IASP PRESS® • SEATTLE

Pain 2008—An Updated Review:Refresher Course SyllabusIASP Refresher Courses on Pain Management held in conjunction with the 12th World Congress on Pain

August 17–22, 2008Glasgow, Scotland

IASP Scientifi c Program Committee

José Castro-Lopes, MD, PhD, Chair, PortugalFernando Cervero, MD, PhD, DSc, CanadaBeverly Collett, MB BS, UKCarlos Maurício de Castro Costa, MD, PhD, BrazilG. Allen Finley, MD, CanadaSusan Fleetwood-Walker, PhD, United KingdomHerta Flor, PhD, GermanyCarmen Green, MD, USATroels Jensen, MD, PhD, Denmark, ex offi cioEija Kalso, MD, DMedSci, FinlandBruce Kidd, DM, FRCP, UKKatherine Kreiter, USA, ex offi cioSteven Linton, PhD, SwedenArthur Lipman, PharmD, USAStephen McMahon, PhD, United KingdomJeff rey Mogil, PhD, CanadaMichael Nicholas, PhD, AustraliaKoichi Noguchi, MD, PhD, JapanPaul Pionchon, DDS, PhD, FranceSrinivasa Raja, MD, USAMartin Schmelz, MD, GermanyTh omas Toelle, PhD, MD, GermanyYou Wan, PhD, MD, ChinaJudith Watt-Watson, RN, PhD, CanadaHarriet Wittink, PhD, PT, Th e Netherlands

© 2008 IASP Press® International Association for the Study of Pain®

Reprinted 2009

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Timely topics in pain research and treatment have been selected for publication, but the information provided and opinions expressed have not involved any verifi cation of the fi ndings, conclusions, and opinions by IASP®. Th us, opinions expressed in Pain 2008—An Updated Review: Refresher Course Syllabus do not necessarily refl ect those of IASP or of the Offi cers and Councilors.

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Library of Congress Cataloging-in-Publication Data

IASP Refresher Courses on Pain Management (2008 : Glasgow, Scotland) Pain 2008--an updated review : refresher course syllabus / IASP Refresher Courses on Pain Management held in conjunction with the 12th World Congress on Pain, August 17-22, 2008, Glasgow, Scotland ; IASP Scientifi c Program Committee, José Castro-Lopes, chair ... [et al.]. p. ; cm. Includes bibliographical references. ISBN 978-0-931092-73-2 (softcover : alk. paper) 1. Pain--Treatment--Congresses. 2. Analgesia--Congresses. I. Castro-Lopes, José, 1959- II. IASP Scientifi c Program Committee. III. World Congress on Pain (12th : 2008 : Glasgow, Scotland) IV. Title. [DNLM: 1. Pain--therapy--Congresses. WL 704 I11p 2008] RB127.I27 2008 616’.0472--dc22 2008020039

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IASP PressInternational Association for the Study of Pain111 Queen Anne Ave N, Suite 501Seattle, WA 98109-4955, USAFax: 206-283-9403www.iasp-pain.org

iii

Contents

Preface viiAcknowledgments viii

Part 1: Neurobiology of Acute and Persistent Pain1. Pain: Basic Mechanisms 3

Allan Basbaum, M. Catherine Bushnell, and Marshall Devor

Part 2: Opioids in Cancer Pain Management2. Opioid Titration in Cancer Pain 13

Sebastiano Mercadante3. Opioids and Breakthrough Pain 19

Giovambattista Zeppetella

Part 3: Pain Imaging4. Functional MRI Studies of Pain Processing 27

Irene Tracey5. Electroencephalography and Magnetoencephalography in Pain Research 33

Markus Ploner6. Molecular Imaging Studies of Pain Processing 39

David J. Scott

Part 4 Musculoskeletal Pain: Basic Mechanisms7. Clinical Applications of Basic Mechanisms of Musculoskeletal Pain 49

Michele Curatolo8. Peripheral and Central Mechanisms of Musculoskeletal Pain 55

Siegfried Mense9. Musculoskeletal Pain: Basic Mechanisms 63

Lars Arendt-Nielsen and Th omas Graven-Nielsen

Part 5: Human Pain Models: Virtues and Limitations10. Human Experimental Pain Models: Virtues and Limitations 77

Karin L. Petersen and Martin Schmelz11. Functional Imaging of Experimental Pain Models 89

Christian Maihöfner

Part 6: Complex Regional Pain Syndrome12. Complex Regional Pain Syndromes: Translation from Science to Clinical Practice 99

Ralf Baron13. Animal Models of Complex Regional Pain Syndrome and Th eir Implications for Underlying Mechanisms and Treatment 109

Dimitris N. Xanthos, Gary J. Bennett, and Terence J. Coderre14. Movement Disorders in Complex Regional Pain Syndrome 121

J. J. van Hilten

Part 7: Migraine: From Genes to Pain Mechanisms and Pathways15. Migraine as a Cerebral Ionopathy with Impaired Central Sensory Processing 129

Michel D. Ferrari and Peter J. Goadsby

iv Contents16. Migraine Prophylaxis with Botulinum Toxin A Is Associated with Perception of Headache 147

Rami Burstein, David Dodick, Moshe Jakubowski, and Stephen Silberstein

Part 8: Persistent Postoperative Pain: Pathogenic Mechanisms and Treatment17. Persistent Postsurgical Pain: Surgical Risk Factors and Strategies for Prevention 153

Henrik Kehlet18. Chronic Pain after Surgery: Epidemiology and Preoperative Risk Factors 159

William Macrae

Part 9: Psychological Interventions for Chronic Pain19. Psychological Interventions for Chronic Pain 169

Robert Kerns, Stephen Morley, and Johan W. S. Vlaeyen

Part 10: Clinical Pharmacology of Pain20. Clinical Pharmacology of Opioids in the Treatment of Pain 185

Eija Kalso21. Nonsteroidal Anti-infl ammatory Agents and Paracetamol (Acetaminophen) 193

Vesa K. Kontinen 22. Clinical Pharmacology of Antiepileptics and Antidepressants 205 in the Management of Neuropathic Pain

Søren H. Sindrup

Part 11: Human Pain Genetics23. Studying Common Genes that Contribute to Human Pain: An Introduction 215

Mitchell B. Max24. Finding Mendelian Disease Genes 225

James Cox, Adeline Nicholas, and Geoff rey Woods25. Whole-Genome Association Studies 233

Ariel Darvasi

Part 12: Glial Dysregulation of Pain and Opioid Actions: Past, Present, and Future26. Glial Dysregulation of Pain and Opioid Actions: Past, Present, and Future 237

Mark R. Hutchinson, Kirk W. Johnson, and Linda R. Watkins

Part 13: Neuropathic Pain: From Basic Mechanisms to Clinical Management27. Neuropathic Pain: Defi nition, Diagnostic Criteria, Clinical Phenomenology, 259 and Diff erential Diagnostic Issues

Per T. Hansson28. Neurobiological Mechanisms of Neuropathic Pain and Its Treatment 265

Anthony H. Dickenson and Lucy A. Bee29. Management of Neuropathic Pain 275

Troels S. Jensen

Part 14: Central Pain: A Multidimensional Challenge30. Epidemiology, Clinical Presentation, and Mechanisms in Central Pain Syndromes 287

Gunnar Wasner and Ralf Baron31. Spinal Cord Injury: A Model for the Pathophysiology and Mechanisms of Central Pain 295

Robert P. Yezierski

vContents

32. Treatment of Central Pain 307Nanna Brix Finnerup

Part 15: Interventional Th erapies for Acute and Chronic Pain: Indications and Effi cacy33. Rational Use of Interventional Modalities for the Treatment of Pain of Spinal Origin 317

