ARC Policy
General Procedures
Considerations Regarding Choice of Analgesics
References

ARC Policy

Personnel involved in animal research have the responsibility to reduce or eliminate pain and distress whenever it does not interfere with study objectives. The Animal Welfare Act Regulations[1], Public Health Service Policy on Humane Care and Use of Laboratory Animals[2], and the Guide for the Care and Use of Laboratory Animals[3] collectively speak to the need to prevent and/or alleviate pain associated with surgical procedures. As such, the ARC requires that postoperative analgesia be provided systemically for at least 48 hours following completion of survival surgery unless scientific justification to withhold analgesia is provided by the investigator and approved by the ARC.

General Procedures

  • Analgesics must be given such that these agents become effective before the animal emerges from anesthesia. Therefore, analgesia must be administered before surgery and re-dosed as needed during the procedure.
  • The use of local pain-relieving drugs such as Marcaine® (bupivacaine), in addition to systemic analgesia, may be indicated for some procedures that will result in significant disruption of the skin (e.g., catheter exteriorization), as these drugs may help to block the onset of the pain cascade due to disruption of the dermal nerve cells. Local analgesics are not intended for use in lieu of systemic analgesics, unless the withholding of systemic analgesia is scientifically justified. Where analgesics are withheld, enrichment should be considered to minimize stress associated with pain.
  • For USDA-regulated species only: In cases where post-operative analgesics cannot be administered for scientific reasons, the animals must be listed in Pain Category E (i.e., pain/distress cannot be relieved by use of anesthetics, analgesics, or tranquilizers as the use of these agents would interfere with the experimental design) and the reason documented in the ARC protocol.
  • All survival surgeries require at least 48 hours of post-operative analgesia, to be extended as needed if the animal still appears to be in pain, unless justification for a shorter duration is approved by the Committee and included in the ARC protocol.
  • Surgeries that involve the potential for significant pain or distress (e.g., spinal cord transection, bone fracture induction, or open abdominal surgeries) require the application of multimodal analgesia unless scientific justification for not using multimodal analgesia is approved by the Committee and included in the ARC protocol.
  • For guidance on selection and use of analgesics, contact the Division of Laboratory Animal Medicine (DLAM). Additional detail regarding the various classes of analgesics is included below.
  • For mice and rats, all administration of surgical analgesics, including pre-/intra-operative doses, should be documented either at the room level via a log or cage side by the use of DLAM’s pink "Study Related Care / Information" card (Refer to the UCLA Worksafe training "DLAM Cage Side Communication Cards" for more information). Dosing for covered species should be recorded on the animal’s post-op record as per DLAM training.

Considerations Regarding Choice of Analgesics

Pain has been defined by the International Association for the Study of Pain[4] as "[a]n unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage" and is expanded upon with the following:

  • Pain is always a personal experience that is influenced to varying degrees by biological, psychological, and social factors.
  • Pain and nociception are different phenomena. Pain cannot be inferred solely from activity in sensory neurons.
  • Through their life experiences, individuals learn the concept of pain.
  • A person’s report of an experience as pain should be respected.
  • Although pain usually serves an adaptive role, it may have adverse effects on function and social and psychological well-being.
  • Verbal description is only one of several behaviors to express pain; inability to communicate does not negate the possibility that a human or a nonhuman animal experiences pain.

The fact that different anatomical and neurobiological substrates for pain exist supports the use of targeted pain therapy and explains the variable effectiveness of analgesic drugs depending upon the characteristics of pain. In the research laboratory setting the characteristics of pain will vary with the particular animal (species, age, strain) and the type of potentially painful procedure. Unrelieved pain has been shown to significantly impact stress systems, neuroinflammation, cardiovascular health, cognition, and healing (Henein et al (2022), Chapman et al (2008), Koyama et al (2019), Godbout & Glaser (2006)).

Below is a brief description of the mode of action, indication, contraindication, and side effects of the most commonly used type of analgesics in the UCLA animal facilities. For alternative options and for dosage and regimen recommendations please contact a DLAM veterinarian.

  1. p-Aminophenol Derivatives – Included in this group is acetaminophen. Acetaminophen has analgesic and anti-pyretic activity. Available in the form of tablets, capsules, suppositories, chewable tablets, wafers, elixirs, and solutions, in combination with other drugs. Effective against pain of low to moderate intensity; recommended only for minor surgical procedures[5].
  2. Non steroidal anti-inflammatory drugs (NSAIDS) – Agents that reduce inflammation and provide analgesia primarily by inhibiting one or more steps in the metabolism of arachidonic acid through inhibition of inflammatory cytokine synthesis. NSAIDs do not contain the molecular steroid ring structure and do not have the immunosuppressive and metabolic side effects associated with corticosteroids. Most NSAIDs act primarily to reduce the biosynthesis of prostaglandins (PG) by inhibiting cyclooxygenase (COX). NSAIDs most commonly used in veterinary medicine include:
    1. Propionic acid derivatives – Ibuprofen, ketoprofen, and carprofen are included in this group, and all three can be dosed in injectable form, via the subcutaneous route (SubQ). Carprofen and ibuprofen are available in oral tablets, including bacon-flavored tablets formulated for mice and rats (Bio-Serv: https://www.bio-serv.com/product/RRMD.html); carprofen is also available from DLAM in ready-made edible gel cups. Ketoprofen and ibuprofen inhibit both isoforms of cyclooxygenase (COX-1 and COX-2). Carprofen is claimed to be predominately COX-2 selective drug, but it does inhibit COX-1 slightly. Efficacy against orthopedic and postoperative pain compares favorably in clinical studies with some opioids such as buprenorphine. Most of these drugs can alter platelet function and bleeding time.
    2. Oxicams – The most commonly used drug used in veterinary medicine in this group is Meloxicam. Meloxicam is available in parenteral, tablet, and oral suspension. This drug is a selective inhibitor of COX-2 in humans. It is as effective an analgesic as buprenorphine for post-operative pain resulting from soft tissue surgery.
  3. Opioids – Opioids are the most effective analgesics available for the systemic treatment of acute pain in many species. Opioids activate specific receptors (mu, delta and kappa) in the brain, spinal cord, and periphery, altering the transmission and perception of pain. The clinical effects of opioids vary between the mu opioid receptor agonist, partial mu agonists, and agonist-antagonists. Repeated use of opioids may induce tolerance in some species, although tolerance is dependent on dose and frequency of administration. The most common side effects associated with the use of opioids include respiratory depression, constipation, sedation, euphoria, dysphoria, excitement, and pica. Buprenorphine is a partial mu agonist and kappa antagonist that is widely used in laboratory animal medicine due to its relatively long duration of action. Buprenorphine is available in standard and extended-release parenteral formulations. Opioids are controlled substances and can only be ordered by PI laboratories that have registered with the Drug Enforcement Administration (DEA) – refer to the Controlled Substance Program for Research website for more information.
  4. Gabapentinoids – A class of anticonvulsant medications that are central nervous system depressants and derivatives of the inhibitory neurotransmitter, GABA. Gabapentin and pregabalin are used to treat neuropathic pain, musculoskeletal pain, and focal seizures. Side effects can include sedation, ataxia, respiratory depression, edema, nystagmus, and allergic reactions. Both gabapentin and pregabalin are available in oral capsules, tablets, and solutions.

