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Recognition and Alleviation of Pain in Laboratory Animals Committee on Recognition and Alleviation of Pain in Laboratory Animals Institute for Laboratory Animal Research Division on Earth and Life Studies

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Govern- ing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineer- ing, and the Institute of Medicine. The members of the Committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This study was supported by the American Veterinary Medical Association; Aventis Pharmaceuticals; the Bosack-Kruger Foundation; Bristol-Myers Squibb; GlaxoSmith- Kline; Humane Society of the United States; Scientists Center for Animal Welfare; Wyeth-Ayerst Pharmaceuticals; Department of Agriculture, Animal and Plant Health Inspection Service; and Department of Health and Human Services, National Insti- tutes of Health through Contract Number N01-OD-4-2139 Task Order #161. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of the organizations or agencies that provided support for the project. The content of this publication does not necessarily reflect the views or policies of the National Institutes of Health, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. Library of Congress Cataloging-in-Publication Data Institute for Laboratory Animal Research (U.S.). Committee on Recognition and Alleviation of Distress in Laboratory Animals. Recognition and alleviation of pain in laboratory animals / Committee on Recognition and Alleviation of Pain in Laboratory Animals, Institute for Laboratory Animal Research, Division on Earth and Life Studies, National Research Council of the National Academies. p. cm. Includes bibliographical references and index. ISBN-13: 978-0-309-12834-6 (pbk.) ISBN-10: 0-309-12834-X (pbk.) ISBN-13: 978-0-309-12835-3 (pdf) ISBN-10: 0-309-12835-8 (pdf) 1. Laboratory animals—Health. 2. Laboratory animals—Effect of stress on. 3. Pain in animals—Treatment. 4. Animal welfare. I. Title. SF406.I565 2009 636.088’5—dc22 2009042189 Additional copies of this report are available from The National Academies Press, 500 Fifth Street, NW, Lockbox 285, Washington, DC 20001; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap. edu Copyright 2009 National Academy of Sciences. All rights reserved. Printed in the United States of America

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Acad- emy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineer- ing programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is presi- dent of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Insti- tute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sci- ences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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COMMITTEE ON RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS Gerald F. Gebhart (Chair), University of Pittsburgh Allan I. Basbaum, University of California Stephanie J. Bird, Waltham, Massachusetts Paul Flecknell, Newcastle University, United Kingdom Lyndon Goodly, University of Illinois Alicia Z. Karas, Tufts University Stephen T. Kelley, University of Washington Jane Lacher, Dow Chemical Company Georgia Mason, University of Guelph, Canada Lynne U. Sneddon, University of Liverpool, United Kingdom Sulpicio G. Soriano, Harvard University Consultant Heidi L. Shafford, Veterinary Anesthesia Specialists, LLC Staff Joanne Zurlo, Director Lida Anestidou, Study Director Kathleen Beil, Administrative Coordinator Cameron H. Fletcher, Senior Editor Rhonda Haycraft, Senior Project Assistant 

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INSTITUTE FOR LABORATORY ANIMAL RESEARCH COUNCIL Stephen W. Barthold (Chair), University of California–Davis Kathryn A. Bayne, Association for Assessment and Accreditation of Laboratory Animal Care International, Frederick, Maryland Myrtle A. Davis, National Institutes of Health, Bethesda, Maryland Jeffrey I. Everitt, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina James G. Fox, Massachusetts Institute of Technology, Cambridge Nelson L. Garnett, Consultant, Laboratory Animal Care and Use Programs, Dickerson, Maryland Estelle B. Gauda, Johns Hopkins University, Baltimore, Maryland Coenraad F.M. Hendriksen, Netherlands Vaccine Institute, Bilthoven (to June 2008) Jon H. Kaas, Vanderbilt University, Nashville, Tennessee (to June 2008) Joseph W. Kemnitz, University of Wisconsin, Madison Judy A. MacArthur Clark, Animals Scientific Procedures Inspectorate, London, United Kingdom Martha K. McClintock, University of Chicago, Illinois Leticia V. Medina, Abbott Laboratories, Abbott Park, Illinois Timo Olavi Nevalainen, University of Kuopio, Finland Bernard E. Rollin, Colorado State University, Fort Collins Abigail L. Smith, University of Pennsylvania, Philadelphia Stephen A. Smith, Virginia Polytechnic Institute and State University, Blacksburg James E. Womack, Texas A&M University, College Station Staff Joanne Zurlo, Director Lida Anestidou, Program Officer Kathleen Beil, Administrative Coordinator Cameron H. Fletcher, Managing Editor, ILAR Journal Rhonda Haycraft, Senior Project Assistant i