James P. Rathmell34. Rational Use of Interventional Modalities for the Treatment 327 of Complex Regional Pain Syndrome and Cancer Pain

Richard Rauck35. Continuous Peripheral Nerve Blocks for Treating Acute Pain 337 in the Hospital and the Ambulatory Environment

Brian M. Ilfeld

Part 16: Essentials of Addiction Medicine for the Pain Clinician36. Pain and Addiction: Prevalence, Neurobiology, and Defi nitions 347

Roman D. Jovey37. Reducing the Risks of Opioids by Screening and Risk Stratifi cation 353

Steven D. Passik38. Balancing Safety with Pain Relief When Prescribing Opioids 361

Jonathan Bannister

Part 17: Chronic Abdominal Pain: Evaluation and Management of Common Gastrointestinal and Urogenital Disease39. Chronic Abdominal Pain: Evaluation and Management 369 of Common Gastrointestinal and Urogenital Diseases

Asbjørn Mohr Drewes, Oliver H.G. Wilder-Smith, and Camilla Staahl

Part 18: Low Back Pain: Assessment and Management: From Secondary Prevention to Clinical Rehabilitation40. Back Pain 383

Chris J. Main, Michael K. Nicholas, and Paul J. Watson

José M. Castro-Lopes, MD, PhD obtained his training at the Faculty of Medicine of the University of Porto, Portugal. He is currently full professor and chair of Histology and Embryology and coordinator of the postgraduate course on pain medicine of the same faculty. He is also coordinator of the National Program for Pain Control of the Portuguese Ministry of Health, and participated actively in the recent establishment of the Competence on Pain Medicine by the Portuguese Medical Association.

Prof. Castro-Lopes has been president of the Portuguese Association for the Study of Pain (IASP Chapter) and honorary treasurer of the European Federation of IASP Chapters (EFIC). He is chair of the Scientifi c Program Committee of the 12th World Congress on Pain® (Glasgow, 2008) and will chair the Local Organizing Com-mittee of Pain in Europe VI, the 6th Congress of EFIC (Lisbon, 2009). He has also served on several other committees of IASP and EFIC.

Th e main research fi eld of Prof. Castro-Lopes is the neurobiology of pain, in particular the changes induced in the central nervous system by chronic pain. He has made some contributions on the plasticity of the spinal GABAergic system in experimental pain models, as well as changes in other neurotransmitter systems at the supraspinal level. He has held positions at the Max-Planck Institute for Psychiatry in Munich, at Unit 162 of INSERM in Paris, and at the School of Pharmacy in London. He has coordinated several national and European research projects and authored over 50 original or review articles, book chapters, and books.

Editors

Martin Schmelz, MD, PhD, is Professor at the Department of Anesthesiology at the University of Heidelberg’s Mannheim campus. He was awarded the Daimler-Chrysler-endowed Karl-Feuerstein professorship for pain research in 2002. He also serves as visiting professor at the University of Uppsala, Sweden and University of Oslo, Norway. Previously he served as Assistant Professor at the Department of Physiology, University of Erlangen, Germany. He obtained his MD training at the Faculty of Medicine, University of Erlangen. He completed his internship in the Department of Occupational Medicine and his doctoral thesis in the Department of Human Genetics at the University of Erlangen.

Dr. Schmelz’s fi elds of research interest include the neurobiology of pain and infl ammation, itch, and translational pain research, and he has published many papers on those topics in peer-reviewed journals. Dr. Schmelz is a member of the Scientifi c Program Committee for the 12th World Congress on Pain.

Srinivasa N. Raja, MD, is Professor of Anesthesiology and Neurology, and Director of the Division of Pain Medicine in the Department of Anesthesiology and Critical Care Medicine at the Johns Hopkins University

School of Medicine in Baltimore, Maryland, USA. He received his residency train-ing in anesthesiology at the University of Washington, Seattle, and his postdoctoral training at the University of Virginia School of Medicine.

Dr. Raja’s clinical interests include management of chronic pain states, such as sympathetically maintained pain, postherpetic neuralgia, and postamputation pain. His recent research eff orts are aimed at understanding the peripheral and central mechanisms of neuropathic pain and in determining the role of opioid and adrenergic receptor mechanisms in mediating or maintaining chronic neuropathic pain states. He has also conducted controlled clinical trials to develop better evidence-based practice for the pharmacological treatment of neuropathic pain.

In 1993, Dr. Raja joined the editorial board of Anesthesiology as an Associate Editor and subsequently served as an Editor from 1998 to 2006. He is also an As-

sociate Editor for Pain. Dr. Raja has published more than 130 articles in peer-reviewed journals, has edited three books, and has written numerous book chapters. He received the Wilbert E. Fordyce Clinical Investigator Award at the annual meeting of the American Pain Society in May 2008. Dr. Raja is a member of the Scientifi c Program Committee for the 12th World Congress on Pain.

Preface

vii

Th e chapters in this volume have been written by the contributors to the refresher courses of-fered in conjunction with the 12th World Con-gress on Pain, held on August 17–22, 2008, in Glasgow, Scotland.

A diverse collection of topics has been assembled for the refresher courses, from the basic pain mechanisms to the most advanced therapeutic interventions, from human mod-els to clinical studies, from psychological inter-ventions to pharmacological and interventional therapies, from genetics to imaging, and from musculoskeletal pain to complex regional pain syndrome. Th e selection of topics refl ects the breadth of the expertise within the membership of the International Association for the Study of Pain (IASP) and highlights the complex and interdisciplinary nature of pain management. Moreover, it emphasizes the intention of the IASP to bridge the gap between basic research and clinically oriented approaches. Th e Scientifi c Program Committee, mindful of the multidisci-plinary audience that usually attends the World Congresses on Pain, aimed to ensure that each participant could identify at least one refresher course that could be useful for his or her scien-tifi c or clinical enrichment.

In addition, speakers were selected based not only on their expertise in the fi eld but also on their ability to communicate eff ectively with such a diverse audience. We are very grate-ful for the educational eff orts of all the lecturers

who accepted our invitation, both for giving the course and for providing the manuscripts that have been included in this book. In this way, their contributions will have lasting eff ects on a wider audience, and will be very useful not only for the course participants but also for all those willing to update or increase their knowledge in the many aspects of pain addressed in the book. Th is book is likely to be of particular benefi t to those who wished to attend more than one course but were unable to do so because the courses were scheduled for the same time.

We wish to express our thanks to Troels Jensen, IASP President, for his trust and con-tinuous support, and our colleagues on the Sci-entifi c Program Committee for their suggestions and advice. We thank Michael Serpell, chair of the Local Arrangements Committee in Glasgow, for his local insight. Our thanks also to Kathy Kreiter, the “new” IASP Executive Director, with whom one of us shared her fi rst day on the job during a site visit to Glasgow, and to Terry Onustack, another newcomer who has quickly adapted to his new responsibilities, hence mak-ing our job much easier. Many thanks also to Elizabeth Endres for her editorial assistance and to Rich Boram, Kris Lukarilla, and Sarah Reebs at the IASP headquarters in Seattle.

Jose Castro-Lopes, MD, PhDSrinivasa Raja, MDMartin Schmelz, MD

fMRI Studies of Pain Processing 29

fi eld and causes a loss of signal. Th us, the decrease of deoxygenated hemoglobin leads to higher signal intensities that contrast against surrounding tissue. During image analysis, the BOLD signal that is ex-pected to result from the stimulus is modeled math-ematically. Th e model is compared to the signal that is measured during the experiment itself. Statistical maps are constructed and superimposed on a struc-tural brain image to indicate where the measured sig-nal best fi ts the model. Further details regarding data analysis and background information on fMRI can be found at http://www.fmrib.ox.ac.uk/fsl.

