Motor control exercises
Motor control exercises (MCE) are a form of training designed to improvemuscle function in the deep muscles of the trunk, such as the transverse abdominal, the internal oblique, and multifidus muscles for the purpose of improv-

RCT：randomized controlled
trial

ing the stability of the spine. In a quantitative systematic review of RCT studies on its effects on chronic low back pain1), they found that compared withgeneral therapeutic exercise, short‒term (six weeks～fow months) and medium‒
term interventions (4～8 months) were more effective in improving pain andphysical function. Furthermore, compared with a group who did not undergo
treatment and those who underwent patient education, researchers found2)that it was more effective in improving pain and physical function, too. On theother hand, there was also a study3) that compared MCE with general exercise,such as aerobic exercise, muscle‒strengthening exercise and stretching, andthey reported that there was not much difference in effect. There was norecognizable difference in pain alleviation, compared with spinal manipulative

Ⅴ．Rehabilitation

therapy but they did find that it was effective in improving physical function.
However, when MCE was combined with general therapeutic exercise, there
was no difference in its effect on improving pain, compared with therapeutic
exercise alone4,5).
2) Yoga
In an RCT study on its effect on chronic low back pain, compared with general care, they found that by doing yoga (Iyengar Yoga) for three months or
six months, it was effective in reducing pain and improving physical function6).
Compared with general therapeutic exercise, there have been claims that it iseffective in reducing pain but the level of evidence for this is low1,7‒10). Additionally, in a quantitative systematic review of RCTs, compared with patient
education, at twelve weeks (short‒term follow‒up) and at twelve months after
intervention (long‒term follow‒up), there was a slight improvement in pain andphysical function through yoga11).
As for its effects on chronic cervical pain12), and osteoarthritis (OA) of theknee13), yoga (Iyengar Yoga, Hatha Yoga) has been shown to be effective in reducing pain.
3) Tai Chi
In some RCTs1, 14‒16), compared with a waiting‒list group, they found that patients with chronic low back pain experienced a moderate improvement in
pain and a slight improvement in physical function through Tai Chi. Comparedwith jogging and walking backwards, they found that by 6 months after intervention, Tai Chi had had a slight effect on reducing pain and improving physical function1).
In a quantitative systematic review17) of RCT studies and cluster RCTs16),
they found that compared with patient education and a group which did notundergo treatment, a 20‒week ‘Sun Style Tai Chi Program’ was effective in reducing pain16,17) and improving physical function17) in patients with knee osteoarthritis (OA).
4) Qigong (breathing exercises)
Compared with general therapeutic exercise, such as aerobic exercise, muscle‒strengthening exercise and stretching, they did not find that Qigong had asignificant difference on reducing pain in patients with chronic low back pain
but it did have a recognizable effect on improving physical function18).
As for its effects on cervical pain, in a quantitative systematic review of
RCTs, they found that compared with a waiting‒list group, it was effective
over the short‒term and mid‒term in reducing pain but was not effective in
improving physical function19).
5) Pilates method
To give a general overview of several RCTs on the effect of Pilates method

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on chronic low back pain, compared with a combination of patient educationand physical activity, there are some RCTs which showed that it had a slighteffect on reducing pain at the conclusion of treatment, and some RCTs inwhich it was not shown to be effective, and so a definite conclusion on its effects has yet to be reached20). Compared with the McKenzie method21), andgeneral exercise (aerobic exercise, stretching and muscle‒strengthening etc.)22),
they did not find a significant difference in pain reduction. On the other hand,in a quantitative systematic review of RCTs, compared with a supervised exercise program and exercise using equipment, it was found to be effective overthe short‒term in improving pain and function without adverse events23).
6) Radio calisthenics (TV calisthenics)
Radio calisthenics (TV calisthenics) is something, which has been developed
and passed down only in Japan, is well known among Japanese people and istherefore a familiar form of exercise to them. It is a form of aerobic exercise
which extensively uses the whole body and if all exercises cannot be completed in the standing position, people can choose to conduct as much exercise as
they can, for example through alternative methods such as in the sitting position. In addition, as it is a simple and safe form of exercises, which can be performed by anybody, anytime and anywhere, we recommend that it be implemented.
References
1）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 : 493‒5052）Byström MG, et al : Motor control exercises reduce pain and disability inchronic and recurrent low back pain : A meta‒analysis. Spine（Phila Pa
1976）2013 ; 38 : E350‒E358
3）Unsgaard‒Tøndel M, et al : Motor control exercises , sling exercises, andgeneral exercises for patients with chronic low back pain : A randomized
controlled trial with 1‒year follow‒up. Phys Ther 2010 ; 90 : 1426‒1440
4）Koumantakis GA, et al : Trunk muscle stabilization training plus general
exercise versus general exercise only : Randomized controlled trial of patients with recurrent low back pain. Phys Ther 2005 ; 85 : 209‒225
5）Cairns MC, et al : Randomized controlled trial of specific spinal stabilization exercises and conventional physiotherapy for recurrent low backpain. Spine（Phila Pa 1976）2006 ; 31 : E670‒E681
6）Williams K, et al : Evaluation of the effectiveness and efficacy of Iyengar
yoga therapy on chronic low back pain. Spine（Phila Pa 1976）2009 ; 34 :2066‒2076
7）Sherman KJ, et al : Comparing yoga, exercise, and a self‒care book forchronic low back pain : A randomized, controlled trial. Ann Intern Med
2005 ; 143 : 849‒8568）Sherman KJ, et al : A randomized trial comparing yoga, stretching, anda self‒care book for chronic low back pain. Arch Intern Med 2011 ; 171 :2019‒2026

Ⅴ．Rehabilitation

9）Nambi GS, et al : Changes in pain intensity and health related quality oflife with Iyengar yoga in nonspecific chronic low back pain : A randomized controlled study. Int J Yoga 2014 ; 7 : 48‒5310）Aboagye E, et al : Cost‒effectiveness of early interventions for non‒specific low back pain : A randomized controlled study investigating medical yoga, exercise therapy and self‒care advice. J Rehabil Med 2015 ; 47 :167‒173
11）Cramer H, et al : A systematic review and meta‒analysis of yoga for low
back pain. Clin J Pain 2013 ; 29 : 450‒46012）Côté P, et al : Management of neck pain and associated disorders : A
clinical practice guideline from the Ontario Protocol for Traffic Injury
Management（OPTIMa）Collaboration. Eur Spine J 2016 ; 25 : 2000‒2022
13）Cheung C, et al : Yoga for managing knee osteoarthritis in older women : A pilot randomized controlled trial. BMC Complement Altern Med
2014 ; 14 : 160
14）Hall AM, et al : Tai Chi exercise for treatment of pain and disability inpeople with persistent low back pain : A randomized controlled trial. Arthritis Care Res（Hoboken）2011 ; 63 : 1576‒1583
15）Weifen W, et al : Effectiveness of Tai Chi practice for non‒specific chronic low back pain on retired athletes : A randomized controlled Study. J
Musculoskeletal Pain 2013 ; 21 : 37‒4516）Tsai PF, et al : A pilot cluster‒randomized trial of a 20‒week Tai Chi
program in elders with cognitive impairment and osteoarthritic
knee : Effects on pain and other health outcomes. J Pain Symptom Manage 2013 ; 45 : 660‒66917）Kang JW, et al : T’ai Chi for the treatment of osteoarthritis : A systematic review and meta‒analysis. BMJ Open 2011 ; 1 : e000035
18）Blödt S, et al : Qigong versus exercise therapy for chronic low back pain
in adults‒-a randomized controlled non‒inferiority trial. Eur J Pain. 2015 ;19 : 123‒13119）Yuan QL, et al : Traditional Chinese medicine for neck pain and low
back pain : A systematic review and meta‒analysis. PLoS On 2015 ; 10 :e0117146
20）Chou R, et al : Noninvasive treatments for low back pain [internet].
（AHRQ comparative effectiveness reviews. ）Agency for Healthcare
Research and Quality（US）, 2016 Feb. Report No. 16‒EHC004‒EF21）Rajpal N, et al : The study on efficacy of Pilates and McKenzie exercise
in postural low back pain : A rehabilitative protocol. Physiotherapy andOccupational Therapy Journal 2008 ; 1 : 33‒5622）Wajswelner H, et al : Clinical Pilates versus general exercise for chronic
low back pain : Randomized trial. Med Sci Sports Exerc 2012 ; 44 : 1197‒120523）Kamioka H, et al : Effectiveness of Pilates exercise : A quality evaluationand summary of systematic reviews based on randomized controlled trials. Complement Ther Med 2016 ; 25 : 1‒19
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

MEDLINE, CINAHL, PEDro2010‒2017
guideline, meta‒analysis, RCT, randomized controlled trial, chronic pain treatment, exercise, aerobic, resistance, isometric, stabilization, tai chi, yoga, Pilates, qigong
From these results, we ran a search and selected the references.

