Evaluation of Antinociceptive Effect of the Ketorolac-Topiramate Combination in the Rat Formalin Test

Abstract

Combination therapy approaches to manage acute and chronic pain are commonly used. To characterize the interaction between ketorolac and topiramate in the formalin test, female Wistar rats (200-300 g) were submitted to 1% formalin test. Antinociceptive effect was determined by the administration of ketorolac (3, 10, 30 and 100 mg/kg), topiramate (25, 50, 100 and 200 mg/kg) and their combination by oral route; or ketorolac (25, 50, 100 and 200 µg/paw), topiramate (10, 30, 100 and 300 µg/paw) and their combination by local peripheral route. Isobolographic analysis was used in a fixed dose combination (0.5:0.5) to analyze the nature of the interaction of the combination based on the ED 50 of ketorolac (62.8±21.9 mg/kg) and topiramate (24.3±8.5 mg/kg) by oral administration; or the ED 30 of ketorolac (67.0±7.97 µg/paw) and topiramate (391.3±51.7 µg/paw) by local peripheral route. Combination of these two drugs significantly reduced the number of flinches in second phase of the test. Theoretical ED 50 of the oral combination (ED 50 T) was 43.5±11.7 mg/kg. Experimentally, the ED 50 of the combination (ED 50 E) had a significantly lower value: 16.7±4.0 mg/kg; indicating the presence of supra additive effects (interaction index was 0.38). For local peripheral route, ED 30 T was 229.21±64.99 µg/kg. Experimentally, the ED 30 E had a significantly lower value: 62.00±15.72 µg/paw; indicating synergistic effects (interaction index was 0.27). Results show that oral and local peripheral administration of the combination can interact synergistically to reduce inflammatory pain in the rat formalin test.