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Mission Statement of IASP Press速 The International Association for the Study of Pain (IASP) is a nonprofit, interdisciplinary organization devoted to understanding the mechanisms of pain and improving the care of patients with pain through research, education, and communication. The organization includes scientists and health care professionals dedicated to these goals. The IASP sponsors scientific meetings and publishes newsletters, technical bulletins, the journal Pain, and books. The goal of IASP Press is to provide the IASP membership with timely, high-quality, attractive, low-cost publications relevant to the problem of pain. These publications are also intended to appeal to a wider audience of scientists and clinicians interested in the problem of pain.

Sleep and Pain


Gilles Lavigne, DMD, PhD, FRCD(c)

Trauma Research Unit and Center for Sleep Studies, Sacré-Coeur Hospital, and Department of Oral Health, Faculties of Dentistry and Medicine, University of Montreal, Montreal, Quebec, Canada

Barry J. Sessle, MDS, PhD, DSc(hc), FRSC, CAHS Faculty of Dentistry, Faculty of Medicine, and Centre for the Study of Pain, University of Toronto, Toronto, Ontario, Canada

Manon Choinière, PhD

Department of Anesthesiology, Faculty of Medicine, University of Montreal; Research Center, Montreal Heart Institute, Montreal, Quebec, Canada

Peter J. Soja, PhD

Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada


© 2007 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 Sleep and 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 Sleep and pain / Gilles Lavigne, Barry J. Sessle, Manon Choinière, Peter J. Soja, editors. Includes bibliographical references and index. ISBN 978-0-931092-80-0 (alk. paper) 1. Sleep--Physiological aspects. 2. Sleep disorders. 3. Pain--Treatment. I. Lavigne, Gilles. RC547.S5185 2007 616.2'09--dc22 2007061300

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

Printed in the United States of America

This volume is dedicated to the memory of Professor Mircea Steriade (1924–2006), late of the Department of Physiology, Faculty of Medicine, Université Laval, Quebec, Canada

The editors would like to dedicate this book to the memory of Mircea Steriade, who died on April 14, 2006. Mircea had an exceptional career, first in his native Romania, and since 1968, at Université Laval. At the time of his death, he was recognized as one of the world’s leading neuroscientists. Mircea was widely acknowledged as a pioneer in, among other fields, the neuroscience of sleep and sensory integration, devoting his life to understanding issues such as brain activity and sensory processing during awake and sleep states, an issue critical to the theme of this volume. If, in this volume, we have seen further, it is only by standing on the shoulders of giants such as Mircea. Mircea was an energetic individual with a passion for research, continuing to hold operating grants into the eighth decade of his life. His high standards of excellence in research and his passion for new discoveries are among the legacies he leaves to the next generation of neuroscientists, and the many ways in which he advanced our understanding of the brain have already been engraved in the history of science. Au revoir, Mircea, et merci pour le chemin tracé!

Contents List of Contributing Authors Foreword Preface

ix xiii xv

Part I The Science of Sleep and Pain 1. What Is Sleep, and Why Do We Sleep? John Peever and Dennis McGinty


2. What Is Pain, and Why and How Do We Experience Pain? Barry J. Sessle


3. Modulation of Prethalamic Sensory Inflow during Sleep versus Wakefulness Peter J. Soja


4. Pain and Its Interaction with Thalamocortical Excitability States David B. Rye and Amanda A.H. Freeman


5. Neurochemical Mechanisms Mediating Opioid-Induced REM Sleep Disruption Ralph Lydic and Helen A. Baghdoyan


6. Pain Perception during Sleep and Circadian Influences: The Experimental Evidence Alison J. Bentley


7. Effects of Impaired Sleep Quality and Sleep Deprivation on Diurnal Pain Perception Bernd Kundermann and Stefan Lautenbacher


8. Pain Imaging in Relation to Sleep Eric A. Nofzinger and Stuart W.G. Derbyshire


9. Modulation of Pain-Related Cortical Activity by Sleep and Attention Ryusuke Kakigi, Xiaohong Wang, Koji Inui, and Yunhai Qiu


10. Electroencephalographic Correlates of Pain and Sleep Interactions in Humans Michael T. Smith and Luis F. Buenaver


11. Sleep Fragmentation and Arousal in the Pain Patient Liborio Parrino, Marco Zucconi, and Mario Giovanni Terzano





Part II Clinical Aspects of Sleep Disorders and Pain 12.

Tools and Methodological Issues in the Investigation of Sleep and Pain Interactions Gilles Lavigne, Samar Khoury, Danielle Laverdure-Dupont, Ronald Denis, and Guy Rouleau


13. Epidemiology of Pain and Sleep Disturbances and Their Reciprocal Interrelationships Manon Choinière, Mélanie Racine, and Isabelle Raymond-Shaw


14. Sleep and Pain Interactions in Medical Disorders: The Examples of Fibromyalgia and Headache Yves Dauvilliers and Bertrand Carlander