Th e Cerebral Signature for Pain PerceptionOver the last decade, MRI and PET functional imag-ing studies have revealed the large distributed brain network that is accessed during processing of noxious input. Several cortical and subcortical brain regions are commonly activated by noxious stimulation, in-cluding the anterior cingulate cortex (ACC), insu-lar cortex, frontal and prefrontal cortices (PFC), pri-mary and secondary somatosensory cortices (S1 and S2, respectively), thalamus, basal ganglia, cerebellum, amygdala, hippocampus, and regions within the pa-rietal and temporal cortices. Th is network is thought to refl ect the complexity of pain as an experience and is often called the “pain matrix.” Th e matrix can be simplistically thought of as having lateral compo-nents (sensory-discriminatory, involving areas such as the primary and secondary somatosensory corti-ces, thalamus, and posterior parts of the insula) and medial components (aff ective-cognitive-evaluative,

involving areas such as the anterior parts of the in-sula, ACC, and PFC) [1]. However, because diff erent brain regions play a more or less active role depend-ing upon the precise interplay of the factors involved in infl uencing pain perception (e.g., cognition, mood, injury, and so forth), the “pain matrix” is not a defi ned entity. A recent meta-analysis of human data from dif-ferent imaging studies provides clarity regarding the regions most commonly found active during an acute pain experience as measured by PET and fMRI [2]. Th ese areas include the primary and secondary so-matosensory cortices, insular cortex, ACC, and PFC, as well as the thalamus. Th is is not to say that these areas are the fundamental core network of human nociceptive processing (and if ablated would cure all pain), although studies investigating acute pharma-cologically induced analgesia do show predominant eff ects in this core network that suggest their overall importance in infl uencing pain perception [3]. Other regions such as the basal ganglia, cerebellum, amyg-dala, hippocampus, and areas within the parietal and temporal cortices can also be active depending upon the particular set of circumstances for that individu-al. A “cerebral signature” for pain is perhaps how we should defi ne the network; it is necessarily unique for each individual [4]. Th is unique signature is particularly relevant, given the very recent awareness of how great a role our genes play in the perception of pain related to a noxious stimulus or due to injury. For example, in-dividuals homozygous for the met158 allele of the cat-echol-O-methyltransferase (COMT) polymorphism (val158met) showed diminished regional mu-opioid system responses to pain (measured using PET) and higher sensory and aff ective ratings for experimentally

Table I Comparison of fMRI and PET imaging techniques

Modality BOLD fMRI 15O-Water PET Working principle Detects changes in the magnetic field

due to variations in the oxyhemoglobin/ deoxyhemoglobin ratio

Detects the radioactive isotopes that is tagged onto molecule of interest

Availability Most tertiary medical centers Isotopes are short-lived and must be generated by a nearby cyclotron

Invasiveness Completely non-invasive Employs radioisotopes; requires intravenous access as minimum

Spatial resolution 1–2 mm 5 mm at best Temporal resolution

Hundreds of milliseconds Minutes

Experimental design

Flexible; limited mainly by noise and magnetic environment

Limited by tracer half-life and radiation dose

Derived data Unable to quantify the physiological baseline

Able to quantify the physiological baseline

Abbreviations: BOLD fMRI = blood-oxygenation-level-dependent functional magnetic resonance imaging; PET = positron emission tomography.

52 Michele Curatolo

is uncertain. Nevertheless, data below the 95% confi -dence interval of pain thresholds of the healthy popu-lation are very likely to be abnormal. Th e use of senso-ry tests as well as the assessment of local and referred pain areas can be considered useful tools to assess the pain reactivity of patients and give indications on the presence and magnitude of central sensitization. Th e inherent limitations of these methods should be taken into consideration.

Mechanism-Based TreatmentBackgroundA logical translation of basic knowledge is treatment. In this respect, the concept of a mechanism-based therapeutic approach is increasingly being proposed: the diagnostic process would lead to the identifi ca-tion of the pain mechanisms, which could then be targeted by specifi c treatments. However, the mech-anism-based therapeutic approach is associated with an uncertain outcome, basically for two reasons. First, the ability of most of the available diagnos-tic methods to identify pain mechanisms is limited. Second, the effi cacy of most of the current therapeu-tic approaches remains modest, even when the pain mechanism is clarifi ed.

Th ese limitations should not discourage the clinician from using basic knowledge to establish a working hypothesis on pain mechanisms and try to implement a targeted treatment. A possible algorithm is illustrated in Fig. 1.

Clinical AspectsWhenever infl ammation is documented, nonsteroidal anti-infl ammatory drugs (NSAIDs) or steroids can be used. However, infl ammation is evident in only a minority of musculoskeletal pain conditions. Typically, there are no clear signs of infl ammation in chronic low back or cervical pain, nor can infl ammation be easily ruled out. In other words, we do no have the diagnostic tools to diagnose or rule out infl ammation in such conditions. It should also be considered that NSAIDs also act centrally and are therefore potentially useful in non-infl ammatory conditions as well.

Neuropathic components can be present in musculoskeletal pain states. For instance, disk pathol-ogy may induce both diskogenic and radicular pain in the same person. Basic investigations have shown that disk pathology may induce lesions of the nerves that supply the disk [22], leading to the hypothesis that neuropathy may be involved in pain syndromes traditionally considered to be nociceptive. In an ani-mal model, infl ammation of the zygapophysial joints induced radicular pain as a result of spread of infl am-mation to the epidural space [39].

Unfortunately, in clinical conditions the pres-ence of neuropathic mechanisms may be diffi cult to identify and to diff erentiate from nociceptive com-ponents. Whenever neuropathic components are identifi ed or suspected, specifi c treatment should be implemented. Antidepressants are typically eff ective in neuropathic pain [16]. Nerve lesions cause an ab-normal expression of calcium and sodium channels

Fig. 1. Proposed mechanism-based assessment and treatment algorithm.Th e limitations of this approach are discussed in the text.

78 Karin L. Petersen and Martin Schmelz

and have no predictive value for the analgesic eff ect of the test compound.

Pain models that are set up to mimic certain aspects of pathophysiological pain states through re-versible induction of peripheral or central neuronal sensitization may be more relevant to clinical pain conditions. Peripheral or central neuronal sensitiza-tion mechanisms are thought to contribute to both acute and chronic pain conditions [10,52]. In these models the endpoints of the stimulus-evoked hyper-sensitivity in the periphery (primary hyperalgesia) and in the central nervous system (secondary hyper-algesia) provide a correlate to the clinical picture of stimulus-evoked hypersensitivity and have therefore been regarded as surrogate markers of clinical pain states. Th e strength of the correlation between these surrogate markers and clinical pain states has major

implications for the predictive value of the models. Th e limiting factor in the use of human experimental pain models is the degree to which mechanisms that have been identifi ed in chronic pain patients can be mimicked in human pain models. Unfortunately, our knowledge about clinically operational pain mecha-nisms in patients remains very limited and does not yet include molecular targets. Th ere is no doubt that the current human pain models do not mimic the entire complex pain pathophysiology of clinical pain conditions (Fig. 1). Crucial aspects of clinical pain states, such as spontaneous pain, cannot be mimicked in human pain models because injuries resulting in structural and thus lasting changes in the nervous sys-tem are ethically unacceptable in healthy volunteers.

In this review we will describe models of physiological nociceptor activation separately from

Fig. 1. (A) Schematic view of neuronal changes leading to chronic pain and possible read out variables. (B) Schematic view of aspects cov-ered by human experimental models. For structural changes and spontaneous pain, there are no adequate human models.

