Look Inside CRPS by IASP

Wilson Stanton-Hicks Harden

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CRPS: Current Diagnosis and Therapy

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CRPS: Current Diagnosis and Therapy Peter R. Wilson Michael Stanton-Hicks R. Norman Harden Editors

32 IASP PRESS ®

Progress in Pain Research and Management V O L U M E 32

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Progress in Pain Research and Management Volume 32

CRPS: Current Diagnosis and Therapy Editors

Peter R. Wilson, MB, BS, PhD Division of Pain Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

Michael Stanton-Hicks, MB, BS, Dr med, FRCA, ABPM, FIPP Department of Pain Management, Division of Anesthesiology, Cleveland Clinic Foundation; Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA

R. Norman Harden, MD Department of Physical Medicine and Rehabilitation, Northwestern University Medical School; Rehabilitation Institute of Chicago, Chicago, Illinois, USA

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All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the publisher. Timely topics in pain research and treatment have been selected for publication, but the information provided and opinions expressed have not involved any verification of the findings, conclusions, and opinions by IASPÂŽ. Thus, opinions expressed in CRPS: Current Diagnosis and Therapy do not necessarily reflect those of IASP or of the Officers and Councillors. No responsibility is assumed by IASP for any injury and/or damage to persons or property as a matter of product liability, negligence, or from any use of any methods, products, instruction, or ideas contained in the material herein. Because of the rapid advances in the medical sciences, the publisher recommends that there should be independent verification of diagnoses and drug dosages. Library of Congress Cataloging-in-Publication Data CRPS : current diagnosis and therapy / editors, Peter R. Wilson, Michael Stanton-Hicks, R. Norman Harden. p. ; cm. -- (Progress in pain research and management ; v. 32) Includes bibliographical references and index. ISBN 0-931092-55-8 (alk. paper) 1. Reflex sympathetic dystrophy. [DNLM: 1. Complex Regional Pain Syndromes--diagnosis. 2. Complex Regional Pain Syndromes--therapy. WL 544 C954 2004] I. Title: Complex Regional Pain Syndrome. II. Wilson, Peter R., 1941- III. Stanton-Hicks, Michael dâ&#x20AC;&#x2122;A. IV. Harden, R. Norman, 1954- V. Series. RC422.R43C77 2004 616'.0472--dc22 2004062439

Published by: IASP Press International Association for the Study of Pain 4XHHQ $QQH $YHQXH 1, Suite Seattle, WA 9810 - USA 3KRQH: 206- - )D[ - :HE www.LDVS SDLQ.org ERRNV Printed in the United States of America

Contents List of Contributing Authors Preface

vii ix

Part I Overview of Taxonomy of Syndromes and Diseases Section Editor: Peter R. Wilson 1. Introduction John D. Loeser 2. Taxonomy and Complex Regional Pain Syndrome Harold Merskey 3. Retrospection, Science and Epidemiology of CRPS Peter R. Wilson and Nikolai Bogduk

3 9 19

Part II Taxonomy and Diagnosis: Clinical Experience Section Editor: Peter R. Wilson 4. Diagnostic Criteria: The Statistical Derivation of the Four Criterion Factors R. Norman Harden and Stephen P. Bruehl 5. Factor I: Sensory Changes—Pathophysiology and Measurement Anne Louise Oaklander and Frank Birklein 6. Factor II: Vasomotor Changes—Pathophysiology and Measurement Gunnar Wasner and Ralf Baron 7. Factor III: Sudomotor Changes and Edema—Pathophysiology and Measurement Paola Sandroni and Peter R. Wilson

45 59 81

107

Factor IV: Movement Disorders and Dystrophy—Pathophysiology and Measurement Jacobus J. Van Hilten, Helmut Blumberg, and Robert J. Schwartzman

119

Laboratory Tests for Complex Regional Pain Syndrome Oliver Rommel, Heinz-Joachim Häbler, and Matthias Schürmann

139

Part III Management of CRPS Section Editor: R. Norman Harden 10. The Rationale for Integrated Functional Restoration R. Norman Harden

