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Effects of terbinafine and itraconazole on the pharmacokinetics of orally administered tramadol

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

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.

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Acknowledgments

We thank Mrs. Elina Kahra (medical laboratory technologist, Clinical Pharmacology, TYKSLAB, Hospital District of Southwest Finland, Turku, Finland) and Mr. Jouko Laitila laboratory technician, Clinical Pharmacology, University of Helsinki, Helsinki, Finland) for their skillful technical assistance.

Funding

This study received funding from theTurku University Hospital research fund EVO 13821, Turku, Finland, and Helsinki University Central Hospital Research Fund, Helsinki, Finland.

Author information

Authors and Affiliations

  1. 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, Teijo I. Saari & Nora M. Hagelberg

  2. Department of Clinical Pharmacology, HUSLAB, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland

    Janne T. Backman & Pertti J. Neuvonen

  3. Department of Pharmacology, Drug Development, and Therapeutics, University of Turku, Turku, Finland

    Mika Scheinin & Kari Laine

  4. TYKSLAB, Turku University Hospital, Turku, Finland

    Mika Scheinin

  5. Department of Anaesthesiology and Intensive Care, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland

    Klaus T. Olkkola

  6. Medbase Ltd., Turku, Finland

    Kari Laine

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  1. Tuukka Saarikoski
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  2. Teijo I. Saari
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Correspondence to Tuukka Saarikoski.

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Saarikoski, T., Saari, T.I., Hagelberg, N.M. et al. Effects of terbinafine and itraconazole on the pharmacokinetics of orally administered tramadol. Eur J Clin Pharmacol 71, 321–327 (2015). https://doi.org/10.1007/s00228-014-1799-2

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  • DOI: https://doi.org/10.1007/s00228-014-1799-2

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