15. Sleep Disorders that Can Exacerbate Pain Gina Chen and Christian Guilleminault


16. Pediatric and Geriatric Pain in Relation to Sleep Disturbances Lucia Gagliese and Christine T. Chambers


17. Pain in Dreams and Nightmares Antonio Zadra and Christane Manzini


18. Alteration of Sleep Quality by Pain Medication: An Overview Brian E. Cairns


19. Pharmacological Management of Sleep and Pain Interactions Pierre Beaulieu and Jean-Sébastien Walczak


20. Pain and Sleep Disorders: Clinical Consequences and Maintaining Factors Steven J. Linton and Shane MacDonald


21. Cognitive-Behavioral Treatment for Insomnia and Pain Michael T. Smith and Jennifer A. Haythornthwaite




Contributing Authors Helen A. Baghdoyan, PhD Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan, USA Pierre Beaulieu, MD, PhD, FRCA Departments of Anesthesiology and Pharmacology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada Alison J. Bentley, MB BCh School of Physiology, University of Witwatersrand, Parktown, South Africa Luis Buenaver, PhD Behavioral Medicine Research Laboratory and Clinic, Johns Hopkins School of Medicine, Baltimore, Maryland, USA Brian E. Cairns, PhD, RPh Department of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada; Surrey Memorial Hospital, Surrey, British Columbia, Canada Bertrand Carlander, MD Neurology Service, Gui-de-Chauliac Hospital, Montpellier, France Christine T. Chambers, PhD Departments of Pediatrics and Psychology, Dalhousie University and IWK Health Centre, Halifax, Nova Scotia, Canada Gina Chen, MD Stanford University Sleep Medicine Program, Stanford, California, USA Manon Choinière, PhD Department of Anesthesiology, Faculty of Medicine, University of Montreal; Research Center, Montreal Institute of Cardiology, Montreal, Quebec, Canada Yves Dauvilliers MD, PhD Neurology Service, Gui-de-Chauliac Hospital, Montpellier, France; INSERM, Montpellier, France Ronald Denis, MD Trauma Research Center and Center for Sleep Studies, SacrÊCoeur Hospital, Montreal, Quebec, Canada Stuart W.G. Derbyshire, PhD School of Psychology, University of Birmingham, Edgbaston, Birmingham, United Kingdom Amanda A.H. Freeman, PhD Department of Neurology and Program in Sleep, Emory University School of Medicine, Atlanta, Georgia, USA Lucia Gagliese, PhD School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada; Department of Anaesthesia and Behavioural Sciences and Health Research Division, University Health Network, and Departments of Anaesthesia and Psychiatry, University of Toronto, Toronto, Ontario, Canada Christian Guilleminault, MD, BiolD Stanford University Sleep Medicine Program, Stanford, California, USA




Jennifer A. Haythornthwaite, PhD Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Koji Inui, MD, PhD Department of Integrative Physiology, National Institute for Physiological Sciences, Myodaiji, Okazaki, Japan; Department of Physiological Sciences, School of Life Sciences, The Graduate University for Advanced Studies, Hayama, Kanagawa, Japan Ryusuke Kakigi, MD, PhD Department of Integrative Physiology, National Institute for Physiological Sciences, Myodaiji, Okazaki, Japan; Department of Physiological Sciences, School of Life Sciences, The Graduate University for Advanced Studies, Hayama, Kanagawa, Japan; Research Institute of Science and Technology for Society, Japan Samar Khoury, BSc Trauma Research Center and Center for Sleep Studies, SacréCoeur Hospital, Montreal, Quebec, Canada Bernd Kundermann, PhD Department of Psychiatry and Psychotherapy, PhilippsUniversity Marburg, Marburg, Germany Stefan Lautenbacher, PhD Department of Physiological Psychology, University of Bamberg, Bamberg, Germany Daniele Laverdure-Dupont, BSc, MSc Trauma Research Center and Center for Sleep Studies, Sacré-Coeur Hospital, Montreal, Quebec, Canada Gilles Lavigne, DMD, PhD, FRCD(C) Trauma Research Unit and Center for Sleep Studies, Sacré-Coeur Hospital, Montreal; Neurosciences Research Center, Faculties of Medicine and Dentistry, University of Montreal; Brain Study Center, Centre Hospitalier de l’Université de Montréal (CHUM), Montreal, Quebec, Canada Steven J. Linton, PhD Department of Behavioral, Social, and Legal Sciences—Psychology, Örebro University, and Department of Occupational and Environmental Medicine, Örebro University Hospital, Örebro, Sweden Ralph Lydic, PhD Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan, USA Shane MacDonald, BSc Department of Behavioral, Social, and Legal Sciences—Psychology, Örebro University, and Department of Occupational and Environmental Medicine, Örebro University Hospital, Örebro, Sweden Christane Manzini, Research Assistant, Department of Oral Health, Faculty of Dental Medicine, University of Montreal, and Center for the Study of Sleep and Biorhythms, Sacré-Coeur Hospital, Montreal, Quebec, Canada Dennis McGinty Neurobiology Research, Department of Psychology, University of California, Los Angeles, and VA Medical Center, Greater Los Angeles Healthcare System, Sepulveda, North Hills, California, USA Eric A. Nofzinger, MD Sleep Neuroimaging Research Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA



