Spinal synergy between nonselective cyclooxygenase inhibitors and morphine antinociception in mice

The antinociception induced by the intrathecal coadministration of combinations of morphine with the nonsteroidal anti-inflammatory drugs (NSAIDs) naproxen, piroxicam, metamizol, diclofenac and ketoprofen was studied by isobolographic analysis in the acetic acid writhing test of mice. The effective dose that produced 50% antinociception (ED50) was calculated from the log dose-response curve of intrathecally administered fixed ratio combinations of morphine with each NSAID. By isobolographic analysis, this ED50 was compared to the theoretical additive ED50 calculated from the ED50 of morphine and of each NSAID alone. As shown by isobolograms, all the combinations were synergistic, the experimental ED50's being significantly smaller than the theoretically calculated ED50's. The results of this study demonstrate potent interactions between morphine and NSAIDs and validate the clinical use of the combinations of opioids and NSAIDs in pain treatment, even by the intrathecal route.