References

  1. Bill, R.P. NSAIDs--Keeping Up With All the Changes, in Atlantic Coast Veterinary Conference 2008. 2008. Atlantic City, New Jersey.
  2. Budsberg, S.C. Review of NSAIDS: COX Selectivity and Systemic Effects Beyond Analgesia (S22C). in Western Veterinary Conference 2009. 2009. Las Vegas, NV.
  3. Chapman CR, Tuckett RP, Song CW. Pain and Stress in a Systems Perspective: Reciprocal Neural, Endocrine and Immune Interactions. J Pain. 2008;9(2):122-145.
  4. Fish, R.E.B., Marilyn J.; Danneman, Peggy J.; Karas, Alicia Z., Anesthesia and Analgesia in Laboratory Animals. 2nd ed. American College of Laboratory Animal medicine Series, ed. A. Press. Vol. 1. 2008, Amsterdam, Boston, Heidelberg, London, New York, Oxford, Paris, San Diego, San Francisco, Singapore, Sydney, Tokyo. Elsevier. 268-275.
  5. Godbout JP, Glaser R. Stress-induced immune dysregulation: implications for wound healing, infectious disease and cancer. J Neuroimmune Pharmacol. 2006;1(4):421-427. PMID: 18040814.
  6. Henein, M. Y., Vancheri, S., Longo, G., & Vancheri, F. (2022). The Impact of Mental Stress on Cardiovascular Health—Part II. Journal of Clinical Medicine, 11(15), 4405.
  7. Koyama T, et al. Acute postoperative pain exacerbates neuroinflammation and related delirium-like cognitive dysfunction in rats. J Anesth. 2019;33(3):482-486. PMID: 30911820.
  8. MERCK, Nonsteroidal Anti-Inflammatory Drugs, in The Merck Veterinary Manual, S.E. Aiello, Editor. 2005, Merck & Co., INC. New Jersey. p. 2131-2137.
  9. Reid J, Nolan AM, Hughes JML, et al. Development of the short-form Glasgow Composite Measure Pain Scale (CMPS-SF) and derivation of an analgesic intervention score. Anim Welfare. 2007.
  10. Sam McMillan, V.A., DAVN(Med), RVN. NSAIDS: What are the Options? in British Small Animal Veterinary Congress. 2008. Birmingham, UK: Quedgeley: British Small Animal Veterinary Association 2008.
[1] USDA Animal Welfare Act Regulations §2.31(d)(1)(iv)(A) and (ix): "Procedures that may cause more than momentary or slight pain or distress to the animals will be performed with appropriate sedatives, analgesics, or anesthetics, unless withholding such agents is justified for scientific reasons, in writing, by the principal investigator and will continue for only the necessary period of time…Activities that involve surgery include appropriate provision for pre-operative and post-operative care of the animal in accordance with established veterinary medical and nursing practices."

[2] PHS Policy IV.C.1.a-b: "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 the animals will be performed with appropriate sedation, analgesia, or anesthesia, unless the procedure is justified for scientific reasons in writing by the investigator."

[3] Guide for the Care and Use of Laboratory Animals, p. 120: "An integral component of veterinary medical care is prevention or alleviation of pain associated with procedural and surgical protocols…Pain is a stressor and, if not relieved, can lead to unacceptable levels of stress and distress in animals. Furthermore, unrelieved pain may lead to ‘wind-up,’ a phenomenon in which pain sensitization results in a pain response to otherwise nonpainful stimuli…For these reasons, the proper use of anesthetics and analgesics in research animals is an ethical and scientific imperative…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."

[4] IASP Announces Revised Definition of Pain

[5] "Minor survival surgery does not expose a body cavity and causes little or no physical impairment; this category includes wound suturing, peripheral vessel cannulation, percutaneous biopsy, routine agricultural animal procedures such as castration, and most procedures routinely done on an "outpatient" basis in veterinary clinical practice. Animals recovering from these minor procedures typically do not show significant signs of postoperative pain, have minimal complications, and return to normal function in a relatively short time." The Guide, page 117

Approved 6/9/03; Revised 10/27/03, 11/24/03, 8/24/09, 5/4/26; Updated 1/18/11