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ILAR Journal V40(3) 1999
Animal Models of Pain

Ethics and Pain Research in Animals
Jerrold Tannenbaum

Jerrold Tannenbaum, J.D., was in the Department of Environmental and Population Health, Tufts University School of Veterinary Medicine, North Grafton, Massachusetts, when he wrote this article. He is currently a Professor in the Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California.

Introduction

Pain research in animals raises distinctive and sometimes difficult ethical issues for institutional animal care and use committees (IACUCs¹)^, attending veterinarians, and investigators. In this paper, I explore and defend a number of widely accepted ethical principles regarding animal pain. I develop from these principles guidelines for use by IACUCs in assessing the humaneness of pain research in animals. Relevant ethical standards in current US laws and regulations and in policy statements of professional research associations are also examined.

Ethics and Animal Research

Attention to ethics is an essential part of the work of IACUCs, veterinarians, animal researchers, and all who affect the lives of research animals. The entire enterprise of animal research is motivated by an ethical principle--the belief that it is not only appropriate but morally obligatory to try to understand, alleviate, and prevent conditions that harm and kill so many. It would be incongruous and inconsistent to engage in animal research for this ethical reason and deny the importance of dealing ethically with the animals essential to this research. Moreover, virtually everyone accepts the principle that we have a fundamental ethical obligation to treat properly animals we use for our own benefit. Many scientists and veterinarians believe that it is a privilege to use animals in research (Dubner 1983). Regarding animal use as a privilege involves treating research animals with appreciation, gratitude, respect, and a genuine concern for their needs and welfare.

Legal Recognition of the Importance of Ethics in Animal Research

Congress and agencies that regulate animal research have recognized the importance of ethics by articulating a number of ethical rules IACUCs and others involved in animal research are expected to follow. The Preamble to the federal Animal Welfare Act (AWA¹) declares that the entire statute and its regulatory structure are intended "to insure that animals intended for use in research facilities or for exhibition purposes or for use as pets are provided humane care and treatment" (7 USC 2131(1)). The terms "humane care and treatment" and treating animals "humanely" are used by most people, and clearly by the AWA, as synonyms for ethical care and treatment and treating animals as we are ethically obligated to do (Tannenbaum 1995, p 120-121,419-420). The statute and its regulations contain many ethical obligations made legally enforceable, such as the requirements that procedures "will avoid or minimize discomfort, distress, and pain to the animals" (9 CRR 2.31 (d)(1)(i)) and that "animals' living conditions will be appropriate for their species and contribute to their health and comfort" (2.31(d)(1)(vi)).

Public Health Service (PHS¹) policies also contain ethical standards, many of which are set forth in the US Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training (PHS 1996). For example, "procedures involving animals should be designed and performed with due consideration of the relevance to human or animal health, the advancement of knowledge, or the good of society" (PHS 1996, p i). This principle requires that what is done to animals in research be justified by practical or theoretical results. The first sentence of the Guide for the Care and Use of Laboratory Animals (Guide¹), which institutions covered by PHS rules must consult, proclaims an ethical principle intended to underlie the Guide's recommendations: "all who care for or use animals in research, teaching, or testing must assume responsibility for their well-being" (NRC 1996, p 1).

Attention to the ethical treatment of animals in research is not just morally obligatory. It is required by law.

Pain in Animals: General Ethical Principles

In discussing ethical considerations relating to pain research in animals, it is important to begin with general ethical principles. An essential part of ethical deliberation involves giving reasons for ethical beliefs, which involves appealing to underlying principles. If the soundness of these principles can be maintained independently of particular applications, the principles can then be applied confidently to these applications. In the area of pain research, there is a special reason to begin with general ethical principles. Although laws and regulations contain ethical rules for IACUCs and investigators regarding animal pain, these rules do not specifically address the intentional causation of pain that is characteristic of much pain research in animals. The rules instead invoke general and widely held ethical standards relating to animal pain. Application of these governmental ethical rules to pain research in animals requires an understanding of the underlying ethical standards that give these rules meaning and specificity.

Centrality of Animal Pain in Our Ethical Framework

People apply many different ethical principles to their interactions with animals. One significant recent development in animal ethics is growing acceptance by the public and members of the biomedical research community of the view that animals used in research should be provided enriched environments and positive psychological experiences (Rollin 1995, p 3-26). However, this view is recent and is not yet universally extended to all species. For at least the past 100 yr, most people in Western societies have believed their primary ethical obligation to all animals is not to cause them unnecessary or unjustifiable pain (Tannenbaum 1995, p 120-122). Most laws relating to animal use (such as cruelty-to-animals statutes, humane slaughter laws, and most laws and regulations governing animal research) require that animals used for legitimate purposes not be caused pain if possible and not be caused unnecessary pain if some pain is unavoidable. The view that the capacity of animals to feel pain is the primary source of our ethical obligations to them was argued by the 18th century English philosopher Jeremy Bentham, who maintained that the important question regarding animals is not "Can they reason? nor Can they talk? but Can they suffer?" (1948, p 311, emphases in original). Bentham also argued that there is no ethical issue whatsoever if an animal raised or used in research does not feel pain, distress, or discomfort. This position is accepted widely (but by no means universally) by the general public and biomedical scientists today.

Reality of Animal Pain

The principle that our primary obligation to animals is not to cause them unjustifiable pain presupposes that animals can experience pain. It may seem obvious that animals feel pain. Moreover, using animals in pain research as a model for human pain clearly presupposes that animals feel pain; if they did not, the model would be pointless. Nevertheless, there still exist among some scientists remnants of behaviorist notions that animals do not feel pain, or that feelings of pain in animals are of no practical significance because they are incapable of expression in the language of chemistry or physics (Rollin 1987, 1997). Many IACUC members have encountered investigators who, when asked whether their work might cause animals pain, respond that one cannot really know what animals feel or be certain that they feel pain at all. They might look scruffy, depressed, or agitated, it is sometimes said, but who can know what they feel if they feel anything? Such statements recognize the ethical relevance of causing pain but attempt to lessen or negate ethical issues by questioning the reality of animal pain. Although doubts about animal pain are less likely among pain researchers who use animal models for human pain than among investigators whose work may secondarily cause animals pain, questioning whether animals feel pain, or feel pain "as we do," can be a tempting neutralizer of unsettling ethical aggravations.

Pain As a Fundamental Evil

Pain is not only an evil--something that is bad or a harm--but is an evil in itself. Pain is an evil simply because of the way pain feels and not for some other reason (although pain can have additional bad effects and for these reasons be evil). Pain is sometimes beneficial in signaling the presence of some problem such as injury or disease. However, the experience of pain is bad in and of itself, which is why humans and animals generally avoid it. We do not ask why pain is bad, not just because we know that it is bad but because we cannot say anything more about it than that it is pain. If someone asked you to explain why feeling pain is a bad thing, and if you took the question seriously, you would respond that it is bad because it feels the way it does--that pain is bad because it is pain. In other words, it is self-evident that pain is evil in and of itself.

