Pharmacokinetics of a single high oral dose of tramadol hydrochloride in rabbits (Oryctolagus cuniculus) is compatible with analgesic effect and innocuity.

OBJECTIVE

To describe the pharmacokinetic parameters of tramadol and its main metabolites, O-desmethyltramadol (M1) and N-desmethyltramadol, and clinically detectable adverse effects after a single orally administered high dose of tramadol in rabbits (Oryctolagus cuniculus).

METHODS

6 experimental and 1 control healthy intact male rabbits of commercial origin were included in February 2025. Following administration of a 30-mg/kg oral dose of tramadol, plasma concentrations of tramadol, M1, and N-desmethyltramadol were determined by UHPLC-MS at 12 predetermined time points. Pharmacokinetic parameters were calculated using commercial software. Fecal production and sedation were evaluated before and after the experiment.

RESULTS

The mean tramadol maximum plasmatic concentration was 91 ± 38 ng/mL, the average time to reach maximum plasmatic concentration was 40 minutes, the terminal half-life was 4.0 ± 2.4 hours, and the mean area under the curve from the first dose to infinity was 192 ± 45 ng/hmL. The M1 metabolite reached concentrations compatible with previously described analgesic effects in rabbits after 10 minutes and for up to 3 hours after administration in some individuals, whereas tramadol did not reach analgesic concentrations. Mild sedation was detected in 4 rabbits at the 20 minute- to 6-hour time points, and fecal production increased from 24 to 48 hours after tramadol administration. No clinically relevant adverse effects were noted.

CONCLUSIONS

Administration of 30 mg/kg tramadol, PO, in rabbits results in plasma concentrations of M1 compatible with analgesia.

CLINICAL RELEVANCE: The short duration of action warrants further studies with long-acting formulations of tramadol.