Department of Pharmacology, University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, P.O. Box 146, 11221 Belgrade, Serbia.
Biomed Pharmacother. 2022 Sep;153:113441. doi: 10.1016/j.biopha.2022.113441. Epub 2022 Aug 12.
Metformin (a widely used antidiabetic drug) has demonstrated efficacy in models of painful diabetic neuropathy (PDN), as well as certain clinical efficacy in relieving/preventing PDN. This study aimed to determine the type of interaction between metformin and duloxetine/oxycodone/eslicarbazepine acetate [ESL]/vitamin B in relieving diabetic pain hypersensitivity. Antihyperalgesic efficacy was determined using a Von Frey apparatus in mice with streptozotocin-induced PDN. We examined metformin's efficacy following oral (acute and prolonged 7-day treatment) and local (spinal and peripheral) application. The examined analgesics were administered in a single oral dose, whereas vitamin B was intraperitoneally administered for 7 days. In combination experiments, metformin (prolonged treatment) and analgesics/vitamin B were co-administered in fixed-dose fractions of their ED values and the type of interaction was determined using isobolographic analysis. Metformin produced dose-dependent antihyperalgesic effects in diabetic mice after oral (acute and prolonged 7-day treatment) and local spinal/peripheral application. Two-drug metformin combinations with analgesics/vitamin B also dose-dependently reduced mechanical hyperalgesia. The isobolographic analysis revealed that metformin synergises with analgesics/vitamin B, with a 6-7 fold dose reduction of both drugs in the examined combinations. In conclusion, metformin reduces hyperalgesia in diabetic animals, most likely by acting at the spinal and peripheral level. Additionally, it synergizes with duloxetine/oxycodone/ESL/vitamin B in reducing hyperalgesia. Metformin co-treatment may increase analgesic efficacy and enable the use of lower (and potentially safer) analgesic doses for treating PDN. Combined metformin-vitamin B use may provide more effective pain relief and mitigate metformin-induced vitamin B deficiency.
二甲双胍（一种广泛使用的抗糖尿病药物）已在痛性糖尿病周围神经病变（PDN）模型中显示出疗效，并且在缓解/预防 PDN 方面具有一定的临床疗效。本研究旨在确定二甲双胍与度洛西汀/羟考酮/依佐加滨[ESL]/维生素 B 之间在缓解糖尿病痛觉过敏中的相互作用类型。使用 Von Frey 仪器在链脲佐菌素诱导的 PDN 小鼠中确定抗痛觉过敏疗效。我们检查了二甲双胍在口服（急性和长期 7 天治疗）和局部（脊髓和外周）应用后的疗效。检查的镇痛药以单次口服剂量给予，而维生素 B 则以腹腔内方式给予 7 天。在组合实验中，二甲双胍（长期治疗）和镇痛药/维生素 B 以其 ED 值的固定剂量分数共同给予，并使用等辐射分析确定相互作用类型。二甲双胍在糖尿病小鼠中经口服（急性和长期 7 天治疗）和局部脊髓/外周应用后产生剂量依赖性的抗痛觉过敏作用。两种药物的二甲双胍组合与镇痛药/维生素 B 也剂量依赖性地降低机械性痛觉过敏。等辐射分析表明，二甲双胍与镇痛药/维生素 B 协同作用，在检查的组合中，两种药物的剂量减少了 6-7 倍。总之，二甲双胍可降低糖尿病动物的痛觉过敏，很可能通过作用于脊髓和外周水平。此外，它与度洛西汀/羟考酮/ESL/维生素 B 协同作用，降低痛觉过敏。二甲双胍共同治疗可能会提高镇痛效果，并使治疗 PDN 能够使用更低（可能更安全）的镇痛剂量。二甲双胍与维生素 B 的联合使用可能会提供更有效的疼痛缓解，并减轻二甲双胍引起的维生素 B 缺乏。
