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OCR for page 165
APPENDIX 2. U.S. regulations and guidelines
regarding recognition and alleviation of pain
in laboratory animals
The requirement or recommendation to consider the recognition and
alleviation of pain in laboratory animals when conducting research in the
United States is constituted in federal law, regulations, and guidelines,
enforced by the U.S. Public Health Service Policy and promulgated by various
professional organizations as outlined in the following paragraphs.
Legal requirements and agency guidelines
U.S. Animal Welfare Act
The primary federal regulation concerning the care and use of laboratory
animals in the United States is the Animal Welfare Act (AWA; Public Law 89-544
as amended, 7 U.S.C. Ch. 54). The AWA is implemented through the Animal
Welfare Act Regulations, published in the Code of Federal Regulations (CFR),
Title 9, Chapter 1, Subchapter A. The Act covers pets and warmblooded
animals used for research, testing, and exhibition purposes. The Act does not
protect a number of animal species, and for the purposes of this report
specifically excludes rats of the genus Rattus, mice of the genus Mus, and birds
specifically bred for use in research. The Animal Welfare Regulations consider
painful procedures and methods to alleviate pain in several sections as follows:
§2.31(a), (d): Registered research institutions must have an Institutional
Animal Care and Use committee (IACUC) that reviews and approves all
procedures conducted using laboratory animals.
§2.31(d)(i): “Procedures involving animals will avoid or minimize
discomfort, distress or pain to animals”
§2.31 (d)(ii): “The principal investigator has considered alternatives to
procedures that may cause more than momentary or slight pain”.
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166 Recognition and Alleviation of Pain in Laboratory Animals
§2.31(e): “A proposal to conduct an activity involving animals…must
contain…a description of procedures designed to assure that discomfort
and pain to 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 animals”.
§2.33(a): “Each research facility shall have an attending veterinarian
who shall provide adequate veterinary care to animals in compliance
with this section”.
§2.33(b)(4): The attending veterinarian shall provide “guidance to
principal investigators and other personnel involved in the care and use
of animals regarding handling, immobilization, anesthesia,
tranquilization, and euthanasia”.
The United States Department of Agriculture (USDA) is responsible for
the administration and enforcement of this act through the Animal and Plant
Health Inspection Service (APHIS).
USDA Policies
The USDA through APHIS periodically issues and updates policies to
clarify the provisions of the Animal Welfare Regulations and provide improved
guidance to USDA personnel that inspects the regulated research programs.
Two USDA polices address the requirement to recognize the potential to cause
pain in association with research activities.
Policy 11 - “Painful Procedures”
Policy #11 (issue dated: April 14, 1997) defines a painful procedure as
“any procedure that would reasonably be expected to cause more than slight or
momentary pain and/or distress in a human being to which the procedure is
applied”. The policy requires the IACUC to ensure that investigators have
considered appropriate alternatives to any procedure that may cause more
than slight or momentary pain or distress. The policy lists examples of
procedures that are likely to cause more than momentary or slight pain,
including but not limited to terminal surgery (alleviated by anesthesia), use of
complete Freund’s adjuvant (depending on the product, procedure, and
species), and ocular and skin irritancy testing. The policy further states the
expectation that animals exhibiting signs of pain or discomfort will receive
appropriate pain relief unless justified scientifically, in writing, and approved
by the IACUC. Policy #11 also requires the reporting of animals subjected to
procedures that may cause pain which were alleviated through use of
anesthetics, analgesics, sedatives, and/or tranquilizers, as well as the separate
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APPENDIX 2: US REGULATIONS AND GUIDELINES 167
reporting of animals subjected to such procedures in which pain-relieving
agents were not administered for IACUC-approved research requirements.
Policy 12 - “Considerations of Alternatives to Painful/Distressful Procedures”
This policy (issue dated: June 21, 2000) provides guidance for the AWA
requirement that principal investigators consider alternatives to painful
procedures. Such alternatives should include some aspect of replacement,
reduction, or refinement of animal use to minimize animal pain consistent with
research goals. For procedures that may cause pain, the policy states that
“any proposed animal activity, or significant changes to an ongoing animal
activity, must include: a description of procedures or methods designed to
assure that discomfort and pain 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”. The policy also
requires that proposed animal use include “a written description of the
methods and sources used to consider alternatives to procedures that may
cause more than momentary or slight pain to animals”.