Liborio Parrino, MD, PhD Sleep Disorders Center, Department of Neurology, University of Parma, Italy John H. Peever, PhD Systems Neurobiology Laboratory, Departments of Physiology and Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada Yunhai Qiu, MD, PhD Department of Integrative Physiology, National Institute for Physiological Sciences, Myodaiji, Okazaki, Japan Isabelle Raymond-Shaw, PhD Daiichi Sankyo, Inc. Guy Rouleau, MD, PhD Brain Study Center, Centre Hospitalier de l’Université de Montréal (CHUM); Montreal, Quebec, Canada David Rye, MD, PhD Department of Neurology and Program in Sleep, Emory University School of Medicine, Atlanta, Georgia, USA Barry J. Sessle, MDS, PhD, DSc(hc), FRSC, CAHS Faculty of Dentistry, Faculty of Medicine, and Centre for the Study of Pain, University of Toronto, Toronto, Ontario, Canada Michael T. Smith, PhD, CBSM Behavioral Medicine Research Laboratory and Clinic, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Peter J. Soja, PhD Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada Mario Giovanni Terzano, MD, PhD Sleep Disorders Center, Department of Neurology, University of Parma, Italy Jean-Sébastien Walczak, PhD Department of Anesthesiology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada Xiaohong Wang, MD, PhD Department of Integrative Physiology, National Institute for Physiological Sciences, Myodaiji, Okazaki, Japan Antonio Zadra, PhD Department of Psychology, Faculty of Dental Medicine, University of Montreal, and Center for the Study of Sleep and Biorhythms, SacréCoeur Hospital, Montreal, Quebec, Canada Marco Zucconi, MD Sleep Disorders Center, Department of Neurology, H San Raffaele Institute, Milan, Italy

Foreword Nearly everyone has first-hand experience of the effects of pain on sleep, and perhaps without realizing it, of the effects of sleep loss on pain. I had such an experience recently, which brought home to me how critical it is that we achieve a greater understanding—from the mechanistic to clinical level—of the relationship between sleep and pain. Recently, I attended an international scientific meeting in Beijing, China. After sleeping the first night following 24 hours of travel from Philadelphia to Beijing, I discovered that a combination of the hard sleeping surface in the hotel and my jet lag resulted in my experiencing considerable muscle pain during sleep, which seemed to worsen across consecutive nights. The pain disrupted my sleep, and the sleep loss made it more difficult to cope with the 12-hour circadian phase shift. Fortunately, the pain decreased after a few days, and I began sleeping more soundly. The experience made me wonder how often pain disturbs sleep among the more than 5 billion humans on Earth. Surely, this is a common occurrence, yet why, I wondered, has it taken so long for a book like this to appear that sheds scientific light on the relationship of sleep and pain? Although it is obvious that a pain-free night of restorative sleep is among the best of life’s natural panaceas, clinical research on and concern for effective pain management, and on understanding and treatment of sleep disorders, have only occurred relatively recently. Fortunately, in the past 25 years both fields have been transformed from areas of medical neglect to areas of medical importance, and both areas are increasingly evolving scientific knowledge and evidence-based clinical practice. However, a telling illustration of how far both fields have come, but yet how little has been done on their relationship to each other, comes from a tally of publications in peer-reviewed journals. As of this writing, there are more than 100,000 citable references to publications on pain and more than 69,000 citable references on sleep. Remarkably, there are fewer than 2,700 citable references that involve both sleep and pain. This is less than 0.04% of citable references in the sleep and pain literatures. Given the many ways in which sleep-wake biology and pain biology may interact—as evident in the chapters of this book—there is no question that much more attention needs to be paid to basic and clinical research on the sleep-pain nexus. When one considers the high prevalence of sleep disorders and the high incidence of pain reactions, it is imperative that research on the relationship of the two domains be carried out to identify how each can affect the other.




As evident from the diversity of experts contributing to this seminal text, scientific work on the biological relationships of sleep and pain will require many kinds of expertise—from neurobiologists and physiologists to pharmacologists, neurologists, psychiatrists, psychologists, epidemiologists, and others. A thorough understanding of the manner in which pain affects sleep and sleep affects pain has the potential to shed light on fundamental scientific questions about these two homeostatic processes and to relieve a great deal of suffering in a great many people. David F. Dinges, PhD Division of Sleep and Chronobiology Unit for Experimental Psychiatry Department of Psychiatry University of Pennsylvania School of Medicine Philadelphia, Pennsylvania, USA

Preface Advances in knowledge regarding the interaction of sleep and pain disorders have made the time ripe for a multi-authored book designed to foster a rapid translation of information to clinicians and their patients. This book addresses both basic scientists and clinicians involved in pain or sleep disorders; its prime function is to serve as a bridge to help span the gulf between pain and sleep specialists. We hope that it inspires more collaborative research that will clarify the interactions between sleep and pain, and that it encourages the emergence of more interdisciplinary management approaches for the treatment of disorders involving both pain and sleep problems. The relevance of sleep and pain interactions is made clear by findings that chronic pain affects approximately one-fifth of the adult population and that approximately two-thirds of chronic pain patients report poor sleep and fatigue as secondary complaints. These interactions are described as a night of poor sleep followed by a day with more intense and variable pain, or as a day with intense pain followed by a night of poor sleep. This type of cyclic relationship is found in patients with recent severe burns and in a high percentage of chronic pain patients. Pain is defined by the International Association for the Study of Pain as an unpleasant and emotional experience that is associated with and described in terms of actual or potential tissue damage. Although often thought of as a sensation, pain reflects a complex, multidimensional experience, of which the sensory component is just one element. Chronic pain may be associated with prolonged neuroplastic changes in the central nervous system and with behavioral and even psychosocial consequences. And, unlike acute pain, which serves a protective value by alerting the individual to damaging or potentially damaging stimuli, chronic pain appears to serve little, if any, biological function. Some of the complex neural circuits and numerous neurotransmitters involved in pain also are some of the same neural substrates underlying sleep. However, whereas pain (particularly acute pain) serves as a “wake-up call� to a vigilant individual, sleep is defined as the partial isolation of an individual from the external milieu. Several recent animal and human studies using electrophysiological or imaging techniques have revealed a dissociation of pain processes and vigilance networks from sleep mechanisms. During sleep, in order to preserve sleep continuity, most peripheral sensory inputs do not reach the upper brain. Brainstem and subthalamic mechanisms are mostly independent of neuronal thalamocortical trafficking. However, despite the fact that sleep is xv



