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

BACKGROUND 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. METHODS Neuropathic pain was induced by L5 nerve ligation in Sprague-Dawley rats. To determine their ED(50) 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, 1/4×ED(50), 1/2×ED(50), 1.5×ED(50), and 2×ED(50) to determine the ED(50) and ED(75) values of the drugs in combination. Allodynia was determined using the von Frey hair test and dose-effect 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. RESULTS At ED(50) levels, carbamazepine and pregabalin did not exhibit synergism, but doses higher than ED(75) 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 ED(75). 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. CONCLUSIONS Carbamazepine and pregabalin ameliorate neuropathic pain synergistically at higher doses.