Pain relief is one of the basic tenants of veterinary medicine, and veterinarians are constantly striving to improve their ability to alleviate pain in their patients. One of the most common classes of drugs used by veterinarians for analgesia is NSAIDs.1 These drugs work centrally and peripherally to prevent pain and have analgesic and anti-inflammatory effects.2,3 They are used to prevent and treat postoperative pain, most often associated with musculoskeletal disease.4–7 Results of several studies8–10 have indicated that NSAIDs are effective in treating postoperative pain in dogs and cats, without producing adverse effects such as sedation, ileus, dysphoria, and hypothermia, which are typically associated with opioids and can be profound. The NSAIDs reduce inflammation by inhibition of the action of COX enzymes, which convert arachidonic acid into prostanoids.1,4,8 Cyclooxygenase has 2 forms, COX-1 and COX-2. The form associated with homeostasis, COX-1, produces eicosanoids that are often protective. Although COX-2 is the form of the enzyme most often associated with inflammation, homeostatic effects of COX-2 eicosanoids, including maintenance of gastrointestinal, platelet, and renal function, are also important. Therefore, toxic effects of NSAIDs are most commonly associated with nonselective inhibition of both COX-1 and COX-2, whereas analgesia associated with NSAIDs is primarily attributable to inhibition of COX-2,1,8,10–14 and an approach to achieving the desired effect of analgesia is to specifically target the inhibition of COX-2 while maintaining activity of COX-1 to provide the beneficial effects of eicosanoids.
The adverse effects associated with NSAIDs most commonly involve gastrointestinal tract injury and, occasionally, impairment of renal blood flow.4,11,15 Gastrointestinal perforation, ulceration, and bleeding have been associated with NSAID-induced depression of normal prostaglandin E2-mediated mucosal protective mechanisms as well as direct local irritation.11,15 Because maintenance of gastrointestinal mucosal integrity is largely the result of COX-1 activity, COX-2 selective NSAIDs are associated with fewer gastrointestinal complications.11 Nonsteroidal anti-inflammatory drugs may also cause nephropathy, especially with chronic use.11 Acute hepatic toxicity has been reported in several breeds of dogs but occurs much less frequently than adverse gastrointestinal and renal effects.16 Because NSAIDs have the potential to produce adverse gastrointestinal effects, the concurrent use of other NSAIDs or corticosteroids (which also produce adverse gastrointestinal effects) is not recommended.14 The adverse effects of NSAIDs are usually dose dependent, so it is important to know the pharmacokinetics of each medication before it is used in a particular species.17
Recently, meloxicam, a COX-2 selective NSAID, has become more frequently administered in veterinary medicine. Meloxicam's anti-inflammatory, analgesic, and antipyretic properties have been established in experimental and clinical studies in dogs and cats.5–10,12 Because of meloxicam's COX-2 selectivity, its use may be associated with a decreased occurrence of adverse effects such as inhibition of platelet function and adverse gastrointestinal effects.1–3,11 Meloxicam is metabolized extensively in the liver into 4 metabolites, none of which have anti-inflammatory or analgesic properties.3,17
Safe and effective pain relief should ideally be based on sound research that has been conducted to determine a therapeutic dose that does not cause adverse effects. The plasma or serum half-life of meloxicam is species specific, and it is difficult to extrapolate data across species.2,6,11,14,17,18 However, there are very few research studies on the pharmacokinetics of NSAIDS in exotic small animal species. Where data are available, they are often derived from studies in rodents. In particular, despite their popularity as companion animals, few studies on NSAIDs have been performed in rabbits (Oryctolagus cuniculus), and only 3 studies2,17,19 on the pharmacokinetics of meloxicam in this species have been reported. In 1 recent study,19 the pharmacokinetics of meloxicam in rabbits after oral administration (1.0 mg/kg, q 24 h, for 5 days) was determined. The results of that study19 indicated that peak plasma concentrations of meloxicam at the described dose were similar to therapeutic concentrations in other species. Considering those results, a dose of 1.0 mg/kg, PO, was hypothesized to be necessary to reach therapeutic concentrations of meloxicam in rabbits. However, because of the possibility that meloxicam could accumulate in plasma or tissues with multiple doses, this dosage needed to be evaluated to demonstrate clinical safety beyond 5 days of use.
The objectives of the study reported here were to determine the pharmacokinetics and safety of meloxicam in rabbits at a dosage of 1 mg/kg, PO, every 24 hours for a 29-day period. We performed plasma biochemical analysis and gross and histologic examinations to assess possible adverse effects of the drug at this dosage. Our hypotheses were that administration of meloxicam under this regimen would cause high plasma concentrations of the drug and that meloxicam concentrations would accumulate in plasma during the treatment period. We also hypothesized that there would be no adverse biochemical, gross, or histopathologic effects of meloxicam at this dosage.
Area under the plasma concentration-versus-time curve from administration of the last dose to 24 hours after administration of the last dose
Area under the plasma concentration-versus-time curve extrapolated to infinity after administration of a single dose
Observed maximum plasma concentration
Essentials – Young Rabbit Food, Oxbow Animal Health, Murdock, Neb.