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CQ42：Are physical modalities effective in managing chronic pain?
Answer：There is a lack of evidence indicating that physical modalities are
effective on chronic pain and dysfunction and therefore we do not actively recommend implementation.
Summary of recommendation grades and overall evidence：
1) Thermotherapy：2D (Non‒execution is weakly recommended)
2) Cryotherapy：2D (Non‒execution is weakly recommended)3) Therapeutic ultrasound therapy：2C (Non‒execution is weakly recommended)
4) Transcutaneous electrical nerve stimulation (TENS)：2C (Non‒execution is
weakly recommended)

5) Low‒level laser therapy (LLLT)：2C (Execution is weakly recommended)
6) Traction therapy：2D (Execution is weakly recommended)
Commentary：
1) Thermotherapy
Short-wave diathermy

Two clinical research studies have reported1,2) that shortwave diathermy inwhich deep heating is performed by irradiation with shortwaves had a slighteffect in reducing pain in patients with chronic low back pain but in both studies, their control group settings and blinded tests were conducted insufficiently
so the quality of evidence is low.

balneotherapy / spa therapy

No difference in reduction of pain or improvement of physical function for agroup of patients with osteoarthritis (OA) of the knee was found between aplacebo‒controlled group and a group of patients with OA of the knee who underwent shortwave diathermy3). However, compared with a placebo group (inwhich tap water was used), they found a difference in its effect on reducing
pain when patients underwent balneotherapy (hot spring bathing containing
minerals), and even at six months follow‒up after the conclusion of treatment,
they found that it was effective in reducing pain4). Compared with home exercises, they found that it had a slight effect in reducing pain5,6) but looking at
the individual RCTs, there are issues with a lack of uniformity between the results and small sample sizes used and therefore the quality of evidence is low6).
2) Cryotherapy
Compared with a group which did not undergo treatment, they found thatcryotherapy was effective in improving muscle strength in patients with OA of
the knee, but they did not find any effect on reducing pain7).
3) Therapeutic ultrasound therapy
Compared with a placebo‒controlled group, they did not find that therapeutic ultrasound therapy was effective in reducing pain in patients with chronic
low back pain8). Researchers also did not find any effect in reducing pain, when

Ⅴ．Rehabilitation

313

comparing it with general exercise 8). Furthermore, when they compared a
combination of therapeutic ultrasound therapy and therapeutic exercise withtherapeutic exercise alone, they did not find that it was effective in reducing
pain8).
It was found to be effective in reducing pain in patients with OA of theknee9). As for the therapeutic ultrasound conditions, they found that it was effective in reducing pain under low‒intensity conditions (＜1 W/cm2) and underpulsed mode10). Furthermore, compared with continuous mode, they haveshown that the effects obtained from pulsed mode persist for a longer time after treatment has been concluded, but in each individual RCT the methodology
used was of poor quality and on top of this, the sample size used was small andso the quality of evidence is low11). On the other hand, in a quantitative systematic review12), compared with the placebo‒controlled group, they did not findthat it was effective in reducing pain, and so we have yet to reach a consensus
on the effects of therapeutic ultrasound therapy.
4) Transcutaneous electrical nerve stimulation (TENS)
Compared with a placebo group, they found that TENS was not effective in
reducing pain and improving dysfunction in patients with chronic low backpain13) and chronic cervical pain14).
In a quantitative systematic review of its effects on OA of the knee, theyfound that it was effective in reducing pain but people have pointed out the
low quality of the analytical methods used in each individual RCT and so thequality of evidence is low. In recent years, there was an RCT study whichfound that compared with a placebo group and a group which did not undergo
treatment, TENS did not have an effect on reducing pain15).
5) Low‒level laser therapy (LLLT)
In a quantitative systematic review, they found that compared with a placebo‒controlled group, LLLT was effective in reducing pain in patients withchronic low back pain16) and chronic cervical pain14). However, each of the
RCTs on chronic cervical pain contained a high level of statistical variation andso the quality of evidence is low17). In two reports comparing the effects onchronic low back pain in a group of patients who underwent a combination of
LLLT and therapeutic exercise with a group of patients who underwent placebo irradiation and therapeutic exercise, they verified its effects at three months
follow‒up and showed that it was effective in producing a weak reduction in
pain18,19). However, the quality of evidence in these reports is low.
In a systematic review on the effects of LLLT on OA of the knee, they did
not find that it had a recognizable effect in improving pain and dysfunction either at immediately after the conclusion of treatment or at follow‒up20). In an
RCT which compared the effects on chronic cervical pain of a combination of

LLLT：Low level laser
treatment

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Ⅴ．Rehabilitation

LLLT and therapeutic exercise with a combination of placebo irradiation andtherapeutic exercise, they showed that there was no effect in both cases, immediately after treatment21).
6) Traction
Compared with a group that received a placebo treatment and a groupwhich did not undergo treatment at all, they found that traction had a slighteffect in improving pain in patients with chronic low back pain without symptoms of radiculopathy22).
References
1）Shakoor MA, et al : Effects of deep heat therapy on the patients withchronic low back pain. Mymensingh Med J 2008 ; 17 : S32‒S382）Ahmed MS, et al : Evaluation of the effects of shortwave diathermy inpatients with chronic low back pain. Bangladesh Med Res Counc Bull
2009 ; 35 : 18‒203）Atamaz FC, et al : Comparison of the efficacy of transcutaneous electrical nerve stimulation, interferential currents, and shortwave diathermy
in knee osteoarthritis : A double‒blind, randomized, controlled, multicenter study. Arch Phys Med Rehabil 2012 ; 93 : 748‒7564）Sherman G, et al : Intermittent balneotherapy at the Dead Sea area forpatients with knee osteoarthritis. Isr Med Assoc J 2009 ; 11 : 88‒935）Falagas ME, et al : The therapeutic effect of balneotherapy : Evaluationof the evidence from randomised controlled trials. Int J Clin Pract2009 ; 63 : 1068‒1084
6）Harzy T, et al : Short‒and long‒term therapeutic effects of thermal mineral waters in knee osteoarthritis : A systematic review of randomized
controlled trials. Clin Rheumatol 2009 ; 28 : 501‒5077）Zhang W, et al : OARSI recommendations for the management of hipand knee osteoarthritis : Part II : OARSI evidence‒based, expert consensus guidelines. Osteoarthritis Cartilage 2008 ; 16 : 137‒1628）Ebadi S, et al : Therapeutic ultrasound for chronic low‒back pain. Cochrane Database Syst Rev 2014 ; 3 : CD009169
9）Rutjes AW, et al : Therapeutic ultrasound for osteoarthritis of the kneeor hip. Cochrane Database Syst Rev 2010 ; 1 : CD003132
10）Loyola‒Sanchez A, et al : Efficacy of ultrasound therapy for the management of knee osteoarthritis : A systematic review with meta‒analysis.
Osteoarthritis Cartilage 2010 ; 18 : 1117‒1126
11）Zeng C, et al : Effectiveness of continuous and pulsed ultrasound for the
management of knee osteoarthritis : A systematic review and networkmeta‒analysis. Osteoarthritis Cartilage 2014 ; 22 : 1090‒1099
12）Ulus Y, et al : Therapeutic ultrasound versus sham ultrasound for the
management of patients with knee osteoarthritis : A randomized double‒
blind controlled clinical study. Int J Rheum Dis 2012 ; 15 : 197‒20613）van Middelkoop M, et al : A systematic review on the effectiveness ofphysical and rehabilitation interventions for chronic non‒specific low
back pain. Eur Spine J 2011 ; 20 : 19‒3914）Côté P, et al : Management of neck pain and associated disorders : A
clinical practice guideline from the Ontario Protocol for Traffic Injury

Ⅴ．Rehabilitation

Management（OPTIMa）Collaboration. Eur Spine J 2016 ; 25 : 2000‒2022
15）Zeng C, et al : Electrical stimulation for pain relief in knee osteoarthritis : Systematic review and network meta‒analysis. Osteoarthritis Cartilage 2015 ; 23 : 189‒20216）Qaseem A, et al : Noninvasive treatments for acute, subacute, and chronic low back pain : A clinical practice guideline from the American College of Physicians. Ann Intern Med 2017 ; 166 : 514‒53017）Kadhim‒Saleh A, et al : Is low‒level laser therapy in relieving neck pain
effective? : Systematic review and meta‒analysis. Rheumatol Int
2013 ; 33 : 2493‒2501
18）Djavid GE, et al : In chronic low back pain, low level laser therapy combined with exercise is more beneficial than exercise alone in the longterm : A randomised trial. Aust J Physiother 2007 ; 53 : 155‒16019）Vallone F, et al : Effect of diode laser in the treatment of patients with
nonspecific chronic low back pain : A randomized controlled trial. Photomed Laser Surg 2014 ; 32 : 490‒49420）Huang Z, et al : Effectiveness of low‒level laser therapy in patients withknee osteoarthritis : A systematic review and meta‒analysis. Osteoarthritis Cartilage 2015 ; 23 : 1437‒144421）Klein RG, et al : Low‒energy laser treatment and exercise for chronic
low back pain : Double‒blind controlled trial. Arch Phys Med Rehabil
1990 ; 71 : 34‒3722）Wegner I, et al : Traction for low‒back pain with or without sciatica. Cochrane Database Syst Rev 2013 ; 8 : CD003010
Database
PeriodWords searchedby the combination
with ‘chronic pain’

＊

Notes

MEDLINE, CINAHL, PEDro2010‒2017
systematic review, meta analysis, guideline, cryotherapy, icing,
crymotherapy, ice pack, cooling, cryoanalgesia, cold therapy, thermotherapy, heat therapy, thermal therapy, shortwave, microwave, paraffin, hotpack, hot‒pack, spa therapy, balneotherapy,
balneology, hot‒spring therapy, infrared therapy, infrared, mudbath, shock wave therapy, short‒wave therapy, YAG laser, diodelaser, diathermy, low level laser, laser therapy, low‒level laser
therapy, LLLT, low‒level light, phototherapy, electrical stimulation, TENS, electrotherapy, transcutaneous electrical nerve stimulation, muscular electrical stimulation, electrical muscle stimulation, middle frequency stimulation, electric stimulation, EMS, neuromuscular electrical stimulation, NMES, transcranial electricalstimulation, TES, functional electrical stimulation, FES, interferential current, magnetic therapy, magnetic stimulation, ultrasound,ultrasonic, traction, vibration
We ran a search based on these results and selected the references.

