HUMAN PHARMACOKINETIC STUDY OF IMMEDIATE-RELEASE (CODEINE PHOSPHATE) AND SUSTAINED-RELEASE (CODEINE CONTIN) CODEINE

The authors compared, in a double-blind, randomized, crossover study in 13 healthy adult volunteers, the single- and multiple-dose pharmacokinetics, relative bioavailability and side effects of a new oral sustained-release formulation of codeine (SRC) containing 150 mg codeine base, with oral immediate-release codeine phosphate (IRC). Sustained-release codeine was given at a dose of 150 mg every 12 hours for 5 doses; IRC was given at a dose of 60 mg (2 x 30 mg) every 4 hours for the first 3 doses, and 30 mg every 4 hours thereafter for 12 doses. Plasma codeine levels were determined using a sensitive and specific high-performance liquid chromatography method and corrected for dose administered and codeine base equivalent. Mean values for single-dose pharmacokinetic parameters for SRC and IRC, respectively, were: C-max of 217.8 and 138.8 ng/mL; T-max of 2.3 and 1.1 hours; AUC(0-inf) of 1202.3 and 1262.4 ng.mL(-1).hour(-1); and t(1/2)el of 2.6 hours for both formulations. Their respective mean steady-state pharmacokinetic parameters were: C-max of 263.8 and 222.9 ng/mL; T-max of 3.2 and 1.1 hours; AUC(0-12h) of 1576.4 and 1379.1 ng.mL(-1) hour(-1); and t(1/2)el of 2.8 and 2.3 hours. These results indicate comparable bioavailability between both formulations with SRC providing delayed peak plasma levels. The sustained-release character of SRC can be explained by a delayed absorption, which is not limiting to drug elimination. Sustained-release codeine provides higher plasma codeine levels over a broader time interval and is expected to improve pain management.