Chen Yong, Chan Sui Y, Ho Paul C
Department of Pharmacy, National University of Singapore, Singapore.
J Pharm Pharmacol. 2002 May;54(5):623-31. doi: 10.1211/0022357021778934.
Owing to different mechanisms of analgesia, we hypothesized that the combination of ketamine and tramadol could produce synergistic or additive antinociceptive effects. Swiss albino mice were administered intraperitoneally with ketamine, tramadol, a combination of ketamine and tramadol, or saline, and the resulting antinociceptive effects were tested in the mouse tail-flick and formalin tests. The potencies of the two drugs alone or in combination were obtained by fitting data to the Sigmoid Emax equation. Isobolographic analysis was performed to evaluate the interaction. CNS depression was also monitored. Results showed that tramadol exhibited apparent dose-dependent effects in the tail-flick test, and in phase 1 and phase 2 of the formalin test. Ketamine dose-dependently inhibited the phase 2 responses, but failed to modify the phase 1 and tail-flick responses. Combination of tramadol and ketamine produced significant synergistic interactions only in phase 2 of the formalin test (P < 0.05). The synergistic combinations also displayed less CNS depression than when an equianalgesic dose of ketamine was administered alone. We conclude that in the acute thermal or chemical pain model, ketamine is not effective and the net effect of ketamine and tramadol in combination was simply additive after systemic administration. However, the coadministration produced synergistic antinociception in the chemical-induced persistent pain model.
由于镇痛机制不同，我们推测氯胺酮和曲马多联合使用可能产生协同或相加的镇痛作用。给瑞士白化小鼠腹腔注射氯胺酮、曲马多、氯胺酮与曲马多的组合或生理盐水，并在小鼠甩尾试验和福尔马林试验中测试由此产生的镇痛效果。通过将数据拟合到Sigmoid Emax方程来获得两种药物单独或联合使用时的效价。进行等效应线分析以评估相互作用。同时监测中枢神经系统抑制情况。结果显示，曲马多在甩尾试验以及福尔马林试验的第1阶段和第2阶段表现出明显的剂量依赖性效应。氯胺酮剂量依赖性地抑制第2阶段反应，但未能改变第1阶段反应和甩尾反应。曲马多和氯胺酮的组合仅在福尔马林试验的第2阶段产生了显著的协同相互作用（P < 0.05）。与单独给予等效镇痛剂量的氯胺酮相比，协同组合也表现出较少的中枢神经系统抑制。我们得出结论，在急性热痛或化学性疼痛模型中，氯胺酮无效，全身给药后氯胺酮和曲马多的总体效应只是相加。然而，联合给药在化学诱导的持续性疼痛模型中产生了协同镇痛作用。
