Puig M M, Pol O, Warner W
Department of Anesthesiology, Hospital Universitario del Mar, IMIM, Barcelona, Spain.
Anesthesiology. 1996 Dec;85(6):1403-12. doi: 10.1097/00000542-199612000-00022.
Combinations of drugs are frequently used to achieve effective analgesia while minimizing side effects. Although the analgesic effects of morphine and clonidine seem to be synergistic, few studies have investigated other effects. Their role in inhibiting gastrointestinal transit was evaluated using different methods of analysis.
Percentage inhibition of transit induced by morphine, clonidine, or their combination was measured in mice that had been given an intragastric charcoal meal. Dose-response curves were obtained for each drug individually; for morphine:clonidine at 1:3, 1:1, and 1:0.33 ratios; and for morphine in the presence of 0.0138 mg/kg clonidine. The interaction was evaluated by isobolograms, combination indexes, and fixed-dose analysis.
Each drug and their combinations inhibited transit in a dose-related manner. Combinations of morphine and clonidine produced interaction that depended on the ratio and level of response. The interaction analyzed by isobolograms and combination indexes showed that combinations in 1:1 and 1:3 proportions were synergistic at the median effective doses or less and were antagonistic at larger doses. Fixed-dose analysis using different ratios showed similar results. The effects of the combination (median effective dose at 1:1 ratio) were antagonized by efaroxan but not by naloxone, suggesting a predominant role of alpha-2-mediated effects.
Investigations into drug interactions should include several levels of response and combinations at different ratios. Isobolographic analysis permits the statistical evaluation of results without making assumptions about mechanisms of action of the drugs or their interactions. In this study, the combination of morphine and clonidine should produce synergy, antagonism, or no interaction depending on the relative doses and the level of effect.
联合使用药物常用于在使副作用最小化的同时实现有效的镇痛效果。尽管吗啡和可乐定的镇痛作用似乎具有协同性，但很少有研究探究其他作用。使用不同的分析方法评估了它们在抑制胃肠转运方面的作用。
在给予胃内炭末餐的小鼠中测量吗啡、可乐定或其组合诱导的转运抑制百分比。分别获得每种药物的剂量-反应曲线；吗啡与可乐定比例为1:3、1:1和1:0.33时的组合曲线；以及在存在0.0138mg/kg可乐定情况下吗啡的曲线。通过等效应线图、组合指数和固定剂量分析评估相互作用。
每种药物及其组合均以剂量相关的方式抑制转运。吗啡和可乐定的组合产生的相互作用取决于比例和反应水平。通过等效应线图和组合指数分析的相互作用表明，1:1和1:3比例的组合在半数有效剂量及以下时具有协同作用，而在较大剂量时具有拮抗作用。使用不同比例的固定剂量分析显示了类似的结果。该组合（1:1比例时的半数有效剂量）的作用可被阿法罗定拮抗，但不能被纳洛酮拮抗，提示α-2介导的效应起主要作用。
对药物相互作用的研究应包括几个反应水平和不同比例的组合。等效应线图分析允许对结果进行统计学评估，而无需对药物的作用机制或其相互作用做出假设。在本研究中，吗啡和可乐定的组合根据相对剂量和效应水平应产生协同、拮抗或无相互作用。
