BACKGROUND:Postoperative pain management remains a challenge for clinicians due to unpredictable patient responses to opioid therapy. Some of this variability may result from single nucleotide polymorphisms (SNPs) of the human opioid mu-1 receptor (OPRM1) that modify receptor binding or signal transduction. The OPRM1 variant with the highest frequency is the A118G SNP. However, previous studies have produced inconsistent results regarding the clinical effects of A118G on opioid response. We hypothesized that measurement of serum opioid concentrations, in addition to determining total opioid consumption, may provide a more precise method of assessing the effects of A118G on analgesic response. The current study evaluated the relationship of analgesia, side effects, total hydrocodone consumption, quantitative serum hydrocodone and hydromorphone concentrations, and A118G SNP in postoperative patients following Cesarean section. METHODS:158 women scheduled for Cesarean section were enrolled prospectively in the study. The patients had bupivacaine spinal anesthesia for surgery and received intrathcal morphine with the spinal anesthetic or parenteral morphine for the first 24 hours after surgery. Thereafter, patients received hydrocodone/acetaminophen for postoperative pain control. On postoperative day 3, venous blood samples were obtained for OPRM1 A118G genotyping and serum opioid concentrations. RESULTS:131 (82.9%) of the subjects were homozygous for the 118A allele of OPRM1 (AA) and 27 (17.1%) carried the G allele (AG/GG). By regression analysis, pain relief was significantly associated with total hydrocodone dose in the AA group (P = 0.01), but not in the AG/GG group (P = 0.554). In contrast, there was no association between pain relief and serum hydrocodone concentration in either group. However, pain relief was significantly associated with serum hydromorphone concentration (a metabolite of hydrocodone) in the AA group (P = 0.004), but not in the AG/GG group (P = 0.724). Conversely, side effects were significantly higher (P < 0.04) in the AG/GG group (mean = 6.4) than in the AA group (mean = 4.4), regardless of adjustment for BMI, pain level, or total dose of hydrocodone. CONCLUSION:This study found a correlation between pain relief and total hydrocodone dose in patients homozygous for the 118A allele (AA) of the OPRM1 gene, but not in patients with the 118G allele (AG/GG). However, pain relief in 118A patients did not correlate with serum hydrocodone concentrations, but rather with serum hydromorphone levels, the active metabolite of hydrocodone. This suggests that pain relief with hydrocodone may be due primarily to hydromorphone. Although pain relief did not correlate with opioid dose in AG/GG patients, they had a higher incidence of opioid side effects. The correlations identified in this study may reflect the fact that serum opioid concentrations were measured directly, avoiding the inherent imprecision associated with relying solely on total opioid consumption as a determinant of opioid effectiveness. Thus, measurement of serum opioid concentrations is recommended when assessing the role of OPRM1 variants in pain relief. This study supports pharmacogenetic analysis of OPRM1 in conjunction with serum opioid concentrations when evaluating patient responses to opioid therapy.

译文

背景:由于患者对阿片类药物治疗的反应无法预测,术后疼痛管理仍然是临床医生面临的挑战。这种可变性中的某些可能是由于人类阿片样物质mu-1受体(OPRM1)的单核苷酸多态性(SNP)改变了受体结合或信号转导。频率最高的OPRM1型号是A118G SNP。但是,先前的研究在A118G对阿片样物质反应的临床效果方面产生不一致的结果。我们假设测量血清阿片类药物的浓度,除了确定阿片类药物的总消耗量外,还可以提供一种更精确的方法来评估A118G对镇痛作用的影响。本研究评估了剖宫产术后患者的镇痛,副作用,氢可酮总消耗量,血清氢可酮和氢吗啡酮定量浓度以及A118G SNP的关系。
方法:158名预定剖腹产的妇女被纳入研究对象。患者接受布比卡因脊柱麻醉以进行手术,并且在手术后的最初24小时内接受鞘内注射吗啡和脊髓麻醉剂或肠胃外吗啡。此后,患者接受氢可酮/对乙酰氨基酚进行术后疼痛控制。术后第3天,获得静脉血样本以进行OPRM1 A118G基因分型和血清阿片样物质浓度。
结果:131名受试者(82.9%)与OPRM1(AA)的118A等位基因是纯合的,其中27名(17.1%)带有G等位基因(AG / GG)。通过回归分析,在AA组中疼痛缓解与氢可酮的总剂量显着相关(P = 0.01),而在AG / GG组中则没有(P = 0.554)。相反,两组的疼痛缓解和血清氢可酮浓度之间均无关联。但是,AA组(P = 0.004)而血清氢吗啡酮浓度(氢可酮的代谢产物)与疼痛缓解显着相关(P = 0.004),而AG / GG组则没有(P = 0.724)。相反,无论BMI,疼痛程度或氢可酮总量如何调整,AG / GG组(平均= 6.4)的副作用均显着高于AA组(平均= 4.4)(P = 0.04)。
结论:本研究发现,对于OPRM1基因118A等位基因(AA)纯合的患者,止痛与总氢可酮剂量之间存在相关性,而对于118G等位基因(AG / GG)的患者而言,止痛与总氢可酮剂量之间没有相关性。然而,118A患者的疼痛缓解与血清氢可酮浓度无关,而与血清氢吗啡酮水平(氢可酮的活性代谢产物)相关。这表明氢可酮缓解疼痛可能主要归因于氢吗啡酮。尽管在AG / GG患者中疼痛缓解与阿片类药物剂量无关,但他们具有更高的阿片类药物副作用发生率。在这项研究中确定的相关性可能反映了直接测量血清阿片类药物浓度的事实,避免了仅依赖于总阿片类药物的消耗量来确定阿片类药物有效性的内在不精确性。因此,在评估OPRM1变异体在缓解疼痛中的作用时,建议测量血清阿片类药物的浓度。这项研究在评估患者对阿片类药物治疗的反应时,结合血清阿片类药物浓度支持OPRM1的药物遗传学分析。

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