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 Scientific Program Committee José Castro-Lopes, MD, PhD, Chair, Portugal Fernando Cervero, MD, PhD, DSc, Canada Beverly Collett, MB BS, UK Carlos Maurício de Castro Costa, MD, PhD, Brazil G. Allen Finley, MD, Canada Susan Fleetwood-Walker, PhD, United Kingdom Herta Flor, PhD, Germany Carmen Green, MD, USA Troels Jensen, MD, PhD, Denmark, ex officio Eija Kalso, MD, DMedSci, Finland Bruce Kidd, DM, FRCP, UK Katherine Kreiter, USA, ex officio Steven Linton, PhD, Sweden Arthur Lipman, PharmD, USA Stephen McMahon, PhD, United Kingdom Jeffrey Mogil, PhD, Canada Michael Nicholas, PhD, Australia Koichi Noguchi, MD, PhD, Japan Paul Pionchon, DDS, PhD, France Srinivasa Raja, MD, USA Martin Schmelz, MD, Germany Thomas Toelle, PhD, MD, Germany You Wan, PhD, MD, China Judith Watt-Watson, RN, PhD, Canada Harriet Wittink, PhD, PT, The Netherlands
IASP PRESS® • SEATTLE
© 2008 IASP Press® International Association for the Study of Pain® Reprinted 2009 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 IASP®. Thus, opinions expressed in Pain 2008—An Updated Review: Refresher Course Syllabus do not necessarily reflect those of IASP or of the Officers and Councilors. 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 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 Scientific 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. CastroLopes, José, 1959- II. IASP Scientific 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
Published by: IASP Press International Association for the Study of Pain 111 Queen Anne Ave N, Suite 501 Seattle, WA 98109-4955, USA Fax: 206-283-9403 www.iasp-pain.org
Contents Preface Acknowledgments
vii viii
Part 1: Neurobiology of Acute and Persistent Pain 1. Pain: Basic Mechanisms Allan Basbaum, M. Catherine Bushnell, and Marshall Devor
3
Part 2: Opioids in Cancer Pain Management 2. Opioid Titration in Cancer Pain Sebastiano Mercadante 3. Opioids and Breakthrough Pain Giovambattista Zeppetella
13 19
Part 3: Pain Imaging 4. Functional MRI Studies of Pain Processing Irene Tracey 5. Electroencephalography and Magnetoencephalography in Pain Research Markus Ploner 6. Molecular Imaging Studies of Pain Processing David J. Scott
27 33 39
Part 4 Musculoskeletal Pain: Basic Mechanisms 7. Clinical Applications of Basic Mechanisms of Musculoskeletal Pain Michele Curatolo 8. Peripheral and Central Mechanisms of Musculoskeletal Pain Siegfried Mense 9. Musculoskeletal Pain: Basic Mechanisms Lars Arendt-Nielsen and Thomas Graven-Nielsen
49 55 63
Part 5: Human Pain Models: Virtues and Limitations 10. Human Experimental Pain Models: Virtues and Limitations Karin L. Petersen and Martin Schmelz 11. Functional Imaging of Experimental Pain Models Christian Maihรถfner
77 89
Part 6: Complex Regional Pain Syndrome 12. Complex Regional Pain Syndromes: Translation from Science to Clinical Practice Ralf Baron 13. Animal Models of Complex Regional Pain Syndrome and Their Implications for Underlying Mechanisms and Treatment Dimitris N. Xanthos, Gary J. Bennett, and Terence J. Coderre 14. Movement Disorders in Complex Regional Pain Syndrome J. J. van Hilten
99
109 121
Part 7: Migraine: From Genes to Pain Mechanisms and Pathways 15. Migraine as a Cerebral Ionopathy with Impaired Central Sensory Processing Michel D. Ferrari and Peter J. Goadsby iii
129
iv 16. Migraine Prophylaxis with Botulinum Toxin A Is Associated with Perception of Headache Rami Burstein, David Dodick, Moshe Jakubowski, and Stephen Silberstein
Contents 147
Part 8: Persistent Postoperative Pain: Pathogenic Mechanisms and Treatment 17. Persistent Postsurgical Pain: Surgical Risk Factors and Strategies for Prevention Henrik Kehlet 18. Chronic Pain after Surgery: Epidemiology and Preoperative Risk Factors William Macrae
153 159
Part 9: Psychological Interventions for Chronic Pain 19. Psychological Interventions for Chronic Pain Robert Kerns, Stephen Morley, and Johan W. S. Vlaeyen
169
Part 10: Clinical Pharmacology of Pain 20. Clinical Pharmacology of Opioids in the Treatment of Pain Eija Kalso 21. Nonsteroidal Anti-inflammatory Agents and Paracetamol (Acetaminophen) Vesa K. Kontinen 22. Clinical Pharmacology of Antiepileptics and Antidepressants in the Management of Neuropathic Pain Søren H. Sindrup
