ILAR Journal Online, Volume 33(4) 1991

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ILAR Journal V33(4) 1991

Recognition and Alleviation of Pain and Distress in Laboratory Animals

Committee on Pain and Distress in Laboratory Animals Institute of Laboratory Animal Resources, National Research Council, National Academy of Sciences

The Committee on Pain and Distress in Laboratory Animals, established under the auspices of the National Research Council, was asked to develop species-specific approaches to the prevention, recognition, and alleviation of pain and distress in laboratory animals for investigators, veterinarians, research directors, animal care and use committees, and technicians. The report of the 10-member committee, whose members number among the nation's leading specialists in pain, stress, animal behavior, and laboratory animal medicine, will be released by the National Academy Press this summer.

Recognition and Alleviation of Pain and Distress in Laboratory Animals, organized into seven chapters, is a summary of issues considered essential to ensuring the well-being of laboratory animals, rather than a detailed review of the pharmacology of anesthetics, the anatomy of pain, or the physiology of stress. It addresses pain-induced and non-pain-induced stress in laboratory animals; clearly defines pain, stress, and distress; emphasizes the importance of distress; and discusses species-typical signs of pain and its pharmaceutical and non-pharmaceutical alleviation. It also highlights deficiencies in our knowledge of animal well-being and species-typical behavior, especially regarding the interaction of an animal with its environment.

As the committee deliberated these issues it was guided by four imperatives: (1) Animals deserve to be free from preventable pain and distress; (2) People who use animals in research have an ethical responsibility to treat them humanely; (3) The public places great demands and expectations on those who use animals; and (4) Stress and distress are unwanted variables in most studies.

The following is a brief overview of some of the key issues included in the committee's report, Recognition and Alleviation of Pain and Distress in Laboratory Animals.

DEFINITIONS

Stress is often detrimental, but some stress serves an adaptive function and is likely necessary for well-being.
It should not, therefore, be eliminated altogether. What then is the goal of stress management? The report clearly defines terms in order to put this issue in perspective.

It has long been known that biological systems are constantly seeking equilibrium. This dynamic process, called homeostasis, refers to the body's tendency to maintain behavioral and physiological equilibrium, or well-being. Stressors are external (environmental) or internal (physiological or psychological) events that stimulate homeostasis. In most cases, laboratory animal stressors are either pain- or environmentally-induced. If an animal or biological system functions without undue effort it is considered to be in a reasonable state of equilibrium, or well-being, even though it may be under some stress. Stress, a natural and often healthy condition, is simply the effect produced by external or internal stressors that alter biological equilibrium. Distress occurs when homeostasis is unable to return the body to a state of comfort and results in maiadaptive behaviors. For example, a new mother exhibits signs of severe distress if, instead of nursing, she abuses or kills her infant because she is unable to adapt to her environment. When any distress is evident, alleviation is essential.

Diagnosing and understanding distress is aided by examining preexisting conditions that may have caused an animal to be unable to adapt to or control its environment. Damaging early experiences and fear of the current situation because of these previous experiences are considered major causes of distress.

If types of stress were scaled, placing those to which an animal readily adapts (or well-being as defined above) on one end, and severe distress as indicated by maiadaptive behaviors (such as killing young) on the other end there would be many different kinds of stress on the points between. While this summary touches on pain-induced and environmentally-induced models of stress, the committee's report includes descriptions of these other kinds of stress, ranging from acute to chronic, and includes species-typical examples and recommendations for prevention and alleviation of these models of stress.

PAIN-INDUCED STRESS

Pain is a powerful stressor and a potential cause of severe stress. The committee's report reviews the pain pathways through the central and peripheral nervous system, emphasizes the interaction and integration of ascending and descending impulses, and discusses the role of endogenous opioids and other chemicals in conveying and modulating the sensory and motivational components of pain, collectively referred to as nociception.