Health Research Extension Act
The Health Research Extension Act, Public Law 99-158, November 20,
1985, “Animals in Research” provides the statutory mandate for the Public
Health Service Policy on Humane Care and Use of Laboratory Animals (OLAW
2002 reprint of PHS Policy; preface). The Act mandates that “the Secretary (of
the US Department of Health and Human Services), acting through the Director
of NIH, shall establish guidelines for the following…(in procedures that may
cause pain): the proper treatment of animals while being used in
research…shall require the appropriate use of tranquilizers, analgesics,
anesthetics, paralytics, and euthanasia for animals…”. The PHS Policy
(outlined in subsequent paragraphs) defines procedures to implement this
mandate.
Public Health Service Policy on Humane Care and Use of
Laboratory Animals
The Public Health Service Policy on Humane Care and Use of Laboratory
Animals (PHS Policy) (DHHS 2002) was introduced in 1973 and has been revised
multiple times (most recently in 2002). The Policy applies to all institutions
that use animals in research supported by any component of the PHS (e.g., NIH,
CDC, FDA) and “requires institutions to establish and maintain proper measures
to ensure the appropriate care and use of all animals involved in research,
training, and biological testing”. While the PHS Policy mandates compliance
with the AWA and AWA regulations, it employs a broader definition of an
animal: “any live, vertebrate animal used or intended for use in research,
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168 Recognition and Alleviation of Pain in Laboratory Animals
training, experimentation, or biological testing”. Further, the Policy endorses
the U.S. Government Principles for the Utilization and Care of Vertebrate
Animals Used in Testing, Research, and Training (see below) and requires
institutions to base their animal care and use programs on the National
Research Council’s Guide for the Care and Use of Laboratory Animals (NRC
1996).
The NIH Office of Laboratory Animal Welfare (OLAW) is responsible for
administering the PHS Policy. The PHS Policy defines procedures for submission
of the Animal Welfare Assurance statement, which is required of all institutions
that conduct PHS-funded research, training, or testing with animals. For
potentially painful procedures on animals, the PHS policy requires the IACUC to
determine that “procedures with animals will avoid or minimize discomfort,
distress, and pain to the animals, consistent with sound research design;
procedures that may cause more than momentary or slight pain or distress to
animals will be performed with appropriate sedation, analgesia, or anesthesia,
unless the procedure is justified for scientific reasons in writing by the
investigator; and 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”. The PHS Policy
further states that “methods of euthanasia used will be consistent with the
recommendations of the American Veterinary Medical Association” (AVMA
2007). Additionally, with respect to potentially painful procedures, the PHS
Policy requires applications and proposals for PHS awards to include “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”.
U.S. Government Principles for the Utilization and Care of
Vertebrate Animals Used in Testing, Research, and Training.
The U.S. Government Principles for the Utilization and Care of
Vertebrate Animals Used in Testing, Research, and Training (U.S. Government
Principles) were drafted in 1985 by the Interagency Research Animal
Committee (IRAC 1985). The document addresses compliance with federal
laws, policies, and guidelines and establishes overarching principles to consider
when using animals in research, testing, and training. Principles 4, 5, and 6
relate to the potential to cause pain in laboratory animals.
Principle #4: “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
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APPENDIX 2: US REGULATIONS AND GUIDELINES 169
pain or distress in human beings may cause pain or distress in other
animals”.
Principle #5: “Procedures with animals that may cause more than
momentary or slight pain or distress should be performed under
appropriate sedation, analgesia, or anesthesia. Surgical or other painful
procedures should not be performed on unanesthetized animals
paralyzed by chemical agents”.
Principle #6: “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”.
