The purpose of this report is to review current literature and clinical experience with use of analgesic agents in nonhuman primates. The use of analgesics in animals has received much attention in recent years, especially in laboratory animals where pain management is mandated by law and regulations.9,10,13,14 Successful management of pain has been shown to help maintain normal physiologic and cardiovascular stability, decreasing postoperative recovery time.3,14 Assessment of pain in animals is difficult, especially in nondomestic species that may have evolved to protect themselves by showing minimal overt evidence of pain or discomfort. While there are attempts at general guidelines for assessment of pain in animals including nonhuman primates, it is best to consider that procedures and injuries that cause pain in humans cause similar levels of pain in animals.2,4,10,12 A literature review of analgesic use in nonhuman primates includes work done on specific analgesics and their receptors, but there are few controlled studies of clinical assessment of pain, control of pain, or side effects of analgesics in nonhuman primates. Agents, dosages and indications have been extrapolated from human and domestic animal literature.
Common situations or procedures where analgesics are required in nonhuman primate medicine include management of perioperative and postsurgical pain (cesarean section or other laparotomy, orthopedic surgery, digit amputation, etc.), minor surgical and diagnostic procedures such as laceration repair, biopsies, dental and ophthalmic procedures, and management of pain associated with disease (including osteoarthritis) or trauma. Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen, opioids, and corticosteroids are the most commonly used analgesic agents in nonhuman primate medicine.1,4,7,9,14,15 The use of alternative methods for achieving analgesia in nonhuman primates has not been well studied, although the reversal of acupuncture induced analgesia with naloxone was reported.6 There are a number of anesthetic agents that provide little or no analgesia beyond the period of general anesthesia. These include inhalant anesthetics and propofol. When these agents are used for procedures, an analgesic agent must be given perioperatively. Ketamine and α2-adrenergic agonists like xylazine and medetomidine do have some analgesic properties, but in general these agents do not provide adequate analgesia for anything more than minor procedures and cannot be used postoperatively due to their anesthetic properties.8,16
NSAIDs and acetaminophen are excellent choices for relief of mild to moderate pain such as minor surgical procedures and premenstrual anorexia and pain. Increasing doses will eventually result in a limit on their maximum analgesic effect.11 Acetaminophen has good analgesic properties but is not anti-inflammatory like the true NSAIDs. While gastrointestinal upset and bleeding from platelet dysfunction are possible side effects of this class, there are few reports of these occurring in clinical cases in nonhuman primates.14,15 At Wisconsin Regional Primate Research Center one of the newer veterinary NSAIDs, carprofen, has been used successfully in rhesus monkeys in the treatment of severe osteoarthritis that is no longer responsive to aspirin. Liver and kidney parameters are being followed through carprofen therapy. After 6 months there is no evidence of toxicity. NSAIDs can be effectively combined with other agents to produce better analgesia. Acetaminophen/codeine and flunixin/buprenorphine have been reported to be effective combinations for mild to moderate postoperative pain in great apes.14
The pure opioid agonist morphine is the standard by which analgesics are measured.8,11 Synthetic opioids like oxymorphone, and agonist-antagonists like butorphanol and buprenorphine are effective analgesics in nonhuman primates. They are frequently used perioperatively with or followed by NSAIDs upon recovery. Opioids are very useful in the postoperative period after major surgery. Complications include CNS and respiratory depression, although oxymorphone and buprenorphine are reportedly less depressive than other opioids. Epidural morphine is reported to provide good analgesia for up to 24 hours in macaques.14 There is anecdotal evidence that fentanyl patches are very useful in providing long-term postoperative analgesia in macaques. They are kept in place with jackets (D. Clemmons, Covance Labs, Madison, WI, personal communication).
Not technically classified as analgesics, corticosteroids do provide anti-inflammatory properties that reduce pain due to inflammation and/or steroid responsive tumors. Concurrent use with NSAIDs is contraindicated due to the increased risk of gastrointestinal upset and ulceration.8,15
In conclusion, the use of analgesic agents is an important aspect of primate medicine and surgery. Analgesic agents and dosages are presented in Table 1; however, it must be stressed that dosages require clinical evaluation and may need to be revised.
Table 1. Agents useful in nonhuman primate analgesia
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2. Eisele, P.H. 1997. Signs of pain in small mammals. Proceedings of the North American Veterinary Conference. Orlando, FL. Pp. 795–796.
3. Eisele, P.H. 1997. Analgesia in small mammals. Proceedings of the North American Veterinary Conference. Orlando, FL. Pp. 796–799.
4. Flecknell, P.A. 1984. The relief of pain in laboratory animals. Lab. Anim. 18: 147–160.
5. Golub, M.S., J.H. Eisele, J.M. Donald. 1988. Obstetric analgesia and infant outcome in monkeys: Neonatal. American Journal of Obstetrics and Gynecology. 158(5): 1219–1225.
6. Ha, H., E-C. Tan, H. Fukunaga, O Aochi. 1981. Naloxone reversal of acupuncture analgesia in the monkey. Experimental Neurology. 73: 298–303.
7. Heard, D.J. 1993. Principles and techniques of anesthesia and analgesia for exotic pet practice. The Veterinary Clinics of North America, Small Animal Practice. 23(6): 1301–1327.
8. Heavner, J.E. 1997. Pharmacology of analgesics. In: Anesthesia and analgesia in nonhuman primates. In: Kohn, D.F., S.K. Wixson, W.J. White, G.J. Benson, eds. Anesthesia and Analgesia in Laboratory Animals. Academic Press, New York, NY. Pp. 43–56.
9. Hubbell, A. E., W. Muir. 1996. Evaluation of a survey of the diplomates of the American College of Laboratory Animal Medicine on use of analgesic agents in animals used in biomedical research. J. Am. Vet. Med. Assoc. 209(5): 918–921.
10. Institute of Laboratory Animal Resources. 1996. Guide for the Care and Use of Laboratory Animals. National Academy Press. Washington, DC. Pp. 10,11,64,65.
11. The Medical Letter. 1993. Drugs for pain. The Medical Letter on Drugs and Therapeutics. 35(887): 1–6.
12. Morton, D.B., P.H.M. Griffiths. 1985. Guidelines on the recognition of pain, distress and discomfort in experimental animals and a hypothesis for assessment. The Veterinary Record. 116(16): 431–436.
13. National Research Council. 1992. Recognition and Alleviation of Pain and Distress in Laboratory Animals. National Academy Press, Washington, DC. Pp. 1–10, 32–85.
14. Popilskis, S.J., D.F. Kohn. 1997. Anesthesia and Analgesia in Nonhuman Primates. In: Kohn, D.F., S.K. Wixson, W.J. White, G.J. Benson, eds. Anesthesia and Analgesia in Laboratory Animals. Academic Press, New York, NY. Pp. 233–255.
15. Rosenberg, D.P. 1991. Nonhuman primate analgesia. Lab. Anim. 20: 22–32.
16. Steelman, R., N.S. Seale, L. Bellinger, M. Harris, M. Wagner, F. Williams. 1991. Conscious sedation and analgesia with rectal ketamine in the Macaca fuscata monkey. Anesth. Prog. 38: 50–56.