Definition of Pain and Distress and Reporting Requirements for Laboratory Animals: Proceedings of the Workshop Held June 22, 2000 (2000)

Marcelo Couto

Scientific Advisory Committee

American Association for Laboratory Animal Science

Associate Director, Comparative Medicine Department of Animal Resources

Scripps Research Institute, La Jolla, Calif.

I want to thank ILAR and NIH for jointly organizing this workshop. This meeting is a great opportunity for scientists, regulators, and animal care representatives to come together and present their views on the important issue of recognizing and alleviating pain and distress in laboratory animals. I hope that at the end of the workshop, we will be better equipped to do a good job.

AALAS has produced this position paper to outline the difficulties in recognizing pain and distress in laboratory animals, to clarify certain definitions, and to stimulate the laboratory animal community and regulatory authorities to find appropriate means for addressing this problem and create lines of communication for sharing information that may advance this cause. We also urge the regulatory agencies to revise the current pain and distress categorization system in the USDA annual report.

The assessment of pain and distress is a very individual matter, both from the standpoint of the individual animal and the observer. When evaluating pain and distress, it is very difficult to make general statements because different species and different individuals within a species often exhibit different thresholds and different tolerances to pain. Determining what constitutes pain or distress in animals is further complicated by the fact that there are no universally agreed-on criteria for assessing or determining what is or is not painful or distressful to an animal.

An additional, complicating issue is that pain and distress, as well as the drugs used to alleviate them, can introduce a variable in a study. Limited pilot

studies and well-controlled experiments may be helpful in sorting out any confounding effects caused by either pain or by the pain-relieving drugs.

The complex nature of modern animal experimentation requires accurate reporting of animal use. I am sure that by now most people agree that the USDA categories are not totally informative. The public at large is especially concerned with the intensity and duration of any pain that research animals may have undergone in the course of experimentation, regardless of whether the animals received medication or not. Essentially, people want to know how much the animals really suffer. To provide that information accurately, the USDA categories would have to be changed or modified to resolve the public concern.

It is important to note that the alleviation of pain and/or distress is not limited just to the use of drugs. In fact, the alleviation of pain and distress is often a very diverse task that includes environmental enrichment, the provision of nesting material and social enhancement in addition to or in lieu of drugs. I was pleased to learn that the proposed changes to Policy 11 actually might include nondrug treatment modalities under Column D of the USDA annual report. Presently, animals experiencing pain or distress and for which drugs have been withheld for scientific reasons are automatically placed in column E (unalleviated pain and/or distress) regardless of whether other treatment approaches were used. Of course, the appropriate categorization of experiments can be made only after appropriate veterinary monitoring of the study in conjunction with the investigator and the IACUC.

Laboratory animal veterinarians, animal care personnel, and investigators have a legal as well as moral obligation to alleviate pain and distress in animals. Alternatives to animal use in biomedical research should also be sought. Investigators will generally not use animals unless they have no other viable alternatives or unless they are unwilling to change the way they conduct their research. Animal research is expensive, it is much more difficult to control than in vitro experiments, and it is subject to a plethora of regulations. Reasonable investigators will try to avoid doing animal research if they can answer the same scientific question using in vitro methods instead. However, once the investigator has made a decision to use animals and the project is approved and funded, then the experiments must be done as humanely as possible.

Among federal requirements is the provision that the IACUCs must assure the proper training of all personnel using laboratory animals. This mandate

certainly includes the recognition and alleviation of pain and distress, and it applies to technicians, researchers, and veterinarians. To be sure, we cannot expect investigators or technicians to prescribe pain-relieving medications; this responsibility rests with the veterinarian. However, they should seek information and/or assistance when needed.

