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::

• adverse side effects
• CYP2D6
• IGNITE
• INGENIOUS
• pharmacogenetics; opioids
• pharmacogenomics
• phenoconversion

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at:

www.futuremedicine.com/doi/suppl/10.2217/pgs-2018-0205

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.

Ethical disclosure

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Author contributions

CR Fulton, MT Eadon, Y Zang, Z Desta and MB Rosenman performed analysis of data and manuscript preparation. AM Holmes, BS Decker, TC Skaar, PR Dexter, KD Levy and JT Callaghan conducted the trial. VM Pratt and BT Gufford reviewed and edited final manuscript. All authors provided approval of the final version.

Additional information

Funding

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.