CQ43：Is manipulative therapy effective in managing chronic pain?
Answer：There is insufficient evidence showing that manipulative therapy iseffective on chronic pain and dysfunction, and so we cannot say that it is more
effective than other conservative forms of medical treatment and therefore we
do not actively recommend its implementation.

315

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Ⅴ．Rehabilitation

Summary of recommendation grades and overall evidence：1) Spinal manipulation, mobilization：2C (Non‒execution is weakly recommended)
2) Massage：2C (Execution is weakly recommended)
Commentary：1) Spinal manipulation, mobilization
Regarding the effects of spinal manipulation and mobilization on rotator cuff
injury, researchers found weak evidence1)that there was no difference in its effects from medium‒ to long‒term interventions on pain, shoulder joint function
QOL：quality of life

(for example active abduction range of motion), and quality of life (QOL) compared with steroid injection, therapeutic exercise, arthroscopic subacromial decompression, dietary instruction, acupuncture, supplements, and the internal

NSAIDs：nonsteroidal
anti-inflammatory drugs

administration of nonsteroidal anti‒inflammatory drugs (NSAIDS).
Compared with a control group, researchers found that manipulative therapy alone, and in combination with therapeutic exercise displayed weak short‒term effects (less than three months) on pain and dysfunction in patients withosteoarthritis (OA) of the hip but there was weak evidence that there was nodifference in effect over the medium‒ to long‒term (four months or more)2,3).
There are no good‒quality interventional grounds for its effects on pain,
range of motion (ROM) limitations, and orofacial dysfunction in patients withtemporomandibular disorder and therefore its effects are unknown4).
As for its effects on cervicogenic headache, it was found to have a weak interventional effect on intensity and frequency of pain, compared with traditional physiotherapy and a placebo treatment5).
Compared with sham manipulation, it was found to have short‒term analgesic effects on non‒specific low back pain6). Furthermore, by combining manipulative therapy with another active treatment (for example therapeutic exercise), they found that, compared with just implementing the intervention alone,
it was effective in improving pain and dysfunction one month later, threemonths later, and twelve months later7). However, due to issues with sample
sizes and their blinded tests, as well as differences in method, frequency andperiod of intervention used, and a lack of uniformity among the results, it isdifficult to undertake a meta‒analysis. As there were only a few studies whichhave been analyzed, careful attention needs to be paid with interpreting thefindings. Furthermore, there have also been reports of complications, including
adverse events such as local malaise and fatigue, vertebral body fracture, neuropathy due to intervertebral disc herniation, stroke and headache, and vertebral artery dissection8,9).
2) Massage
According to the clinical treatment guidelines of the Ottawa Panel in 201210)

Ⅴ．Rehabilitation317

on the effects of massage on chronic cervical pain, it remains unclear whether
it has long‒term effects or not and there is low evidence supporting this treatment.
As for its effects on sub‒acute to chronic low back pain, they found medium‒level evidence that, compared with manipulation, therapeutic exercise, relaxation, acupuncture, and physical modalities (TENS etc.), it has weak analgesic
effects and improved function over the short‒term11,12). Furthermore, whenmassage is combined with therapeutic exercise, exercise and patient education,and standard treatment, they found weak evidence that these produce superior analgesic effects over the short‒term than when each of these methods areused alone11).
As for its effects on fibromyalgia, researchers found that it tended to produce a short‒term improvement in pain, sleep and well‒being, without side effects, in comparison with standard treatment, a combination of standard treatment plus phone call patient consultations, TENS and sham TENS, and pro13)

gressive muscle relaxation . However, because the massaging method, amountof intervention, results displayed and methods of analysis were unclear in alarge number of the previous studies and as it is difficult to remove the bias,
the scientific grounds are limited and therefore we cannot prove that it has
therapeutic effects on fibromyalgia.
References
1）Page MJ, et al : Manual therapy and exercise for rotator cuff disease. Cochrane Database Syst Rev 2016 ; 6 : CD012224
2）Beumer L, et al : Effects of exercise and manual therapy on pain associated with hip osteoarthritis : A systematic review and meta‒analysis. Br
J Sports Med 2016 ; 50 : 458‒4633）Sampath KK, et al : The effects of manual therapy or exercise therapy
or both in people with hip osteoarthritis : A systematic review and meta‒
analysis. Clin Rehabil 2016 ; 30 : 1141‒1155
4）Armijo‒Olivo S, et al : Effectiveness of manual therapy and therapeutic
exercise for temporomandibular disorders : Systematic review and meta‒
analysis. Phys Ther 2016 ; 96 : 9‒255）Garcia JD, et al : Mobilization and manipulation of the cervical spine inpatients with cervicogenic headache : Any scientific evidence ? Front
Neurol 2016 ; 7 : 40
6）Ruddock JK, et al : Spinal manipulation vs sham manipulation for nonspecific low back pain : A systematic review and meta‒analysis. J Chiropr Med 2016 ; 15 : 165‒1837）Rubinstein SM, et al : Spinal manipulative therapy for chronic low‒back
pain. Cochrane Database Syst Rev 2011 ; 2 : CD008112
8）Nielsen SM, et al : The risk associated with spinal manipulation : An
overview of reviews. Syst Rev 2017 ; 6 : 64
9）Stevinson C, et al : Risks associated with spinal manipulation. Am J Med
2002 ; 112 : 566‒571

TENS：transcutaneouselectrical nerve stimulation

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10）Brosseau L, et al : Ottawa Panel evidence‒based clinical practice guidelines on therapeutic massage for neck pain. J Bodyw Mov Ther 2012 ;16 : 300‒32511）Furlan AD, et al : Massage for low‒back pain. Cochrane Database Syst
Rev 2008 ; 4 : CD001929
12）Yoon YS, et al : Development and application of a newly designed massage instrument for deep cross‒friction massage in chronic non‒specific
low back pain. Ann Rehabil Med 2012 ; 36 : 55‒6513）Terry R, et al : An overview of systematic reviews of complementary
and alternative medicine for fibromyalgia. Clin Rheumatol 2012 ; 31 : 55‒66
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

MEDLINE, CINAHL, PEDro2010‒2017
guideline, systematic review, meta‒analysis, manual therapies,
manual therapy, manipulation, spinal manipulation, massage
We ran a search based on these results and selected the references.

CQ44：Is the introduction of cognitive behavioral therapy and education
into rehabilitation and its application to treatment effective inmanaging chronic pain?
CBT：cognitive behavioral
therapy(For more details related to
CBT, refer to CQ34)

Answer：Introducing the theory of cognitive behavioral therapy (CBT) into
rehabilitation is expected to improve its effectiveness. Within rehabilitation,
while CBT can be effective in improving pain, physical dysfunction and a patient’s psychological state when implemented alone or in combination, for example, with patient education and exercise, it is unclear whether its effects differ from those of other forms of treatment. On the other hand, when patient
education is implemented independently, its effects are poor in comparison
with other forms of treatment but when used additively with other forms oftreatment, we expect that it enhances the therapeutic effects for patients.
Summary of recommendation grades and overall evidence：
1) Cognitive behavioral therapy (CBT)：1B (Execution is strongly recommended)
2) Patient education：1B (Execution is strongly recommended)
Commentary：1) Cognitive behavioral therapy (CBT)Compared with a waiting‒list group and a group which did not undergo
treatment, researchers showed that CBT had a medium‒level effect on improving pain and a slight improvement on physical function in patients with chronic low back pain, although the level of evidence was low1‒3). Furthermore, compared with a waiting‒list group and a group which did not undergo treatment,
although operant therapy did reduce pain slightly, there was no difference in319

Ⅴ．Rehabilitation

its effect on improving dysfunction1‒3). When CBT was used in combination
with other forms of treatment (such as education, problem‒solving training,
coping techniques, images, relaxation, cognitive pain control, and exercise), similar to when CBT was used alone, it was found to have medium‒level effects
on reducing pain, in comparison with a waiting‒list group and a group which
did not undergo treatment, but it remains unclear whether it has a different
effect on improving dysfunction or not1‒3). In a treatment which combined CBTwith therapeutic exercise, researchers found that it had a small effect on improving physical function, compared with total disc replacement and lumbar
fusion, but over the long‒term, it had approximately the same level of improvement on pain and physical function as lumbar fusion4). In addition, a combination of CBT and therapeutic exercise was found to be more effective in improving pain and physical function than general physiotherapy4).
As for its effects on chronic cervical pain, compared with a group which did
not undergo treatment, it was found to be effective on improving pain andphysical function over the short‒term, and effective on improving quality of life
(QOL), but they did not find a clear difference in its effects on improving kine5)

siophobia and stress . It remains unclear whether it is effective in improving
pain and physical function over the short‒term and mid‒term, compared withother treatments5). However, it does improve kinesiophobia over the mid‒termand over the short‒term it is more effective in improving depression than other types of treatment5), indicating its effects on psychosocial factors. Furthermore, they have not found whether CBT used in combination with other typesof treatment (invasive treatment, pharmacotherapy, physiotherapy, therapeutic
exercise, and manipulative therapy) has a clearly different effect on improving
pain and physical function than other types of treatment, or not5). On the other
hand, researchers have shown that compared with other types of treatment, itis effective in improving pain over the short‒term in patients with sub‒acute
cervical pain but it remains unclear whether there is a clear difference in its
effects on improving physical function and psychosocial factors, or not. However, as researchers have shown5) that it is more effective than manipulative
therapy in improving pain and physical function over the long‒term, we expect
it to be effective in preventing chronic pain.
2) Patient education
Patient education, when implemented in isolation, does not have any different effects on the various forms of chronic pain over the short‒term and mid‒term in terms of improving pain, physical function, and psychosocial factors(catastrophizing, self‒efficiency, depression)6).
Yoga2,3,7) and mindfulness3,8,9) are more effective than education in improving pain and physical function in patients with chronic low back pain but over

