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appendix
B
US Regulations and Guidelines
Regarding Recognition
and Alleviation of Pain in
Laboratory Animals
T
he 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 guide-
lines, enforced by the US Public Health Service Policy, and promulgated by
various professional organizations as outlined below.
LEGAL REqUIREMENTS AND AGENCY GUIDELINES
US Animal Welfare Act
The primary federal regulation concerning the care and use of labora-
tory animals in the United States is the Animal Welfare Act (AWA; Public
Law 89-544 as amended, 7 USC Ch. 54). The AWA is implemented through
the Animal Welfare Act Regulations, published in the Code of Federal Regu-
lations (CFR), Title 9, Chapter 1, Subchapter A. The Act covers pets and
warm-blooded animals used for research, testing, and exhibition purposes,
but does not protect a number of animal species; for example, it specifically
excludes rats of the genus Rattus, mice of the genus Mus, and birds bred
for use in research.
The Animal Welfare Regulations consider painful procedures and meth-
ods to alleviate pain in several sections:
• §2.31(a), (d): Registered research institutions must have an institu-
tional animal care and use committee (IACUC) that reviews and
approves all procedures conducted using laboratory animals.
1
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160 RECOGNITION AND ALLEVIATION OF PAIN IN 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 alterna-
tives to procedures that may cause more than momentary or slight
pain.”
• §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 tran-
quilizing drugs where indicated and appropriate to minimize dis-
comfort and pain to animals.”
• §2.33(a): “Each research facility shall have an attending veterinar-
ian who shall provide adequate veterinary care to animals in com-
pliance 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 its 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 who inspect the regulated research
programs. Two USDA policies address the requirement to recognize the
potential for pain in association with research activities.
Policy #11—“Painful Procedures”
Policy #11 (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” and requires the IACUC to ensure that investigators have consid-
ered appropriate alternatives to such procedures. 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
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161
APPENDIX B
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 and its alleviation through
the use of anesthetics, analgesics, sedatives, and/or tranquilizers, as well
as the separate reporting of animals subjected to such procedures in which
pain-relieving agents were not administered, for IACUC-approved research
requirements.
Policy #12—“Considerations of Alternaties to Painful/Distressful
Procedures”
This policy (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 ani-
mal 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 (see below) 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 Labora-
tory Animals (PHS Policy) (DHHS 2002) was introduced in 1973 and has
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162 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS
been revised multiple times (most recently in 2002). The Policy applies to
all institutions that use animals in research that is supported by any compo-
nent of the PHS (e.g., NIH, CDC, FDA) and it “requires institutions to estab-
lish 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 uses a broader definition of an animal: “any live, vertebrate animal used
or intended for use in research, training, experimentation, or biological
testing.” Further, the Policy endorses the US 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 PHS Policy defines procedures for submission of the Animal Wel-
fare Assurance statement, which is required of all institutions that conduct
PHS-funded research, training, or testing with animals. For potentially pain-
ful 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 investiga-
tor; 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 recom-
mendations 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 descrip-
tion 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.”
The NIH Office of Laboratory Animal Welfare (OLAW) is responsible
for administering the PHS Policy.
US Government Principles for the Utilization and Care of
Vertebrate Animals Used in Testing, Research, and Training
The US Government Principles for the Utilization and Care of Verte-
brate Animals Used in Testing, Research, and Training (US Government
Principles) were drafted in 1985 by the Interagency Research Animal Com-
mittee (IRAC 1985). The document addresses compliance with federal laws,
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APPENDIX B
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 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 pain-
lessly 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 Ani-
mal Research to promote the humane care and use of laboratory animals.
The Guide emphasizes the application of performance standards and profes-
sional judgment and encourages 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 US
Government Principles (IRAC 1985; outlined above). 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 calls for the establishment of an IACUC, which must ensure
the appropriate application of sedation, analgesia, and anesthesia when
reviewing protocols (p. 9), and notes that “ethical, humane, and scientific
considerations sometimes require the use of sedatives, analgesics, or anes-
thetics in animals” (p. 12). The Guide (p. 64) also devotes a section to the
consideration of pain, analgesia, and anesthesia, and states that “an integral
component of veterinary medical care is prevention or alleviation of pain
associated with procedural and surgical protocols.” Although recognizing
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164 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS
such pain is complex and can be challenging, the Guide indicates that
the ability to experience and respond to pain is widespread in the animal
kingdom. The Guide therefore stipulates 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.
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 (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
itself define standards but rather uses the Guide as its primary assessment
resource along with other peer-reviewed reference standards. Additionally,
when conducting assessments of accredited programs, AAALAC Interna-
tional requires that institutions comply with applicable principles, regula-
tions, 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 require-
ments for board certification as specialists in laboratory animal medicine.
ACLAM has issued position statements regarding Adequate Veterinary Care
and Pain and Distress in Laboratory Animals.
ACLAM Report on Adequate Veterinary Care
The 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
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16
APPENDIX B
suffering in research animals, provided such intervention is not specifi-
cally 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
The ACLAM Position Statement on Pain and Distress in Laboratory Ani-
mals details the expectations of the College concerning pain in laboratory
animals (ACLAM 2001):
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 anal-
gesics, 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 Com-
mittee (IACUC) prior to initiation of the protocol. Paramount in the deci-
sion 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 mea-
sure 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 informa-
tion 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 over-
riding precedence.
REFERENCES
ACLAM (American College of Laboratory Animal Medicine). 1996. ACLAM Report on Ad-
equate Veterinary Care. Available at www.aclam.org/education/guidelines/position.html.
Accessed June 9, 2008.
ACLAM. 2001. ACLAM Position Statement on Pain and Distress in Laboratory Animals. Avail-
able at www.aclam.org/education/guidelines/position_pain-distress.html. Accessed June
9, 2008.
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166 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS
AVMA (American Veterinary Medical Association). 2007. AVMA Guidelines on Euthana-
sia. Available at www.avma.org/issues/animal_welfare/euthanasia.pdf. Accessed June 9,
2008.
AWA (Animal Welfare Act). 1990. Animal Welfare Act. Available at www.nal.usda.gov/awic/
legislat/awa.htm. Accessed June 9, 2008.
DHHS/NIH/OLAW (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.
IRAC (Interagency Research Animal Committee). 1985. The U.S. Government Principles for
the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training.
Federal Register Vol. 50, No. 97 (May 20, 1985). Available at http://grants.nih.gov/grants/
olaw/references/phspol.htm#USGovPrinciples. Accessed June 9, 2008.
NRC (National Research Council). 1996. Guide for the Care and Use of Laboratory Animals.
Washington: National Academy Press.
USDA (US Department of Agriculture). 2005a. 9 CFR 2.31. (Title 9, Volume 1, Part 2.31):
Institutional Animal Care and Use Committee. Available at www.aphis.usda.gov/ani-
mal_welfare/downloads/awr.9cfr2.31.txt. Accessed January 5, 2009.
USDA. 2005b. 9 CFR 2.33. (Title 9, Volume 1, Part 2.33): Attending Veterinarian and Ad-
equate Veterinary Care. Available at www.aphis.usda.gov/animal_welfare/downloads/
awr.9cfr2.33.txt. Accessed January 5, 2009.
USDA-APHIS (USDA-Animal and Plant Health Inspection Service). 1997. APHIS Policy
#11, “Painful Procedures” (dated: April 14, 1997). Available at 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” (dated: June 21, 2000). Available at www.aphis.usda.gov/animal_welfare/
downloads/policy/policy12.pdf. Accessed June 9, 2008.
