CYP2D6 drug interactions and response to hydrocodone, ondansetron

Published: August 24th, 2014

Category: Stories

Joseph Ladd, University of Florida College of Pharmacy 2015 PharmD Candidate

The CYP2D6 enzyme is involved in the metabolism of roughly 25% of all medications, including codeine, hydrocodone, oxycodone, and ondansetron. Evidence of a clinical effect of CYP2D6 genetic variability on drug metabolism differs for each drug. While studies support the presence of clinically relevant effects of CYP2D6 variability on codeine metabolism, the data are less clear for other agents.

Monte and colleagues conducted a prospective, observational study of patients with self-reported pain or nausea who presented to an academic emergency department (ED) in the US between 2012 and 2013. Investigators identified patients who had taken CYP2D6 enzyme substrates, inhibitors, or inducers within the previous 48 hours and followed individuals receiving oxycodone, hydrocodone, or ondansetron throughout their stay. Pain and/or nausea were assessed using a 100-mm visual analogue scale (VAS) prior to drug administration and 30 minutes to 90 minutes after administration. CYP2D6 genotyping was conducted in a randomized subgroup of patients using the CYP2D6/CYP2C19 Amplichip. The primary study outcome was clinically significant VAS change between CYP2D6 medication users and nonusers.

A total of 502 patients were included, of which 250 (49.8%) had taken a CYP2D6 medication in the preceding 48 hours. Individuals who had taken a CYP2D6 medication were less likely to respond to hydrocodone (OR = 0.33; 95% CI 0.1–0.8) and more likely to respond to ondansetron (OR = 3.4; 95% CI 1.3–9.1), with no differences observed in patients receiving oxycodone. A total of 53 patients were genotyped, of which 48 received a study medication. When investigators controlled for the presence of CYP2D6 drug–drug interactions, intermediate and extensive CYP2D6 metabolizer status was significantly associated with increased ondansetron effectiveness (P = 0.03).

Clinical Implications

Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP2D6–codeine mention both hydrocodone and oxycodone, but state that it is difficult to determine based on current evidence whether CYP2D6 metabolizer phenotype affects analgesia or toxicity risk with these agents. CPIC guideline authors point out that, “differences in reported associations of CYP2D6 phenotype with hydrocodone and oxycodone analgesia as compared with that of codeine may be due to differing relative roles of the parent drug and the circulating metabolites in analgesia.”

Although CPIC guidelines are not available for CYP2D6–ondansetron, this drug–gene pair is designated as CPIC Level B and is associated with Level 1A evidence according to the Pharmacogenomics KnowledgeBase. Additional evidence for these drug–gene pairs is available through the PharmGKB website.


Monte AA et al. The effect of CYP2D6 drug–drug Interactions on hydrocodone effectiveness. Acad Emerg Med. 2014 Aug;21:879–85.