described as a state of partial isolation from the external milieu, the sleeping brain does not lose the capacity to initiate various levels of arousal reactivation, from brief micro-arousals to a completely awake “fight or flight� reaction if a potentially threatening situation should occur. For years, based on studies using sound or a brief nociceptive stimulation, it was believed that pain was not perceived as such during sleep. Researchers also believed that pain evoked more sleep arousal responses in light rather than in deep or REM sleep stages. However, recent work shows that if painful stimulation, administered while a subject is asleep, lasts long enough, it triggers a clear arousal reaction in all sleep stages, probably by providing sufficient processing time for the sensory information at the level of the central nervous system. Animal findings also support the idea that the reticular activating system is associated with the pain response, most probably as a mechanism to preserve body integrity. At the same time, there is also evidence that the brain actively filters subthalamic sensory inflow during both sleep and waking states. More research is needed to fully understand these state-related sensory filtering processes and to exploit them for better pain management. A number of controversies remain unresolved. For example, it is unclear whether it is the loss of non-REM sleep as opposed to disturbed REM sleep, or if it is sleep fragmentation (due to frequent micro-arousals, shifts between sleep stages, body movements, or respiratory disturbances) or a combination of all these factors that contributes to the exacerbation of pain intensity, reduced vigilance, and poor sleep. There is also no clear consensus regarding the management of combined pain and sleep problems. Daytime sleepiness with cognitive impairments, including fatigue and memory dysfunction, and the resulting risk of accidents at work and behind the wheel, are among the conditions that need to be addressed. The benefits of cognitive-behavioral therapies are recognized individually for managing sleep or pain complaints, but for both there is a paucity of data. Several pain or sleep medications help patients, but the combination of both may be deleterious for some sleep disorders or may impair daytime vigilance (e.g., opioids in patients with sleep apnea). Thus, when the clinician has to deal with the combination of pain and sleep complaints, selecting medications with the lowest potential to exacerbate one or the other problem remains a major challenge. More research is needed on many fronts. What is the best time to administer pain medications so as to be most efficacious without aggravating sleep disorders? Which sleep medications are best for inducing sleep while also minimizing next-day sleepiness? Which sleep and pain treatments work best in combination, minimizing their effects on the other condition? These various connections and controversies are among the challenges that inspired this book.



Some of the sleep terminology employed in this book may be unfamiliar to those readers who come from the pain community and vice versa. Therefore, we start Part I by providing a brief summary chapter from a leading expert in each community. In subsequent chapters we examine the underlying biological mechanisms as shown in animal models, followed by an examination of the evidence obtained in humans, including electrophysiological, psychophysiological, and brain imaging studies. Special attention is given to sleep deprivation and pain perception during sleep. Part II is written by clinician-scientists with a view to providing the widest possible clinical perspective on the problem. Chapters review the relevant epidemiology, medical conditions and sleep disorders, pediatric and geriatric aspects, and dreams and nightmares, as well as the effects of medications and psychological influences on sleep and pain interactions. We believe that Part II of this volume will be an important desk reference for any clinician trying to manage the complex interactions of pain and sleep disorders, while Part I will serve as a good starting point for any researcher interested in exploring the subject. In closing, we would like to thank the many individuals who made this project possible: our chapter authors for the high quality of their chapters and for their diligence in responding to our strict deadlines; the staff at IASP Press for their effective collaboration and attention to the myriad publishing details necessary in finalizing this book, and especially Elizabeth Endres for her copy editing; our desk coordinator, Sid Parkinson, for his relentless efforts in bringing this book to fruition; and the Committee on Publications of IASP and Editor-inChief of IASP Press, Dr Catherine Bushnell, without whose generous support this book would never have been initiated. We hope that this book will enhance the level of knowledge on sleep and pain interactions among all who work in these two fields, eventually contributing to improved quality of life and sounder sleep to all patients suffering from pain and sleep disturbances.

Gilles Lavigne Barry J. Sessle Manon Choinière Peter J. Soja

Gilles Lavigne, DMD, PhD, FRCD(c), is Professor in the Departments of Oral Health, Physiology, and Psychiatry at the University of Montreal. He is also Director of the Trauma Research Axis (orthopedics, neurosurgery, emergency medicine, and intensive care) at SacrĂŠ Coeur Hospital, co-directs the CIHR New Emerging Team in Placebo Mechanisms in Pain and Sleep, and is the current president of the Canadian Sleep Society. He holds a Canada Research Chair in Pain, Sleep and Trauma. Dr. Lavigne is internationally recognized as an expert in sleep and pain interactions and for his research on sleep bruxism.

Barry J. Sessle, MDS, PhD, DSc(hc), FRSC, CAHS, is Professor and Canada Research Chair in the Faculties of Dentistry and Medicine and a member of the Centre for the Study of Pain at the University of Toronto. Dr. Sessle is well-known internationally for his research into orofacial pain mechanisms and neural processes underlying orofacial sensorimotor function. He has served as president of IASP and of the International Association for Dental Research, and is president of the Canadian Pain Society. He is also a member of the Canadian Academy of Science, a Fellow of the Royal Society of Canada, and a Fellow of the Canadian Academy of Health Sciences.