QOL：quality of life

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the long‒term, researchers did not find a clear difference between yoga andeducation in terms of how much they improved pain2,3,7).
Compared with multimodal care, patient education has low costs but only asmall effect on patients with acute to sub‒acute cervical pain, without any accompanying neurological symptoms, but the therapeutic effects of implementing patient education alone, remain unclear10‒12). Similarly, in patients withacute to sub‒acute cervical pain with accompanying neurological symptoms, itremains unclear whether patient education alone is effective or not and researchers have not found10,11) it to be effective compared with physical modalities, supervised exercise and massage conducted in isolation. Therefore, an intervention using patient education alone in the acute phase is insufficient inpreventing chronic cervical pain.
Therefore, patient education can be effective when used additively with other types of treatment10,11). On patients with acute to sub‒acute cervical pain,
researchers have shown that it can be effective in reducing pain when used in
combination with for example range of motion (ROM) exercises and manipulation, mobilization, and short‒term progressive muscle relaxation 10). Furthermore, education using videos has also been effective in reducing pain whenused in addition to urgent care10,11), and by using it additively in the acutestage of treatment, we expect that this will lead to a rapid reduction in pain
and prevent chronic cervical pain. However, there have also been claims thatphysical modalities including self‒care are more effective than oral advice provided to patients on one occasion10,11). Similarly with chronic cervical pain, it isrecommended10) that patient education be used in combination with othertypes of treatment (ROM exercises, muscle strengthening exercise, yoga, multimodal care, massage, physical modalities, drugs etc.) and a program which
combines self‒management based on an educational booklet has shown to be
as effective as multimodal physiotherapy10,11).
When it comes to the details and methods of patient education, it is recommended that patients are educated on their pain symptoms at the beginning oftreatment, given an outline of the treatment plan and supported with their decision‒making13). It is also important to give patients a feeling of reassurance
by explaining to them the predictions for recovery11,12) and also educate themon the efficacy of maintaining their activity level10‒12). Comparing the effects ofpatient education according to the contents of the education program, neurophysiological education on pain, has shown to be more effective than otherforms of education, in bringing about an immediate improvement in dysfunction and a medium‒term improvement in catastrophizing thoughts in patientswith chronic pain6). However, it remains unclear whether the contents of theeducation program have a different effect on improving the patient’s feelings

Ⅴ．Rehabilitation

about their own health and social function, or not6). In elderly patients as well,it remains unclear whether the contents of education programs have a different effect on improving their pain and physical dysfunctions, or not6).
References
1）Henschke N, et al : Behavioural treatment for chronic low‒back pain. Cochrane Database Syst Rev 2010 ; 7 : CD002014
2）Chou R, et al : Nonpharmacologic therapies for low back pain : A systematic review for an American College of Physicians clinical practiceguideline. Ann Intern Med 2017 ; 166 : 493‒5053）Qaseem A, et al : Noninvasive treatments for acute, subacute, and chronic low back pain : A clinical practice guideline from the American College of Physicians. Ann Intern Med 2017 ; 166 : 514‒5304）Rihn JA, et al : Comparative effectiveness of treatments for chronic low
back pain : A multiple treatment comparison analysis. Clin Spine Surg2017 ; 30 : 204‒2255）Monticone M, et al : Cognitive‒behavioral treatment for subacute andchronic neck pain : A Cochrane review. Spine（Phila Pa 1976）2015 ; 40 :1495‒1504
6）Geneen LJ, et al : Effects of education to facilitate knowledge aboutchronic pain for adults : A systematic review with meta‒analysis. Syst
Rev 2015 ; 4 : 132
7）Cramer H, et al : A systematic review and meta‒analysis of yoga for low
back pain. Clin J Pain 2013 ; 29 : 450‒4608）Morone NE, et al : A mind‒body program for older adults with chronic
low back pain : A randomized clinical trial. JAMA Intern Med 2016 ; 176 :329‒3379）Morone NE, et al : A mind‒body program for older adults with chronic
low back pain : Results of a pilot study. Pain Med 2009 ; 10 : 1395‒1407
10）Côté P, et al : Management of neck pain and associated disorders : A
clinical practice guideline from the Ontario Protocol for Traffic Injury
Management（OPTIMa）Collaboration. Eur Spine J 2016 ; 25 : 2000‒202211）Yu H, et al : Does structured patient education improve the recovery
and clinical outcomes of patients with neck pain? : A systematic review
from the Ontario Protocol for Traffic Injury Management（OPTIMa）
Collaboration. Spine J 2016 ; 16 : 1524‒1540
12）Lamb SE, et al : Managing injuries of the neck trial（MINT）: A randomised controlled trial of treatments for whiplash injuries. HealthTechnol Assess 2012 ; 16 : 1‒14113）Stiggelbout AM, et al : Shared decision making : Really putting patientsat the centre of healthcare. BMJ 2012 ; 344 : e256
Database
PeriodWords searchedby the combination
with ‘chronic pain’
＊

Notes

MEDLINE, PubMed, PEDro2010‒2017
guideline, meta‒analysis, RCT, randomized controlled trial, chronic pain treatment, lecture, CBT, cognitive behavioral therapy, behavioral medicine approach, behavior management, pacing, lifestyle management
We ran a search based on these results and selected the references.

321

322

Ⅴ．Rehabilitation

CQ45：Is orthotic therapy/taping effective in managing chronic pain ?
Answer：Even though there is insufficient evidence on the therapeutic effects of lumbar fixing belts and taping on chronic low back pain, there havebeen no reports of adverse events or side effects. Rather than benefits, as cervical collars have side‒effects such as immobilization, and a decline in self‒efficacy, we do not recommend them for cervical pain derived from whiplash‒associated disorders (traumatic cervical syndrome), regardless of whether neurological symptoms are present or not.
Summary of recommendation grades and overall evidence：
1) Lumbar fixing belt, corset：No clear evidence for recommendation
2) Taping：No clear evidence for recommendation
3) Cervical collar：No clear evidence for recommendation
Commentary：
1) Lumbar fixing belt, corset
There is insufficient evidence to judge the therapeutic effects of lumbar fixing belt and corset on chronic low back pain1). While the evidence is low, they
did not find a difference in effect on pain and function at the eighth week andthird month between patients who underwent stretching alone and patients
who did stretching with a lumbar fixing belt fastened1). Furthermore, when
they compared a lumbar fixing belt with physical modalities, there was not aclear difference between their effects2‒4).
Like with other forms of rehabilitation and psychotherapy, while the evidence is low, there are no reports of serious adverse events due to the use of alumbar fixing belt5‒9).
2) Taping
Kinesio taping, in which mainly the site of pain is radially taped, did notshow any different effect compared with lumbar taping (taped on the horizontal axis), at the fifth week and twelfth week10,11). There were also reports12,13),which showed with low evidence that compared with exercise, kinesio taping
did not show any difference in effect on pain and dysfunction in patients with
WAD：whiplash-associateddisorders (traumatic cervicalsyndrome)

chronic low back pain and whiplash‒associated disorders (WAD).
3) Cervical collar
As for its effects on WAD, in cases where there are no neurologic findings
within three months after injury, we do not recommend a cervical collar, andpatient education, which incorporates for example range of motion (ROM) exercise, is important. In cases where neurologic findings are present, in addition topatient education, it is important to conduct phased muscle‒strengthening
training of the neck muscles under supervision. In any case, cervical collars areⅤ．Rehabilitation

not effective and therefore not recommended. Furthermore, even when neurologic findings are present after injury, a cervical collar is not recommended
and in the event that neck pain persists for three months or longer after injury
and neurologic findings are present, the patient should undergo tests and treatment. There is one bias RCT with low evidence conducted on patients withneck pain persisting for up to three months or more after injury and with neurologic findings present, in which a multimodal program of therapeutic exercise and patient education, conducted individually over the short‒to long‒term,
had similar therapeutic effects15,17).
As for its effects on cervical radiculopathy within one month of onset, by using a combination of a semi‒hard cervical collar and rest, in addition to neck‒muscle strengthening training conducted twice a week, over a six‒week course
under supervision, it was found to have similar effects to at‒home stretching,muscle‒strengthening training, and relaxation14).
However, as cervical collars have the latent risk that they might cause detrimental effects such as iatrogenic disorders, inactivity, poor physical health, anda lack of self‒efficacy, they are not recommended15‒17). In addition, they are also
not recommended from the logical viewpoint that their harmful effects outweigh their benefits18).
References
1）Chou R, et al : Noninvasive treatments for low back pain : AHRQ comparative effectiveness reviews. Agency for Healthcare Research andQuality, Rockville, 2016 ; Feb. No. 16‒EHC004‒EF2）Hsieh CY, et al : Functional outcomes of low back pain : Comparison offour treatment groups in a randomized controlled trial. J Manipulative
Physiol Ther 1992 ; 15 : 4‒93）Doran DM, et al : Manipulation in treatment of low back pain : A multicentre study. Br Med J 1975 ; 2 : 161‒1644）Coxhead CE, et al : Multicentre trial of physiotherapy in the management of sciatic symptoms. Lancet 1981 ; 1 : 1065‒1068
5）Qaseem A, et al : Noninvasive treatments for acute, subacute, and chronic low back pain : A clinical practice guideline from the American College of Physicians. Ann Intern Med 2017 ; 166 : 514‒5306）Oleske DM, et al : Are back supports plus education more effective thaneducation alone in promoting recovery from low back pain? : Resultsfrom a randomized clinical trial. Spine（Phila Pa 1976）2007 ; 32 : 2050‒
20577）Calmels P, et al : Effectiveness of a lumbar belt in subacute low backpain : An open, multicentric, and randomized clinical study. Spine（Phila
Pa 1976）2009 ; 34 : 215‒2208）Sato N, et al : Effects of long‒term corset wearing on chronic low backpain. Fukushima J Med Sci 2012 ; 58 : 60‒659）Castro‒Sánchez AM, et al : Kinesio Taping reduces disability and pain
slightly in chronic non‒specific low back pain : A randomised trial. J

