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PREPUBLICATION COPY
Recognition and Alleviation of Pain
in Laboratory Animals
PREPUBLICATION COPY
Committee on Recognition and Alleviation of Pain in Laboratory Animals
Institute for Laboratory Animal Research
Division on Earth and Life Studies
THE NATIONAL ACADEMIES PRESS
Washington, D.C.
www.nap.edu
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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 Governing Board of the National Research Council,
whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, 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; GlaxoSmithKline; 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 Institutes 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 Institues of Health, nor does mention of trade names,
commercial products, or organizations imply endorsement by the US government.
Recognition and Alleviation of Pain in Laboratory Animals /
Committee on Recognition and Alleviation of Pain in Laboratory Animals, Institute of Laboratory Animal Research,
Division on Earth and Life Studies.
[Library of Congress Cataloging-in-Publication Data]
International Standard Book Number
International Standard Book Number
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
Prepublication Copy
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scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general
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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
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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
Lyndon Goodly, University of Illinois
Alicia Z. Karas, Tufts University
Stephen T. Kelley, University of Washington
Jane Lacher, The Dow Chemical Company
Georgia Mason, University of Guelph
Lynne U. Sneddon, University of Liverpool
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 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, Center for Comparative
Medicine, Davis, California
Kathryn A. Bayne, Association for Assessment and Accreditation of Laboratory Animal
Care International, Frederick, Maryland
Myrtle A. Davis, National Cancer Institute, National Institutes of Health, Bethesda,
Maryland
Jeffrey I. Everitt, GlaxoSmithKline Research and Development, Comparative Medicine
and Investigator Support, Research Triangle Park, North Carolina
James G. Fox, Massachusetts Institute of Technology, Division of Comparative
Medicine, Cambridge, Massachusetts
Nelson L. Garnett, Consultant, Laboratory Animal Care and Use Programs, Dickerson,
MD
Estelle B. Gauda, Johns Hopkins University School of Medicine, Johns Hopkins
Hospital, Baltimore, Maryland
Coenraad F.M. Hendriksen, Netherlands Vaccine Institute, Bilthoven, The Netherlands
(to June 2008)
Jon H. Kaas, Vanderbilt University, Nashville, Tennessee (to June 2008)
Joseph W. Kemnitz, University of Wisconsin, Primate Research Center, Madison,
Wisconsin
Judy A. MacArthur Clark, Animals Scientific Procedures Inspectorate, London, United
Kingdom
Martha K. McClintock, Institute of Mind and Body, The University of Chicago,
Chicago, Illinois
Leticia V. Medina, Abbott Laboratories, Abbott Park, Illinois
Timo Olavi Nevalainen, National Laboratory Animal Center, University of Kuopio,
Kuopio, Finland
Bernard E. Rollin, Colorado State University, Department of Animal Sciences, Fort
Collins, Colorado
Abigail L. Smith, University of Pennsylvania, School of Veterinary Medicine,
Philadelphia, Pennsylvania
Stephen A. Smith, Virginia Polytechnic Institute and State University, Department of
Biomedical Sciences and Pathobiology, Blacksburg, Virginia
James E. Womack, Texas A&M University, College Station, Texas
Staff
Joanne Zurlo, Director
Lida Anestidou, Program Officer
Kathleen Beil, Administrative Coordinator
Cameron Fletcher, Managing Editor, ILAR Journal
Rhonda Haycraft, Senior Project Assistant
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INSTITUTE FOR LABORATORY ANIMAL RESEARCH PUBLICATIONS
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)
Guide for the Care and Use of Laboratory Animals (1996)
Guide for the Care and Use of Laboratory Animals — Korean Edition (1996)
Guide for the Care and Use of Laboratory Animals — Chinese Version (1996)
Guide for the Care and Use of Laboratory Animals — Spanish Version (1996)
Guide for the Care and Use of Laboratory Animals — Russian Version (1996)
Guide for the Care and Use of Laboratory Animals — French Version (1996)
Guide for the Care and Use of Laboratory Animals — Taiwanese Edition (1996)
Guide for the Care and Use of Laboratory Animals — Portuguese Edition (1996)
Guide for the Care and Use of Laboratory Animals — Japanese Edition (1996)
Rodents (1996)
Nutrient Requirements of Laboratory Animals, Fourth Revised Edition (1995)
Laboratory Animal Management: Dogs (1994)
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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 may be ordered from the National Academies Press
(800) 624-6242 or (202) 334-3313
www.nap.edu
Prepublication Copy viii
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ACKNOWLEDGEMENTS
In preparation for this report, the committee invited experts to present
their perspectives on the concepts of nociception, pain, consciousness, and
awareness. The Committee thanks:
A. Vania Apkarian, Northwestern University
Colin Allen, Indiana 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 Council
(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, Arkansas Childern’s Hospital Research Institute
George J. DeMarco
Ronald Dubner, University of Maryland
Sherril Green, Stanford School of Medicine
C. Terrance Hawk, GlaxoSmithKline Pharmaceuticals R&D
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, The University of British Columbia
Tony L. Yaksh, University of California San Diego
Although the reviewers listed above have provided many constructive
comments and suggestions, they were not asked to endorse the report’s
conclusions 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 considered.
