Gabapentin enhances the analgesic effect of morphine in healthy volunteers
Gabapentin enhances the analgesic effect of morphine in healthy volunteers
复制标题
DOI：
10.1097/00000539-200007000-00035
复制
发表时间：
2000-07-01
影响因子：
5.7
通讯作者：
Mikus, G
中科院分区：
文献类型：
--
作者：
Eckhardt, K;Ammon, S;Mikus, G
治疗剧烈疼痛最有效的药物是阿片类镇痛药。然而，由于疼痛增加和耐受性发展，它们对神经性疼痛和慢性疼痛的作用减弱，因此其使用受到限制。加巴喷丁 (GBP) 在慢性疼痛的实验模型和神经性疼痛的临床研究中均有效。因此，我们在一项随机、安慰剂对照、双盲研究中研究了 GBP 和吗啡在 12 名健康男性志愿者中的药效学和药代动力学相互作用。上午 8:00 给予吗啡（60 mg，控释）或安慰剂，上午 10:00 给予 GBP（600 mg）或安慰剂，从而通过冷压试验比较安慰剂 + GBP（600 mg）与安慰剂 + 安慰剂以及吗啡（60 mg）+ GBP 与吗啡 + 安慰剂的镇痛效果。通过使用视觉模拟量表评估副作用的持续时间和强度。通过疼痛耐受性曲线下面积的变化（h x %；药物1前0%基线）来评估镇痛效果。与安慰剂 + 安慰剂（4.7% x h，95% CI：-16.7 至 26.1）相比，安慰剂 + GBP（18.9% x h，95% 置信区间 [CI]：-2.5 至 40.3）没有表现出任何显着的镇痛效果。与吗啡+ GBP 组合（75.5% x h，95% CI：54.0-96.9）与吗啡+安慰剂（40.6% x h，95% CI：19.2-62.0）相比，观察到疼痛耐受性显着增加。安慰剂+GBP后观察到的不良事件与安慰剂+安慰剂相比没有显着差异。吗啡+安慰剂会导致预期的阿片类药物介导的副作用。与安慰剂 + 安慰剂相比，它们明显更明显，但与吗啡 + GBP 组合相比没有显着差异。关于吗啡及其葡萄糖醛酸苷的药代动力学变量，吗啡+安慰剂与吗啡+GBP之间没有观察到显着差异，而GBP曲线下面积（43.9+/-5.3 vs 63.4+/-16.2mu.h(-1).mL(-1)，P<0.05）显着增加，表观口服清除率（230.8+/-29.4）当同时给予吗啡时，GBP 的 mL/min vs 178 +/- 97.9 mL/min，P = 0.06）和表观肾清除率（86.9 +/- 20.6 vs 73.0 +/- 24.2 mL/min，P = 0.067）降低。这些结果表明药代动力学相互作用有两个不同的位点——一个在吸收水平，另一个在消除水平。我们的研究揭示了吗啡和 GBP 之间的药效学和药代动力学相互作用，导致吗啡 + GBP 的镇痛效果增强。这些结果和 GBP 良好的耐受性应该有利于研究吗啡和 GBP 联合治疗严重疼痛的临床相关性的临床试验。
The most effective group of drugs for the treatment of severe pain is opioid analgesics. Their use, however, is limited by decreased effects in neuropathic and chronic pain as a result of increased pain and development of tolerance. Gabapentin (GBP) is effective in both experimental models of chronic pain and clinical studies of neuropathic pain. Therefore, we investigated, in a randomized, placebo-controlled, double-blinded study, the pharmacodynamic and pharmacokinetic interaction of GBP and morphine in 12 healthy male volunteers. Morphine (60 mg, controlled release) or placebo was administered at 8:00 AM, and GBP (600 mg) or placebo was administered at 10:00 AM, thus comparing the analgesic effect of placebo + GBP (600 mg) with placebo + placebo and morphine (60 mg) + GBP in comparison to morphine plus placebo by using the cold presser test. The duration and intensity of the side effects were assessed by using visual analog scales. The analgesic effect was evaluated by the change in the area under the curve (h x %; 0% baseline before Medication 1) of pain tolerance. Placebo + GBP (18.9% x h, 95% confidence interval [CI]: -2.5 to 40.3) did not present any significant analgesic effect compared with placebo + placebo (4.7% x h, 95% CI: -16.7 to 26.1). A significant increase in pain tolerance was observed comparing the combination of morphine and GBP (75.5% x h, 95% CI: 54.0-96.9) with morphine + placebo (40.6% x h, 95% CI: 19.2-62.0). The observed adverse events after placebo + GBP were not significantly different compared with placebo + placebo. Morphine + placebo led to the expected opioid-mediated side effects. They were significantly more pronounced compared with placebo + placebo but did not differ significantly compared with the combination of morphine + GBP. Concerning the pharmacokinetic variables of morphine and its glucuronides, no significant difference between morphine + placebo and morphine + GBP was observed, whereas the area under the curve of GBP (43.9 +/- 5.3 vs 63.4 +/- 16.2 mu . h(-1) . mL(-1), P < 0.05) significantly increased, and apparent oral clearance (230.8 +/- 29.4 mL/min vs 178 +/- 97.9 mL/min, P = 0.06) and apparent renal clearance (86.9 +/- 20.6 vs 73.0 +/- 24.2 mL/min, P = 0.067) of GBP decreased when morphine was administered concomitantly. These results suggest two different sites for the pharmacokinetic interaction-one at the level of absorption and the other at the level of elimination. Our study reveals both a pharmacodynamic and pharmacokinetic interaction between morphine and GBP, leading to an increased analgesic effect of morphine + GBP. These results and the good tolerability of GBP should favor clinical trials investigating the clinical relevance of the combination of morphine and GBP for treating severe pain.