Oxycodone is a widely used opioid for the management of chronic pain. Analgesic effects observed following the administration of oxycodone are mediated mostly by agonistic effects on the μ-opioid receptor. Wide inter-subject variability observed in oxycodone efficacy could be explained by polymorphisms in the gene coding for the μ-opioid receptor (OPRM1). In humans, oxycodone is converted into several metabolites, particularly into oxymorphone, an active metabolite with potent μ-opioid receptor agonist activity. The CYP2D6 enzyme is principally responsible for the conversion of oxycodone to oxymorphone. The CYP2D6 gene is highly polymorphic with encoded protein activities, ranging from non-functioning to high-functioning enzymes. Several pharmacogenetic studies have shown the importance of CYP2D6-mediated conversion of oxycodone to oxymorphone for analgesic efficacy. Pharmacogenetic testing could optimize oxycodone therapy and help achieve adequate pain control, avoiding harmful side effects. However, the most recent Clinical Pharmacogenetics Implementation Consortium guidelines fell short of recommending pharmacogenomic testing for oxycodone treatment. In this review, we (1) analyze pharmacogenomic and drug-interaction studies to delineate the association between CYP2D6 activity and oxycodone efficacy, (2) review evidence from CYP3A4 drug-interaction studies to untangle the nature of oxycodone metabolism and its efficacy, (3) report on the current knowledge linking the efficacy of oxycodone to OPRM1 variants, and (4) discuss the potential role of CYP2D6 brain expression on the local formation of oxymorphone. In conclusion, we opine that pharmacogenetic testing, especially for CYP2D6 with considerations of phenoconversion due to concomitant drug administration, should be appraised to improve oxycodone efficacy.

中文翻译：

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CYP2D6 功能活性对羟考酮在疼痛治疗中疗效的贡献：遗传多态性、表型转化和组织选择性代谢

羟考酮是一种广泛使用的阿片类药物，用于治疗慢性疼痛。施用羟考酮后观察到的镇痛作用主要是通过对μ-阿片受体的激动作用介导的。羟考酮功效中观察到的广泛受试者间差异可以通过编码μ-阿片受体（OPRM1）的基因多态性来解释。在人体中，羟考酮转化为多种代谢物，特别是羟吗啡酮，这是一种具有有效μ阿片受体激动剂活性的活性代谢物。CYP2D6 酶主要负责将羟考酮转化为羟吗啡酮。CYP2D6基因具有高度多态性，编码的蛋白质活性范围从无功能酶到高功能酶。多项药物遗传学研究表明 CYP2D6 介导的羟考酮转化为羟吗啡酮对于镇痛功效的重要性。药物遗传学测试可以优化羟考酮治疗并帮助实现充分的疼痛控制，避免有害的副作用。然而，最新的临床药物遗传学实施联盟指南并未推荐羟考酮治疗的药物基因组学测试。在本综述中，我们 (1) 分析药物基因组学和药物相互作用研究，以描述 CYP2D6 活性与羟考酮功效之间的关联，(2) 回顾 CYP3A4 药物相互作用研究的证据，以阐明羟考酮代谢的性质及其功效，(3 ) 报告目前将羟考酮功效与OPRM1变体联系起来的知识，以及 (4) 讨论 CYP2D6 大脑表达对羟吗啡酮局部形成的潜在作用。总之，我们认为应该评估药物遗传学检测，特别是CYP2D6检测，并考虑伴随给药引起的表型转化，以提高羟考酮疗效。