title: Effects of terbinafine and itraconazole on the pharmacokinetics of orally administered tramadol.
abstract: BACKGROUND
  Tramadol is widely used for acute, chronic, and neuropathic pain. Its primary active metabolite is O-desmethyltramadol (M1), which is mainly accountable for the μ-opioid receptor-related analgesic effect. Tramadol is metabolized to M1 mainly by cytochrome P450 (CYP)2D6 enzyme and to other metabolites by CYP3A4 and CYP2B6. We investigated the possible interaction of tramadol with the antifungal agents terbinafine (CYP2D6 inhibitor) and itraconazole (CYP3A4 inhibitor).
  
  
  METHODS
  We used a randomized placebo-controlled crossover study design with 12 healthy subjects, of which 8 were extensive and 4 were ultrarapid CYP2D6 metabolizers. On the pretreatment day 4 with terbinafine (250 mg once daily), itraconazole (200 mg once daily) or placebo, subjects were given tramadol 50 mg orally. Plasma concentrations of tramadol and M1 were determined over 48 h and some pharmacodynamic effects over 12 h. Pharmacokinetic variables were calculated using standard non-compartmental methods.
  
  
  RESULTS
  Terbinafine increased the area under plasma concentration-time curve (AUC0-∞) of tramadol by 115 % and decreased the AUC0-∞ of M1 by 64 % (P < 0.001). Terbinafine increased the peak concentration (C max) of tramadol by 53 % (P < 0.001) and decreased the C max of M1 by 79 % (P < 0.001). After terbinafine pretreatment the elimination half-life of tramadol and M1 were increased by 48 and 50 %, respectively (P < 0.001). Terbinafine reduced subjective drug effect of tramadol (P < 0.001). Itraconazole had minor effects on tramadol pharmacokinetics.
  
  
  CONCLUSIONS
  Terbinafine may reduce the opioid effect of tramadol and increase the risk of its monoaminergic adverse effects. Itraconazole has no meaningful interaction with tramadol in subjects who have functional CYP2D6 enzyme.
authors.affiliation: Department of Anaesthesiology, Intensive Care, Emergency Care, and Pain Medicine, Turku University Hospital, University of Turku, P.O. Box 52, Kiinamyllynkatu 4-8, FI-20520, Turku, Finland, tuukka.saarikoski@fimnet.fi.
authors.forename: Tuukka
authors.initials: T
authors.lastname: Saarikoski
authors.forename: Teijo I
authors.initials: TI
authors.lastname: Saari
authors.forename: Nora M
authors.initials: NM
authors.lastname: Hagelberg
authors.forename: Janne T
authors.initials: JT
authors.lastname: Backman
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: Mika
authors.initials: M
authors.lastname: Scheinin
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Olkkola
authors.forename: Kari
authors.initials: K
authors.lastname: Laine
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics; D000935:Antifungal Agents; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D065690:Cytochrome P-450 CYP2D6 Inhibitors / Q000494:pharmacology; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D009483:Neuropsychological Tests; D000077291:Terbinafine; D014147:Tramadol / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D000935:Antifungal Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D009281:Naphthalenes; D017964:Itraconazole; D014147:Tramadol; D019389:Cytochrome P-450 CYP2D6; D000077291:Terbinafine