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

Kazutaka Nozawa,1 Yusuke Karasawa,1 Yuka Shidahara,2 Takahiro Ushida3 1Medical Affairs, Viatris Pharmaceuticals Japan Inc., Minato-ku, Tokyo, Japan; 2Bioscience Business Division, KAC Co., Ltd, Ritto, Shiga, Japan; 3Multidisciplinary Pain Center, Aichi Medical University, Nagakute, Aichi, JapanCorrespondence: Kazutaka Nozawa, Medical Affairs, Viatris Pharmaceuticals Japan Inc, Minato-ku, Tokyo, Japan, Tel +81 80-5001-3029, Email Kazutaka.Nozawa@viatris.comPurpose: 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 (ED50s) 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 ED50 of each combination was determined experimentally. Isobolographic analyses were conducted to assess the synergistic potential of the drug combinations, excluding pregabalin-celecoxib, since the ED50 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 t