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OCR for page 1
SUMMARY
This report is the response to a request by the New Jersey Association
for Biomedical Research that the Institute for Laboratory Animal Research
(ILAR) form a consensus committee to update the 1992 National Research
Council (NRC) report Recognition and Alleviation of Pain and Distress in
Laboratory Animals. This report follows the release of the 2008 National
Research Council (NRC) report Recognition and Alleviation of Distress in
Laboratory Animals. In the 16 years since the first report was published, there
has been significant scientific progress in the areas of animal welfare, stress,
distress, and pain to warrant a fresh look at the topics of that report. Although
the numerous regulations, policies, and guidelines that govern animal use in
research in the United States address distress and pain jointly, from a scientific
perspective the two concepts are quite distinct. According to the International
Association for the Study of Pain, pain in humans is “an unpleasant sensory and
emotional experience associated with actual or potential tissue damage, or
described in terms of such damage” (IASP 1979). Pain is mediated through the
activity of specialized sensory receptors, called nociceptors, involves the
possibility of bodily injury, and depends on the interaction between those
nociceptors and higher processing centers in the brain to generate the negative
emotional component associated with the potential harm. While pain can be
detrimental to animal welfare, distress always is, as it is a measure of the
animal’s inability to cope with a stressor.
Adopting an approach similar to that taken by the authors of the
Recognition and Alleviation of Distress in Laboratory Animals report, this
report focuses on the management and avoidance of pain wherever
scientifically possible. Continuing in the steps of the 1992 committee, the
current committee embraces the idea that in most experimental and husbandry
situations laboratory animals need not experience pain, and that its alleviation
and prevention are an ethical and moral imperative that is embodied in the
relevant regulations and policies. In fact, this approach was codified in the
statement of task for this project:
“The … report will update information based on the current
scientific literature on recognizing and alleviating pain in laboratory
animals. The report will discuss the physiology of pain in commonly
used laboratory species. Specific emphasis will be placed on the
identification of humane endpoints, pharmacologic and non-
pharmacologic principles to control pain, and principles to utilize in
minimizing pain associated with experimental procedures. As with the
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2 SUMMARY
first report [on Distress], general guidelines and examples will be given
to aid IACUC members, investigators and animal care staff in making
decisions about protocols using laboratory animals under current
federal regulations and policies”.
Approach to this study
The committee collected and evaluated scientific evidence from peer-
reviewed published literature, evidence-based veterinary practices, and expert
opinions. The committee adopted a consistent terminology, defined in the
Glossary and Chapter 1, and examined the occurrence of pain in vertebrates
alone, for a number of reasons: one, the current regulations affect only the
vertebrate phylum; two, the majority of laboratory animal species used in
research, education and training are vertebrates; and three, there is ongoing
debate about whether pain occurs in subjects that may or may not have
consciousness (readers are urged to explore studies from adult humans with
persistent vegetative state or dementia and think on the implications of these
data for non-verbal populations such as laboratory animals). As it was beyond
the task of this committee to evaluate and analyze the last question, the
underlying premise of this report is that all vertebrates should be considered
capable of experiencing the aversive state of pain.
Although most of the information used in the report reflects studies and
observations in mammals, currently available, albeit very limited, data on
birds, fish, reptiles, and amphibians are also included. The Committee decided
against including information on the treatment and management of pain of
each laboratory species, because for the commonest of those there are plenty
of referenced and peer-reviewed publications, professional societies’
guidelines, books, and book chapters that the audience can easily obtain and
refer to. Instead, it opted to expand on those species for which the body of
peer-reviewed work is still small and for which guidelines are still lacking.
Therefore, the report contains practical information on birds, amphibians, fish,
and reptiles in order to help the scientific and veterinary community better
care for these laboratory species.
Pain in animal research
The Committee acknowledges that pain in animals is difficult to access,
mostly due to lack of methods that can validate and objectively measure it.
Until such tools are developed, behavioral indices and careful extrapolation
from the human experience should be used to assess pain in research animals.
It should be kept in mind that pain may not only be caused as part of a
research procedure, but also may be a by-product of husbandry or other
unrelated factors (e.g., aging). Pain may arise not only in response to a
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Recognition and Alleviation of Pain in Laboratory Animals 3
noxious stimulus, but also in situations where increased sensitivity to pain is
observed (i.e., hyperlgesia), such as following injury and inflammation.
Psychological factors likely contribute to pain under these circumstances.
Pain is the result of a cascade of physiological, immunological,
cognitive, and behavioral effects that potentially make uncontrolled pain a
source of experimental error. Although there are circumstances in which
withholding treatment is necessary (as, for example, when pain itself is the
focus of the study), routinely withholding analgesics after surgery or other
invasive procedures with anticipated moderate to severe pain is detrimental to
the welfare of the research subjects and contrary to the regulatory mandate.
