Therapeutic Review Carprofen Mark A. Mitchell DVM, MS, PhD

ntiinflammatory compounds are routinely of COX-2 enzymes were solely associated with al- used in veterinary medicine to manage tering antiinflammatory activity. However, more traumatic injuries, provide analgesia, alter recent work suggests that the activity of the en- A 2 glucose metabolism, control allergies, and treat a zymes is not that well delineated. The identifica- variety of disease presentations. Historically, ste- tion of selective COX-2 inhibitors has become a roidal antiinflammatory agents were used to man- primary concern for pharmaceutical companies, age the majority of the cases described above; as these compounds are less likely to induce the however, these compounds have lost favor in vet- negative side effects associated with COX-1 inhi- erinary medicine because of their potential side bition. Wilson and coworkers3 found carprofen to effects. One significant concern limiting their use be five times more selective for COX-2 inhibition relates to their negative effect on the immune compared with COX-1 activity in different canine system. The potential immunosuppressive action tissues, while Kay-Mugford and coworkers4 found associated with steroidal antiinflammatories in- that carprofen was only 1.75 times more selective clude the suppression of T-lymphocytes, limiting for COX-2 than COX-1 using a canine DH82 the migration of inflammatory cells, the reduc- monocyte/macrophage cell line. Kay-Mugford tion of chemotaxins, and decreased antigen pro- and coworkers4 also reported that meloxicam, an- cessing.1 other NSAID, inhibited COX-2 activity twelve Nonsteroidal antiinflammatory drugs (NSAIDs) do times more effectively than COX-1 in the cell line. not produce the same negative immunosuppres- In dogs, carprofen is well absorbed via the sive effects and are finding greater acceptance in gastrointestinal tract, and peak levels are achieved veterinary medicine. The NSAIDs are not only within a few hours.1 This drug is metabolized by being used to provide antiinflammatory proper- the liver, and primarily excreted via the feces. A ties, but analgesic and antipyretic properties too. small percentage of the drug is excreted via the These compounds are generally thought to work urine. by inhibiting the synthesis of prostaglandins, cy- Carprofen is primarily used to manage pain in clooxygenase, and phospholipase A2. Their effec- dogs. A study evaluating the clinical efficacy of tiveness varies depending on how well they inhibit carprofen, meloxicam, and a neutraceutical found the inflammatory response. that carprofen and meloxicam both had an effect Carprofen is a nonsteroidal antiinflammatory on ground reaction forces in affected joints, but compound that is licensed for use in dogs with only dogs treated with meloxicam had a full return osteoarthritis and as a postoperative analgesic. to normal.5 Horstman and coworkers6 found that This NSAID is from the propionic acid class, dogs given carprofen following cranial cruciate sur- which includes ibuprofen, ketoprofen, and naproxen. Carprofen is soluble in alcohol, but practically insoluble in water. The mechanism of From the School of Veterinary Medicine, Department of action of this compound is likely attributed to the Veterinary Clinical Sciences, Louisiana State University, Ba- ton Rouge, LA 70803 USA inhibition of cyclooxygenase (COX) activity. Address correspondence to: Dr. Mark Mitchell, School of There are two different COX enzymes that have Veterinary Medicine, Department of Veterinary Clinical Sci- been described in mammals: COX-1 and COX-2. ences, Louisiana State University, Baton Rouge, LA 70803. Historically, compounds with activity against E-mail: [email protected]. COX-1 enzymes were believed to affect the syn- © 2005 Elsevier Inc. All rights reserved. thesis of prostaglandins important to normal gas- 1055-937X/05/1401-00089$30.00 trointestinal and renal function, while inhibition doi:10.1053/j.saep.2005.12.010

