Pain and Palliation Research Group, Medical Faculty, Norwegian University of Science and Technology, Trondheim, Norway Department of Oncology, Oslo University Hospital, Oslo, Norway Rehabilitation and Palliative Care Unit, National Cancer Institute, Milan, Italy The Royal Marsden Hospital, Fulham Road, London, UK Kliniken Essen-Mitte, Essen, Germany Department of Palliative Medicine, Stockholms Sjukhem Foundation, Stockhalm, Sweden Department of Oncology Pathology, Karolinska Intitute, Stockhalm, Sweden Palliative Care Unit, Valerio Grassi Hospice, Forlimpopoli, Italy Department of Palliative Medicine, RWTH Aachen University, Aachen, Germany Comprehensive Pain Center, University Hospital "Carl Gustav Carus", Dresden, Germany Palliative Care Unit, National University Hospital of Iceland, Reykjavik, Iceland Oncological Palliative Medicine, Oncology, Department Internal Medicine and Palliative Care Center, Cantonal Hospital, St. Gallen, Switzerland Department of Public Health University of Aberdeen, Aberdeen, UK Department of Anaesthesiology and Emergency Medicine, St. Olavs University Hospital, Trondheim, Norway Department of Oncology, St. Olavs University Hospital, Trondheim, Norway.
Pain. 2011 May;152(5):1139-1145. doi: 10.1016/j.pain.2011.01.040. Epub 2011 Mar 12.
Cancer pain patients need variable opioid doses. Preclinical and clinical studies suggest that opioid efficacy is related to genetic variability. However, the studies have small samples, findings are not replicated, and several candidate genes have not been studied. Therefore, a study of genetic variability with opioid doses in a large population using a confirmatory validation population was warranted. We recruited 2294 adult European patients using a World Health Organization (WHO) step III opioid and analyzed single nucleotide polymorphisms (SNPs) in genes with a putative influence on opioid mechanisms. The patients' mean age was 62.5 years, and the average pain intensity was 3.5. The patients' primary opioids were morphine (n=830), oxycodone (n=446), fentanyl (n=699), or other opioids (n=234). Pain intensity, time on opioids, age, gender, performance status, and bone or CNS metastases predicted opioid dose and were included as covariates. The patients were randomly divided into 1 development sample and 1 validation sample. None of 112 SNPs in the 25 candidate genes OPRM1, OPRD1, OPRK1, ARRB2, GNAZ, HINT1, Stat6, ABCB1, COMT, HRH1, ADRA2A, MC1R, TACR1, GCH1, DRD2, DRD3, HTR3A, HTR3B, HTR2A, HTR3C, HTR3D, HTR3E, HTR1, or CNR1 showed significant associations with opioid dose in both the development and the validation analyzes. These findings do not support the use of pharmacogenetic analyses for the assessed SNPs to guide opioid treatment. The study also demonstrates the importance of validating findings obtained in genetic association studies to avoid reporting spurious associations as valid findings. To elicit knowledge about new genes that influence pain and the need for opioids, strategies other than the candidate gene approach is needed.
癌症疼痛患者需要不同剂量的阿片类药物。临床前和临床研究表明，阿片类药物的疗效与遗传变异性有关。然而，这些研究样本量小，研究结果无法复制，并且有几个候选基因尚未研究。因此，有必要在一个大的人群中使用验证人群来研究与阿片类药物剂量相关的遗传变异性。我们招募了 2294 名欧洲成年患者，使用世界卫生组织（WHO）第三阶段阿片类药物进行研究，并分析了对阿片类药物机制有潜在影响的基因中的单核苷酸多态性（SNP）。患者的平均年龄为 62.5 岁，平均疼痛强度为 3.5。患者的主要阿片类药物为吗啡（n=830）、羟考酮（n=446）、芬太尼（n=699）或其他阿片类药物（n=234）。疼痛强度、使用阿片类药物的时间、年龄、性别、表现状态以及骨或中枢神经系统转移预测阿片类药物剂量，并作为协变量纳入。患者被随机分为 1 个开发样本和 1 个验证样本。在 25 个候选基因 OPRM1、OPRD1、OPRK1、ARRB2、GNAZ、HINT1、Stat6、ABCB1、COMT、HRH1、ADRA2A、MC1R、TACR1、GCH1、DRD2、DRD3、HTR3A、HTR3B、HTR2A、HTR3C、HTR3D、HTR3E、HTR1 或 CNR1 中，没有 112 个 SNP 与开发和验证分析中的阿片类药物剂量显著相关。这些发现不支持使用药物遗传学分析来指导阿片类药物治疗。该研究还表明，验证遗传关联研究中的发现对于避免报告虚假关联为有效发现非常重要。为了获得有关影响疼痛和阿片类药物需求的新基因的知识，需要采用候选基因方法以外的策略。
