Synergistic interaction between tapentadol and flupirtine in the rat orafacial formalin test

Combination therapy with two or more analgesics is widely used for conditions associated with moderate to severe pain. Combinations of diverse analgesics with different modes of action can improve the risk-benefit ratio of analgesic treatments. The aim of this study is to evaluate the antinociceptive effect of tapentadol (TAP) and flupirtine (FLP), when administered separately or in combination, as well as their synergistic interaction in the orofacial formalin test in rats. After i.p. injection of TAP at different doses (2, 5, 10 and 15 mg/kg), the biphasic nociceptive behavior was reduced in a dose-dependent manner in both phase I and II. Conversely, i.p. injection of FLP at different doses (0.6, 1.6, 3.3, 6.6, 16.6 and 22.2 mg/kg) induced a dose-dependent antinociceptive effect in phase II only. TAP was found to be more effective than FLP. The interaction between TAP and FLP was synergistic in phase II with an interaction index (γ) of 0.50±0.24. The data reported in this study indicate that FLP enhances the antinociceptive effect of TAP and this drug combination might be potentially useful in the treatment of chronic pain.