Enhancement of antinociception but not constipation by combinations containing tramadol and metamizole in arthritic rats

Background and Aims: The use of a combination of analgesics could provide an optimal pain treatment with minimal side effects. Combinations of tramadol and some nonsteroidal anti-inflammatory drugs have demonstrated synergistic antinociceptive effects as well as a significantly reduced occurrence of adverse effects. The purpose of this study was to investigate the antinociceptive and constipation effects of tramadol and metamizole alone or in combination in rats and to discern among the types of drug interactions that exist using dose-response curves and an isobolographic analysis. Methods: The antinociceptive effects of tramadol and metamizole, alone or in various combination ratios, were quantitatively evaluated using the " pain-induced functional impairment model in the rat." Additionally, the constipation effect was evaluated using the charcoal meal test. Results: Tramadol (3.2-56.2 mg/kg) and metamizole (56.2-562.3 mg/kg) demonstrated a dose-dependent response with tramadol being more efficacious and potent than metamizole. Twenty-five different combinations of tramadol with metamizole were analyzed, and the evaluated combinations exhibited antinociceptive effects that were either additive or potentiative. An optimal combination was established with 3.2 mg/kg of tramadol and 316.2 mg/kg of metamizole. However, the constipation observed with this combination was more severe than that observed with the administration of tramadol alone. Our results reveal a possible interaction between the two drugs, which may be pharmacokinetic and/or pharmacodynamic in nature. Conclusions: The preclinical antinociceptive interaction and adverse effects produced by the combination of tramadol and metamizole suggests that caution should be exercised when using this combination in the clinical therapy of pain.