Look Inside Pain 2012 by IASP

The resulting book, Pain 2012, gathers the presentations that these experts gave at the refresher courses preceding the World Congress on Pain in Milan, Italy, in August 2012. IASP Press published all of these articles in one book for use at the refresher courses themselves, as well as for pain researchers and clinicians everywhere who are unable to come to the Congress. Â IASP website:Â http://www.iasp-pain.org/books

ISBN 978-0-931092-93-0

90000

Pain 2012

Refresher Courses 14th World Congress on Pain

Pain 2012 Refresher CourseS

Every two years, the International Association for the Study of Pain (IASP) creates a benchmark publication of articles summarizing the status of pain research and management throughout the world. IASP has brought together many of the foremost authorities on pain to write about the latest thinking in their specific fields.

Irene Tracey, Editor

IASP Scientific Program Committee

9 780931 092930

Irene Tracey, Editor

International Association for the Study of Pain International association for The study Of pain

Pain 2012 Refresher Courses 14th World Congress on Pain

Edited by Irene Tracey, PhD Chair, Scientiﬁc Program Committee

® • SEATTLE

IASP PRESS

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 2012: Refresher Courses, 14th World Congress on Pain 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 (2012 : Milan, Italy) Pain 2012 : refresher courses : 14th World Congress on Pain : IASP Refresher Courses held in conjunction with the 14th World Congress on Pain, August 27-31, 2012 Milan, Italy / IASP Scientiﬁc Program Committee, Irene Tracey ... [et al.]. p. ; cm. Includes bibliographical references and index. ISBN 978-0-931092-93-0 I. Tracey, Irene. II. IASP Scientiﬁc Program Committee. III. World Congress on Pain (14th : 2012 : Milan, Italy) IV. Title. [DNLM: 1. Pain Management--Congresses. WL 704.6] 616’.0472--dc23 2012026464

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 Printed in Italy

Contents Preface

vii

Part 1: An Update on the Neurobiology of Acute and Persistent Pain 1. Nociceptors, the Spinal Dorsal Horn, and Descending Modulation Frank Porreca 2. Dorsal Horn Plasticity and Neuron-Microglia Interactions Michael W. Salter Part 2: Pain Genes for Unraveling Pain: A Course for Non-Geneticists 3. What Are “Pain Genes,” and Why Are They Interesting? Marshall Devor

3 15

4. Progress and Challenges in Genome-wide Association Studies of Pain Shad B. Smith, Inna E. Tchivileva, William Maixner, and Luda Diatchenko

5. Genetic Studies in Migraine with Relevance to Other Pain Disorders Else Eising, Boukje de Vries, Arn M.J.M. van den Maagdenberg, and Michel D. Ferrari

Part 3: Pain Psychology for Non-Psychologists 6. Pain Psychology for Non-Psychologists Amanda C. de C. Williams, Lance M. McCracken, and Johan W.S. Vlaeyen

Part 4: Neuropathic Pain Update: From Basic Mechanisms to Clinical Management 7. Neuropathic Pain Update: From Basic Mechanisms to Clinical Management Nadine Attal, David Bennett, and Rolf-Detlef Treede

Part 5: Fundamentals of Neuropathic Pain Assessment and Diagnosis 8. Diagnosing Neuropathic Pain: Clinical Examination, Neurophysiology, and Neuroimaging Maija Haanpää and Michael Rowbotham 9. Neuropathic Pain Screening Tools Didier Bouhassira

111 123

Part 6: Persistent Postoperative Pain: Pathogenic Mechanisms and Preventive Strategies 10. Persistent Postoperative Pain: Pathogenic Mechanisms and Preventive Strategies Henrik Kehlet, Robert R. Edwards, and Asokumar Buvanendran

133

Part 7: Chronic Musculoskeletal Pain Update: From Basic Science to Management 11. Musculoskeletal Pain Mechanisms and Quantitative Assessment Thomas Graven-Nielsen and Lars Arendt-Nielsen

147

12. Diagnosing and Treating Chronic Pain on the Basis of the Underlying Mechanisms: Are We There Yet? Daniel J. Clauw

157

13. Nonpharmacological Treatment of Chronic Musculoskeletal Pain Kim Bennell

iii

169

Contents

Part 8: Update on the Management and Treatment of Complex Regional Pain Syndrome 14. Treatment of Complex Regional Pain Syndrome: Where Are We At, and Where To Now? 179 Frank Birklein, Frank J. Huygen, G. Lorimer Moseley, Candy McCabe, and Marlies den Hollander Part 9: Low Back Pain: Basic Mechanisms, Treatment, and Management 15. Low Back Pain: Basic Mechanisms, Treatment, and Management Steven J. Linton, Chris G. Maher, and Jan van Zundert

195

Part 10: Pathophysiology, Diagnosis, and Treatment of Persistent Abdominal/Pelvic Pain 16. Chronic Abdominopelvic Pain in Women Fred M. Howard and Karen Berkley

209

17. Gastrointestinal Tract Pain: Basic Science and Clinical Implications Emeran A. Mayer and Kirsten Tillisch Part 11: Orofacial Pain for Physicians 18. Neurovascular Craniofacial and Orofacial Pain Rafael Benoliel

225

239

19. Pain Associated with Temporomandibular Disorders Antoon De Laat

251

20. Neuropathic Orofacial Pain Eli Eliav

257

Part 12: Headache Update: Diagnosis and Therapy 21. Trigeminal Autonomic Cephalalgias Peter J. Goadsby

271

22. Tension-Type Headache Rigmor Jensen and Lars Bendtsen

279

23. Migraine: An Update Zaza Katsarava

287

Part 13: Cancer Pain Update: From Mechanisms to Treatment 24. Mechanisms of Cancer Pain Sital Patel and Anthony H. Dickenson

