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Page 1: Look Inside Sleep & Pain
Page 2: Look Inside Sleep & Pain

Mission Statement of IASP Press®

The International Association for the Study of Pain (IASP) is a nonprofit, interdisci-plinary 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.

Page 3: Look Inside Sleep & Pain

Sleep and Pain

IASP PRESS® • SEATTLE

Editors

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, CAHSFaculty of Dentistry, Faculty of Medicine,

and Centre for the Study of Pain, University of Toronto, Toronto, Ontario, Canada

Manon Choinière, PhDDepartment of Anesthesiology, Faculty of Medicine,

University of Montreal; Research Center, Montreal Heart Institute, Montreal, Quebec, Canada

Peter J. Soja, PhDFaculty of Pharmaceutical Sciences, The University of British Columbia,

Vancouver, British Columbia, Canada

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© 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, photocopy-ing, 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.

Published by:

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

Printed in the United States of America

Library of Congress Cataloging‑in‑Publication Data

Sleep and pain / Gilles Lavigne, Barry J. Sessle, Manon Choinière, Peter J. Soja, editors. p.cm. 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--dc222007061300

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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 mem-ory 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 activ-ity 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!

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List of Contributing Authors ix Foreword xiiiPreface xv

Part I The Science of Sleep and Pain1. What Is Sleep, and Why Do We Sleep? John Peever and Dennis McGinty 3

2. What Is Pain, and Why and How Do We Experience Pain? Barry J. Sessle 23

3. Modulation of Prethalamic Sensory Inflow during Sleep versus Wakefulness Peter J. Soja 45

4. Pain and Its Interaction with Thalamocortical Excitability States David B. Rye and Amanda A.H. Freeman 77

5. Neurochemical Mechanisms Mediating Opioid-Induced REM Sleep Disruption Ralph Lydic and Helen A. Baghdoyan 99

6. Pain Perception during Sleep and Circadian Influences: The Experimental Evidence Alison J. Bentley 123

7. Effects of Impaired Sleep Quality and Sleep Deprivation on Diurnal Pain Perception Bernd Kundermann and Stefan Lautenbacher 137

8. Pain Imaging in Relation to Sleep Eric A. Nofzinger and Stuart W.G. Derbyshire 153

9. Modulation of Pain-Related Cortical Activity by Sleep and Attention Ryusuke Kakigi, Xiaohong Wang, Koji Inui, and Yunhai Qiu 175

10. Electroencephalographic Correlates of Pain and Sleep Interactions in Humans Michael T. Smith and Luis F. Buenaver 189

11. Sleep Fragmentation and Arousal in the Pain Patient Liborio Parrino, Marco Zucconi, and Mario Giovanni Terzano 213

Contents

vii

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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 235

13. Epidemiology of Pain and Sleep Disturbances and Their Reciprocal Interrelationships Manon Choinière, Mélanie Racine, and Isabelle Raymond-Shaw 267

14. Sleep and Pain Interactions in Medical Disorders: The Examples of Fibromyalgia and Headache Yves Dauvilliers and Bertrand Carlander 285

15. Sleep Disorders that Can Exacerbate Pain Gina Chen and Christian Guilleminault 311

16. Pediatric and Geriatric Pain in Relation to Sleep Disturbances Lucia Gagliese and Christine T. Chambers 341

17. Pain in Dreams and Nightmares Antonio Zadra and Christane Manzini 361

18. Alteration of Sleep Quality by Pain Medication: An Overview Brian E. Cairns 371

19. Pharmacological Management of Sleep and Pain Interactions Pierre Beaulieu and Jean-Sébastien Walczak 391

20. Pain and Sleep Disorders: Clinical Consequences and Maintaining Factors Steven J. Linton and Shane MacDonald 417

21. Cognitive-Behavioral Treatment for Insomnia and Pain Michael T. Smith and Jennifer A. Haythornthwaite 439

Index 459

viii COnTenTS

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ix

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 Pharmacol-ogy, 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, Montpel-lier, 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, Univer-sity of Montreal; Research Center, Montreal Institute of Cardiology, Montreal, Quebec, Canada