12Complex Regional Pain Syndromes: Translation from Science to Clinical Practice

Ralf Baron, Dr MedDivision of Neurological Pain Research and Th erapy, Department of Neurology, Christian-Albrechts University, Kiel, Germany

Pain 2008—An Updated Review: Refresher Course Syllabus,edited by José M. Castro-Lopes, Srinivasa Raja, and Martin Schmelz,IASP Press, Seattle, © 2008

99

Educational ObjectivesTh is refresher course is designed to provide an inter-disciplinary audience with up-to-date information about pathophysiological mechanisms and medical management for the condition of complex regional pain syndrome (CRPS). New concepts derived from animal experimental work will be discussed. Success-ful management of motor dysfunction is one of the most important prognostic factors for CRPS. New pathophysiological ideas as well as treatment ap-proaches for tremor, coordination defi cits, and dysto-nia will be presented. What can we learn from basic science to improve our therapies? Recent treatment innovations for CRPS will be evaluated in the light of modern research.

IntroductionTh e term “complex regional pain syndrome” describes a variety of painful conditions following injury that appear regionally, with a distal predominance of ab-normal fi ndings. Th e symptoms exceed in both mag-nitude and duration the expected clinical course of the inciting event and often result in signifi cant impair-ment of motor function. Th e disorder shows a variable progression over time. Th ese chronic pain syndromes comprise diff erent additional clinical features includ-ing spontaneous pain, allodynia, hyperalgesia, edema, autonomic abnormalities, and trophic signs. In CRPS

type I (refl ex sympathetic dystrophy) minor injuries or fractures of a limb precede the onset of symptoms (Table I, Fig. 1). CRPS type II (causalgia) develops af-ter injury to a major peripheral nerve [7,8,39].

Th e most common precipitating event of CRPS type I (refl ex sympathetic dystrophy) is a trau-ma aff ecting the distal part of an extremity (65%), especially fractures, postsurgical conditions, contu-sions, and strain or sprain. Less common causes are central nervous system lesions including spinal cord injuries and cerebrovascular accidents as well as car-diac ischemia [75].

CRPS-I patients develop asymmetrical dis-tal extremity pain and edema without presenting an overt nerve lesion. Th ese patients often report a

Fig. 1. Clinical picture of a patient with CRPS type I of the upper left extremity following distortion of the left wrist.

154 Henrik Kehlet

Th is chapter presents a short updated review of the intraoperative risk factors for developing a persistent postsurgical pain state. Although the main emphasis will be on nerve damage and the possibili-ties for avoiding or reducing it, the data should be seen in a broader perspective (Table I) because nerve damage may only be a prerequisite for developing a chronic pain state. Th us, probably only about 10% of patients with a well-documented nerve damage will develop a chronic neuropathic pain state [18]. Also, it should be emphasized that present knowledge on the relative role of infl ammation from the surgi-cal area for developing a chronic pain state is very limited due to diffi culties in assessing the degree of chronic infl ammation.

Postamputation PainChronic pain after limb amputation is a well-known postsurgical pain syndrome combined with stump pain and phantom pain. Th e incidence is in the range of 30–50% [21,23,28,33]. Th e pathogenesis is probably multifactorial, with preamputation pain known to have a specifi c role. Many eff orts have been made to study perioperative analgesic tech-niques to reduce phantom limb pain, but without any fi rm conclusions [11].

Interestingly, despite the obligatory transec-tion of major nerves in leg amputation, no attention at all has been paid in phantom limb studies to in-traoperative handling of the nerves. Th is lack of at-tention is particularly surprising, given that various nerve ligature models have been used to study chron-ic neuropathic pain in experimental studies. A recent survey among Danish orthopedic surgeons showed a surprisingly high use (about 30%) of ligation of the big nerves during leg amputation [35], which accord-ing to experimental data is just calling for develop-ment of chronic neuropathic pain. Surprisingly, ma-jor orthopedic textbooks recommend ligation of the nerves during amputation. Since a clean nerve cut may probably lead to less persistent pain compared to a ligature or crush nerve injury, there is an ur-gent need for clinical studies investigating the role of nerve handling as a risk factor for phantom limb pain after limb amputation.

Postmastectomy PainSeveral studies have shown mastectomy to be fol-lowed by a chronic pain state in about 10–30% of

patients, including phantom pain or other sequelae such as arm pain or lymphedema [19,21,23,33]. Risk factors include nerve injury to the intercostobrachial nerve, but postoperative chemotherapy or radiation therapy may also contribute. Other risk factors are preoperative depression and anxiety and the intensity of preoperative pain. Th e problem, however, is that most studies are retrospective, and no prospective study has included all risk factors (Table I). Th at nerve injury plays an important role is suggested by a small study showing more abnormal sensations in patients with proximal transection of the intercostobrachial nerve compared with limited peripheral transections, with the most normal sensation in patients where the nerve was preserved [32]. A relatively small-scale study that included diff erent patient groups (diff er-ent types of surgery and adjuvant therapies) also em-phasized the correlation between postmastectomy pain and sensory disturbances; that study is the only available quantitative sensory testing (QST) study [16]. Furthermore, the treatment of breast cancer has changed considerably within the last 5 years, with an increased use of lumpectomy as well as less use of conventional axillary dissection due to the introduc-tion of the sentinel node technique. A recent retro-spective study emphasized three categories of pain complaints: phantom breast pain, scar pain, and other mastectomy-related pain [22].

In summary, there is an urgent need for large-scale prospective detailed studies including all known potential risk factors and in relevant subgroups with modern treatment regimes for breast cancer. Such studies will provide conclusions about the sever-ity and incidence of postmastectomy pain and guide strategies for its prevention and treatment.

Post-Th oracotomy PainTh oracotomy is another operation with well-docu-mented high incidence (about 20–50%) of chronic pain complaints [17,21,23,33,37]. A review of surgi-cal aspects concluded that no one technique of tho-racotomy led to a defi nite reduction of chronic post-thoracotomy pain [37]. A recent review [17] agreed, but claimed that the incidence over the years has been falling, without an obvious explanation. Th at signifi cant nerve injury occurs intraoperatively has been elegantly demonstrated by changes in sensory thresholds and somatosensory evoked responses to electrical stimulation that correlate with chronic pain [8]. One study documented that the rib retractor leads

186 Eija Kalso

receptors in the dorsal horn of the spinal cord have a central role in the modulation of pain, which is the basis for spinal administration of opioids to produce segmental analgesia. Opioid receptors in the brain-stem are involved in the regulation of arousal, res-piration, and both anti- and pronociceptive eff ects. Opioids receptors are found almost everywhere in the cerebral cortex and cerebellum. In the periphery, opioids are involved in the regulation of gastrointes-tinal function. Activation of MORs in the gut leads to increased absorption of water from the stools and spasticity of the gut. Opioid receptors in the peripher-al nervous system are regulated by infl ammation and the immune system.

Opioids in the Clinic: Alleviation of Acute and Chronic PainOpioids remain the main analgesics in the treatment of moderate to severe acute pain and cancer pain. Th ey have a restricted role in the management of other chronic pains.

Acute Postoperative and Other Trauma-Related PainOpioids are usually added to non-opioid treatment such as paracetamol (acetaminophen) and nonste-roidal anti-infl ammatory drugs. Other adjuvant anal-gesics such as corticosteroids [39], ketamine [2], and gabapentin or pregabalin [45] are increasingly used to improve analgesia and reduce opioid-related ad-verse eff ects. Short-acting opioids (e.g., remifentanil,

sufentanil, fentanyl, alfentanil) are usually adminis-tered intravenously (i.v.) perioperatively. Patient-con-trolled analgesia (PCA) can be used postoperatively to optimize analgesia because interindividual variation is considerable. Oral administration is preferred when feasible. Mild to moderate pain can be alleviated with codeine combinations or tramadol. Oral oxycodone and morphine are available for moderate to strong pain. Several other opioids are also used (e.g., ketobe-midone, piritramide), but these more unusual opioids will not be discussed in this chapter.

