Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
Eur J Pharmacol. 2010 Feb 25;628(1-3):75-82. doi: 10.1016/j.ejphar.2009.11.016. Epub 2009 Nov 14.
Antiepileptic and antidepressant drugs are the primary treatments for pain relief in diabetic neuropathy. Combination therapy is a valid approach in pain treatment, where a reduction of doses could reduce side effects and still achieve optimal analgesia. We examined the effects of two-drug combinations of gabapentin, oxcarbazepine, and amitriptyline on nociception in diabetic mice and aimed to determine the type of interaction between components. The nociceptive responses in normal and diabetic mice were assessed by the tail-flick test. The testing was performed before and three weeks after the diabetes induction with streptozotocin (150mg/kg; i.p.), when the antinociceptive effects of gabapentin, oxcarbazepine, amitriptyline and their two-drug combinations were examined. Gabapentin (10-40mg/kg; p.o.) and oxcarbazepine (20-80mg/kg; p.o.) produced a significant, dose-dependent antinociception in diabetic mice while amitriptyline (5-60mg/kg; p.o.) produced weak antinociceptive effect. In normal mice, neither of the drugs produced antinociception. Gabapentin and oxcarbazepine, co-administered in fixed-dose fractions of the ED(50) to diabetic mice, induced significant, dose-dependent antinociception. Isobolographic analysis revealed synergistic interaction. Oxcarbazepine (10-60mg/kg; p.o.)+amitriptyline (5mg/kg; p.o.) and gabapentin (10-30mg/kg; p.o.)+amitriptyline (5mg/kg; p.o.) combinations significantly and dose-dependently reduced nociception in diabetic mice. Analysis of the log dose-response curves for oxcarbazepine or gabapentin in a presence of amitriptyline and oxcarbazepine or gabapentin applied alone, revealed a synergism in oxcarbazepine-amitriptyline and additivity in gabapentin-amitriptyline combination. These findings provide new information about the combination therapy of painful diabetic neuropathy and should be explored further in patients with diabetic neuropathy.
抗癫痫药和抗抑郁药是治疗糖尿病性周围神经病变疼痛的主要药物。联合治疗是疼痛治疗的一种有效方法，减少剂量可以减少副作用，同时仍能达到最佳的镇痛效果。我们研究了两种药物组合（加巴喷丁、奥卡西平、阿米替林）对糖尿病小鼠的伤害感受的影响，并旨在确定药物成分之间的相互作用类型。使用尾巴闪烁测试评估正常和糖尿病小鼠的伤害感受反应。测试在链脲佐菌素（150mg/kg；腹腔注射）诱导糖尿病后 3 周进行，在此期间检查了加巴喷丁、奥卡西平、阿米替林及其两种药物组合的抗伤害作用。加巴喷丁（10-40mg/kg；口服）和奥卡西平（20-80mg/kg；口服）在糖尿病小鼠中产生了显著的、剂量依赖性的镇痛作用，而阿米替林（5-60mg/kg；口服）产生了较弱的镇痛作用。在正常小鼠中，这些药物都没有产生镇痛作用。在糖尿病小鼠中，以固定剂量分数给予 ED50 的加巴喷丁和奥卡西平联合给药，可诱导显著的、剂量依赖性的镇痛作用。等比图形分析显示协同作用。奥卡西平（10-60mg/kg；口服）+阿米替林（5mg/kg；口服）和加巴喷丁（10-30mg/kg；口服）+阿米替林（5mg/kg；口服）联合显著且剂量依赖性地降低了糖尿病小鼠的伤害感受。对奥卡西平和加巴喷丁在单独使用和与阿米替林联合使用时的剂量反应曲线进行对数分析，发现奥卡西平和阿米替林的联合作用具有协同性，而加巴喷丁和阿米替林的联合作用具有相加性。这些发现为治疗糖尿病性周围神经病变疼痛的联合治疗提供了新的信息，应该在糖尿病周围神经病变患者中进一步探索。