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INSTITUTE FOR LABORATORY ANIMAL RESEARCH PUBLICATIONS Scientific and Humane Issues in the Use of Random Source Dogs and Cats in Research (2009) Recognition and Alleviation of Distress in Laboratory Animals (2008) Toxicity Testing in the 21st Century: A Vision and a Strategy (2007) Overcoming Challenges to Develop Countermeasures Against Aerosolized Bioterrorism Agents: Appropriate Use of Animal Models (2006) Guidelines for the Humane Transportation of Research Animals (2006) Science, Medicine, and Animals: Teacher’s Guide (2005) Animal Care and Management at the National Zoo: Final Report (2005) Science, Medicine, and Animals (2004) The Development of Science-based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop (2004) Animal Care and Management at the National Zoo: Interim Report (2004) National Need and Priorities for Veterinarians in Biomedical Research (2004) Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research (2003) International Perspectives: The Future of Nonhuman Primate Resources, Proceedings of the Workshop Held April 17-19, 2002 (2003) Occupational Health and Safety in the Care and Use of Nonhuman Primates (2003) Definition of Pain and Distress and Reporting Requirements for Laboratory Animals: Proceedings of the Workshop Held June 22, 2000 (2000) Strategies That Influence Cost Containment in Animal Research Facilities (2000) Microbial Status and Genetic Evaluation of Mice and Rats: Proceedings of the 1999 US/Japan Conference (2000) Microbial and Phenotypic Definition of Rats and Mice: Proceedings of the 1998 US/Japan Conference (1999) Monoclonal Antibody Production (1999) The Psychological Well-Being of Nonhuman Primates (1998) Biomedical Models and Resources: Current Needs and Future Opportunities (1998) Approaches to Cost Recovery for Animal Research: Implications for Science, Animals, Research Competitiveness and Regulatory Compliance (1998) Chimpanzees in Research: Strategies for Their Ethical Care, Management, and Use (1997) Occupational Health and Safety in the Care and Use of Research Animals (1997) ii

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Guide for the Care and Use of Laboratory Animals (1996) Guide for the Care and Use of Laboratory Animals translations: Korean, Chinese, Spanish, Russian, French, Taiwanese, Portugese, Japanese, Arabic, Turkish (1996) Rodents (1996) Nutrient Requirements of Laboratory Animals, Fourth Revised Edition (1995) Laboratory Animal Management: Dogs (1994) Recognition and Alleviation of Pain and Distress in Laboratory Animals (1992) Education and Training in the Care and Use of Laboratory Animals: A Guide for Developing Institutional Programs (1991) Companion Guide to Infectious Diseases of Mice and Rats (1991) Infectious Diseases of Mice and Rats (1991) Immunodeficient Rodents: A Guide to Their Immunobiology, Husbandry, and Use (1989) Use of Laboratory Animals in Biomedical and Behavioral Research (1988) Animals for Research: A Directory of Sources, Tenth Edition and Supplement (1979) Amphibians: Guidelines for the Breeding, Care and Management of Laboratory Animals (1974) Copies of these reports can be ordered from the National Academies Press (800) 624-6242 or (202) 334-3313 www.nap.edu iii

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Acknowledgments I n preparation for this report, the committee invited experts to present their perspectives on the concepts of nociception, pain, consciousness, and awareness. The committee thanks: Colin Allen, Indiana University A. Vania Apkarian, Northwestern University David Borsook, McLean Hospital This report was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the Report Review Committee of the National Research Coun- cil (NRC). The purpose of this independent review is to provide candid and critical comments that will assist the committee in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberation process. The committee thanks the following individuals for their review of this report: K. S. Anand, University of Arkansas for Medical Sciences George J. DeMarco, Pfizer, Inc. Ronald Dubner, University of Maryland Sherril Green, Stanford School of Medicine C. Terrance Hawk, GlaxoSmithKline Pharmaceuticals R&D ix

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x ACKNOWLEDGMENTS B. Duncan X. Lascelles, North Carolina State College of Veterinary Medicine Jerald Silverman, University of Massachusetts Medical School William S. Stokes, National Institute of Environmental and Health Sciences Daniel M. Weary, University of British Columbia, Canada Tony L. Yaksh, University of California—San Diego Although the reviewers listed above provided many constructive com- ments and suggestions, they were not asked to endorse the report’s conclu- sions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Hilton J. Klein, Taconic, and Harley W. Moon, Iowa State University (emeritus). Appointed by the NRC, they were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully con- sidered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution. This report is the product of committee members who gave generously of their time and effort. The committee rapidly developed into a colle- gial, hard-working group, freely shared ideas, debated contentious issues enthusiastically, and strived to make this report both useful and informa- tive to readers. We grew in the process and learned from each other. I deeply appreciate the members’ contributions and insistence on applying an evidence-based approach to the content and recommendations in the report. Their efforts would not have been successful without the invaluable help of ILAR staff and committee consultants, particularly Lida Anestidou and Heidi Shafford, respectively, who each deserve our sincere thanks. I am deeply appreciative of the opportunity to have been a part of this effort and anticipate that the report will meet its principal objectives. Gerald F. Gebhart, Chair Committee on Recognition and Alleviation of Pain in Laboratory Animals