Spinal opioid analgesia is used for major sur-gery. Morphine is used both for subarachnoid and epi-dural administration, whereas fentanyl is used to im-prove epidural analgesia with local anesthetic agents. Opioids are also administered locally, even though their eff ectiveness has not been confi rmed [18].

Cancer-Related PainOpioids are the main analgesics in cancer pain, even though other drugs (e.g., nonsteroidal analgesics in bone-related pain) and drugs that are used to treat neuropathic pain have an important role, too. Con-trolled-release formulations (e.g. morphine, oxyco-done, oxymorphone, and hydromorphone orally and fentanyl/buprenorphine transdermally) are used to provide stable pain relief. Fast-acting formulations (e.g., oral morphine or oxycodone, and transmucosal fentanyl) are used for breakthrough pain. If oral ad-ministration is not possible opioids can be adminis-tered transdermally and subcutaneously. Spinal opioids can also be used. Th e use of opioids in cancer-related

Table I Competitive displacement (Ki) of [3H]-diprenorphine from its binding to membranes prepared from culture cells expressing MOR, DOR, and KOR subtypes by oxycodone, oxymorphone, and morphine, and opioid-receptor-subtype-specific ligands (DAMGO for MOR, DPDPE, for DOR,

and U50.488 for KOR)

[3H]-Diprenorphine Displacement

(Ki) (nmol/L) [35S]GTPS Binding

to hMOR1 Ligand hMOR1 mDOR1 hKOR1 EC50 (nmol/L) Emax (%) Oxycodone 16.0 ± 2.9 >1000 >1000 343 ± 7.9 234 Oxymorphone 0.36 ± 0.01 118 ± 20 148 ± 17 42.8 ± 0.8 261 Morphine 3.19 0.43 94.2 ± 1.9 252 DAMGO 0.21 ± 0.03 96.6 ± 1.4 315 DPDPE 2.0 ± 0.8 U50,488 0.78 ± 0.31 Fentanyl* 0.67 ± 0.19 91.6 ± 3.89 77.2 ± 6.38 Methadone* 1.89 ± 0.3 76.1 ± 1.73 299.8 ± 66.7 Source: Adapted from [24] and [47]. Abbreviations: h = human, m = mouse. MOR, DOR, and KOR = mu, delta, and kappa opioid receptor, respectively. * Mouse only; different experimental design.

Finding Mendelian Disease Genes 229

which gives an amplifi cation sample of good-quality DNA to continue linkage. However, an aliquot of the original sample should always be held back for defi ni-tive testing.

Mapping To fi nd the location of human disease-causing genes, you must remember that you are mapping one or more mutations, not the normal or wild-type gene. Th e gene that contains the mutation(s) is the disease gene you seek. Mapping fi nds that part of the genome that contains the gene. For an X-linked disorder the gene is obviously somewhere on the X chromosome, which is only 1/20th of the nuclear DNA. For mito-chondrial inherited conditions, the gene will be with-in the mitochondrial genome, which is tiny, contain-ing only about two dozen genes. Autosomal dominant and recessive genes can be anywhere on the 22 auto-somal chromosomes. Finding the location of the gene is known as “mapping the disease locus.” If the con-dition can be caused by diff erent genes then it shows genetic heterogeneity, and the locations of those genes are the gene loci. Th is matter of heterogeneity is im-portant and will be dealt with later in this section.

What Is Linkage?First, what is linkage? Linkage is a situation in which a disease and a genetic marker allele are co-inher-ited. Let’s say we have a marker on chromosome 3 with two alleles, A and B. If we fi nd that every time a person has the disease he or she also inherits the B allele, then we have linkage between the disease and the genetic locus. Th erefore, the disease-causing gene (containing the family mutation) and the marker are close to each other on chromosome 3. Let’s con-sider meiosis, the special type of mitosis where eggs or sperm are made. Chromosomes pair up with each other, a chromosome 1 with a chromosome 1, a chro-mosome 2 with a chromosome 2, and so on. When they are paired, lengths of chromosome are swapped over between the two original chromosomes; this process is called a crossover. Th us, for each chromo-some pair, the original two chromosomes that a per-son has are mixed together in the eggs or sperm they produce. In that way, we mix up and pass on diff erent chromosomes to the ones we inherited from our par-ents. When these crossovers occur at meiosis, genetic regions on the same chromosome can either remain together or be separated, one to each of the newly derived chromosomes. Th e further apart two regions

are, the more likely this is to occur. An extreme ex-ample would be two loci on diff erent chromosomes which will randomly be passed into eggs or sperm and will not be linked to each other. Th e opposite extreme is where your genetic marker is somewhere within your disease gene. In this case they will almost never part from each other on their chromosome.

Crossover does not occur randomly, and it is more likely to occur in some chromosomal regions than others. Also, the chromosomes behave slightly diff erently between the sexes. Studying large numbers of meioses allows the pattern of crossovers to be ob-served and a genetic map of each chromosome to be derived. Th e distance between two loci on a chromo-some can be measured both physically (the number of bases they are apart) and genetically (the chance they will be split per meiosis). Th e physical distance is mea-sured in bases, usually megabases (1 MB is 1,000,000 bases), and the genetic distance in centimorgans (100 cM is the distance apart where two loci will randomly segregate and are not linked). Th e closer two loci are together on a chromosome, the smaller the genetic distance will be. Looking at this the other way round, if two loci are 1 cM apart they will only divide in one in a hundred meioses. Usually physical and genetic distance are roughly equivalent (1 Mb = 1 cM), but only at certain places in the genome. At the telomeres of most chromosomes, genetic distance can be much greater than physical distance. Conversely, around the centromeres of chromosomes, physical distance tends to be much greater than genetic distance. Th is infor-mation is important because linkage works in genetic, not physical, distance.

Initial LinkageWe need to fi nd a genetic marker that is always, or almost always, inherited with our disease in a single large family. We already know the disease status from clinical studies of our family. All we need now is to fi nd the linked genetic marker. Currently, the marker is found by analyzing a set of genetic markers spaced throughout the human genome. Th e number of mark-ers varies from hundreds (for polymorphic micro-satellite markers), to hundreds of thousands if single nucleotide polymorphisms (SNPs) are used. Until re-cently, polymorphic microsatellite markers were the best tools we had, but they have been almost com-pletely superseded by SNP methodologies. Th ese allow simultaneous analysis of which alleles are present at 100–500,000 SNP loci spread throughout the human genome in a single experiment. Diff erent platforms for

248 Mark R. Hutchinson et al.

compounds, if they are able to penetrate the blood-brain barrier, may eff ectively alter spinal cord glial function. However, it should be recognized at the out-set that systemically administered drugs would also alter brain and peripheral immune cell/glial function as well. Th us, there will be advantages and disadvan-tages to every therapy discussed.

Disrupting Glial ActivationTwo compounds block glial activation. One is fl uo-rocitrate, a glial metabolic inhibitor that blocks pain facilitation [91,113,118]. However, it is not appropri-ate for human use because it can block glial uptake of excitatory amino acids, which is an essential function of glia in the maintenance of normal CNS homeosta-sis. Removal of excitatory amino acid transport by glia can lead to neuroexcitability and seizures [15]. Th is

case illustrates that glia serve important functions un-der basal conditions that need to be maintained dur-ing any therapeutic strategy directed at controlling clinical pain.

