INTRATHECAL ADMINISTRATION OF LIPOSOMAL MORPHINE IN A MOUSE MODEL

The authors determined the duration of analgesia toxicity, and neuraxi al distribution of liposomal morphine after intrathecal administration in the mouse. Analgesic duration was determined using the tail-flick test after intrathecal injection of 12.5, 25, or 50 mu g of plain or L iposomal morphine (n = 6 mice/dose/formulation). Toxicity of the formu lations was compared by estimating LD50. Neuraxial morphine distributi on was determined after 20 mu g of plain or liposomal morphine. The ex cised spinal cord and brain were divided into five segments at 1 min, and at 1, 4, and 8 h after injection for both formulations. In additio n, for the liposomal morphine, similar sections were obtained at 24 h (n = 6 mice/formulation/time point). Segmental morphine concentration was quantified using radioimmunoassay. Liposomal encapsulation signifi cantly prolonged duration of analgesia for the 25-mu g (13.4 +/- 1.64 [SE] vs 4.1 +/- 0.5 h) and 50-mu g doses (16.8 +/- 4.0 vs 4.6 +/- 1.0 h). The estimated LD50 was 200 (confidence interval 151-257 mu g) for plain morphine, but was not determinable for the liposomal formulation , since no deaths occurred at the largest dose level which could be te sted (371 mu g). For plain morphine, the drug was not confined to aspe cific neuraxial segment, and segmental levels declined rapidly. After liposomal morphine, the most morphine was concentrated and persisted i n the low spinal cord segment at each time interval. These results sho w that a single dose of liposomal morphine produces prolonged analgesi a with decreased toxicity compared to the plain formulation.