323

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Ⅴ．Rehabilitation

Physiother 2012 ; 58 : 89‒9510）Parreira Pdo C, et al : Kinesio Taping to generate skin convolutions is
not better than sham taping for people with chronic nonspecic low backpain : A randomised trial. J Physiother 2014 ; 60 : 90‒9611）Paoloni M, et al : Kinesio Taping applied to lumbar muscles influences
clinical and electromyographic characteristics in chronic low back pain
patients. Eur J Phys Rehabil Med 2011 ; 47 : 237‒24412）Kachanathu SJ, et al : Comparison between Kinesio Taping and a traditional physical therapy program in treatment of nonspecific low backpain. J Phys Ther Sci 2014 ; 26 : 1185‒1188
13）Southerst D, et al : Is exercise effective for the management of neck pain
and associated disorders or whiplash‒associated disorders? : A systematic review by the Ontario Protocol for Traffic Injury Management（OPTIMa）Collaboration. Spine J 2016 ; 16 : 1503‒1523
14）Wong JJ, et al : Are manual therapies, passive physical modalities, or
acupuncture effective for the management of patients with whiplash‒associated disorders or neck pain and associated disorders? : An update of
the Bone and Joint Decade Task Force on Neck Pain and Its AssociatedDisorders by the OPTIMa Collaboration. Spine J 2016 ; 16 : 1598‒1630
15）Persson LC, et al : Cervical radiculopathy : Pain, muscle weakness andsensory loss in patients with cervical radiculopathy treated with surgery, physiotherapy or cervical collar : A prospective, controlled study.
Eur Spine J 1997 ; 6 : 256‒26616）Kuijper B, et al : Cervical collar or physiotherapy versus wait and see
policy for recent onset cervical radiculopathy : Randomised trial. BMJ
2009 ; 339 : b3883
17）Cassidy JD : Mobilisation or immobilisation for cervical radiculopathy?
BMJ 2009 ; 339 : b3952
18）Côté P, et al : Management of neck pain and associated disorders : A
clinical practice guideline from the Ontario Protocol for Traffic Injury
Management（OPTIMa）Collaboration. Eur Spine J 2016 ; 25 : 2000‒2022
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

MEDLINE, CINAHL, PEDro2010‒2017
guideline, meta‒analysis, RCT, randomized controlled trial, chronic pain treatment, rehabilitation, physical therapy, physiotherapy,
noninvasive therapies, nonpharmacological therapies
We ran a search based on these results and selected the references.

CQ46：Is multidisciplinary rehabilitation effective in managing chronic
pain?
Answer：Multidisciplinary rehabilitation consists of not only a rehabilitation
therapist but also a team of various medical practitioners who provide supportin executing a rehabilitation program, towards achieving a common goal. Compared with general pain care and regular rehabilitation, as multidisciplinary rehabilitation is more effective in reducing pain and dysfunction in patients withchronic pain, it is recommended.

Ⅴ．Rehabilitation

325

Summary of recommendation grades and overall evidence：1A (Execution isstrongly recommended)

Commentary：
Multidisciplinary rehabilitation is a form of rehabilitation performed by ateam of medical practitioners who work in several different specialized fields.
It can also be called multidisciplinary biopsychosocial rehabilitation, but the
program contents and the types of medical occupations of which the team isbio-psycho-social rehabilitation

comprised are not clearly defined. Therefore, there has been variance1) in thedetails of multidisciplinary rehabilitation conducted in each RCT.
1)

In a systematic review

on the effects of multidisciplinary rehabilitation on

RCT：randomized controlled
trial

chronic low back pain persisting for twelve weeks or longer, compared withgeneral pain care and regular rehabilitation (therapeutic exercise, physical modalities, manipulative therapy), they positively evaluated its effects on pain,
dysfunction and helping patients return to work. Compared with general pain
care and regular rehabilitation, pain had improved through multidisciplinary
rehabilitation at three months after intervention and at twelve months after intervention, compared with prior to intervention. Dysfunction (evaluated by the
Roland‒Morris Disability Questionnaire [RDQ]) had also improved three months
after intervention. In each case, it was unclear whether it was effective in help-

RDQ：Roland-Morris Disability Questionnarie

ing patients return to work. In light of these results, a systematic review1) concluded that there was high evidence indicating its effect on pain and dysfunction. The results were the same in other systematic reviews2,3). In addition,
there are some other RCTs4,5) which have reported that it was effective in preventing pain from becoming chronic in patients suffering from low back painin the sub‒acute phase.
According to a systematic review6) on its effects on adult fibromyalgia, they
recommend that treatment is multifaceted and multidisciplinary and listed thelevel of evidence as ‘A1’ (RCT meta‒analysis) and gave a recommendation
grade of ‘A’ (implementation is strongly recommended). Furthermore, multidisciplinary treatment improved pain and dysfunction (evaluated by the Fibromyalgia Impact Questionnaire [FIQ]) more than treatments conducted inde6)

pendently . To be more specific, a non‒pharmacological form of treatment
should be prioritized, and among non‒pharmacological treatments, the largest
evidence exists for therapeutic exercise and cognitive behavioral therapy(CBT). As these treatments improved FIQ scores which evaluate pain and dysfunction, researchers state that multidisciplinary treatment including theseshould first be conducted and if this fails to alleviate pain and other symptoms,
then it is okay to use pharmacotherapy6). Furthermore, some guidelines7) havestated that the principles of self‒management, using multidisciplinary treat-

FIQ：Fibromyalgia Impact
Questionnaire

326

Ⅴ．Rehabilitation

ment, should be incorporated when treating fibromyalgia.
Considering the above, we hope that multidisciplinary rehabilitation is spreadthroughout Japan.
References
1）Kamper SJ, et al : Multidisciplinary biopsychosocial rehabilitation forchronic low back pain. Cochrane Database Syst Rev 2014 ; 9 : CD000963
2）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 : 493‒5053）Qaseem A, et al : Noninvasive treatments for acute, subacute, and chronic low back pain : A clinical practice guideline from the American College of Physicians. Ann Intern Med 2017 ; 166 : 514‒5304）Eisenberg DM, et al : A model of integrative care for low‒back pain. J
Altern Complement Med 2012 ; 18 : 354‒3625）Gatchel RJ, et al : Treatment‒and cost‒effectiveness of early intervention
for acute low‒back pain patients : A one‒year prospective study. J Occup Rehabil 2003 ; 13 : 1‒96）Ángel García D, et al : Clinical approach to fibromyalgia : Synthesis of
Evidence‒based recommendations, a systematic review. Reumatol Clin2016 ; 12 : 65‒717）Fitzcharles MA, et al : 2012 Canadian Guidelines for the diagnosis andmanagement of fibromyalgia syndrome : Executive summary. Pain Res
Manag 2013 ; 18 : 119‒126
Database
PeriodWords searchedby the combination
with ‘chronic pain’＊
Notes

MEDLINE, CINAHL, PEDro2010‒2017
guideline, meta‒analysis, randomized controlled trial, chronic pain
treatment, rehabilitation, physical therapy, physiotherapy, noninvasive therapies, nonpharmacological therapies
We ran a search based on these results and selected the references.

Chapter Ⅰ

Overview：CQ1～CQ7

Chapter Ⅱ

Pharmacotherapy：CQ8～CQ21

Chapter Ⅲ

Interventional Management：CQ22～CQ33

Chapter Ⅳ

Psychological Approach：CQ34～CQ39

Chapter Ⅴ

Rehabilitation：CQ40～CQ46

Chapter Ⅵ

Multidisciplinary Treatment：CQ47～CQ51

328

Ⅵ．Multidisciplinary Treatment

CQ47：What does the multidisciplinary team for chronic pain management consist of ?

And what are the roles of its staff members?

