Recognition and Alleviation of Pain and Distress in Laboratory Animals

Committee on Pain and Distress in Laboratory Animals

Institute of Laboratory Animal Resources

Commission on Life Sciences

National Research Council

NATIONAL ACADEMY PRESS
Washington, D.C. 1992



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Recognition and Alleviation of Pain and Distress in Laboratory Animals Recognition and Alleviation of Pain and Distress in Laboratory Animals Committee on Pain and Distress in Laboratory Animals Institute of Laboratory Animal Resources Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington, D.C. 1992

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Recognition and Alleviation of Pain and Distress in Laboratory Animals NATIONAL ACADEMY PRESS 2101 Constitution Avenue, NW Washington, DC 20418 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, National Academy of Engineering, and Institute of Medicine. The members of the committee responsible for the report were chosen for their special competencies and with regard for appropriate balance. This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, National Academy of Engineering, and Institute of Medicine. This project was supported by the National Center for Research Resources, National Institutes of Health (Grant R24 RR04523-02); American Veterinary Medical Association; Animal and Plant Health Inspection Service, U.S. Department of Agriculture (Grants 12-34-93-0090-IA and 12-34-61-001-GR); Center for Veterinary Medicine, Food and Drug Administration and Animal Welfare Information Service, National Agricultural Library, U.S. Department of Agriculture (Combined Grant 59-32U4-7-125); Association of American Veterinary Medical Colleges; Charles River Laboratories, Inc.; and E. I. du Pont de Nemours & Company. The views, opinions, and findings contained in this report are those of the committee and should not be construed as an official position, policy, or decision of the sponsoring organizations unless so designated by other documentation. Library of Congress Cataloging-in-Publication Data Recognition and alleviation of pain and distress in laboratory animals /Committee on Pain and Distress in Laboratory Animal, Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council. p. cm. Includes bibliographical references and index. ISBN 0-309-04275-5 1. Laboratory animals—Diseases. 2. Pain in animals. 3. Laboratory animals—Effect of stress on. 4. Animal welfare. I. Institute of Laboratory Animal Resources (U.S.). Committee on Pain and Distress in Laboratory Animals. [DNLM: 1. Animals, Laboratory. 2. Animal Welfare. 3. Pain— prevention & control 4. Stress—veterinary. QY 54 R311] SF996.5R43 1992 636.088´5—dc20 DNLM/DLC for Library of Congress 92-8266 CIP Copyright © 1992 by the National Academy of Sciences Printed in the United States of America First Printing, June 1992 Second Printing, January 1993

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Recognition and Alleviation of Pain and Distress in Laboratory Animals This report is respectfully dedicated to the memory of HYRAM KITCHEN September 24, 1932–February 8, 1990 Who dedicated his life to education for the benefit of animals

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Recognition and Alleviation of Pain and Distress in Laboratory Animals 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 Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Frank Press 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 engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Robert M. White is president 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 Institute 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. Kenneth I. Shine is president of the Institute of Medicine. The National Research Council was established by the National Academy of Sciences 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 National Academy of Engineering in the conduct of their 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. Frank Press and Dr. Robert M. White are chairman and vice-chairman, respectively, of the National Research Council.

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Recognition and Alleviation of Pain and Distress in Laboratory Animals COMMITTEE ON PAIN AND DISTRESS IN LABORATORY ANIMALS Arthur L. Aronson (Chairman), North Carolina State University, Raleigh, North Carolina J. Derrell Clark, University of Georgia, Athens, Georgia Ronald Dubner, National Institutes of Health, Bethesda, Maryland G. F. Gebhart, University of Iowa, Iowa City, Iowa Howard C. Hughes, JR., SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania William A. Mason, University of California, Davis, California J. Anthony Movshon, New York University, New York, New York Andrew N. Rowan, Tufts University, North Grafton, Massachusetts Jeri A. Sechzer, Cornell University Medical College, New York, New York Lawrence R. Soma, University of Pennsylvania, Kennett Square, Pennsylvania Staff Thomas L. Wolfle, Director, Institute of Laboratory Animal Resources Dorothy D. Greenhouse, Senior Program Officer Mara L. Aimone, Senior Staff Assistant Amanda E. Huli, Senior Staff Assistant Roberta J. Kahlow, Administrative Secretary (Budget) Carol M. Rozmiarek, Secretary Norman Grossblatt, Editor