In the context of laboratory animals, pain is generally judged to be both predictable and avoidable. Investigators generally can foresee that an experimental procedure will cause pain and know when alleviation of that pain will interfere with the research results. Peer-review committees evaluate research protocols for the scientific merit of the research, and animal care and use committees evaluate the cost-benefit of the research to the animal and to society. Public Health Service policy and U.S. Department of Agriculture regulations require that institutional animal care and use committees permit an investigator to conduct experimental procedures involving unrelieved pain only when the investigator has presented scientific justification for the necessity to do so. For procedures in which alleviation of pain will not interfere with the results or for unpredictable and unavoidable clinical conditions such as acute enteritis and arthritis, pain relief must be provided. Veterinarians and those who use animals must be able to recognize species-typical signs of pain and know how to relieve that pain.

Pharmacological Control of Pain

Pain is best prevented by modifying or refining painful procedures. The committee emphasizes that in experiments involving the study of pain in which the animal cannot limit the magnitude and duration of the stimulus, the investigator must not permit the intensity and duration of the pain to exceed tolerance levels. When pain is not the purpose of the study, but it is impossible to avoid painful procedures appropriate pharmacological agents such as analgesics and anesthetics, should be administered. The report provides 20 tables of species-specific drug recommendations and dosages.

There are several important issues to consider when discussing the use of anesthetics and analgesics. For example, the nervous system of neonates is widely believed to be too underdeveloped to provide nociception. It is often stated that neonates do not feel pain. This attitude, combined with concern for the safety of the neonate, has led to infrequent use of anesthetics and analgesics in neonates for procedures for which they would be routinely used in adult animals. The committee concluded that the most prudent practice would be to use analgesics and anesthetics in neonates if, under the same circumstances, they would be used in older individuals. Because protective mechanisms are underdeveloped in the fetus and the neonate (including drug biotransforming enzymes, the blood brain barrier, and renal excretory mechanisms), well-established drug regimes that are safe for and tolerated by adults can be toxic or fatal to neonates or fetuses. For this reason, selection of the proper anesthetic or analgesic agents is crucial. Local and inhalation anesthetics should be considered in fetal surgery, and the potent opioid fentanyl has been used with success in preterm human babies.

Another issue addressed in the report is the use of ketamine for surgery. Ketamine is considered a dissociative anesthetic, which means it does not exhibit the classic signs of anesthesia. Rather, it produces a cataleptic anesthetic state with rather severe hypertonicity of the antigravity muscles and an apneustic respiratory pattern. It is commonly used for restraint of nonhuman primates and cats, but should be combined with other agents such as diazepam or xylazine for surgical anesthesia. Its analgesic and anesthetic properties in most rodents is poor.

One of the issues that remains unresolved by the committee is the question of pain in cold-blooded vertebrates and invertebrates. While fish have neuropeptides in their central nervous systems similar to those found in mammals, it is not known whether they feel pain. Although fish demonstrate avoidance behaviors to aversive stimuli, they behave quite normally when severely wounded. Caution should be the rule and good anesthetics such as MS 222 exist for these species.

Control of Pain by Nonpharmacological Methods

As alternative means of controlling pain, the committee considered the use of animal hypnosis (tonic immobility), hypothermia, and acupuncture. Evidence exists that tonic immobility may be effective when performing some types of examinations in which minor pain or discomfort can occur. Hypothermia has a wide margin of safety and appears to be effective for surgery in altricial neonates. However, its use in cold-blooded animals should be restricted to restraint or as an adjunct to anesthetics. Acupuncture is limited primarily to the treatment of specific chronic painful disorders in horses and dogs. It is not curative and has to be repeated on a periodic basis.

NON-PAIN-INDUCED STRESS

Stress can be caused by many conditions other than pain. In fact, environmental stressors are of most concern for the management of animals in captivity. Although stress may be undesirable, it is a normal part of all life and can be either harmful or beneficial, a discrimination that is not always easy for colony managers and investigators to make. Desirable stress accompanies such ordinary situations as the introduction of different foods or new cage mates. Undesirable stress can be caused both by internal conditions and external influences, such as pain or loss of a companion. It can produce physiological and psychological changes in some animals, but not in others. Depending primarily on previous experiences and anticipations, what is stressful to one animal may be enjoyable for another.

