Presented at the 2012 AAPM Annual Meeting « Back

The Effects of Cytochrome P450 (CYP) 2D6 Inhibitors on the Metabolism of Codeine to Its Active Metabolites in Patients with Chronic Pain

David A. Yee, BS, dayee@ucsd.edu¹, Rabia S. Atayee, PharmD BCPS², Joseph D. Ma, PharmD³, Brookie M. Best, PharmD MAS⁴, Amadeo J. Pesce, PhD DABCC⁵, (1) UCSD Skaggs School of Pharmacy, San Diego, California, (2) UCSD Skaggs School of Pharmacy, La Jolla, California, (3) Pharmacy, La Jolla, California, (4) UC San Diego, La Jolla, California, (5) Millennium Research Institute, San Diego, California

Introduction: Codeine, which is an inactive compound, is metabolized by cytochrome P450 (CYP) 2D6 to its major active metabolite morphine. Inhibition of codeine metabolism may lead to decreased production of active metabolites and may therefore decrease analgesia. The objective of this study was to determine if the distribution of metabolites is affected by concomitant use of medications that inhibit CYP2D6. Materials and Methods: IRB-exempt status was granted by the UCSD Human Research Protection Program. This retrospective analysis compared physician-reported codeine use with or without the CYP2D6 inhibitors, methadone, paroxetine, or fluoxetine (n = 1800). In de-identified urine specimens analyzed between September 2010 and July 2011 by LC MS/MS at Millennium Laboratories, molar fractions of morphine due to codeine use were calculated and used as an indication of metabolism through CYP2D6. Results: The geometric mean morphine molar fraction in specimens positive for codeine was 0.23 (n = 1,350 specimens). The geometric mean morphine molar fraction in specimens positive for codeine and CYP2D6 strong inhibitors, paroxetine or fluoxetine, was 0.081 (n = 39), a difference of -0.14 (two sample t-test p<0.001). The geometric mean morphine molar fraction in specimens positive for codeine and methadone was 0.13 (n = 43), a difference of -0.10 (p = 0.01). Conclusions: Concomitant use of codeine and CYP2D6 inhibitors showed decreased fraction of morphine in the urine. This may lead to decreased analgesic effects when treating patients with codeine for chronic pain who are also taking methadone.

Funding: An unrestricted grant was given to the UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences to fund the summer internships by Millennium Laboratories, Inc.