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DEFINITION OF PAIN AND DISTRESS AND REPORTING REQUIREMENTS FOR LABORATORY ANIMALS: PROCEEDINGS OF THE WORKSHOP HELD JUNE 22, 2000 Assessing Pain and Distress: A Veterinary Behaviorist's Perspective Kathryn Bayne Associate Director American Association for the Accreditation of Laboratory Animal Care International “Fundamental to the relief of pain in animals is the ability to recognize its clinical signs in specific species” (NRC 1996). I thought I would set the tone for my presentation this morning with this quotation from the Guide because although today's objective is to provide federal regulators and policy makers with input regarding definitions of pain and distress, our larger goal as a research community is the prevention or relief of unnecessary pain and distress in laboratory animals. Although I will be discussing both pain and distress briefly this morning, the speaker who follows me, Dr. Gerry Gebhart, is much more knowledgeable about pain than I, so at the end I will offer up only a definition of distress. ASSESSING PAIN AND DISTRESS Carstens and Moberg (2000) suggest that a reasonable, although imperfect, approach to measuring the stress associated with pain and distress is to evaluate responses in four basic systems: the autonomic nervous system, the neuroendocrine system, the immune system, and behavior. All of these systems reflect arousal of the animal; however, this morning I will focus on that area I know best—animal behavior. The Dilemma of Definitions As has been stated many times, much of the difficulty in achieving a broadly accepted approach to categorizing, and then addressing, pain and distress is due
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DEFINITION OF PAIN AND DISTRESS AND REPORTING REQUIREMENTS FOR LABORATORY ANIMALS: PROCEEDINGS OF THE WORKSHOP HELD JUNE 22, 2000 to the absence of a concise definition. From a behavioral perspective, this inability to arrive at a “Webster's Dictionary” type of definition is due in part to the fact that: 1) pain and distress are not discrete states, but are a continuum of experience; 2) signs differ between species, and most animals hide signs of pain because such a sign of weakness may provoke an attack from predators or subordinate members of the group; 3) there is a lack of specific behavioral indicators of pain; 4) interobserver variability can be large; and 5) there is a tendency to anthropomorphize, which is encouraged by US Government Principle IV. That principle states that “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. ” Issues with Assessing Pain It is a well-established and accepted practice to use human experience to judge an animal's experience of pain and distress. Although I completely support this principle, I think we need to use this kind of assessment as a starting, not an end, point. We need to encourage investigators to include studies of pain and distress as they perform their research and to publish their findings. Currently, there are several variables associated with pain assessment: Assessments vary with the scale used, and they can be very subjective. What one person may view as a procedure that evokes moderate pain or distress, another may view as one that elicits minor pain or distress. As Flecknell (1994) has noted, the absence of preprocedural scoring results in a lack of validation scores. There are no control data, so frequently confounding variables (such as those produced by analgesics) cannot be identified. For example, some of the consequences of surgery in rats, such as loss of body weight and suppression of food and water intake (signs frequently interpreted to be indicative of pain and/or distress), can also be produced in normal, unoperated rats by administration of opioid analgesics. Chronic signs can be subtle and hard to detect. Changes in behavior due to pain and/or distress can be slow, incremental, and, individually, virtually undetectable. Whereas, The dramatic, sudden onset of signs of pain is readily recognizable. Issues with Assessing Distress Distress is a generic term that can encompass anxiety, fear, boredom, frustration, and so forth. Thus, there are potentially multiple expressions of distress. Causes of distress that have been proposed include heat, light, sound, thirst, hunger, pain, novelty, exercise, pursuit, disease, and so there are also potentially multiple causes. But remember, the difficulties we continue to have in defining
