Addiction Research Center, IRP, NIDA, NIH, Baltimore, MD, USA

Codeine was detected ca. 30 min after dosing with peak drug concentrations occurring typically at 1 to 2 hr. The mean peak codeine concentration (Cmax ± S.E.M.) for five subjects was 147 ± 50 ng/mL following the low dose and 378 ± 101 ng/mL after the high dose. The mean AUC (ng-min/mL) ± S.E.M. for the low and high dose was 28,326 ± 8,784 and 108,088 ± 18,346 respectively. Cmax and AUC measures for codeine were significantly greater (p < 0.05) following the high dose compared to the low dose.

Norcodeine was the primary codeine metabolite in plasma, and norcodeine concentrations were less than 10% of codeine. Normorphine was detected in some specimens, but concentrations were low relative to norcodeine. Morphine was not generally detected.

The primary pharmacological effect of codeine was miosis. Significant decreases (p < 0.05) in pupil size occurred at 15 min, 1 h, and 2 h after the high dose. Peak changes in heart rate, pupil diameter, "Liking" and "High" measures consistently occurred after peak plasma codeine concentrations resulting in counterclockwise hysteresis effects. The observed hysteresis may be related to metabolism of codeine to a pharmacologically active metabolite(s) or due to delayed distribution of codeine from blood to effector sites in the central nervous system.