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x ACKNOWLEDGEMENTS
Responsibility for the final content of this report rests entirely with the
authoring Committee and the instituion.
This report is the product of committee members who gave generously
of their time and effort. The committee rapidly developed into a collegial,
hard-working group, freely shared ideas, debated contentious issues
enthusiastically, and strived to make this report both useful and informative to
readers. We grew in the process and learned from each other. I deeply
appreciate their 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
for the opportunity to have been a part of this effort and anticipate 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 in the context
described below (see consciousness). It is similar to the colloquial use of the
term “emotion”.
Allodynia: pain produced by normally non-noxious stimuli (e.g., touch).
Analgesic: a drug or endogenous mediator that relieves/reduces pain without
concomitant loss of consciousness (e.g., morphine). However, opioid
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 (thus distinguishes pain from nociception). This report uses
“awareness” and “consciousness” interchangeably.
Central sensitization: Increased excitability of CNS neurons and consequent
amplification of input initiated by sensitized nociceptors.
Consciousness: This term potentially has a range of meanings; in this report it
is used to refer to the experience of sensation widely shared by most animals.
Hyperalgesia: Increased sensitivity and response to a noxious stimulus
contributed to 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).
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GLOSSARY xii
Nociception: The detection of a noxious event by nociceptors. Nociception
represents the peripheral and central nervous system processing of information
about the internal or external environment generated by nociceptor activation.
Nociceptor sensitization: Increased excitability and response of nociceptors
produced by endogenousmediators (e.g., prostaglandins, protons).
Noxious stimulus and nociceptors: An event that damages, or threatens to
damage tissues and which 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 with low intensity.
2. Post-procedural/post-surgical 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 post-
procedural pain).
4. Chronic pain: pain of long duration (i.e., days to weeks to months),
typically associated with degenerative diseases, without relief, difficult
to manage clinically.
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CONTENTS
GLOSSARY .................................................................................. xi
SUMMARY.................................................................................... 1
Approach to this study .............................................................. 2
Pain in animal research ............................................................. 2
Recommendations. .................................................................. 3
References ............................................................................ 5
INTRODUCTION............................................................................. 7
Organization of the report ......................................................... 8
References ............................................................................ 9
CHAPTER 1. Pain in research animals: General principles and considerations
...................................................................................... 11
Why is it important to recognize and alleviate animal pain? ................11
What is pain?.........................................................................12
Animal pain ..........................................................................21
Causes of pain in research animals...............................................25
Is pain in animals ever justifiable? ...............................................28
Conclusions and recommendations...............................................29
References ...........................................................................29
CHAPTER 2. Mechanisms of pain ..................................................... 35
Nociception or pain .................................................................35
The development of persistent pain .............................................40
Ontogeny of pain ....................................................................42
Modulatory influences on pain: Anxiety, fear, and stress ....................43
Conclusions and recommendations...............................................45
References ...........................................................................46
CHAPTER 3. Recognition and assessment of pain ................................ 49
Introduction..........................................................................49
Pain recognition: Clinical signs and behavior ..................................50
Pain assessment methods..........................................................53
Pain assessment: Species-specific clinical signs ...............................59
Conclusions and recommendations...............................................65
References ...........................................................................66
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xiv CONTENTS
CHAPTER 4. Effective pain management ........................................... 73
Introduction..........................................................................73
Clinical veterinary pain management ...........................................73
Strategies for managing pain in laboratory animals ...........................75
Methods for the prevention or management of pain ..........................82
Practical applications and considerations for pain management ...........92
Limitations of available information........................................... 105
Conclusions and recommendations............................................. 106
References ......................................................................... 107
CHAPTER 5. Humane endpoints for animals in pain ............................125
Introduction........................................................................ 125
Guidance documents and guidelines........................................... 127
Pilot studies........................................................................ 129
Humane endpoints ................................................................ 130
Euthanasia.......................................................................... 136
Conclusions and recommendations............................................. 136
References ......................................................................... 141
APPENDIX 1. Models of pain..........................................................147
Introduction........................................................................ 147
Animal models of persistent pain .............................................. 148
References ......................................................................... 158
APPENDIX 2. U.S. regulations and guidelines regarding recognition and
alleviation of pain in laboratory animals..................................165
Legal requirements and agency guidelines ................................... 165
Other relevant guidelines and statements .................................... 170
References ......................................................................... 171
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