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DEFINITION OF PAIN AND DISTRESS AND REPORTING REQUIREMENTS FOR LABORATORY ANIMALS: PROCEEDINGS OF THE WORKSHOP HELD JUNE 22, 2000 psychological well-being are due to a lack of direct reporting of the state of well-being by the subject (no language), not knowing what minor changes in well-being really mean to the animal, and not knowing what the impact is of levels of well-being on the research (which probably varies with the study). There are advantages to using animal behavior as an assessment tool. For example, behavioral assessment is probably the least intrusive measure; and in the hands of a skilled, knowledgeable observer, behavior as an indicator of well-being (or lack thereof) can be reliable and powerful. A knowledgeable observer has the expertise to use different criteria in different species and to gauge their significance, and the skilled observer will predicate his/her assessment on the animal 's milieu, including its physical environment, the research it is used in, and the animal's own status (e.g., its age and health). However, there are also some disadvantages to using animal behavior as the assessment tool. Early experience (which may not be known), age, and physiological state can influence the behavioral response of an animal leading to interand intra-animal variability. For example, some research indicates that young animals are more responsive to pain stimuli than older animals and that sick animals may also be more responsive than healthy counterparts. As has often been noted, correlations of specific pain-related behavior with intensity of the pain experience cannot be made. There is no behavior expressed by animals that indicates the severity of pain being experienced. Even the assessment of the efficacy of an analgesic is based on rather crude analgesiometric tests such as a hot plate or tail flick test. There are too many amateur behaviorists, which can lead to overconfidence in their abilities. One lecture or even one course in animal behavior does not turn someone into an expert, just as the college courses I took in accounting and economics did not turn me into an Alan Greenspan. Our exposure to animal behavior through the popular press and television lulls us into a belief that we all have knowledge in the field and skills in understanding animal behavior. Indicators of Pain When evaluation criteria for pain are sought, a common approach is the use of general behavior that is extrapolated into indicators of pain in several species of laboratory animals. The problem is that this approach is rife with subjective criteria and/or contradictions. For example, Morton and Griffiths' (1985) seminal article, “Guidelines on the Recognition of Pain, Distress and Discomfort in Experimental Animals and an Hypothesis for Assessment,” which has influenced numerous working group reports and reviews over the years, includes a table of specific, summarized behavioral signs indicative of pain and distress. Categories of behavioral criteria used by the authors are posture, vocalizations, temperament, locomotion, and other. Several of the behavioral criteria, such as dormouse
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DEFINITION OF PAIN AND DISTRESS AND REPORTING REQUIREMENTS FOR LABORATORY ANIMALS: PROCEEDINGS OF THE WORKSHOP HELD JUNE 22, 2000 posture, anxious glances, hangdog look, urgent squealing, and distinctive cry, are clearly open to a wide range of possible interpretations. As recently as this year, a publication in ILAR Journal by Carstens and Moberg (2000) attempts to refine the Morton and Griffiths table by blending in elements from the NRC report Recognition and Alleviation of Pain and Distress in Laboratory Animals (1992); the FELASA working group report on “The Assessment and Control of the Severity of Scientific Procedures on Laboratory Animals” (Wallace and others 1990); and a Laboratory Animal Science article by Soma (1987) on assessing pain and distress. Carstens and Moberg propose different categories of criteria: general behavior, appearance, and physiology. This broader evaluation scheme may be more reliable than basing a judgment solely on one type of measure; however, it too contains some inherent difficulties for the evaluator. Specifically, the behavioral signs the authors report as indicators of pain in animals of the same species can be diametrically opposed; yet, both can be observed during experiences of pain. For example, the rat may express reduced activity or increased aggression; the guinea pig may squeal and stampede or go quiet; the dog may whimper, howl, growl or become quiet; and the cat may hiss or spit or become quiet. These inherent contradictions underscore the point that no single behavior is a reliable indicator of pain and that gauging pain requires a skilled observer not only to accurately record the signs but also to interpret them correctly. It should be noted that behaviors used to assess pain are also not expressed exclusively during painful episodes (e.g., vocalizations). Stafleu and others (1992) make this point using the example of pig vocalizations. If you have ever worked with swine, you are aware that a minimum of restraint, sometimes even simply picking up a piglet, can result in very intensive screaming by the animal. Is the pig in pain? No. Stafleu and colleagues suggest that