Norman Nomof

Actions and metabolism of heroin administered by continuous intravenous infusion to man

The effects of heroin given to human subjects by continuous intravenous infusion are described. Progressive CNS depression eventually required reversal with levallorphan. There was no indication of development of acute tolerance to the depressant effects of heroin. Blood and urine specimens were collected for analysis of metabolites and analyzed for morphine, 6‐monoacetylmorphine, and heroin by gas‐liquid chromatography. Blood concentrations were too low to identify any heroin or metabolites, but about fifty per cent of the dose was recovered in the urine mostly as bound morphine with small amounts of 6‐monoacetylmorphine and heroin present in some specimens. Rate of excretion of total morphine indicated that man can metabolize about 6 mg. per 93 Kg. per hour of heroin.

Blood and Urine Concentrations of Subjects Receiving Barbiturates, Meprobamate, Glutethimide, or Diphenylhydantoin

(1970). Blood and Urine Concentrations of Subjects Receiving Barbiturates, Meprobamate, Glutethimide, or Diphenylhydantoin. Clinical Toxicology: Vol. 3, No. 1, pp. 131-145.

The local effect of morphine, nalorphine, and codeine on the diameter of the pupil of the eye

We have demonstrated that morphine (but not codeine) when applied locally to the coniunctival sac in a solution containing polysorbate produces a small but definite degree of miosis. This is apparently a local effect, since it is significantly greater in the treated than in the untreated eye. Locally applied nalorphine may also produce miosis by direct action; but this drug appears to be absorbed more readily than morphine, and its systemic effect largely masks its local effect. Locally (but not systemically) administered nalorphine, however, antagonizes the miosis produced by local application of morphine.

Comparison of the nalorphine test and urinary analysis in the detection of narcotic use

Several parameters of the nalorphine test for narcotic use were evaluated in prisoners with histories of prior narcotic use. Measurement of changes in pupillary diameter caused by narcotics alone or in combination with narcotic antagonists was correlated with chemical analysis of the urine for narcotics or metabolites. After one dose of morphine, the pupillary test remained positive about 4 hours, while urinalysis usually detected a single dose for as long as 36 hours. However, when morphine was administered every 6 hours for 5 days, some sub;ects gave positive pupillary tests 20 hours after the last dose. Negative pupillary tests were obtained after as many as three doses of codeine, but when codeine was given every 6 hours for 5 days more positive tests were obtained each day. Positive pupillary tests were obtained 2 to 4 hours after single in;ections of meperidine, heroin, and oxycodone, and 6 hours after methadone. The pupillary test is a useful method of screening for narcotic use, which might well be combined with chemical tests for narcotics in the urine.

Actions and metabolism of codeine (methylmorphine) administration by continuous intravenous infusion to humans.

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.

Correlation of the nalorphine test with concentration of metabolites of codeine in the urine after single doses and continuous administration of codeine.

Single doses of codeine cause miosis which is not reversed by nalorphine, as the miosis with other morphinelike drugs is. When codeine was given four times a day, most subjects gave positive nalorphine (pupil) tests on the third day. Urinalysis for codeine and its metabolite morphine revealed that subjects with the highest urine drug levels had the most strongly positive pupil tests, but the gradual development of a positive pupil test was not related to increasing concentrations of morphine in the urine. When codeine was infused continuously (30 mg. per hour) to produce “acute tolerance,” the pupil test was positive in 8 hours. In the dog, a species which forms norcodeine but not morphine from codeine, the pupil test was negative after a single injection of codeine but became positive after 2 to 3 days of intermittent injections. The data suggest that positive nalorphine tests occur only in subjects tolerant to codeine.

Distribution of CO and Radiochromium in Blood and Tissues of Rabbit and Dog. I. Carbon Monoxide.

Summary 1. Carbon monoxide gas and autogenous red cells tagged with Cr51 were administered simultaneously to rabbits and to dogs. Blood and homogenized tissues from various organs were analyzed for radioactivity and for CO content. 2. The volume of distribution of CO was 13% larger than the volume of distribution of Cr51 in the rabbit. The discrepancy is the same as that found in man and the splenectomized dog. 3. CO accumulated in red skeletal muscle and myocardium in amounts sufficient to account for the discrepancy between distribution volumes. 4. Evidence was found pointing to slight accumulation of Cr51 in spleen and lung. Further studies of this phenomenon are described in part II of this report.

Distribution of CO and radiochromium in blood and tissues of rabbit and dog. II. Radiochromium.

Summary 1. Carbon monoxide and autogenous red cells labeled with Cr51 were administered simultaneously to dogs and rabbits; tissue homogenates and blood were then analyzed for radioactivity and CO content. 2. Small amounts of Cr51 accumulated regularly in spleen and lung and, when the cells were delivered via the portal vein, in the liver. No sequestration occurred in brain, kidneys or extremities. 3. Prolonged storage of tagged cells, particularly when suspended in saline rather than plasma, increased the loss of Cr51 from the cells in vitro and by early sequestration after injection of the cells into their donors. 4. When cells were stored in saline for only 1 day, combined losses caused by in vitro leakage and sequestration were too small to influence the results of blood volume determinations.