title: Pharmacokinetics and antinociceptive effects of tramadol and its metabolite O-desmethyltramadol following intravenous administration in sheep.
abstract: Although sheep are widely used as an experimental model for various surgical procedures there is a paucity of data on the pharmacokinetics and efficacy of analgesic drugs in this species. The aims of this study were to investigate the pharmacokinetics of intravenously (IV) administered tramadol and its active metabolite O-desmethyltramadol (M1) and to assess the mechanical antinociceptive effects in sheep. In a prospective, randomized, blinded study, six healthy adult sheep were given 4 and 6 mg/kg tramadol and saline IV in a cross-over design with a 2-week wash-out period. At predetermined time points blood samples were collected and physiological parameters and mechanical nociceptive threshold (MNT) values were recorded. The analytical determination of tramadol and M1 was performed using high performance liquid chromatography. Pharmacokinetic parameters fitted a two- and a non-compartmental model for tramadol and M1, respectively. Normally distributed data were analysed by a repeated mixed linear model. Plasma concentration vs. time profiles of tramadol and M1 were similar after the two doses. Tramadol and M1 plasma levels decreased rapidly in the systemic circulation, with both undetectable after 6 h following drug administration. Physiological parameters did not differ between groups; MNT values were not statistically significant between groups at any time point. It was concluded that although tramadol and M1 concentrations in plasma were above the human minimum analgesic concentration after both treatments, no mechanical antinociceptive effects of tramadol were reported. Further studies are warranted to assess the analgesic efficacy of tramadol in sheep.
authors.affiliation: Department of Animal Medicine, Productions and Health, University of Padua, Viale dell'Università 16, Agripolis, 35020 Legnaro, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Bortolami
authors.affiliation: Department of Veterinary Medicine, University of Perugia, via S. Constanzo 4, Perugia, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Della Rocca
authors.affiliation: Department of Veterinary Medicine, University of Perugia, via S. Constanzo 4, Perugia, Italy. Electronic address: alessandra.disalvo@unipg.it.
authors.forename: A
authors.initials: A
authors.lastname: Di Salvo
authors.affiliation: Department of Veterinary Sciences, University of Pisa, via Livornese 1, San Piero a Grado, 56122 Pisa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Giorgi
authors.affiliation: College of Veterinary Medicine, Chungnam National University, Daejeon, South Korea.
authors.forename: T W
authors.initials: TW
authors.lastname: Kim
authors.affiliation: Department of Animal Medicine, Productions and Health, University of Padua, Viale dell'Università 16, Agripolis, 35020 Legnaro, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Isola
authors.affiliation: Department of Animal Medicine, Productions and Health, University of Padua, Viale dell'Università 16, Agripolis, 35020 Legnaro, Italy.
authors.forename: G M
authors.initials: GM
authors.lastname: De Benedictis
mesh_terms: D061605:Administration, Intravenous; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D005260:Female; D010147:Pain Measurement / Q000662:veterinary; D012756:Sheep; D034561:Sheep, Domestic; D014147:Tramadol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000701:Analgesics, Opioid; C080580:O-demethyltramadol; D014147:Tramadol
keywords: Analgesia; Mechanical nociceptive threshold; Pharmacokinetics; Sheep; Tramadol