Bortolami E, Della Rocca G, Di Salvo A, Giorgi M, Kim T W, Isola M, De Benedictis G M
Department of Animal Medicine, Productions and Health, University of Padua, Viale dell'Università 16, Agripolis, 35020 Legnaro, Italy.
Department of Veterinary Medicine, University of Perugia, via S. Constanzo 4, Perugia, Italy.
Vet J. 2015 Sep;205(3):404-9. doi: 10.1016/j.tvjl.2015.04.011. Epub 2015 Apr 14.
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.
尽管绵羊被广泛用作各种外科手术的实验模型，但关于该物种中镇痛药的药代动力学和疗效的数据却很少。本研究的目的是研究静脉注射曲马多及其活性代谢物O-去甲基曲马多（M1）的药代动力学，并评估其对绵羊的机械性抗伤害感受作用。在一项前瞻性、随机、双盲研究中，六只健康成年绵羊采用交叉设计，分别静脉注射4和6mg/kg曲马多以及生理盐水，洗脱期为2周。在预定时间点采集血样，并记录生理参数和机械性伤害感受阈值（MNT）值。采用高效液相色谱法对曲马多和M1进行分析测定。药代动力学参数分别采用二室模型和非房室模型对曲马多和M1进行拟合。对正态分布的数据采用重复混合线性模型进行分析。两种剂量给药后，曲马多和M1的血浆浓度-时间曲线相似。曲马多和M1的血浆水平在体循环中迅速下降，给药后6小时均无法检测到。各组间生理参数无差异；各时间点组间MNT值无统计学意义。得出的结论是，尽管两种治疗后血浆中曲马多和M1的浓度均高于人类最低镇痛浓度，但未报告曲马多有机械性抗伤害感受作用。有必要进一步研究以评估曲马多对绵羊的镇痛效果。