293

25. ClassiďŹ cation and Assessment of Cancer Pain Anne Kari Knudsen, PĂĽl Klepstad, Cinzia Brunelli, Nina Aass, Augusto Caraceni, and Stein Kaasa

297

26. Treatment of Cancer Pain Michael I. Bennett

301

Part 14: Rational Opioid Therapy for Cancer and Noncancer Pain 27. Is Chronic Opioid Therapy Comfort Care? Jane Ballantyne and Mark Sullivan

307

28. Role and Management of Opioids in Chronic Pain Seddon R. Savage

313

29. Opioid Therapy for Cancer Pain Mary Lynn McPherson

319

Contents

Part 15: Clinical Pharmacology: Evidence-Based Guidelines and Deﬁning the Proper Outcome 30. Clinical Pharmacology of Antidepressants and Anticonvulsants for the Management of Pain 327 Ian Gilron 31. Clinical Pharmacology of Opioids in the Treatment of Pain Eija Kalso

345

32. Clinical Pharmacology of Nonsteroidal Anti-Inﬂammatory Drugs Stephan A. Schug

355

Part 16: Interventional Therapies for Chronic Pain: Indications and Eﬃcacy 33. Interventional Therapies for Chronic Spinal Pain Maarten van Kleef

363

34. Interventional Pain Techniques in Cancer Patients Richard L. Rauck

369

35. Spinal Cord Stimulation and Evidence-Based Medicine Richard B. North and Jane Shipley

379

Part 17: Treating Pain in Children: An Update 36. The Biological Basis of Pain in Infants and Children Maria Fitzgerald

391

37. Treating Pain in Infants and Young Children: Current Practice, Recent Advances, and Ongoing Debates Denise M. Harrison

401

38. Psychological and Nonpsychological Interventions for Chronic Pediatric Pain Christiane Hermann

411

Part 18: The Basics of Neuroimaging and Brain Interference Techniques 39. Functional and Structural MRI Techniques for the Investigation of Pain Petra Schweinhardt

425

40. Electrocortical Responses to Nociceptive Stimulation in Humans Giandomenico D. Iannetti

431

41. Advances in the Use of Noninvasive Brain Stimulation for the Management of Pain Gabriela Bravo and Felipe Fregni

439

Part 19: Emergent Alternative Therapies for Chronic Pain 42. Emergent Integrative Therapies for Chronic Pain Vitaly Napadow, Karen Sherman, and Ted Kaptchuk

449

Index

461

Acknowledgments

472

Irene Tracey, PhD, FRCA, holds the Nuﬃeld Chair in Anaesthetic Science, is Director of the Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB), and is Head of the Nuffield Division of Anaesthetics at the University of Oxford, England. Over the past 10 years her multidisciplinary research team has contributed to a better understanding of pain perception, pain relief, and nociceptive processing within the injured and non-injured human central nervous system using neuroimaging techniques. The FMRIB Centre is recognized as one of the world’s leading neuroimaging laboratories that integrates research into key neurological and neuroscientiﬁc problems with cutting-edge developments in magnetic resonance physics and image analysis (http://www.fmrib.ox.ac.uk). The Centre has approximately 100 scientists and clinicians from a range of backgrounds, and Professor Tracey has been their Director for the past seven years. Irene Tracey was born in 1966 and performed her undergraduate and graduate studies in Biochemistry at the University of Oxford, where she graduated with First Class Honours, winning the Gibbs Prize for joint top-First. She held a postdoctoral position at Harvard Medical School before returning to the United Kingdom in 1996 to help establish the FMRIB Centre. She is an elected Councilor to the International Association for the Study of Pain (IASP). In 2008, she was awarded the triennial Patrick Wall Medal from the Royal College of Anaesthetists, and in 2009 she was made an FRCA for her contributions to the discipline. She is Deputy Chair of the UK’s Medical Research Council’s Neuroscience and Mental Health Board. She is married to Professor Myles Allen, a climate physicist, and they have three wonderful yet irrepressible children: a daughter, Colette, and two sons, John and Jim.

Preface Every two years the world’s leading pain scientists and clinicians gather for the International Association for the Study of Pain (IASP) World Congress to discuss the latest research and best clinical practice for the understanding and treatment of acute and chronic pain. Such is the pace of new discoveries in this field that we believe there is value in providing refresher courses on core topics at the congress. This enables new and seasoned pain researchers and clinician to be introduced to and updated on specific aspects of this multidisciplinary field. The course spans a wide range of topics from basic nociception through to clinical diagnosis and treatment; certain conditions are highlighted at each congress alongside the more commonly treated ones. Each authoritative speaker at the refresher course prepares a written narrative of their topic, and these documents are collected and edited into this volume. The material in each chapter is written such that a beginner can quickly get up to speed on the topic, while a more experienced pain researcher is quickly updated on the latest findings and practice, with helpful references for further reading. I wish to thank all the speakers for their professionalism and the care taken in preparing their material, and I trust that you, like me, will find the chapters both interesting and informative. I want to thank all members of the Scientific Program Committee for their tireless efforts in producing an excellent scientific program for Milan 2012. Finally, I wish to acknowledge and thank Elizabeth Endres for her excellent editorial work and Ivar Nelson for such careful general production. Irene Tracey Oxford, June 28, 2012