Equality Principle

Several important ethical principles follow from the fact that pain is an evil in itself. What I call the "Equality Principle" holds that a given amount or duration or severity of pain is equally an evil for any being--human or animal---experiencing it. As philosopher Joel Feinberg explains,

If the essential character of pain and suffering themselves make them evil--evil not for their consequences but in their intrinsic natures--then it follows that given magnitudes of pain and suffering are equally evil in themselves whenever and wherever they occur. An intense toothache is an evil in a young person or an old person, a man or a woman, a Caucasian or a Negro, a human being or a lion. A skeptic might deny that a toothache hurts a lion as much as it does a human being, but once one concedes that lion pain and human pain are equally pain--in the same sense and the same degree--then one cannot deny that they are equally evils in themselves· All this follows necessarily from the view that pain as such is an intrinsic evil, and not evil only because it tends to produce bad effects of other kinds (Feinberg 1980, p 194).

If animals of a "lower" species experience less pain than those of a "higher" species under certain circumstances, this fact could be relevant to determining whether a pain research experiment is justified on them, because it causes them insignificant pain, or is better done on them than on animals of a species that would experience more pain. However, one cannot regard an experience of pain as less a harm or evil, and therefore raising a less serious ethical issue, because that experience would occur in rats, for example, rather than in cats or primates.

Justification Principle

The nature of pain as a fundamental evil also implies what I call the "Justification Principle": Because pain is an evil, anyone who causes pain in a being that can experience it must show that it is necessary and justifiable to cause this pain. Feinberg observes that we

...condemn and conscientiously avoid inflicting unnecessary pain and suffering on other human beings simply because we regard pain and suffering as an intrinsic evil. That is, we judge pain and suffering to be evil simply because they are pain and suffering. In the case of human beings, at least, we never ask for any further reason that a given condition is evil and therefore to be avoided or corrected after we learn that it is a painful condition. The question "What's wrong with pain anyway?" is never allowed to arise (Feinberg 1980, p 194, emphases in original).

It is a basic ethical wrong--perhaps the most basic ethical wrong of all--to harm another being without justification. Because pain is an evil, we act wrongly if we cause any animal we use for our own benefit or for the benefit of other animals unnecessary or unjustifiable pain. It is difficult to state generally how strong a justification must be given for the infliction of pain. It can, however, be said that causing any pain is not a trivial matter and requires not trivial but substantial justification.

Value Principle

From the Justification Principle and the fact that pain is an evil to animals follows a critically important ethical principle that is often invoked by IACUCs when they consider research likely to cause animals pain. Because pain is an evil, more or more severe pain is a greater evil than less or less severe pain. Therefore, the more pain an experiment will cause animals, the greater must be the justification. Expressed another way by what I call the "Value Principle," the more pain an experiment or test will cause, the greater must be its value. Saying that the value of an experiment must justify the level or kind of pain the experiment causes is of course just to begin ethical deliberation. People disagree about whether certain kinds of animal uses are sufficiently valuable to justify a certain level of animal pain. Some people, for example, believe that testing cosmetics is of sufficient value to justify animal pain; others disagree. Some people believe that animal pain can never be justified by basic research that does not promise practical benefits for people or other animals; others disagree. It is possible to argue not only about whether such goals are sufficiently valuable to justify a certain level of animal pain, but also about the relative ranking of these goals. Thus, one can maintain that although basic knowledge may be valuable, it is not as valuable as practical knowledge in the sense that it justifies causing animals pain and cannot justify as much animal pain as would applied medical research.

There are other difficult issues in assessing and comparing the value of medical research relative to justification of animal pain (Tannenbaum 1995, p 485-486). For example, although research that could bring relief from suffering to many people may often seem of greater value than research that would benefit only a few, if those few suffer grievously and lack means of relief, the urgency and value of research to help them may be greater. However we decide to characterize the value of research, because pain is an evil to animals and because more pain is a greater evil to them than less pain, the value of research causing that pain must be greater when the pain for the animals is worse.

Components of Value in Research

There are two components of the kind of value that is needed to justify animal pain caused by research: the value of the aims of the research and the level of its scientific soundness. Research that causes animals pain to test a new and potentially more effective pain-killing drug for cancer patients will likely have an aim that is sufficiently valuable to justify the infliction of some animal pain. A project that would cause animals pain simply to amuse a "researcher" who enjoys watching animals suffer has no value and would not justify the infliction of any pain. However, good aims are not enough for the value that is required to justify animal pain. Ethically acceptable research must also have some level of scientific soundness (sometimes termed "scientific merit"). Although the results of research are often unpredictable, research that will cause animals pain must be based on accurate scientific knowledge, involve scientifically defensible hypotheses, and use scientifically appropriate techniques. An investigator who wants to find better ways of alleviating pain in cancer patients (a valuable aim) is no more justified causing pain to animals than one who has a foolish aim if the proposed research of the former investigator is scientifically inept. The infliction of pain on the animals will still be pointless, and unjustified. Performing scientific experiments that are sufficiently valuable to justify animal pain includes being competent to do the scientific work. Bad science cannot be good ethics, certainly when it involves causing animals pain.

Minimization Principle

From the Justification Principle follows the ethical principle that is employed most frequently in current laws and regulations governing animal research. What I call the "Minimization Principle" holds that we should minimize pain experienced by research animals. Assuming one is justified in doing harm, doing less harm to a being is always better than doing more harm. Less pain is less a harm or evil than greater pain. Therefore, one can never justify causing more pain to an animal than one needs to cause. The Minimization Principle is best considered after the Value Principle because whether a certain amount or kind of pain is deemed necessary and therefore justified will depend on whether the infliction of any pain on an animal is justified by proposed research. Once causing some pain is justified, the Minimization Principle requires that it be minimized, but this minimized level or amount of pain must also be justified by the value of the research. The Minimization Principle requires that no pain be caused if this is possible under the circumstances because no pain is the ultimate minimization of pain.

Conceptual Problems of Minimization

Although the Minimization Principle is persuasive, it will sometimes be difficult or impossible to apply it confidently to pain research in animals. This difficulty stems from the fact that experiences of pain have a number of different possible components, including duration and severity, and a variety of different characteristics, such as sharp, dull, piercing, throbbing, and burning. Given a specified severity and kind of pain (such as intense and sharp pain), we can say with confidence that such pain experienced for 1 min is less than such pain experienced for 10 min. Given a specified duration of pain, the Minimization Principle requires causing this duration of dull pain rather than sharp and burning pain, because we characterize the former as less pain. The principle is difficult to apply, however, when we compare different durations with different intensities and kinds of pain. For example, is 1 min of sharp and intense pain "less" pain than 10 min of dull pain? Is dull pain more or less pain than throbbing pain? Does it become more after a certain intensity or time? When we add to the mix different numbers of animals, the task of comparing and minimizing can become even more difficult. For example, how many cats experiencing sharp and burning pain for 10 min will constitute more pain than 50 cats experiencing dull pain for several hours? When we attempt to make such comparisons across species (to determine, for example, whether pain would be minimized by doing an experiment on rats rather than cats), the problems are magnified further because it may not be clear how to compare pain felt by different species even when we know that they feel pain.