Answer：A multidisciplinary treatment team consists of a wide variety of
specialists from various fields and occupations such as doctors (physicians andpsychiatrists and psychosomatic medical practitioners), dentists, nurses, clinicalpsychologists, physiotherapists and occupational therapists, pharmacists, managerial dieticians, social workers, and psychiatric social workers. Each team varies from institution to institution but in many cases, it fundamentally consistsof doctors, nurses, physiotherapists, and clinical psychologists.
Commentary：
A multidisciplinary team for managing chronic pain consists of doctors, dentists, nurses, physiotherapists, occupational therapists, clinical psychologists,
pharmacists, managerial dieticians, social workers, and psychiatric social workers . Each respective member of staff has an understanding of chronic painfrom the biopsychosocial model and it is important that they make the mostuse of their knowledge and skills from their own specialty, when making evaluations and conducting treatment interventions1‒9).
Physicians such as orthopaedic surgeons, anaesthesiologists (pain clinic),
rehabilitation doctors, neurologists and dentists etc.
Physicians evaluate biological pathophysiology. They also carry out the necessary tests and make a diagnosis on the pathology, manage the prescriptionof drugs, treat biological pathologies and undertake patient education.
Psychiatrists, Psychosomatic medical practitioners
They evaluate psychosociological, psychosomatic, and psychiatric pathologies, diagnose psychiatric diseases and treat these diseases.
Nurses
They listen carefully to patients’ concerns and complaints, take and assesspatients’ medical history, collect data on vital signs, assist with tests and treatment as well as provide patient education, including for the patients’ families,
and guidance on lifestyle habits.
Physiotherapists
They run tests on and evaluate musculoskeletal function, realign the musculoskeletal system, teach patients self‒care such as stretching, analyze one’s
work and lifestyle environment and provide physical realignment for this, andundertake physiotherapy education.
Occupational therapists
They train patients on the actions they need to take in order to lead a hindrance‒free daily life.

Ⅵ．Multidisciplinary Treatment

Clinical psychologists
They provide psychosocial evaluations, counseling and patient education.
Pharmacists
They evaluate drug prescriptions such as when many drugs are being usedin combination, provide suitable advice to doctors about drugs, and provide
drug education for patients.
Managerial dieticians
They revise meals (nutrition), which form the basis of people’s lives, and provide patient education to make them improve this.
Social workers
They provide patients with advice on things such as being accepted by thesocial security system for when they, for example, experience a reduction inincome due to a leave of absence.
Psychiatric social workers
Psychiatric social workers assist patients suffering from mental health issues
by helping them solve problems in their daily lives, and advising them on activities which will help them participate in society. They act as a liaison between the patients’ healthcare and regional lifestyles.
References
1）Turk DC, et al : Interdisciplinary pain management. American Pain Society, Glenview, http : //americanpainsociety.org/uploads/about/position‒statements/interdisciplinary‒white‒paper.pdf
2）Jeffery MM, et al : Multidisciplinary pain programs for chronic noncancer pain. Agency for Healthcare Research and Quality（US）, Rockville,
20113）Stanos S, et al : Multidisciplinary and interdisciplinary management ofchronic pain. Phys Med Rehabil Clin N Am 2006 ; 17 : 435‒4504）Wickson‒Griffiths A, et al : Interdisciplinary approaches to managing
pain in older adults. Clin Geriatr Med 2016 ; 32 : 693‒704
5）Arai YC, et al : The review of innovative integration of Kampo medicine
and Western medicine as personalized medicine at the first multidisciplinary pain center in Japan. EPMA J 2014 ; 5 : 10
6）Ushida T, et al : The effect of guidance regarding home exercise and
ADL on adolescent females suffering from adverse effects after HPV
vaccination in Japanese Multidisciplinary Pain Centers. Pain Res Manag2016 ; 3689352
7）Arai K, et al : Problems and prospects in multidisciplinary pain center inJAPAN. Pain Clinic 2013 ; 34 : 753‒7598）Japan Association for Study of Pain, Core Curriculum for Education in
Pain Editorial Committee : Multidisciplinary Pain Management : Core
Curriculum for Education in Pain. Shinko Trading Company Ltd., Publication Department of Medical Books, Tokyo, 20169）Takahashi N, et al : 星総合病院での入院型ペインマネジメントプログラ
ム．Pain Res 2017 ; 32 : 41‒51

329

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Ⅵ．Multidisciplinary Treatment

CQ48：Is multidisciplinary treatment effective on chronic pain?
Answer：There is at least medium‒level evidence which clearly shows theefficacy of multidisciplinary treatment on chronic pain.
Summary of level of recommendation and overall evidence：1B (Execution isstrongly recommended)

Commentary：
According to a systematic review from 2008 on multidisciplinary treatment,
compared with a waiting-list group of patients and a group of patients who
underwent regular treatment, there was strong evidence that multidisciplinary
treatment was effective on chronic pain (chronic low back pain and fibromyalgia). Furthermore, there is at least medium‒level evidence that multidisciplinary treatment was effective in comparison with physiotherapy, which included discussions held with the patients, and non‒multidisciplinary treatment
such as patient education. There is also medium‒level evidence indicating that
hospitalization programs are more effective than outpatient programs. In thisreport, cognitive behavioral therapy (CBT) was the main form of treatment
conducted under multidisciplinary treatment. With outpatient programs, theduration of treatment was between 4 ～ 15 weeks, while with hospitalization
programs, it was between 3 ～ 8 weeks. For doctors, part of this involves belonging to a treatment team, and their role is to manage and decrease dosagesof drugs, and provide information on the pathophysiology behind the formationof chronic pain. In an investigation of the individual treatment contents, it was
unclear whether there was a variance in treatment contents1) or not. In a report of a meta‒analysis which compared the methods of treating chronic pain,
they did not find a clear difference in pain and dysfunction among threegroups which used a combination of physiotherapy, behavioral therapy andpsychotherapy2). However, strictly classifying the treatment content of thesethree groups is difficult. In a meta‒analysis of multidisciplinary treatment conducted on patients who were on leave of absence due to chronic pain, multidisciplinary treatment was found to be clearly useful in helping them return tobio-psycho-social rehabilitation

work3). In a meta‒analysis of intensive multidisciplinary treatment using biopsychosocial rehabilitation, they found strong evidence that it was effective on
physical function due to chronic low back pain. There was also medium‒level
evidence of its effects on pain4). In a systematic review on treatment of headache accompanying cervical pain, researchers showed that therapeutic exercise was essential, and multidisciplinary treatment was useful5). As for thecosts incurred by multidisciplinary treatment, as the contents of the multidisciplinary treatment and the health insurance system in each country is different,

Ⅵ．Multidisciplinary Treatment

331

this needs to be investigated in future6).
There are no RCTs in Japan, but there are several case reports, which have
7,8)

reported on the efficacy of multidisciplinary treatment.

References
1）Scascighini L, et al : Multidisciplinary treatment for chronic pain : A systematic review of interventions and outcomes. Rheumatology（Oxford）
2008 ; 47 : 670‒678
2）O’Keeffe M, et al : Comparative effectiveness of conservative interventions for nonspecific chronic spinal pain : Physical, behavioral/psychologically informed, or combined? : A systematic review and meta‒analysis. J
Pain 2016 ; 17 : 755‒7743）Norlund A, et al : Multidisciplinary interventions : Review of studies ofreturn to work after rehabilitation for low back pain. J Rehabil Med
2009 ; 41 : 115‒1214）Guzman J, et al : Multidisciplinary bio‒psycho‒social rehabilitation forchronic low back pain. Cochrane Database Syst Rev 2002 ; 1 : CD000963
5）Varatharajan S, et al : Are non‒invasive interventions effective for the
management of headaches associated with neck pain? : An update of theBone and Joint Decade Task Force on Neck Pain and Its AssociatedDisorders by the Ontario Protocol for Traffic Injury Management（OPTIMa）Collaboration. Eur Spine J 2016 ; 25 : 1971‒1999
6）Almazrou S, et al : Cost effectiveness of multidisciplinary pain management services for chronic back pain : Systematic review. Value Health2015 ; 18 : A661
7）Arai YC, et al : The review of innovative integration of Kampo medicine
and Western medicine as personalized medicine at the first multidisciplinary pain center in Japan. EPMA J 2014 ; 5 : 10
8）Ushida T, et al : The effect of guidance regarding home exercise and
ADL on adolescent females suffering from adverse effects after HPV
vaccination in Japanese Multidisciplinary Pain Centers. Pain Res Manag2016 ; ID3689352
Database

Cochrane Central Register of Controlled Trials, PubMed, EMBASE, etc
Period
2005～2017
Words searched
RCTs, multidisciplinary, interdisciplinary, patient care team, backby the combination pain, fibromyalgia, chronic pain syndrome, physical / behavioral /with ‘chronic pain’ psychological / combined intervention, spinal pain, chronic, RCT,back pain, rehabilitation, return to work, sick leave, work injury,
disability pension＊
Notes
We ran a search based on these results and selected the references.

