A Pain in the Rat
Dr. Peter Paul Price came to Great Eastern
University from the Southern Cape A&M School of Medicine. He
came with money, people, his Southern Cape-approved IACUC protocol,
and a problem for the Great Eastern IACUC.
It was Great Easterns policy to give new
investigators a 60-day window to rewrite their existing IACUC
protocols on Great Eastern forms. The protocols then went through
the regular IACUC approval process. During those 60 days,
investigators could perform their research, as long as they had an
IACUC-approved protocol from their previous institution; the
previous institution was NIH-Assured; and, if applicable, the
institution was USDA-registered. In the past, the Great Eastern
IACUC had occasionally requested some small changes to protocols,
but nothing with which the investigator had trouble complying.
Prices protocol was different. Southern Cape had an NIH Assurance,
and the protocol was properly approved, but the approval did not
include the use of postoperative analgesia, and Price was performing
some rather extensive cranial and brain surgery. Price had justified
this exclusion to Southern Cape, and now to Great Eastern, on two
grounds. First, he said that in his many years of experience, his
rats always recovered uneventfully from surgery and were eating and
acting normally within a day. Second, since he subsequently would
record brain electrical activity from induced pain (using a tail
flick test), and his surgical procedure caused the tail flick to be
most sensitive 10 days after surgery, he could not risk any residual
effects of postoperative analgesics.
After some consideration, the IACUC asked Price to
do a pilot study using analgesia to determine if his recordings
would be affected. Price wanted to know who would pay for the study;
how many analgesics he would have to try if the first had an adverse
effect on his research; what would be a reasonable number of animals
to use; and how many studies that he performed in past years would
have to be repeated, since he tested different analgesics and
psychoactive drugs as part of his standard research
protocol.
Should the Great Eastern IACUC agree with the
Southern Cape IACUC, or is there another way of approaching the
issue of postoperative pain relief?
Wheres the Pilot? Robin Minkel and Karen Krueger, DVM
It is unclear whether Price completed a search of
the literature for alternatives. Under USDA guidelines, pain and
distress must be alleviated, unless scientifically justified. The
defense given by Pricethat he has always performed his studies
without analgesiadoes not alone carry enough scientific
justification. The Attending Veterinarian (AV) should be consulted
to suggest analgesics that have less residual effects and to assist
Price with the alternative search by suggesting key words. It is
possible that the alternative search will generate newer methods or
data that support the use of analgesia for postoperative pain
management. It is also possible that the search will provide further
support to the investigators claim that analgesics will affect the
study, or that the surgical procedure does not produce any pain or
distress, resulting in further justification for withholding
analgesia.
If the literature does not provide any clear
alternatives to the use of analgesics nor demonstrates that the
procedure does not cause pain or distress, it is appropriate for the
IACUC to request a pilot study. A pilot study that repeats previous
experimental situations with the addition of analgesia, with close
monitoring by the AV, would carry more weight and also demonstrate
good scientific practices. By working together, the AV,
investigator, and IACUC should establish clear criteria for
monitoring the animals with specific limits and guidelines that can
be easily interpreted. These guidelines should be used to evaluate
all animals in each test group. The pilot study would need, at
minimum, two test groups: one that undergoes the surgery without the
benefit of postoperative analgesia, and one that receives analgesia
minimally the day of surgery. The results of the tail flick test
conducted on day 10 can then be a direct comparison to determine if
the analgesia had any effect. These results should be well
documented and sent to the IACUC for review.
As the IACUC is requesting the pilot study,
ideally, they should be the group to fund the project. However, very
few IACUCs have their own allocation of resources to allow this. As
such, the burden falls back onto Price. As the number of animals
needed would be minimal, the burden is not likely to be great.
Perhaps a grant search could be conducted that would allow the pilot
study to proceed (with the results then made available to other
research facilities) and be incorporated as a refinement or serve as
justification for withholding analgesics for these types of studies.
Another question that Price raises deals directly with the nature of
his research. If the pilot study concludes that analgesics, in fact,
do not have residual effects, would that compromise the integrity of
his previous work? A short answer should be, "No." It is unclear if
the surgical procedure caused any pain or distress, as indicated by
Prices account that the animals were eating and acting normally
within a day of surgery. The animals involved in the previous
experiments may have experienced pain during surgery or immediately
postoperatively that could have been alleviated, but during the
testing phase there would have been no changes in the results. If
the pilot study indicates that the use of analgesics do have a
significant residual effect, then Price was justified in withholding
pain relief.
