Antihypernociceptive synergy between ibuprofen, paracetamol and codeine in rats

We investigated the effects of intraperitoneal injections of a combination of two cyclo-oxygenase inhibitors, ibuprofen and paracetamol, with a weak opiate, codeine, on nociception in Sprague Dawley rats. Administration of paracetamol (11, 44, and 88 mg/kg), ibuprofen (8.75, 35, and 140 mg/kg) or codeine (0.44, 1.75, and 3.5 mg/kg) alone caused a dose-dependent inhibition of reperfusion hypernociception. Administration of a combination of 0.44 mg/kg codeine + 8.75 mg/kg ibuprofen + 11 mg/kg paracetamol, drug doses that did not significantly reduce reperfusion hypernociception when administered individually or in pairs, abolished reperfusion hypernociception, such that the antihypernociceptive efficacy of the combination was ∼ 2.5-fold greater than that of the sum of the antihypernociceptive efficacy of the individual drugs. Coordinated motor function, tested using a rotarod, was not impaired at the doses we used. Thus, we have demonstrated that codeine, paracetamol and ibuprofen act synergistically to induce antihypernociception in rats at doses which do not affect motor function.