Rodrigues Rafaela F, Kawano Taila, Placido Rodrigo V, Costa Lellis H, Podesta Marcia H M C, Santos Rafaela S, Galdino Giovane, Barros Carlos M, Boralli Vanessa B
Department of Clinical and Toxicological Analysis, Federal University of Alfenas, MG, Brazil.
Department of Pharmaceutical Sciences, Federal University of Alfenas, MG, Brazil.
Pain Physician. 2021 Jul;24(4):E511-E520.
Amitriptyline, duloxetine, and pregabalin are among the most pharmacotherapeutic, effective treatments for neuropathic pain control. However, the evaluation of synergism by combining these treatments is still poorly investigated.
To evaluate the pharmacokinetics of the combination of pregabalin plus duloxetine and pregabalin plus amitriptyline, as well as the effect of these on neuropathic pain on rodent model.
The experimental study.
The research took place in the research laboratories at the Federal University of Alfenas after ethics committee approval.
This study used male Wistar rats weighing between 220 and 250 g. The animals were randomly divided into the following groups: monotherapy (pregabalin, amitriptyline, duloxetine), combined therapy (pregabalin + amitriptyline, pregabalin + duloxetine), and vehicle (ultrapure water). Pharmacokinetic analysis of pregabalin or combination (pregabalin + amitriptyline or pregabalin + duloxetine) in the plasma were performed by ultraperformance liquid chromatography tandem mass spectrometry. Neuropathic pain was induced by sciatic nerve constriction (chronic constriction injury [CCI]) model, and nociceptive threshold was measured by von Frey filaments test. In addition, to evaluate the influence of the treatments on the motor coordination, the rotarod test was used.
The pharmacokinetic disposition of pregabalin was changed in the association with amitriptyline, presenting a clearance reduction and consequently an increase in bioavailability. Furthermore, after the 14th day of CCI, pregabalin was administered orally and induced antiallodynic effect after 1, 2:15, 4, and 8 hours of its administration and showed the greatest antiallodynic effect after 4 hours of its administration. Moreover, this effect was prolonged (up to 8 hours) by combination with amitriptyline. Additionally, pregabalin and pregabalin + duloxetine showed a hypoalgesic effect in sham rats. In addition, the rotarod test results showed that drugs did not influence the motor coordination of the rats.
Potential competition mechanisms during the excretion of pregabalin, when pregabalin was combined with amitriptyline, were not investigated in this study.
The data demonstrated that combined therapy of pregabalin plus amitriptyline improved the bioavailability of pregabalin and potentiated the efficacy of the antiallodynic effect of pregabalin alone, proving to be advantageous for the treatment of sciatic neuropathic pain.
阿米替林、度洛西汀和普瑞巴林是用于控制神经性疼痛的最具药物治疗效果的疗法。然而，对这些疗法联合使用时的协同作用评估仍研究不足。
评估普瑞巴林联合度洛西汀以及普瑞巴林联合阿米替林的药代动力学，以及它们对啮齿动物模型神经性疼痛的影响。
实验研究。
本研究在阿尔费纳斯联邦大学的研究实验室进行，并经伦理委员会批准。
本研究使用体重在220至250克之间的雄性Wistar大鼠。动物被随机分为以下几组：单一疗法组（普瑞巴林、阿米替林、度洛西汀）、联合疗法组（普瑞巴林 + 阿米替林、普瑞巴林 + 度洛西汀）和溶剂对照组（超纯水）。通过超高效液相色谱串联质谱法对血浆中的普瑞巴林或联合用药（普瑞巴林 + 阿米替林或普瑞巴林 + 度洛西汀）进行药代动力学分析。通过坐骨神经缩窄（慢性缩窄损伤[CCI]）模型诱导神经性疼痛，并通过von Frey细丝试验测量痛觉阈值。此外，为评估治疗对运动协调性的影响，采用了转棒试验。
普瑞巴林与阿米替林联用时，其药代动力学特征发生改变，清除率降低，生物利用度增加。此外，在CCI第14天后，口服普瑞巴林，给药后1、2:15、4和8小时产生抗痛觉过敏作用，给药后4小时抗痛觉过敏作用最强。而且，与阿米替林联合使用时，这种作用延长（长达8小时）。此外，普瑞巴林和普瑞巴林 + 度洛西汀在假手术大鼠中显示出镇痛作用。另外，转棒试验结果表明药物不影响大鼠的运动协调性。
本研究未调查普瑞巴林与阿米替林联合使用时普瑞巴林排泄过程中的潜在竞争机制。
数据表明，普瑞巴林联合阿米替林的联合疗法提高了普瑞巴林的生物利用度，并增强了普瑞巴林单独使用时的抗痛觉过敏效果，证明对坐骨神经神经性疼痛的治疗具有优势。
