Actions and Metabolism of Codeine (Methylmorphine) Administration by Continuous Intravenous Infusion to Humans

Abstract

Miosis produced by codeine is not antagonized by nalorphine until large oral doses are administered for several days. This experiment was conducted to further study this characteristic of the codeine effect. Eight healthy male volunteers, who were former drug users, were divided into 2 groups. Subjects in the 1st group were given a continuous infusion of codeine, 30 mg/h for 11-16 h. No subjective effects were reported by the volunteers. In 3 of the individuals definite miosis antagonized by nalorphine was observed at 9.5 h. The dose of codeine for the 2nd group was 60 mg/h for 11 h. Mild but definite subjective effects were experienced by each of the participants in this group. Miosis appeared between 2 and 6 h. Challenges at 4 and 6 h were positive in 2 subjects and negative or equivocal in the other 2. Codeine was excreted in the urine as free and conjugated codeine, morphine and norcodeine. Maximum rates of excretion were similar for both groups, suggesting that the maximum amount of codeine that can be metabolized is equal or less than 30 mg/h. Also codeine clearance, being greater than creatinine clearance, suggests that codeine might be excreted by glomerular filtration and tubular secretion. Blood levels of codeine in the 60 mg/h group were about 10 times those reported as therapeutic. Morphine or norcodeine were not detectable by the methods used.