vii

IASP Scientific Program Committee Irene Tracey, PhD, FRCA, UK, Chair Qasim Aziz, PhD, FRCP, UK Rafael Benoliel, BDS, Israel Mary Cardosa, MBBS, Malaysia Daniel Clauw, MD, USA Roger Fillingim, PhD, USA Maria Fitzgerald, PhD, UK Michael Gold, PhD, USA Kazuhide Inoue, PhD, Japan Satu Jääskeläinen, MD, PhD, Finland Eija Kalso, MD, PhD, Finland, ex officio Kathy Kreiter, USA, ex officio Jeffrey Mogil, PhD, Canada, ex officio Lorimer Moseley, PhD, Australia Noriyuki Ozaki, MD, PhD, Japan Barbara Przewlocka, PhD, Poland Srinivasa Raja, MD, USA Andrew Rice, MBBS, MD, FRCA, FFPMRCA, UK Juergen Sandkühler, MD, PhD, Austria Claudia Sommer, MD, Germany Audun Stubhaug, MD, Norway Manoel Teixeira, MD, PhD, Brazil Jose Tesseroli de Siqueira, DDS, PhD, Brazil Johannes Vlaeyen, PhD, Belgium

viii

Nociceptors, the Spinal Dorsal Horn, and Descending Modulation Frank Porreca, PhD Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, Arizona, USA

Educational Objectives 1) Describe the normal function and pathobiology of primary aﬀerent nociceptors. 2) Discuss nociceptive processing and neuroplasticity in the spinal dorsal horn. 3) Describe current understanding and concepts in neuron-glia and neuron-immune cell interactions in acute and chronic experimental pain models. 4) List the brain neural networks involved in nociceptive processing, and describe how these networks change in chronic pain. 5) Discuss descending inhibitory and excitatory control mechanisms and their role in chronic pain

Introduction Pain is deﬁned by the International Association for the Study of Pain (IASP) as: “An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” [74]. Whereas pain is considered to be an experience with sensory, cognitive, and emotional components, nociception refers to the neural process by which stimuli that can elicit pain are detected by the nervous system. Specialized primary aﬀerent sensory neurons, termed “nociceptors,” are normally activated by high-threshold stimuli and transmit excitatory signals to the dorsal spinal cord. Sensory neurons have their cell bodies in the dorsal root ganglion (DRG) or Pain 2012: Refresher Courses, 14th World Congress on Pain Edited by Irene Tracey IASP Press, Seattle, © 2012

the trigeminal ganglion. The peripheral sensory neurons are pseudounipolar, with an axonal stalk that bifurcates and sends axonal projections to peripheral sites and a central projection to the dorsal horn of the spinal cord or to the medullary dorsal horn. Consequently, excitation of these sensory fibers can result in release of transmitters at both central and peripheral sites, the latter eliciting “neurogenic inflammation.” High-intensity heat or mechanical stimuli or chemicals that can produce damage to tissues are termed “noxious” and are selectively detected by specific transducers localized at the peripheral terminals of nociceptors. Nociceptors are capable of encoding noxious stimuli, and, critically, stimulation of nociceptors reliably elicits sensations of pain in humans. While most sensations are affectively neutral, pain is unpleasant at threshold. It is this unpleasantness that serves as the teaching signal that allows avoidance of stimuli that can damage tissues [32,33]. Thus, pain is an important physiological mechanism that increases chances of survival.

Anatomical Characterization of Nociceptors Primary afferent sensory neurons can be classified by many criteria. Generally, however, classification has been based on the anatomical and electrophysiological characteristics of these neurons. The Aβ fibers are large-diameter myelinated fibers with fast 3

Dorsal Horn Plasticity and Neuron-Microglia Interactions nerve injury (PNI) [19,34,35], with the non-receptor tyrosine kinase, Src, and the phosphatase, striatal-enriched tyrosine phosphatase (STEP), having major roles [48]. Src and STEP are themselves subject to regulation, and they provide a point of convergence through which sustained enhancement of NMDARs may facilitate excitatory synaptic transmission in nociceptive neurons (see Fig. 1). The facilitation may occur through the enhanced NMDAR currents per se (Fig. 1, middle) or by triggering enhancement of AMPA-receptor currents (Fig. 1, right). Importantly, the basal sensory thresholds and acute nociceptive behavior are not dependent upon Src phosphorylation-mediated upregulation of NMDAR function (Fig. 1, left), indicating that the kinase is not essential for acute pain but rather is important in chronic pain hypersensitivity [34]. Src-dependent phosphorylation of NMDARs is involved in both inflammatory pain and neuropathic pain, as inferred from the effects of a 10-aminoacid peptide derived from Src unique domain fused with the protein transduction domain of HIV Tat protein (Src40-49Tat), rendering the peptide membrane permeant [34]. Src40-49Tat uncouples Src from the NMDAR complex, thereby inhibiting Src-mediated upregulation of NMDARs [18]. Administering Src40-49Tat reverses inflammation- and PNI-induced

Basal

mechanical, thermal and cold pain hypersensitivity, without changing basal sensory thresholds or acute nociception. Furthermore, no confounding sedation, motor deﬁcit, or learning and memory impairment was observed at doses that suppress pain hypersensitivity. Thus, uncoupling Src from the NMDAR complex prevents phosphorylation-mediated enhancement of these receptors, and thereby inhibits pain hypersensitivity while avoiding the deleterious consequence of directly blocking NMDARs [28].

