Combined carbamazepine and pregabalin therapy in a rat model of neuropathic pain

Carbamazepine and pregabalin have proven effects against neuropathic pain. Carbamazepine blocks voltage-dependent Na channels, whereas pregabalin blocks voltage-dependent Ca-2 channels. The authors hypothesized that the co-administration of these drugs would synergistically reduce neuropathic pain. Neuropathic pain was induced by L5 nerve ligation in SpragueDawley rats. To determine their ED50 values, carbamazepine and pregabalin were orally administered at 0.3, 3, 10, or 30 mg kg(1). The drugs were then co-administered at 0, 1/4ED(50), 1/2ED(50), 1.5ED(50), and 2ED(50) to determine the ED50 and ED75 values of the drugs in combination. Allodynia was determined using the von Frey hair test and doseeffect curves and isobolograms were used to investigate drug interactions. Levels of the acute reactive protein c-Fos in the dorsal horn were evaluated as an indicator of pathological nerve excitation. At ED50 levels, carbamazepine and pregabalin did not exhibit synergism, but doses higher than ED75 were found to be synergistic. The combination index was 0.18 (strong synergy) and dose reductions were 35.7-fold for carbamazepine and 6.8-fold for pregabalin when co-administered when compared with a single administration at ED75. The percentage allodynia relief was only 60 for carbamazepine and 80 for pregabalin by single administration, whereas their co-administration relieved allodynia by 100. Furthermore, treatment decreased c-Fos expression in the dorsal horn, but expressional differences between animals treated with carbamazepine plus pregabalin were not significantly different from those treated with single drug. Carbamazepine and pregabalin ameliorate neuropathic pain synergistically at higher doses.