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 10 mg/kg orally every 12 h for 5 days 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 10 mg/kg tramadol developed mild colic. Following tramadol at 5 and 10 mg/kg, respectively, maximum plasma concentrations (Cmax ) of tramadol ranged from 82-587 and 127-1280 ng/mL, nonconjugated M1 ranged from 2.51-26.7 and 4.88-34.3 ng/mL, and nonconjugated M2 from 12.5-356 and 35.4-486 ng/mL. Corresponding minimum plasma concentrations (Cmin ) of tramadol at 12 h following each dose ranged from 0.8-24 and 3-117 ng/mL. Tramadol accumulated considerably over time, more markedly when given at 10 mg/kg than at 5 mg/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.

Plasma concentrations, analgesic and physiological assessments in horses with chronic laminitis treated with two doses of oral tramadol

“…Plasma tramadol concentrations were consistently measured with both doses and were comparable to those reported previously . Also, doubling the dose of tramadol caused a proportional increase in plasma concentrations of tramadol, M1 and M2, also akin to previous data . Hence, as suggested before , low bioavailability is not the likely reason underlying the limited pain relief with 5 mg/kg bwt tramadol observed here and previously .…”

“…Although there were no changes in physiological variables and no adverse events were observed during the entire study period, the small sample size precludes conclusions regarding the safety of multiple tramadol administrations in horses. Multiple oral administrations of 5 mg/kg bwt tramadol were not associated with adverse events , but transient colic signs were observed with 10 mg/kg bwt such that this dose should be used cautiously.…”

Effects of age on the pharmacokinetics of tramadol and its active metabolite,O‐desmethyltramadol following intravenous administration to foals

“…In the mature horse, the most common tramadol metabolites appear to be M1, M1G and M2 . Due to the reported immaturity of metabolic enzymes in young animals , we hypothesised that administration to young foals may result in a different metabolic profile and, while not assessed here, potentially differing analgesic effectiveness, compared with mature horses.…”

“…The analgesic effects of tramadol are believed to be a result of the parent drug as well as its active metabolite, O-desmethyltramadol (M1). Although the exact metabolic pathway for tramadol has not yet been described in horses, the pharmacokinetics of the parent compound and the M1 metabolite have been well described in this species [4][5][6][7][8][9][10]. Reports of the analgesic efficacy of tramadol in mature horses are limited [11].…”

Pharmacokinetic evaluation and safety of topical 1% morphine sulfate application on the healthy equine eye

“…In addition, morphine concentrations above 1.0 ng/mL (lower limit of assay detection) were more consistently detected on days two and three, than day one of administration. It is possible that repeated application of morphine may result in accumulation over time, similar to that demonstrated with oral tramadol administration in horses . There is one report in the literature of systemic quantification of morphine following a single ocular administration, with no reports having assessed systemic absorption following repeated administration …”