<em>CYP2D6</em> phenotypes are associated with adverse outcomes related to opioid medications

Abstract

BackgroundVariation 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.Materials and methodsWe 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.ResultsOverall, 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).ConclusionOur 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.

<p>Sex Differences in Associations Between CYP2D6 Phenotypes and Response to Opioid Analgesics</p>

“…Our results are consistent with the results of previous research suggesting associations between CYP2D6 phenotypes and response to opioid use. 10 However, the proportion of individuals experiencing adverse reactions and poor pain control among those with CYP2D6 poor and ultra-rapid metabolizer phenotypes differed from the proportions reported by previous research. For example, VanderVaart et al 8 reported that 100% of CYP2D6 poor metabolizers experienced no analgesia, whereas 67% of ultra-rapid metabolizers reported adverse reactions.…”

“…To address differences in CYP2D6 classification between studies, we also investigated associations between CYP2D6 activity scores and response to opioids, and found that these associations corroborated the results using CYP2D6 phenotype categorizations reported in the current study and in previous research. 8,10 However, we note that higher CYP2D6 activity scores were not significantly associated with adverse reactions or poor pain control. Despite our large sample size, the relatively small number of outcomes may have resulted in an inability to detect a statistically significant association.…”

“…9 Our own investigations of patient response related to codeine, tramadol, hydrocodone, and oxycodone in a cohort of 257 patients found that more than 30% of those with a CYP2D6 poor or ultra-rapid phenotype experienced either adverse reactions or lack of pain relief related to opioid use. 10 In short, these results suggest poor pain control in individuals with CYP2D6 poor metabolizer status and more adverse reactions in individuals with CYP2D6 ultra-rapid metabolizer status.…”

“…First, low event rates and small sample sizes result in a large degree of effect estimate uncertainty, making the findings difficult to generalize to the general population. [8][9][10] In addition, our previous research collapsed ultra-rapid metabolizers and poor metabolizers when comparing to normal metabolizers due to phenotype rarity, limiting the interpretation of results. 10 Third, previous research has used different classifications of CYP2D6 phenotypes, such that results may not be comparable across studies.…”

“…[8][9][10] In addition, our previous research collapsed ultra-rapid metabolizers and poor metabolizers when comparing to normal metabolizers due to phenotype rarity, limiting the interpretation of results. 10 Third, previous research has used different classifications of CYP2D6 phenotypes, such that results may not be comparable across studies. [11][12][13] Fourth, pain relief and adverse reactions related to opioid medications occur differently in men and women, but very few studies have investigated sex differences in response to opioids.…”