Sex Differences in Associations Between CYP2D6 Phenotypes and Response to Opioid Analgesics
Sex Differences in Associations Between CYP2D6 Phenotypes and Response to Opioid Analgesics
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DOI：
10.2147/pgpm.s239222
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发表时间：
2020-01-01
影响因子：
1.9
通讯作者：
St Sauver, Jennifer L.
中科院分区：
文献类型：
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作者：
Lopes, Guilherme S.;Bielinski, Suzette J.;St Sauver, Jennifer L.
背景：之前有几项小型研究调查了细胞色素 P450 2D6 (CYP2D6) 代谢与阿片类药物反应之间的关联。我们使用大量患者样本来研究 CYP2D6 表型和估计的 CYP2D6 酶活性评分与疼痛控制以及与可待因和曲马多使用相关的不良反应之间的关联。我们进行了额外的分析，以确定我们的结果在男性和女性中是否一致。方法：我们使用了 RIGHT 方案中 2,877 名参与者的数据，这些参与者在 2005 年 1 月 1 日至 2017 年 12 月 31 日期间服用了可待因和/或曲马多，并且在阿片类药物处方前 1 年内没有服用过 CYP2D6 抑制剂。 CYP2D6 表型类别分为四组：(1) 超快速和快速 (n = 61)、(2) 正常和中到正常 (n = 1,448)、(3) 中和中到差 (n = 1,175) 和 (4) 代谢状态较差 (n = 193)。阿片类药物相关的结果包括疼痛控制不佳或与药物使用相关的不良反应的迹象。我们使用逻辑回归对每个结果的风险进行建模，并根据年龄、性别、种族和民族进行调整。 结果：结果揭示了 CYP2D6 表型从差到超快和快速的趋势，其中不良反应的风险逐渐增加，疼痛控制不良的风险逐渐降低。这一趋势在女性（而非男性）参与者中达到了统计显着性。在正常和中等至正常代谢者中，相对于男性，更大比例的女性经历不良反应。讨论：我们重复并扩展了先前研究的结果，表明 CYP2D6 表型与阿片类药物反应之间存在关联。此外，观察到的关联在女性中比在男性中更强。我们建议在未来研究药物基因组学与药物反应之间的关联时考虑性别差异。
Background: Several small studies have previously investigated associations between the cytochrome P450 2D6 (CYP2D6) metabolism and response to opioids. We used a large sample of patients to study associations between CYP2D6 phenotypes and estimated CYP2D6 enzymatic activity scores with pain control and adverse reactions related to codeine and tramadol use. We conducted additional analyses to determine whether our results were consistent among men and women.Methods: We used data from 2,877 participants in the RIGHT Protocol who were prescribed codeine and/or tramadol between 01/01/2005 and 12/31/2017 and who were not prescribed CYP2D6 inhibitors within 1 year prior to the opioid prescription. CYP2D6 phenotype categories were condensed into four groups: (1) Ultra-rapid and Rapid (n = 61), (2) Normal and Intermediate to Normal (n = 1,448), (3) Intermediate and Intermediate to Poor (n = 1,175), and (4) Poor metabolizer status (n = 193). Opioid-related outcomes included indications of poor pain control or adverse reactions related to medication use. We modeled the risk of each outcome using logistic regression, adjusting for age, sex, race, and ethnicity.Results: The results revealed a trend from poor to ultra-rapid and rapid CYP2D6 phenotypes in which the risk of adverse reactions incrementally increased and the risk of poor pain control incrementally decreased. This trend reached statistical significance among female (but not male) participants. Among normal and intermediate to normal metabolizers, a larger proportion of women experienced adverse reactions relative to men.Discussion: We replicated and extended the findings of previous research indicating associations between CYP2D6 phenotypes and response to opioids. In addition, the observed associations were stronger in women than in men. We recommend sex differences to be factored in future research investigating associations between pharmacogenomics and response to medications.