Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin, WI 53226, USA.
Pharmacogenomics. 2009 Jul;10(7):1157-67. doi: 10.2217/pgs.09.64.
The use of medication in pain management currently involves empirical adjustment based on observed clinical outcome and the presence of adverse drug reactions. In this study, pharmacogenomics and therapeutic drug monitoring were used to evaluate the clinical effectiveness of genotyping chronic pain patients on analgesic therapy. It was hypothesized that patients who have inherited polymorphisms in CYP2D6 that make them poor or intermediate metabolizers of opioid medications would have higher steady-state concentrations of those opioids and may be more likely to experience adverse drug reactions.
MATERIALS & METHODS: In an attempt to investigate the relationship between the polymorphic enzymes, steady-state drug concentrations, therapeutic effects and side effects, 61 patients were clinically evaluated and genotyped, and drug concentrations were measured and outcomes analyzed. Samples were collected and DNA extracted from whole blood using a Puregene DNA isolation kit. CYP2D6 genotyping (*3, *4, *5, *6, *7, *8 and gene duplication) were carried out using Pyrosequencing. Steady-state plasma concentrations of methadone, oxycodone, hydrocodone and tramadol were determined by HPLC tandem mass spectrometry.
The results demonstrated the prevalence of CYP2D6 polymorphisms in the population undergoing pain management was not statistically different from the general population. The majority of the pain patients (54%) were extensive metabolizers; 41% were intermediate metabolizers and 5% poor metabolizers. Poor metabolizers in general tended to have the highest steady-state drug concentrations compared with extensive metabolizers (poor metabolizers > intermediate metabolizers > extensive metabolizers) although this wasn't statistically significant. Also, a relationship between oxycodone steady-state drug concentrations and pain relief was found. A total of 80% of patients reporting adverse drug reactions also had impaired CYP2D6 metabolism. The remaining 20% with adverse drug reactions had other cofactors (i.e., drug-drug interactions) that could explain the toxicity.
These results suggest that patient care may be improved by genotyping and following therapeutic drug concentrations. Benefits include increased efficiency in proper drug selection, dose optimization and minimization of adverse drug reactions to improve patient outcome and safety. In addition, this study clearly demonstrated a relationship between oxycodone steady-state drug concentrations and pain relief. Future large-scale prospective studies are needed to confirm the clinical value of using genetic information to guide pain management therapy.
目前在疼痛管理中使用药物治疗涉及根据观察到的临床结果和不良反应的存在进行经验性调整。在这项研究中，我们使用药物基因组学和治疗药物监测来评估对接受镇痛治疗的慢性疼痛患者进行基因分型的临床效果。研究假设，具有使阿片类药物代谢不良或中等代谢的 CYP2D6 遗传多态性的患者，其阿片类药物的稳态浓度会更高，并且更有可能出现不良反应。
为了研究多态性酶、稳态药物浓度、治疗效果和副作用之间的关系，对 61 名患者进行了临床评估和基因分型，并测量了药物浓度和分析了结果。使用 Puregene DNA 分离试剂盒从全血中采集和提取 DNA。使用 Pyrosequencing 进行 CYP2D6 基因分型（*3、*4、*5、*6、*7、*8 和基因重复）。通过 HPLC 串联质谱法测定美沙酮、羟考酮、氢可酮和曲马多的稳态血浆浓度。
结果表明，接受疼痛管理的人群中 CYP2D6 多态性的流行率与一般人群没有统计学差异。大多数疼痛患者（54%）为广泛代谢者；41%为中间代谢者，5%为不良代谢者。一般来说，与广泛代谢者相比，不良代谢者的稳态药物浓度最高（不良代谢者>中间代谢者>广泛代谢者），尽管这没有统计学意义。此外，还发现了羟考酮稳态药物浓度与疼痛缓解之间的关系。报告不良反应的患者中有 80%存在 CYP2D6 代谢受损。其余 20%出现不良反应的患者有其他协同因素（即药物-药物相互作用），这可以解释其毒性。
这些结果表明，通过基因分型和监测治疗药物浓度，可以改善患者的治疗效果。其益处包括提高药物选择、剂量优化的效率，并最大程度减少不良反应，以改善患者的预后和安全性。此外，本研究还清楚地表明了羟考酮稳态药物浓度与疼痛缓解之间的关系。需要进行大规模前瞻性研究以确认使用遗传信息指导疼痛管理治疗的临床价值。