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Glossary Affect: The positive (i.e., preferred) and negative (i.e., avoided) states experienced by animals. Affect is a conscious experience (see conscious- ness). It is similar to the colloquial use of the term “emotion.” Allodynia: Pain produced by normally nonnoxious stimuli (e.g., touch). Analgesic: A drug or endogenous mediator that relieves/reduces pain without concomitant loss of consciousness (e.g., morphine). However, opi- oid analgesics, as well as most drugs used to relieve pain, have sedative- hypnotic properties at greater doses. Anesthetic: A drug that eliminates sensation, including the experience of pain; depending on its activity, it may or may not eliminate pain by inducing loss of consciousness (e.g., local anesthetic vs. barbiturate). Animal welfare: In this report we use “welfare” to mean “well-being.” Anxiolytics: Drugs that reduce anxiety, often used in combination with other drugs to manage pain. Awareness: Feeling, or the experienced state that accompanies pain and other sensations (and thus distinguishes pain from nociception). This report uses “awareness” and “consciousness” interchangeably. Central sensitization: Increased excitability of central nervous system xi

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xii GLOSSARY (CNS) neurons and consequent amplification of input initiated by sensitized nociceptors. Consciousness: This term has a range of meanings; in this report it refers to the experience of sensation widely shared by most animals. Hyperalgesia: Increased sensitivity and response to a noxious stimulus enhanced by sensitization of peripheral nociceptors and central neurons (opposite is hypoalgesia). Inappetence: Lack of appetite. Neuraxis: The central nervous system (CNS; the spinal cord and the brain). Nociception: The detection of a noxious event by nociceptors. Nocicep- tion represents the peripheral and central nervous system processing of information about the internal or external environment generated by noci- ceptor activation. Nociceptor sensitization: Increased excitability and response of nocicep- tors produced by endogenous mediators (e.g., prostaglandins, protons). Noxious stimulus and nociceptors: An event that damages or threatens to damage tissues and that activates specialized sensory nerve endings called nociceptors. Operant conditioning: The use of positive and negative consequences to modify behavior through learning. Pain: An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Pain descriptors 1. Momentary pain: short-lasting, brief, transient (e.g., seconds) and usually of low intensity. 2. Postprocedural/postsurgical pain: longer-lasting than momentary (hours to days to weeks), a consequence of tissue injury due to surgery or other procedures. 3. Persistent pain: lasts for days to weeks such as encountered in studies that investigate pain (and caused by mechanisms other than postprocedural pain). 4. Chronic pain: pain of long duration (i.e., days to weeks to months), typically associated with degenerative diseases, without relief, dif- ficult to manage clinically.

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Contents GLOSSARY xi SUMMARY 1 Approach to This Study, 2 Pain in Animal Research, 3 Recommendations, 4 References, 5 INTRODUCTION 7 Organization of the Report, 8 References, 9 1 Pain in Research Animals: General Principles and Considerations 11 Why Is It Important to Recognize and Alleviate Animal Pain?, 11 What Is Pain?, 13 Animal Pain: Do All Vertebrates Experience Pain?, 20 Causes of Pain in Research Animals, 24 Is Pain in Animals Ever Justifiable?, 26 Conclusions and Recommendations, 27 References, 27 2 Mechanisms of Pain 33 Nociception or Pain, 33 The Development of Persistent Pain, 38 xiii

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xi CONTENTS Ontogeny of Pain, 40 Modulatory Influences on Pain: Anxiety, Fear, and Stress, 42 Conclusions and Recommendations, 43 References, 44 3 Recognition and Assessment of Pain 47 Introduction, 47 Pain Recognition: Clinical Signs and Behavior, 48 Pain Assessment Methods, 50 Pain Assessment: Species-specific Clinical Signs, 56 Conclusions and Recommendations, 63 References, 64 4 Effective Pain Management 71 Introduction, 71 Clinical Veterinary Pain Management, 72 Strategies for Managing Pain in Laboratory Animals, 73 Methods for the Prevention or Management of Pain, 79 Practical Applications and Considerations for Pain Management, 91 Analgesia in Selected Nonmammalian Species, 99 Limitations of Available Information, 104 Conclusions and Recommendations, 106 References, 106 5 Humane Endpoints for Animals in Pain 119 Guidelines and Reference Documents, 119 Pilot Studies, 124 International Regulations and Guidelines for Safety Assessment, 124 Humane Endpoints in Toxicology Studies, 126 Humane Endpoints in Infectious Disease Research, 128 Humane Endpoints in Vaccine Safety and Potency Testing, 129 Humane Endpoints in Cancer Research, 130 Humane Endpoints in Pain Research, 130 Euthanasia, 130 Conclusions and Recommendations, 131 Addendum, 133 References, 137 APPENDIXES A Models of Pain 143 Introduction, 143

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x CONTENTS Animal Models of Persistent Pain, 146 References, 154 B US Regulations and Guidelines Regarding Recognition and Alleviation of Pain in Laboratory Animals 159 Legal Requirements and Agency Guidelines, 159 Other Relevant Guidelines and Statements, 164 References, 165 C About the Authors 167 INDEX 171

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