Evaluation of the interaction between acemetacin and opioids on the hargreaves model of thermal hyperalgesia

It has been shown that the association of opioids analgesic agents with non-steroidal anti-inflammatory drugs (NSAIDs) can increase their antinociceptive activity, allowing the use of lower doses and thus limiting side effects. Therefore, the goal of the present study was to examine the possible pharmacological interaction between acemetacin and two opioids in the Hargreaves model of thermal hyperalgesia in the mouse. Acemetacin, codeine, nalbuphine or fixed-dose ratios acemetacin–codeine and acemetacin–nalbuphine combinations were administrated systemically to mice and the antihyperalgesic effect was evaluated using the thermal hyperalgesia test. All treatments produced a dose-dependent antihyperalgesic effect. ED40 values were estimated for all the treatments and an isobologram was constructed. The derived theoretical ED40 for the acemetacin–codeine and acemetacin–nalbuphine combinations were 55.9 ± 4.9 mg/kg and 40.3 ± 3.8 mg/kg, respectively, being significantly higher than the actually observed experimental ED40, 14.5 ± 1.7 mg/kg and 12.7 ± 2.2 mg/kg, respectively. These results correspond to synergistic interactions between acemetacin and opioids on the Hargreaves model of thermal hyperalgesia. Highest doses of the individual drugs or the combinations did not affect motor coordination in the balancing test on a rota-rod. Data suggest that low doses of the acemetacin–opioids combination can interact synergistically at systemic level and therefore this drugs association may represent a therapeutic advantage for the clinical treatment of inflammatory pain.