Effects of Celecoxib and Etoricoxib on the Pharmacokinetics and Pharmacological Effects of Orally Administered Tramadol: A Randomised Controlled Trial.

Tramadol is a widely used analgesic whose bioactivation to O-desmethyltramadol is primarily mediated by cytochrome P450 2D6 (CYP2D6). Genetic variability and drug-drug interactions affecting CYP2D6 may influence tramadol pharmacokinetics and pharmacological effects. Cyclooxygenase-2 inhibitors are frequently co-administered with tramadol in multimodal analgesia, but their potential to affect tramadol disposition and effects remains incompletely characterised. Celecoxib has been reported to act as a weak inhibitor of CYP2D6 in vivo. This randomised, single-blind, placebo-controlled crossover study evaluated the effects of 8-day pretreatment with celecoxib or etoricoxib (200 and 120 mg once daily, respectively), compared with placebo, on the pharmacokinetics and pharmacological effects of a single 100 mg oral dose of tramadol in 12 healthy volunteers. Plasma concentrations of tramadol and O-desmethyltramadol were measured, and pharmacological effects were assessed using visual analogue scales, psychomotor testing (digit symbol substitution test) and cold pressor pain models. Celecoxib pretreatment did not change tramadol exposure but reduced the formation of O-desmethyltramadol, decreasing the geometric mean AUC ratio (GMR) of O-desmethyltramadol to tramadol (AUCm/AUCp) by 24% relative to placebo (90% CI, 0.69-0.84; p < 0.001). Etoricoxib had minimal effects on tramadol exposure or metabolism (GMR 0.92; 90% CI, 0.84-1.02; p = 0.13). In conclusion, celecoxib modestly inhibited the bioactivation of tramadol, but not etoricoxib. Differences in pharmacological effects were negligible.