185 193 205
Part 11: Human Pain Genetics 23. Studying Common Genes that Contribute to Human Pain: An Introduction Mitchell B. Max 24. Finding Mendelian Disease Genes James Cox, Adeline Nicholas, and Geoffrey Woods 25. Whole-Genome Association Studies Ariel Darvasi
215 225 233
Part 12: Glial Dysregulation of Pain and Opioid Actions: Past, Present, and Future 26. Glial Dysregulation of Pain and Opioid Actions: Past, Present, and Future Mark R. Hutchinson, Kirk W. Johnson, and Linda R. Watkins
237
Part 13: Neuropathic Pain: From Basic Mechanisms to Clinical Management 27. Neuropathic Pain: Definition, Diagnostic Criteria, Clinical Phenomenology, and Differential Diagnostic Issues Per T. Hansson 28. Neurobiological Mechanisms of Neuropathic Pain and Its Treatment Anthony H. Dickenson and Lucy A. Bee 29. Management of Neuropathic Pain Troels S. Jensen
259
265 275
Part 14: Central Pain: A Multidimensional Challenge 30. Epidemiology, Clinical Presentation, and Mechanisms in Central Pain Syndromes Gunnar Wasner and Ralf Baron 31. Spinal Cord Injury: A Model for the Pathophysiology and Mechanisms of Central Pain Robert P. Yezierski
287 295
Contents 32. Treatment of Central Pain Nanna Brix Finnerup
v 307
Part 15: Interventional Therapies for Acute and Chronic Pain: Indications and Efficacy 33. Rational Use of Interventional Modalities for the Treatment of Pain of Spinal Origin James P. Rathmell 34. Rational Use of Interventional Modalities for the Treatment of Complex Regional Pain Syndrome and Cancer Pain Richard Rauck 35. Continuous Peripheral Nerve Blocks for Treating Acute Pain in the Hospital and the Ambulatory Environment Brian M. Ilfeld
317 327
337
Part 16: Essentials of Addiction Medicine for the Pain Clinician 36. Pain and Addiction: Prevalence, Neurobiology, and Definitions Roman D. Jovey 37. Reducing the Risks of Opioids by Screening and Risk Stratification Steven D. Passik 38. Balancing Safety with Pain Relief When Prescribing Opioids Jonathan Bannister
347 353 361
Part 17: Chronic Abdominal Pain: Evaluation and Management of Common Gastrointestinal and Urogenital Disease 39. Chronic Abdominal Pain: Evaluation and Management of Common Gastrointestinal and Urogenital Diseases Asbjørn Mohr Drewes, Oliver H.G. Wilder-Smith, and Camilla Staahl
369
Part 18: Low Back Pain: Assessment and Management: From Secondary Prevention to Clinical Rehabilitation 40. Back Pain Chris J. Main, Michael K. Nicholas, and Paul J. Watson
383
Editors 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 Scientific Program Committee of the 12th World Congress on Pain (Glasgow, 2008) and will chair the Local Organizing Committee of Pain in Europe VI, the 6th Congress of EFIC (Lisbon, 2009). He has also served on several other committees of IASP and EFIC. The main research field 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.
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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 training 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 efforts 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 evidencebased 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 Associate 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 Scientific Program Committee for the 12th World Congress on Pain. 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 fields of research interest include the neurobiology of pain and inflammation, 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 Scientific Program Committee for the 12th World Congress on Pain.
Preface 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 effects 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. This book is likely to be of particular benefit 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 continuous support, and our colleagues on the Scientific 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 first 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 making 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.