Seminars in Avian and Exotic Pet Medicine, Vol 14, No 1 ( January), 2005: pp 61–64 61 62 M. Mitchell gery had improved limb function postoperatively, Whereas there has been a significant amount although the difference was not statistically differ- of work evaluating the effects of carprofen in ent. The authors used 20 dogs for the experimental dogs, there are relatively few studies evaluating trial, and a power analysis suggested that 35 animals this drug in avian and exotic species. To date, would have been necessary to detect the differences there have only been carprofen studies in rats and in the study group. Although the difference in re- poultry. Even in the absence of legitimate re- sponse postoperatively was not significantly differ- search, carprofen remains a popular NSAID in ent, the carprofen did appear to provide some ben- avian and exotic medicine. efit to the dogs postoperatively. In a study evaluating Rats are commonly used as research animals the effect of perioperative carprofen on postopera- and kept as pets. Because these animals are rou- tive pain in dogs undergoing a cranial cruciate re- tinely used for surgical procedures in research, pair surgery, there was no difference in the mea- there is a need for appropriate analgesic com- sures used to assess pain between the two groups.7 pounds. Pet rats are also routinely presented for The authors suggested that the measures used to surgical procedures, including castration, ovario- assess pain in the two groups were not sensitive hysterectomy, and mass removal, and therefore enough to detect differences if they existed. would also benefit from the administration of Although not approved for cats, carprofen has analgesics. Characterizing pain in rats can be dif- been used to manage pain postoperatively in fe- ficult, as these animals can be stoic. Liles and 14 line cases. There were no measureable differences Flecknell evaluated the effectiveness of several in pain or sedation scores between cats given analgesics in rats postoperatively. Based on a be- carprofen (4 mg/kg) or meloxicam (0.3 mg/kg).8 lief that depression in food and water consump- Parton and coworkers9 also reported no signifi- tion may be associated with the presence of post- operative pain, the authors tested the hypothesis cant differences in the endoscopic examination of that rats offered analgesics, such as carprofen, the stomach or duodenum, or hematologic and would be less likely to have decreased food and serum biochemistry values in cats given carprofen water consumption postoperatively. The authors (4 mg/kg). found that rats provided carprofen following a The side effects associated with carprofen in laporotomy procedure were less likely to have mammals are primarily associated with the gastro- depressed food and water consumption than intestinal and hematopoietic systems. Gastric side those controls offered saline. effects are a concern when using carprofen long Surgical procedures can be associated with sig- term. Although carprofen is more selective for nificant postoperative morbidity. Flecknell and COX-2 activity, the potential for COX-1 selection coworkers15 found that rats not provided analge- 10 is a concern. Guerios and coworkers evaluated sia lost approximately 3% of their body weight. the potential gastric side effects of long-term The weight loss was attributed to a reduction in carprofen administration in canines. Dogs were the consumption of food and water. Rats given given 2.2 mg/kg carprofen for 30 days. Gastro- carprofen orally were less likely to have reduced scopic examination of the dogs did not reveal any water consumption in comparison, but did still negative side effects. Hematologc side effects are reduce their water consumption by 13%. Rats another concern associated with carprofen. When given carprofen subcutaneously did not