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Purpose: Tramadol is mainly metabolized by the cytochrome P450 (CYP) 2D6, CYP2B6 and CYP3A4 enzymes. The aim of this study was to evaluate the effect of enzyme induction with rifampicin on the pharmacokinetics and pharmacodynamics of oral and intravenous tramadol., Methods: This was a randomized placebo-controlled crossover study design with 12 healthy subjects. After pretreatment for 5 days with rifampicin (600 mg once daily) or placebo, subjects were given tramadol either 50 mg intravenously or 100 mg orally. Plasma concentrations of tramadol and its active main metabolite O-desmethyltramadol (M1) were determined over 48 h. Analgesic and behavioral effects and whole blood 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were measured., Results: Rifampicin reduced the mean area under the time-concentration curve (AUC0-∞) of intravenously administered tramadol by 43 % and that of M1 by 58 % (P < 0.001); it reduced the AUC0-∞ of oral tramadol by 59 % and that of M1 by 54 % (P < 0.001). Rifampicin increased the clearance of intravenous tramadol by 67 % (P < 0.001). Bioavailability of oral tramadol was reduced by rifampicin from 66 to 49 % (P = 0.002). The pharmacological effects of tramadol or whole blood serotonin concentrations were not influenced by pretreatment with rifampicin., Conclusions: Rifampicin markedly decreased the exposure to tramadol and M1 after both oral and intravenous administration. Therefore, rifampicin and other potent enzyme inducers may have a clinically important interaction with tramadol regardless of the route of its administration.