Pharmacokinetics of two novel rectal controlled-release morphine formulations

Abstract

Administration of morphine by the oral route is not possible in cancer patients who are unable to swallow or are intolerant of oral morphine. Thus, there is a need for reliable alternate routes of drug administration. We compared the bioavailability of two prototype 30-mg morphine sulfate controlled-release suppository formulations (high and low viscosity) with 30-mg oral controlled-release morphine sulfate tablets in a 14-subject single-dose randomized, three-way crossover study. Venous blood samples were obtained immediately prior to and for 24 hr following each dose. Morphine concentrations were determined by radioimmunoassay. Compared with oral controlled-release morphine, the high- and low-viscosity suppository formulations had significantly greater bioavailability (AUC0-24 72.7 +/- 13.2 for the oral preparation versus 98.6 +/- 35.7 and 105.8 +/- 37.3 ng.hr/mL for the suppositories, respectively, P < 0.05), later peak concentration (tmax 2.3 +/- 0.8 versus 3.1 +/- 2.3 and 5.0 +/- 1.5 hr, respectively, P < 0.05), and longer half-value duration (4.3 +/- 1.6 versus 10.4 +/- 5.5 and 9.5 +/- 4.3 hr, respectively, P < 0.05). Peak concentration for the high-viscosity suppository formulation (Cmax 7.75 +/- 2.66 ng/mL) was significantly lower than the low-viscosity suppository (Cmax 9.23 +/- 2.85 ng/mL) and the oral tablet (Cmax 10.4 +/- 2.78 ng/mL) formulations (P < 0.05). The increased bioavailability observed with the two controlled-release suppositories may be the result of partial avoidance of hepatic biotransformation with rectal administration.