The chapters in this volume have been written by the contributors to the refresher courses offered in conjunction with the 12th World Congress 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 models to clinical studies, from psychological interventions to pharmacological and interventional therapies, from genetics to imaging, and from musculoskeletal pain to complex regional pain syndrome. The selection of topics reflects 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. The Scientific Program Committee, mindful of the multidisciplinary 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 scientific or clinical enrichment. In addition, speakers were selected based not only on their expertise in the field but also on their ability to communicate effectively with such a diverse audience. We are very grateful for the educational efforts of all the lecturers
Jose Castro-Lopes, MD, PhD Srinivasa Raja, MD Martin Schmelz, MD
vii
fMRI Studies of Pain Processing
29 Table I Comparison of fMRI and PET imaging techniques
Modality
BOLD fMRI
15
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
O-Water PET
Abbreviations: BOLD fMRI = blood-oxygenation-level-dependent functional magnetic resonance imaging; PET = positron emission tomography.
field and causes a loss of signal. Thus, the decrease of deoxygenated hemoglobin leads to higher signal intensities that contrast against surrounding tissue. During image analysis, the BOLD signal that is expected to result from the stimulus is modeled mathematically. The model is compared to the signal that is measured during the experiment itself. Statistical maps are constructed and superimposed on a structural brain image to indicate where the measured signal best fits the model. Further details regarding data analysis and background information on fMRI can be found at http://www.fmrib.ox.ac.uk/fsl.
The Cerebral Signature for Pain Perception Over the last decade, MRI and PET functional imaging 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, including the anterior cingulate cortex (ACC), insular cortex, frontal and prefrontal cortices (PFC), primary and secondary somatosensory cortices (S1 and S2, respectively), thalamus, basal ganglia, cerebellum, amygdala, hippocampus, and regions within the parietal and temporal cortices. This network is thought to reflect the complexity of pain as an experience and is often called the “pain matrix.” The matrix can be simplistically thought of as having lateral components (sensory-discriminatory, involving areas such as the primary and secondary somatosensory cortices, thalamus, and posterior parts of the insula) and medial components (affective-cognitive-evaluative,
involving areas such as the anterior parts of the insula, ACC, and PFC) [1]. However, because different brain regions play a more or less active role depending upon the precise interplay of the factors involved in influencing pain perception (e.g., cognition, mood, injury, and so forth), the “pain matrix” is not a defined entity. A recent meta-analysis of human data from different imaging studies provides clarity regarding the regions most commonly found active during an acute pain experience as measured by PET and fMRI [2]. These areas include the primary and secondary somatosensory cortices, insular cortex, ACC, and PFC, as well as the thalamus. This 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 pharmacologically induced analgesia do show predominant effects in this core network that suggest their overall importance in influencing pain perception [3]. Other regions such as the basal ganglia, cerebellum, amygdala, hippocampus, and areas within the parietal and temporal cortices can also be active depending upon the particular set of circumstances for that individual. A “cerebral signature” for pain is perhaps how we should define the network; it is necessarily unique for each individual [4]. This 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, individuals homozygous for the met158 allele of the catechol-O-methyltransferase (COMT) polymorphism (val158met) showed diminished regional mu-opioid system responses to pain (measured using PET) and higher sensory and affective ratings for experimentally
52
Michele Curatolo
is uncertain. Nevertheless, data below the 95% confidence interval of pain thresholds of the healthy population are very likely to be abnormal. The use of sensory 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. The inherent limitations of these methods should be taken into consideration.
Mechanism-Based Treatment Background A 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 identification of the pain mechanisms, which could then be targeted by specific treatments. However, the mechanism-based therapeutic approach is associated with an uncertain outcome, basically for two reasons. First, the ability of most of the available diagnostic methods to identify pain mechanisms is limited. Second, the efficacy of most of the current therapeutic approaches remains modest, even when the pain mechanism is clarified. These 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 Aspects Whenever inflammation is documented, nonsteroidal anti-inflammatory drugs (NSAIDs) or steroids can be used. However, inflammation is evident in only a minority of musculoskeletal pain conditions. Typically, there are no clear signs of inflammation in chronic low back or cervical pain, nor can inflammation be easily ruled out. In other words, we do no have the diagnostic tools to diagnose or rule out inflammation in such conditions. It should also be considered that NSAIDs also act centrally and are therefore potentially useful in non-inflammatory conditions as well. Neuropathic components can be present in musculoskeletal pain states. For instance, disk pathology 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 animal model, inflammation of the zygapophysial joints induced radicular pain as a result of spread of inflammation to the epidural space [39]. Unfortunately, in clinical conditions the presence of neuropathic mechanisms may be difficult to identify and to differentiate from nociceptive components. Whenever neuropathic components are identified or suspected, specific treatment should be implemented. Antidepressants are typically effective in neuropathic pain [16]. Nerve lesions cause an abnormal expression of calcium and sodium channels
Fig. 1. Proposed mechanism-based assessment and treatment algorithm. The limitations of this approach are discussed in the text.
