Lopes Guilherme S, Bielinski Suzette J, Moyer Ann M, Black Iii John Logan, Jacobson Debra J, Jiang Ruoxiang, Larson Nicholas B, St Sauver Jennifer L
Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
Pharmgenomics Pers Med. 2020 Mar 13;13:71-79. doi: 10.2147/PGPM.S239222. eCollection 2020.
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.
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.
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.
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.
此前已有多项小型研究探讨了细胞色素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，研究CYP2D6表型及估计的CYP2D6酶活性评分与可待因和曲马多使用相关的疼痛控制及不良反应之间的关联。我们还进行了额外分析，以确定我们的结果在男性和女性中是否一致。
我们使用了RIGHT方案中2877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日期间被开具了可待因和/或曲马多处方，且在阿片类药物处方前1年内未被开具CYP2D6抑制剂。CYP2D6表型类别被浓缩为四组：（1）超快代谢型和快速代谢型（n = 61），（2）正常代谢型和中间代谢型至正常代谢型（n = 1448），（3）中间代谢型和中间代谢型至慢代谢型（n = 1175），以及（4）慢代谢型状态（n = 193）。阿片类药物相关结局包括疼痛控制不佳的迹象或与药物使用相关的不良反应。我们使用逻辑回归对每个结局的风险进行建模，并对年龄、性别、种族和民族进行了调整。
结果显示，从慢代谢型到超快代谢型和快速代谢型的CYP2D6表型呈现出一种趋势，即不良反应风险逐渐增加，疼痛控制不佳的风险逐渐降低。这种趋势在女性参与者中具有统计学意义（在男性参与者中则没有）。在正常代谢型和中间代谢型至正常代谢型者中，女性发生不良反应的比例高于男性。
我们重复并扩展了先前研究的结果，这些结果表明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，应考虑性别差异。