Guide for the Care and Use of Laboratory Animals
The recommendations and guidelines of the Guide for the Care and Use
of Laboratory Animals (7th ed.; NRC 1996; the Guide) were drafted by a
committee of the National Research Council’s Institute for Laboratory Animal
Research to promote the humane care and use of laboratory animals. The
Guide emphasizes the application of performance standards and professional
judgment encouraging users and institutions to achieve excellent standards of
animal care and use by determining how best to achieve these goals within the
scope and capabilities of the particular institution. The Guide also endorses
the responsibilities of investigators as stated in the U.S. Government Principles
for Utilization and Care of Vertebrate Animals Used in Testing, Research, and
Training (IRAC 1985) and previously outlined. Both the PHS Policy and the
Association for Assessment and Accreditation of Laboratory Animal Care
International (AAALAC International) require institutions to base their programs
of animal care and use on the recommendations detailed in the Guide.
The Guide (page 9) mandates establishing an IACUC and that the IACUC
ensure the appropriate application of sedation, analgesia, and anesthesia when
reviewing protocols. The Guide (page 12) acknowledges that “ethical,
humane, and scientific considerations sometimes require the use of sedatives,
analgesics, or anesthetics in animals”. The Guide (page 64) also devotes a
section to the consideration of pain, analgesia, and anesthesia asserting that
“an integral component of veterinary medical care is prevention or alleviation
of pain associated with procedural and surgical protocols”. Although
recognizing that pain is a complex experience, the Guide indicates that the
ability to experience and respond to pain is widespread in the animal kingdom.
The Guide also asserts that the proper use of anesthetics and analgesics in
research animals is an ethical and scientific imperative and that in general,
unless the contrary is known or established, it should be assumed that
procedures that cause pain in humans also cause pain in animals.
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170 Recognition and Alleviation of Pain in Laboratory Animals
Other relevant guidelines and statements
Association for the Assessment and Accreditation of Laboratory
Animal Care, International
The Association for the Assessment and Accreditation of Laboratory
Animal Care, International (AAALAC International) is a private, nonprofit
organization that promotes the humane care and use of laboratory animals
through a program of voluntary assessment and accreditation. AAALAC
International does not have its own standards but uses the Guide as its primary
assessment resource along with other peer-reviewed reference standards.
Additionally, when conducting assessments of accredited programs, AAALAC
International requires that institutions comply with applicable principles,
regulations, standards, policies and guidelines concerning pain in laboratory
animals.
American College of Laboratory Animal Medicine
The American College of Laboratory Animal Medicine (ACLAM) is the
professional organization of veterinarians who have completed the
requirements to become board certified as specialists in laboratory animal
medicine. ACLAM has issued position statements regarding Adequate
Veterinary Care and of Pain and Distress in Laboratory Animals.
ACLAM Report on Adequate Veterinary Care
The ACLAM Report on Adequate Veterinary Care (ACLAM 1996) details
the expectations and requirements of an institution’s veterinary care program,
including the expectation that the veterinarian will have the authority to
ensure the proper use of anesthetics, analgesics, tranquilizers, and methods of
euthanasia. The report further states that “written guidelines regarding the
selection and use of anesthetics, analgesics and tranquilizing drugs and
euthanasia practices for all species used must be provided and periodically
reviewed by the veterinarian”. Additionally, “the veterinarian must have the
responsibility and authority to assure that handling, restraint, anesthesia,
analgesia and euthanasia are administered as required to relieve pain and such
suffering in research animals, provided such intervention is not specifically
precluded in protocols reviewed and approved by the IACUC. The veterinarian
must exercise good professional judgment to select the most appropriate
pharmacologic agent(s) and methods to relieve animal pain or distress in order
to assure humane treatment of animals, while avoiding undue interference
with goals of the experiment”.
