Piperine (1‐peperoyl piperidine), an alkaloid extracted from Piper nigrum Linn is an inhibitor of hepatic and other enzymes involved in the biotransformation of drugs. In the present study piperine showed a dose dependent synergistic effect on nimesulide induced antinociception, in the acetic acid induced writhing test in mice. Piperine at a dose of 10 mg/kg significantly (p < 0.001) increased the analgesic activity of nimesulide administered at a submaximal dose of 6.5 mg/kg. In the formalin test, nimesulide alone (10 mg/kg, oral) did not modify phase I or nociceptor mediated pain while a combination of nimesulide (10 mg/kg) with piperine (10 mg/kg) significantly decreased it. In phase II or inflammatory pain, duration of formalin induced behaviour was 80 ± 7 s, 61 ± 7.3 s and 5.33 ± 3.3 s in control, nimesulide treated and piperine plus nimesulide treated groups respectively, indicating a synergistic activity of piperine with nimesulide. The antinociceptive effect correlated well with increased plasma concentration of nimesulide. The plasma concentration after oral administration of nimesulide (10 mg/kg) alone was 8.03 ± 0.99 ug/mL. However, when it was administered with piperine (10 mg/kg), the plasma concentration of nimesulide increased to 11.9 ± 0.23 ug/mL. This indicates that piperine inhibits the biotransformation and metabolism of nimesulide leading to significantly (p < 0.05) higher levels of drug in the systemic circulation. The findings of the present study suggest that piperine could be used as a biological enhancer when coadministered with nimesulide. © 1998 John Wiley & Sons, Ltd.