Solhaug Vigdis, Molden Espen
Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.
Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway; Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway.
Scand J Pain. 2017 Oct;17:193-200. doi: 10.1016/j.sjpain.2017.09.009. Epub 2017 Oct 17.
As pain is often a comorbid condition, many patients use opioid analgesics in combination with several other drugs. This implies a generally increased risk of drug interactions, which along with inherent pharmacogenetic variability and other factors may cause differences in therapeutic response of opioids.
To provide an overview of interactions and pharmacogenetic variability of relevance for individual differences in effect and tolerability of opioid analgesics, which physicians and other healthcare professionals should be aware of in clinical practice.
The article was based on unsystematic searches in PubMed to identify literature highlighting the clinical impact of drug interactions and pharmacogenetics as sources of variable response of opioid analgesics.
Cytochrome P450 (CYP)-mediated metabolism is an important process for both clinically relevant interactions and pharmacogenetic variability of several opioids. Concomitant use of CYP inhibitors (e.g. paroxetine, fluoxetine and bupropion) or inducers (e.g. carbamazepine, phenobarbital and phenytoin) could counteract the clinical effect or trigger side effects of analgesics in the same manner as genetically determined differences in CYP2D6-mediated metabolism of many opioids. Moreover, combination treatment with drugs that inhibit or induce P-glycoprotein (ABCB1), a blood-brain barrier efflux transporter, may alter the amount ('dose') of opioids distributed to the brain. At the pharmacodynamic level, it is crucial to be aware of the potential risk of interaction causing serotonergic syndrome when combining opioids and serotonergic drugs, in particular antidepressants inhibiting serotonin reuptake (SSRIs and SNRIs). Regarding pharmacogenetics at the receptor level of pain treatment, the knowledge is currently scarce, but an allelic variant of the μ1 opioid receptor (OPRM1) gene has been associated with higher dosage requirement to achieve analgesia.
Drug interactions and pharmacogenetic differences may lead to therapeutic failure or serious side effects of opioid analgesics. Many interactions involve combinations with antidepressants and antiepileptics, which are highly relevant drugs in patients suffering from pain. To prevent unfavourable drug interactions it is important that clinicians pay close attention and use electronic drug interaction checkers when treatments are initiated or discontinued. For the management of issues related to pharmacogenetic differences, blood-based CYP genotyping is available as routine test at many laboratories, and provide a valuable tool for proper choice of drugs and doses for treatment of pain and other diseases.
由于疼痛常为一种共病状况，许多患者会将阿片类镇痛药与其他几种药物联合使用。这意味着药物相互作用的总体风险增加，而这与内在的药物遗传学变异性及其他因素一起，可能导致阿片类药物治疗反应的差异。
概述与阿片类镇痛药效应和耐受性个体差异相关的相互作用及药物遗传学变异性，医生和其他医疗保健专业人员在临床实践中应了解这些内容。
本文基于在PubMed中进行的非系统检索，以识别突出药物相互作用和药物遗传学作为阿片类镇痛药可变反应来源的临床影响的文献。
细胞色素P450（CYP）介导的代谢对于几种阿片类药物的临床相关相互作用和药物遗传学变异性而言都是一个重要过程。同时使用CYP抑制剂（如帕罗西汀、氟西汀和安非他酮）或诱导剂（如卡马西平、苯巴比妥和苯妥英）可能抵消镇痛药的临床效果或引发副作用，这与许多阿片类药物CYP2D6介导的代谢中由基因决定的差异的作用方式相同。此外，与抑制或诱导P-糖蛋白（ABCB1，一种血脑屏障外排转运蛋白）的药物联合治疗，可能会改变分布到大脑的阿片类药物的量（“剂量”）。在药效学层面，必须意识到联合使用阿片类药物和5-羟色胺能药物，特别是抑制5-羟色胺再摄取的抗抑郁药（SSRIs和SNRIs）时，相互作用导致5-羟色胺能综合征的潜在风险。关于疼痛治疗受体水平的药物遗传学，目前了解较少，但μ1阿片受体（OPRM1）基因的一个等位基因变体与达到镇痛所需的更高剂量相关。
药物相互作用和药物遗传学差异可能导致阿片类镇痛药治疗失败或严重副作用。许多相互作用涉及与抗抑郁药和抗癫痫药的联合使用，而这些药物在疼痛患者中是高度相关的药物。为防止不良药物相互作用，临床医生在开始或停止治疗时密切关注并使用电子药物相互作用检查器非常重要。对于处理与药物遗传学差异相关的问题，许多实验室可将基于血液的CYP基因分型作为常规检测，这为正确选择治疗疼痛和其他疾病的药物及剂量提供了一个有价值的工具。