Manon Choinière, PhD, is Associate Professor in the Department of Anesthesiology at the University of Montreal and is a clinical scientist in the Research Center of the Montreal Heart Institute. Dr. Choinière is known world-wide for her expertise in the field of burn pain, most recently having conducted a series of studies on the relationship between pain, opioid analgesia, and sleep in this population of patients and in healthy subjects. Dr. Choinière is also known for her work on the assessment and management of postoperative pain and chronic pain.

Peter J. Soja, PhD, is Professor in the Faculty of Pharmaceutical Sciences at the University of British Columbia (UBC), a member of the UBC Brain Research Institute, and a member of the International Collaboration of Repair Discoveries (ICORD), Vancouver. He is also Director of Sensory and Pain Science, WebSciences International, Los Angeles. Dr. Soja is internationally recognized for his research on how the brain controls somatosensory inflow and motor outflow during sleep versus wakefulness, and on how this process may differ in other states such as general anesthesia, spinal cord injury pain, and sleep-related disorders (e.g., restless legs syndrome or periodic limb movement disorder).

Sleep and Pain, edited by Gilles Lavigne, Barry J. Sessle, Manon Choinière, and Peter J. Soja, IASP Press, Seattle, Š 2007.

1 Why Do We Sleep? John H. Peevera and Dennis McGintyb,c a

Systems Neurobiology Laboratory, Departments of Physiology and Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada; bNeurobiology Research, Department of Psychology, University of California, Los Angeles; c VA Medical Center, Greater Los Angeles Healthcare System, Sepulveda, North Hills, California, USA

What is sleep, and why do we need it? These questions have intrigued philosophers, religious leaders, scientists, and physicians for over 2,000 years. The need for sleep is so powerful that it is possible to fall asleep even when doing so could be life-threatening, such as when operating a motor vehicle. Although sleep physiologists do not fully understand why we sleep, accumulating data are providing clues about the basic brain mechanisms that orchestrate this essential behavior. This chapter will provide an overview of the types and patterns of sleep, describe how sleep is generated by the brain, and explain what functions sleep may play in normal physiology.


The average person spends almost a third of his or her life sleeping. That means that someone who lives for 75 years will spend a total of 25 years asleep. Sleep is not merely a passive or inactive state that follows waking; rather, it is a carefully controlled and highly orchestrated serious of states that occurs in a cyclical fashion each night. Sleep is generally defined by behavioral quiescence that is accompanied by closed eyes, recumbent posture, limited muscular activity, and a reduced responsiveness to sensory stimuli; however, unlike coma, sleep can be readily and quickly reversed. Within sleep there are two separate and distinct states: non-rapid eye movement (non-REM) and rapid-eye movement (REM) sleep. Each is characterized by distinct behavioral, neurochemical, physiological, and electrophysiological attributes.


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Sleep onset is associated with decreased skeletal muscle activity, heart rate, breathing frequency, body temperature, and blood pressure; during non-REM sleep these variables remain remarkably stable (Ogilvie 2001). Non-REM sleep is characterized by four separate stages (1–4) that can be defined by particular electroencephalogram (EEG) patterns (Fig. 1). The hallmark of non-REM sleep is a synchronous EEG pattern that is marked by high-amplitude, slow-frequency waves and by sleep spindles and K-complexes (Rechtschaffen and Kales 1968; see the chapter by Smith and Buenaver in this volume for a description of EEG wave forms and frequencies that characterize sleep architecture). Stages 1 and 2 are considered “light sleep,” whereas stages 3 and 4 are considered “deep sleep.” As such, arousal thresholds are lowest in stage 1 and highest in stage 4. Unlike REM sleep, non-REM sleep is associated with minimal mental activity, and individuals awoken from this state rarely report vivid, complex story-like dreaming (Dement and Kleitman 1957). Non-REM sleep is often considered the period when most body and brain processes are restored or recuperated (Siegel 2005a). Awake Stage 1 K complex

Stage 2

Stage 3

Delta Activity

Stage 4


Theta Activity 100 μV 5 sec

Fig. 1. Typical examples of electroencephalographic (EEG) activity during wakefulness, nonREM sleep (stages 1–4), and REM sleep in a healthy human adult. Note the changes in the frequency and amplitude of the EEG signals among the different sleep states. During waking, the EEG comprises low-voltage, high-frequency waves; on entrance into non-REM sleep, the frequency of the signal slows and the amplitude increases. In stage 2 non-REM sleep, Kcomplexes appear, and during stages 3 and 4, delta waves dominant the EEG trace. The EEG pattern in REM sleep resembles that of waking states; however, unlike during waking states, muscle tone is minimal or absent and there are characteristic rapid eye movements.

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Thalamus ARAS

Hypothalamus ARAS Mesial temporal cortex


Insular cortex Mesial temporal cortex



Fig 7. Brain structures that do not show decreased metabolic rate from waking to sleep in insomniacs. All regions shown reach statistical significance at the corrected P < 0.05 level of significance. ARAS = ascending reticular activating system. Red to yellow color gradation indicates increasing levels of statistical significance.

the hypothalamus. This study supports the concept that persistent activity in this basic arousal network may be responsible for the impaired objective and subjective sleep in insomnia patients. Activation of this arousal network within sleep by the experience of pain would be expected to disrupt sleep in a manner similar to that of primary insomnia. LIMBIC AND PARALIMBIC SYSTEM

Behaviorally, maintaining an alert brain serves broader functions than a simple homeostatic purpose related to sleep at night. It allows an individual to adapt in an efficient manner to a variety of salient eventsâ&#x20AC;&#x201D;including the experience of painâ&#x20AC;&#x201D;in real time while awake. The basic biology of arousal can be modified by neural systems that regulate emotional and goal-directed behavior. These systems may play an important role in modulating or perpetuating the increased arousal of pain patients. As reviewed above, the ascending pain system, specifically, comprises spinothalamic and trigeminothalamic projections to limbic cortices, and these projections are hypothesized to add an affective or motivational component to the experience of pain. Human sleep neuroimaging studies support a role for the limbic and paralimbic systems in sleep processes. Non-REM sleep correlates negatively with blood flow in the ACC (Braun et al. 1997; Hofle et al. 1997; Maquet 1997), the amygdala (Maquet et al. 1997), and the orbitofrontal cortex (Braun et al.