Application of the Minimization Principle presupposes that we can determine whether a given use of animals involves more or less pain than another. However, we cannot always clearly say that some animals experience more pain than others because it is not clear that the term "pain" (even when properly applied) always refers to the same entity of which the relative amounts can be compared and then "lessened" or "minimized." It is not clear what it means to say that 10 min of dull pain is the same amount of pain or is more or less than 1 min of excruciating pain, except that we think it is better--or more accurately, less bad--to experience the former duration and type. It is not clear that the 1 min of excruciating pain and the 10 min of dull pain are the same thing or can be converted into amounts of the same thing and compared for quantity.

When it seems difficult to determine whether one approach minimizes pain because it is difficult to compare the amount of one kind of pain experience with another kind, we must fall back on intuitive judgments and reliable behavioral evidence regarding what appears better or worse for an animal or human to experience. Because the underlying motivation of the Minimization Principle is to assure that animals feel no worse than necessary, this approach seems reasonable.

Fairness to Individual Animals

The Minimization Principle must be qualified by another important ethical principle. Talk of pain "minimization" may lead some people to think that the real ethical concern is the total amount of pain experienced and that our moral obligation is to minimize this total. The following example illustrates why this view is incorrect. Suppose a pain experiment could achieve satisfactory results either by causing excruciating pain in five animals for 1 hr or moderate and well-tolerated pain in 20 animals for 1 day. It might be correct in such circumstances to say that more total pain would be caused by using the 20 animals. However, I would argue that using the 20 animals would be ethically preferable, because each individual animal will be harmed less. The ethical problem in causing animals pain arises not from causing total amounts of pain but from causing individual animals pain. There is no such thing as a totality of pain that exists in the world. Individuals feel pain, and what makes pain evil is that it is an evil to the individual experiencing it. Therefore, in determining whether the infliction of animal pain is justified, we must ask whether what we are doing is fair to the individual animals we use. Sometimes considerations of fairness to these individuals will mean that we demand too much of each animal by subjecting it to a great amount of pain if we can accomplish the same end by having each animal used suffer less.

The important ethical principle of fairness to individuals is embodied in the provision of the AWA regulations that "no animal will be used in more than one major operative procedure from which it is allowed to recover" (9 CFR 2.3 l(d)(1)(x)) in the absence of scientific justification. This prohibition recognizes that although the total amount of pain or distress, and indeed the total number of animals, may be lessened if fewer animals are subjected repeatedly to major procedures, it can be unfair to each individual animal used to do this. In pain as in other kinds of research, fairness to individual animals may sometimes require using more rather than fewer animals, extending rather than shortening the duration of an experiment, and not minimizing total pain and distress.

Associated Negative Feelings

In considering ethical responsibilities relating to causing animals pain, it is important to take into account unpleasant mental states that typically accompany pain. Some of these states (such as distress) may occur so frequently with feelings of pain that they may sometimes properly be described as part of the pain experience itself. Others (like discomfort, fear, or anxiety) may sometimes be easier to separate phenomenologically from pain or be better viewed as reactions to pain. What is ethically important about pain--what makes it an evil to animals as well as to humans--is that it feels bad. Other unpleasant feelings such as distress or discomfort also feel bad, and the same ethical principles apply to causing them in animals as apply to causing pain. Therefore, in determining whether causing animal pain in an experiment is ethically justifiable, we must include in our deliberations other unpleasant or negative animal experiences. The presence of such feelings is likely to increase the total evil an animal will be caused and thus increase the required minimum level of justification and value of a proposed experiment. The Minimization Principle requires pain researchers to minimize these associated negative feelings (while still causing necessary pain) if minimization of such associated feelings is possible given justified experimental aims.

The need to include negative feelings associated with pain in ethical assessment of pain research causes no small conceptual, scientific, and practical problems. If there is disagreement among philosophers and scientists about the meaning of the term "pain" in animals and lack of knowledge about its nature and causes, there is even greater disagreement about the meaning and causes of psychological states in animals such as distress, discomfort, fear, or anxiety (Tannenbaum 1995, p 416-418). Nevertheless, such disagreements and lack of knowledge do not diminish the strength of the ethical principle that bad or unpleasant feelings inflicted on animals must be justified and minimized. Indeed this ethical principle requires us to learn as much as possible about negative mental states associated with pain so that they too can be minimized in research.

Imprecision in Ethical Deliberation Relating to Animal Pain

Aristotle warned that different kinds of investigations require different levels or degrees of precision and that ethical discussions are unreliable if they seek more precision than the subject allows (Aristotle 1952, Book I, p 339). The ethical principles relating to pain discussed above are widely accepted and seem eminently reasonable. Their acceptance, however, does not mean that they can always be applied precisely. For example, sometimes knowing how to minimize pain is easy: If an animal is fully anesthetized, its pain is minimized during the time of anesthesia. But when animals feel pain--a situation common in pain research--it is often impossible to know whether they are being caused absolutely the minimum amount of pain necessary even when comparisons of amounts of pain seem possible. There is still much to be discovered about what behavioral and physiological signs indicate the presence of pain in various species. Pain behavior (and presumably pain perception) varies significantly among different individuals within species (Soma 1987). Much remains to be learned about what kinds of chemical and environmental interventions can lessen animal pain. However, the most serious problem for precisely estimating and then minimizing animal pain results from the fact that animals cannot talk about their pain. Adult humans can usually describe precisely when pain begins and ends, where it is located, and how it feels. We estimate the severity of human pain in terms of more intense versus less intense, sharp versus dull, piercing versus diffuse, throbbing versus steady, and with many other kinds of descriptions. All such information can be critical to determining whether pain is being lessened or minimized. Perhaps many of these discriminations will some day be applied to animals based on similarities between their physiological states or behavior and those of humans when we make these discriminations. In light of the inherent inability of animals to describe their pain, it seems unlikely that we will ever be able to make such determinations with anything approaching the precision we make them regarding pain in humans.

Ethical consideration of animal pain in pain research, like the research itself, must often settle for imprecise or gross estimates of how much and what kind of pain and associated negative feelings animals experience. It is therefore more accurate to say that one' s ethical obligation regarding animal pain is not to minimize it but to try to minimize it in light of best knowledge and practice. Moreover, because pain is a fundamental evil to animals as it is to humans, the following ethical principle seems appropriate: If there is reasonable scientific question about whether animals under certain circumstances are or are not feeling pain or are feeling more or less pain, we should err on the side of judging that they feel this pain or that they are feeling the worst or largest amount of reasonably attributable pain. By assuming the presence of such pain and requiring sufficient justification for it, we may be able to assure that the research is ethically justified whether or not it actually results in this pain.

