Inadequate control of postoperative pain remains a major clinical problem. A reliable method of providing long-lasting postoperative analgesia with a single dose would be very useful. We synthesized a liposomal morphine formulation and compared it to free morphine with regard to duration of analgesia in the mouse. Analgesia was assessed after intraperitoneal injection using the tail-flick test. The systemic toxicity after administration of liposomal and free morphine was compared. The release rate of morphine from liposomes in vitro was also evaluated. The lethal intraperitoneal dose of free morphine in 50% of mice (LD50) was 400 mg/kg. The maximum safe (non-lethal) 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 significantly 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 decreased systemic toxicity for liposomal morphine are explained by sustained release of morphine from the liposomal depot. These results suggest that liposomal narcotic formulations may provide prolonged analgesia with single-dose administration.