Clinical Usefulness and evaluation of pharmacogenetics on the personalized therapy of opioid analgesics.

阿片类镇痛剂通过与μ-阿片受体(MOR)结合发挥其治疗作用。μ受体基因(OPRM1)已被鉴定出100多个变异体，其中包括至少20个引起氨基酸替换从而影响μ受体反应的多态突变。研究了OPRM1基因第1外显子A118G导致40位天冬氨酸替换为天冬氨酸的临床应用价值。118G等位基因在日本健康志愿者中的频率为41%，而在高加索人中的频率为10-20%。为了研究A118G基因突变的功能意义，对健康受试者和癌症患者进行了临床研究。我们发现，使用羟考酮或芬太尼治疗118GG的癌痛患者，其恶心、呕吐和嗜睡等不良反应的发生率低于118AA，尽管在痛阈值上没有明显差异。此外，我们还研究了μ受体部分激动剂丁丙诺啡对118GG或118AA的健康志愿者的影响。虽然两组丁丙诺啡的药代动力学相似，但118GG组痛阈值敏感性和嗜睡、疲劳、恶心、欣快感VAS评分显著低于对照组。OPRM1c.118位基因多态性可能影响μ阿片受体的敏感性，可能成为阿片类疼痛治疗中有用的生物标志物。

Opioid analgesics exert their therapeutic effects by binding to theμ-opioid receptor(MOR). More than 100 variants in theμ-receptor gene(OPRM1) have been identified, which include at least 20 polymorphic mutants that cause amino acid substitutions, thereby affecting the response of theμ-receptor. The clinical usefulness of A118G in exon-1 of the OPRM1 gene which result in an amino acid substitution from asparagine to aspartate at position 40(Asn40Asp) was studied. The allele frequency of 118G is 41% in our Japanese healthy-volunteers, on the other hand, 10-20% of Caucasian is reported. In order to examine the functional significance of the A118G gene mutation, clinical studies have been conducted in both healthy subjects and cancer patients. We have founded that cancer pain patients with 118GG who were treated with oxycodone or fentanyl were observed less frequency of adverse reactions including nausea, vomiting and sleepiness than that with 118AA, although no clear difference was observed on the pain threshold. Moreover, we have studied the effects of buprenorphine,μreceptor partial agonist, in healthy volunteers with 118GG or 118AA. Although pharmacokinetics of buprenorphine of the two groups were similar, 118GG group were significantly lower sensitiveness of pain threshold and VAS ratings of sleepiness, fatigue, nausea and euphoria. The genetic polymorphism of OPRM1 c. 118 position may affect the sensitivity ofμopioid receptor and may become a useful biomarker in the opioid pain therapy.