Skarke Carsten, Darimont Jutta, Schmidt Helmut, Geisslinger Gerd, Lötsch Jörn
pharmazentrum frankfurt, Institute of Clinical Pharmacology, Johann Wolfgang Goethe University, Germany.
Clin Pharmacol Ther. 2003 Jan;73(1):107-21. doi: 10.1067/mcp.2003.5.
Our objective was to quantify the extent and time course of the effects of morphine-6-glucuronide and morphine on pain threshold, pain tolerance, pupil diameter, and side effects.
In a double-blind, placebo-controlled, randomized, 3-way crossover study, 12 healthy volunteers (6 men and 6 women) received 63 to 112 mg of morphine-6-glucuronide or 26 to 66 mg of morphine as an intravenous bolus, followed by an infusion of the same medication for 1.8 to 6.4 hours. Analgesia was assessed every 30 minutes for up to 16 hours by means of transcutaneous electrical stimulation (sine wave, 5 Hz; intensity, 0-9.99 mA). Pupil diameter and side effects were recorded concomitantly.
At the administered doses, morphine-6-glucuronide and morphine had comparable effects on pain tolerance, pupil diameter, and side effects. The delay between the time course of the plasma concentrations and the time course of the effects was longer for morphine-6-glucuronide than for morphine (transfer half-life, 8.2 hours versus 2.6 hours for pain tolerance and 7.7 hours versus 2.8 hours for pupil diameter). The slope of the linear concentration versus effect relationship for pain tolerance was flatter for morphine-6-glucuronide than for morphine (0.05% versus 0.6% increase in pain tolerance per nanomole per liter of morphine-6-glucuronide and morphine at effect site, respectively). Morphine-6-glucuronide was less potent than morphine in producing pupil constriction (mean concentration at half-maximum effect, 745 nmol/L versus 26.4 nmol/L for morphine-6-glucuronide and morphine, respectively). In carriers of the mutated G118 allele of the mu-opioid receptor, the potency of the pupil-constricting effects of morphine-6-glucuronide and morphine was significantly smaller, and carriers of the G118 allele reported less nausea and vomited less often after administration of morphine-6-glucuronide.
Morphine-6-glucuronide clearly produced analgesic effects in healthy volunteers. However, the high amounts of systemic morphine-6-glucuronide needed to produce the same effects as morphine suggest that morphine-6-glucuronide barely contributes to the central nervous opioid effects after administration of analgesic doses of morphine.
我们的目的是量化吗啡 - 6 - 葡萄糖醛酸苷和吗啡对痛阈、疼痛耐受性、瞳孔直径及副作用影响的程度和时间进程。
在一项双盲、安慰剂对照、随机、三向交叉研究中，12名健康志愿者（6名男性和6名女性）静脉推注63至112毫克吗啡 - 6 - 葡萄糖醛酸苷或26至66毫克吗啡，随后输注相同药物1.8至6.4小时。每隔30分钟通过经皮电刺激（正弦波，5赫兹；强度，0 - 9.99毫安）评估长达16小时的镇痛效果。同时记录瞳孔直径和副作用。
在所给剂量下，吗啡 - 6 - 葡萄糖醛酸苷和吗啡对疼痛耐受性、瞳孔直径及副作用的影响相当。与吗啡相比，吗啡 - 6 - 葡萄糖醛酸苷血浆浓度的时间进程与效应的时间进程之间的延迟更长（转移半衰期，疼痛耐受性方面分别为8.2小时和2.6小时，瞳孔直径方面分别为7.7小时和2.8小时）。吗啡 - 6 - 葡萄糖醛酸苷的疼痛耐受性线性浓度 - 效应关系斜率比吗啡更平缓（效应部位每纳摩尔每升吗啡 - 6 - 葡萄糖醛酸苷和吗啡引起的疼痛耐受性增加分别为0.05%和0.6%）。吗啡 - 6 - 葡萄糖醛酸苷在引起瞳孔收缩方面的效力低于吗啡（半数最大效应时的平均浓度，吗啡 - 6 - 葡萄糖醛酸苷和吗啡分别为745纳摩尔/升和26.4纳摩尔/升）。在μ - 阿片受体G118等位基因突变携带者中，吗啡 - 6 - 葡萄糖醛酸苷和吗啡的瞳孔收缩效应效力显著较小，且G118等位基因携带者在给予吗啡 - 6 - 葡萄糖醛酸苷后报告的恶心较少且呕吐频率较低。
吗啡 - 6 - 葡萄糖醛酸苷在健康志愿者中明显产生了镇痛作用。然而，产生与吗啡相同效果所需的大量全身性吗啡 - 6 - 葡萄糖醛酸苷表明，在给予镇痛剂量的吗啡后，吗啡 - 6 - 葡萄糖醛酸苷对中枢神经系统阿片类效应的贡献微乎其微。