163

11. Physical and Occupational Therapies Jan H.B. Geertzen and R. Norman Harden

173

12. Evidence-Based Pharmacotherapy for CRPS and Related Conditions Anne Louise Oaklander

181

CONTENTS

13. Psychological Interventions Stephen P. Bruehl

201

14. Traditional Interventional Therapies Allen W. Burton, Timothy R. Lubenow, and P. Prithvi Raj

217

15. Implanted Therapies Timothy R. Lubenow, Asokumar Buvanendran, and Michael Stanton-Hicks

235

16. Miscellaneous and Experimental Therapies Michael Stanton-Hicks, Richard L. Rauck, Mark Hendrickson, and Gabor Racz

255

17. Management of Pediatric Patients with CRPS Robert T. Wilder and Gunnar Olsson

275

Part IV Epilogue Section Editor: Peter R. Wilson 18. Future Perspectives Wilfrid J채nig

293

Index

309

Contributing Authors Ralf Baron, Dr med Department of Neurological Pain Research and Therapy, Neurological Clinic, University of Schleswig-Holstein, Kiel, Germany Frank Birklein, MD, PhD Department of Neurology, University of Mainz, Mainz, Germany Helmut Blumberg, MD Department of Neurosurgery, University of Freiburg, Freiburg, Germany Nikolai Bogduk, MD, PhD Department of Neurology, University of Newcastle, and Newcastle Bone and Joint Institute, Royal Newcastle Hospital, Newcastle, New South Wales, Australia Stephen P. Bruehl, PhD Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA Allen W. Burton, MD Department of Anesthesiology, M.D. Anderson Cancer Center, University of Texas, Houston, Texas, USA Asokumar Buvanendran, MD Section of Pain Medicine, Department of Anesthesiology, Rush University Medical Center, Chicago, Illinois, USA Jan H.B. Geertzen, MD, PhD Center for Rehabilitation, University of Groningen, Groningen, The Netherlands Heinz-Joachim H채bler, MD Bonn-Rhein-Sieg University of Applied Sciences, Rheinbach, Germany R. Norman Harden, MD Department of Physical Medicine and Rehabilitation, Northwestern University Medical School, and Rehabilitation Institute of Chicago, Chicago, Illinois, USA Mark Hendrickson, MD Department of Orthopaedic Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA Wilfrid J채nig, Dr med Department of Physiology, Christian-Albrechts University, Kiel, Germany John D. Loeser, MD Departments of Neurological Surgery and Anesthesia, University of Washington, Seattle, Washington, USA Timothy R. Lubenow, MD Section of Pain Medicine, Department of Anesthesiology, Rush University Medical Center, Chicago, Illinois, USA Harold Merskey, DM, FRCPC, FRCPsych Professor Emeritus of Psychiatry, University of Western Ontario, London, Ontario, Canada Anne Louise Oaklander, MD, PhD Nerve Injury Unit, Departments of Anesthesiology, Neurology, and Neuropathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

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CONTRIBUTINGAUTHORS AUTHORS CONTRIBUTING

Gunnar L. Olsson, MD, PhD Department of Pediatric Anesthesiology, Astrid Lindgren Children’s Hospital, Stockholm, Sweden; Karolinska Institute, Stockholm, Sweden Gabor Racz, MD Pain Services, Department of Anesthesiology, Texas Tech University Health Sciences, Lubbock, Texas, USA P. Prithvi Raj, MD Department of Anesthesiology and Pain Medicine, Texas Tech University Health Sciences Center School of Medicine, and World Institute of Pain, Lubbock, Texas, USA Richard L. Rauck, MD Piedmont Pain Consultants, Winston-Salem, North Carolina, USA Oliver Rommel, Dr med Departments of Neurology and Pain Therapy, Rommel Clinic, Bad Wildbad, Germany Paola Sandroni, MD Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA Matthias Schürmann, Dr med Department of Accident and Rehabilitation Surgery, Hof Clinic, Hof, Germany Robert J. Schwartzman, MD Department of Neurology, Drexel University College of Medicine, Philadelphia, USA Michael Stanton-Hicks, MB:BS, Dr med, FRCA, ABPM, FIPP Department of Pain Management, Cleveland Clinic Foundation; Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA J.J. van Hilten, MD Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands Gunnar Wasner, Dr med Department of Neurological Pain Research and Therapy, Neurological Clinic, University of Schleswig-Holstein, Kiel, Germany Robert T. Wilder, MD, PhD Mayo Clinic and Mayo Eugenio Litta Children’s Hospital, Rochester, Minnesota, USA Peter R. Wilson, MB:BS, PhD Division of Pain Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

