Synergistic antinociceptive effect and gastric safety of the combination of docosahexaenoic acid and indomethacin in rats

The use of analgesics is limited by the presence of significant adverse side effects. Thus, combinations of non-steroidal anti-inflammatory drugs (NSAIDs) with other antinociceptive agents are frequently used to decrease these adverse reactions. The aims of this work were to evaluate the antinociceptive interaction of the systemic administration of the combination of DHA and indomethacin through an isobolographic analysis of the theoretical and experimental antinociceptive effect and to demonstrate the gastric safety of the mixture compared with indomethacin alone. Female Wistar rats were orally administered indomethacin (1-10 mg/kg), DHA (100-300 mg/kg), or the DHA-indomethacin mixture at a fixed-ratio combination (1:1, 1:3, 3:1), and the antinociceptive effects of these treatments were evaluated through the formalin (1%) test. An isobolographic analysis was performed to characterize the antinociceptive interaction between DHA and indomethacin. The degree of gastric injury in all of the rats was determined 1 h after the formalin test. The theoretical ED₃₀ values (Zadd) for the 1:1, 1:3, and 3:1 combinations were 73.48 ± 8.96, 37.75 ± 4.50, and 109.2 ± 13.43 mg/kg, p.o., respectively, and the experimental ED₃₀ values (Zexp) were 43.63 ± 5.18, 13.13 ± 1.61, and 54.20 ± 6.53, respectively. The isobolographic analysis showed that the three fixed-ratio combinations studied exhibited a synergistic interaction. Furthermore, the gastric damage induced by indomethacin was abolished when this drug was combined with DHA. These data suggest that the systemic administration of the DHA-indomethacin combination induces a synergistic and gastric safety effect.