experi- Labrador retrievers were given 2.2 mg/kg carpro- ence any reduction in water consumption. fen, there were mild, nonsignificant alterations in Carprofen is routinely used to provide analge- the hematologic and serum biochemistries.11 One sia in exotic pet mammals. The current dosing exception was a delayed platelet aggregation. Al- regimens are primarily based on the results of the though NSAIDs have been associated with alter- studies performed on rats (Table 1). Because our ations in capillary bleeding times, there was no understanding of this drug is limited, it is impor- significant difference in this measurement in dogs tant to use caution when dosing different species given 4 mg/kg carprofen.12 Hepatic side effects of rodents, marsupials, lagomorphs, and carni- were reported in 21 dogs after receiving carpro- vores. fen (1.57-3.1 mg/kg) orally every 12 hours for 3 to Studies evaluating the analgesic properties of 180 days.13 Affected dogs were anorectic, vomited, carprofen in birds are limited to poultry. Danbury had diarrhea, and in some cases developed renal and coworkers16 evaluated the effectiveness of tubular disease. Improvement was noted in most providing carprofen in the diet of broilers, and of the dogs after the drug was discontinued. found that plasma concentrations were linearly Carprofen 63

Table 1. Carprofen Dosages for Exotic will be used anecdotally, as there are limited re- sources to thoroughly investigate these drugs in and Avian Species avian and exotic species. Veterinarians prescrib- Class Dose ing these compounds should address the off-label usage of these drugs and their potential side ef- Avian 5-10 mg/kg PO20 fects with their clients. Veterinarians should also Ferrets 1 mg/kg PO q12-24h21 share their experiences with other veterinarians 4 mg/kg IM, SC q24h22 by publishing any available data so that a safe, Rodents 4 mg/kg SC q24h (chinchillas)23 albeit anecdotal, dosing regimen can be devel- 5-10 mg/kg PO14 oped. The recommended doses for avian and ex- Rabbits 2.2 mg/kg PO q24h24 otic species found in Table 1 appear to be based 4 mg/kg SC, q24h22 on this concept. Reptiles 1-4 mg/kg PO, SC, IM, IV18 2-4 mg/kg PO, SC, IM q24-72h19 References

1. Plumb D: Glucocorticoids, in Veterinary Drug correlated to the amount of food that the birds Handbook, 4th edition. (ed) Donald C. Plumb, consumed. In addition, lame birds were more Ames, IA, Iowa State Press, pp 387-389, 2002 2. Hawkins MG, Machin KL: Avian pain and analge- likely to selectively consume the diet with the drug sia. Proc Assoc Avian Vet, New Orleans, LA, pp than sound broilers, and birds with a lameness 165-174, 2004 improved when fed a diet supplemented with 3. Wilson JE, Chandrasekharan NV, Westover KD, carprofen. Carprofen was also found to shorten Eager KB, Simmons DL: Determination of expres- Ϫ Ϫ the time required for broilers with lameness to sion of cyclooxygenase 1 and 2 isoenzymes in 17 canine tissue and their differential sensitivity to traverse an obstacle course. Healthy birds com- nonsteroidal anti-inflammatory drugs. Am J Vet pleted the course in 11 seconds, while lame birds Res 65(6):810-818, 2004 receiving no treatment completed the course in 4. Kay-Mugford P, Benn SJ, LaMArre J, Conlon P: In 34 seconds. The administration of carprofen to vivo effects of nonsteroidal anti-inflammatory the lame birds shortened the time required to 18 drugs on cyclooxygenase activity in dogs. Am J Vet Res 61(7):802-810, 2000 seconds. 