Yves Dauvilliers MD, PhD Neurology Service, Gui-de-Chauliac Hospital, Montpel-lier, France; INSERM, Montpellier, France

Ronald Denis, MD Trauma Research Center and Center for Sleep Studies, Sacré-Coeur 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

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x COnTRIBUTInG AUTHORS

Jennifer A. Haythornthwaite, PhD Department of Psychiatry and Behavioral Sci-ences, 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 Physiologi-cal Sciences, School of Life Sciences, The Graduate University for Advanced Studies, Hayama, Kanagawa, Japan; Research Institute of Science and Technol-ogy for Society, Japan

Samar Khoury, BSc Trauma Research Center and Center for Sleep Studies, Sacré-Coeur Hospital, Montreal, Quebec, Canada

Bernd Kundermann, PhD Department of Psychiatry and Psychotherapy, Philipps-University 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, Facul-ties of Medicine and Dentistry, University of Montreal; Brain Study Center, Cen-tre Hospitalier de l’Université de Montréal (CHUM), Montreal, Quebec, Canada

Steven J. Linton, PhD Department of Behavioral, Social, and Legal Sciences—Psy-chology, 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—Psy-chology, 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 Pitts-burgh School of Medicine, Pittsburgh, Pennsylvania, USA

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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 Uni-versity 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, Uni-versity of Montreal, and Center for the Study of Sleep and Biorhythms, Sacré-Coeur Hospital, Montreal, Quebec, Canada

Marco Zucconi, MD Sleep Disorders Center, Department of Neurology, H San Raf-faele Institute, Milan, Italy

COnTRIBUTInG AUTHORS xi

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Foreword

xiii

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 con-secutive 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 effec-tive 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.

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xiv FOReWORD

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 pharma-cologists, 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

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Preface

Advances in knowledge regarding the interaction of sleep and pain disor-ders 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 ad-dresses 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 sensa-tion, 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 in-volved 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 elec-trophysiological 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

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xvi PReFACe

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 trig-gers 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 pro-cesses 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, re-duced 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 condi-tions 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 im-pair 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 effica-cious 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.

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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 evi-dence 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, pe-diatric 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-in-Chief 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

PReFACe xvii

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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.

Lavigne

Sessle

ChoiniereSoja

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 Sacré 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.

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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).

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.

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3

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

1

Why Do We Sleep?

John H. Peevera and Dennis McGintyb,c

aSystems 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; cVA 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 phi-losophers, 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.

WHAT IS SLEEP?

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 defi ned by behavioral quiescence that is accompanied by closed eyes, recumbent posture, limited muscular ac-tivity, 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 move-ment (REM) sleep. Each is characterized by distinct behavioral, neurochemical, physiological, and electrophysiological attributes.

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4 J.H. PEEVER AND D. MCGINTY

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 defi ned 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).

Stage 1

Awake

Stage 2

Stage 3

Stage 4

REM

5 sec

100 μV

K complex

Delta Activity

Theta Activity

Stage 1

Awake

Stage 2

Stage 3

Stage 4

REM

5 sec

100 μV

K complex

Delta Activity

Theta Activity

Fig. 1. Typical examples of electroencephalographic (EEG) activity during wakefulness, non-REM 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, K-complexes 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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PAIN IMAGING IN RELATION TO SLEEP 165

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 effi cient manner to a variety of salient events—including the expe-rience of pain—in real time while awake. The basic biology of arousal can be modifi ed 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 sys-tem, specifi cally, 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 fl ow in the ACC (Braun et al. 1997; Hofl e et al. 1997; Maquet 1997), the amygdala (Maquet et al. 1997), and the orbitofrontal cortex (Braun et al.

ARAS ARAS

Thalamus

Mesial temporal cortex

Hypothalamus

Cingulate

Mesial temporal cortex

Hypothalamus

ARAS

Insular cortex

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

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SLEEP FRAGMENTATION AND AROUSAL 221

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 fi nally, 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 frag-mentation, increased time spent in wakefulness during the night, and a higher incidence of periodic leg movements that are consistently associated with arous-als during sleep. Moreover, a decrease in slow-wave sleep characterizes the sleep of patients affected by chronic musculoskeletal pain, including arthrosis, arthritis, and fi bromyalgia (Drewes and Arendt-Nielsen 2001). Because muscu-loskeletal 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 superfi cial 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, impair-ing 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 conduc-tion 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 sensorimo-tor 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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276 M. CHOINIÈRE ET AL.