Western Timothy Hay, Oxbow Animal Health, Murdock, Neb.
Metacam, 1.5 mg/mL oral suspension, Boehringer Ingelheim Vetmedica, St Joseph, Mo.
Shimadzu Prominence, Shimadzu Scientific Instruments Inc, Columbia, Md.
API 2000, Applied Biosystems Inc, Foster City, Calif.
WinNonlin, version 5.2, Pharsight Corp, Mountain View, Calif.
Sigma Plot 12, Systat Software Corp, Chicago, Ill.
1. Streppa HK, Jones CJ, Budsberg SC. Cyclooxygenase selectivity of nonsteroidal anti-inflammatory drugs in canine blood. Am J Vet Res 2002; 63: 91–94.
2. Carpenter JW, Pollock CG, Koch DE, et al. Single and multiple-dose pharmacokinetics of meloxicam after oral administration to the rabbit (Oryctolagus cuniculus). J Zoo Wildl Med 2009; 40: 601–606.
3. Davies NM, Skjodt NM. Clinical pharmacokinetics of meloxicam; a cyclo-oxygenase-2 preferential nonsteroidal anti-inflammatory drug. Clin Pharmacokinet 1999; 36: 115–126.
4. Luna SPL, Basilio AC, Steagall PVM, et al. Evaluation of adverse effects of long-term oral administration of carprofen, etodolac, flunixin meglumine, ketoprofen, and meloxicam in dogs. Am J Vet Res 2007; 68: 258–264.
5. Peterson KD, Keefe TJ. Effects of meloxicam on severity of lameness and other clinical signs of osteoarthritis in dogs. J Am Vet Med Assoc 2004; 225: 1056–1060.
6. Doig PA, Purbrick KA, Hare JE, et al. Clinical efficacy and tolerance of meloxicam in dogs with chronic osteoarthritis. Can Vet J 2000; 41: 296–300.
7. Moreau M, Dupuis J, Bonneau NH, et al. Clinical evaluation of a nutraceutical, carprofen and meloxicam for the treatment of dogs with osteoarthritis. Vet Rec 2003; 152: 323–329.
8. Caulkett N, Read M, Fowler D, et al. A comparison of the analgesic effects of butorphanol with those of meloxicam after elective ovariohysterectomy in dogs. Can Vet J 2003; 44: 565–570.
9. Carroll GL, Howe LB, Peterson KD. Analgesic efficacy of preoperative administration of meloxicam or butorphanol in onychectomized cats. J Am Vet Med Assoc 2005; 226: 913–919.
10. Mathews KA, Pettifer G, Foster R, et al. Safety and efficacy of preoperative administration of meloxicam, compared with that of ketoprofen and butorphanol in dogs undergoing abdominal surgery. Am J Vet Res 2001; 62: 882–888.
11. Jones CJ, Budsberg SC. Physiologic characteristics and clinical importance of the cyclooxygenase isoforms in dogs and cats. J Am Vet Med Assoc 2000; 217: 721–729.
12. Jones CJ, Streppa HK, Harmon BG, et al. In vivo effects of meloxicam and aspirin on blood, gastric mucosal, and synovial fluid prostanoid synthesis in dogs. Am J Vet Res 2002; 63: 1527–1531.
13. Engelhardt G. Pharmacology of meloxicam, a new non-steroidal anti-inflammatory drug with an improved safety profile through preferential inhibition of COX-2. Rheumatology 1996; 35 (suppl 1): 4–12.
15. Forsyth SF, Guilford WG, Haslett SJ, et al. Endoscopy of the gastroduodenal mucosa after carprofen, meloxicam and ketoprofen administration in dogs. J Small Anim Pract 1998; 39: 421–424.
16. MacPhail CM, Lappin MR, Meyer DJ, et al. Hepatocellular toxicosis associated with administration of carprofen in 21 dogs. J Am Vet Med Assoc 1998; 212: 1895–1901.
17. Turner PV, Chen HC, Taylor MW. Pharmacokinetics of meloxicam in rabbits after single and repeat oral dosing. Comp Med 2006; 56: 63–67.
18. Toutain PL, Reymond N, Laroute V, et al. Pharmacokinetics of meloxicam in plasma and urine of horses. Am J Vet Res 2004; 65: 1542–1547.
19. Fredholm DV, Carpenter JW, KuKanich B, et al. Pharmacokinetics of meloxicam in rabbits after oral administration of single and multiple doses. Am J Vet Res 2013; 74: 636–641.
21. Montoya L, Ambrose L, Kreil V, et al. A pharmacokinetic comparison of meloxicam and ketoprofen following oral administration to healthy dogs. Vet Res Commun 2004; 28: 415–428.
22. Giraudel JM, Diquelou A, Laroute V, et al. Pharmacokinetic/pharmacodynamic modelling of NSAIDs in a model of reversible inflammation in the cat. Br J Pharmacol 2005; 146: 642–653.