The ACLAM Position Statement on Pain and Distress in Laboratory Animals
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APPENDIX 2: US REGULATIONS AND GUIDELINES 171
The ACLAM Position Statement on Pain and Distress in Laboratory
Animals details the expectations of the College regarding pain in laboratory
animals (ACLAM 2001). The relevant text of this document regarding pain in
animals is as follows:
“Procedures expected to cause more than slight or momentary pain
(e.g., pain in excess of a needle prick or injection) require the
appropriate use of pain-relieving measures unless scientifically justified
in an approved animal care and use protocol. Requests for exceptions
to the use of analgesics, tranquilizers, anesthetics or non-chemical
means of providing relief from pain and/or distress must be
scientifically justified by the Principal Investigator and approved by the
Institutional Animal Care and Use Committee (IACUC) prior to initiation
of the protocol. Paramount in the decision to provide relief from pain
and distress is the professional judgment of a trained laboratory animal
veterinarian. The Guide for the Care and Use of Laboratory Animals
(NRC 1996) and the Animal Welfare Act emphasize the vital role of the
veterinarian in this process -the attending veterinarian, or his/her
designee, should recommend the pain or distress-relieving measure or
agent, dose, frequency, and duration of administration according to
his/her professional judgment and clinical assessment of the research
subject(s). Thus, veterinary participation is needed in the planning
phase of those experiments with the potential to produce pain or
distress and in the ongoing review of the animal's condition.
Consideration should be given to preventing pain or distress by using
preemptive measures whenever possible. While the animal care and
use protocol must provide information on types of pain and distress-
relieving medications and treatments intended to be used, the
veterinarian's clinical assessment and judgment regarding what is in the
best interest of the animal should be given overriding precedence”.
References
ACLAM [American College of Laboratory Animal Medicine]. 1996. ACLAM Report
on Adequate Veterinary Care. Available online
(http://www.aclam.org/education/guidelines/position.html), accessed
June 9, 2008.
ACLAM. 2001. ACLAM Position Statement on Pain and Distress in Laboratory
Animals. Available at:
http://www.aclam.org/education/guidelines/position_pain-
distress.html. Accessed June 9 2008.
AVMA [American Veterinary Medical Association]. 2007. AVMA Guidelines on
Euthanasia. Available at:
http://www.avma.org/issues/animal_welfare/euthanasia.pdf. Accessed
June 9 2008.
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172 Recognition and Alleviation of Pain in Laboratory Animals
AWA [Animal Welfare Act]. 1990. Animal Welfare Act. Available at:
http://www.nal.usda.gov/awic/legislat/awa.htm. Accessed June 9
2008.
CFR [Code of Federal Regulations]. Title 9, Chapter 1, Subchapter A, Parts 1 –
4. Available at: http://www.access.gpo.gov/usecose/uscmain.html.
Accessed June 9, 2008.
DHHS [Department of Health and Human Services], National Institutes of
Health, Office of Laboratory Animal Welfare. 2002. Public Health Service
Policy on Humane Care and Use of Laboratory Animals. Available at:
http://grants.nih.gov/grants/olaw/references/phspol.htm. Accessed
June 9 2008.
NRC [National Research Council]. 1996. Guide for the Care and Use of
Laboratory Animals. Washington, DC: National Academies Press.
USDA [U.S. Department of Agriculture]. 2005. 9CFR2.31. Code of Federal
Regulations, title 9, Volume 1, part 2, subpart C, section 2.31:
Institutional Animal Care and Use Committee. Available at:
http://www.aphis.usda.gov/animal_welfare/downloads/awr.9cfr2.31.tx
t. Accessed January 5 2009.
USDA. 2005. 9CFR2.31. Code of Federal Regulations, title 9, Volume 1, part 2,
subpart C, section 2.33: Attending veterinarian and adequate veterinary
care. Available at:
http://www.aphis.usda.gov/animal_welfare/downloads/awr.9cfr2.33.tx
t. Accessed January 5 2009.
USDA-APHIS [USDA-Animal and Plant Health Inspection Service]. 1997. APHIS
Policy #11, “Painful Procedures” (issue dated: April 14, 1997). Available
at:
http://www.aphis.usda.gov/animal_welfare/downloads/policy/policy11
.pdf. Accessed June 9 2008.
USDA-APHIS. 1997. APHIS Policy #12, “Considerations of Alternatives to
Painful/Distressful Procedures” (issue dated: June 21, 2000). Available
at:
http://www.aphis.usda.gov/animal_welfare/downloads/policy/policy12
.pdf. Accessed June 9 2008.
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