5. Moreau M, Dupuis J, Bonneau NH, Desnoyers To date, there have been no studies to evaluate M: Clinical evaluation of a neutraceutical, the efficacy of carprofen in psittacines, although it carprofen and meloxicam for the treatment of is routinely used to manage pain. Current dosing dogs with osteoarthritis. Vet Record 152(11): regimens are consistent with mammalian doses 323-329, 2003 6. Horstman CL, Conzemius MG, Evans R, Gordon (Table 1). The positive results reported in poultry WJ: Assessing the efficacy of perioperative oral suggest that this drug may prove useful in carprofen after cranial cruciate surgery using psittacines. noninvasive, objective pressure platform gait anal- Lawton18 and Redrobe19 recommended dosing ysis. Vet Surg 33(3):286-292, 2004 reptiles with 1 to 4 mg/kg and 2 to 4 mg/kg, 7. Gaynor JS, Brevard S, Mallinckrodt C, Baker G, Wander K: Effect of perioperative pain in dogs respectively (Table 1). The dosing interval at undergoing surgery for stabilization of ruptured these concentrations was 24 to 72 hours.19 It is cranial cruciate ligaments. Vet Therapeut 3(4): important to consider that these recommenda- 425-434, 2002 tions are anecdotal, as there have been no studies 8. Slingsby LS, Waterman-Pearson AE: Comparison done to determine the pharmacokinetics of these between meloxicam and carprofen for post-oper- ative analgesia after feline ovariohysterectomy. J drugs in reptiles. When using carprofen in rep- Sm Anim Pract 43(7):286-289, 2002 tiles, it is important to evaluate these patients for 9. Parton K, Balmer TV, Boyle J, Whittem T, Ma- the same potential side effects described in mam- chon R: The pharmacokinetics and effects of in- mals. travenously administered carprofen and salicylate on gastrointestinal mucosa and selected biochem- ical measurements in healthy cats. J Vet Pharma- Conclusion col Therap 23(2):73-79, 2000 10. Guerios SD, Sprea G, Deconto I, Okar RG: Gas- troscopic examination after oral administration of With the advent of new compounds, there is al- nonsteroidal anti-inflammatory agents in dogs. ways the desire to evaluate them in new species. Arch Vet Science 7(2):53-58, 2002 Unfortunately, the majority of these compounds 11. Hickford FH, Barr SC, Erb HN: Effect of carpro- 64 M. Mitchell

fen on hemostatic variables in dogs. Am J Vet Res 19. Redrobe S: Anesthesia and analgesia, in Girling 62(10):1642-1646, 2001 SJ, Raiti P (eds), BSAVA Manual of Reptiles. 12. Redin M: Capillary bleeding time in anesthetized Gloucester, England, British Small Animal Veter- dogs given carprofen. Dansk veterinaer 83(13): inary Association, pp131-146, 2004 13-14, 2000 20. Lawton MPC: Anesthesia, in: Beynon PH, Forbes 13. MacPhail CM, Lappin MR, Meyer DJ, Smith SG, NA, Harcourt-Brown NH (eds), BSAVA Manual of Webster CRL, Armstrong PJ: Hepatocellular tox- Raptors, Pigeons and Waterfowl. Ames, IA, Iowa icosis associated with administration of carprofen State University Press, pp 79-88, 1996 in 21 dogs. JAVMA 212(12):1895-1901, 1998 21. Brown SA: Ferret drug dosages, in Antinoff N, 14. Liles JH, Flecknell PA: A comparison of the effects Bauck L, Boyer TH (eds): Exotic Formulary. Lake- of buprenorphine, carprofen and flunixin follow- wood, CO, AAHA Press, 1999, pp 43-61, 1999 ing laporotomy in rats. J Vet Pharmacol Therap 22. Heard DJ: Anesthesia, analgesia, and sedation of 17(4):284-290, 1994 small animals, in Quesenberry KE, Carpenter JW 15. Flecknell PA, Orr HE, Rougham JV, Stewart R: (eds). Ferrets, Rabbits, and Rodents Clinical Med- Comparison of the effects of oral or subcutaneous nd carprofen or ketoprofen in rats undergoing lapa- icine and Surgery, 2 ed. St. Louis, MO, Saun- rotomy. Vet Record 144(3):65-67, 1999 ders, pp 356-369, 2004 16. Danbury TC, Weeks CA, Chambers JP: Self-selection 23. Richardson VCG: Chinchillas: Anesthesia and of the analgesic drug carprofen by lame broiler drug treatments, in Sutton JB, Swift ST (eds), chickens. Vet Record 146(11):307-311, 2000 Diseases of Small Domestic Rodents. Malden 17. McGeown D, Danbury TC, Waterman-Pearson AE, MA, Blackwell Science Publications, pp 40-51, Kestin SC: Effect of carprofen on lameness in 1997 broiler chickens. Vet Record 144(24):668-671, 1999 24. Paul-Murphy J, Ramer C: Urgent care of the pet 18. Lawton MPC: Pain management after surgery. rabbit. Vet Clinics N Am Ex An Pract 1:127-152, Proc N Am Vet Conf: 782, 1999 1998