Bossard Anne-Elisabeth, Guirimand Frédéric, Fletcher Dominique, Gaude-Joindreau Valérie, Chauvin Marcel, Bouhassira Didier
Centre d'Evaluation et de Traitement de la Douleur et Service d'Anesthésie Réanimation, Chirurgicale Hôpital Ambroise Paré, 92104 Boulogne, France.
Pain. 2002 Jul;98(1-2):47-57. doi: 10.1016/s0304-3959(01)00472-9.
Experimental studies in animals have suggested that a combination of morphine and N-methyl-D-aspartate (NMDA) receptor antagonists may have additive or synergistic analgesic effects. To further study the nature of the interaction between these two classes of analgesic agents, we analyzed the effects of morphine, ketamine and their combination on electrophysiological recordings of the nociceptive flexion RIII reflex in 12 healthy volunteers. Morphine (0.1 mg/kg), ketamine (0.1 mg/kg followed by 4 microg/kg/min) or their combination were administered intravenously according to a double-blind, placebo controlled and cross-over design. The RIII reflex was recorded from the biceps femoris and elicited by electrical stimulation of the sural nerve. The effects of the drugs were tested on: (1) the stimulus-response curves of the reflex up to the tolerance threshold (frequency of stimulation: 0.1Hz); (2) the progressive increase of the reflex and painful sensations (i.e. wind-up phenomenon) induced by a series of 15 electrical stimuli at a frequency of 1Hz (intensity: 20% above threshold). The stimulus-response curve of the nociceptive RIII reflex was significantly reduced after injection of a combination of ketamine and morphine, but was not modified when placebo or each of the active drugs was administered alone. The wind-up of the RIII reflex and painful sensation was not significantly altered after the injection of placebo, ketamine, morphine or their combination. In conclusion, the present electrophysiological results in humans demonstrate a synergistic interaction between morphine and ketamine, which tends to confirm the interest of using this type of combination in the clinical context. The differential effects observed on the recruitment curve and wind-up indicate, however, that the mechanisms of the interaction between opiates and NMDA receptor antagonists are not univocal but depend on the modality of activation of the nociceptive afferents.
动物实验研究表明，吗啡与N-甲基-D-天冬氨酸（NMDA）受体拮抗剂联合使用可能具有相加或协同的镇痛作用。为了进一步研究这两类镇痛药物之间相互作用的本质，我们分析了吗啡、氯胺酮及其联合用药对12名健康志愿者伤害性屈肌RIII反射电生理记录的影响。根据双盲、安慰剂对照和交叉设计，静脉注射吗啡（0.1mg/kg）、氯胺酮（0.1mg/kg，随后以4μg/kg/min的速度给药）或它们的组合。从股二头肌记录RIII反射，并通过电刺激腓肠神经诱发。测试药物对以下方面的影响：（1）直至耐受阈值的反射刺激-反应曲线（刺激频率：0.1Hz）；（2）由一系列15次频率为1Hz的电刺激（强度：高于阈值20%）引起的反射和疼痛感觉的逐渐增加（即累加现象）。注射氯胺酮和吗啡的组合后，伤害性RIII反射的刺激-反应曲线显著降低，但单独给予安慰剂或每种活性药物时未改变。注射安慰剂、氯胺酮、吗啡或它们的组合后，RIII反射的累加和疼痛感觉没有显著改变。总之，目前在人体中的电生理结果表明吗啡和氯胺酮之间存在协同相互作用，这倾向于证实这种联合用药在临床环境中的应用价值。然而，在募集曲线和累加方面观察到的不同效应表明，阿片类药物与NMDA受体拮抗剂之间相互作用的机制并非单一，而是取决于伤害性传入神经的激活方式。