because piglets run a great risk of being crushed by their mother, they have evolved a low threshold for screaming to alarm the mother. The screaming might indicate some stress (“anxiety”), but even that behavior cannot be judged on this one measure. In addition, of course, the fact that pigs scream rather readily should not lead to the assumption that they are never in pain when they scream. Vocalizations are simply not a sufficiently sensitive measure to use solely in an assessment of pain. Indicators of Distress Indicators of distress are no less complex. Expressed behaviors that vary from the norm are generally used as indicators of distress. However, the observer must first establish what is normal for the animal (e.g., free-ranging vs. captive, aged animal vs. young animal) and then determine whether the behavior is not only atypical, but also maladaptive. This distinction is important because it is the expression of maladaptive behaviors that is likely to reflect a detriment in the well-being of the animal (e.g., high levels of locomotion vs. locomotion to the
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DEFINITION OF PAIN AND DISTRESS AND REPORTING REQUIREMENTS FOR LABORATORY ANIMALS: PROCEEDINGS OF THE WORKSHOP HELD JUNE 22, 2000 point where the animal is nonresponsive to potentially important external signals). Several scientific studies suggest that the expression of some atypical behaviors may be a coping mechanism of the animal either to increase or decrease its sensory input. Although this expression may signal that re-evaluation of the animal's environment is necessary, such coping activity may actually be an indicator of a lack of distress (Novak and Suomi 1988). If the behavior profile expressed by the animal is narrow, it is important to identify which behaviors are lacking and whether their lack is a problem for the animal. One should ask what it means to the animal if certain behaviors are not performed. The animal should also be evaluated for changes in its behavior. Several small, incremental changes over time can result in an animal expressing significantly different behavior. Again, what does the change mean to the animal? Change in behavior should not necessarily be equated with behavioral pathology. Degrees of Stress As previously mentioned, stress is a continuum of experience. I would consider a mild stressor one that results in a short-term physiological response on the part of some animals and slight to no behavioral adjustment. Examples might include room entry and regular husbandry activities which have been shown to cause an increase in heart rate (Line and others 1989). A moderate stressor may include a minor procedure on the animal or a more significant procedure that is accompanied by pain relief and perhaps unconsciousness during the procedure. A moderate stressor would evoke behavioral adjustment on the part of the animal and physiological recovery or adaptation by the animal. The animal may experience limited distress (or perhaps eustress) associated with restraint. A severe stressor is one for which no relief is provided to the animal either through the ability to physically remove itself from the stressor or by modifications in its environment that would reduce the stress (e.g., use of nesting material to modulate cage temperature or treatment of a disease state). In such a case, there is inadequate adaptation by the animal to the stressor and distress results. I would, therefore, define distress as a state in which the animal is unable to adapt to the stressor and the animal may exhibit maladaptive behavior. The animal is not coping—behaviorally or physiologically. Using Behavior to Assess Pain and Distress So, how can we successfully use behavior as an indicator of pain and/or distress? I concur with the literature that recognizes two critical factors: (1) Individuals making the behavioral assessments must be knowledgeable and skilled in the interpretation of behavior; and (2) assessments should not be influenced by
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DEFINITION OF PAIN AND DISTRESS AND REPORTING REQUIREMENTS FOR LABORATORY ANIMALS: PROCEEDINGS OF THE WORKSHOP HELD JUNE 22, 2000 the personal biases of the observer (i.e., what the animal is perceiving vs. what the observer is feeling when observing the animal [Sanford and others 1986]). Thus, behavior should be just one assessment tool used in the process by which pain and distress are assessed, monitored, and relieved. An overarching precept is that performance standards should be used in the assessment balanced with our scientific knowledge of animals ' behavior. A workable process for pain and distress management involves use of the IACUC. Specifically, The IACUC should review protocols for the appropriate use of pain-relieving agents. The committee should consider the criteria and determine a process for timely intervention, removal of animals