Microglia-Neuron Signaling Mediates Enhanced Transmission after Peripheral Nerve Injury The dominant theme in research on pain, as in all of neurobiology, for most of the past 100 years has been to understand the role of neurons. Until recently, glial cells were generally considered to serve primarily housekeeping roles in the nervous system. However, this view has changed radically in the last half-decade, in particular for the role of microglia in pain resulting from PNI. In the healthy CNS, microglia are not dormant [11,42], as was thought until recently, but instead are in continuous surveillance of

Sensitized

Glu

Intense Peripheral Nociceptive Stimulation

Glu

Mg2+ NMDAR

AMPAR KAIR

ND2

Csk CAKE E

PTPĮ

GPCR, EphB and other signaling

Src

Na+

STEP

ND2

Src

ND2

Src

+ CAKE

Ca2+

CAKE

AMPAR KAIR

Fig. 1. A model for the role of sensitization of nociceptive dorsal horn neurons in pain hypersensitivity. Left: Under basal conditions, NMDA-receptor (NMDAR) activity is suppressed by partial blockade of the channel by Mg2+ and by the activity of striatal-enriched protein tyrosine phosphatase (STEP) and the kinase, Csk. AMPAR, AMPA receptor; KAIR, kainate receptor. Middle: Nociceptive input increases NMDAR-mediated currents (1) by relief of Mg2+ inhibition; (2) by activation of Src (Src*) via the actions of PTPα (protein tyrosine phosphatase-α) and activated cell adhesion kinase-β (CAKβ-P), which overcomes the suppression by STEP; and (3) by sensitizing the NMDARs to raised intracellular [Na+]. GPCR, G-protein-coupled receptor. Right: Upregulation of NMDAR function allows a large boost in entry of Ca2+, which binds to calmodulin (CaM), causing activation of CaMKII, not illustrated. The enhancement of glutamatergic transmission is ultimately expressed through an increased number of AMPA/KAIRs in the postsynaptic membrane and/or enhanced AMPA/KAIR activity.

Genetic Studies in Migraine

53 - Linkage analysis - Next generation sequencing

Only few examples known

Effect size

Mendelian mutations

FHM CACNA1A ATP1A2 SCN1A

High effect common variants influencing common disease

Other SCN9A

5 3 1.5

Rare variants with small effects

Common variants

1 rare

very rare 0.1%

Migraine GWAS MTDH, TRPM8, PRDM16, LRP1 Candidate genes MTHFR, SLC6A4, TRPV1, SCN9A

common low frequency 5% 50% 0.5%

Allele frequency Very hard to detect

- Candidate gene association studies - Genome-wide association studies

Fig. 1. The frequency and effect size of genetic risk factors determine which genetic approach can be used for their identification. Mendelian mutations with low frequency and high effect size can be detected by linkage analysis, as well as by next generation sequencing (NGS). Susceptibility variants underlying common disorders, with high frequency and low effect sizes, can be detected by an association approach; either in candidate gene or genome-wide association studies. For both types of causal DNA variants, examples are given from studies on migraine and other pain disorders. DNA variants with low frequency and low effect size are hard to detect with current techniques.

function upon activation is to mediate Ca2+ entry at the nerve terminal, triggering the release of neurotransmitters [7]. CACNA1A has been associated with a wide range of clinical phenotypes, including, besides FHM, episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) [106]. To date, some 20 CACNA1A mutations—all missense mutations—have been reported in FHM1 patients exhibiting a wide clinical spectrum from pure hemiplegic migraine (i.e., in patients with the R192Q mutation) [72] to hemiplegic migraine with associated cerebellar ataxia, epilepsy, and mild head-trauma-induced edema that can lead to coma and may sometimes be fatal (i.e., in patients with the S218L mutation) [46] (for a review, see [14]). Functional studies in various cellular model systems revealed that FHM1 mutations manifest as a gain-of-function by shifting voltage-dependence toward more negative membrane potentials and by enhancing channel open probability (for a review, see [75,76,97]). This situation would lead to increased neuronal Ca2+ inﬂux and increased neurotransmission, predictions conﬁrmed by studies in transgenic knockin mice carrying either the human FHM1 R192Q or S218L mutation in the orthologous Cacna1a gene

[94,98,99]. Neuronal Ca2+ inﬂux and neurotransmission phenotypes in FHM1 mutant mice are more pronounced in those with the S218L mutation than those with the R192Q mutation, which coincides well with the more severe phenotype in FHM1 patients with the S218L mutation. Notably, the S218L mutant mice exhibited also the migraine-associated phenotypes seen in patients with this mutation. Consistent with the increased central excitability, the FHM1 mutant mice are highly susceptible to the induction of CSDs upon topical cortical application of KCl or current injection into the cortex [20,98,99]. Experimental CSD also caused a temporary hemiparesis, but only in FHM1 mutant mice [20]. Pharmacological blocking of excess cortical glutamate in slices was capable of preventing the increased susceptibility to CSD [94], indicating that it indeed was the increased neurotransmission phenotype that underlies the increased susceptibility of CSD in FHM1 mutant mice. In the same study, it was shown that inhibitory neurotransmission was not aﬀected by the FHM1 mutation, and thus an imbalance of excitatory and inhibitory neurotransmission appears to underlie FHM. Notably, in line with the female preponderance in migraine patients, CSD susceptibility was more

Exposure in Vivo with Behavioral Experiments Graded exposure to back-stressing movements has been tested as a treatment approach for back pain patients reporting substantial fear of movement/(re) injury. Such a cognitive-behavioral treatment usually consists of at least four steps: (1) defining treatment goals; (2) education about the paradoxical effects of safety-seeking behaviors; (3) establishing a fear hierarchy; and (4) exposure to activities with increasing levels of perceived harmfulness, according to the fear hierarchy. A detailed description of the treatment can be found elsewhere [125]. A series of studies using replicated single-case experimental designs revealed that decreases in pain-related fear occurred during the exposure module only. Additionally, these improvements were related to decreases in pain disability, pain vigilance, and an increase in physical activity [4]. In one study, patients with complex regional pain syndrome were able to take up desired functional activities after pain-related fear went down, but before pain levels decreased below 50%, suggesting that fear of pain is more disabling than the pain itself [29]. So far, the published RCTs on the effectiveness of exposure in chronic low back pain have found mixed results. Woods and Asmundson [136] randomly assigned 44 patients to graded exposure in vivo, graded activity, or a wait-list condition. They found that, in comparison with the graded activity condition, patients in the graded in vivo exposure condition demonstrated significantly greater improvements on measures of fear of pain/movement, fear avoidance beliefs, and pain-related anxiety, but only trend differences for pain-related disability and pain self-efficacy. When graded exposure in vivo was compared to the waiting-list control group, exposure showed significantly greater improvements on measures of fear-avoidance beliefs, fear of pain/ movement, pain-related anxiety, pain catastrophizing, pain experience, anxiety, and depression. Over a 3-month follow up, the exposure condition maintained improvements. Leeuw et al. [68] conducted a multicenter trial in which 85 participants were included in either a graded exposure or a graded activity program, and reported similar findings. Exposure resulted in a significantly decreased perceived harmfulness of activity, while the difference between both treatments in improved function almost reached statistical significance. A recent review on treatments available to address fear-avoidance beliefs in patients with chronic musculoskeletal pain suggests that