The AALAS position paper also emphasizes veterinary assistance of investigators, not only during the planning of potentially painful experiments, which is mandated by law, but also as soon as a study is under way. The statement also advocates adequate veterinary monitoring. Animal care and use protocols should be reviewed by the IACUC, and a pain category based on the expected pain level should be assigned at this time, that is, in a prospective manner. As soon as the study is funded and the investigator is ready to order animals, the veterinarian should arrange with the research laboratory to monitor or oversee the first few experiments or procedures in an attempt to ascertain the actual degree of pain or distress experienced by the animals. Whenever refinements are possible, the veterinarian should make pertinent recommendations to the researcher.

The results of this monitoring, as well as all associated recommendations, should be reported to the IACUC in a timely fashion. Based on this report, the IACUC should review the pain level category assigned originally and change it if necessary, in a retrospective manner, before submission of the USDA annual report. Therefore, more meaningful information can be forwarded to this regulatory agency. Involving the animal research staff in this process serves not only as an opportunity to train the laboratory personnel but also helps increase their awareness regarding the humane treatment of the animals. The primary monitoring responsibility may ultimately be delegated to the research laboratory, after the veterinarian and IACUC deem that its training is adequate. All observations and communications should be documented in a monitoring log. The veterinarian should continue to monitor these procedures, albeit more sporadically.

When designing monitoring schedules before the start of a new project the veterinarian should meet with the investigator and decide which pain- or distress-relieving medications could be used safely, without undue interference with the study. The responsibility for determining which drugs are appropriate rests with the investigator. Of course, the veterinarian must be familiar with the mode of action and pharmacological effects of these drugs so that he/she can make a valuable contribution toward this goal.

An important factor in reducing distress to the animals is their appropriate conditioning before a procedure. In other words, we should try to get them accustomed to the new procedure or the new environment in advance of the actual experiment. This acclimatization will also result in more reliable research data.

An important refinement that should be implemented whenever possible is the use of early endpoints, that is, ending the experiment at the earliest point that the desired data can be collected and before the animals are subjected to unnecessary pain and distress. Preferably, death should be avoided as an endpoint for animal experiments. Alternatives to death as an endpoint, such as behavioral changes, fluctuations in body temperature, HID₅₀ (hypothermia-inducing dose 50 as opposed to LD₅₀) should be sought. Body condition scoring and weight loss patterns should be taken into consideration and evaluated to determine whether they can be implemented as a refinement. Pilot studies should be conducted under veterinary supervision whenever a novel procedure is planned that has the potential to be painful or distressful. For procedures that are known to be painful without the benefit of analgesics (e.g., sternal thoracotomy), pain-relieving drugs should be used preemptively.

As we all agree, to optimize the humane treatment of laboratory animals, more research is needed in the area of recognition and assessment of pain and distress.

DR. KARAS (Alicia Karas, Tufts University): With regard to your statement that analgesics and anesthetics could interfere with research results, I think the important point is that we understand quite well the effects of anesthetics and analgesics. However, the big unknown is how pain and distress affect research results. It appears to me that aspect of the issue should be included in the statement.

DR. COUTO: Your point is excellent. For the sake of clarity, this issue was addressed by the Scientific Advisory Committee and was included in the position statement. I did mention before that pain and distress, as well as the drugs used to alleviate them, can interfere. As a corollary to that, I should say that the effect of the drugs as well as the effects of the pain should be assessed or evaluated at least in a limited pilot study.

DR. ANDERSON (Lynn C. Anderson, Merck Research Laboratories): You said that animal reporting is the responsibility of the IACUC and the attending veterinarian, but you did not mention the investigator. I believe it is very important to stress that there is a real partnership between the investigator, the attending veterinarian, and the IACUC to monitor pain and distress; and that the burden is not on just the IACUC, the attending veterinarian, or the investigators, as suggested earlier.

DR. COUTO: You are correct. The burden for monitoring is shared, which is why we should involve research personnel in addition to the veterinarian and animal care technician. Sometimes when we can involve the investigator himself or herself, we should try to do that. Most often, however, principal investigators may not go to the animal room very often. It is easier to work with the contact person, a research associate, or the technician who is actually in contact with the animals.