from the study, or euthanasia if painful or distressful outcomes are anticipated. The committee's deliberations should be documented. The IACUC should ensure that a system to monitor and provide feedback is in place so that modifications in procedures can be requested as necessary. Guidelines should be in place that provide assistance in categorizing pain and/or distress for use by investigators and IACUC members. A classification system should be reasonable and consistently applied throughout the institution. A mechanism for prompt reporting of compromised animals should be developed and implemented. Personnel (research staff, animal care staff, IACUC members) should be trained in pain and distress management. A Program of Pain and Distress Management I believe our focus and that of the USDA needs to be on the experience of the animal. We should consider an entire program of pain and distress management, of which the animal's behavior will likely play a role in each of the following program elements: recognition, assessment, relief (if possible), and a feedback loop to animal care and use. Responsibility for and oversight of animal well-being—and more specifically the minimization of pain and distress—is shared by several key institutional components: the research staff, the IACUC, the veterinarian, and other animal care staff. Their roles are separate, yet they overlap. There should be a flow of information and synergy among these components that results in a strong program to identify potential pain or distress-inducing circumstances, implement change (where possible) to minimize/eliminate the pain or distress, and include follow-up and monitoring to ensure that the goals of minimization are achieved. It is critical to avoid a splintered program in which these various institutional
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DEFINITION OF PAIN AND DISTRESS AND REPORTING REQUIREMENTS FOR LABORATORY ANIMALS: PROCEEDINGS OF THE WORKSHOP HELD JUNE 22, 2000 elements operate in different directions, rather than building and supporting a uniform, cohesive, and proactive program of pain and distress management. REFERENCES Carstens E., and G.P. Moberg. 2000. Recognizing pain and distress in laboratory animals. ILAR J 41: 62-71. Flecknell P. A. 1994. Refinement of animal use— assessment and alleviation of pain and distress. Lab Anim 28: 222-231. Line W., K.W. Morgan, H. Markowitz, and S. Strong. 1989. Heart rate and activity of rhesus monkeys in response to routine events. Lab Primate News 28: 9-12. Morton D.B., and P.H.M. Griffiths. 1985. Guidelines on the recognition of pain, distress and discomfort in experimental animals and an hypothesis for assessment. Vet Rec 116: 431-436. NRC [National Research Council.] 1992. Recognition and Alleviation of Pain and Distress in Laboratory Animals . Washington, D.C.: National Academy Press. NRC [National Research Council.] 1996. Guide for the Care and Use of Laboratory Animals. 7th ed. Washington, D.C.: National Academy Press. Novak M.A., and S.J. Suomi. 1988. Psychological well-being of primates in captivity. Am Psychol 43: 765-773. Sanford J., R. Ewbank, V. Molony, W.D. Tavenor, and O. Uvarov. 1986. Guidelines for the recognition and assessment of pain in animals. Vet Rec 118: 334-338. Soma L.R. 1987. Assessment of animal pain in experimental animals. Lab Anim Sci 37: 71-74. Stafleu F.R., E. Rivas, T. Rivas, J. Vorstenbosch, F.R. Heeger, and A.C. Beynen. 1992. The use of analogous reasoning for assessing discomfort in laboratory animals. Anim Welfare 1: 77-84. Wallace J., J. Sanford, M.W. Smith, and K.V. Spencer. 1990. The assessment and control of the severity of scientific procedures on laboratory animals. Lab Anim 24: 97-130. QUESTIONS AND ANSWERS DR. COUTO (Marcelo Couto, Scripps Institute and AALAS): Will AAALAC encourage institutions to use certified behaviorists to evaluate their enrichment programs, or will they trust amateurs as well? DR. BAYNE: Although I am not here to speak on behalf of AAALAC, I am trying to discourage institutions from relying on amateurs without giving them appropriate training. There are many behaviorists who are not laboratory animal specialists. AAALAC looks at an institution 's processes and at whether the outcomes conform with Guide recommendations and the other referenced resources that we list on our Web site. The Council does, in fact, encounter instances about which they feel compelled to comment, either as a mandatory item or as a suggestion for improvement regarding an institution's program of pain and distress management. They frequently include their observations on pain and distress management when they comment on the IACUC's operations. DR. TAYLOR (James Taylor, NIH): I would only clarify that in looking at an institution's process, we actually look at the results of that process. If they appear to be inadequate or absent, then we are going to communicate with the institution.