Those who must recognize and decide whether or not to relieve stress must be well trained in stress physiology and psychology and in species- and individual-specific signs of both normal behaviors and stress-related behaviors. The greatest challenge to veterinarians, technicians, and investigators is to decide what procedures and environments are perceived by animals as stressors and, having accomplished that, to decide whether intervention is required. This requires an understanding of the critical balance between "good stress" (eustress), which animals and people seek out and to which they readily adapt, and "bad stress", from which they cannot escape in the short term (acute stress) or to which they cannot adapt in the longer term (distress).

Pharmacological Control of Non-Pain-Induced Stress

Stress caused by pain can be relieved by analgesics--but how is stress from non-pain-causes relieved'? Stress can often be ameliorated by the use of tranquilizers and sedatives. Their use, however, is most effective when combined with changes in the environment and with behavior modification. In the report, four groups of tranquilizers and sedatives most commonly used are included, and species-specific recommendations for each are provided. The report makes it clear, however, that the most effective treatment of environmentally-induced stress is through nonpharmacological means.

Nonpharmacological Control of Non-Pain-Induced Stress

When considering management of non-pain-induced stress, the concept of adaptation and its role in stress must be understood. Stress to which an animal readily adapts is normally of little concern; however, animals often must be taught to adapt. For example, dogs must be socialized when they are young to enable them to adapt to being restrained by people as adults. Enticed by favorite treats, nonhuman primates are taught to enter a transfer cage and sit quietly in a restraint chair. As part of the process of adaptation, animals may develop stereotypical behaviors as they adapt to confinement. Some behaviors are readily recognized as adaptation, but distinguishing these from maiadaptive behaviors is often difficult. For example, a monkey may pace in its cage to adapt to captivity, or the pacing may indicate that the animal is unable to adapt and could lead to maiadaptive behaviors such as self-mutilation, continual pulling of the hair, and killing young. Thus, diagnosing all pacing as adaptive may ignore its role as an antecedent to more severe signs.

The environment, which is often used in discussing the behavior and well-being of animals, does not just refer to an animal's immediate surroundings. It may also convey a sense of time, because adaptation to an environment frequently depends on the previous experiences and expectations of the animal. Fear and anxiety are often products of previous experiences and uncertain expectations about the future. In order to alleviate these fears and anxieties, animals can be adapted to certain situations. Thus, what is presumed to be cage-induced stereotypical behavior may, in fact, result from experiences in the wild or from inappropriate captive rearing. The report emphasizes that stereotypical behaviors be approached with an appreciation for their complexity. Prevention is the key, and the knowledge gained from studying animals displaying maiadaptive behaviors can be used to help prevent similar occurrences in future generations. No single approach can be expected to work for all situations. While tranquilizers and anxiolytics may help, the solution more often lies in modification of the environment and behavior.

In order to eliminate the confusion that may result by referring to all non-pain-induced stress as environmen-tally-caused, one must clarify the concepts of habitat and ecology. Habitat refers to the measurable features of an environment excluding its inhabitants. Several classes of animals generally occupy the same habitat. Ecology, on the other hand, refers to the interrelationships between a species and the environment. Owl monkeys and squirrel monkeys are active at different times of the day and differ in their social lives, the food they require, and the ways in which they gather food. Thus, these two species differ in their ecologies, although they have the same habitat. For laboratory animals, the habitat is generally designed to safely hold animals in sanitary conditions. It is useful, however, to consider what ecology this provides by considering the normal interrelationships of the animal with its surroundings.

The ecology of the laboratory animal is an organized, dynamic entity. One must invoke intuition, professional judgement, and empathy when assessing the adequacy of an ecology, but there are objective measures as well. Any interruption of the following six ecological relationships is considered a primary source of stress in laboratory animals:

1. Relationships with conspecifics. This includes consideration of social space and social stimulation; crowding; deprivation, including nurturance and early social experiences and disruption of both infant, parental, and adult bonds with other animals or people.

