The influence of a single and chronic administration of venlafaxine on tramadol pharmacokinetics in a rabbit model

Abstract Background The combined use of tramadol with selective serotonin and norepinephrine reuptake inhibitors e.g . venlafaxine may be associated with serotonin syndrome. No previous studies exist examining the influence of a weak CYP2D6 inhibitor venlafaxine on the pharmacokinetics of tramadol. Therefore, the aim of this study was to determine the effect of a single and chronic administration of venlafaxine on the pharmacokinetics of tramadol using a rabbit model. Methods Adult New Zealand white rabbits of both sexes (n = 21) were used. Animals received 100 mg of tramadol per os (one slow release tablet) and 75 mg of venlafaxine (one prolonged release capsule), and were divided into four groups: control group – a single dose of tramadol alone, 1 day group – a single dose of tramadol and venlafaxine, 7 and 14 days groups – seven and fourteen days administration of venlafaxine once daily plus a single dose of tramadol on the last day of the study. Results Venlafaxine administration over a period of 7 and 14 days resulted in faster elimination of tramadol compared to the control group: significantly higher values of k el , and lower values of t 1/2 kel and MRT for the 7 and 14 days group were observed. Although no differences in bioavailability of tramadol were obtained. Conclusion Using a rabbit model, there is no evidence that the combined administration of tramadol and venlafaxine may increase the plasma exposure of tramadol and therefore increase the risk of serotonin syndrome.