PREVALENCE OF CHRONIC INSOMNIA

Chronic insomnia has been variously defi ned 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 defi ning severe insomnia (Ancoli-Israel 2006). Although prevalence estimates for chronic insomnia are clearly affected by differences in operational defi nitions, 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 com-plaints in individuals who have a medical illness, and in many cases pain may be the main cause of insomnia. Moffi t 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 signifi cant factor contributing to pain was arthritis. In a Swed-ish 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 Sur-vey (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-re-lated factors signifi cantly associated with diffi culties in initiating or maintaining sleep. In a more recent study, Ohayon (2005) surveyed 8,989 individuals from fi ve European countries. Chronic pain was defi ned in terms of duration (≥6 months), while chronic insomnia was defi ned 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., diffi culty 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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EPIDEMIOLOGY OF PAIN AND SLEEP DISORDERS 277

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 conclu-sions from these large epidemiological studies. First, all the results are based on self-report, which may be subject to bias. Second, operational defi nitions 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 infl uence 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 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 interac-tions in fi bromyalgia and headache.

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

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371

Sleep and Pain, edited by Gilles Lavigne, Barry J. Sessle, Manon Choinière, and Peter J. Soja, IASP Press, Seattle, © 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 signifi -cantly 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 ar-chitecture, 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 excep-tions, 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 fi eld. The readers are invited to see the Beaulieu and Walczak chapter in this volume for an overview of medication effects on sleep and pain.

PHARMACOLOGY OF SLEEP

NON-RAPID EYE MOVEMENT SLEEP

To better understand the effect of pain medications on sleep, it is helpful to briefl y 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

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372 B.E. CAIRNS

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 wakeful-ness, as witnessed by the signifi cant 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 neu-ropeptide called hypocretin or orexin are proposed to play an important role in modulating wakefulness by altering the tone of monoaminergic neurotransmit-ters, 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 neurotrans-mitters, 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 me-tabolites 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 struc-tures (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

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

Wakefulness

Non-REM

Sleep

REM

Tone

High

Low

AdenosinePGD2GABA

Transition

Cholinergic

serotonergicnoradrenergichistaminergic

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402 P. BEAULIEU AND J.-S. WALCZAK

ANTIDEPRESSANTS

Antidepressants, like anticonvulsants, are part of a group of drugs common-ly referred to as adjuvant analgesics. None of the antidepressants was initially developed as an analgesic agent. Their therapeutic effi cacy 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 an-tidepressants, whose effi cacy 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 iden-tifi able 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, modifi cation 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, antide-pressants 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 effi cacy.

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 ami-triptyline, imipramine, and doxepin have been shown to be effective as anal-gesics 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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DRUGS FOR SLEEP/PAIN INTERACTIONS 403

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 (fl uoxetine, paroxetine, citalopram) and bupropion may actually worsen sleep continuity (Winokur et al. 2001). Therefore, in pa-tients 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-HT

2

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 posi-tive effects on sleep, and decrease anxiety (Thase 1998).

Table III Antidepressants used for the treatment of insomnia and chronic pain

Antidepressants Sedation Pain Relief Anticholinergic

Effects Comments

Tricyclics Amitriptyline +++++ ++++ +++++ Clomipramine ++++ ++++ +++++ Imipramine +++ ++++ +++Nortriptyline ++ +++ +++Trimipramine ++++ ++++ +++

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

Selective Serotonin Reuptake InhibitorsFluoxetine – + –Paroxetine + + +Sertraline + + –

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

Serotonin Receptor Modulators Nefazodone +++ ++ + SNRITrazodone ++++ –/+ – May induce insomnia,

“sundowning,” and aggression

OthersBupropion – ++ – May induce insomnia Venlafaxine + ++ + 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.

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