Animal Pain Research: Ethical Dilemma and Paradox

The general ethical principles discussed above help explain why pain research in animals can be so ethically troublesome. Because pain is a fundamental evil, understanding and alleviating pain is among the most important tasks of biomedical science. Estimates of the psychological and economic costs of pain are staggering. Data from the US National Center for Health Statistics and other sources reveal that

...in 1988 112 million Americans (45 percent) experienced acute pain requiring medical care caused by 40 million injuries, 2 million bums, 5 million dental disorders, 10 million nontraumatic musculoskeletal diseases, 3 million childbirths, 15 million with acute pain in the postoperative period, and 37 million cases of visceral disease. Among this group 59 million, or 25 percent of the total population, experienced pain that was moderate to severe or excruciating and required major therapy in the form of opioids and other therapeutic modalities (Bonica 1992, p 2).

An additional study estimated that in the same year, approximately 65 million Americans suffered chronic pain from back disorders, arthritis, cancer, heart disease, and other disorders. Of this group, 48 million (19% of the total population) were partially disabled at least for weeks or months, and chronic painful conditions among Americans resulted in more than 5 billion days of limited or bed disability and more than 900 million lost workdays (Bonica 1992, p 2). A 1998 National Institutes of Health Program Announcement for pain research states that

... pain is the most common reason individuals seek medical care, with millions of medical visits annually; costing the American public more than $100 billion each year in health care, compensation and litigation .... Pain-related disability presents a significant and costly liability to workers, employers and society. In the workplace, a significant proportion of employees, about 14%, take time off from their jobs due to pain conditions. In hospitalized patients, pain has been associated with increased length of stay, longer recovery time, and poorer patient outcomes, all of which have health care quality and cost implications (NINDS and others 1998).

It is also clear that progress in understanding and alleviating pain in humans and animals requires the use of animals. Only live animals feel pain and behave in ways that are similar to humans' behavior when experiencing pain. Pain research in animals has been essential in improved understanding of the neural basis of pain and the "development of better narcotic and nonnarcotic analgesic drugs, the introduction of pain-relief procedures using electrical stimulation of peripheral nerves, sensory pathways or neural centers in the brain, and the recognition and exploitation of endogenous pain-suppressing chemicals such as enkephalines in the brain" (Sessle 1987, p 75-76). Improved understanding of and ability to deal with pain require continued research on animals (Bonica 1992; Dubner 1983, 1987; Sessle 1987; Sternbach 1976; Zimmermann 1986)·

Unfortunately, it is often impossible to do pain research on animals without the animals experiencing pain. Some important knowledge regarding pain mechanisms and modulation has been gained from studies on animals that cannot feel pain because they have been anesthetized or rendered unconscious by decerebration or decortication. However, much of what needs to be known requires awake and conscious animals, especially in research on pain neurophysiology at levels above the spinal cord (Dubner 1987; Sessle 1987; Zimmermann 1986). Although some pain studies can allow animals to escape or to avoid painful stimuli when they presumably become too uncomfortable, several areas of pain research require unavoidable painful experiences. Some research into pain-suppressing pathways and mechanisms requires activation of painful and nonpainful stresses, including inescapable noxious stimuli. Studies of chronic pain often require experiences of pain and can involve such techniques as intermittent or continuous electrical stimulation of nerves or tissues; manipulation of nerves and tissues to produce chronic pain such as induction of neuromas or intradermal inoculation of bacterial toxins; and changes in sensory pathways by such methods as peripheral nerve deafferentiation, production of lesions, or injection of convulsive drugs, toxins, and chemicals resulting in neural hyperexcitability (Dubner 1987; Sessle 1987; Zimmermann 1986). Animal models that can involve unrelieved pain include some for amputation pain (Blumberg and Janig 1982; Wall and Gutnick 1974), arthritis pain (Coderre and Wall 1987; Colpaert 1987; DeCastro Costa and others 1981), cardiac pain (Uchida and Murao 1974), chronic pain (Sweet 1981), deafferentiation pain (Brinkus and Zimmerman 1983; Wiesenfeld and Lindblom 1980), muscle pain (Mense and Schmidt 1974), neuropathic pain (Bennett and Xie 1988), stress-induced analgesia (Lewis and others 1980), trigeminal neuralgia (Black 1974), and visceral pain (DeLeo and others 1992).

Pain research thus places us between horns of a troublesome ethical dilemma (Dubner 1983; Zimmermann 1986). We appear obligated to do something--pain research on animals--that will sometimes involve doing something else--causing pain--that we are generally obligated not to do. To do great good we must sometimes cause great harm. And although causing such harm may often be justified, the nature of the needed justification sometimes makes the ethical dilemma more troublesome: As the problem of pain for humans and animals becomes greater, the pain we can justify causing animals when they are used in valuable pain research increases. Moreover, although the Minimization Principle applies even when pain is justifiably inflicted on animals, in pain research this principle may often fail to accomplish its ultimate goal, which is to spare animals significant or substantial pain.

None of this means that it is inherently wrong to cause animals pain in pain research. However, as Feinberg (1980, p 194) observes, although causing "some pain does more good on balance.., what follows is that justifiable pain is a necessary evil, not that some pain is good in itself." That causing animals pain, even when justified, is a necessary evil explains why we should be unhappy about the need to do it and why we should feel unsettled by it (which is not the same as saying we should feel guilty about doing it). That causing animals pain in pain research may sometimes be a necessary evil also implies that IACUC members and investigators must pay special attention to their ethical obligations of minimizing harm to animals.

Ethical Guidelines for IACUCs

In the following enumerated recommendations, I use the general ethical principles defended above to propose ethical standards for IACUC members in their consideration of pain research. These recommendations are provided to assist committees and scientists in developing their own approaches. Although intended specifically for use by committees as required by laws and regulations in the United States, the recommendations, like the general ethical principles on which they rest, are universally applicable. I assume, however, as a given that the interests of research animals and of the general public in assuring the appropriate use of animals require that animal research proposals be reviewed for humaneness by local institutional committees.

1. The IACUC should apply to the consideration of any pain research proposal the fullest and most complete consideration available under its operating procedures. Because the deliberate infliction of animal pain is the infliction of a fundamental harm and evil, an IACUC should take all reasonable steps to assure that any pain research on animals performed at the institution is ethically appropriate, without question. There should not be expedited review of such research, nor review by a delegated member, committee, or subgroup of the IACUC. So that the best scientific, technical,-and ethical questions can be asked, all members of the IACUC should attend the review of pain research proposals. It is especially important for all nonaffiliated members to be present. The principle that animals should not be caused unnecessary pain is a deeply held ethical standard of the public, and pain research is typically justified on the grounds that it benefits the public. The community representatives on the IACUC should be available to apply this ethical standard and consider the sufficiency of this justification. Unaffiliated and certainly nonscientist members are also likely to insist on descriptions of any pain the animals may experience in lay terms that not only are understandable to them but also reflect the public's concern about what animals might actually feel. If necessary, an expert consultant should be invited to assist the committee if members require additional knowledge regarding pain research or mechanisms of pain avoidance, alleviation, or minimization. In light of the ethical significance of deliberately causing animals pain, any animal pain research must receive meticulous review by a committee, even if the research is not covered by federal laws and regulations because the institution does not receive PHS funds and the work is done on species currently not subject to US Department of Agriculture regulation.

