Koppert Wolfgang, Sittl Reinhard, Scheuber Karin, Alsheimer Monika, Schmelz Martin, Schüttler Jürgen
Department of Anesthesiology, University Clinic of Erlangen, Germany.
Anesthesiology. 2003 Jul;99(1):152-9. doi: 10.1097/00000542-200307000-00025.
Experimental studies and clinical observations suggest a possible role for opioids to induce pain and hyperalgesia on withdrawal. The authors used a new experimental pain model in human skin to determine the time course of analgesic and hyperalgesic effects of the mu-receptor agonist remifentanil alone or in combination with the N-methyl-D-aspartate-receptor antagonist S-ketamine or the alpha(2)-receptor agonist clonidine.
Thirteen volunteers were enrolled in this randomized, double-blind, placebo-controlled study. Transcutaneous electrical stimulation at a high current density (2 Hz, 67.3 +/- 16.8 mA, mean +/- SD) induced acute pain (numerical 11-point rating scale: 5-6 out of 10) and stable areas of mechanical hyperalgesia to punctate stimuli and touch (allodynia). The magnitude of pain and area of hyperalgesia were assessed before, during, and after drug infusion (remifentanil at 0.1 microg x kg-1 x min-1 and S-ketamine at 5 microg x kg-1 x min-1 over a period of 30 min, respectively; clonidine infusion at 2 microg/kg for 5 min).
Remifentanil reduced pain and areas of punctate hyperalgesia during infusion. In contrast, postinfusion pain and hyperalgesia were significantly higher than control. During infusion of S-ketamine, pain and hyperalgesia decreased and gradually normalized after infusion. When given in combination, S-ketamine abolished postinfusion increase of punctate hyperalgesia but did not reduce increased pain ratings. Clonidine alone did not significantly attenuate pain or areas of hyperalgesia. However, when given in combination with remifentanil, clonidine attenuated postinfusion increase of pain ratings.
Opioid-induced postinfusion hyperalgesia could be abolished by S-ketamine, suggesting an N-methyl-d-aspartate-receptor mechanism. In contrast, elevated pain ratings after infusion were not reduced by ketamine but were alleviated by the alpha(2)-receptor agonist clonidine. The results of this study suggest different mechanisms of opioid-induced postinfusion antianalgesia and secondary hyperalgesia.
实验研究和临床观察表明，阿片类药物在戒断时可能会诱发疼痛和痛觉过敏。作者使用一种新的人体皮肤实验性疼痛模型，以确定μ受体激动剂瑞芬太尼单独使用或与N-甲基-D-天冬氨酸受体拮抗剂S-氯胺酮或α₂受体激动剂可乐定联合使用时镇痛和痛觉过敏作用的时间进程。
13名志愿者参与了这项随机、双盲、安慰剂对照研究。高电流密度（2Hz，67.3±16.8mA，均值±标准差）的经皮电刺激诱发急性疼痛（数字11点量表评分：10分中的5 - 6分）以及对点状刺激和触摸的机械性痛觉过敏稳定区域（异常性疼痛）。在药物输注前、输注期间和输注后评估疼痛程度和痛觉过敏区域（分别以0.1μg·kg⁻¹·min⁻¹的速度输注瑞芬太尼和以5μg·kg⁻¹·min⁻¹的速度输注S-氯胺酮，持续30分钟；以2μg/kg的剂量输注可乐定，持续5分钟）。
输注瑞芬太尼期间疼痛和点状痛觉过敏区域减轻。相比之下，输注后疼痛和痛觉过敏显著高于对照组。输注S-氯胺酮期间，疼痛和痛觉过敏减轻，输注后逐渐恢复正常。联合使用时，S-氯胺酮消除了输注后点状痛觉过敏的增加，但未降低疼痛评分的升高。单独使用可乐定并未显著减轻疼痛或痛觉过敏区域。然而，与瑞芬太尼联合使用时，可乐定减轻了输注后疼痛评分的升高。
S-氯胺酮可消除阿片类药物诱发的输注后痛觉过敏，提示存在N-甲基-D-天冬氨酸受体机制。相比之下，氯胺酮并未降低输注后升高的疼痛评分，但α₂受体激动剂可乐定可缓解该评分。本研究结果提示阿片类药物诱发的输注后抗镇痛和继发性痛觉过敏存在不同机制。
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