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DEFINITION OF PAIN AND DISTRESS AND REPORTING REQUIREMENTS FOR LABORATORY ANIMALS: PROCEEDINGS OF THE WORKSHOP HELD JUNE 22, 2000 DR. GEBHART (Gerry Gebhart, University of Iowa): Dr. Bayne, I inferred from your comments that you believe the definition for distress proposed by the USDA might be inappropriate. In my opinion, that definition is more likely to represent stress, rather than distress, of an animal. Is that a fair interpretation? DR. BAYNE: Yes, thank you for highlighting that distinction. The USDA should review the language to reflect that the animal's inability to adapt or cope is distress due to the anxiety, fear, change, and novelty Dr. DeHaven described. All of those states are considered by ethologists to be stressors (not distressors). Only when an animal is unable to cope will it slide into the category of distress. DR. GLUCK (John Gluck, Kennedy Institute of Ethics): You were very critical of the Morton and Griffiths papers, but I do not understand the nature of your criticism. Certain postures or eye movements appear to be relatively structural definitions that do not require a great deal of functional interpretation. Please describe your criticisms more explicitly. DR. BAYNE: I believe the Carstens and Moberg paper is actually better because, with 15 years of additional information, it relies on the physiology of the animal in addition to behavior. The Morton and Griffiths paper, however, relies strictly on behavior and on the use of terms that are inherently subjective for assessing an animal 's state of pain or distress. I am not sure I know what a “dormouse posture” is. I would have to go back into Walker's Mammals to see what a dormouse looks like. I am not sure we would all agree on an “anxious look.” I think many Bassett hounds look anxious, and they are not; it is simply the expression. The amount of subjectivity in the criteria they proposed and the tremendous influence of the paper on many other, particularly European, positions are disturbing to me. I believe David Morton has evolved his position and has, in recent years, developed very elaborate, detailed score sheets for rodents. However, they are not extrapolatable to all laboratory animal species. They, in fact, include other physiological dimensions of the animal 's state. Frequently, there is a great deal of reliance in the literature on such criteria as reproduction. However, if you deliberately preclude reproduction, then it becomes a moot point. Again, I would question the use of sole reliance on behavioral criteria because they vary from species to species. As I attempted to imply, there is even intra-animal variability based on an animal's experience as it ages, so our criteria must shift accordingly to avoid over- or underinterpreting. DR. GLUCK: I am not trying to defend David Morton, but I think the overall impact of that paper and some of his other publications successfully draw attention to later, more formalized procedures whereby the experimenter, researcher, or staff member is required to check an animal's conduct in one form or another. DR. BAYNE: I do not argue that point at all. I simply do not want institutions to go back and use those tables, which is what the authors were proposing. DR. NELSON (Randall Nelson, University of Tennessee, ILAR Council, and IACUC member): You made a very good point, which is that we should
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DEFINITION OF PAIN AND DISTRESS AND REPORTING REQUIREMENTS FOR LABORATORY ANIMALS: PROCEEDINGS OF THE WORKSHOP HELD JUNE 22, 2000 assess the animal's behavior based on what is normal for that individual animal. How then do we deal with the assessment of who has the expertise to make the appropriate distinction between normal and abnormal? I submit that sometimes the investigator, although biased, may have much more knowledge about the animal's normal behavior than the veterinarian or the IACUC member. DR. BAYNE: I agree, and if I were an IACUC member, I would not want to rely on just one source person. For example, the expertise of rodent caretakers is different from that of primate behaviorists. An institution probably has many, many different resources which the IACUC should use. With regard to PIs, they have typically studied certain animals in graduate school, they tend to work with the same species, and they know their animal models very well indeed. Transgenic animals, of course, are developing a variety of behavioral profiles that are different from what we consider those of the standard mice. If that development is normal for that transgenic animal, then it becomes your baseline. As in any good scientific study, you need to evaluate your baseline. You need to be certain that your baseline is not changing and that you do not apply the same one to every study. A good IACUC is going to be very proactive in probing, asking questions, and becoming very knowledgeable in their institution's talent and the relevant published literature.
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