Recognition of pain in animals and provision of appropriate analgesia are becoming increasingly important issues in veterinary medicine. Recognition of pain in certain small mammals, such as rabbits and rodents, can be challenging because many small mammals are prey species and have evolved to hide signs of illness and pain.1 Once pain is detected, numerous analgesics are available to treat affected animals; however, the usefulness of many analgesics is limited by associated adverse effects, difficulty of administration, or high cost. Few analgesics have been evaluated in small mammals.
Although tramadol has routinely been used for the relief of moderate to severe pain in humans for the last 2 decades,2,3 its use in veterinary medicine is relatively new. Tramadol is a centrally acting analgesic that has agonist activity at opioid M-receptors and also inhibits reuptake of norepinephrine and serotonin.4 Numerous metabolites of tramadol have been identified, including M1 through M5; however, to the authors' knowledge, M1 (O-desmethyltramadol) is the only metabolite that has analgesic properties.5,6 Although tramadol has adverse effects similar to those of other commonly used opioids, little sedation or respiratory depression has been associated with administration of tramadol in humans.5 Also unlike several commonly used opioids, tramadol is not a controlled drug, is inexpensive, and can be administered orally.
Few studies have been designed to investigate the analgesic effects and metabolism of tramadol in nonhuman animals, but recommended dosages based on pharmacokinetic studies are available for cats and dogs.7,8 One study9 revealed that tramadol provided analgesia approximately equal to that of morphine in dogs with no adverse effects. Results of another study10 indicated that epidurally administered tramadol provided adequate relief for perineal and lumbosacral pain in horses. Respiratory depression associated with IV administration of tramadol has been reported in cats,11 and abuse of tramadol in the racehorse industry has been reported.12 The purpose of the study reported here was to determine the pharmacokinetics of an orally administered dose of tramadol in domestic rabbits (Oryctolagus cuniculus).
Area under the plasma concentration– time curve from time 0 to 120 minutes after drug administration
Area under the plasma concentration– time curve from time 0 to infinity
Area under the first moment time curve from 0 to infinity
Maximum plasma concentration
High-performance liquid chromatography
Time to reach maximum plasma concentration
Tramadol hydrochloride, 50-mg tablets, Caraco Pharmaceutical Laboratories Ltd, Detroit, Mich.
Ora-Blend SF, Paddock Laboraties Inc, Minneapolis, Minn.
Iso Flo, Abbott Laboratories, North Chicago, Ill.
Monoject, Kendall, Mansfield, Mass.
2695 separations module, Waters Corp, Milford, Mass.
2475 fluorescence detector, Waters Corp, Milford, Mass.
Empower, version 2, Waters Corp, Milford, Mass.
US Pharmacocopeia, Rockville, Md.
Symmetry C18 high-performance liquid chromatography column, US Pharmocopeia, Rockville, Md.
Symmetry C18 guard column, US Pharmocopeia, Rockville, Md.
Gruenthal, Aachen, Germany.
WinNonlin, version 4.1, Pharsight Corp, Mountain View, Calif.
Roughan JV, Flecknell PA. Evaluation of a short duration behaviour-based post-operative pain scoring system in rats. Eur J Pain 2003;7:397–406.
Gibson TP. Pharmacokinetics, efficacy, and safety of analgesia with a focus on tramadol HCl. Am J Med 1996;101(supp 1A):47S–53S.
Tramadol [package insert]. Detroit: Caraco Pharmaceutical Laboratories Ltd, 2006.
Wu WN, McKown LA, Gauthier AD, et al. Metabolism of the analgesic drug, tramadol hydrochloride, in rat and dog. Xenobiotica 2001;31:423–441.
Kukanich B, Papich MG. Pharmacokinetics of tramadol and the metabolite O-desmethyltramadol in dogs. J Vet Pharmacol Ther 2004;27:239–246.
Mastrocinque S, Fantoni DT. A comparison of preoperative tramadol and morphine for the control of early postoperative pain in canine ovariohysterectomy. Vet Anaesth Analg 2003;30:220–228.
Natalini CC, Robinson EP. Evaluation of the analgesic effects of epidurally administered morphine, alfentanil, butorphanol, tramadol, and U50488H in horses. Am J Vet Res 2000;61:1579–1586.
Teppema LJ, Nieuwenhuijs D, Olievier CN, et al. Respiratory depression by tramadol in the cat: involvement of opioid receptors. Anesthesiology 2003;98:420–427.
Russo CI, Wynne PM. Tramadol: metabolism and excretion in the horse, in Proceedings. 13th Int Conf Racing Analysts Vet 2001;453–457.
Wagner DS, Johnson CE, Cichon-Hensley BK, et al. Stability of oral liquid preparations of tramadol in strawberry syrup and a sugar-free vehicle. Am J Health Syst Pharm 2003;60:1268–1270.
Grond S, Meuser T, Uragg H, et al. Serum concentrations of tramadol enantiomers during patient-controlled analgesia. Br J Clin Pharmacol 1999;48:254–257.
Fernandez-Varon E, Bovaira MJ, Espuny A, et al. Pharmacokinetic-pharmacodynamic integration of moxifloxicin in rabbits after intravenous, intramuscular and oral administration. J Vet Pharmacol Ther 2005;28:343–348.
Abd El-Aty AM, Goudah A, El-Sooud KA, et al. Pharmacokinetics and bioavailability of florfenicol following intravenous, intramuscular and oral administration in rabbits. Vet Res Commun 2004;28:515–524.
Park BK, Lim JH, Kim MS, et al. Pharmacokinetics of florfenicol and its major metabolite, florfenicol anime, in rabbits. J Vet Pharmacol Ther 2007;30:32–36.
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.