Flupirtine antinociception in the rat orofacial formalin test: an analysis of combination therapies with morphine and tramadol.

Combination therapy with two drugs is a straightforward strategy to improve the risk-benefit ratio of analgesic treatments. Flupirtine is a non-opioid analgesic drug acting via the enhancement of so-called M currents, associated to Kv7 potassium channels in the central nervous system. In this study we used the orofacial formalin test as a model of acute inflammatory pain in the rat; putative synergistic interactions between flupirtine and morphine or tramadol, given in various combinations, were investigated. We found that flupirtine exerts antinociception in the second phase of the test, whereas morphine and tramadol induced analgesia both in the first and in the second phase. An isobolographic analysis of data was carried out, showing a synergistic interaction between flupirtine and morphine, as well as between flupirtine and tramadol, in the second phase of the test. Conversely, in the first phase of the test only a single combination of morphine plus flupirtine, but not any of the combinations of tramadol and flupirtine, resulted in a synergistic interaction. Our data clearly indicate that flupirtine enhances in a synergistic manner the acute antinociceptive effects exerted by opioids in this paradigm.