2. Any proposal of pain research in animals should contain clear and convincing statements of the justification and value of the research, including the relevance of the work to practical benefits or important theoretical knowledge, the soundness of the science, and the competence and ability of research and animal care personnel to monitor and minimize animal pain. The greater the pain experienced by the animals, the greater must be the justification and value of the research. Because of the obvious general need for pain research, some investigators and IACUCs may be tempted to settle for quick, boilerplate justifications of experiments that assert in the most abstract terms the importance of pain and pain research. However, such statements are unacceptable. An investigator should explain to the IACUC what kind or kinds of pain are being investigated, why such pain is in great need of understanding or alleviation, and how it is hoped that the proposed research will contribute to this process. Because of the clear ethical cost of inflicting pain, investigators must be prepared to demonstrate knowledge of any experiments or tests that are similar or related to their proposed experiments and to show that their work is designed to verify or contribute relevant and important knowledge.

There is disagreement among IACUCs and commentators about whether committees can and should consider the scientific soundness of research proposals (Prentice and others 1992; Tannenbaum 1995, p 495,501). In my view, it is obvious that an IACUC must assure itself to at least some extent of the scientific soundness of research that will cause animals pain. It is difficult to imagine an IACUC responding to an experiment that would cause a large number of animals considerable and long-lasting pain with the statement that "we know there will be great pain here but we must leave it completely to a study section (initial review group) to decide whether there is any scientific or practical reason to do this work," or "we know that there will be great pain here but we cannot express any position on whether there is a good scientific reason to cause this pain." I believe that such responses are as unacceptable as they would be unusual. US laws require IACUCs (and not someone else) to determine whether proposed animal experiments are humane (that is, ethical). Infliction of pain cannot be ethical unless it is justified, and an IACUC that is unwilling to undertake any consideration of the scientific or practical reasons for inflicting pain simply cannot determine whether that pain is justified.

In assuring that proposed research is likely to be sufficiently sound to justify infliction of pain, an IACUC may ask the principal investigator to demonstrate familiarity with pain research. Students, research associates, and less experienced investigators who propose or work on animal pain research experiments should either demonstrate sufficient knowledge of pain research and the value of a proposed experiment that will cause animals pain or be closely supervised by a scientist with such knowledge. The IACUC should assure that the investigator and other personnel who work on an experiment that will cause pain are knowledgeable regarding methods of assessing and alleviating pain; otherwise, even the most justifiable experiment could result in unnecessary pain.

3. IACUCs should encourage investigators to demonstrate in experiments that will cause animals pain or distress a level of justification and value that is as high as possible. Estimating animal pain is and will likely always be imprecise. Moreover, it is sometimes difficult to estimate the potential theoretical and practical benefits of scientific experimentation. Some experiments fail, and much basic research has brought practical results that could not have been predicted at the time it was done (Comroe and Dripps 1976). There are significant conceptual issues regarding how to define such states as pain, distress, discomfort, and anxiety in animals (Tannenbaum 1995, p 416-418; Wall 1992). People disagree on ethical grounds whether certain kinds of research justify animal pain or some degree of animal pain.
In light of these uncertainties and controversies, the higher the level of justification and value of the research an investigator can demonstrate, the easier it will be for the IACUC to feel confident in the ethical appropriateness of the work---because the uncertainties and controversies become less likely to affect the final decision whether a piece of research is ethically justified. An experiment that is part of a general research program that has already led to medically significant improvements in treating pain and is proposed by a scientist with demonstrated expertise and success in the area will likely overcome issues regarding precisely how much pain is being produced, whether the animals are feeling some distress as well as pain, or whether the negative feelings experienced by the animals will be absolutely minimized. If the research has great value, what the animals experience will probably be viewed as justified, provided that all reasonable steps are taken to try to minimize their pain and distress.

4. Investigators should characterize and estimate the likely pain and associated negative feelings that will be experienced by the animals as completely and accurately as reasonably possible. Investigators and IACUCs should consider a wide range of evidence, including inferences from similar pain experiences in humans and the best available scientific data regarding behavioral and physiological signs of animal pain. To determine that the research is justified, the IACUC must try to determine when the pain will start and end, how intense it is likely to be, and any other information about its phenomenological character. Investigators should assure the IACUC that they know how to assess and characterize pain in animals. Investigators should be familiar with normal behavior patterns in species in which they cause pain and with the kinds of deviations from such behaviors thought to be associated with pain (Morton and Griffiths 1985; Sanford 1992; Sanford and others 1986; Soma 1987; Spinelli 1987; Spinelli and Markowitz 1987; Wright and others 1985). As a number of prominent animal pain researchers and specialists argue, one should not reject all anthropomorphism in describing the pain of animal subjects (Dubner 1987; Soma 1987; Zimmermann 1986). The purpose of most pain research is to understand pain in humans, and it is often scientifically reasonable to assume that what the animals feel is similar to what humans feel.

Numerous schemes for scoring various levels or severity of animal pain have been proposed to assist IACUCs and investigators in estimating and minimizing pain. Some of these (Orlans 1993, p 87-88; SCAW 1987; Swedish Classification for Research Techniques 1984) were devised in an attempt to correlate levels of pain with standard kinds of surgical or experimental procedures. Others (DeLeo and others 1992; Morton and Griffiths 1985) specify kinds of animal behavior that are presumed reflective of levels of pain. They direct investigators to locate what animals feel in an appropriate pain level category on the basis of observed behavior.

Investigators should also consider the possibility that pain in animals may sometimes be worse for them than pain in humans experienced under similar circumstances. Because animals may not know (or be able to know) why they are suffering pain or that the pain will end, pain may so completely dominate the animal's psychology that it may sometimes be appropriate to view its entire life for some period of time as a painful experience--as Rollin (1989, p 60) aptly puts it, to view the animal as its pain. Analogizing from human experience may sometimes increase the estimate of expected harm to animals and thereby increase the level of required value of an experiment. For example, people who experience relatively low levels of pain for extended periods of time can become annoyed, depressed, and unhappy--they can suffer--because of the seemingly unending pain. The total negative experience can be worse than if one considered just the intensity and duration of the pain itself. Although one must be careful imputing to animals sophisticated emotional reactions to pain, neither should one preclude the possibility of such reactions.

The International Association for the Study of Pain (IASP¹) recommends that in pain research on conscious animals for "most non-invasive stimuli causing acute pain," the investigator "should try the pain stimulus on himself" (Zimmermann 1983, p 109). As a nonscientist, I cannot assess the general validity of such an approach in estimating animal pain, but I can report an incident in which several members of an IACUC asked to receive an electric shock (not part of a pain study) that an investigator proposed to give to rabbits. They found the stimulus, when repeated several times as would have occurred in the experiment, so distressing that they asked the investigator to convincingly demonstrate the value of the research. (The investigator withdrew the proposal.) Perhaps IACUC members as well as investigators can try certain proposed painful stimuli on themselves if knowledge about the species and individuals used does not cast doubt on extrapolation of human reactions to what may be experienced by the animals. It might also be helpful for IACUC members to view animals that are subjected to painful procedures either before approving a proposal if possible or afterwards so that members can assure themselves that pain experienced by the animals is justified.