Minkel is IACUC Administrator and Krueger is a
member of the veterinary staff at Genetics Institute, Andover and
Cambridge, MA.
Pass the Baton
Kerry Taylor, DVM, MSc, DACLAM, and Axel Wolff,
MS, DVM
Unfortunately, this scenario did not identify a
funding source. If we assume that Prices project is supported by a
Public Health Service (PHS) agency, such as the National Institutes
of Health (NIH), this scenario would not play out; Great Easterns
policy to allow new investigators a 60-day window for processing
paperwork through their IACUC would be noncompliant with the PHS/NIH
grants policy as well as the PHS Policy and the Great Eastern Animal
Welfare Assurance on file with OLAW.
Requests for transfer of PHS/NIH-supported research
must follow specific procedures. First, a transfer requires the
prior approval of the PHS/NIH funding component which would trigger
a number of additional steps to ensure full compliance with grants
policy prior to funding, such as determining that Great Eastern has
an Assurance, that the IACUC approved the protocol, and that Great
Eastern has all the resources necessary to fulfill the goals of the
grant. In addition, the institution relinquishing the grant must do
so prior to the issuance of a new award. If the request to transfer
the grant was approved, the new grantee, with an approved Assurance,
must assure that an IACUC is in place and certify that the protocol
has been reviewed and approved. These PHS/NIH grants policies would
have challengedif not eliminatedGreat Easterns policy and would have
forced a Great Eastern IACUC review in accordance with the PHS
Policy. The issue of reducing the burden of dual review is not
pertinent; once Southern Cape A&M relinquishes the grant, and
NIH issues a new award, all accountability transfers to Great
Eastern. The Great Eastern IACUC must conduct a review that
satisfies the PHS Policy for the transfer of the grant to be
effective, and for Price to be able to continue his work at the
gaining institution. Regarding the evaluation of pain in the rats,
the previous IACUC may have agreed to an earlier accepted
interpretation concerning pain alleviation in rodents, an issue
frequently debated in todays research climate. As science advances
and more information is available about animal pain, protocols must
necessarily be evaluated (or re-evaluated) against a higher
standard, using more complete criteria.
As an Assured institution, Great Eastern must
follow PHS Policy, which specifically states that, "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." The burden of proof is on Price to
convince the new IACUC that analgesia is not necessary or must be
withheld.
In addition, the US Government Principles states, "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." Prices study may fit this category, but if exceptions are
to be made, they must be IACUC-approved.
If the IACUC has concerns about the study design,
well-executed pilot studies are certainly a reasonable request, and
can often provide useful information. Pilot studies are generally
funded by the investigator, and the numbers necessary (both animals
and experimental agents) depend on the quantity of data needed for
an informed IACUC decision. Price and his colleagues would be
expected to have sufficient expertise for a pilot design, but other
experts in the field could be consulted. Price would not likely need
to repeat prior studies if the scientific information was
acceptable. If he has already tested analgesics as part of the
protocol, he is in a good position to recommend an effective
postoperative drug for the animals under study. The AV must be
intimately involved in oversight of the protocol, to advise,
monitor, and assess the level of postoperative pain experienced by
the animals, rather than accepting the investigators assertion that
the animals were "normal." In addition, studies designed to
characterize behavioral and physiological parameters for the purpose
of pain assessment have demonstrated that an unbiased, medical
assessment of the animals condition can readily validate that
analgesics either are not necessary or must be withheld.
Taylor is Deputy Director, Office of Animal Care
and Use, and Wolff is Senior Assurance Officer, Division of Animal
Welfare, NIH, Bethesda, MD.
