Human Pharmacokinetic Study of Immediate‐Release (Codeine Phosphate) and Sustained‐Release (Codeine Contin) Codeine

Abstract

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: Cmax of 217.8 and 138.8 ng/mL; Tmax of 2.3 and 1.1 hours; AUC0-inf of 1202.3 and 1262.4 ng.mL-1.hour-1; and t1/2el of 2.6 hours for both formulations. Their respective mean steady-state pharmacokinetic parameters were: Cmax of 263.8 and 222.9 ng/mL; Tmax of 3.2 and 1.1 hours; AUC0-12h of 1576.4 and 1379.1 ng.mL-1.hour-1; and t1/2el 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.

La codéine à libération contrôlée est équivalente à de l’acétaminophène plus de la codéine pour l’analgésie postcholécystectomie

“…The controlled-release formulation has demonstrated equivalent bioavailability to immediate-release tablet or liquid codeine formulations in single dose and steady-state studies. 21 In acute pain models, the median time to onset of analgesia with controlled-release codeine was 30 to 40 min, similar to immediaterelease preparations.…”

Is it farewell to codeine?

“…The pharmacokinetics of codeine are poorly described in children despite use over decades. A volume of distribution (V) of 3.6 L/kg, a clearance (CL) of 0.85 L/h and a plasma half-life is 3–3.5 h26 have been described in adults, but there are few data detailing paediatric pharmacokinetic developmental changes. The neonatal half-life is longer due to immature clearance (eg, 4.5 h), while that of an infant is shorter (eg, 2.6 h)27 attributable to size factors 28…”

Pro–con debate: is codeine a drug that still has a useful role in pediatric practice?

“…Oral codeine is rapidly absorbed with approximately 50% of the dose undergoing first pass metabolism. Peak plasma concentrations occur ∼1 h, and the plasma half‐life is 3–3.5 h in adults (29). IM absorption speed is similar to that by the rectal route, although the latter is associated with variable absorption (30).…”