d-propoxyphene and dipyrone co-administration produces greater antinociception and fewer adverse effects than single treatments in rats

d-propoxyphene is a commonly prescribed opiate analgesic. Its use is limited by unwanted side effects at high doses and tolerance development after chronic administration. Dipyrone (also known as metamizol) is a non-steroidal anti-inflammatory drug extensively used in Latin America and Europe. The objective of this work was to evaluate the antinociceptive efficacy of a dipyrone/d-propoxyphene combination and the development of tolerance to its repeated administration in the tail flick test in rats. Male Wistar rats (200 ± 20 g) were i.v. injected twice daily (8 h apart) with 0.31 mg/kg d-propoxyphene, 400 mg/kg dipyrone, or the combination of these drugs, at the same doses, until complete tolerance was observed. A time course of the effects for each administration was determined. At the doses tested, d-propoxyphene and dipyrone produced mild antinociception per se. Repeated administration resulted in complete tolerance to their antinociceptive effects by the sixth dose. The d-propoxyphene/dipyrone combination produced more antinociception than expected by the sum of individual drug effects. With this treatment, tolerance developed at the 15th administration. In animals already tolerant to d-propoxyphene or dipyrone alone, subsequent administration of the combination partially restored the antinociceptive effect. These results suggest that the use of this combination provides advantages over single drug therapies.