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Recognition and Alleviation of Pain and Distress in Laboratory Animals INSTITUTE OF LABORATORY ANIMAL RESOURCES COUNCIL Steven P. Pakes (Chairman), University of Texas Southwestern Medical Center, Dallas, Texas June R. Aprille, Tufts University, Boston, Massachusetts Melvin W. Balk, Charles River Laboratories, Inc., Wilmington, Massachusetts J. Derrell CLARK, University of Georgia, Athens, Georgia Lester M. Crawford, National Food Processors Association, Washington, D.C. Neal First, University of Wisconsin, Madison, Wisconsin Thomas J. Gill III, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Alan M. Goldberg, Johns Hopkins University, Baltimore, Maryland Jon W. Gordon, Mt. Sinai School of Medicine, New York, New York John P. Hearn, Wisconsin Regional Primate Research Center, Madison, Wisconsin Margaret Z. Jones, Michigan State University, East Lansing, Michigan Michael D. Kastello, Merck Sharp & Dohme, Rahway, New Jersey J. Wesley Robb, University of Southern California, Los Angeles, California John L. Vandeberg, Southwest Foundation for Biomedical Research, San Antonio, Texas Thomas L. Wolfle, Director, Institute of Laboratory Animal Resources The Institute of Laboratory Animal Resources (ILAR) was founded in 1952 under the auspices of the National Research Council. Its mission is to provide expert counsel on the scientific, technologic, and ethical use of laboratory animals within the context of the interests and the mission of the National Academy of Sciences, which is to promote the application of science for the public welfare. ILAR promotes the high-quality and humane care of laboratory animals, the appropriate use of laboratory animals, and the exploration of alternatives in research, testing, and teaching. ILAR serves as an advisory group to the federal government, the biomedical research community, and the public.

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Recognition and Alleviation of Pain and Distress in Laboratory Animals COMMISSION ON LIFE SCIENCES Bruce M. Alberts (Chairman), University of California, San Francisco, California Bruce N. Ames, University of California, Berkeley, California J. Michael Bishop, University of California Medical Center, San Francisco, California Michael T. Clegg, University of California, Riverside, California Glenn A. Crosby, Washington State University, Pullman, Washington Leroy E. Hood, California Institute of Technology, Pasadena, California Donald F. Hornig, Harvard School of Public Health, Boston, Massachusetts Marian E. Koshland, University of California, Berkeley, California Richard E. Lenski, Michigan State University, East Lansing, Michigan Steven P. Pakes, University of Texas Southwestern Medical Center, Dallas, Texas Emil A. Pfitzer, Hoffmann-LaRoche Inc., Nutley, New Jersey Thomas D. Pollard, Johns Hopkins University Medical School, Baltimore, Maryland Joseph E. Rall, National Institutes of Health, Bethesda, Maryland Richard D. Remington, University of Iowa, Iowa City, Iowa Paul G. Risser, University of New Mexico, Albuquerque, New Mexico Harold M. Schmeck, JR., Armonk, New York Richard B. Setlow, Brookhaven National Laboratory, Upton, New York Carla J. Shatz, University of California, Berkeley, California Torsten N. Wiesel, Rockefeller University, New York, New York John E. Burris, Executive Director, Commission on Life Sciences

