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Summary T his report is the response to a request by the New Jersey Associa- tion for Biomedical Research that the Institute for Laboratory Animal Research form a consensus committee to update the 1992 National Research Council (NRC) report Recognition and Alleiation of Pain and Distress in Laboratory Animals. In the 16 years since the first report was pub- lished, there has been significant scientific progress in the areas of animal welfare, stress, distress, and pain to warrant a fresh look at the topics of that report. This report follows the release of the 2008 NRC report Recognition and Alleiation of Distress in Laboratory Animals. Although the numerous regulations, policies, and guidelines that govern animal use in research in the United States address distress and pain jointly, from a scientific perspective the two concepts are quite distinct. According to the International Association for the Study of Pain, pain in humans is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” (IASP 1979). Pain is mediated through the activity of specialized sensory receptors, called nociceptors, involves the possibility of bodily injury, and depends on the interaction between those nociceptors and higher processing cen- ters in the brain to generate the negative emotional component associated with the potential harm. While pain can be detrimental to animal welfare, distress always is, as it is a measure of the animal’s inability to cope with a stressor. Adopting an approach similar to that of the 2008 report, the committee that prepared this report focused on the management and avoidance of pain wherever scientifically possible. Continuing in the steps of the 1992 com- 1

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2 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS mittee, the current committee embraced the idea that in most experimental and husbandry situations laboratory animals need not experience pain, and that its alleviation and prevention are an ethical and moral imperative that is embodied in the relevant regulations and policies. In fact, this approach was codified in the statement of task for this project: The . . . report will update information based on the current scientific litera- ture on recognizing and alleviating pain in laboratory animals. The report will discuss the physiology of pain in commonly used laboratory species. Specific emphasis will be placed on the identification of humane end- points, pharmacologic and non-pharmacologic principles to control pain, and principles to utilize in minimizing pain associated with experimental procedures. As with the first report [on Distress], general guidelines and examples will be given to aid IACUC members, investigators and animal care staff in making decisions about protocols using laboratory animals under current federal regulations and policies. APPROACH TO THIS STUDY The committee collected and evaluated scientific evidence from peer- reviewed published literature, evidence-based veterinary practices, and expert opinions, and defined a consistent terminology in the Glossary and Chapter 1. The committee examined the occurrence of pain in vertebrates alone, for several reasons: (1) the current regulations affect only the verte- brate phylum; (2) most laboratory animal species used in research, educa- tion, and training are vertebrates; and (3) there is ongoing debate about whether pain occurs in subjects that may or may not have consciousness (readers are urged to explore studies of adult humans in a persistent vegeta- tive state or with dementia and consider the implications of those data for nonverbal populations such as laboratory animals). As it was beyond the task of this committee to evaluate and analyze the last question, the under- lying premise of this report is that all vertebrates should be considered capable of experiencing the aversive state of pain. Although most of the information used in the report reflects studies and observations in mammals, currently available (albeit very limited) data on birds, fish, reptiles, and amphibians are also included. The committee decided against including information on the treatment and management of pain for each laboratory species, because for the commonest of these many referenced and peer-reviewed publications, professional societies’ guidelines, books, and book chapters are readily available for reference. Instead, the committee opted to expand on species for which the body of peer-reviewed work is still small and for which guidelines are lacking. This report therefore provides practical information on birds, amphibians, fish, and reptiles in order to help the scientific and veterinary community better care for these laboratory species.