78 and have no predictive value for the analgesic eect of the test compound. Pain models that are set up to mimic certain aspects of pathophysiological pain states through reversible induction of peripheral or central neuronal sensitization may be more relevant to clinical pain conditions. Peripheral or central neuronal sensitization mechanisms are thought to contribute to both acute and chronic pain conditions [10,52]. In these models the endpoints of the stimulus-evoked hypersensitivity in the periphery (primary hyperalgesia) and in the central nervous system (secondary hyperalgesia) provide a correlate to the clinical picture of stimulus-evoked hypersensitivity and have therefore been regarded as surrogate markers of clinical pain states. The strength of the correlation between these surrogate markers and clinical pain states has major
Karin L. Petersen and Martin Schmelz implications for the predictive value of the models. The limiting factor in the use of human experimental pain models is the degree to which mechanisms that have been identiďŹ ed in chronic pain patients can be mimicked in human pain models. Unfortunately, our knowledge about clinically operational pain mechanisms in patients remains very limited and does not yet include molecular targets. There 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 system 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 covered by human experimental models. For structural changes and spontaneous pain, there are no adequate human models.
12
Complex Regional Pain Syndromes: Translation from Science to Clinical Practice Ralf Baron, Dr Med
Division of Neurological Pain Research and Therapy, Department of Neurology, Christian-Albrechts University, Kiel, Germany
Educational Objectives This refresher course is designed to provide an interdisciplinary 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. Successful management of motor dysfunction is one of the most important prognostic factors for CRPS. New pathophysiological ideas as well as treatment approaches for tremor, coordination deficits, and dystonia 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.
type I (reflex sympathetic dystrophy) minor injuries or fractures of a limb precede the onset of symptoms (Table I, Fig. 1). CRPS type II (causalgia) develops after injury to a major peripheral nerve [7,8,39]. The most common precipitating event of CRPS type I (reflex sympathetic dystrophy) is a trauma affecting the distal part of an extremity (65%), especially fractures, postsurgical conditions, contusions, and strain or sprain. Less common causes are central nervous system lesions including spinal cord injuries and cerebrovascular accidents as well as cardiac ischemia [75]. CRPS-I patients develop asymmetrical distal extremity pain and edema without presenting an overt nerve lesion. These patients often report a
Introduction The term “complex regional pain syndrome” describes a variety of painful conditions following injury that appear regionally, with a distal predominance of abnormal findings. The symptoms exceed in both magnitude and duration the expected clinical course of the inciting event and often result in significant impairment of motor function. The disorder shows a variable progression over time. These chronic pain syndromes comprise different additional clinical features including spontaneous pain, allodynia, hyperalgesia, edema, autonomic abnormalities, and trophic signs. In CRPS Pain 2008—An Updated Review: Refresher Course Syllabus, edited by José M. Castro-Lopes, Srinivasa Raja, and Martin Schmelz, IASP Press, Seattle, © 2008
Fig. 1. Clinical picture of a patient with CRPS type I of the upper left extremity following distortion of the left wrist.
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154 This 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 possibilities 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. Thus, 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 inflammation from the surgical area for developing a chronic pain state is very limited due to difficulties in assessing the degree of chronic inflammation.
Postamputation Pain Chronic pain after limb amputation is a well-known postsurgical pain syndrome combined with stump pain and phantom pain. The incidence is in the range of 30–50% [21,23,28,33]. The pathogenesis is probably multifactorial, with preamputation pain known to have a specific role. Many efforts have been made to study perioperative analgesic techniques to reduce phantom limb pain, but without any firm conclusions [11]. Interestingly, despite the obligatory transection of major nerves in leg amputation, no attention at all has been paid in phantom limb studies to intraoperative handling of the nerves. This lack of attention is particularly surprising, given that various nerve ligature models have been used to study chronic 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 according to experimental data is just calling for development of chronic neuropathic pain. Surprisingly, major 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 urgent need for clinical studies investigating the role of nerve handling as a risk factor for phantom limb pain after limb amputation.
