Miosis produced by
codeine is not antagonized by
nalorphine until large oral doses are administered for several days. The present experiment was conducted in order to further study this characteristic of the
codeine effect. Eight healthy male volunteers, who were former drug users, were divided into two groups. Subjects in the first group were given a continuous infusion of
codeine, 30 mg/hr for 11-16 hr. No subjective effects were reported by the volunteers. In three of the individuals definite
miosis antagonized by
nalorphine was observed at 9.5 hr. The dose of
codeine for the second group was 60 mg/hr for 11 hr. Mild but definite subjective effects were experienced by each of the participants in this group.
Miosis appeared between 2 and 6 hr. Challenges at 4 and 6 hr were positive in two subjects and negative or equivocal in the other two.
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/hr. 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/hr group were about 10 times those reported as therapeutic. However,
morphine or
norcodeine were not detectable by the methods used.