Synergism between paracetamol and nonsteroidal anti-inflammatory drugs in experimental acute pain

The antinociception induced by the intraperitoneal coadministration of combinations of paracetamol with the nonsteroidal anti-inflammatory drugs (NSAIDs) diclofenac, ibuprofen, ketoprofen, meloxicam, metamizol, naproxen, nimesulide, parecoxib and piroxicam was studied by isobolographic analysis in the acetic acid abdominal constriction test of mice (writhing test). The effective dose that produced 50% antinociception (ED₅₀) was calculated from the log dose-response curves of fixed ratio combinations of paracetamol with each NSAID. By isobolographic analysis, this ED₅₀ was compared to the theoretical additive ED₅₀ calculated from the ED₅₀ of paracetamol and of each NSAID alone obtained from ED ₅₀ dose-response curves. As shown by isobolographic analysis, all the combinations were synergistic, the experimental ED₅₀s being significantly smaller than the theoretically calculated ED₅₀s. The results of this study demonstrate potent interactions between paracetamol and NSAIDs and validate the clinical use of combinations of these drugs in the treatment of pain conditions.