Postmastectomy Pain Several studies have shown mastectomy to be followed by a chronic pain state in about 10–30% of
Henrik Kehlet 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. The problem, however, is that most studies are retrospective, and no prospective study has included all risk factors (Table I). That 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 different patient groups (different types of surgery and adjuvant therapies) also emphasized 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 introduction of the sentinel node technique. A recent retrospective 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 largescale 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 severity and incidence of postmastectomy pain and guide strategies for its prevention and treatment.
Post-Thoracotomy Pain Thoracotomy is another operation with well-documented high incidence (about 20–50%) of chronic pain complaints [17,21,23,33,37]. A review of surgical aspects concluded that no one technique of thoracotomy led to a definite reduction of chronic postthoracotomy pain [37]. A recent review [17] agreed, but claimed that the incidence over the years has been falling, without an obvious explanation. That significant 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
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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 brainstem are involved in the regulation of arousal, respiration, and both anti- and pronociceptive effects. Opioids receptors are found almost everywhere in the cerebral cortex and cerebellum. In the periphery, opioids are involved in the regulation of gastrointestinal 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 peripheral nervous system are regulated by inflammation and the immune system.
Opioids in the Clinic: Alleviation of Acute and Chronic Pain Opioids remain the main analgesics in the treatment of moderate to severe acute pain and cancer pain. They have a restricted role in the management of other chronic pains.
Acute Postoperative and Other Trauma-Related Pain Opioids are usually added to non-opioid treatment such as paracetamol (acetaminophen) and nonsteroidal anti-inflammatory drugs. Other adjuvant analgesics such as corticosteroids [39], ketamine [2], and gabapentin or pregabalin [45] are increasingly used to improve analgesia and reduce opioid-related adverse effects. Short-acting opioids (e.g., remifentanil,
sufentanil, fentanyl, alfentanil) are usually administered intravenously (i.v.) perioperatively. Patient-controlled 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., ketobemidone, piritramide), but these more unusual opioids will not be discussed in this chapter. Spinal opioid analgesia is used for major surgery. Morphine is used both for subarachnoid and epidural administration, whereas fentanyl is used to improve epidural analgesia with local anesthetic agents. Opioids are also administered locally, even though their effectiveness has not been confirmed [18].
Cancer-Related Pain Opioids 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. Controlled-release formulations (e.g. morphine, oxycodone, 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 administration is not possible opioids can be administered transdermally and subcutaneously. Spinal opioids can also be used. The 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) Ligand
hMOR1
mDOR1
hKOR1
[35S]GTPS Binding to hMOR1 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 which gives an amplification sample of good-quality DNA to continue linkage. However, an aliquot of the original sample should always be held back for definitive testing.
Mapping To find 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. The gene that contains the mutation(s) is the disease gene you seek. Mapping finds 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 mitochondrial inherited conditions, the gene will be within the mitochondrial genome, which is tiny, containing only about two dozen genes. Autosomal dominant and recessive genes can be anywhere on the 22 autosomal chromosomes. Finding the location of the gene is known as “mapping the disease locus.” If the condition can be caused by different genes then it shows genetic heterogeneity, and the locations of those genes are the gene loci. This matter of heterogeneity is important 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-inherited. Let’s say we have a marker on chromosome 3 with two alleles, A and B. If we find 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. Therefore, the disease-causing gene (containing the family mutation) and the marker are close to each other on chromosome 3. Let’s consider 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 chromosome 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. Thus, for each chromosome pair, the original two chromosomes that a person has are mixed together in the eggs or sperm they produce. In that way, we mix up and pass on different chromosomes to the ones we inherited from our parents. 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. The further apart two regions
229 are, the more likely this is to occur. An extreme example would be two loci on different chromosomes which will randomly be passed into eggs or sperm and will not be linked to each other. The 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 differently between the sexes. Studying large numbers of meioses allows the pattern of crossovers to be observed and a genetic map of each chromosome to be derived. The distance between two loci on a chromosome can be measured both physically (the number of bases they are apart) and genetically (the chance they will be split per meiosis). The physical distance is measured 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). The 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. This information is important because linkage works in genetic, not physical, distance.
