Antinociceptive tolerance to NSAIDs in the rat formalin test is mediated by the opioid mechanism.

Background: In the past decade it has been shown that tolerance develops to the antinociceptive effect of repeated systemic administration of commonly used non-steroidal anti-inflammatory drugs (NSAIDs) in acute pain models using rats. This is similar to the tolerance observed with opioid-induced analgesia. In the present study, we investigated the development of tolerance to the analgesic effects of NSAIDs diclofenac, ketorolac and xefocam in a chronic inflammatory pain model, the formalin test.

Methods: Male Wistar rats receiving intraplantar formalin were tested for antinociception following intraperitoneal injection of NSAIDs in thermal paw withdrawal (Hargreaves) test and mechanical paw withdrawal (von Frey) test. Repeated measures analysis of variance with post-hoc Tukey-Kramer multiple comparison tests were used for statistical evaluations.

Results: Treatment with each NSAID significantly elevated the thermal paw withdrawal latency and mechanical paw withdrawal threshold on the first day, followed by a progressive decrease in the analgesic effect over a 4-day period, i.e., tolerance developed. With daily intraplantar injections of formalin, there was a trend toward reduced antinociceptive effects of diclofenac and ketorolac while xefocam exhibited a significant reduction (tolerance). It is noteworthy that the NSAID tolerant groups of rats still exhibited a strong hyperalgesia during phase I formalin following administration of each NSAID, an effect not observed in non-tolerant rats. Pretreatment with naloxone completely prevented the analgesic effects of these three NSAIDs in both behavioral assays.

Conclusions: The present findings support the notion that the development of tolerance to the antinociceptive effects of NSAIDs in an inflammatory pain model is mediated via an endogenous opioid system possibly involving descending pain modulatory systems.