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Recognition and Alleviation of Pain and Distress in Laboratory Animals Preface Animals contribute in important ways to the advancement of biology and to the understanding, prevention, and treatment of diseases of humans and other animals. Beginning with the work of Jenner, Pasteur, and Koch in animals over 200 years ago, vaccines have controlled or eliminated human scourges of smallpox, rabies, yellow fever, poliomyelitis, tetanus, and measles. Today, biotechnology and the use of transgenic animals offer new promise, not dreamed of just a few years ago, for the control of genetic disorders, cancers, and infectious diseases. With the use of animals come responsibilities for their husbandry, care, and humane treatment. Elaborate safeguards have been implemented by the Animal Welfare Act and the Health Research Extension Act. Those acts give animal care and use committees power to oversee animal use and give investigators and veterinarians new responsibilities in ensuring that animals are not used for trivial purposes and that pain and distress are avoided or minimized. However, some animals used in research to prevent and reduce suffering of humans and animals will be subjected to conditions that cause them pain and distress. There is general agreement on the need to minimize pain and distress, but it has been difficult to bring the necessary melange of information together and to disseminate it throughout the scientific community. For 40 years the Institute of Laboratory Animal Resources (ILAR) has developed guidelines for the humane use of animals in research, and in 1988 a group was assembled to advise ILAR on whether it should recommend strategies for complying with the new laws. Federal agencies, humane associations, academic institutions, private companies, and national biomedical associations that use or

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Recognition and Alleviation of Pain and Distress in Laboratory Animals regulate the use of laboratory animals were consulted about the advisability of this project, and ILAR was encouraged to appoint an expert committee. The Committee on Pain and Distress in Laboratory Animals was thereupon formed and asked to prepare this guide as a method of communicating, to persons with widely differing backgrounds and interests, a deeply held ethical conviction that pain and distress in research animals must be avoided whenever possible and that, when it is not possible to avoid them, every effort must be made to recognize and alleviate them—both for the animals' well-being and to avoid effects of stress on the validity of research data. The committee was asked to address both pharmacologic and nonpharmacologic methods of prevention and alleviation; to identify techniques or procedures likely to cause pain or distress; to develop a formulary of anesthetics, analgesics, and tranquilizers for laboratory animals; and to discuss known side effects of drugs or techniques that could confound research results. It quickly became clear to the committee that definitions would have to be developed for pain, stress, distress, well-being, and other terms. The committee proposes that stress progresses from acute stress to chronic stress and to distress when the physiologic cost of adapting becomes too high, at which time the animal manifests maladaptive behavior and intervention is indicated. Professional judgment (as used in the text to emphasize that the recommendations of this report should be interpreted in a manner most appropriate for the welfare of animals and the goals of science) is intended to refer to the collective wisdom and experience of the principal investigator, study director, attending veterinarian, and institutional animal care and use committee. Also, and perhaps most important, the committee felt that, to address nonpharmacologic means of prevention and alleviation, especially in regard to non-pain-induced (environmentally induced) stress, it would have to develop criteria and therapeutic strategies quite different from those used for the recognition and treatment of pain. This volume is intended to increase the awareness and sensitivity of all those working with laboratory animals; provide a ready source of information on appropriate behavioral, biochemical, and physiologic indexes of pain and distress; and present and categorize the methods available for the prevention, reduction, or elimination of pain and distress in various laboratory animal species. The text is organized so as to summarize the scientific basis, recognition, alleviation, and control of pain, stress, and distress in laboratory animals. Chapter 7 discusses the use of euthanasia as a humane strategy of last resort for alleviating pain or distress and presents techniques to reduce stress in animals and in those who must euthanatize them. General criteria for animal well-being are presented with the understanding that this involves more than good health and the absence of pain and distress and that the refinement of any procedure to improve the well-being of an animal is imperative. The refinement of experimental procedures, husbandry practices, and handling is consistent with the humane goals of Russell and Burch, who proposed

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Recognition and Alleviation of Pain and Distress in Laboratory Animals the 3 Rs of replacement, reduction, and refinement to serve as responsible guidelines for the use of animals. This volume focuses on the third R, refinement. We anticipate that this guide will be of interest to researchers, veterinarians, technicians, animal care and use committees, granting agencies, inspectors, site visitors, and others. The committee hopes that it will be useful in the planning or review of experimental procedures and housing and husbandry practices. Shortcomings of the volume include incompleteness regarding drug side effects and how they can compromise the validity of research results. There is a paucity of information in this regard, but responsibility for it must be left to investigators. Perhaps future revisions of the volume can include more information on side effects and on the pharmacokinetic basis of dosage as additional relevant information becomes available. Readers should note that the report is intended to be a basic guide—it is not encyclopedic. Some readers will want more detailed discussions on some points or the inclusion of more drugs or animal species in the dosage tables. For those readers, an extensive bibliography is provided. The report does not treat the complex topics in cookbook fashion. Rather, it must be interpreted and applied with professional judgment. The committee extends its appreciation to the contributors, sponsors, and reviewers of this volume; to Jennifer Fujimoto, Office of Campus Veterinary Services, School of Medicine, University of California, San Diego, for contributions to the dosages and references for various species; and to Norman Grossblatt for editing the manuscript. Thomas L. Wolfle and the ILAR staff assisted the committee, and their dedication and contributions made this book possible. Arthur L. Aronson, Chairman Committee on Pain and Distress in Laboratory Animals