Initial Linkage We need to find 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 find the linked genetic marker. Currently, the marker is found by analyzing a set of genetic markers spaced throughout the human genome. The number of markers varies from hundreds (for polymorphic microsatellite markers), to hundreds of thousands if single nucleotide polymorphisms (SNPs) are used. Until recently, polymorphic microsatellite markers were the best tools we had, but they have been almost completely superseded by SNP methodologies. These allow simultaneous analysis of which alleles are present at 100–500,000 SNP loci spread throughout the human genome in a single experiment. Different platforms for
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compounds, if they are able to penetrate the bloodbrain barrier, may effectively alter spinal cord glial function. However, it should be recognized at the outset that systemically administered drugs would also alter brain and peripheral immune cell/glial function as well. Thus, there will be advantages and disadvantages to every therapy discussed.
Disrupting Glial Activation Two compounds block glial activation. One is fluorocitrate, a glial metabolic inhibitor that blocks pain facilitation [91,113,118]. However, it is not appropriate 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 homeostasis. Removal of excitatory amino acid transport by glia can lead to neuroexcitability and seizures [15]. This
case illustrates that glia serve important functions under basal conditions that need to be maintained during any therapeutic strategy directed at controlling clinical pain. The second compound is minocycline. Minocycline selectively targets microglia, disrupting microglial activation and production of proinflammatory cytokines and nitric oxide. It effectively 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 astrocytes 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 Latest Developments
Ongoing Work
Refs.
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 microgliaselective inhibitor in animal models (fails to show potential for reversing pain).
None known
152, 204
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 sitespecifically, 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 IL10 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
Strategy
Pros
Cons
Disrupt glial activation
If basal homeostatic functions of glia are left intact, could be promising.
Block proinflammatory cytokine actions
Abbreviations: BBB = blood-brain barrier; IL-10 = interleukin-10; MAP = mitogen-activated protein; TNF = tumor necrosis factor.
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the NNT values have been calculated for different 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 efficacy are briefly summarized.
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
Antidepressants Antidepressants have a well-established beneficial effect in various neuropathic pain states. Antidepressants used in neuropathic pain treatment include tricyclic antidepressants (TCAs) (e.g., amitriptyline and imipramine) and the selective serotonin norepinephrine reuptake inhibitors (SNRIs) (duloxetine and venlafaxine), while the effect of the selective serotonin reuptake inhibitors (SSRIs) is lower. Antidepressants relieve pain independently of their antidepressant effect. However, because of their dual effect, antidepressants may be the first drug choice in patients with coexisting depression. TCAs, of which there are several (amitriptyline, imipramine, clomipramine, nortriptyline, etc.), are characterized by their multiple modes of action, with a particular ability to inhibit reuptake of monoamines (serotonin and norepinephrine) from presynaptic terminals. In addition, TCAs block several receptors (cholinergic, adrenergic, histaminergic) and ion channels, including Na+ channels.
Surgical Interventions Decompression Sympathectomy Denervation Neuroma removal Dorsal root entry zone lesions Chordotomy Radiofrequency lesions Psychological and Other Treatments Cognitive behavioral therapy Physiotherapy
TCAs have been widely used to treat various types of neuropathic pain, and efficacy 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 several side effects; the most important ones are cardiac conduction disturbances, dry mouth, urine retention, sedation, dizziness, and orthostatic hypotension.
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 (3.97.4)
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.
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in the central nervous system” [42]. Recently, a group of experts from the neurological and pain communities suggested to omit “dysfunction” from the definition and suggested a redefinition of central neuropathic pain: “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system.” This revised definition fits 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 diagnostic tool for neuropathic pain [57]. It remains to be seen whether this redefinition will become widely accepted.
Epidemiology There are multiple etiologies for central pain, including 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 system” into the definition, also painful epileptic seizures (approximately 1% of epileptic patients) are ranked among central pain syndromes. However, due to recent neuroimaging techniques, structural cerebral lesions are detected in an increasing number of epileptic patients, and time will show whether this will also be the case for this subgroup of patients suffering 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 fibromyalgia [29]. Whether these pain states should be included under the umbrella of central pain syndromes is an actual debate. Central pain is directly related to a central lesion. Therefore, pains arising secondarily after a 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.]
central process are not included in the definition, such as painful spasticity in multiple sclerosis or shoulderhand syndrome following stroke. Also, changes within the CNS secondary to a peripheral lesion, e.g. changes in the dorsal horn in peripheral neuropathic pain syndromes, are not among central pain syndromes. It should be kept in mind that several of the central diseases are often associated with pains other than central pain. Therefore, in the following sections some central pain etiologies will be described in more detail.
