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Proceedings for Pain Management and Humane Endpoints

Pain Management and Humane Endpoints: PHS Policy Perspective

Nelson L. Garnett, DVM
Director, Division of Animal Welfare Office for Protection from Research Risks National Institutes of Health

Avoidance and minimization of pain in animals are fundamental concepts of the Public Health Service Policy on Humane Care and Use of Laboratory Animals. This presentation will explore the various federal laws, policies and guidelines applicable to animal-related activities conducted or supported by PHS agencies.

Many of the concepts related to subject of Pain Management and Humane Endpoints are also important considerations in the more general discussion of Alternatives. For the sake of discussion, I think what we are talking about these two days could be generally equated to the "Refinement" R of the "three Rs". We should be able to assume that, before we get to the question of pain management and humane endpoints, there has already been a process for determining that there are no suitable nonanimal alternatives, and that the appropriate number of animals needed has already been properly established.

Health Research Extension Act 1985

"The Director of NIH shall require each applicant for a grant, contract, or cooperative agreement involving research on animals which is administered by NIH or any national research institute to include in its application or contract proposal:

  1. assurances satisfactory to the Director of NIH that: (B) Scientists, animal technicians, and other personnel involved with animal care, treatment, and use by the applicant have available to them instruction or training in the humane practice of animal maintenance and experimentation, and the concept, availability, and use of research or testing methods that limit the use of animals or limit animal distress; and
  2. a statement of the reasons for the use of animals in research to be conducted with funds provided under such grant or contract.

Don't try to read the slide. It is just to illustrate that the HREA, also known as the PHS Act, the law that authorizes the PHS Policy, contains specific references to what we commonly refer to as Alternative... including the availability of training in the concept, availability, and use of research or testing methods that limit the use of animals or limit animal distress, and... a requirement for grant applications to include a statement of the reasons for use of animals in research conducted with funds under the PHS grant or contract.

"such guidelines shall not be construed to prescribe methods of research" (PL 99-158), Sec 495.(a)(2)

The law also includes this language which attempts to balance the needs of science with the welfare of animals.

This statement has to be interpreted with some care, however, because it could leave the impression that all "scientific justifications" provided by PIs must, by statutory requirement, be accepted by the IACUC. Some of you may remember a Protocol Review article in the March 1998 issue of Lab Animal magazine, in which an animal rights lawyer attempted to make that case.

I want to make it perfectly clear, as was stated by myself and Ron DeHaven of USDA in a sidebar to that article, that IACUCs are expected to critically review assertions related to the proposed use of animals, especially in the area of pain and humane endpoints, and cannot be compelled to approve anything against their will.

"U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training" (page I, PHS Policy)

#III. "The animals selected for a procedure should be of an appropriate species and quality and the minimum number required to obtain valid results. Methods such as mathematical models, computer simulation, and in vitro biological systems should be considered.

The US Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training predate the PHS Policy and are incorporated in it. They are almost identical to the International Guiding Principles.

Most of the scientific professional societies have very similar provisions in their position statements and editorial policies regarding the use of animals by their membership.

Principle #3 refers specifically to minimizing the number of animals and to consideration of in vitro systems.

#IV. "Proper use of animals, including the avoidance or minimization of discomfort, distress, and pain when consistent with sound scientific practices, is imperative."

Principle #4 really says it all -- To me, this is the simplest way of describing the three Rs and the concept of alternatives: "Proper use of animals, including the avoidance or minimization of discomfort, distress, and pain when consistent with sound scientific practices, is imperative." It then goes on to make a statement, as pointed out by Dr. Gebhart this morning, that is clearly anthropomorphic, but which provides a starting point for making the necessary pain assessment prior to figuring out how to avoid or minimize that pain: "Unless the contrary is established, investigators should consider that procedures that cause pain and distress in human beings may cause pain or distress in animals."

#V. "Procedures with animals that may cause more than momentary or slight pain or distress should be performed with appropriate sedation, analgesia, or anesthesia."

Principle V then goes on to call for appropriate sedation, analgesia, and anesthesia for animals subjected to more than momentary or slight pain; and to admonish against performing surgery or painful procedures on unanesthetized animals paralyzed by chemical agents.

And Principle VI states that 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. This Principle certainly has implications for this meeting's consideration of humane endpoints.

PHS Policy (1996)

IV., A., 1., g. (Animal Welfare Assurance) The program description must include the following:
"...a synopsis of training or instruction in the humane practice of animal care and use, as well as training or instruction in research or testing methods that minimize the number of animals required and minimize animal distress offered to scientists, animal technicians, and other personnel involved in animal care, treatment, or use;"

Now to the PHS Policy itself, this language mimics the statute but incorporates those same elements into the institutional Assurance which establishes the foundation for institutional eligibility for PHS funding.

IV., C., 1., a. and b. (IACUC review criteria)

  1. Procedures with animals will avoid or minimize discomfort, distress, and pain to the animals, consistent with sound research design.
  2. 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."

Again, in the Policy, we have guidance directed to the IACUC for protocol review criteria, including avoidance or minimization of pain, distress, and discomfort, consistent with sound research design.

It then goes on to address the need for appropriate sedation, analgesia, or anesthesia, unless there is a scientific justification to do otherwise...

...and the requirement to intervene after, or during, the procedure as appropriate, if severe or chronic pain or distress cannot be relieved.

Methods of Euthanasia must be consistent with the AVMA Panel on Euthanasia, unless a deviation is justified for scientific reasons in writing by the investigator, and approved by the IACUC.