Preface Complex regional pain syndrome (CRPS) has been extensively studied and discussed since the publication of Reflex Sympathetic Dystrophy: A Reappraisal (W. JĂ¤nig and M. Stanton-Hicks [Eds]; Seattle: IASP Press, 1996). This volume presents the results of changes brought about by the diagnostic reclassification and redefinition of CRPS based on clinical and basic research. CRPS can now regarded as a systemic condition involving the entire neuraxis with manifestation of all the inflammatory changes described centrally and in the periphery. Unfortunately, CRPS cannot yet be reduced to a single mechanism involving only one system. It is a syndrome that represents a spectrum of changes involving nervous, endocrine, vascular, and musculoskeletal systems. The proportion of each involvement determines those criteria that make up the definition of CRPS types I and II. Changes to the diagnostic criteria of CRPS suggested in this volume have resulted from prospective multicenter epidemiological studies that have identified four clinically and statistically distinct subgroups or factors within the existing IASP criteria. Each factor consists of subjective symptoms and/ or objective signs. They comprise: (1) hyperalgesia and hyperesthesia, (2) temperature asymmetry and color changes, (3) edema and sweating, and (4) motor dysfunction and trophic changes. The stimulus to review what has been 10 yearsâ&#x20AC;&#x2122; progress in our understanding of CRPS comes from these observations and changing clinical and research views. Treatment decisions now can be based on an improved understanding of the pathophysiology, rather than on consensus (although consensus is still important, in the absence of evidence-based outcome data). Most of the contributors to this volume deliberated at a consensus conference over two days to decide what changes should be made, if any, to the existing IASP diagnostic criteria. Sensitivity has been improved, and the issues of specificity have been clarified so that the new criteria can be recommended to the Committee on Taxonomy of the IASP. Also, the second charge for this group was to provide a critical analysis of non-interventional and interventional methods that are currently employed for the treatment of CRPS. Given the time constraints and number of aspects to cover, a remarkable level of understanding and cooperation formed the basis for the contents of the four parts that comprise this text. This book is designed as a reference, not only for clinicians, pain specialists, and others in the health care industry, but also for anyone seeking information that is current and relevant on the day of its publication. ix

PREFACE

This book is divided into four parts. Part I—Overview of Taxonomy of Syndromes and Diseases lays the foundation historically and in context with scientific and epidemiological facts that were not previously known. Part II—Taxonomy and Diagnosis: Clinical Experience provides the background data for making a proposal to the Committee on Taxonomy of the IASP. There are minor structural changes to the existing taxonomy that will, as described above, improve its specificity. Part III addresses the management of CRPS, as far as possible on the basis of evidence-based practice. It describes the different modalities that are currently used to manage a “syndrome” that awaits a defining mechanism. Part IV—Epilogue, is an overview by the doyen of CRPS basic research, Wilfrid Jänig, who is indefatigable in his efforts to understand the relationship of the autonomic nervous system to disease states. His persuasive educational skills have mentored innumerable clinicians and scientists, many of whom have contributed to this volume. This chapter provides a roadmap for further studies that will lead to a full understanding of CRPS. Grading of the evidence used to justify treatment modalities is a deliberately simplified version of the basic methodology used by the Cochrane Collaboration. The highest level of evidence (level 1) is from systematic review or meta-analysis of properly designed controlled randomized trials, while level 2 reflects evidence from one or more such trials. The next level (level 3) is from cohort studies, nonrandomized trials, or open-label trials. The lowest level (level 4) is from individual patient data (case reports). There is little, if any, reliance placed on “clinical experience” or “usual practice.” This volume was not intended to apply meta-analytic techniques to all available published data, but to filter the information for general applicability. The editors acknowledge the timeliness, cooperation, and insights of all the authors, and their patience with the process. The production of this volume would not have been possible without their support and the additional invaluable technical assistance and guidance from Elizabeth Endres of the IASP Press. The editors wish to gratefully acknowledge the support that was provided in the form of an unrestricted educational grant by the Medtronic Corporation toward the publication of this book. PETER WILSON, MB, BS, PHD MICHAEL STANTON-HICKS, MB, BS, DR MED, FRCA, ABPM, FIPP R. NORMAN HARDEN, MD