2. Predator/prey relationships. An understanding of what triggers fear in a prey or attack in a predator can alleviate stress in many animals.

3. Shelters, dens, and covers. These provide important retreats for different purposes including safety, giving birth, infant care, and sleep.

4. Space. Space represents a significant dimension in the daily lives of animals. The volume of space that is utilized, the distribution of activities within that space, and the kinds of activities that occur within it vary with species. More attention should be given to the volume of a cage, rather than just floor space, but it seems unlikely that an animal's well-being will be improved by simply providing additional space.

5. Feeding Patterns. An understanding of these patterns can provide a wealth of information for knowledgeable and observant colony managers. Foraging occupies the majority of the waking day for many animals in the wild. Their time budget and social structure may revolve around this single, important activity. In laboratory situations food is provided and foraging is typically neither required nor allowed. This may leave a considerable amount of free time during which unusual or undesirable activities may occur.

6. Novelty, predictability, and control over the environment. A constant in the wild, these provide animals with the possibility of a rich repertoire of behaviors. In the laboratory environment, however, habitats normally provide little opportunity for animals to interact with their environment. In general, studies indicate that the absence of novelty and predictability and a lack or loss of control by the animal over its environment result in an increase in the activity of the stress-responsive physiological systems and can induce alterations in behavior.

Distress produced by any of these six ecological sources of stress, which the report discusses in greater detail, should be alleviated through management and change in the source of the stressors. Like pain, distress is best prevented, but once manifest it must be diagnosed and appropriate actions taken quickly. Maiadap-tive behaviors that temporarily reduce distress may become self-rewarding habits, and can become increasingly resistant to treatment the longer they are permitted to occur. Tranquilizers help, especially during periods of adaptation, but will not succeed in eliminating distress.

IMPORTANT RESEARCH NEEDS

The Committee concurred that although the treatment of pain and distress is important, identifying unknowns in the study of pain and distress is equally valuable. The following is a partial list of questions, each of which requires extensive research.

Individual-specific requirements. What are the environmental and rearing conditions that predispose individuals of a species to prefer one environmental setting over another?
Species-specific requirements. What are the environments and ecologies that enhance well-being in each species of research animals (e.g., nonhuman primates, dogs, invertebrates, and cold-blooded cold-blooded vertebrates)'?
What management strategies enable enrichment of social species?
What is the proper role of people in reducing stress in all species?
How can we better utilize cage volume to define the proper habitat for laboratory animals?
How can we recognize whether changes in behaviors are adaptive (or serve to establish behavioral and physiological equilibrium) or whether these behaviors portend the development of severe distress?
How can optimum feeding patterns be defined?
What are the acceptable trade-offs between housing conditions that address the animal's point of view and those that provide acceptable levels of sanitation and safety?
How does boredom affect animals'? How is it manifest?
When stress is an essential component of a protocol, what alternatives to the use of animals are available?

CONCLUSION

Readers of Recognition and Alleviation of Pain and Distress in Laboratory Animals will find the definitions and discussions of pain- and environmentally-induced stress somewhat novel. The report strives to be pragmatic and applicable to laboratory animals, but often uses analogies to wild animals and pharmacological treatments of domestic animals for illustration. The 24 tables and figures, several of which are drug combinations and dosages, are very useful. Those willing to read further will be rewarded by the thoughtful treatment of species-specific signs of pain, and perhaps most of all by broad discussions of the causes of distress, its recognition, and its alleviation.

While much is known about laboratory animals and how to care for them, many unanswered questions remain. Compassion, professional judgement, and an understanding of the manner in which animals are reared and are adapted to novel environments is critical. Recognition and Alleviation of Pain and Distress in Laboratory Animals provides a good beginning for a solid understanding of species-typical behaviors, which enables questions to be asked the animal's perspective rather than from our own.