Paroxetine, a Cytochrome P450 2D6 Inhibitor, Diminishes the Stereoselective O‐demethylation and Reduces the Hypoalgesic Effect of Tramadol

Objective Tramadol hydrochloride (INN, tramadol) exerts its antinociceptive action through a monoaminergic effect mediated by the parent compound and an opioid effect mediated mainly by the O‐demethylated metabolite (+)‐M1. O‐demethylation is catalyzed by cytochrome P450 (CYP) 2D6. Paroxetine is a very potent inhibitor of CYP2D6. The objective of this study was to investigate the influence of paroxetine pretreatment on the biotransformation and the hypoalgesic effect of tramadol. Methods With and without paroxetine pretreatment (20 mg daily for 3 consecutive days), the formation of M1 and the analgesic effect of 150 mg of tramadol were studied in 16 healthy extensive metabolizers of sparteine in a randomized, double‐blind, placebo‐controlled, 4‐way crossover study by use of experimental pain models. Results With paroxetine pretreatment, the area under the plasma concentration‐time curve (AUC) of (+)‐ and (−)‐tramadol was increased (37% [P = .001] and 32% [P = .002], respectively), and the corresponding AUCs of (+)‐ and (−)‐M1 were decreased (67% [P = .0004] and 40% [P = .0008], respectively). (+)‐M1 and (−)‐M1 could be determined in all subjects throughout the study period regardless of paroxetine pretreatment. The sums of differences between postmedication and premedication values of pain measures differed between the placebo/tramadol and the placebo/placebo combination, with median values as follows: pressure pain tolerance threshold, 390 kPa (95% confidence interval [CI], 211 to 637 kPa) versus −84 kPa (95% CI, − 492 to −32 kPa) (P = .001); single sural nerve stimulation pain tolerance threshold, 25.8 mA (95% CI, 15.3 to 29.8 mA) versus 9.0 mA (95% CI, 1.5 to 14.8 mA) (P = .005); pain summation threshold, 10.7 mA (95% CI, 5.2 to 17.6 mA) versus 5.0 mA (95% CI, 2.8 to 11.2 mA) (P = .066); cold pressor pain, −4.2 cm · s (95% CI, −6.8 to −1.9 cm · s) versus −0.4 cm · s (− 1.4 to 1.4 cm · s) (P = .002); and discomfort, −4.7 cm (95% CI, −10.6 to −2.8 cm) versus 0.5 cm (−0.1 to 1.4 cm) (P = .002). The sums of differences of the paroxetine/tramadol combination also differed from placebo/tramadol for some of the measures, with median values as follows: cold pressor pain, −2.2 cm · s (95% CI, −3.7 to −0.4 cm · s) (P = .036, compared with placebo/tramadol); and discomfort, −2.0 cm (95% CI, −5.6 to −1.2 cm) (P = .056). For the other measures, the hypoalgesic effect was retained on the paroxetine/tramadol combination, with median values as follows: pressure pain to