3 Retrospection, Science and Epidemiology of CRPS Peter R. Wilsona and Nikolai Bogdukb a

Division of Pain Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA; bDepartment of Neurology, University of Newcastle, and Newcastle Bone and Joint Institute, Royal Newcastle Hospital, Newcastle, New South Wales, Australia

Widespread pain following injury has long been an enigma in medicine, particularly when, to the patient and physician alike, its extent seems disproportionate to the nature of the precipitating injury. When such pain is accompanied by what appear to be features mediated by the sympathetic nervous system, such as swelling, discoloration, and temperature changes, it appears to constitute a distinctive syndrome. This type of pain has been recorded for hundreds of years under numerous descriptors, as documented in a masterly doctoral thesis (Veldman 1995). Veldman suggests that the first description may have been by Ambrose Paré in 1598. Nonetheless, three linguistically distinct variants began to be described in the American, French, and German literature. These schools were founded on the observations of Mitchell et al. (1864), Charcot (1890), and Sudeck (1900). There are at least 79 descriptors in the English literature, 32 in the French, and 49 in the German (Veldman 1995). The term reflex sympathetic dystrophy (RSD) appears to have been coined by Evans in 1947. It became more widely accepted after the publication of Bonica’s Textbook of Pain in 1953. RSD became the term eventually adopted by the Index Medicus and Medline for a painful syndrome with widespread distribution of pain associated with so-called sympathetic features. Causalgia is a term with different clinical and pathophysiological connotations. It has been used to describe the burning nature of the pain syndrome that commonly occurs after peripheral nerve injuries. It was adopted to describe a particular subtype of RSD in which the precipitating injury 19

4 Diagnostic Criteria: The Statistical Derivation of the Four Criterion Factors R. Norman Hardena and Stephen P. Bruehlb a

Department of Physical Medicine and Rehabilitation, Northwestern University Medical School, and Rehabilitation Institute of Chicago, Chicago, Illinois, USA; b Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

Complex regional pain syndrome has been known by many names, such as algodystrophy mineures, mimocausalgia, sympathalgia, post-traumatic spreading neuralgia, and most commonly reflex sympathetic dystrophy and causalgia. It has historically been diagnosed using a variety of nonstandardized, idiosyncratic, or incompatible diagnostic systems (e.g., Bonica 1953; Kozin et al. 1981; Blumberg 1991; Gibbons and Wilson 1992). Claude Bernard first mentioned a syndrome characterized by the association of pain and the sympathetic nervous system. Lucid descriptions of “causalgia” by one of Bernard’s students, Silas Weir-Mitchell (1829–1914), came out of the American Civil War. The name “reflex sympathetic dystrophy” (RSD) is attributed to Evans (1946), but this terminology is problematic. If there is a “reflex” involved in CRPS, it is complicated, multisynaptic, and not fully characterized. The “sympathetic” or autonomic changes may be epiphenomena and may not be causative or perpetuating, and true “dystrophy” occurs in only about 10% of cases. After much discussion in the literature and at scientific meetings, the name was ultimately changed to complex regional pain syndrome (CRPS) at a consensus workshop in Orlando, Florida in 1993 (Merskey and Bogduk 1994; Stanton-Hicks et al. 1995; Jänig and Stanton-Hicks 1996). This name for the syndrome was meant to be descriptive and general, and was not intended to imply any etiopathology (including any direct role for the sympathetic nervous system).

R.N. HARDEN AND S.P. BRUEHL Table III Proposed changes to the diagnostic criteria

