Pharmacokinetics and efficacy of epidurally delivered sustained-release encapsulated morphine in dogs.

BACKGROUND: We evaluated the epidural effects of a multivesicular liposome-based sustained-release preparation of morphine (C0401) on behavior and lumbar cerebrospinal fluid and serum kinetics of morphine.
METHODS: Beagle dogs were prepared with lumbar epidural catheters with subcutaneous injection ports and lumbar intrathecal catheters. Each dog (n = 6) received the following by the epidural route: 5 mg/3 ml morphine sulfate in saline (MS-5), 10 mg/3 ml C0401 (C0401-10), and 30 mg/3 ml C0401 (C0401-30). Behavioral and physiologic parameters and nociceptive responses (skin twitch latency) were evaluated, and morphine concentrations were determined in lumbar cerebrospinal fluid and serum.
RESULTS: All morphine treatments blocked the skin twitch response. Time to onset was 1.3 +/- 0.3 h for C0401-30; 2.6 +/- 0.6 h for C0401-10; and 0.4 +/- 0.2 h for MS-5. Duration of action was 62 +/- 0.3 h for C0401-30; 27 +/- 2 h for MS-5. All treatments produced a modest reduction in arousal, muscle tone, and coordination, with the duration of the C0401-30 preparation being longer lasting. Respiratory rate was mildly depressed by all treatments, and moderate hypotension was noted. Time to peak cerebrospinal fluid morphine concentration was 11 h for C0401-30; 3 h for C0401-10; and 5 min for MS-5. Peak lumbar cerebrospinal fluid level was 34,992 +/- 5,578 ng/ml for MS-5; 14,483 +/- 3,438 ng/ml for C0401-30; and 10,730 +/- 2,888 ng/ml for C0401-10. Morphine mean residence time in lumbar cerebrospinal fluid was 0.8 +/- 0.1 h for MS-5; 8.9 +/- 1.0 h for C0401-30. DISCUSSION: Kinetics studies showed that multivesicular liposome sequestration results in a restrained and persistent release of morphine from the epidural space. This extended release corresponded with an extended duration of analgesia without an attendant increase in the incidence of side effects.