CQ49：Is group cognitive behavioral therapy (teaching group education
behavior) effective on chronic pain?
Answer：With the management of chronic pain, group cognitive behavioral
therapy (CBT) has approximately the same effects (medium‒level efficacy) as
individual treatment. On the other hand, from a cost‒effectiveness perspective,

RCT：randomized controlled
trial

332

Ⅵ．Multidisciplinary Treatmentgroup treatment programs are clearly superior to individual treatment.
Summary of recommendation grades and overall evidence：1B (Execution isstrongly recommended)

Commentary：
A meta‒analysis has medium‒level evidence that group cognitive behavioral
therapy is effective in treating chronic pain1). When they investigated the effects of a multidisciplinary program, which had incorporated both cognitive behavioral therapy and physiotherapy, conducted over several weeks, on individuals and groups, they found a significant improvement in both cases. The individual multidisciplinary program and the group multidisciplinary program had
approximately the same efficacy2,3). In addition, in other research reports inwhich RCTs were conducted, they reported that group treatment programs
were more effective than standard treatments but they did not find a significant difference when comparing them with multidisciplinary programs conducted by individual patients4,5). However, from a cost‒effectiveness perspective, group treatment programs are clearly superior. In Japan, although it was
RCT：randomized controlled
trial

not a RCT research study, there was one report that group multidisciplinary
treatment was effective6).
References
1）Scascighini L, et al : Multidisciplinary treatment for chronic pain : A systematic review of interventions and outcomes. Rheumatology 2008 ; 47 :670‒678
2）Kääpä EH, et al : Multidisciplinary group rehabilitation versus individual
physiotherapy for chronic nonspecific low back pain : A randomized trial. Spine（Phila Pa 1976）2006 ; 31 : 371‒3763）Turner‒Stokes L, et al : Outpatient cognitive behavioral pain management programs : A randomized comparison of a group‒based multidisciplinary versus an individual therapy model. Arch Phys Med Rehabil
2003 ; 84 : 781‒7884）Perry KN1, et al : Comparison of a pain management program with usual care in a pain management center for people with spinal cord injury‒
related chronic pain. Clin J Pain 2010 ; 26 : 206‒2165）Johnson RE, et al : Active exercise, education, and cognitive behavioral
therapy for persistent disabling low back pain : A randomized controlled
trial. Spine（Phila Pa 1976）2007 ; 32 : 1578‒1585
6）Inoue M, et al : The efficacy of a multidisciplinary group program for patients with refractory chronic pain. Pain Res Manag 2014 ; 19 : 30230‒302
Database

Cochrane Central Register of Controlled Trials, PubMed, EMBASE, etc
Period
2006～2017
Words searched
RCTs, multidisciplinary, interdisciplinary, patient care team, backby the combination pain, fibromyalgia, chronic pain syndrome
with ‘chronic pain’＊
Notes
We ran a search from these results and selected the reference.

Ⅵ．Multidisciplinary Treatment

CQ50：How should we begin multidisciplinary treatment in managing
chronic pain?
Answer：When commencing multidisciplinary treatment on chronic pain,
healthcare professionals from each discipline who are involved in multidisciplinary treatment, need to acquire anatomical and physiological knowledge on
the perception of pain. They also need to have an understanding of the psychosocial factors which can have an effect on pain perception, and after they havean understanding of the fundamental principles of pain treatment, it is important that they have a shared awareness of treating patients along the lines of abiopsychosocial model.
Commentary：
When commencing multidisciplinary treatment, there is a need to bring together practitioners from various medical specialties who are both knowledgeable and willing to treat patients suffering from chronic pain. Furthermore, itgoes without saying that healthcare professionals from various disciplines whoare involved in multidisciplinary treatment need to have knowledge of the areaof their respective specialty, an understanding of anatomical and physiologicalknowledge, the psychosocial factors which can have an effect on pain perception, and need to continue to have a sound understanding of the basic principles of pain treatment. As for the areas of expertise practiced by other practitioners participating in multidisciplinary treatment, one needs to have a soundunderstanding of what kind of basic treatment interventions they are conducting within multidisciplinary treatment as a whole1,2). On top of this, it is also
necessary to have a shared awareness of conducting treatment along the lines
of a biopsychosocial model. Therefore, they need to share their philosophies,
work duties and treatment goals and need to secure enough time and space inorder to be able to discuss how to put these things into practice adequately.
As for treating individual patients, healthcare professionals from each discipline involved in multidisciplinary treatment need to have an understanding of
the patients’ backgrounds, the pathology of patients with chronic pain, thetreatment plans, the treatment methods and types, as well as the overall ultimate aims and also need to be unified when proceeding with treatment.
References
1）Turk DC, et al : Interdisciplinary pain management. American Pain Society, Glenview, http : //americanpainsociety.org/uploads/about/position‒statements/interdisciplinary‒white‒paper.pdf
2）Leo RJ : Clinical manual of pain management in psychiatry. American
Psychiatric Association Publishing August, Arlington, 2007 ; 20

333

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Ⅵ．Multidisciplinary Treatment

CQ51：What are the purposes and ultimate goals of multidisciplinary
treatment for chronic pain?
Answer：The purpose of multidisciplinary treatment is to improve the patient’s physical and emotional function, and its ultimate goal is to bring about
Note 19：refer to p.182
QOL：quality of life

an overall improvement in quality of life (QOL)Note 19.
Commentary：
The degree to which we are able to improve QOL varies from patient to patient and so prior to treatment, we need to conduct a multidisciplinary evaluation of the factors causing the patient’s pain and then decide on the ultimate
goals.
In general pain syndromes such as chronic low back pain, it is difficult tocompletely remove the pain but when patients try to stop moving as little aspossible in order to avoid the pain, physical function sharply declines out of
disuse. If patients are dominated by their pain, their emotional function also becomes impaired and their overall QOL declines. Therefore, a purpose of chronic pain treatment is, first of all, to improve their physical function, and even if
there is pain, by making them experience some degree of activity, they areable to regain their confidence. As a result of this, they are able to recover
their emotional function, which had been impaired by their pain1‒3). By enacting control over their pain through pharmacotherapy and control over their
physical function through therapeutic exercise, our final goals for the treatment is to create a situation in which patients become independent in their everyday lives, and fulfill the roles (jobs) they can do by themselves. It is possible
to foster independence among elderly patients and patients with developmental brain disorders by using a support system such as a regional comprehensive support center. We could also consider using administrative services, suchas hiring social workers. Furthermore, in cases where patients are on leave ofabsence from their jobs or have left their jobs due to pain, our ultimate goal isalso to improve their physical and emotional functions up until the time when
they are able to return to work or find new employment.
References
1）Turk DC, et al : Interdisciplinary pain management. American Pain Society, Glenview, http : //americanpainsociety.org/uploads/about/position‒statements/interdisciplinary‒white‒paper.pdf
2）Jeffery MM, et al : Multidisciplinary pain programs for chronic noncancer pain. Agency for Healthcare Research and Quality（US）, Rockville,
20113）Stanos S, et al : Multidisciplinary and interdisciplinary management ofchronic pain. Phys Med Rehabil Clin N Am 2006 ; 17 : 435‒450

339

Index
benzodiazepine

A
abuse

290, 292, 301, 303, 318, 330

biofeedback therapy

234

acceptance and commitment therapy
acetaminophen
ACNES

290, 303

biopsychosocial model

BMS

208, 215, 233

ACT

300

activity of daily living

175, 182, 294

acute cutaneous nerve entrapment
syndrome
acute pain

174
273

adhesive capsulitis

281, 282

adverse events

301

CPSP

272, 274

Brachial plexus avulsion injury

275

CRPS

218, 233, 251, 254, 262, 272,

buprenorphine

228

274

buprenorphine patche

228

204
192

175, 180, 293, 319,

320

222, 224, 225, 226, 228, 229, 230,

CBT

306, 310

242

184, 290, 292, 293, 301, 303,

318, 319, 330
CDC

191

alexithymia

CRPS in the upper extremitie

211, 222

234

centers for disease control and preven181

tion

American College of Physician

208,

215, 233

234

central post‒stroke pain

191

American Psychological Association
291
American Society of Anesthesiologists
183
sia and Pain Medicine
amitriptyline
anitcholinergic

183

211

182, 218

226

CYP3A4

231

191

D
DBS

274

DBT

301

decision‒making

320

deep brain stimulation

274

degree of loss in ADL

180

dependence

225, 234
181

descending pain inhibitory system
208, 226

323

dextromethorphan

217

cervicogenic headache

316

diabetic neuropathy

225, 228, 254,

chronic cancer pain

173

chronic cervical pain

307, 319, 320

256

173, 291

chronic low back pain

291, 293, 298, 306, 319, 322
chronic neck pain

diagnostic block

246

diagnostic criteria

194, 228, 290,

chronic musculoskeletal pain

213

CYP2D6

cervical radiculopathy

chronic headache

American Society of Regional Anesthe-272, 274

252

312

depressive disorder

central sensitization

American Headache Society

cryotherapy

cyclooxygenase‒2

caudal epidural injections

232, 233, 238, 246, 298, 310, 322

192

borderline personality disordercatastrophizing

182, 188, 189, 190,

191

COX‒2 highly selective

cardiovascular event

242

173

294

177

diagnostic medial branch block
diagnostics

dialectical behavior therapy
disability

301

175

220

chronic neuropathic pain

173

disc herniation

245, 246, 268

antiepileptic drugs

204chronic non‒cancer pain

234

discogenic pain

242

190

chronic pain 172, 174, 175, 177, 288,

discography

277

APA

291

290, 300, 302, 306, 328, 330, 331,

disuse

ASA

183

333

dorsal root entry zone lesion

ASRA

183

chronic pain due to spinal cord injury

atypical odontalgia

211

avoiding their own pain

312

behavioral therapy

290

173

175, 334

dorsal root ganglion
DPIS

chronic postsurgical and posttraumaticpain

Bbalneotherapy

303
293

208

DREZ

275

DRG

266

173

drug therapy

clinical psychologist

329

drug‒metabolizing enzyme
184,

275

266

chronic primary pain

cognitive behavioral therapy

249

177

antianxiety agent

anti‒inflammatory drug

218,

233, 251, 254, 262, 272, 274
COX‒2

198, 202, 206, 208, 209, 216, 219,

aerobic exercise

325,

211, 222

carbamazepine

175, 182, 183, 294

291

complex regional pain syndromeC

adaptive stimulation

290

communication skill

179, 333

burning mouth syndrome259

administer steroid

cognitive therapy

330

193, 194

259

ACP

AHS

220

bio‒psycho‒social rehabilitation

300

ADL

221

benzodiazepine type drug

dry needling

185
258

226

340

Index

duloxetine

207

dysthymic (pain) disorder

181

IBS

298, 303

IDET

278

mindfulness based cognitive therapy
298, 301

idiopathic odontalgiaE

immobilization

educate patient
education318

epiduroscopy

334

298, 301
230

mindfulness‒based stress reduction

improving pain and dysfunction

307

293

interlaminar epidural injection

242

mixed pain172

mobilization

316, 320

International Association for the Study

268, 269, 270

exercise therapy

mindfulness based stress reduction

175

impaired renal function

183

emotional function

211

of Pain

185

172, 182, 277

MOH

extract from inflamed cutaneous tissue

interventional therapyof rabbits inoculated with vacciniainterventional treatment