General Definition of the Syndrome CRPS describes an array of painful conditions that are characterized by a continuing (spontaneous and/or evoked) regional pain that is seemingly disproportionate in time or degree to the usual course of any known trauma or other lesion. The pain is regional (not in a specific nerve territory or dermatome) and usually has a distal predominance of abnormal sensory, motor, sudomotor, vasomotor, and/or trophic findings. The syndrome shows variable progression over time. There are two versions of the proposed diagnostic criteria: a clinical version meant to maximize diagnostic sensitivity with adequate specificity, and a research version meant to more equally balance optimal sensitivity and specificity. Proposed Modified Clinical Diagnostic Criteria for CRPS 1) Continuing pain, which is disproportionate to any inciting event. 2) Must report at least one symptom in three of the four following categories: Sensory: Reports of hyperesthesia and/or allodynia. Vasomotor: Reports of temperature asymmetry and/or skin color changes and/or skin color asymmetry. Sudomotor/Edema: Reports of edema and/or sweating changes and/or sweating asymmetry. Motor/Trophic: Reports of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nails, skin). 3) Must display at least one sign* at time of evaluation in two or more of the following categories: Sensory: Evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or deep somatic pressure and/or joint movement). Vasomotor: Evidence of temperature asymmetry and/or skin color changes and/or asymmetry. Sudomotor/Edema: Evidence of edema and/or sweating changes and/or sweating asymmetry. Motor/Trophic: Evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nails, skin). 4) There is no other diagnosis that better explains the signs and symptoms. Proposed Modified Research Diagnostic Criteria for CRPS 1) Continuing pain, which is disproportionate to any inciting event. 2) Must report at least one symptom in each of the four following categories: Sensory: Reports of hyperesthesia an/or allodynia. Vasomotor: Reports of temperature asymmetry and/or skin color changes and/or skin color asymmetry. Sudomotor/Edema: Reports of edema and/or sweating changes and/or sweating asymmetry. Motor/Trophic: Reports of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nails, skin).

FOUR DIAGNOSTIC CRITERION FACTORS

Table III Continued 3) Must display at least one sign* at the time of evaluation in two or more of the following categories: Sensory: Evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or deep somatic pressure and/or joint movement). Vasomotor: Evidence of temperature asymmetry and/or skin color changes and/or asymmetry. Sudomotor/Edema: Evidence of edema and/or sweating changes and/or sweating asymmetry. Motor/Trophic: Evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nails, skin). 4) There is no other diagnosis that better explains the signs and symptoms. * A sign is counted only if observed at time of diagnosis.

be valuable for future work to address how these specific patterns may relate to the patient subtypes identified. In summary, while these results are preliminary, they are consistent with limited previous empirical work that argues against three sequential stages of CRPS (Veldman et al. 1993; Bickerstaff and Kanis 1994; Zyluk 1998). Future application of similar analytic techniques to the problem of CRPS may allow identification of distinct CRPS subgroups that have potential utility in targeting treatment more effectively. The Budapest consensus group considered these data too preliminary to justify codifying these subtypes in formal diagnostic criteria. However, the consensus group did discuss the old CRPS subtypes described at the Orlando conference and in the IASP criteria (Merskey and Bogduk 1994). There was general agreement that there are problems with making a distinction between CRPS type I (without distinct major nerve damage, most like the old RSD) versus type II (with major nerve damage, most like the old causalgia; see Table I). Specifically, the definition is rather vague as to what characterizes â&#x20AC;&#x153;majorâ&#x20AC;? nerve damage and how this should be objectively defined. The problem of distinguishing CRPS types I and II is complicated clinically by the fact that the definitive tests of nerve damage, such as EMG, are considered unnecessarily painful for patients, and even cruel. Moreover, this diagnostic distinction does not currently influence the specific therapeutic approach employed. Despite these limitations, the distinction between these two existing CRPS subtypes was retained by the Budapest group, with eventual reevaluation of this issue planned as more data become available regarding its clinical importance. Another subtype of CRPS was added by the consensus group out of concern that lowering the sensitivity would leave some previously

INTEGRATED FUNCTIONAL RESTORATION

165

Reactivation Contrast Baths Desensitization Exposure Therapy

Flexibility Edema Control Isometric Strengthening Correction of Postural Abnormalities Diagnosis and Treatment of Secondary Myofascial Pain

ROM (gentle) Stress Loading Isotonic Strengthening General Aerobic Conditioning Postural Normalization & Balanced Use

Ergonomics Movement Therapies Normalization of Use Vocational/Functional Rehabilitation

Fig. 1. A sample, step-wise, functional restoration algorithm. From the outset, in appropriate cases, the patient should have access to injections, oral medications, and psychotherapy. If the patient fails to progress, at any step or in any regard, the clinical team should consider more or different interventions, stronger medications, or more intensive psychotherapies. ROM (gentle) denotes gentle exercises to improve range of motion.