"Guide" continued: Although scientists have also developed nonanimal models for research, teaching, and testing...., these models often cannot completely mimic the complex human or animal body, and continued progress in human and animal health and well-being requires the use of living animals. Nevertheless, efforts to develop and use scientifically valid alternatives, adjuncts, and refinements to animal research should continue. Guide at 1.

1996 "Guide" protocol review criteria

The following topics should be considered in the preparation and review of animal care and use protocols: ... availability or appropriateness of the use of less invasive procedures, other species, isolated organ preparation, cell or tissue culture, or computer simulation..." Guide at 10.

IV., D., 1., b. and d. (5 points in grant application) "Applications and proposals for awards submitted to the PHS that involve the care and use of animals shall contain the following information:

b. rationale for involving animals, and for the appropriateness of the species and numbers to be used;d. a description of procedures designed to assure that discomfort and injury to animals will be limited to that which is unavoidable in the conduct of scientifically valuable research, and that analgesic, anesthetic, and tranquilizing drugs will be used where indicated and appropriate to minimize discomfort and pain to animals;"

Another PHS Policy, and NIH Grants Policy, provision that is not often mentioned is the requirement for investigators to address five very specific animal-related points in the vertebrate animal section of the NIH grant application.

Study sections are expected to evaluate this information, along with other components of the application; and applications without this information should be considered incomplete.

The statement at b. asks for a rationale for using animals at all, and forces consideration of the opposite option, that is, not using them.

at d. the PI is asked to describe procedures designed to assure that discomfort and injury to animals is limited to that which is unavoidable in the conduct of scientifically valuable research.

This is to be followed by e., a description of any euthanasia methods to be employed.

 

What kinds of justifications should IACUCs accept?

But how do IACUCs apply these federal laws, policies, and guidelines to their review of protocols, and their evaluation of scientific justifications for unavoidable pain?

The following language was lifted from the November 1997 Dear Colleague letter on monoclonal antibody production (part of handout material) because it is also applicable to the review of all proposals involving animals, especially those with potential for pain.

Prior to approval of proposals which include animals, IACUCs must determine that (i) the proposed use is scientifically justified, (ii) methods that avoid or minimize discomfort, distress, and pain (including in vitro methods) have been considered, and (iii) the latter have been found unsuitable. Fulfillment of this three-part IACUC responsibility, with appropriate documentation, is considered central to an institution's compliance with its Animal Welfare Assurance and the PHS Policy.

The Three Rs

The federal mandate to avoid or minimize discomfort, pain, and distress in experimental animals, consistent with sound scientific practices, is, for all practical purposes, synonymous with a requirement to consider alternative methods that reduce, refine, or replace the use of animals.

Consideration of these issues should be incorporated into IACUC review, investigator training, research proposals, and ongoing monitoring of the institutional animal care and use program.

IACUCs, acting as agents of institutions, are expected to implement and routinely evaluate these aspects of the institutional animal care and use program to ensure compliance with the PHS Policy.

These longstanding requirements are central to the federal oversight of all animal-related activities in research, testing, and training.

Pain Scale: Plateaus vs Continuum

I'm sure that this issue will receive more attention on the program tomorrow but I want to mention a few points on it now.

There is clearly a need for PIs and IACUCs, as well as laboratory animal veterinarians, to have tools available to them to assess the degree of pain that an animal either is experiencing, or can reasonably be expected to experience.

Therefore, the concept of pain scales, which attempt to categorize pain by degree of severity, has gained some popularity and momentum. The current USDA requirement for annual reporting of the numbers of animals used, broken down into column C, D, and E is one of the simplest examples of such a scale.

While these tools can be extremely valuable to us all, there are a few pitfalls that I think we should work hard to avoid.

Most of the systems that I am aware of rely on a series of plateaus, with examples at each level, representing escalating levels of pain or distress. As carefully worded and well intended as they may be, it is almost impossible to list an example which doesnÕt either overestimate, or underestimate the level of pain or distress under certain circumstances.

Freund's complete adjuvant, electric shock, routine blood draws, food and water regulation, restraint, mouse ascites antibody production, are all examples that can be all over the pain and distress map depending on the methodology, skill of the technician, and numerous other variables.

So my plea is to think very carefully about examples of different levels of pain and the contexts in which they may be applied...

...and to factor in all of the relevant variables, including human elements, that might be predicted to have an influence on the animal's experience.

My preference for addressing the pain scale issue is to apply the U.S. Government Principles and PHS Policy language rather literally: "The avoidance or minimization of discomfort, distress and pain, consistent with sound scientific practices, is imperative."

I believe that the focus should be on the elimination of all unnecessary pain and distress.

This would give us a pain scale that is more of a smooth continuum, without the somewhat arbitrary and often inaccurate steps or plateaus.

It would also force us to recognize that there is no room for unnecessary pain or distress. In all cases pain would be limited to that which is unavoidable, based on the aims of the study.

Coupled with a conscientious effort to find suitable alternatives, this approach may provide a more practical application of the concept of the three Rs.

Avoid Unnecessary Use

I'd like to close now with two final slides that I think summarize the commitments made by the biomedical community, and which also describe the bottom line, or outcome-based objectives, of all the various federal laws and policies dealing with animal welfare oversight:

Avoid Unnecessary Use

and...

Avoid Unnecessary Pain, Distress, and Discomfort

I realize that the policy part of this equation is the easy part. The hard part, actual implementation by PIs, IACUCs, and veterinarians, is what this conference is all about. And I hope that the results of this conference will assist us all in accomplishing these goals.

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