Zárate Edith, Granados-Soto Vinicio, Arias-Carrión Oscar
Psicofarma S.A. de C.V., Mexico City, Mexico.
Neurobiology of Pain Laboratory, Departamento de Farmacobiología, Cinvestav, South Campus, Mexico City, Mexico.
Front Pharmacol. 2025 Sep 1;16:1675015. doi: 10.3389/fphar.2025.1675015. eCollection 2025.
Neuropathic pain is a chronic and often disabling condition that remains refractory to monotherapy because of limited efficacy and dose-limiting adverse effects. Combination therapies that engage complementary mechanisms of action offer a rational strategy to enhance efficacy while minimizing toxicity. Pregabalin, a ligand of αδ subunits of voltage-gated calcium channels, reduces presynaptic calcium influx and glutamate release. In contrast, thioctic acid (α-lipoic acid), a potent antioxidant with anti-inflammatory properties, modulates TRPV1 channel expression and activity and inhibits CaV3.2 T-type calcium channels. Both agents exert antiallodynic effects in preclinical models, yet their pharmacodynamic interaction has not been systematically evaluated. Given their distinct but convergent actions on neuronal excitability and pain signalling, quantitative synergy analysis is warranted to define the therapeutic potential of their combined use.
We evaluated the antiallodynic efficacy of pregabalin and thioctic acid, alone and in combination, in female Wistar rats subjected to L5-L6 spinal nerve ligation. Mechanical withdrawal thresholds were measured using von Frey filaments up to 8 h post-oral administration. Dose-response curves were generated for each monotherapy and its 1:1 fixed-ratio combination. Isobolographic analysis was conducted to quantify pharmacodynamic interactions. All behavioural testing was performed under blinded conditions, and adverse effects were qualitatively monitored.
Both compounds produced dose-dependent increases in mechanical withdrawal thresholds (antiallodynic effects), with ED values of 2.45 ± 0.23 mg/kg for pregabalin and 57.49 ± 5.59 mg/kg for thioctic acid. The 1:1 fixed-ratio combination yielded an ED of 15.7 ± 1.0 mg/kg and a maximal %MPE of 72.3% ± 4.8%. Isobolographic analysis demonstrated a synergistic interaction, with an interaction index (γ) of 0.524 (95% CI: 0.41-0.66; p < 0.05 vs. theoretical ED). No overt adverse effects were observed at combination doses, whereas mild sedation occurred only at the highest pregabalin monotherapy dose.
These findings provide robust preclinical evidence that co-administration of pregabalin and thioctic acid produces synergistic antiallodynic effects in a validated model of neuropathic pain. This interaction enables effective analgesia at reduced doses, supporting a potential tolerability advantage. Our data support further investigation of this combination in chronic dosing paradigms, inclusion of both sexes, and clinical translation.
神经性疼痛是一种慢性且常导致功能障碍的疾病，由于疗效有限和剂量限制性不良反应，单一疗法往往难以奏效。采用互补作用机制的联合疗法是一种合理的策略，可在降低毒性的同时提高疗效。普瑞巴林是电压门控钙通道αδ亚基的配体，可减少突触前钙内流和谷氨酸释放。相比之下，硫辛酸是一种具有抗炎特性的强效抗氧化剂，可调节瞬时受体电位香草酸亚型1（TRPV1）通道的表达和活性，并抑制CaV3.2 T型钙通道。两种药物在临床前模型中均具有抗痛觉过敏作用，但其药效学相互作用尚未得到系统评估。鉴于它们对神经元兴奋性和疼痛信号传导具有不同但趋同的作用，有必要进行定量协同分析以确定联合使用的治疗潜力。
我们评估了普瑞巴林和硫辛酸单独及联合使用对接受L5-L6脊神经结扎的雌性Wistar大鼠的抗痛觉过敏疗效。在口服给药后长达8小时内，使用von Frey细丝测量机械性缩足阈值。为每种单一疗法及其1:1固定比例组合生成剂量-反应曲线。进行等效线图分析以量化药效学相互作用。所有行为测试均在盲法条件下进行，并对不良反应进行定性监测。
两种化合物均使机械性缩足阈值呈剂量依赖性增加（抗痛觉过敏作用），普瑞巴林的半数有效剂量（ED）为2.45±0.23mg/kg，硫辛酸为57.49±5.59mg/kg。1:1固定比例组合的ED为15.7±1.0mg/kg，最大%最大可能效应（%MPE）为72.3%±4.8%。等效线图分析显示存在协同相互作用，相互作用指数（γ）为0.524（95%置信区间：0.41-0.66；与理论ED相比，p<0.05）。联合用药剂量下未观察到明显不良反应，而轻度镇静仅在普瑞巴林单一疗法的最高剂量时出现。
这些发现提供了有力的临床前证据，表明普瑞巴林和硫辛酸联合给药在经过验证的神经性疼痛模型中产生协同抗痛觉过敏作用。这种相互作用能够在降低剂量的情况下实现有效镇痛，支持潜在的耐受性优势。我们的数据支持在慢性给药模式、纳入两性以及临床转化方面对这种联合用药进行进一步研究。