Amanda C. de C. Williams, et al. graded exposure in vivo and ACT result in the best outcomes for treating pain-related fear [4].

Challenges and Future Directions Depression and Persistent Pain The subject of depression in pain has been extensively described over several decades of pain research and treatment, and the interested reader is directed to reviews [13,115]. Rather than being characterized as a comorbidity, depressed mood is closely linked to pain on many levels [91], from experience and symptoms to common neurotransmitters [13]. It is more helpfully understood within a broader context that includes fears and restricted activity; persistent pain implies losses of role, of pleasant activities, and often of an anticipated active future, to the extent that the patient describes a changed identity [85]. Rehabilitation usually brings an improvement in mood, with recovery of activities and of hopes [86], emotional disengagement and acceptance, and less rumination and “stuckness” [128].

An Affective-Motivational Approach A number of authors have recently called for an expanded affective-motivational approach with a prominent focus on behavior in the context of multiple goals [23,117,124]. In their attempt to resume daily life activities, pain patients engage in various goals, some of which are directly related to dealing with pain, whereas others are not pain-related. These multiple goals may facilitate each other, or they can be conflicting. For example, the goal to satisfy others by resuming workrelated activities may conflict with the goal to protect bodily integrity by staying safely at home. Unfortunately, unresolved pain-related goal conflicts may fuel fear [63]. An emerging and intriguing question is whether cognitive-behavioral therapies aimed at the re-evaluation of major life goals and at the resolution of enduring goal conflicts help to counter fear-driven and disabling avoidance behavior [117,124]. When patients are pursuing a goal that competes with the goal to reduce pain, both attentional bias toward pain cues and pain behavior are inhibited [97,118]. It would be worthwhile to examine whether the effects of fear-reduction treatments can be enhanced by adding a motivational component focused at the resolution of goal conflicts [98].

Persistence Versus Avoidance Finally, it is diﬃcult to apply fear-avoidance principles to musculoskeletal pain syndromes associated with

116

Maija Haanpää and Michael Rowbotham Identification of Pain and Allodynia Area Situate patient Ensure patient is comfortable, willing to move clothes away from the PHN area, or change into a gown. Photograph With a digital camera, photograph PHN area the PHN areas from as many angles as required to obtain clear views of the entire painful area. Ask patient to Print photographs on a color printer draw on and ask the patient to outline the photograph maximal area of spontaneous pain on the photograph using a BLACK marker. Ask the patient to outline on the photographs the area of the skin that feels unpleasant to the touch (allodynic skin) using a RED marker. Locating PHN Using the photographs as a guide and pain on the skin with the patient’s help, outline the most painful area using the following techniques: Use the foam The foam brush should be positioned brush so that the long axis of the brush is parallel to the direction of stroking. Apply enough pressure on the brush The right to where the brush is slightly bent amount of upon contact with the skin. pressure Start brushing outside the area of pain as indicated on the patient’s photograph. If the brush stroke does not feel normal for the patient, move further away from the pain area until an area of the skin without pain is found. Gentle strokes Using approximately 10 cm long strokes, start brushing parallel to the perimeter of the area of pain, and perpendicular to the vector until the patient indicates pain. Move along the vector 1 cm at a time towards the area of pain at a rate of 1 stroke per second. Marking areas Mark the skin at the point where the Be as accurate as you can. patient indicates that the brushing of pain onto feels painful. skin Fig. 3. Pain-mapping procedure.

NCV and SEPs remains of considerable importance in the evaluation of pain patients, for several reasons. First, large and small peripheral fibers are anatomically mixed in nerves, plexuses, and spinal roots, without spatial segregation up to the dorsal root entry zone, and therefore peripheral lesions, in particular traumatic or metabolic, tend to affect large and small fibers indiscriminately. NCV studies are readily available and can be easily obtained, and their abnormality on stimulation of a painful territory provides objective evidence of somatosensory involvement, thus giving strong support to the diagnosis of neuropathic pain.

A standard neurophysiological assessment including NCV and SEPs should remain the ﬁrst-line approach in cases of suspected neuropathic pain, before or in parallel to more selective examinations of the pain and temperature pathways [16]. Clinical examination alone is less sensitive than several complementary tests to document the presence of a somatosensory lesion [11,13,14]. For example, electroneuromyography (ENMG) has been shown to be superior to clinical examination alone for the diagnosis of peripheral neuropathy [14]. This widely available method is the best way to verify a

160

Daniel J. Clauw

As with most illnesses that may have a familial or genetic underpinning, environmental factors may play a prominent role in triggering the development of FMS and other central pain states. Environmental “stressors” temporally associated with the development of either FMS or CFS include early life trauma; physical trauma (especially involving the trunk); certain infections such as hepatitis C, Epstein Barr virus, parvovirus, or Lyme disease; and emotional stress. The disorder is also associated with other regional pain conditions or autoimmune disorders [1,11,13]. Of note, each of these “stressors” only triggers the development of fibromyalgia and/or chronic fatigue syndrome in approximately 5–10% of individuals who are exposed; the overwhelming majority of individuals who experience these same infections or other stressful events regain their baseline state of health. In fact, emerging evidence from a number of different areas in the pain field suggests that the same characteristics that are often attributable to FMS patients, in fact more broadly represents a “pain-prone phenotype.” Fig. 2 portrays the fact that factors including female sex, early life trauma, a personal or family history of chronic pain, a personal history of other centrally mediated symptoms (insomnia, fatigue, memory problems, and mood disturbances), and cognitions such as catastrophizing, are present in subsets of individuals with any chronic pain state and predict which individuals are more likely to transition from acute to chronic pain.