The IASP also recommends that pain studies "in animals paralyzed with a neuromuscular blocking agent should not be performed without a general anesthetic or an appropriate surgical procedure that eliminates sensory awareness" (Zimmermann 1983, p 110). This recommendation is supported by one of its authors on the grounds that because such animals "can be considered to be under stress in the condition of neuromuscular paralysis," any results obtained "would be of no scientific value" (Zimmermann 1986, p 231). Additionally, paralysis removes overt signs of pain and distress and therefore removes one of the major ways to determine the severity, duration, and character of the animals' pain and distress. Because it is difficult if not impossible to characterize what paralyzed animals feel, one cannot determine whether what they feel is justified, whether their pain and distress is being minimized relative to the aims of the experiment, and whether their pain and distress have become so severe that the experiment must at some point be terminated.

5. Investigators should assure the IACUC that they are attempting to minimize pain in the design and performance of the research. Investigators should bear the burden of demonstrating to the IACUC why pain-relieving tools such as analgesia, pain avoidance, and environmental enrichment cannot be used, consistent with justified experimental aims. The veterinary and animal care staff must assure that procedures for pain minimization approved or required by the committee are followed. As Dubner (1987) explains, there is a range of techniques in animal pain research that are associated with different amounts or degrees of pain. Experiments on completely anesthetized animals, which have yielded some significant knowledge, cause no pain and do not raise ethical issues relating to whether pain is justified. Procedures on awake animals that have been given analgesic agents cause minimal pain or distress and can be relevant to certain kinds of information on, for example, neural processes minimally affected by such agents. Some animal pain research involves causing pain to animals that is not relieved but that can be escaped by avoidance behavior (such as tail-flicking or avoiding a painful stimulus) or administration of pain relief by the animal. Experiments involving physical restraint of animals can be quite stressful. The level of stress can sometimes be reduced by training the animals to perform pain detection and pain discrimination tests by, for example, having the animals decide when to initiate the test and when to withdraw from the experiment by ceasing to initiate trials. Experiments in which animals experience unrelieved pain include induction of acute pain of varying levels of severity as well as chronic pain of varying levels of severity and duration.

The Minimization Principle requires investigators to try to design research as far toward the pain-free end of this range of techniques as possible, consistent with justified experimental aims. IACUCs should therefore ask investigators to provide scientific reasons why the research cannot be of a sort that might cause less pain. Even when an experiment is appropriately designed, the investigator should assure the IACUC that all reasonable attempts will be made to minimize pain. Thus, in acute or chronic pain studies, the pain should not last longer than is required and should be alleviated with analgesics whenever or as soon as doing so is consistent with experimental aims. Animals should be allowed to avoid, self-treat, or escape pain when consistent with justified experimental aims. Environmental enrichment and opportunities for species behavior associated with stress reduction can lessen stress and discomfort experienced by the animals (Mench 1998; Zimmermann 1986). Zimmermann (1986, p 230-231) recommends that "animals in a chronic pain state should not be left alone. Wherever possible they should live in a rich environment providing social interaction with members of their own species, and much attention and handling by the scientist and his associates. There are indications that animals in pain suffer less when socially rewarded."

Zimmermann (1986, p 225-226) illustrates how applying the Minimization Principle can offer both possibilities and uncertainties. The leading model for amputation pain involves production of neuromas in rats and cats. After a peripheral nerve is transected under general anesthesia, the nerve fibers in the proximal stump begin to regenerate. This regeneration can cause severe pain, classified in humans as neuropathic pain. Rats and monkeys on which this procedure is done scratch and bite the denervated limb; the degree of self-mutilation is viewed by some scientists as a measure of the degree of pain. However, when a small nerve is lesioned, there is no self-mutilation, which appears to support the conclusion that there is no or minimal pain even though the neuropathophysiology has fully developed. Thus, there may be a way of doing this research that does not involve substantial pain. Nevertheless, because there is evidence that self-mutilation seen after nerve lesions is not always a sign of pain in animals, more work is needed to determine reliable criteria of pain so that we can accurately estimate the ethical costs of this kind of pain research.

Procedures that allow animals to escape pain have provided important data and would ordinarily be preferable to those that inflict unrelieved pain. However, it is not the case that, as suggested by Sessle (1987, p 76), such techniques raise no ethical issue, because ethical guidelines governing pain research in humans approve of painful stimuli that human subjects can avoid or terminate at will (Charlton 1995). Animals do not have the same kind of appreciation of what they are experiencing that can render it less stressful; they do not choose to be subjected to pain; and they cannot tell us that once they avoid or terminate a stimulus, their pain has ended. Although procedures that allow animals to escape or terminate pain may usually be less ethically problematic than those involving unrelieved or continuous pain, the infliction of even temporary pain is still the infliction of pain and must have sufficient ethical justification.

The Justification Principle requires anyone who causes animals pain to provide justification for doing so. The burden of providing sufficient justification should therefore be on the investigator and not the IACUC. Moreover, the likelihood of minimizing animal pain will probably be increased if, as a general policy, an IACUC asks investigators who cause animals pain to show why there is not some means of causing less pain consistent with justified research. Such a policy puts investigators on notice that they are always expected to try to minimize pain.

The Minimization Principle must be applied beyond consideration of research proposals by the IACUC. Pain can be minimized only if veterinary and animal care staff conscientiously and competently assure that the minimization procedures approved or required by the IACUC are followed.

6. In balancing pain and distress caused to animals against the value of the research, and in monitoring pain research in progress, the IACUC should consider whether pain has become so severe that individual animals should be removed from the research or the research itself should be terminated. At some point, the scientific reasons for a study may simply not justify the pain experienced by some or all of the animals.

7. Pain in "lower" species may not be considered less harmful or in need of less justification than pain in "higher" species. The Equality Principle permits differences in species to be taken into account only when relevant to the amount or intensity of pain or the likely presence of other negative experiences or emotions such as distress, fear, depression, or anxiety, which can accompany pain in humans.

8. Investigators and IACUCs should focus on what is fair to individual animals, which may sometimes require lengthening rather than shortening the duration of pain, using more rather than fewer animals, or causing more rather than less total pain. The IASP recommends that "the duration of the experiment must be as short as possible and the number of animals involved kept to a minimum" (Zimmermann 1983, p 110). Minimizing duration and numbers may often lessen the burdens experienced by individual animals used in pain research. However, fairness to individual animals may sometimes obligate investigators and IACUCs to consider alterations in experimental design that may increase or not lessen duration of pain or numbers of animals.

9. IACUCs should attempt to adhere to government ethical rules and should consult relevant professional association ethical guidelines but should view all general rules and guidelines as calling for, and ultimately subject to, independent ethical deliberation. Aside from having the force of law, government ethical rules relating to pain in animal research reflect society's most fundamental ethical views regarding animals. Ethical policies of professional research associations can provide unique perspectives of working scientists. However, laws often set forth minimal standards for behavior, which one may sometimes be ethically obligated to exceed. Both laws and professional association guidelines tend to be general and to fall back on general standards such as the Justification, Value, and Minimization principles. Therefore, to assure the humaneness of pain research in animals, IACUCs and investigators must engage in independent ethical assessment of research. They must apply to particular research situations general ethical principles such as those defended in this article.

