PROLONGED ANALGESIA AND DECREASED TOXICITY WITH LIPOSOMAL MORPHINE INA MOUSE MODEL

Inadequate control of postoperative pain remains a major clinical prob lem. A reliable method of providing longlasting postoperative analgesi a with a single dose would be very useful. We synthesized a liposomal morphine formulation and compared it to free morphine with regard to d uration of analgesia in the mouse. Analgesia was assessed after intrap eritoneal injection using the tail-flick test. The systemic toxicity a fter administration of liposomal and free morphine was compared. The r elease rate of morphine from liposomes in vitro was also evaluated. Th e lethal intraperitoneal dose of free morphine in 50% of mice (LD(50)) was 400 mg/kg. The maximum safe (nonlethal) dose of free morphine was 130 mg/kg. The highest dose of liposomal morphine administered (1650 mg/kg) did not cause death in any animal. Duration of analgesia was si gnificantly prolonged with the highest dose of liposomal morphine (21. 5 +/- 5.3 h) compared to the maximum safe dose of free morphine (3.7 /- 0.75 h), P < 0.01. In vitro experiments showed a slow release rate of morphine from the liposome depot. Prolonged analgesia and deceased systemic toxicity for liposomal morphine are explained by sustained re lease of morphine from the liposomal depot. These results suggest that liposomal narcotic formulations may provide prolonged analgesia with single-dose administration.