Th e second compound is minocycline. Mi-nocycline selectively targets microglia, disrupting microglial activation and production of proinfl amma-tory cytokines and nitric oxide. It eff ectively blocks the development of enhanced pain states [151] (see Table I). However, concern is raised as to its clinical potential. Data from animal models make it clear that minocycline is far more powerful in preventing than reversing pain facilitation. Indeed, such data have led to the hypothesis that microglia are crucially involved in the initiation of pain facilitation, but that astro-cytes become the major glial type involved as the pain state persists [151]. If such a shift from microglial to

Table I Comparison of the different strategies targeting glial enhancement

Strategy

Pros

Cons

Latest Developments

Ongoing Work

Refs.

Disrupt glial activation

If basal homeostatic functions of glia are left intact, could be promising.

Disrupting basal glial intracellular functions is not acceptable. Drugs targeting microglia alone may not be clinically effective in reversing established pain.

Minocycline is being explored as a microglia-selective inhibitor in animal models (fails to show potential for reversing pain).

None known 152, 204

Block proinflammatory cytokine actions

Proinflammatory cytokines are involved in the initiation and maintenance of pain facilitation. This strategy is effective for blocking as well as reversing pain facilitation.

Proinflammatory cytokines are redundant as unblocked cytokines may take over their function; thus, blocking a single cytokine is unlikely to be clinically effective. Current compounds do not cross the BBB.

Antagonists of TNF, IL-1, and IL-6 are being assessed in animal models (TNF and IL-1 are most clearly involved).

None known 119, 122, 175, 200

Inhibit proinflammatory cytokine synthesis

If synthesis of all proinflammatory cytokines could be blocked, pain problems are predicted to be resolved.

No apparent disadvantage as long as treatment is reversible/ controllable to allow expression of cytokines under conditions where they would be beneficial.

Some thalidomide derivatives cross the BBB and might be worth assessing for potential effects on glial function.

Celgene (considering approach for thalidomide derivatives); Aventis (not currently pursuing propentofylline)

126, 176, 200

Disrupt cytokine signaling and synthesis

Broad spectrum approaches to shut down creation or effectiveness of key mediators of pain facilitation. Some p38 MAP kinase inhibitors are orally active and cross the BBB. Intrathecal nonviral gene therapy (controllable by insertion of appropriate control sequences) reversibly generates IL-10 site-specifically, using a safe and reliable outpatient delivery system.

p38 MAP kinase is not the only cascade involved; it may be only transiently involved and not restricted to glia (expressed by neurons); effect of inhibiting neuronal signaling is unknown. IL-10 gene therapy involves an invasive procedure (lumbar puncture).

Efficacy of both p38 MAP kinase inhibitors and IL-10 nonviral gene therapy is being assessed in animal models.

Scios, Cytokine Pharmasciences, and others (p38 MAP kinase inhibitors); Avigen (IL-10 gene therapy)

79, 120, 173, 200

Abbreviations: BBB = blood-brain barrier; IL-10 = interleukin-10; MAP = mitogen-activated protein; TNF = tumor necrosis factor.

278 Troels S. Jensen

the NNT values have been calculated for diff erent neuropathic conditions [11,15,17,29,34,36,54–58,66], and overall the NNT values across pain conditions and drugs vary between 3 and 6. Table II presents an overview of the currently most used treatments for neuropathic pain. In Table III, the agents for which randomized, controlled clinical trials have shown ef-fi cacy are briefl y summarized.

AntidepressantsAntidepressants have a well-established benefi cial ef-fect in various neuropathic pain states. Antidepres-sants used in neuropathic pain treatment include tricyclic antidepressants (TCAs) (e.g., amitriptyline and imipramine) and the selective serotonin norepi-nephrine reuptake inhibitors (SNRIs) (duloxetine and venlafaxine), while the eff ect of the selective serotonin reuptake inhibitors (SSRIs) is lower. Antidepressants relieve pain independently of their antidepressant eff ect. However, because of their dual eff ect, antide-pressants may be the fi rst drug choice in patients with coexisting depression.

TCAs, of which there are several (amitripty-line, imipramine, clomipramine, nortriptyline, etc.), are characterized by their multiple modes of ac-tion, with a particular ability to inhibit reuptake of monoamines (serotonin and norepinephrine) from presynaptic terminals. In addition, TCAs block sev-eral receptors (cholinergic, adrenergic, histamin-ergic) and ion channels, including Na+ channels.

TCAs have been widely used to treat various types of neuropathic pain, and effi cacy has been documented for painful diabetic neuropathy, other neuropathies, nerve injury pain, postherpetic neuralgia, and central poststroke pain [13,15,31–34,39,64]. TCAs have sev-eral side eff ects; the most important ones are cardiac conduction disturbances, dry mouth, urine reten-tion, sedation, dizziness, and orthostatic hypotension.

Table II Treatment of neuropathic pain

Pharmacological Treatment Antidepressants Anticonvulsants GABA agonists Topical agents NMDA antagonists Opioids Other drugs

Stimulation Therapies Transcutaneous nerve stimulation Spinal cord stimulation Intracerebral stimulation Motor cortex stimulation

Surgical Interventions Decompression Sympathectomy Denervation Neuroma removal Dorsal root entry zone lesions Chordotomy Radiofrequency lesions

Psychological and Other Treatments Cognitive behavioral therapy Physiotherapy

Table III Numbers needed to treat (NNTs) using various analgesics for different neuropathies

Drug Trials Central Pain

Peripheral Pain* PPN PHN PNI TN HIVN Mixed

Tricyclic antidepressants

16 crossover/ 4 parallel

4.0 (2.6–8.5)

2.3 (2.1-2.7)

2.1 (1.9–2.6)

2.8 (2.2–3.8)

2.5 (1.4–11)

ND NS NA

SNRIs 2 crossover/ 3 parallel

ND 5.1 (3.9-7.4)

5.1 (3.9–7.4)

ND

NA ND ND ND

Gabapentin/ pregabalin

4 crossover/ 13 parallel

NA 4.0 (3.6–5.4)

3.9 (3.3–4.7)

4.6 (4.3–5.4)

NA ND ND 8.0 (5.9–32)

Opioids 6 crossover/ 2 parallel

ND 2.7 (2.1–3.6)

2.6 (1.7–6.0)

2.6 (2.0–3.8)

3.0 (1.5–74)

ND ND 2.1 (1.5–3.3)

Tramadol 1 crossover/ 2 parallel

ND 3.9 (2.7–6.7)

3.5 (2.4–6.4)

4.8 (2.6–27)

ND ND ND ND

NMDA antagonists 5 crossover/ 2 parallel

ND 5.5 (3.4–14)

2.9 (1.8–6.6)

NS NS ND ND NS

Topical lidocaine 4 crossover ND NA ND NA ND ND NA 4.4 (2.5–17)

Cannabinoids 2 crossover/ 2 parallel

6.0 (3.0–718)

ND ND ND ND ND ND NS

Capsaicin 11 parallel ND 6.7 (4.6–12)

11 (5.5–317)

3.2 (2.2–5.9)

6.5 (3.4–69)

ND NA NA

Abbreviations: HIVN = human immunodeficiency virus-related neuropathy; Mixed = mixed neuropathic pains; NA = dichotomized data not available; ND = no studies done; NS = relative risk not significant; PHN = postherpetic neuralgia; PNI = peripheral nerve injury; PPN = painful polyneuropathy; SNRIs = serotonin-norepinephrine reuptake inhibitors; TN = trigeminal neuralgia. * Peripheral pain: combined NNT in painful polyneuropathy, postherpetic neuralgia, and peripheral nerve injury.

288 Gunnar Wasner and Ralf Baron

in the central nervous system” [42]. Recently, a group of experts from the neurological and pain communi-ties suggested to omit “dysfunction” from the defi ni-tion and suggested a redefi nition of central neuro-pathic pain: “pain arising as a direct consequence of

a lesion or disease aff ecting the somatosensory sys-tem.” Th is revised defi nition fi ts into the nosology of neurological disorders. Further, a grading system of definite, probable, and possible neuropathic pain was proposed, because of the lack of a specific di-agnostic tool for neuropathic pain [57]. It remains to be seen whether this redefinition will become widely accepted.

