Drug-gene and drug-drug interactions associated with tramadol and codeine therapy in the INGENIOUS trial

Abstract

Background: Tramadol and codeine are metabolized by CYP2D6 and are subject to drug-gene and drug-drug interactions. Methods: This interim analysis examined prescribing behavior and efficacy in 102 individuals prescribed tramadol or codeine while receiving pharmaco-genotyping as part of the INGENIOUS trial (NCT02297126). Results: Within 60 days of receiving tramadol or codeine, clinicians more frequently prescribed an alternative opioid in ultrarapid and poor metabolizers (odds ratio: 19.0; 95% CI: 2.8-160.4) as compared with normal or indeterminate metabolizers (p = 0.01). After adjusting the CYP2D6 activity score for drug-drug interactions, uncontrolled pain was reported more frequently in individuals with reduced CYP2D6 activity (odds ratio: 0.50; 95% CI: 0.25-0.94). Conclusion: Phenoconversion for drug-drug and drug-gene interactions is an important consideration in pharmacogenomic implementation; drug-drug interactions may obscure the potential benefits of genotyping.

Keywords: CYP2D6; IGNITE; INGENIOUS; adverse side effects; pharmacogenetics; opioids; pharmacogenomics; phenoconversion.

Conflict of interest statement

Financial & competing interests disclosure

The INGENIOUS trial (NCT02297126) is sponsored by an NIH/NHGRI U01-grant (HG007762). Y Zang, Z Desta, MB Rosenman, AM Holmes, KD Levy, VM Pratt, BT Gufford, PR Dexter and TC Skaar are supported by the NIH-U01 HG007762. MT Eadon was supported by an NIH/NIDDK award (K08DK107864). VM Pratt is also supported by the Indiana University Health-Indiana University School of Medicine Strategic Research Initiative. BT Gufford was also supported by the Indiana Clinical and Translational Sciences Institute Young Investigator Award (NIH-UL1 TR001108). This project was also supported by an NIH/NIGMS award entitled the Indiana University Comprehensive Training in Clinical Pharmacology (T32GM008425), which provided stipend support for CR Fulton. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1.. Inclusion and exclusion criteria for the 102 participants in the analysis.

All participants were enrolled prior to 31 August 2017. Primary trigger medications are medications prompting enrollment. Secondary trigger medication indicates a prescription for tramadol or codeine within 1 year of a subject's trial enrollment for a nonopioid medication. DDI: Drug–drug interaction with a CYP2D6 inhibitor; UDS: Urine drug screen.