that objective functional features and biometric data could be measured longitudinally, that they were sensitive enough to demonstrate change over time (in response to a functional restoration-based interdisciplinary program), and that they were correlated with change in subjective outcomes (decreased pain). These early studies provided the primary rationale for a reliance on functional measures as the foundation of judging success in the treatment of CRPS. Baker et al. (1998) later demonstrated more conclusively the utility of quasi-quantitative and psychometric measures in predicting functional outcome in an open-label sample of musculoskeletal pain. In various uncontrolled studies, CRPS patients benefited from specific physiotherapeutic modalities such as stress loading and isometric techniques (Carlson and Watson 1988). Oerlemans et al. (1999a,b) conducted a prospective

CRPS: Current Diagnosis and Therapy, Progress in Pain Research and Management, Vol. 32, edited by Peter Wilson, Michael Stanton-Hicks, and R. Norman Harden, IASP Press, Seattle, ÂŠ 2005.

16 Miscellaneous and Experimental Therapies Michael Stanton-Hicks,a Richard L. Rauck,c Mark Hendrickson,b and Gabor Raczd Departments of aPain Management and bOrthopedic Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA; cPiedmont Pain Consultants, WinstonSalem, North Carolina, USA; dPain Services, Department of Anesthesiology, Texas Tech University Health Sciences, Lubbock, Texas, USA PRINCIPLES AND GOALS

Failure to understand the fundamental underlying mechanisms of CRPS has spawned a variety of symptom-directed treatments. Some of these treatments are of proven efficacy, as determined either by their longstanding use or through rigorous testing and prospective controlled studies in related applications such as neuropathic pain. With a better understanding of pathological processes, researchers are pursuing a number of pharmacological and interventional approaches. While at least many characteristics of CRPS-I suggest a neuropathic process, CRPS-II is unquestionably a form of neuropathic pain that lends itself to treatment by neuro-augmentation. Frequently, a patient with CRPS is referred for evaluation and management when the pain pattern progresses rather than resolves and various symptoms emerge that suggest involvement of the somatosensory, sympathetic, and somatomotor systems. Diagnosis must be based upon current diagnostic criteria and the time course of the pain syndrome. The static and dynamic levels of pain and functional loss will serve as reference thresholds for clinical improvement. As in other complex problems, interdisciplinary management is the approach most likely to yield optimal clinical and functional outcomes. The primary goal is to significantly alleviate or extinguish pain and to stabilize, then improve, functional deficits. Placing functional improvement before pain control often results in significant pain aggravation. 255

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Rehabilitation entails a graded therapy program with goal-specific measures for functional improvement without causing a resurgence of pain. The stability of the reduction in pain and improvement in function must be monitored. The long-established empirical association between CRPS and dysfunction of the sympathetic nervous system has suggested both the α1 and α2 adrenoceptors as targets for pharmacological modulation. The N-methyl-Daspartate (NMDA) receptor, a common site for neuropathic pain research, has been singled out as a recent clinical experimental target. Similarly, some of the deep-seated pain reported by CRPS patients, and thought by some to be related to osseous changes, has resulted in empiric treatment with some success by bisphosphonates, an established therapy for some osteosclerotic conditions (see Chapter 12).

TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION

Transcutaneous electrical nerve stimulation (TENS) therapy may be useful as an adjunct to the pharmacological management of CRPS and may be a helpful treatment for mononeuropathic pain in some cases of CRPS-II. The most useful application for TENS therapy in CRPS is for symptomatic management of the frequently associated myofascial syndrome. In CRPS-II, TENS may provide sufficient analgesia to allow compliance with physical therapy. In our experience it is also useful in predicting the success of peripheral nerve stimulation. In the original description by Wall and Sweet (1967), TENS can achieve analgesia by stimulating Aβ fibers. It is most effective in treating mononeuropathies, as shown by level 3 clinical evidence (Anderson et al. 1976; Thorsteinsson et al. 1977; Eriksson et al. 1979; Long et al. 1979; Johnson et al. 1991a,b). In our experience, it is important to perform a trial of adequate length, at least 3–4 weeks, to determine whether TENS is a suitable modality, particularly when attempting to manage symptoms of myofascial dysfunction. It is important that the pain is not aggravated, that the patient becomes familiar with the system, and that suitable electrode placement is achieved. Initially, TENS should be used for 1 hour three times per day, but frequency and duration of application may be extended with experience. Most patients will select a range between 40 and 70 Hz (Thorsteinsson et al. 1977; Johnson et al. 1991a). Although tolerance is seen less frequently with TENS than with pharmacological agents, Eriksson et al. (1979) reported that 55% of patients received adequate pain relief at 2 months, dropping to 41% at 12 months.

