Oxymorphazone: A long-acting opiate analgesic

1. Treating rat brain homogenates in vitro with oxymorphazone, the hydrazone derivative of oxymorphone, selectively inhibited in a long-acting manner the highaffinity (mu₁) binding of a number of³H-opioids. This inhibition was not affected by extensive wash procedures which did effectively reverse classical opiates such as morphine and naloxone. 2. A similar, persistent inhibition of binding was observed following in vivo administration of the drug. Both systemically and intracerebroventicularly, oxymorphazone produced a dose-dependent analgesia. 3. Acutely, oxymorphazone (ED₅₀, 0.6 mg/kg, sc) was approximately half as potent as oxymorphone (ED₅₀, 0.3 mg/kg, sc) in the tail-flick assay. 4. Administered at their ED₅₀ doses, both compounds had the same durations of action. As the doses of drug were increased, however, the time course of oxymorphazone's analgesia became far more prolonged than that of oxymorphone. 5. Following the administration of oxymorphazone (100 mg/kg), over 50% of the mice remained analgesic for greater than 24 hr, as opposed to none of the mice given oxymorphone (100 mg/kg). 6. Oxymorphazone was far more potent intraventricularly (icv) than systemically. Fifty percent of the mice remained analgesic for greater than 20 hr following the injection of 40 μg/mouse (icv), whereas no mice remained analgesic after 20 hr following doses of oxymorphone as high as 50 μg/mouse (icv). 7. These long-lasting analgesic actions of oxymorphazone could not be easily explained on pharmacokinetic grounds. Repeated administration of oxymorphazone daily for 3 days resulted in significant tolerance.