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3 SUMMARY PAIN IN ANIMAL RESEARCH The committee acknowledges that pain in animals is difficult to assess, mostly because of a lack of methods to validate and objectively measure it. Until such tools are developed, behavioral indices and careful extrapolation from the human experience should be used to assess pain in research ani- mals. It is important to bear in mind that pain may be not only the result of a research procedure but also a byproduct of husbandry or other unrelated factors (e.g., aging). Pain may arise in response to a noxious stimulus and in situations likely to cause increased sensitivity to pain (i.e., hyperalgesia), such as injury and inflammation. Psychological factors also likely contribute to pain under these circumstances. Pain is the result of a cascade of physiological, immunological, cogni- tive, and behavioral effects that may make uncontrolled pain a source of experimental error. Although there are circumstances in which withhold- ing treatment is necessary (as, for example, when pain itself is the focus of the study), routinely withholding analgesics after surgery or other invasive procedures with anticipated moderate to severe pain is detrimental to the welfare of the research subjects, contrary to the regulatory mandate, and unethical. A useful assumption is that the magnitude of the clinical signs (see Chapter 3) and behavioral changes observed correlates closely with the intensity of pain. Current best practices to assess pain entail a structured clinical examination combined with solid knowledge of the normal appear- ance and behavior of the species. Anticipating the potential intensity of pain is important in designing the most appropriate approach to its management or prevention. Common interventions to treat pain include the use of anesthetics, analgesics, anxio- lytics, and nonpharmacological methods. Although regulations specify that only nonbrief, procedural pain requires treatment, pain of any duration or intensity—including multiple episodes of momentary pain—merits consid- eration and potential treatment. As in Recognition and Alleiation of Distress in Laboratory Animals, this report stresses the importance of the Three Rs (replacement, refinement, and reduction) as the standard for identifying, modifying, minimizing, and avoiding most causes of pain in laboratory animals. To this end, the com- mittee believes that adoption of humane endpoints is critical, particularly in studies where significant pain is anticipated. Because humane endpoints are unique to individual research projects, pilot studies should be undertaken to identify and incorporate them in the study design. In this as in all stages of the research, good communication between researchers, veterinarians, animal care personnel, and institutional animal care and use committee (IACUC) members is crucial.

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4 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS RECOMMENDATIONS Based on the information analyzed and discussed in this report, the committee makes overarching consensus recommendations above and beyond those at the end of individual chapters: • Current scientific evidence strongly suggests that mammals, includ- ing rodents (the most commonly used laboratory animals), are able to experience pain. Researchers, veterinarians, animal care person- nel, and IACUC members should heed the 4th Government Prin- ciple1 and use professional judgment and best practices to avoid or minimize unnecessary pain. Researchers conducting studies in which more than momentary pain is anticipated should, in addition to providing appropriate analgesia, consider and enforce (where possible) humane endpoints to protect the welfare of the laboratory animals. • Knowledge about pain in nonmammalian species is incomplete and in the absence of evidence they should be treated humanely with serious consideration of, and attention to, the potentially pain- ful implications of noxious stimuli and invasive procedures. • Any study that will likely result in pain for the animal subjects should have clearly determined, appropriate humane endpoints. The importance of pilot studies to determine such endpoints is par- amount. Teamwork and open communication between researchers, veterinarians, animal care staff, and the IACUC can facilitate and expedite the definition, validation, and implementation of appropri- ate endpoints. • Funding is particularly difficult for projects that investigate the understanding, recognition, and alleviation of pain, especially if the beneficiaries of such studies are the laboratory animals them- selves. However, lack of knowledge of drug effects and doses in many mammalian and especially nonmammalian species, and the potentially confounding effects of analgesics and anesthetics on study variables, limit effective pain management. Given the impact of better animal welfare on science as well as the growing public interest in the treatment of laboratory animals, federal agencies and foundations that support biomedical and behavioral research should make funds available for pain-related studies (see also NRC 2008). 1 US Government Principle #4 states that “Proper use of animals, including the avoidance or minimization of discomfort, distress, and pain when consistent with sound scientific practices, is imperative. Unless the contrary is established, investigators should consider that procedures that cause pain or distress in human beings may cause pain or distress in other animals.”

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 SUMMARY • Lack of adequate funding also hinders efforts to develop and vali- date alternatives (methods, procedures, and research strategies); such efforts must continue in order to ensure the incorporation of alternatives in research projects and safety assessment tests. • It is necessary to educate investigators, veterinarians, and animal care staff about the basic physiologic principles, causes, signs, and availability of diverse treatment options and potential deleterious effects of those treatments on pain. As the field of pain medicine benefits from new insights and methods of prevention and treat- ment for humans, so should laboratory animals benefit from the research for which they are a currently indispensable underpinning. As laboratory animal veterinarians enhance their understanding of pain management and regulatory policy is updated, the ability to minimize pain in laboratory animals can proceed in tandem with scientific progress. REFERENCES IASP (International Association for the Study of Pain). 1979. IASP Pain Terminology. Available at http://www.iasp-pain.org/AM/Template.cfm?Section=Pain_Definitions&Template=/CM/ HTMLDisplay.cfm&ContentID=1728#Pain. Accessed January 8, 2009. NRC (National Research Council). 2008. Recognition and Alleviation of Distress in Laboratory Animals. Washington: National Academies Press.

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