Bioavailability of tramadol after i.m. injection in comparison to i.v. infusion

Objectives and methods: The bioavailability of tramadol after i.m. injection of tramadol-HCl was determined from serum concentration data in a balanced two-period crossover study with 12 healthy male subjects in comparison to the 30-min i.v. infusion. Additionally, the tramadol concentrations in saliva and urine samples were measured. The subjects received single doses of 50 mg after an overnight fast, the washout period was one week. Serum, saliva and urine concentrations of tramadol were analyzed by gas chromatography, and pharmacokinetic (PK) evaluation was carried out model-independently. Descriptive statistical evaluation was performed by calculating geometric means with standard deviations (x g (SD g )) or medians with ranges (x (min, max)) and the extent of systemic availability (F) was tested for bioequivalence using the ANOVA log -based 90% confidence interval (Cl). Results: Retrospective sparteine phenotyping revealed two of the subjects as poor metabolizers (PM). Nevertheless, all subjects were considered on statistical evaluation since the PM results were within the range of the extensive metabolizers (EM). The 90% CI of F = AUC i.m. /AUC i was 92.9 -105.4% (x g = 99.0%) and was thus within the range of 80-125% generally accepted for a positive bioequivalence decision. After i.m. injection the serum concentration peaks were reached after t max = 0.75 (0.25, 1.50) h and amounted to c max = 166 (1.24) ng/ml; the corresponding results after i.v. infusion were t max = 0.50 (0.33, 1.50) h and c max = 293 (1.35) ng/ml. Thus, the results reflect the different invasion kinetics of the two modes of administration. However, the observed difference is not therapeutically relevant since in both cases minimal effective serum concentrations are already reached after a few minutes and are maintained for 9 - 10 h on the average. The i.v. results for all PK parameters agreed well with those of previous studies. Tramadol concentrations in saliva and urine were considerably higher than in serum. Therefore, saliva and urine samples are very suitable for the qualitative proof of tramadol intake in therapeutic drug monitoring and forensic toxicology. Conclusions: Tramadol is rapidly and almost completely absorbed after i.m. injection. The i.m. injection and the 30-min i.v. infusion are bioequivalent with respect to the extent of systemic availability. The differences in the times of onset and duration of action to be expected due to a slightly slower invasion after i.m. injection are small and probably therapeutically irrelevant.