Ethical Guidelines in Current Laws and Regulations

US federal laws, regulations, and policies governing animal research contain many ethical guidelines applicable to pain research in animals. The AWA requires that regulations be effected that assure "animal pain and distress are minimized, including adequate veterinary care with the appropriate use of anesthetic, analgesic, tranquilizing drugs, or euthanasia" (7 USC 2143(a)(3)(A)); that "the principal investigator considers alternatives to any procedure likely to produce pain to or distress in an experimental animal" (7 USC 2143(a)(3)(B)); that "in any practice which could cause pain to animals," a veterinarian be consulted in the planning of such procedures (7 USC 2143(a)(3)(C)(i)) and that these procedures provide for "the use of tranquilizers, analgesics, and anesthetics" (7 USC 2143(a)(3)(C)(ii)); and that "the withholding of tranquilizers, anesthesia, analgesia, or euthanasia when scientifically necessary shall continue for only the necessary period of time" (7 USC 2143(a)(3)(C)(v)). These provisions, all of which express the Minimization Principle, are elaborated in regulations that reiterate and sometimes apply this principle more concretely with, for example, the requirements that "procedures involving animals will avoid or minimize discomfort, distress, and pain to the animals" (9 CFR 2.31 (d)(1)(i)); that investigators provide the IACUC a written narrative showing that they have considered "alternatives to procedures that may cause more than momentary or slight pain to the animals" (9 CFR 2.31(d)(1)(ii)); and that an animal research proposal contain a "description of the procedures designed to assure that discomfort and pain to the animals will be limited to that which is unavoidable for the conduct of scientifically valuable research, including provision for the use of analgesic, anesthetic, and tranquilizing drugs where indicated and appropriate to minimize discomfort and pain to the animals" (9 CFR 2.31(d)(1)(x)). Other provisions of the AWA or regulations, which appear to have been intended at least in part to avoid unnecessary pain, include the prohibition of the use of paralytics without anesthesia (7 USC 2143(a)(3)(C)(iv), 9 CFR 2.3 l(d)(1)(iv)); the requirement that animals "that would otherwise experience severe or chronic pain or distress that cannot be relieved will be painlessly euthanized at the end of the procedure, or, if appropriate, during the procedure" (9 CFR 2.31 (d)(1)(v)); the requirement that activities involving surgery include "appropriate provision for pre-operative and post-operative care of the animals in accordance with established veterinary medical and nursing practices" (9 CFR 2.3 l (d)(1)(ix)); and the directive that methods of euthanasia involve no pain or distress (9 CFR 2.31(d)(l)(xi), 9 CFR 1.1. "Euthanasia"). The AWA describes the purpose of the IACUC's mandatory semiannual inspection in terms of minimizing pain. Although the statute requires that an inspection uncover all deficiencies, the only matters specifically mentioned are inspection of "practices involving pain to animals" and "the condition of animals, to ensure compliance with the provisions of this chapter to minimize pain and distress to animals" (7 USC 2143(a)(7)A)). The primary purpose of the AWA and regulations to minimize animal pain, distress, and discomfort is underscored by the requirement that all institutions file the annual report, which must contain not only an assurance that the facility has adhered to all standards and regulations under the Act, but also a statement that there has been "appropriate use of anesthetic, analgesic, and tranquilizing drugs, prior to, during, and following actual research..." (9 CFR 2.36(b)(1)) and that "each principal investigator has considered alternatives to painful procedures" (9 CFR 2.36(b)(2)). The main feature of the report is the specification of numbers of animals with respect to experiences of pain. The Minimization Principle lies squarely behind inclusion in the report of the category of animals that experience "pain or distress ... for which the use of appropriate anesthetic, analgesic, or tranquilizing drugs would have adversely affected the procedures, results, or interpretations" of research projects, and the requirement that a statement explaining why such drugs were not used be attached to the report (9 CFR 2.36(b)(7)).

PHS ethical guidelines for animal research also focus on the minimization of pain and distress. These policies incorporate the requirements of the AWA regulations and state explicitly that "procedures with animals will avoid or minimize discomfort, distress, and pain to the animals, consistent with sound research design"; that "procedures that may cause more than momentary or slight pain or distress to the animals will be performed with appropriate sedation, analgesia, or anesthesia, unless the procedure is justified for scientific reasons in writing by the investigator"; and that "animals that would otherwise experience severe or chronic pain or distress that cannot be relieved will be painlessly killed at the end of the procedure or, if appropriate, during the procedure" (PHS 1996, p 9). The US Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training declare that (1) "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"; (2) "procedures with animals that may cause more than momentary or slight pain or distress should be performed with appropriate sedation, analgesia, or anesthesia. Surgical or other painful procedures should not be performed on unanesthetized animals paralyzed by chemical agents"; and (3) "animals that would otherwise suffer severe or chronic pain or distress that cannot be relieved should be painlessly killed at the end of the procedure or, if appropriate, during the procedure" (PHS 1996, p i). The Minimization Principle also appears to underlie the statement of the Guide that "an integral component of veterinary medical care is prevention or alleviation of pain . . . The proper use of anesthetics and analgesics in research animals is an ethical and scientific imperative" (NRC 1996, p 64).

Pain Research in the Laws and Regulations

The frequent invocation of the Minimization Principle in AWA regulations and PHS policies reflects the centrality of this principle in society's ethical framework relating to animals. However, although federal ethical guidelines emphasize minimization of pain, they contain no standards or suggestions relating specifically to pain research in animals. Even the policy statement of the Animal and Plant Health Inspection Service that addresses painful or distressful procedures in research does not include pain research in its examples of painful or potentially painful procedures (APHIS 1998).

The absence in US laws and regulations of specific ethical guidelines relating to animal pain research means that investigators and IACUCs must apply to pain experimentation on animals more general ethical principles that relate to animal pain. Some of these general principles are enunciated in the laws and regulations relating to animal research. Ethical guidance in evaluating the humaneness of animal pain research also requires use of normative principles of the kind developed in this article. Another important source of ethical guidance are policies of professional scientific groups. Such policies reflect the experience and focused interests of scientists who sometimes deal with animal pain in distinctive investigational contexts.