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W. JÄNIG

to correct this mismatch can reverse the changes. Moseley’s and related studies (Schwoebel et al. 2001; McCabe et al. 2003b,c) are opening new ways to investigate the mechanisms underlying the sensory, motor, and autonomic changes in CRPS-I patients.

FUTURE RESEARCH DIRECTIONS

CRPS patients exhibit changes that occur in systems processing noxious, tactile, and thermal information, in sympathetic systems innervating blood vessels, sweat glands, and possibly other targets, and in the somatomotor system, indicating that the central representations of these systems are altered. The way these central changes are triggered by a peripheral trauma, which is often minor compared to the dramatic expression of the clinical phenomena, remains an enigma. Furthermore, how these central changes relate to the peripheral inflammatory and immunological changes is unclear. Finally, we cannot explain why pain and the other changes associated with the sympathetic nervous system (including swelling), the motor system, and the somatosensory system may disappear, in CRPS patients with sympathetically maintained pain (SMP), after sympathetic blockade (e.g., with a local anesthetic or with guanethidine). Hypotheses must be formulated about the underlying mechanisms of clinical changes that can be measured quantitatively. These hypotheses should be tested by using a multidisciplinary approach combining clinical experimentation, human models, and various types of animal models (in vivo and in vitro). This type of integrative research is a necessity if we are to unravel the mechanisms that operate in CRPS and if we are to find the organizing pathophysiological principles that orchestrate the different changes. It is essential that basic research in animal models and in humans and clinical studies of CRPS should be closely aligned (Fig. 3). Such an approach is imperative if we are to achieve a mechanismbased diagnostic classification of CRPS and ultimately develop a mechanism-based therapeutic strategy. New research should focus on the following areas (Baron et al. 2002b; Jänig and Baron 2004): Draft a consensus definition of CRPS with standardized diagnostic criteria. Neurologists, anesthesiologists, and others agree about the minimal clinical criteria (signs and symptoms) that define CRPS (Stanton-Hicks et al. 1995; Bruehl et al. 1999; Baron and Jänig 2004). However, without a universally accepted definition and diagnostic criteria and a further validation and extension of the present clinical criteria, it is difficult to accurately identify CRPS patients, select patients for clinical trials, validate experimental

FUTURE PERSPECTIVES

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HUMAN PATIENT Clinical observations

HYPOTHESES Experimental observations on patients Behavioral animal models Reduced animal models in vivo & in vitro

Fig. 3. Hierarchy of human and animal models and clinical investigations in experimental research on the role of the sympathetic nervous system in pain. This hierarchy consists of different levels that interact reciprocally. The scientific questions to be asked are formulated on the basis of clinical observations. The human models and the behavioral animal models mostly focus on one component (e.g., SMP, autonomic abnormalities, motor abnormalities, or edema in CRPS type I or II). On the basis of the experimental behavioral animal models and the experimental human models the questions are formulated for testing in the more reduced animal models. These reduced animal models focus on one component (e.g., sympathetic-afferent coupling in the periphery or in the dorsal root ganglion). The results obtained using the behavioral models must be interpreted in light of the clinical observations; the results obtained using the reduced animal models in vivo must be interpreted in light of behavioral animal models and of the human experimental models; and the results obtained in the reduced animal models in vitro must be interpreted in light of the animal models in vivo. Research performed on the various animal models shapes the clinical research performed on patients with SMP. This interactive research strategy applies to most experimental research that aims to elucidate the pathophysiological processes underlying diseases.

human and animal model systems for research, and formulate testable hypotheses. A symposium to specifically define the clinical and diagnostic criteria, based on what is known, should be a high priority for the field. Once determined, these consensus criteria should be disseminated to the medical, research, and advocacy communities, in particular to those groups involved in epidemiological studies, in the design of appropriate models for symptoms in CRPS, in research on underlying mechanisms, and in the design of CRPS therapies to be tested in prospective clinical trials. Perform epidemiological studies using well-defined diagnostic criteria. Epidemiological studies are urgently needed to identify the characteristics of patients at high risk for developing CRPS, to better define the relationship between certain clinical signs and disease onset, progression, and distribution on the body, and to determine the incidence of patients with CRPS.