Pharmacokinetics and physiological effects of repeated oral administrations of tramadol in horses

Abstract

This study evaluated the pharmacokinetics and physiological effects of tramadol during repeated oral administrations in horses. Nine adult healthy horses were administered tramadol at 5 and 10mg/kg orally every 12h for 5days in a randomized, crossover design with a 3-week washout between treatments. Plasma concentrations of tramadol, O- and N-desmethyltramadol (M1 and M2) were measured using Liquid-Chromatography-Mass Spectrometry at predetermined time points following each tramadol administration. Cardiovascular, respiratory and gastrointestinal physiological variables were monitored and adverse events were recorded. Data were analysed with two-way repeated measures anova or Kruskal-Wallis one-way anova on ranks with P<0.05 considered statistically significant. There were no significant effects of tramadol on the physiological variables. One horse receiving 10mg/kg tramadol developed mild colic. Following tramadol at 5 and 10mg/kg, respectively, maximum plasma concentrations (Cmax ) of tramadol ranged from 82-587 and 127-1280ng/mL, nonconjugated M1 ranged from 2.51-26.7 and 4.88-34.3ng/mL, and nonconjugated M2 from 12.5-356 and 35.4-486ng/mL. Corresponding minimum plasma concentrations (Cmin ) of tramadol at 12h following each dose ranged from 0.8-24 and 3-117ng/mL. Tramadol accumulated considerably over time, more markedly when given at 10mg/kg than at 5mg/kg (accumulation indexes of 3.51 and 1.73 respectively). There was no accumulation of M1 but substantial accumulation of M2. In conclusion, there was accumulation and increase in exposure to tramadol and M2, but not M1, during repeated oral administrations in horses.