Antinociceptive Synergy Between Metamizole and Hesperidin in a Model of Visceral Pain in Mice

Background: Metamizole is used to relieve the visceral pain but its adverse effects limit its use. An alternative to improve its efficacy with lower doses is to combine it with a natural product as hesperidin. Aim of the study. The aim of this study was to evaluate the antinociceptive interaction between metamizole and hesperidin in a visceral pain model using an isobolographic analysis. Methods: Antinociception was evaluated in the writhing model using acetic acid (1%) to induce writhes in mice. Metamizole (1–316 mg/kg), hesperidin (3–300 mg/kg), or combinations with a fixed-dose ratio of 1:1 were administered intraperitoneally 30 min before the acetic acid and the number of writhes was counted for 30 min. Isobolographic analysis was employed to define the nature of the compound interaction. Results: Metamizole and hesperidin in individual administration induced dose-dependent antinociceptive effects, reached an efficacy of 84.2 ± 5.9% and 66.3 ± 7.4%, respectively. The ED₅₀ values calculated from their dose-response curves were 84.5 ± 22.7 and 108.9 ± 17.9 mg/kg, respectively. The analysis of DRC for the metamizole + hesperidin combination, in a ratio 1:1 showed a ED_{50 COMB} value lower than the ED_{50 ADD} estimated from the additivity line from the isobologram (46.7 ± 6.3 vs. 96.7 ± 11.9 mg/kg, respectively). In addition, the pharmacological interaction calculated was of 0.48. These results suggest a synergistic interaction for the antinociceptive activity of metamizole + hesperidin combination. Conclusion: These data suggest that metamizole + hesperidin combination could be useful in treating visceral pain as it can interact synergistically using low dose of both drugs with the possibility of reducing the risk of adverse effects.