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amounts of stage 3 and 4 and REM sleep and increased duration of stages 1 and 2, a higher number of body movements, delta-alpha sleep, more arousals, and finally, increased CAP rate (see Smith and Buenaver chapter and Lavigne et al., this volume; Mahowald et al. 1989). Some studies indicate that the sleep of patients complaining of pain is less disturbed than that of patients suffering from psychiatric disease (Wittig 1982). For a critical review of the relationship between pain and disturbed sleep, see Mahowald and Mahowald (2000). In the following section we will review several pain-related conditions to illustrate alterations of sleep variables at both macro- and microstructural levels. SLEEP MACROSTRUCTURE ALTERATIONS FOUND IN DIFFERENT CONDITIONS WITH PAIN

Rheumatic and musculoskeletal diseases. Patients with primary Sjögren’s syndrome, osteoarthritis, ankylosing spondylitis, and gout experience sleep fragmentation, increased time spent in wakefulness during the night, and a higher incidence of periodic leg movements that are consistently associated with arousals during sleep. Moreover, a decrease in slow-wave sleep characterizes the sleep of patients affected by chronic musculoskeletal pain, including arthrosis, arthritis, and fibromyalgia (Drewes and Arendt-Nielsen 2001). Because musculoskeletal pain is mostly related to posture and movement, immobilization and increased prostaglandin secretion during the night seem to modify the regular sleep-wake cycles (Rotem et al. 2003; Marin et al. 2006). Cardiac diseases. Coronary diseases (angina pectoris, acute myocardial infarction) seem to be associated with a decrease in slow-wave sleep and an increase in sleep fragmentation and in the duration of superficial sleep, i.e., stages 1 and 2 (Broughton and Baron 1978). It has been reported that ischemic episodes occur more frequently in REM sleep than in the other sleep stages (Murao et al. 1972). Neuropathic pain. Conditions such as peripheral neuropathy, carpal tunnel syndrome, and trigeminal neuralgia may interfere with sleep structure, impairing sleep adequacy (Zelman et al. 2006). Sleep fragmentation was reported in questionnaire format by 34 patients referred for operative treatment of carpal tunnel syndrome. However, no impairment in median and ulnar nerve conduction could be observed during nocturnal awakenings due to pain or numbness in the hands (Lehtinen et al. 1996). Peripheral neuropathy can also be involved in the physiopathological mechanisms of restless legs syndrome, a sensorimotor disorder characterized by a complaint of a nearly irresistible urge to move the legs. The urge to move the limbs worsens in the evening and profoundly disturbs the patient’s ability to go to sleep or return to sleep after an awakening (Allen et al. 2003).

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Chronic insomnia has been variously defined by frequency (usually at least 3 times a week) and duration (usually 1 month or longer) and typically involves some degrees of daytime dysfunction (see review by Ancoli-Israel 2006; see also Chen and Guilleminault, this volume). However, persistence appears to be the most important criterion for defining severe insomnia (Ancoli-Israel 2006). Although prevalence estimates for chronic insomnia are clearly affected by differences in operational definitions, the most conservative estimates are between 8% and 10% in Western Europe (Ohayon 2005) and in the United States (Ford and Kamerow 1989; Simon and Vonkorff 1997; Ancoli-Israel and Roth 1999; see also review by Walsh 2004). All these studies also show that insomnia problems are usually more frequent in women than men and that their frequency increases with age. PREVALENCE OF SLEEP DISTURBANCES IN CHRONIC PAIN CONDITIONS

The literature describing the prevalence of sleep disturbances in chronic pain disorders is much more abundant than in acute pain conditions. The data are derived from large-scale epidemiological studies in the general population and from clinical studies of patients with chronic pain of various origins. Community-based surveys have shown a high prevalence of sleep complaints in individuals who have a medical illness, and in many cases pain may be the main cause of insomnia. Moffit et al. (1991), who surveyed a sample of 1,765 Australians, found that pain was the strongest predictor of a sleep problem and that the most significant factor contributing to pain was arthritis. In a Swedish survey of 10,216 elderly persons, Asplund (1996) found that individuals with neck, back, or hip pain were twice as likely to report daytime sleepiness than those with no pain or other symptoms (all OR ≥ 2.0). Sutton et al. (2001) analyzed the cross-sectional data from the 1991 Canadian General Social Survey (n = 11924 subjects aged ≥15 years) and found that severe pain (versus no pain) had the second-highest adjusted odds ratio (OR = 1.99; 99% CI = 1.45, 2.73) among various sociodemographic, lifestyle, stress-related, and health-related factors significantly associated with difficulties in initiating or maintaining sleep. In a more recent study, Ohayon (2005) surveyed 8,989 individuals from five European countries. Chronic pain was defined in terms of duration (≥6 months), while chronic insomnia was defined in terms of frequency (≥3 nights a week) and duration (≥1 month). Twenty-three percent of those who had chronic pain reported at least one insomnia symptom (i.e., difficulty initiating sleep, disrupted sleep, early morning awakening, and unrefreshing sleep). Conversely, 40.2% of the individuals with insomnia symptoms reported at least one type of

