Antinociceptive activity of buprenorphine and lumiracoxib in the rat orofacial formalin test: A combination analysis study

Combination of two or more analgesics is widely used for the treatment of moderate and severe pain syndromes, allowing usage of lower doses of each compound and thereby limiting side effects; there is currently a large interest in investigating the potential advantages of combinations between opioids and non-steroidal inflammatory drugs (NSAIDs), coxibs in particular. The rat orofacial formalin test is a useful pre-clinical model of inflammatory trigeminal pain for evaluating antinociceptive activity of analgesics and their combinations. Injection of formalin in the rat wiskerpad induces a stereotyped response (rubbing), consisting of two distinct phases: a first 'phasic' phase and a second 'tonic' phase. In this work we tested a partial agonist to μ-opioid receptors, buprenorphine, and a selective cyclo-oxygenase-2 inhibitor, lumiracoxib, each of which given i.p. either alone or in combination. Buprenorphine reduced nociception both in the first and in the second phase, whereas lumiracoxib induced antinociception in the second phase only. The interaction between the two drugs was assessed through isobolographic analysis after combined administration at a fixed dose ratio. Such combination produced a dose-dependent antinociceptive effect in both phases. We observed a statistical difference between the theoretical and the experimental ED₅₀, which indicated synergistic interaction in the second phase. Concerning the first phase, we assumed that the antinociceptive effects were almost completely to be attributed to buprenorphine, since lumiracoxib was ineffective when administered alone. However, we found an unexpected difference between the theoretical and experimental ED₅₀, suggesting synergism in the first phase as well.