A useful assumption is that the magnitude of the clinical signs (see Chapter 3)
and behavioral changes observed correlates closely with the intensity of pain.
Current best practices to assess pain are based on a structured clinical
examination combined with solid knowledge of the normal appearance and
behavior of the species used.
Anticipating the potential intensity of pain is important in designing the
most appropriate approach to its management or prevention. Common
interventions to treat pain include the use of anesthetics, analgesics,
anxiolytics and non-pharmacological methods. It should be noted that,
although regulations assert that only non-brief, procedural pain requires
treatment, pain of any duration or intensity merits consideration and potential
treatment including animals subjected to multiple episodes of momentary pain
that may also benefit from measures to alleviate such pain.
In a fashion similar to the emphasis stated in Recognition and Alleviation
of Distress in Laboratory Animals, the Committee stresses the importance of
the Three Rs (replacement, refinement, and reduction) as the standard for
identifying, modifying, minimizing and avoiding most causes of pain in
laboratory animals. To this end, the Committee believes that adoption of
humane endpoints is critical, particularly in those studies where significant
pain is anticipated. Because humane endpoints are unique to individual
research projects, pilot studies should be undertaken to identify and
incorporate them into the study design. Good communication between
researchers, veterinarians, animal care personnel and institutional animal care
and use committees (IACUCs) is crucial to this process.
Recommendations
In light of the information analyzed and discussed in this report, the
committee makes overarching consensus recommendations that go above
and beyond the recommendations found at the end of individual chapters:
Current scientific evidence strongly suggests that mammals, including
rodents (which are the most commonly used laboratory animals), are
able to experience pain. Researchers, veterinarians, animal care
personnel, and IACUCs should remember the cautionary tone of the
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4 SUMMARY
4th Government Principle1 and use professional judgment and best
practices to avoid or minimize unnecessary pain. Studies in which
more than momentary pain is anticipated, in addition to providing
appropriate analgesia, should also consider and enforce (where
possible) humane endpoints to protect the welfare of the laboratory
animals.
Knowledge about pain in non-mammalian species is incomplete and in
the absence of evidence they should be treated humanely with
serious consideration of, and attention to, the potentially painful
implications of noxious stimuli and invasive procedures.
Increased efforts should be undertaken to identify appropriate
humane endpoints. The importance of pilot studies in this regard
cannot be overemphasized. Teamwork and open communication
between researchers, veterinarians, animal care staff, and the IACUC
can facilitate and expedite this process.
Funding is particularly difficult for projects that investigate the
understanding, recognition, and alleviation of pain, especially if the
beneficiaries of such projects are the laboratory animals themselves.
However, lack of knowledge of drug effects and doses in many
mammalian and especially in non-mammalian species, as well as the
potentially confounding effects of analgesics and anesthetics on
study variables, limit effective pain management. Given the impact
of better animal welfare on science as well as the growing public
interest in the treatment of laboratory animals, federal agencies and
large foundations that support biomedical and behavioral research
should make funds available for pain-related studies (see also the
recommendations in the Recognition and Alleviation of Distress
report, NRC 2008).
Lack of adequate funding also hinders the development and
validation of alternatives (methods, procedures, and research
strategies), which should be incorporated into research projects and
safety assessment tests. Efforts must continue to develop and
validate alternatives that can be incorporated into research projects
and safety assessment tests.
1
U.S. Government Principle #4 states that: “Proper use of animals, including the avoidance or
minimization of discomfort, distress, and pain when consistent with sound scientific practices,
is imperative. Unless the contrary is established, investigators should consider that procedures
that cause pain or distress in human beings may cause pain or distress in other animals”.
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Recognition and Alleviation of Pain in Laboratory Animals 5
It is necessary to educate investigators, veterinarians and animal
care staff as to the basic physiologic principles, causes, signs, and
availability of diverse treatment options and potential deleterious
effects of those treatments on pain. As the field of pain medicine
benefits from new insights and methods of prevention and treatment
for humans, so should laboratory animals benefit from the research
for which they are a currently indispensable underpinning. By urging
laboratory animal veterinarians to understand current pain
management, and by suitably updating regulatory policy, the ability
to minimize pain in laboratory animals can proceed in tandem with
advancing scientific progress.
References
IASP [International Association for the Study of Pain]. 1979. IASP Pain
Terminology. Available at: http://www.iasp-
pain.org/AM/Template.cfm?Section=Pain_Deefinitions&Template=/CM/H
TMLDisplay.cfm&ContentID=1728#Pain. Accessed January 8 2009.
NRC [National Research Council]. 2008. Recognition and Alleviation of Distress
in Laboratory Animals. Washington, DC: National Academies Press.
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