Phenacetin, acetaminophen and dipyrone: analgesic and rewarding effects.

The antinociceptive and rewarding effects of phenacetin, a mild analgesic with abuse liability, were compared with those of acetaminophen, dipyrone and indomethacin in the formalin and conditioned place preference tests. Phenacetin, acetaminophen and dipyrone attenuated the pain response, beginning at 50, 50 and 100 mg/kg, respectively. Systemically active drugs produced weaker antinociception when injected into the paw or intracerebroventricularly at doses approximately 10(3) lower than those required for systemic effects; dose effect relations were bell-shaped by the intracerebroventricular route. By all three routes, there was a clear ceiling to the effects of acetaminophen that is consistent with its clinical efficacy. Systemic phenacetin and acetaminophen produced a conditioned place preference at doses that produced antinociception. Dipyrone produced a place aversion by the systemic route and a place preference intracerebroventricularly. The latter had a bell-shaped dose effect relationship identical to that in the formalin test. Indomethacin was inactive in all tests, except for mild hyperalgesia by the intraventricular route. The results indicate that the antinociceptive effects of phenacetin, acetaminophen and dipyrone reflect a combination of peripheral and central actions, neither of which involves inhibition of cyclooxygenase. The central component of the antinociceptive effects may be related to activation of brain mechanisms that are involved in reinforcement.