Interaction between metamizol and tramadol in a model of acute visceral pain in rats.

Tramadol (TRM) and metamizol (MTZ) are drugs with complex mechanisms of action, extensively used in combination in pain management. In the present investigation we have evaluated the interaction between MTZ:TRM in the ethacrinic acid writhing test in rats. Dose-response curves (s.c.) were obtained for each drug individually, combined in fixed potency ratios (1:0.3, 1:1, 1:3), and for MTZ in presence of a fixed-dose of TRM (3.5 mg/kg). Interactions were analysed using isobolograms, interaction indexes (INT-I) and ANOVA. We used naloxone (1 mg/kg s.c.) to determine the opioid-component of the effects (ED80). Isobolograms demonstrated antagonism at the ED20, for 1:0.3 and 1:3 mixtures (p<0.01), whereas 1:1 was additive. At the ED50 and ED80 all combinations showed synergy. Fixed-dose experiments demonstrated that treatment (p<0.0001), dose (p<0.0001), and their interaction (p<0.0001) were statistically significant. Naloxone partially antagonized TRM (67%), but not MTZ; the percentage reversal of the combinations was directly related to the dose of TRM in the combination. The results show that the MTZ:TRM interaction on antinociception is synergistic or antagonistic depending on the level of effect. Synergy is demonstrated at 50% or higher levels, thus supporting the results obtained in humans by our group. Below the ED50 antagonism or additivity is present depending on the ratio of the combination. The mechanisms of the interaction remain unknown.