Maves T J, Pechman P S, Meller S T, Gebhart G F
Department of Anesthesia, University of Iowa, Iowa City 52242.
Anesthesiology. 1994 May;80(5):1094-101. doi: 10.1097/00000542-199405000-00018.
Combinations of opioids and nonsteroidal antiinflammatory drugs (NSAIDs) are commonly used to control pain in the perioperative period, yet there are no quantitative evaluations of the interaction between opioids and nonsteroidal antiinflammatory drugs during visceral nociception. This study evaluated the interaction between morphine and ketorolac during visceral nociception in the rat.
The pressor response to noxious colorectal distention (80 mmHg, 20 s) was evaluated in 29 male Sprague-Dawley rats and dose-response curves were determined for intravenous morphine, ketorolac and the mixture of morphine and ketorolac. The data were interpreted using an isobolographic analysis to establish the nature of the interaction.
Intravenous ketorolac alone (8-32 mg/kg) did not have a significant antinociceptive effect, whereas morphine alone (1-4 mg/kg) produced significant antinociception during noxious colorectal distention (dose yielding a 50% reduction in nociceptive response relative to baseline pressor response = 1.7 +/- 0.6 mg/kg). Isobolographic analysis of the antinociceptive interaction demonstrated a highly significant, naloxone-reversible potentiation of intravenous morphine by ketorolac in the rat during visceral nociception (P < 0.001).
Ketorolac is a powerful potentiator of morphine antinociception during visceral nociception in the rat. However, intravenous ketorolac alone did not demonstrate antinociceptive properties during colorectal distention, a model of acute visceral nociception without a major inflammatory component. These data suggest that ketorolac may have a central modulatory effect on opioid pharmacology and the synergistic effect may be separate from its peripheral antiinflammatory properties. This study encourages further basic as well as clinical evaluations of the improved antinociception provided by combination therapy of opioids and nonsteroidal antiinflammatory drugs.
阿片类药物与非甾体抗炎药（NSAIDs）联合常用于围手术期疼痛控制，但尚无关于阿片类药物与非甾体抗炎药在内脏痛觉感受过程中相互作用的定量评估。本研究评估了吗啡与酮咯酸在大鼠内脏痛觉感受过程中的相互作用。
对29只雄性Sprague-Dawley大鼠评估了对有害性结直肠扩张（80 mmHg，20秒）的升压反应，并确定了静脉注射吗啡、酮咯酸以及吗啡与酮咯酸混合物的剂量-反应曲线。使用等效应线图分析法解释数据，以确定相互作用的性质。
单独静脉注射酮咯酸（8 - 32 mg/kg）无显著的镇痛作用，而单独使用吗啡（1 - 4 mg/kg）在有害性结直肠扩张期间产生了显著的镇痛作用（相对于基线升压反应，使伤害性反应降低50%的剂量 = 1.7 ± 0.6 mg/kg）。对镇痛相互作用的等效应线图分析表明，在大鼠内脏痛觉感受过程中，酮咯酸对静脉注射吗啡具有高度显著的、纳洛酮可逆转的增强作用（P < 0.001）。
在大鼠内脏痛觉感受过程中，酮咯酸是吗啡镇痛作用的强效增强剂。然而，在急性内脏痛觉感受模型（无主要炎症成分的结直肠扩张）中，单独静脉注射酮咯酸未表现出镇痛特性。这些数据表明，酮咯酸可能对阿片类药物药理学具有中枢调节作用，且协同效应可能与其外周抗炎特性无关。本研究鼓励对阿片类药物与非甾体抗炎药联合治疗所提供的增强镇痛作用进行进一步的基础及临床评估。