EpidemiologyTh ere are multiple etiologies for central pain, includ-ing common neurological diseases such as stroke, multiple sclerosis, Parkinson’s disease and traumatic injury of the spinal cord or the brain (Table I). Due to including “dysfunction in the central nervous sys-tem” into the defi nition, also painful epileptic seizures (approximately 1% of epileptic patients) are ranked among central pain syndromes. However, due to re-cent neuroimaging techniques, structural cerebral lesions are detected in an increasing number of epi-leptic patients, and time will show whether this will also be the case for this subgroup of patients suff ering from painful seizures [41]. On the other hand, there are an increasing number of chronic pain diseases in which primary CNS involvement is suggested, such as fi bromyalgia [29]. Whether these pain states should be included under the umbrella of central pain syn-dromes is an actual debate.

Central pain is directly related to a central lesion. Th erefore, pains arising secondarily after a

central process are not included in the defi nition, such as painful spasticity in multiple sclerosis or shoulder-hand syndrome following stroke. Also, changes within the CNS secondary to a peripheral lesion, e.g. changes in the dorsal horn in peripheral neuropathic pain syn-dromes, are not among central pain syndromes.

It should be kept in mind that several of the central diseases are often associated with pains oth-er than central pain. Th erefore, in the following sec-tions some central pain etiologies will be described in more detail.

StrokeAt least 8% of all stroke patients are aff ected by cen-tral pain [49]. Because of the high incidence of stroke (e.g., incidence for ischemic stroke in Germany: 160–240/100,000), central poststroke pain is the most common cause of central pain, accounting for ap-proximately 90% of all central pain syndromes related to lesions in the brain. Th alamic lesions are seen in about 20% of patients [1]. Only in these cases should the term “thalamic syndrome” be used; otherwise, the term “poststroke pain” is more appropriate.

Th e pain is typically located within the area of stroke-related sensory abnormalities. However, noci-ceptive pains such as shoulder-arm syndrome, which often follows subluxation of the scapulohumeral joint, can be found on the aff ected side and must be distin-guished from central pain. Rarely, complex regional pain syndrome (CRPS) of the paretic arm is described, which is suggested to be initiated in the periphery [61]. Further, other peripheral as well as neuropathic pains can occur, such as pain related to spasticity, pa-resis-related malposition, overuse of the unaff ected body site, and fi nally, pain related to diabetic neuropa-thy because of the signifi cant coincidence of diabetes and stroke.

For a detailed study of poststroke pain, the book Central Neuropathic Pain: Focus on Poststroke Pain is recommended [31].

Spinal Cord InjuryTh e estimated number of spinal-cord-injured peo-ple in the member states of the Council of Europe is at least 300,000, with about 11,000 new cases per year. About 35–40% of them suff er from central pain [51,52]. Chronic pain in total is very common and is seen in approximately 70–80% of patients [4,51,55]. It is one of the major reasons for reduced quality of life, decreased ability to participate in daily activities, and unfi tness for work [2,46,51,63]. To distinguish central

Table I Causes of central pain

Vascular lesions in the brain and spinal cord Infarction Hemorrhage Vascular malformation Multiple sclerosis Traumatic spinal cord injury Cordotomy Traumatic brain injury Syringomyelia and syringobulbia Tumors Abscesses Inflammatory diseases other than multiple sclerosis Myelitis causes by viruses or syphilis Epilepsy Parkinson’s disease Source: [31, p. 8.]

290 Gunnar Wasner and Ralf Baron

bodies and the spinal segments diverges in the distal vertebral column, so that a fracture of the 11th thoracic vertebra can directly aff ect spinal segment L3 (Fig. 1). Th erefore, the pain on both medial aspects of the dis-tal thighs (dermatome L3) is classifi ed as at-level due to lesion of the spinal segment L3 (Fig. 1). Th e gir-dle-like pain (dermatome T12) must be due to com-pression/disruption of the spinal roots of L12, where passing the level of the fracture on the way from its origin in the thoracic spinal segments toward its exit route through the intervertebral foramen, and is therefore classifi ed as at-level pain. Finally, the pain within the dorsal aspect of both feet (dermatome L5) is classifi ed as below-level pain, because the spinal segment of L5 was not aff ected by the trauma, and the pain is related to involvement of the ascending central aff erents from L5 while passing the lesioned spinal segment L3 (Fig. 1).

Multiple SclerosisPain in multiple sclerosis is more common than has previously been recognized. About 60% of patients complain about pain during the course of the disease, with central pain found in about 30% [43]. Trigeminal neuralgia, seen in 5%, can be the fi rst manifestation of the disease. It is due to central lesion of the trigeminal pathways in the brainstem, which sometimes can oc-cur bilaterally (Fig. 2).

Parkinson’s DiseaseApproximately 40–75% of Parkinson patients have sensory symptoms, pain being the most common complaint [24,25,39,47,48,54]. Based on evidence of the involvement of the striatonigral dopaminergic system in pain mechanisms, a pathophysiological processing of nociceptive information in Parkinson’s disease is suggested [60]. From a clinical point of view, pain related to motor symptoms can be distin-guished from pain that is unrelated [47]. It is hypoth-esized that some, but not all, of the pains unrelated to motor symptoms are caused by pathological cen-tral pain processing and can be therefore classifi ed as central pain. Clinically, these patients often have bi-lateral pain, mainly in the extremities, though often more intense on the side where the motor symptoms fi rst appeared or are most prominent [15,35,50,54]. Pain is often characterized as diff use, cramplike, ach-ing, or burning [54]. It can be intermittent or persist-ent. Future studies will show whether the underly-ing mechanisms of this pain is comparable to what is known from other central pain conditions.

Clinical Features of Central PainCentral pain has many essential characteristics of neuropathic pain; however, its clinical picture varies considerably, not only from entity to entity, but also from patient to patient.

Onset of PainCentral pain typically develops with a delay after the initial lesion. Th e time frame is diffi cult to determine for some entities such as multiple sclerosis, but was clearly shown for others like spinal cord injury or stroke. Siddall et al., in a longitudinal study on pain following spinal cord injury, reported an onset time of below-level neuropathic pain of 1.8 ± 1.7 years (mean ± SD) [51]. In stroke, most patients develop pain with-in the fi rst 3–6 months after the infarction. Andersen et al. demonstrated that 63% experienced poststroke pain within 1 month, an additional 19% within the fi rst 6 months, and another 19% between 6 and 12 months [1]. However, the individual interval between the stroke episode and the onset of pain can vary con-siderably, as pain has been reported to appear immedi-ately after the stroke or up to several years later [6,34].

Pain DistributionCentral pain is typically localized in an area of abnor-mal sensitivity corresponding to the preceding central

Fig. 2. Magnetic resonance imaging (MRI) scan of a young patient with multiple sclerosis suff ering from bilateral trigeminal neural-gia. Note bilateral demyelinating lesions aff ecting central pathways of trigeminal aff erents (arrows).

322 James P. Rathmell

disability and worry about reinjury [76]. Modalities such as heat, ultrasound, and transcutaneous elec-trical stimulation (TENS) are often used by physical therapists; these approaches may provide short-term symptomatic relief, but there is no evidence that they alter the long-term course of acute or chronic low back pain [36,75].

