Effect of voriconazole and fluconazole on the pharmacokinetics of intravenous fentanyl

Objective Fentanyl is a widely used opioid analgesic, which is extensively metabolized by hepatic cytochrome P450 (CYP) 3A. Recent reports suggest that concomitant administration of CYP3A inhibitors with fentanyl may lead to dangerous drug interactions. Methods The potential interactions of fentanyl with triazole antifungal agents voriconazole and fluconazole were studied in a randomized crossover study in three phases. Twelve healthy volunteers were given 5 mu g/ kg of intravenous fentanyl without pretreatment ( control), after oral voriconazole ( 400 mg twice on the first day and 200 mg twice on the second day), or after oral fluconazole ( 400 mg once on the first day and 200 mg once on the second day). Plasma concentrations of fentanyl, norfentanyl, voriconazole, and fluconazole were determined up to 24 h. Pharmacokinetic parameters were calculated using compartmental methods. Results The mean plasma clearance of intravenous fentanyl was decreased by 23% ( range-22 to 48%; p<0.05) and 16% (-34 to 53%; p<0.05) after voriconazole and fluconazole administration, respectively. Voriconazole increased the area under the fentanyl plasma concentration-time curve by 1.4fold ( p<0.05). The initial plasma concentrations and volume of distribution of fentanyl did not differ significantly between phases. Conclusion Both voriconazole and fluconazole delay the elimination of fentanyl significantly. Caution should be exercised, especially in patients who are given voriconazole or fluconazole during long-lasting fentanyl treatment, because insidiously elevated fentanyl concentration may lead to respiratory depression.