Ethical Guidelines of Professional Groups

IACUCs and investigators should be aware of ethical guidelines applicable to pain research issued by professional research associations. Many of these documents explicitly incorporate or refer to US government laws and regulations. For example, the American Association for Laboratory Animal Science Policy on the Humane Care and Use of Laboratory Animals (AALAS 1997) is identical to the US Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing Research and Training (US Principles¹). The American Physiological Society Guiding Principles for the Care and Use of Animals provide that all US laws and regulations be followed and specify that postoperative care of animals "shall be such as to minimize discomfort and pain" and that "all measures to minimize pain and distress that would not compromise experimental results may be employed" (APS 1996, p 1). The constituent societies of the Federation of American Societies for Experimental Biology have adopted a Statement of Principles for the Use of Animals in Research and Education. These guidelines state that "sound scientific practice and humane considerations require that animals receive sedation, analgesia or anesthesia when appropriate. Animals should not be permitted to suffer severe or chronic pain or distress unnecessarily; such animals should be euthanized" (FASEB 1994, p 2). This document also requires conformance with all applicable laws and, like the US Principles, states that "all work with animals shall be designed and performed in consideration of its relevance to the improvement of human or animal health and the advancement of knowledge for the good of society" (FASEB 1994, p 1). The Society for Neuroscience Policy on the Use of Animals in Neuroscience Research recommends and is based on the PHS Policies and the Guide, and it repeats or paraphrases the requirements of the US Government Principles: "the avoidance or minimization of discomfort, distress, and pain," including use of sedation, analgesia or anesthesia in procedures "that may cause more than momentary or slight pain or distress" (SFN 1997, p 2).

The American Psychological Association Guidelines for Ethical Conduct in the Care and Use of Animals also require compliance with all laws and regulations but add a number of more specific recommendations relating to animal pain. These recommendations include the statements that (1) behavioral procedures "that minimize discomfort to the animal should be used"; (2) when using aversive conditions, "psychologists should adjust the parameters of stimulation to levels that appear minimum"; (3) "psychologists are encouraged to test painful stimuli on themselves, whenever reasonable"; (4) "whenever consistent with the goals of the research, consideration should be given to providing the animals with control of the potentially aversive stimulation"; (5) "procedures involving more than momentary or slight aversive stimulation, which is not relieved by medication or other acceptable methods, should be undertaken only when the objectives of the research cannot be achieved by other methods"; and (6) "experimental procedures that require prolonged aversive conditions or produce tissue damage or metabolic disturbances require greater justification and surveillance. An animal observed to be in a state of severe distress or chronic pain that cannot be alleviated and is not essential to the purposes of the research should be euthanized immediately" (APA 1992, p 5). This last statement embodies the requirements of the Justification and Value Principles that the pain or distress to which animals are subjected must be proportional to the justification and value of the experiment. The American Psychological Association Policy reiterates these principles in its general requirements of justification for the use of animals in proposed experiments, which include the statements that

Research should be undertaken with a clear scientific purpose. There should be a reasonable expectation that the research will a) increase knowledge of the processes underlying the evolution, development, maintenance, alteration, control, or biological significance of behavior; b) determine the replicability and generality of prior research; c) increase understanding of the species under study; or d) provide results that benefit the health or welfare of humans or other animals (APA 1992, p 2);

And

The scientific purpose of the research should be of sufficient potential significance to justify the use of animals (APA 1992, p 2).

IASP Ethical Guidelines

In 1980, the Committee for Research and Ethical Issues of the IASP issued a set of ethical standards for use of animals in experimental pain research (Covino and others 1980). These guidelines were revised in 1983 (Zimmermann 1983). The preface to the current guidelines state that investigators "should make every effort to minimize pain" and should "accept a general attitude in which the animal is regarded not as an object for exploitation, but as a living individual" (Zimmermann 1983, p 109).

The 1983 IASP guidelines are contained in Table 1. Several of the guidelines have already been discussed in this paper. The first guideline endorses the Justification and Value principles and appears to allow ethical evaluation of even scientifically sound research. The IASP guidelines require that investigators demonstrate likely practical benefits of experiments by showing their relevance to pain therapy. I have suggested that a stronger showing of the importance of a piece of basic research must be made when that work would cause pain or discomfort to animals than when research shows prospects of providing medical benefits (Tannenbaum 1995, p 472). However, I have not built this principle or the requirement that pain research causing animal pain must promise practical benefits into my recommendations to IACUCs. There has been very little consideration in the literature of the ethics of causing animal pain in basic research, and our understanding of this issue could benefit from additional discussion. The 1980 IASP guidelines contained the statement that "the investigator should choose a species which is as low as possible in the phylogenic order, compatible with the aim of the investigation. This recommendation infers that the degree of suffering is smaller in lower than in higher animals although this assumption cannot be taken as proven" (Covino and others 1980, p 142). The 1983 guidelines wisely deleted this statement. Although the Equality Principle is consistent with using "lower" species if they do experience less pain or suffer less, allowing investigators to proceed on the basis of an unproved assumption could reinforce the notion that the experience of pain in "lower" animals is less real or less ethically relevant.

Conclusion: The Work Ahead

To an animal, it does not matter whether its pain or distress is part of research designed to understand and treat pain. Moreover, because pain research is but one kind of biomedical research, animals that feel pain as a result of pain research surely represent a small fraction of research animals that feel pain or distress. Pain research, however, can lead the way in our general approach to ethical issues relating to pain in research animals. IACUCs and investigators cannot avoid confronting the reality of animal pain in experiments that intentionally cause such pain. They must engage in ethical deliberation in which animal and human interests are carefully balanced. They are ethically and legally obligated to find and implement techniques of lessening animal pain. Such ethical deliberation and such techniques for pain minimization will surely be applicable to animal pain associated with other kinds of research.

To help the countless people and animals that suffer pain, we need more pain research. The ethical paradox of pain research--that the evil of pain must sometimes be caused to ultimately understand and alleviate it--is for now inescapable. We owe it to the animals to approach the ethics of pain research as seriously as we approach the science.

¹Abbreviations used in this article: AWA, Animal Welfare Act; Guide, Guide for the Care and Use of Laboratory Animals; IACUC, institutional animal care and use committee; IASP, International Association for the Study of Pain; PHS, Public Health Service; US Principles, US Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing Research and Training.

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Table 1 Ethical Guidelines for Investigations of Experimental Pain in Conscious Animals of the Committee for Research and Ethical Issues of the International Association for the Study of Pain^a

(1) It is essential that the intended experiments on pain in conscious animals be reviewed beforehand by scientists and lay-persons. The potential benefit of such experiments to our understanding of pain mechanisms and pain therapy needs to be shown. The investigator should be aware of the ethical need for a continuing justification of his investigations.

(2) If possible, the investigator should try the pain stimulus on himself; this principle applies for most non-invasive stimuli causing acute pain.

(3) To make possible the evaluation of the levels of pain, the investigator should give a careful assessment of the animal's deviation from normal behavior. To this end, physiological and behavioral parameters should be measured. The outcome of this assessment should be included in the manuscript.

(4) In studies of acute or chronic pain in animals, measures should be taken to provide a reasonable assurance that the animal is exposed to the minimal pain necessary for the purposes of the experiment.

(5) An animal presumably experiencing chronic pain should be treated for relief of pain, or should be allowed to self-administer analgesic agents or procedures, as long as this will not interfere with the aim of the investigation.

(6) Studies of pain in animals paralyzed with a neuromuscular blocking agent should not be performed without a general anesthetic or an appropriate surgical procedure that eliminates sensory awareness.

(7) The duration of the experiment must be as short as possible and the number of animals kept to a minimum.

^aReprinted from Pain, Vol. 16, M. Zimmermann, "Ethical guidelines for investigations of experimental pain in conscious animals," p 109-110, 1983, with permission from Elsevier Science.

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