Oertel Bruno G, Schmidt Ronald, Schneider Andreas, Geisslinger Gerd, Lötsch Jörn
pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
Pharmacogenet Genomics. 2006 Sep;16(9):625-36. doi: 10.1097/01.fpc.0000220566.90466.a2.
To investigate whether OPRM1 118A>G polymorphism affects analgesic and respiratory depressive effects of alfentanil and assess its role for the therapeutic range of alfentanil.
In an open-label, single-occasion design, 10 non-carriers, four heterozygous and six homozygous carriers of the variant OPRM1 118G allele received a computerized infusion of alfentanil to achieve target effect-site concentrations of 0, 33.33, 66.67 and 100 ng/ml. At each concentration level, analgesia was assessed by means of electrically and chemically induced pain, and respiratory depression was quantified by hypercapnic challenge and breathing frequency.
The relationship between the percent change of tolerance to electrical stimuli and measured alfentanil concentrations, described by power models, was flatter in carriers of the 118G variant allele than in non-carriers, indicating decreased opioid analgesia (P<0.05). For chemically induced pain, a flatter analgesia versus concentration relationship was found only for homozygous carriers of the 118G allele (P<0.05). The relationship between the percent changes in respiratory parameters was significantly flatter (P<0.01) only in homozygous carriers as compared to heterozygous carriers and non-carriers of the 118G allele. Higher alfentanil concentrations were needed in homozygous carriers as compared to wild-type subjects (2-4 times) to produce the same degree of analgesia, whereas 10-12 times higher alfentanil concentrations were needed to produce the same degree of respiratory depression.
OPRM1 118A>G polymorphism affects both analgesic and respiratory depressive effects of alfentanil. However, while the analgesic effects are already partly decreased in heterozygous carriers, depending on the pain model, the respiratory depressive effects are decreased in homozygous carriers of the variant 118G allele. The therapeutic range of alfentanil was only broadened in homozygous carriers.
研究阿片受体μ1基因（OPRM1）118A>G多态性是否影响阿芬太尼的镇痛及呼吸抑制作用，并评估其在阿芬太尼治疗范围内的作用。
采用开放标签、单次给药设计，10名非携带者、4名杂合子携带者及6名纯合子携带者（均携带OPRM1 118G变异等位基因）接受阿芬太尼的电脑控制输注，以达到0、33.33、66.67和100 ng/ml的目标效应室浓度。在每个浓度水平，通过电刺激和化学刺激诱导疼痛来评估镇痛效果，并通过高碳酸血症激发试验和呼吸频率对呼吸抑制进行量化。
用幂函数模型描述的对电刺激耐受性变化百分比与测得的阿芬太尼浓度之间的关系，在118G变异等位基因携带者中比非携带者更平缓，表明阿片类药物镇痛作用降低（P<0.05）。对于化学诱导疼痛，仅在118G等位基因纯合子携带者中发现镇痛与浓度之间的关系更平缓（P<0.05）。与118G等位基因杂合子携带者和非携带者相比，仅在纯合子携带者中，呼吸参数变化百分比之间的关系显著更平缓（P<0.01）。与野生型受试者相比，纯合子携带者需要更高的阿芬太尼浓度（2 - 4倍）才能产生相同程度的镇痛作用，而产生相同程度的呼吸抑制则需要高10 - 12倍的阿芬太尼浓度。
OPRM1 118A>G多态性影响阿芬太尼的镇痛和呼吸抑制作用。然而，虽然杂合子携带者的镇痛作用已部分降低，但取决于疼痛模型，118G变异等位基因纯合子携带者的呼吸抑制作用降低。阿芬太尼的治疗范围仅在纯合子携带者中有所拓宽。
