Synergistic interaction between metformin and sulfonylureas on diclofenac-induced antinociception measured using the formalin test in rats

Abstract

BACKGROUND: There is evidence that biguanide3 and sulfonylurea: block diclofenac-induced antinociception (DIA) in rat models. However, little i3 known about tke interaction between these hypoglycemics with respect to DIA. OBJECTIVE: To determine whether metformin-sulfonylurea combinations affect DIA during the formalin te3t. METHODS: Rats received the appropriate vehicle or diclofenac before 1% formaldehyde was injected into the paw. Rats were also pretreated with vehicle, glibenclamide, glipizide, metformin or glibenclamide/metformin and glipizide/metformin combinations before the diclofenac and formaldehyde injections, and the effect on antinociception was assessed. Isobolograms of the combinations were constructed to test for a synergistic interaction. RESULTS: Systemic injection of diclofenac resulted in antinociception during the second phase of the test. Systemic pretreatment with the combinations of glibenclamide (0.56 mg/kg to 10 mg/kg )/metform in (10 mg/kg to ISO mg/kg) and glipizide (0.56 mg/kg to 10 mg/kg)/metformin (10 mg/kg to ISO mg/kg) blocked DIA. The derived theoretical effective doses for 50% of subjects (ED50) for the glibenclamide/metformin and glipizide/ metformin combinations were 32.52 mg/kg and 32.42 mg/kg, respectively, and were significantly higher than the actual observed experimental ED50 values (7.57 mg/kg and 8.43 mg/kg, respectively). CONCLUSION: Pretreatment with glibenclamide, glipizide or met-formin blocked DIA in a do3e-dependent manner, and combining either sulfonylurea with metformin produced even greater effects. The observed ED50S for the combinations were approximately fourfold lower than the calculated additive effects. These data indicate that sulfonylureas interact to produce antagonism of DIA. Combination therapy is a common second- line treatment for patients with diabetes and metabolic syndrome, a group that experiences pain from multiple sources. The results suggest that at least some anti-inflammatory agent3 may not be effective in this group. © 2013 Pulsus Group Inc.