Faculty of Pharmacy, Department of Pharmacology, University of Belgrade, Vojvode Stepe 450, Belgrade, Serbia.
Anesth Analg. 2010 Apr 1;110(4):1198-205. doi: 10.1213/ANE.0b013e3181cbd8da. Epub 2010 Feb 8.
Combination therapy is a valid approach in pain treatment, in which a reduction of doses could reduce side effects and still achieve optimal analgesia. We examined the effects of coadministered paracetamol, a widely used non-opioid analgesic, and oxcarbazepine, a relatively novel anticonvulsant with analgesic properties, in a rat model of paw inflammatory hyperalgesia and in a mice model of visceral pain and determined the type of interaction between components.
The effects of paracetamol, oxcarbazepine, and their combinations were examined in carrageenan-induced (0.1 mL, 1%) paw inflammatory hyperalgesia in rats and in an acetic acid-induced (10 mg/kg, 0.75%) writhing test in mice. In both models, drugs were coadministered in fixed-dose fractions of the 50% effective dose (ED(50)), and type of interaction was determined by isobolographic analysis.
Paracetamol (50-200 mg/kg peroral), oxcarbazepine (40-160 mg/kg peroral), and their combination (1/8, 1/4, 1/3, and 1/2 of a single drug ED(50)) produced a significant, dose-dependent antihyperalgesia in carrageenan-injected rats. In the writhing test in mice, paracetamol (60-180 mg/kg peroral), oxcarbazepine (20-80 mg/kg peroral), and their combination (1/16, 1/8, 1/4, and 1/2 of a single drug ED(50)) significantly and dose dependently reduced the number of writhes. In both models, isobolographic analysis revealed a significant synergistic interaction between paracetamol and oxcarbazepine, with a >4-fold reduction of doses of both drugs in combination, compared with single drugs ED(50).
The synergistic interaction between paracetamol and oxcarbazepine provides new information about combination pain treatment and should be explored further in patients, especially with somatic and/or visceral pain.
联合治疗是疼痛治疗的有效方法，其中减少剂量可以减少副作用，同时仍能达到最佳的镇痛效果。我们在爪炎性痛觉过敏的大鼠模型和内脏痛觉的小鼠模型中，研究了广泛使用的非阿片类镇痛药扑热息痛和具有镇痛作用的新型抗惊厥药奥卡西平的联合应用效果，并确定了药物成分之间的相互作用类型。
在大鼠的角叉菜胶诱导的（0.1 mL，1%）爪炎性痛觉过敏和小鼠的醋酸诱导的（10 mg/kg，0.75%）扭体试验中，观察了扑热息痛、奥卡西平和它们的组合的作用。在这两种模型中，药物以 50%有效剂量（ED50）的固定剂量分数联合给药，并通过等效应线分析确定相互作用的类型。
扑热息痛（50-200 mg/kg 口服）、奥卡西平（40-160 mg/kg 口服）及其组合（单一药物 ED50 的 1/8、1/4、1/3 和 1/2）在角叉菜胶注射的大鼠中产生了显著的、剂量依赖性的抗痛觉过敏作用。在小鼠的扭体试验中，扑热息痛（60-180 mg/kg 口服）、奥卡西平（20-80 mg/kg 口服）及其组合（单一药物 ED50 的 1/16、1/8、1/4 和 1/2）显著地、剂量依赖性地减少了扭体的次数。在这两种模型中，等效应线分析显示扑热息痛和奥卡西平之间存在显著的协同相互作用，与单独使用药物 ED50 相比，联合使用两种药物的剂量减少了 4 倍以上。
扑热息痛和奥卡西平之间的协同相互作用提供了关于联合疼痛治疗的新信息，应该在患者中进一步探索，特别是在有躯体和/或内脏疼痛的患者中。
