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CYP2D6 phenotypes are associated with adverse outcomes related to opioid medications.

ABSTRACT: Variation in the CYP2D6 gene may affect response to opioids in both poor and ultrarapid metabolizers, but data demonstrating such associations have been mixed, and the impact of variants on toxicity-related symptoms (e.g., nausea) is unclear. Therefore, we examined the association between CYP2D6 phenotype and poor pain control or other adverse symptoms related to the use of opioids in a sample of primary care patients.We identified all patients in the Mayo Clinic RIGHT Protocol who were prescribed an opioid medication between July 01, 2013 and June 30, 2015, and categorized patients into three phenotypes: poor, intermediate to extensive, or ultrarapid CYP2D6 metabolizers. We reviewed the electronic health record of these patients for indications of poor pain control or adverse symptoms related to medication use. Associations between phenotype and outcomes were assessed using Chi-square tests and logistic regression.Overall, 257 (25% of RIGHT Protocol participants) patients received at least one opioid prescription; of these, 40 (15%) were poor metabolizers, 146 (57%) were intermediate to extensive metabolizers, and 71 (28%) were ultrarapid metabolizers. We removed patients that were prescribed a CYP2D6 inhibitor medication (n=38). After adjusting for age and sex, patients with a poor or ultrarapid phenotype were 2.7 times more likely to experience either poor pain control or an adverse symptom related to the prescription compared to patients with an intermediate to extensive phenotype (odds ratio: 2.68; 95% CI: 1.39, 5.17; p=0.003).Our results suggest that >30% of patients with a poor or ultrarapid CYP2D6 phenotype may experience an adverse outcome after being prescribed codeine, tramadol, oxycodone, or hydrocodone. These medications are frequently prescribed for pain relief, and ~39% of the US population is expected to carry one of these phenotypes, suggesting that the population-level impact of these gene-drug interactions could be substantial.

SUBMITTER: St Sauver JL

PROVIDER: S-EPMC5533497 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Project description:BackgroundPatients with opioid use disorder (OUD) display an interindividual variability in their response to medications for opioid use disorder (MOUD). A genetic basis may explain the variability in this response. However, no consensus has been reached regarding which genetic variants significantly contribute to MOUD outcomes.ObjectivesThis systematic review aims to summarize genome-wide significant findings on MOUD outcomes and critically appraise the quality of the studies involved.MethodsDatabases searched from inception until August 21st, 2020 include: MEDLINE, Web of Science, EMBASE, CINAHL and Pre-CINAHL, GWAS Catalog and GWAS Central. The included studies had to be GWASs that assessed MOUD in an OUD population. All studies were screened in duplicate. The quality of the included studies was scored and assessed using the Q-Genie tool. Quantitative analysis, as planned in the protocol, was not feasible, so the studies were analyzed qualitatively.ResultsOur search identified 7292 studies. Five studies meeting the eligibility criteria were included. However, only three studies reported results that met our significance threshold of p ≤ 1.0 × 10-7. In total, 43 genetic variants were identified. Variants corresponding to CNIH3 were reported to be associated with daily heroin injection in Europeans, OPRM1, TRIB2, and ZNF146 with methadone dose in African Americans, EYS with methadone dose in Europeans, and SPON1 and intergenic regions in chromosomes 9 and 3 with plasma concentrations of S-methadone, R-methadone, and R-EDDP, respectively, in Han Chinese.LimitationsThe limitations of this study include not being able to synthesize the data in a quantitative way and a conservative eligibility and data collection model.ConclusionThe results from this systematic review will aid in highlighting significant genetic variants that can be replicated in future OUD pharmacogenetics research to ascertain their role in patient-specific MOUD outcomes. Systematic review registration number CRD42020169121.

Project description:BACKGROUND AND OBJECTIVES:Patients on hemodialysis frequently experience pain and may be particularly vulnerable to opioid-related complications. However, data evaluating the risks of opioid use in patients on hemodialysis are limited. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Using the US Renal Data System, we conducted a cohort study evaluating the association between opioid use (modeled as a time-varying exposure and expressed in standardized oral morphine equivalents) and time to first emergency room visit or hospitalization for altered mental status, fall, and fracture among 140,899 Medicare-covered adults receiving hemodialysis in 2011. We evaluated risk according to average daily total opioid dose (>60 mg, ?60 mg, and per 60-mg dose increment) and specific agents (per 60-mg dose increment). RESULTS:The median age was 61 years old, 52% were men, and 50% were white. Sixty-four percent received opioids, and 17% had an episode of altered mental status (15,658 events), fall (7646 events), or fracture (4151 events) in 2011. Opioid use was associated with risk for all outcomes in a dose-dependent manner: altered mental status (lower dose: hazard ratio, 1.28; 95% confidence interval, 1.23 to 1.34; higher dose: hazard ratio, 1.67; 95% confidence interval, 1.56 to 1.78; hazard ratio, 1.29 per 60 mg; 95% confidence interval, 1.26 to 1.33), fall (lower dose: hazard ratio, 1.28; 95% confidence interval, 1.21 to 1.36; higher dose: hazard ratio, 1.45; 95% confidence interval, 1.31 to 1.61; hazard ratio, 1.04 per 60 mg; 95% confidence interval, 1.03 to 1.05), and fracture (lower dose: hazard ratio, 1.44; 95% confidence interval, 1.33 to 1.56; higher dose: hazard ratio, 1.65; 95% confidence interval, 1.44 to 1.89; hazard ratio, 1.04 per 60 mg; 95% confidence interval, 1.04 to 1.05). All agents were associated with a significantly higher hazard of altered mental status, and several agents were associated with a significantly higher hazard of fall and fracture. CONCLUSIONS:Opioids were associated with adverse outcomes in patients on hemodialysis, and this risk was present even at lower dosing and for agents that guidelines have recommended for use.

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CYP2D6 phenotypes are associated with adverse outcomes related to opioid medications.

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