Nozawa Kazutaka, Karasawa Yusuke, Shidahara Yuka, Ushida Takahiro
Medical Affairs, Viatris Pharmaceuticals Japan Inc., Minato-ku, Tokyo, Japan.
Bioscience Business Division, KAC Co., Ltd, Ritto, Shiga, Japan.
J Pain Res. 2022 Oct 31;15:3469-3478. doi: 10.2147/JPR.S383981. eCollection 2022.
Neuropathic pain is sometimes difficult to manage because of limited efficacy of analgesic monotherapy even at high doses. Combination therapy may help address this issue, but there is little evidence for its effectiveness. Therefore, we evaluated the efficacy of combination therapy with pregabalin, an anchor drug for treating neuropathic pain, using the rat L5 spinal nerve ligation model.
Experiments were performed on four-week-old L5 spinal nerve ligated male Sprague-Dawley rats. Mechanical allodynia was assessed using the von Frey test, where the 50% withdrawal threshold was evaluated for five drugs: pregabalin, duloxetine, venlafaxine, tramadol, and celecoxib. The single-drug experiment included 112 rats, where each drug was tested independently. Median effective doses (EDs) were determined. Combinations of pregabalin with each of the other four drugs were tested (n=84). The 50% withdrawal threshold in the von Frey test was evaluated. The ED of each combination was determined experimentally. Isobolographic analyses were conducted to assess the synergistic potential of the drug combinations, excluding pregabalin-celecoxib, since the ED of celecoxib could not be determined.
In the single-drug experiment, all drugs except celecoxib resulted in a dose-dependent increase in the 50% withdrawal threshold 2 h after administration, with a maximum possible effect ranging from 4.4% to 79.6%. Similarly, all pregabalin combinations demonstrated a dose-dependent increase in the 50% withdrawal threshold, with pregabalin-tramadol showing the greatest increment. Isobolographic analysis of this combination revealed synergistic effects. Specifically, the combination index was γ=0.4 (<1). Combinations of pregabalin with duloxetine and venlafaxine demonstrated additive (γ=0.9) and antagonistic effects (γ=2.0), respectively.
This study demonstrated that combination of pregabalin with tramadol has synergistic antiallodynic effects, while that with duloxetine has additive effects. Moreover, pregabalin combined with venlafaxine was potentially antagonistic. Pregabalin combined with tramadol may serve as a promising drug combination for the effective management of neuropathic pain.
由于镇痛单一疗法即使在高剂量时疗效有限，神经性疼痛有时难以控制。联合治疗可能有助于解决这一问题，但几乎没有证据表明其有效性。因此，我们使用大鼠L5脊髓神经结扎模型评估了普瑞巴林（一种治疗神经性疼痛的基础药物）联合治疗的疗效。
对四周龄的L5脊髓神经结扎雄性Sprague-Dawley大鼠进行实验。使用von Frey试验评估机械性异常性疼痛，评估了五种药物（普瑞巴林、度洛西汀、文拉法辛、曲马多和塞来昔布）的50%撤药阈值。单药实验包括112只大鼠，每种药物独立进行测试。确定了半数有效剂量（ED）。测试了普瑞巴林与其他四种药物各自的组合（n = 84）。评估了von Frey试验中的50%撤药阈值。通过实验确定每种组合的ED。进行了等效线图分析以评估药物组合的协同潜力，但排除了普瑞巴林-塞来昔布组合，因为塞来昔布的ED无法确定。
在单药实验中，除塞来昔布外，所有药物在给药后2小时均导致50%撤药阈值呈剂量依赖性增加，最大可能效应范围为4.4%至79.6%。同样，所有普瑞巴林组合均显示50%撤药阈值呈剂量依赖性增加，其中普瑞巴林-曲马多显示出最大增幅。对该组合的等效线图分析显示出协同效应。具体而言，组合指数为γ = 0.4（<1）。普瑞巴林与度洛西汀和文拉法辛的组合分别表现出相加效应（γ = 0.9）和拮抗效应（γ = 2.0）。
本研究表明，普瑞巴林与曲马多联合具有协同抗痛觉过敏作用，与度洛西汀联合具有相加作用。此外，普瑞巴林与文拉法辛联合可能具有拮抗作用。普瑞巴林与曲马多联合可能是有效管理神经性疼痛的一种有前景的药物组合。