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Recognition and Alleviation of Pain and Distress in Laboratory Animals Contents 1   INTRODUCTION   1     General Considerations of the Biologic Importance of Pain, Stress, and Distress,   2     Definitions,   3     Stressors,   5     Distress Models,   7     Distress Not Induced by Pain,   7     Distress Induced by Pain,   8 2   THE BASIS OF PAIN   10     Peripheral Mechanisms of Nociception,   10     Mediators of Inflammation and Pain,   11     Dorsal Horn Nociceptive Mechanisms,   12     Thalamocortical Mechanisms,   14     Descending Control Mechanisms,   15 3   THE BASIS OF STRESS AND DISTRESS NOT INDUCED BY PAIN   17     Introduction,   17     Ecology and the Captive Environment,   19     Relationships with Conspecifics,   20     Predator-Prey and Defensive Relationships,   23     Shelter,   24

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Recognition and Alleviation of Pain and Distress in Laboratory Animals     Spatial Architecture,   25     Feeding and Foraging,   26     Environmental Events,   28     Research Approaches,   30 4   RECOGNITION AND ASSESSMENT OF PAIN, STRESS, AND DISTRESS   32     Recognition and Assessment of Pain,   32     Clinical Approaches to the Assessment of Pain,   33     Species-Typical Signs,   37     Recognition and Assessment of Stress and Distress,   45     Diagnosis of Stress and Distress,   46     Physiologic and Biochemical Indicators of Pain and Stress,   50     Pharmacologic Assessment of Distress,   52 5   CONTROL OF PAIN   53     Pharmacologic Control of Pain,   56     General Anesthesia,   57     Barbiturates,   61     Dissociative Anesthetics—Cyclohexamines,   63     Neuroleptanalgesics,   68     Opioid Agonists, Agonist-Antagonists, and Antagonists,   69     Nonsteroidal Anti-inflammatory Drugs,   75     Special Anesthetic Considerations,   78     Nonpharmacologic Control of Pain,   83     Hypothermia,   83     Tonic Immobility,   83     Acupuncture,   84 6   CONTROL OF STRESS AND DISTRESS   85     Pharmacologic Control of Stress and Distress,   86     Phenothiazines,   86     Butyrophenones,   89     Benzodiazepines,   89     α2-Adrenergic Agonists,   90     Nonpharmacologic Control of Stress and Distress,   93     Husbandry and Management Practices,   93     Socialization and Handling,   98     Environmental Enrichment,   99     Experimental Design,   100

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Recognition and Alleviation of Pain and Distress in Laboratory Animals 7   EUTHANASIA   102     General Considerations,   102     Euthanasia as an Option for Alleviation of Pain,   102     When to Perform Euthanasia,   103     Aesthetics of Euthanasia: Training, Skill, and Emotional Impact on People   104     Research Considerations,   104     Avoiding Fear in Other Animals,   105     Adjuncts to Euthanasia,   105     Verification of Death,   105     Selection of Euthanatizing Agents and Methods,   105     Inhalational Agents,   107     Physical Methods,   109     Noninhalational Pharmacologic Agents,   111     Recommendations for Specific Animals,   112     Dogs and Cats,   114     Ferrets,   114     Rabbits,   114     Laboratory Rodents,   114     Nonhuman Primates,   115     Birds,   115     Amphibians, Fish, and Reptiles,   115     REFERENCES   117     INDEX   131

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