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chronic pain. We also refer the reader to the Linton and MacDonald chapter in this volume, which describes some unpublished results of the Middle Sweden Pain and Sleep Project. This study examined the prevalence of pain and sleep problems in 2,406 individuals and found prevalence rates of comorbid pain and sleep problems that were much higher than those reported by Ohayon (2005), perhaps because the two studies used different diagnostic criteria. We must consider several methodological limitations when drawing conclusions from these large epidemiological studies. First, all the results are based on self-report, which may be subject to bias. Second, operational definitions of chronic pain and sleep dysfunctions are not uniform across studies. Finally, none of the studies took into account the presence of preexisting primary sleep disorders or comorbidities (e.g., depression) that are known to influence sleep (Smith and Haythornthwaite 2004; Stiefel and Stagno 2004; Lavigne et al. 2005). Numerous clinical studies have examined sleep disturbances in various painful and nonpainful medical disorders. Review articles on this issue have mushroomed since 2000 (Cohen et al. 2000; Menefee et al. 2000; Drewes and Arendt-Nielsen 2001; Moldofsky 2001; Moore and Dimsdale 2002; Lavigne et al. 2005; Onen et al. 2005; Roehrs and Roth 2005; Ancoli-Israel 2006). Sleep disturbances are common in patients with chronic pain and have been documented—either objectively or subjectively—in a variety of pain conditions (see Table I). Table I Chronic painful conditions in which sleep disturbances have been documented Articular and nonarticular musculoskeletal diseases (osteoarthritis, rheumatoid arthritis, primary Sjögren’s syndrome, ankylosing spondylitis, fibromyalgia, back pain) Headaches (migraine, cluster headache, chronic paroxysmal hemicrania, hypnic headache syndrome) Neurological disorders (neuropathic pain, multiple sclerosis) Visceral diseases (duodenal ulcer, irritable bowel syndrome) Other painful diseases (chronic orofacial pain, cancer pain, dysmenorrhea) Heterogeneous pain clinic referrals Chronic pain without any identified cause

Table II summarizes the major conclusions that can be drawn from the studies on sleep dysfunction in chronic pain patients. More detailed information about the frequency and type of sleep disturbances by type of pain condition are available in the reviews cited above. The chapters by Dauvilliers and Carlander and by Parrino et al. in this volume provide a review of sleep and pain interactions in fibromyalgia and headache.

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Sleep and Pain, edited by Gilles Lavigne, Barry J. Sessle, Manon Choinière, and Peter J. Soja, IASP Press, Seattle, Š 2007.

18 Alteration of Sleep Quality by Pain Medication: An Overview Brian E. Cairns Department of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada; Surrey Memorial Hospital, Surrey, British Columbia, Canada

This chapter provides an overview of the effects of various commonly used pain medications on sleep architecture. It is apparent that ongoing pain significantly alters sleep architecture and that those alterations can increase ongoing pain intensity in an apparent vicious cycle. While it is assumed that analgesic drugs that decrease pain would help reverse pain-related changes in sleep architecture, the interaction between analgesic agents and pain-related changes in sleep architecture has received relatively little systematic study. Those few studies that have been undertaken have been limited, with a few notable exceptions, to investigation of acute pain in relatively small numbers of subjects. Further, the effect of many analgesic drug classes on sleep and wakefulness remains to be evaluated. Therefore, a second function of this chapter is to draw attention to understudied areas of analgesic/sleep interactions with the hope of stimulating new research within this field. The readers are invited to see the Beaulieu and Walczak chapter in this volume for an overview of medication effects on sleep and pain.


To better understand the effect of pain medications on sleep, it is helpful to briefly review some of the neurochemistry associated with changes from the awake state to non-REM and REM sleep. Currently, the neuropharmacological mechanisms underlying the transition from wakefulness to non-REM sleep remain an area of active research (Fig. 1). As described by Peever and McGinty 371

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B.E. CAIRNS Wakefulness







REM Cholinergic

Adenosine PGD2 GABA serotonergic noradrenergic histaminergic

Fig. 1. Changes in monoaminergic and cholinergic tone through the transition from wakefulness to non-rapid eye movement (REM) and then to REM sleep.

in this volume, wakefulness is proposed to be maintained by a combination of cholinergic, noradrenergic, and histaminergic tone in key areas of the cerebral cortex (Mignot et al. 2002; Espana and Scammell 2004; Siegel 2004; Saper et al. 2005). Dopaminergic tone also appears to play an important role in wakefulness, as witnessed by the significant arousal and stimulant effects of drugs such as amphetamines, which block dopamine reuptake (Mignot et al. 2002; Espana and Scammell 2004). Neurons in the lateral hypothalamus that contain a neuropeptide called hypocretin or orexin are proposed to play an important role in modulating wakefulness by altering the tone of monoaminergic neurotransmitters, most notably histamine, and the loss of these neurons is associated with the development of narcolepsy (Mignot et al. 2002; Espana and Scammell 2004; Saper et al. 2005). A decrease in the tone of one or more of these neurotransmitters, for example as a side effect of certain analgesic drugs, can lead to a decrease in arousal and an increase in drowsiness and can promote the transition from wakefulness to light non-REM sleep and ultimately to deep or slow-wave sleep (SWS). In this chapter, SWS refers to stages 3 and 4 of sleep. It is still a matter of debate what triggers the natural decrease in the tone of all these neurotransmitters that coincides with the onset of non-REM sleep. It has been speculated for some time that the accumulation of one or more metabolites produced by brain activity during wakefulness triggers the transition to non-REM sleep (Siegel 2004). There is evidence to support the concept that increased central nervous system (CNS) levels of adenosine, which result from the breakdown of adenosine triphosphate (ATP) for energy during wakefulness, activate adenosine A1 receptors to suppress neuronal activity in key CNS structures (the basal forebrain and brainstem reticular activating system) responsible for the maintenance of the awake state (Basheer et al. 2004). Whether adenosine is the trigger or just one of a myriad of substances that act in concert to promote