virus

intra‒articular hyaluronic acid injection

196

monoamine reuptake inhibitor

185

motor control exercise

280

F

intra‒articular steroid injection

facet (zygapophyseal) joint injection
failed back surgery syndrome268,

failed spinal surgery syndrome254

268, 272

fentanyl patch
fibromyalgia

233

intradiscal therapy

291, 294, 298, 303,

fibromyalgia impact questionnaire
325
FIQ

325

FM

291

278

236

gabapentin

goshajinkigan

237

group cognitive behavioral therapy
331, 332
group therapeutic exercise

290

headache

293, 298

health‒related QOL

294

health‒related quality of life
herpes zoster‒associated pain
266

176
265,

knee osteoarthritis (OA)

nerve root block

242, 246

179, 180

neuropathic pain

172, 197, 200, 201,

197

NMDA

212, 217

low‒level laser therapy

312, 313

NMDA receptor

lumbar spinal stenosis

254

NMDA receptor antagonist

217

N‒methyl‒D‒aspartic acid

212, 217

M
M1

226

218

NNH

201, 202, 205, 208

NNT

191, 201, 202, 205, 208, 212,

225

182, 290

managerial dietician

329

nociceptive

manipulative therapy

315

nociceptive pain

179, 180172

non‒specific low back pain

316

massage

316

MBCT

298, 301

non‒organic factor

MBSR

293, 298, 301

nonsteroidal anti‒inflammatory drugs

MCE

308
274

medical history

migraine

217

mindfulness

297, 298, 301

190, 194, 233, 316

number needed to harm

177

190, 191, 204

224, 266, 269, 274

NSAIDs248

medication overuse headachememantine

182, 183

190, 194, 233, 316
NRS

medial branch block

172, 182, 277

258

208, 233, 295

176, 294I

neuropathic

195

HRQL

302

184

312, 313

MCS

hypnotherapy

306

228

myofascial pain syndrome

309

204

179
176, 294

274

N

holistic
HRQOL

174

multiple sclerosis

musculoskeletal pain

managementH

multiple parenting

muscle‒strengthening exercise

low back pain

221

184, 330,

217

LLLT
204

324,

328

multidisciplinary treatment

281

liver damage

GABAA receptor

multidisciplinary rehabilitationknee OA

lamotrigine

221

274

274

ketamineL

G

MS

multudisciplinary team
298, 303

K

liaison case council

GABA

258

333

kampo medicine

317, 325

motor cortex stimulation
MPS

226

308

325

irritable bowel syndrome

272
FBSS

280

intradiscal electrothermal treatment
278

248, 249

IASP

183

191

191

201, 205,

208
number needed to treat

191, 201,

205, 208, 212, 225
numerical rating scale

224, 266, 269,

341

Index

274

progressive muscle relaxation [PMR]

nurse

328

290

OARSI

psychiatrist

ODT

psychosocial

290, 318

232
224

psychosocial pain

172

328

osteoarthritis

190, 191, 224, 229

osteoarthritis (OA) of the hip

303

osteoarthritis (OA) of the knee

303,

306
osteoarthritis research society international

191

P
pain behavior

pain catastrophizing

175, 180

pain fear‒avoidance model

176

painful diabetic peripheral neuropathy
272, 273
patient education
PDPN

319

278
pharmacist

255

243, 251, 252, 255, 265, 273
177physical function

334

physical modality

312

physicianqigong176, 182, 183, 219, 224, 228,

328
308, 309

post‒spinal cord injury

post‒traumatic syndrome
postherpetic neuralgia
254, 255, 265, 273
postherpetic pain
192

pregabalin
265

198

254

225, 243, 252,

SNRI

208, 215, 234

273, 293, 297, 306, 316, 319, 334
questionnairesocial reinforcemen
social worker

291

328, 329

sodium valproate

180

204

somatic symptom disorderR
308, 310
259, 265

radiofrequency thermocoagulation
190, 193,

somatization disorder181

somatoform disorder295

spa therapy

spinal cord stimulation

272, 274

spinal manipulation

316

spring‒coil catheter

268, 269

SSRI

228, 233, 242, 249, 253, 260, 265,

stellate ganglion block

273, 277, 280, 288, 292, 298, 300,

Stevens‒Jonson syndrome

303, 306, 308, 325, 331, 332

stress coping

252

295

312

197, 204, 208, 212, 214, 217, 220,

215

stretching251
205, 206

288

306, 323

subacromial bursa steroid injection
283

262

190, 193, 197, 204, 208, 212,

sustained‒release tablet

226

214, 217, 220, 225, 228, 233, 242,

sympathetic ganglion block

249, 253, 260, 265, 273, 277, 280,

sympathetically maintained pain

288, 292, 298, 300, 303, 306, 308,
325

red flag254,

190, 191, 250

T

178
291

respiratory depression
respondent therapy

254

255
systematic review

325, 331, 332
RDQ

relaxation therapy
200

312

334

extremities

225

shortwave diathermy
254, 255

RCT

278

247

251

SMP

Raynaud’s Syndrome of the upper

pilates method

208, 215, 234

234, 273, 293, 297, 306, 316, 319,
176, 182, 224, 228,

224

216

serotonin‒noradrenaline re‒uptake

SGB308, 309

range of movement328

physiotherapist

PRF

252

inhibitor

randomized controlled trial

329

physical examination

PLDD

serotonin syndrome

252, 259, 265

phantom breast pain

291

severe complication

radiofrequency denervation

percutaneous laser disc decompression

PHN

265

Q

radio calisthenics

272, 273

175

self‒rating depression scalepulsed radiofrequency method

quality of life

184

183, 293

pulsed radiofrequency

QOL

self‒efficacy

self‒monitoring

psychotherapy

299, 301

215

psychosomatic medical practitioner

322

224

selective serotonin reuptake inhibitor

opioid analgesics [weak]orthotic therapy

272, 274

SDS

second wave of CBT

172173, 303

SCS

174, 319

psychosocial issue

orofacial pain

290, 293

psychosocial factor
232
226

252

S

288

179, 180

opioid analgesics [strong]orally disintegrating tablet

325

288

psychological intervention

operant therapy
opioid329

ROM

psychological approach

328

226

291

Roland‒Morris Disability Questionnaire

328

psychoeducation

191

occupational therapist

PPI

192

psychiatric social worker
190, 191

259, 265

rheumatic disease

proton pump inhibitor

O
OA

RF

230

290

tai chi308

taping322

teaching group education behavior

342

Index

331

(325 mg) tablet

temporomandibular arthritis

303

temporomandibular disorder

316

TEN

205, 206

TENS

312, 313, 317

226video associated endoscopic thoracic

tramadol‒acetaminophen oral tablets(T/A tablets)

224

transcutaneous electrical nerve stimula-tension‒type headachetion
194, 221, 292

The American College of Physician
233

312, 313, 317

transforaminal epidural injection

242

transition to PHN (herpes zoster pain)
265

therapeutic exercise

183, 306, 308,

319
thermotherapy

312

312

third wave of CBT

301

third wave of cognitive‒behavioral

transition to postherpetic neuralgia

therapy297

thoracoscopic sympathectomy

255

243, 251

322

whiplash‒associated disorders

withdrawal or serotonin syndrome288

trigeminal neuralgia

260, 261

Y

trigger point injection

258

yoga

221, 292

308

yokukansan

U

237

Z

202

ultimate aim

333

ZAP

topiramate

204, 205

ultimate goal

334

zoster‒associated pain

TPI

205, 206

258

tractiontramadolultrasonic therapy

312

V

314

traction therapy

312

224

tramadol (37.5mg)/acetaminophen

322

249

tolerability

toxic epidermal necrolysis

266, 269, 282

226

traumatic cervical syndrome

TTH

255

W
WAD

whiplash‒injury(PHN)

therapeutic ultrasound therapy

sympathectomy

visual analogue scale

265
265

記号
γ (gamma)‒aminobutyric acid reuptake

valproate

204

VAS

266, 269, 282

victim181

inhibitor

221

Clinical Practice Guideline for Chronic Pain
The Committee for Clinical Practice Guideline
for Chronic Pain

First Edition first published in 2018
by Publication Department, Shinko Trading Co. Ltd.
Ⓒ The Committee for Clinical Practice Guideline for Chronic Pain
2018 All Right Reserved
These guidelines are prepaired by “Health, Labour and Welfare
Policy Research Grants (Research on chronic pain) in Japan :Research on Constructing a System Base for the Treatment and
Education of Chronic Pain”

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