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Efficacy of Combination Therapy with Pregabalin in Neuropathic Pain: A Preclinical Study in the Rat L5 Spinal Nerve Ligation Model

PURPOSE: 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 pr...

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Detalles Bibliográficos
Autores principales: Nozawa, Kazutaka, Karasawa, Yusuke, Shidahara, Yuka, Ushida, Takahiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9635478/
https://www.ncbi.nlm.nih.gov/pubmed/36338796
http://dx.doi.org/10.2147/JPR.S383981
Descripción
Sumario:PURPOSE: 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. METHODS: 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 (ED(50)s) 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(50) 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(50) of celecoxib could not be determined. RESULTS: 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. CONCLUSION: 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.