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Antidepressants, like anticonvulsants, are part of a group of drugs commonly referred to as adjuvant analgesics. None of the antidepressants was initially developed as an analgesic agent. Their therapeutic efficacy in pain management was rather established subsequent to their use for the treatment of depression. Antidepressants are widely used in chronic pain states, especially tricyclic antidepressants, whose efficacy has been established in numerous clinical trials. Compared to depression, neuropathic pain usually responds more quickly and at lower dosage of antidepressants, suggesting that the antinociceptive actions of these drugs are dissociated from their effects on mood. Moreover, pain relief occurs in both depressed and euthymic patients. There is no unanimously accepted explanation of how antidepressants work. However, we know that clinically effective antidepressants have identifiable acute interactions with central monoaminergic neurons that use either norepinephrine or serotonin (5-HT) as their neurotransmitter, and that these interactions are responsible for their antidepressant activity (Piñeyro and Azzi 2005). The mechanisms implicated in the control of nociception by tricyclic antidepressants are multiple (see Micó et al. 2006 for a review). In particular, therapeutic concentrations of tricyclic antidepressants are known to block Na+ channels in a use-dependent manner and to inhibit neuronal and glial GABA uptake. On the other hand, modification of norepinephrine and/or serotonin neurotransmission, both of which play a regulatory role in pain perception, is characteristic of antidepressants (Piñeyro and Azzi 2005). Furthermore, antidepressants that selectively target monoaminergic neurotransmission—selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs)—lack the additional antinociceptive properties found in tricyclic antidepressants and are therefore often reported as having limited analgesic efficacy. Antidepressants are commonly prescribed for the treatment of insomnia because many of these agents have sedating and sleep-promoting properties (Mayers and Baldwin 2005). Furthermore, as mentioned above, antidepressants are used as adjuvant analgesic drugs for the treatment of chronic pain disorders. Therefore, they are often useful in patients suffering from chronic pain with comorbid insomnia (Table III). Doses for treatment of sleep and pain problems are often below the levels needed for the treatment of depression. Among the different substances, tricyclic antidepressants such as amitriptyline, imipramine, and doxepin have been shown to be effective as analgesics in the treatment of a variety of pain syndromes (Magni 1991; Saarto and Wiffen 2005; Gilron and Flatters 2006; Micó et al. 2006). These sedative antidepressants have anticholinergic side effects and should therefore be used with caution in patients with glaucoma and benign prostatic hyperplasia. Other

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Table III Antidepressants used for the treatment of insomnia and chronic pain Antidepressants Tricyclics Amitriptyline Clomipramine Imipramine Nortriptyline Trimipramine


Pain Relief

+++++ ++++ +++ ++ ++++

++++ ++++ ++++ +++ ++++

Anticholinergic Effects Comments +++++ +++++ +++ +++ +++

First choice of antidepressants for chronic pain; amitriptyline has been studied the most

Selective Serotonin Reuptake Inhibitors Fluoxetine – + Paroxetine + + Sertraline + +

– + –

Gastrointestinal symptoms, paresthesias, and irritability can occur after abrupt discontinuation

Serotonin Receptor Modulators Nefazodone +++ Trazodone ++++

++ –/+

+ –

SNRI May induce insomnia, “sundowning,” and aggression

Others Bupropion Venlafaxine

++ ++

– +

May induce insomnia SNRI

– +

Note: SNRI = serotonin-norepinephrine reuptake inhibitor. Data are adapted from Boldessarini (2001), Sindrup (2003), Boulanger (2005), Katz et al. (2005), Perrot et al. (2006), Watson et al. (2006). The term “sundowning” refers to increasing confusion at the end of the day and into the night.

antidepressants such as nefazodone, trazodone, mianserin, or mirtazapine can also be considered in patients with pain and sleep disorders (see also Cairns, this volume), whereas SSRIs (fluoxetine, paroxetine, citalopram) and bupropion may actually worsen sleep continuity (Winokur et al. 2001). Therefore, in patients already complaining of insomnia, the addition of an SSRI antidepressant may exacerbate sleeplessness (Jaffe and Patterson 2004). Other common side effects of SSRIs include nausea, changes in appetite, nervousness, headache, and sexual dysfunction. In contrast, nefazodone and trazodone are associated with increased sleepiness and few anticholinergic properties. Indeed, these two compounds have a dual mechanism of action. Like the SSRIs, nefazodone and trazodone block the reuptake of serotonin, but they are also antagonists at 5-HT2 receptors (Moller and Volz 1996). This blockade may reduce the stimulating effects seen with the SSRIs. Nefazodone is structurally and pharmacologically similar to trazodone. Overall, these two agents cause some sedation, have positive effects on sleep, and decrease anxiety (Thase 1998).

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