In addition to the study of central pain states, we have made significant advances in our broader understanding of chronic pain pathogenesis. Data from experimental sensory testing and functional neuroimaging studies suggest wide individual variation in sensory sensitivity that adheres to a bell-shape distribution across a wide variety of chronic pain states, with a subset of individuals displaying hyperalgesia or augmented CNS activity across pain states [1,69,78]. The centralized pain states originally identified as having diffuse hyperalgesia/allodynia include FMS, IBS, TMJD, idiopathic low back pain, tension headache, IC, and vulvodynia [28–30,33,43,45,51,52,55,67,72,74]. Functional neuroimaging studies, especially those using functional MRI (fMRI), corroborate these experimental pain testing findings, showing that individuals with central pain states have increased neuronal activity in pain-processing regions of the brain when they are exposed to stimuli that healthy individuals find innocuous [15,30,32,56]. Several meta-analyses of fMRI studies have summarized the brain regions that show activation when experimental pain is applied to human subjects, and these findings generally agree with those of single photon emission computed tomography (SPECT) and PET studies. Activation sites across studies vary to some degree, depending on experimental paradigm and pain stimulus (e.g., heat, cold pressure, electric shock, or ischemia). However, the main components of this “pain matrix” are the primary (S1) and secondary

“Central” Pain-Prone Phenotype Female Genetics Early life trauma Family history of chronic pain and mood disturbances Personal history of chronic centrally mediated symptoms (multifocal pain with neuropathic descriptors, fatigue, sleep disturbances, psychological distress, memory difficulties) Cognitions such as catastrophizing Lower mechanical pain threshold and descending analgesic activity

Exposure to “stressors” or acute, peripheral nociceptive input Psychological and behavioral response to pain or stressor

New or different region of chronic pain

Fig. 2. Female sex, early life trauma, a personal or family history of chronic pain, a personal history of other centrally mediated symptoms (insomnia, fatigue, memory problems, mood disturbances), and cognitions such as catastrophizing can occur in subsets of individuals with any chronic pain state and predict which individuals are more likely to transition from acute to chronic pain.

Low Back Pain activity that provoke pain and more rest (overactivity/underactivity cycle). Pacing involves breaking down an activity into smaller parts and alternating the activity with short breaks. The idea is to learn to take the natural small pauses in an activity that might otherwise normally occur to provide for a stable rate of participation.

Cognitive-Behavioral Therapy Emotional distress is one of the most prevalent psychological components in the development of chronic pain, and cognitive-behavioral therapy offers various forms of emotional support. It also offers specific treatments for a variety of problems including fear of movement. An important aspect is that while psychological factors such as fear, distress, or depression might be thought to dissipate when the pain is treated properly, this is seldom the case [39]. Therefore, it is important to include a cognitive-behavioral program for emotional problems such as distress, depression, and anxiety problems [53].

Routines for Assessment and Treatment of Low Back Pain in Primary Care All guidelines recommend a diagnostic triage when assessing a patient with low back pain. Having first excluded back pain that arises from a structure beyond the back (for example, retroperitoneal structures or the hips), the clinician needs to consider the possibility of serious pathology (such as cancer, infection, or fracture) as the cause of the patient’s back pain. Serious disease is uncommon in patients with acute back pain presenting to primary care, accounting for approximately 1% of cases [25]. Suspicion is raised by the presence of red flags [9] such as unexplained weight loss, fever, or recent infection. Recent evidence suggests that the presence of a single red flag is common in people without serious disease [25]. A cluster of red flags may be a better indicator of serious pathology. Patients with suspected serious pathology should be sent for imaging and/or blood tests relevant for the possible cause [2]. They may need specialist referral to establish a definitive diagnosis. Radiculopathy accounts for approximately 5% of cases seen in primary care. It is diagnosed by the presence of reduced power, reflexes, and sensation in the distribution of the involved spinal nerve. The remaining 94% of patients presenting in primary care are classed as having nonspecific low

199 back pain (NSLBP). This term simply means that the pathoanatomical source of the pain has not been speciﬁed. A pathoanatomical diagnosis is not pursued because there are no tests available to the general practitioner that could establish a diagnosis, and in any case a pathoanatomical diagnosis would not change management. Patients with NSLBP should not routinely be sent for imaging or pathology tests. International clinical practice guidelines [30] uniformly recommend that investigations should be reserved for patients with suspected serious pathology or for those with radiculopathy who are being considered for surgery. A systematic review of trials revealed that routine imaging does not improve clinical outcomes, compared to imaging only when indicated,[12] and therefore it is not recommended.