Stroke At least 8% of all stroke patients are affected by central 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 approximately 90% of all central pain syndromes related to lesions in the brain. Thalamic 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. The pain is typically located within the area of stroke-related sensory abnormalities. However, nociceptive pains such as shoulder-arm syndrome, which often follows subluxation of the scapulohumeral joint, can be found on the affected side and must be distinguished 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, paresis-related malposition, overuse of the unaffected body site, and finally, pain related to diabetic neuropathy because of the significant 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 Injury The estimated number of spinal-cord-injured people 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 suffer 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 unfitness for work [2,46,51,63]. To distinguish central
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bodies and the spinal segments diverges in the distal vertebral column, so that a fracture of the 11th thoracic vertebra can directly affect spinal segment L3 (Fig. 1). Therefore, the pain on both medial aspects of the distal thighs (dermatome L3) is classified as at-level due to lesion of the spinal segment L3 (Fig. 1). The girdle-like pain (dermatome T12) must be due to compression/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 classified as at-level pain. Finally, the pain within the dorsal aspect of both feet (dermatome L5) is classified as below-level pain, because the spinal segment of L5 was not affected by the trauma, and the pain is related to involvement of the ascending central afferents from L5 while passing the lesioned spinal segment L3 (Fig. 1).
Multiple Sclerosis Pain 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 first manifestation of the disease. It is due to central lesion of the trigeminal pathways in the brainstem, which sometimes can occur bilaterally (Fig. 2).
Parkinson’s Disease Approximately 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 distinguished from pain that is unrelated [47]. It is hypothesized that some, but not all, of the pains unrelated to motor symptoms are caused by pathological central pain processing and can be therefore classified as central pain. Clinically, these patients often have bilateral pain, mainly in the extremities, though often more intense on the side where the motor symptoms first appeared or are most prominent [15,35,50,54]. Pain is often characterized as diffuse, cramplike, aching, or burning [54]. It can be intermittent or persistent. Future studies will show whether the underlying mechanisms of this pain is comparable to what is known from other central pain conditions.
Fig. 2. Magnetic resonance imaging (MRI) scan of a young patient with multiple sclerosis suffering from bilateral trigeminal neuralgia. Note bilateral demyelinating lesions affecting central pathways of trigeminal afferents (arrows).
Clinical Features of Central Pain Central 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 Pain Central pain typically develops with a delay after the initial lesion. The time frame is difficult 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 within the first 3–6 months after the infarction. Andersen et al. demonstrated that 63% experienced poststroke pain within 1 month, an additional 19% within the first 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 considerably, as pain has been reported to appear immediately after the stroke or up to several years later [6,34].
Pain Distribution Central pain is typically localized in an area of abnormal sensitivity corresponding to the preceding central
322 disability and worry about reinjury [76]. Modalities such as heat, ultrasound, and transcutaneous electrical 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 Therapy
James P. Rathmell ranging from epidural injection of steroids to percutaneous intradiskal techniques. Some have been rigorously 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 benefit (Table I), they can be highly effective; however, when used haphazardly, they are unlikely to be helpful and, indeed, may cause harm.
Epidural Injection of Steroids
Persistent pain is a problem that often has physical, psychological, and social/occupational components [67]. Two types of behavioral therapy, operant conditioning and cognitive therapy, are used for back pain. Operant conditioning aims to eliminate maladaptive pain behaviors. Cognitive therapy addresses how patients cope with their pain—what they do as a result of their pain and how their thoughts and feelings influence 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, depression) to no treatment [74].