It Doesn't Have to Hurt
Tracy Peace, DVM, MS, DACLAM, and Laurie
Goodchild, DVM
Prices assertion that since his rats are "eating
and acting normally within a day," they therefore do not experience
postoperative pain is akin to the recently disproved notion that
rats are resistant to postoperative infection, since they recover
from nonsterile surgical procedures. Rats are indeed susceptible to
wound infection, as evidenced by measurable changes in physiology
and behavior1. Prices rats eat and act normally within a day of
surgery, but this does not prove that they did not experience
postoperative pain. Postoperative pain likely peaks within the first
24 hours after the procedure, since associated behavioral changes
typically peak at that time2.
Simply stating that the use of anesthetics,
analgesics, or tranquilizers may interfere with research results is
not adequate justification to withhold them. Additionally, according
to animal welfare regulations, procedures that cause pain and
distress in humans are assumed to cause pain and distress in animals
unless proven otherwise. Spinal and cranial surgery in the rat may
result in mild to severe pain, depending on site and amount of
trauma3. Lack of clear scientific justification or proof (i.e.,
objective, measurable data) that the animals are not experiencing
pain, and the use of invasive techniques, should be red flags to any
IACUC.
The Guide4 endorses the use of pilot studies
conducted under IACUC oversight when dealing with procedures that
have the potential to cause pain or distress that cannot be reliably
controlled. Although conducting a pilot study to evaluate the use of
analgesics, anesthetics, or tranquilizers is a valid option, the
optimal first step is to examine objective and easily measured pain
assessment parameters.
Food and water consumption, body weight, and
behavioral/locomotory assessments can be performed in rats.
Decreases in food and water consumption are considered useful
indicators of postoperative pain in rodents5 and are easy to
measure. Furthermore, the administration of analgesics (e.g.,
opiates, nonsteroidal anti-inflammatories) has been proven to reduce
the drop in food and water consumption seen post-surgery, and,
indeed, "If the depression in food and water consumption is related
to the presence of postoperative pain, then these findings suggest
that analgesics should be administered to rats following surgical
procedures6."
The IACUC should ask Price to establish a list of
measurable pain assessment parameters and a schedule for data
collection, allowing his work to continue without disruption while
simultaneously obtaining very valuable information. At the
conclusion of the data collection, the information should be
reviewed by the IACUC. If food and water consumption are
significantly reduced by the surgery and resultant postoperative
pain, the IACUC should then mandate the performance of a pilot study
with pain-relieving drugs. It should also be noted that good
surgical technique minimizes tissue trauma, reduces the length of
the surgical procedure, and has a direct impact on postoperative
pain and distress. The IACUC should verify the surgeons expertise.
If a pilot study using pain-relieving medications is warranted,
Price should be enlightened that the field of pain relief has
evolved from postoperative, to intra-operative, to preemptive
administration. Drugs administered prior to the painful procedure
can prevent sensitization of pain receptors. Also, since Price has
concerns regarding residual effects of analgesics, he should
undertake a careful review of the literature to reveal information
related to the potential interactive effects of various
drugs.
References
1. Bradfield, J.F., et al. Behavioral and
physiologic effects of inapparent wound infection in rats. Lab.
Animal Sci.; 42(6):572-578, 1992. 2. Hansen, B. Through a glass
darkly: using behavior to assess pain. Semin. Vet. Med. Surg. (Small
Animal) 12(2):61-74, 1997. 3. Hobbs, B.A.
Assessment of painful procedures. In: Guttman, H.N., ed. Guidelines
for the Well-Being of Rodents in Research. Scientists Center for
Animal Welfare, Bethesda, MD. pp. 70-79, 1990. 4. Guide for the
Care and Use of Laboratory Animals. National Academy Press.
Washington, DC, 1996. 5. Flecknell, P.A. and Silverman, J. Pain
and distress. In: Silverman, J., Suckow, M.A., and Murthy, S., eds.
The IACUC Handbook. CRC Press, Washington, DC, pp. 221-249,
2000. 6. Liles, J.H. and Flecknell, P.A. A comparison of the
effects of buprenorphine, carprofen and flunixin following
laparotomy in rats. J. Vet. Pharmacol. Ther.; 17(4):284-290, 1994.
Peace is Attending Veterinarian and Goodchild is Training
Coordinator/Clinical Veterinarian, Battelle Memorial Institute,
Columbus OH.
Peace is Attending Veterinarian and Goodchild is
Training Coordinator/Clinical Veterinarian, Battelle Memorial
Institute, Columbus OH.
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