Primary Care Management of Acute Nonspecific Low Back Pain First-Line Care When managing acute NSLBP it is best to start simple, reserving more complex treatments for those who do not respond. Patients should be given advice [61] and education about self-care and should take a full dose of paracetamol (acetaminophen) regularly (1 g four times a day for adults). While nonsteroidal anti-inflammatory drugs (NSAIDs) also have a role in this setting, they are not preferred as first-line drugs due to the risk of adverse effects. Patients should remain active and be scheduled for review within 1 week. If this simple approach is delivered well, patients can recover remarkably quickly. An Australian study conducted in primary care showed that 50% of patients who received this approach were pain-free within 2 weeks [22]. Unfortunately, most people with acute back pain do not get this care. A survey of Australians selfmanaging their low back pain revealed that the majority were not taking adequate doses of the over-thecounter medicines they were using. For example, 82% of those taking paracetamol were underdosing [69]. Another Australian survey of patients managed in primary care revealed that only 21% received advice and only 18% received paracetamol. Instead, the analgesics provided were typically NSAIDs (37%) and opioids (20%) [70]. A key aspect of first-line care is an early review of progress. If patients have followed the simple management approach, there should be a marked improvement in their back pain when they are reviewed

Role and Management of Opioids in Chronic Pain implemented in the absence of an optimum trial of more resolution-oriented care and without a supportive context that might improve their efficacy. There are probably subpopulations of patients who will benefit from the long-term use of opioids and others who will not. In addition, there are subpopulations of patients with substance abuse or addiction problems who are at increased risk for harm as a result of using opioids. In the absence of clear prospective criteria to identify positive responders, however, clinicians must rely on judgment informed by available evidence and clinical experience—the art of medicine—in considering the unique risks and potential benefits for each individual patient.

Strategies for Safe and Effective Opioid Therapy A number of clinical strategies are emerging that may support safe and effective use of opioids when they are indicated, while discouraging misuse and unfavorable outcomes. Further research is needed to determine the ultimate efficacy of such approaches. Current piloted strategies include providing opioids as one component of multidimensional care (as described above); comprehensive assessment that includes screening for risk of opioid misuse; informed consent for treatment and documentation of a written plan of care, including a clear statement of goals (usually integrated into an Opioid Treatment Agreement); careful monitoring, including use of urine toxicology screens; limiting doses to low or moderate doses of opioids; adjustment of structure of care to match risk; and a plan for continuation or discontinuation of treatment depending on progress toward goals.

Risk Screening Research has begun to deﬁne risk factors associated with a greater likelihood of misuse of opioids prescribed for pain treatment [8,12,28]. Among these factors are a history of substance use disorder or unhealthy substance use, a history of mental health conditions, current smoking, an unstable social situation, a history of incarceration, younger age, and male gender. A family history of substance use disorder probably also infers higher risk because some of these disorders are in part genetically mediated, although this risk has not been documented in a pain context. A number of approaches to risk screening may be helpful, including an interview of the patient and signiﬁcant others, a review of medical records, consultation

315 with the Prescription Drug Monitoring Program if available, and the use of a risk-screening tool speciﬁcally developed to detect risk of opioid misuse. A number of risk screening tools are in evolution. Most widely used are the Screener and Opioid Assessment for Patients with Pain (SOAPP) [4], the Opioid Risk Tool (ORT) [31], and Pain Medication Questionnaire (PMQ) [16]. The SOAPP is available in 5-, 14-, and 21-question versions. The ORT is a simple 5-question tool, and the PMQ contains 26 questions, all related to the patient’s experience and use of medication. Each tool has a scoring system that indicates a level of risk with a reasonable level of sensitivity and speciﬁcity; however, as evidence related to the clinical utility of these screening tools is evolving, some experts prefer a comprehensive clinical review to assess risk.

Opioid Treatment Agreement Opioid treatment agreements usually include a process of informed consent for opioid therapy and documentation of a mutually shared agreement on the plan of care. Common items in informed consent include the anticipated benefits or goals of treatment, as well as the potential risks associated with the treatment. Commonly cited goals or intended benefits of chronic opioid therapy include reduced pain, improved function, and enhanced quality of life. It may be helpful to elicit more specific goals, for example engagement in activities valued by the patient such as ability to concentrate while reading, walk for a specified period of time, or sit through a church service or movie. These goals provide an important basis on which to continue or discontinue care. Commonly cited risks of opioid therapy include physical side effects (such as constipation, nausea, or itching), tolerance, physical dependence, addiction, hyperalgesia, sedation and cognitive blurring, victimization by others seeking opioids, potential overdose with misuse, and endocrine changes that may result in osteopenia or hypogonadism. The plan of care commonly documents the indication of a single prescriber and pharmacy; intervals for renewal of the prescription and clinic visits; medication dosing and interval; and an agreement by the patient to undergo periodic urine drug screens, to avoid illicit substances, to use the medication as prescribed, to store safely and not to share or sell the medication, and to permit communication with other care providers and significant others. Some evidence suggests that opioid treatment agreements may help improve care of persons receiving longer-term opioid therapy [25].

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Ian Gilron Table I Pharmacological classification of antidepressant drugs Tricyclic Antidepressants Tertiary Amine Amitriptyline Clomipramine Doxepin Imipramine Trimipramine Secondary Amine Nortriptyline Desipramine Maprotiline Protriptyline Amoxapine Serotonin-Norepinephrine Reuptake Inhibitors Venlafaxine Duloxetine Milnacipran Desvenlafaxine Reboxetine Sibutramine Viloxazine Bicifadine Serotonin Selective Reuptake Inhibitors Fluoxetine Paroxetine Fluvoxamine Citalopram Escitalopram Sertraline Lofepramine Dapoxetine Zimeldine Monoamine Oxidase Inhibitors Phenelzine Tranylcypromine Iproniazid Isocarboxazid Nialamide Moclobemide Selegiline Pirlindole Other Antidepressants Trazodone Nefazodone Mirtazapine Bupropion Atomoxetine Mianserin Note: This list is not exhaustive. The above pharmacological classifications are not clearly delineated, and some compounds may also be considered members of another drug subclass.

sodium channel blockade, and N-methyl-D-aspartate receptor inhibition, among others [82].