Behavioral Th erapyPersistent pain is a problem that often has physical, psychological, and social/occupational components [67]. Two types of behavioral therapy, operant condi-tioning and cognitive therapy, are used for back pain. Operant conditioning aims to eliminate maladaptive pain behaviors. Cognitive therapy addresses how pa-tients cope with their pain—what they do as a result of their pain and how their thoughts and feelings in-fl uence their behavior. Cognitive-behavioral therapy is superior to a wait-list control for reducing short-term pain intensity (SMD, 0.59 [95% CI, 0.10 to 1.09]), but not for improving functional status (SMD, 0.31 [95% CI, –0.20 to 0.82]) [74]. Behavioral outcomes were also superior (e.g., pain behavior, cognitive errors, perceived or observed levels of tension, anxiety, de-pression) to no treatment [74].

Multidisciplinary Pain Treatment ProgramsA typical multidisciplinary treatment program in-cludes a medical manager, usually a physician, over-seeing all aspects of care and working with other health care professionals who deliver physical and behavioral therapies. However, declining reimburse-ment has forced many inpatient programs to transi-tion to the outpatient setting [18]. In a systematic review of 10 high-quality RCTs, intensive multidisci-plinary biopsychosocial rehabilitation (more than 100 hours of therapy) signifi cantly reduced pain and im-proved function long-term (as long as 60 months af-ter program completion) over inpatient or outpatient nonmultidisciplinary approaches or usual care [29]. Multidisciplinary pain treatment programs are an im-portant option for chronic pain patients whose func-tion is signifi cantly impaired.

Interventional Pain Th erapiesInterventional pain therapy refers to a group of tar-geted treatments used for specifi c spine disorders,

ranging from epidural injection of steroids to percuta-neous intradiskal techniques. Some have been rigor-ously tested in RCTs, while others are in widespread use without critical evaluation. When these treatment techniques are used for the disorders they are most likely to benefi t (Table I), they can be highly eff ective; however, when used haphazardly, they are unlikely to be helpful and, indeed, may cause harm.

Epidural Injection of SteroidsNumerous RCTs have examined the effi cacy of epi-dural corticosteroid injection for acute radicular pain. Such injections into the epidural space are thought to combat the infl ammatory response that is associ-ated with acute disk herniation [43]. In acute radicu-lar pain with HNP, the evidence [3,43,79] shows that epidural steroids reduce the severity and duration of leg pain if given between 3 and 6 weeks after onset. Adverse eff ects, such as injection site pain and tran-sient worsening of radicular pain, occur in less than 1% of treated subjects [43]. Beyond 3 months from treatment, there appear to be no long-term reduc-tions in pain or improvements in function [43,34]. Th is therapy has never proven helpful for lumbosacral pain without radicular symptoms

Facet Blocks and Radiofrequency TreatmentPain from the lumbar facet joints aff ects up to 15% of chronic low back pain patients [16]. Patients are iden-tifi ed based on typical patterns of referred pain, with maximal pain located directly over the facet joints and patient report of pain on palpation over the facets; ra-diographic fi ndings are variable, but some degree of facet arthropathy is typically present [17]. A few low-quality studies suggest that the intra-articular injection of anesthetics and corticosteroids leads to intermedi-ate-term (1–3 months) pain relief in patients with an active infl ammatory process [16]. Radiofrequency de-nervation delivers energy through an insulated, small-diameter needle positioned adjacent to the sensory nerve to the facet joint, creating a small area of tissue coagulation that denervates the facet joint. Two sys-tematic reviews concluded that there is moderate evi-dence that radiofrequency denervation provides better pain relief than sham intervention [28,68]. Th e quality of the six available RCTs was deemed adequate, but they were conducted in a technically heterogeneous manner (e.g., varying inclusion criteria, diff ering treat-ment protocols), thus limiting analysis of their fi nd-ings. Approximately 50% of patients treated reported at least 50% pain reduction. Pain typically returns 6

Pain and Addiction 349

Th e Neurochemistry of AddictionAddiction is best described as a chronic disease of brain reward centers, which exist to ensure survival of the organism and species. Reward centers have evolved to grab our attention, dominate motivation, and compel behavior toward survival even in the presence of danger. Eating, sex, social interaction, and unexpected novel stimuli activate these reward circuits under normal circumstances. All of the usual drugs of abuse have an ability to turn on reward cir-cuits to a much greater extent for a longer period of time than natural stimuli. By activating and dysregu-lating endogenous reward centers, addictive drugs hi-jack brain circuits that take over behavior, leading to progressive loss of control over drug intake in spite of medical, emotional, interpersonal, occupational, and legal consequences.

Th e mesolimbic reward pathway connects the ventral tegmental area (VTA) with the nucleus accumbens, amygdala, hippocampus, hypothalamus, and pre frontal cortex. Some of these areas are part of the brain’s traditional memory system. Increasing evi-dence suggests that important aspects of the addictive process may involve powerful emotional memories. Dopamine is released in the VTA and nucleus accum-bens in response to rewarding drugs and appears to infl uence the motivational state of wanting or expec-tation. Th e persistent release of dopamine as a result of chronic drug use eventually results in a reduction in dopamine release in response to drug use (toler-ance), requiring higher drug doses for eff ect. Th is pro-cess progressively recruits limbic brain regions and the prefrontal cortex and “programs” drug cues via glutaminergic mechanisms [14].

Another circuit involving the amygdala, ante-rior cingulate, orbitofrontal cortex, and dorsolateral prefrontal cortex contributes to the obsessive crav-ing for drugs. Persistent dopamine release results in the formation of cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), which dampens reward circuitry in the nucleus ac-cumbens, and delta FosB, which causes prolonged sensitization of reward pathways to re-exposure to drugs. Th us, the abstinent, addicted brain can be trig-gered to return to compulsive drug use via a single ex-posure to the drug, contextual drug cues, cravings, or stress—each originating in a relatively distinct brain region or neural pathway [15]. Th e compulsion to use drugs is complemented by defi cits in impulse control and decision making mediated by the orbitofrontal

cortex and anterior cingulate gyrus [16]. Of interest to clinicians, this set of reward neurons is physically and functionally separate from the areas of the central nerv ous system involved in the phenomena of physi-cal de pendence and tolerance to opioids. Laboratory animals can be bred to exhibit greater and lesser sen-sitivity in parts of the reward pathway, with a corre-spondingly greater or lesser propensity to develop ad-dictive behaviors to chemicals of abuse [17,18]. It is therefore equally likely that certain hu mans are also born with a greater or lesser sensitivity in the reward pathways. Some people are probably biogenetically “wired” to be at increased risk for developing an ad-dictive disorder.

Based on results from the U.S. NHSDUH, regular heroin users make up only 0.14% of the total population. Th ey tend to cluster in the core of larger cities or transporta tion hubs that serve as importation and distribution sites for illicit drugs. Some research-ers believe that these predisposed individuals may be using illicit opi oids to fi ll some type of neurochemi-cal void in their brain chemistry. Unfortunately, the repetitive use of a rapidly absorbed, short-acting opi-oid, such as heroin, by intermittent intravenous bolus dosing, not only contrib utes to devastating second-ary causes of morbidity and mortality, but also causes disruption in other central neu rochemical processes, such as the hypothalamic pituitary axis. Opioid ago-nist therapy with methadone or buprenorphine is therefore not simply the substitution of one safer ad-dicting drug for another. Rather, it may serve to stabi-lize some aspect of defi cient brain chemistry in these predisposed individuals [19].

Fig. 1 illustrates a simplifi ed model of the contributors to the addictive process. To be sure, the presence of an addicting substance or behavior is

BIOGENETICPREDISPOSITION

PERSONALPSYCHOLOGY

SOCIO-CULTURAL

MILIEU

REWARDINGSUBSTANCE/

BEHAVIOR

ADDICTIVEDISEASE

Fig. 1. Th e etiology of addiction—a biopsychosocial disease.