Comparative pharmacokinetics of two modified-release oral morphine formulations (Reliadol (R) and Kapanol (R)) and an immediate-release morphine tablet (Morfin 'DAK') in healthy volunteers

Objective: Reliadol(R) (Nycomed Denmark A/S) is a new modified-release morp hine formulation undergoing clinical evaluation. It consists of a mixture o f rapid- and modified-release microencapsulated granules of morphine. The s tudy aims were to investigate the single-dose pharmacokinetics of morphine, its metabolites morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M 3G), after ingestion of Reliadol(R) (2 x 30mg capsules) compared with Kapan ol(R) (3 x 20mg) [Glaxo Wellcome Australia Ltd] and an immediate-release mo rphine tablet (Morfin 'DAK', 30mg; Nycomed Denmark A/S). Design and Setting: A three-way randomised, crossover study conducted in an inpatient drug studies' unit. Study Participants and Interventions: Twenty-four healthy volunteers took e ach formulation on three separate occasions after an overnight fast. Results: The dose-normalised areas under the plasma concentration Versus ti me curve were equivalent for the three formulations for all three analytes. The time to achieve maximum plasma concentration (C-max) was significantly shorter for Reliadol(R) (mean +/- SD 4.0 +/- 2.2h for morphine; 4.9 +/- 1. 4h for M6G; 6.0 +/- 1.5h for M3G) than for Kapanol(R) (7.9 +/- 2.7h for mor phine; 9.3 +/- 2.0h for M6G; 9.7 +/- 1.9h for M3G), but significantly longe r for the two modified-release formulations than for Morfin 'DAK' (0.83 +/- 0.35h for morphine; 1.6 + 0.4h for M6G; 1.4 +/- 0.4h for M3G). The Cmax of the three analytes was not different for the two modified-release formulat ions but was significantly lower for Morfin 'DAK'. The time over which the plasma concentration exceeded 75% of the Cmax was equivalent for Reliadol(R ) (5.7 +/- 2.6h for morphine; 6.9 +/- 2.0h for M6G; 7.5 +/- 2.0h for M3G) a nd for Kapanol(R) (4.9 +/- 2.2h for morphine; 6.0 +/- 1.8h for M6G; 6.5 +/- 2.1h for M3G), but was significantly shorter for Morfin 'DAK' (0.76 +/- 0. 40h for morphine; 1.4 +/- 0.5h for M6G; 1.4 +/- 0.4h for M3G). The time ove r which plasma concentration exceeded 50% of the C-max and mean residence t ime were equivalent for Reliadol(R) and for Kapanol(R) but significantly sh orter for Morfin 'DAK'. The most common adverse events were nausea and head ache. Conclusions: Reliadol(R) is likely to be suitable for once-daily administra tion in patients with chronic pain because of its unique plasma concentrati on versus time profile resulting from the mixture of rapid- and modified-re lease morphine pellets.