Anticonvulsants Drugs which suppress experimental and clinical seizures, defined as anticonvulsant or antiepileptic drugs, are classified as “first-generation” anticonvulsants (e.g., benzodiazepines, carbamazepine, ethosuximide, phenobarbital, phenytoin, primidone, and valproic acid), which were introduced between 1910 and 1970, and “second-generation” anticonvulsants (e.g., felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, and zonisamide), which were introduced more recently [69]. In addition to reduction in pain intensity, some anticonvulsants have also been shown to improve sleep [93] and reduce anxiety [90], effects that are of clinical relevance to the management of chronic pain. Multiple pharmacological mechanisms (see Table III and Fig. 1) have been elucidated for most anticonvulsant drugs including sodium channel blockade, calcium channel blockade, suppression of glutamatergic transmission, and γ-aminobutyric acid (GABA)ergic modulation [21].

Trial-Based Evidence of Analgesic Efficacy Attempts to describe efficacy of a given treatment often involve systematic review of published high-quality clinical trials (randomized controlled trials; RCTs) and meta-analysis in order to estimate the number-needed-to-treat (NNT) to obtain at least 50% pain relief in one patient (such that a lower NNT suggests better efficacy), or a mean difference between treatment and placebo across multiple trials using a common continuous outcome measure [79]. Several obstacles

Ca++ channel blockade carbamazepine, ethosuximide, valproic acid, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, topiramate, zonisamide

Ca++

GLU NMDA-R

valproic acid, gabapentin, lamotrigine, pregabalin, phenytoin, carbamazepine, oxcarbazepine, felbamate

Na+

as well as reduction of pain intensity [112]. A large body of preclinical research has pointed to several putative analgesic mechanisms of antidepressant drugs (see Table II). These include increased supraspinal availability of norepinephrine (thought to enhance descending inhibitory bulbospinal control), activation of endogenous mu- and delta-opioid receptors,

Decreased glutamate transmission

GABA

Na+ channel blockade carbamazepine, felbamate, lamotrigine, oxcarbazepine, phenytoin, topiramate, zonisamide

GABA potentiation barbiturates, benzodiazepines,felbamate, levetiracetam, topiramate

Fig. 1. Pharmacological mechanisms of anticonvulsants relevant to pain treatment. GABA, gamma-amino butyric acid; GLU, glutamate; NMDA-R: N-methyl-D-aspartate receptor. Modiﬁed from Gilron [32].

442

Fig. 3. In transcranial direct current stimulation (tDCS), a rubber band is placed around the patient’s head. Electrode pads soaked in saline solution are placed over the scalp. A battery-powered device delivers electrical current via two electrodes with opposite electrical charges. Anodal stimulation increases cortical excitability, while cathodal stimulation decreases cortical excitability.

Long-Lasting Effects of Noninvasive Brain Stimulation Associated with Changes in Cortical Excitability A recent study investigated the long-lasting effects of rTMS in patients with fibromyalgia, using neurophysiological outcomes to measure these effects. Fibromyalgia syndrome is characterized by chronic widespread pain on digital palpation in at least 11 of 18 tender point sites; the pain can be accompanied by cognitive problems, unrefreshing sleep, fatigue, and somatic symptoms [53,54]. Although the underlying pathophysiology remains unclear, disturbances in central pain-modulating systems [36], abnormal cortical excitability [37], and dysfunctional pain inhibition may be implicated [25]. Patients with fibromyalgia show a deficit in intracortical modulation [37], and daily unilateral rTMS of the motor cortex (M1) can transiently reduce pain and improve quality of life for up to 2 weeks after treatment. However, no studies have been able to

Gabriela Bravo and Felipe Fregni show a sustained effect on analgesia. Mhalla et al. [37] conducted the first randomized controlled study to assess the long-term maintenance of analgesia with multiple series of daily rTMS in patients with chronic pain. The 14 stimulation sessions were conducted over a 21-week period in two phases: daily stimulations for 5 consecutive days for the induction phase and daily stimulations in three series that took place weekly, fortnightly, and monthly for the maintenance phase. Their results showed a significant decrease in pain intensity with active rTMS vs. sham. Although this effect was sustained for 6 months, the magnitude decreased after the monthly sessions. Quality of life also improved in these patients as they reported decreased interference in daily activities such as walking, relations with other people, enjoyment of life, and sleep. Interestingly, long-lasting pain improvement was directly related to changes in cortical excitability, as indexed by changes in intracortical inhibition. The recent findings by Mhalla et al. [37] confirm the notion that maintenance treatment of TMS may lead to long-lasting effects, as shown by several trials in depression [13] and a case report from Zaghi et al. [55]. Further trials need to establish optimal maintenance regimens and should have longer followup periods to determine maximal duration of effects.

Combination of Noninvasive Brain Stimulation with Pharmacological Treatment An important question not fully addressed in the pain field is whether combination of NIBS with pharmacological treatment may enhance its effects. This question was initially addressed by a case report from Antal et al. [1]. The idea behind this case report is based on previous findings showing that tDCS can effectively modulate cortical excitability and transiently decrease pain perception in patients with various chronic pain conditions. These effects can last from several days to weeks depending on different stimulation parameters [2,16,19,38]. They may involve NMDA-receptor modulation in a similar mechanism to enhancement of synaptic transmission in learning and memory via long-term potentiation [42]. Therefore, Nitsche et al. hypothesized that the combination of presynaptic enhancement via pharmacological stimulation of the NMDA receptor with postsynaptic membrane depolarization by anodal tDCS might potentiate the duration of cortical excitability and increase the

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