Numerous RCTs have examined the efficacy of epidural corticosteroid injection for acute radicular pain. Such injections into the epidural space are thought to combat the inflammatory response that is associated with acute disk herniation [43]. In acute radicular 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 effects, such as injection site pain and transient 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 reductions in pain or improvements in function [43,34]. This therapy has never proven helpful for lumbosacral pain without radicular symptoms
Multidisciplinary Pain Treatment Programs
Pain from the lumbar facet joints affects up to 15% of chronic low back pain patients [16]. Patients are identified 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; radiographic findings are variable, but some degree of facet arthropathy is typically present [17]. A few lowquality studies suggest that the intra-articular injection of anesthetics and corticosteroids leads to intermediate-term (1–3 months) pain relief in patients with an active inflammatory process [16]. Radiofrequency denervation delivers energy through an insulated, smalldiameter needle positioned adjacent to the sensory nerve to the facet joint, creating a small area of tissue coagulation that denervates the facet joint. Two systematic reviews concluded that there is moderate evidence that radiofrequency denervation provides better pain relief than sham intervention [28,68]. The quality of the six available RCTs was deemed adequate, but they were conducted in a technically heterogeneous manner (e.g., varying inclusion criteria, differing treatment protocols), thus limiting analysis of their findings. Approximately 50% of patients treated reported at least 50% pain reduction. Pain typically returns 6
A typical multidisciplinary treatment program includes a medical manager, usually a physician, overseeing all aspects of care and working with other health care professionals who deliver physical and behavioral therapies. However, declining reimbursement has forced many inpatient programs to transition to the outpatient setting [18]. In a systematic review of 10 high-quality RCTs, intensive multidisciplinary biopsychosocial rehabilitation (more than 100 hours of therapy) significantly reduced pain and improved function long-term (as long as 60 months after program completion) over inpatient or outpatient nonmultidisciplinary approaches or usual care [29]. Multidisciplinary pain treatment programs are an important option for chronic pain patients whose function is significantly impaired.
Interventional Pain Therapies Interventional pain therapy refers to a group of targeted treatments used for specific spine disorders,
Facet Blocks and Radiofrequency Treatment
Pain and Addiction
The Neurochemistry of Addiction Addiction 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 circuits to a much greater extent for a longer period of time than natural stimuli. By activating and dysregulating endogenous reward centers, addictive drugs hijack 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. The mesolimbic reward pathway connects the ventral tegmental area (VTA) with the nucleus accumbens, amygdala, hippocampus, hypothalamus, and prefrontal cortex. Some of these areas are part of the brain’s traditional memory system. Increasing evidence suggests that important aspects of the addictive process may involve powerful emotional memories. Dopamine is released in the VTA and nucleus accumbens in response to rewarding drugs and appears to influence the motivational state of wanting or expectation. The persistent release of dopamine as a result of chronic drug use eventually results in a reduction in dopamine release in response to drug use (tolerance), requiring higher drug doses for effect. This process progressively recruits limbic brain regions and the prefrontal cortex and “programs” drug cues via glutaminergic mechanisms [14]. Another circuit involving the amygdala, anterior cingulate, orbitofrontal cortex, and dorsolateral prefrontal cortex contributes to the obsessive craving 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 accumbens, and delta FosB, which causes prolonged sensitization of reward pathways to re-exposure to drugs. Thus, the abstinent, addicted brain can be triggered to return to compulsive drug use via a single exposure to the drug, contextual drug cues, cravings, or stress—each originating in a relatively distinct brain region or neural pathway [15]. The compulsion to use drugs is complemented by deficits in impulse control and decision making mediated by the orbitofrontal
349 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 nervous system involved in the phenomena of physical dependence and tolerance to opioids. Laboratory animals can be bred to exhibit greater and lesser sensitivity in parts of the reward pathway, with a correspondingly greater or lesser propensity to develop addictive behaviors to chemicals of abuse [17,18]. It is therefore equally likely that certain humans 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 addictive disorder. Based on results from the U.S. NHSDUH, regular heroin users make up only 0.14% of the total population. They tend to cluster in the core of larger cities or transportation hubs that serve as importation and distribution sites for illicit drugs. Some researchers believe that these predisposed individuals may be using illicit opioids to fill some type of neurochemical void in their brain chemistry. Unfortunately, the repetitive use of a rapidly absorbed, short-acting opioid, such as heroin, by intermittent intravenous bolus dosing, not only contributes to devastating secondary causes of morbidity and mortality, but also causes disruption in other central neurochemical processes, such as the hypothalamic pituitary axis. Opioid agonist therapy with methadone or buprenorphine is therefore not simply the substitution of one safer addicting drug for another. Rather, it may serve to stabilize some aspect of deficient brain chemistry in these predisposed individuals [19]. Fig. 1 illustrates a simplified model of the contributors to the addictive process. To be sure, the presence of an addicting substance or behavior is
BIOGENETIC PREDISPOSITION
PERSONAL PSYCHOLOGY
ADDICTIVE DISEASE
SOCIOCULTURAL MILIEU
REWARDING SUBSTANCE/ BEHAVIOR Fig. 1. The etiology of addiction—a biopsychosocial disease.