Codeine Administration Research Articles

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.

Investigations on drug produced and subjectively experienced discriminative stimuli: 2. Loperamide, an antidiarrheal devoid of narcotic cue producing actions.

By means of a new behavioral procedure effectively controlling the narcotic stimulus properties of drugs, it was found that the oral administration of fentanyl, morphine, codeine and diphenoxylate produced the narcotic cue. The new antidiarrheal loperamide did not produce this cue in rats as sensitive as being able to detect 0.005 mg/kg s.c. fentanyl. The results are discussed in terms of drug abuse liability.

Studies on the Physical Dependence Liability of Analgesics 4th Report: Electron Microscopic Study on Intramitochondrial Structure of Zona Fasciculata Cells in Adrenal Cortex in Codeine Addicted Rats

Influence of codeine on the fine structure of mitochondria in the cells of zona fasciculata of rat adrenal cortex was studied electronmicroscopically. By the administration of codeine in a dose of 40 mg/kg, the number of intramitochondrial vesicles was decreased, the change being diminished during repeated administration of the drug. Withdrawal of codeine reproduced an extensive transformation, while with a re-injection of the drug, a prompt restoration to the pretreated structure was observed. The feasibility of utilizing this transformation as an index of physical dependence liability has been discussed.

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.

An in vivo assay for thyrotropin releasing factor.

An in vivo method for assaying thyrotropin releasing factor (TRF) in mice has been described. Administration of codeine to mice given 131I and 1 μ thyroxine increased the responsiveness of the pituitary to TRF preparations. There was a linear relationship between the log dose of TRF and the increase in blood radioactivity. When TSH is assayed by this method the dose-response range is linear from 0.05 to 0.8 mU with an index of precision (λ) of 0.2. Purified TRF preparations of porcine, ovine, bovine and human origin raised blood 131I levels in the thyroxine-codeine treated mice but not in hypophysectomized mice prepared in the same manner. These same TRF preparations were also inactive in mice pretreated with large amounts of thyroxine. Doses of vasopressin, α- and β-MSH, known to release 131I from the thyroid gland in mice prepared for the McKenzie TSH assay, did not elicit a significant response in mice given codeine and 1 μg of thyroxine. These results obtained in the codeine-thyroxine assay are in agr...

The composition of ileostomy fluid

The paper presents data on the sodium, potassium, and water content of ileostomy dejecta from 12 patients with new ileostomies and six patients with established ones. The effects of administration...

Transaminase activity after codeine administration.

THE quantitative and serial changes that occur in serum glutamic-oxaloacetic transaminase (SGOT) activity during the course of a myocardial infarction are well recognized. Changes in SGOT activity have been observed in other diseases such as hepatitis and pancreatitis (Wroblewski and LaDue, '955; Chinsky, Shmagranoff and Sherry, 1956) and after the administration of drugs such as chlorpromazine, pyrazinamide and opiates (quoted by Wroblewski, Ross and Gregory, I960). Foulk and Fleisher (I957) showed that opiates given as codeine produced quite a marked increase in SGOT activity in each of six patients who had had a cholecystectomy and who had subsequent abdominal pain. They were unable to account for this phenomenon but considered that transient biliary obstruction due to codeine-induced spasm of the bile ducts and duodenum was probably responsible. They concluded that in the interpretation of a raised SGOT activity the possible role of opiates administered in the preceding 24 hours should be considered. In view of these findings it was decided to study experimentally the effect of codeine phosphate on the SGOT andI SGPT (serum glutamic-pyruvic transaminase) activities in a number of patients.

A Rat Test for Drug Addiction.

Further experiments on the addiction liability of various drugs in the albino rat have been carried out by the method previously described. The test measures objectively progressive changes in the degree of irritability of the animal 24 hours after withdrawal of the drug throughout the period of administration. Advantage is thus taken of the most outstanding part of the abstinence syndrome clinically and experimentally, hyperirritability, to assess the ability of a drug to produce addiction. The irritability of the rat which is normally fairly constant for a series of animals is quantitatively measured by determining the struggle response to a uniformly uncomfortable situation. Such a situation is provided by lashing the animal in the supine position to a small animal board so constructed that the animal is free to struggle but can neither injure nor extricate itself. Graphic records of each struggle are made kymographically by a light lever attached to the skin overlying the xyphoid process. The response of the animal is expressed by the number of struggles per interval and is a quantitative index of the degree of irritability of the animal at that time. Daily administration of morphine, codeine, or heroine results consistently in progressive increase of 24-hour abstinence hyper-irritability as shown by the struggle response to the above described uniformly uncomfortable situation. Control animals receiving injections of water showed only a gradual decrease in irritability under the same experimental conditions. Dihydromorphinone hydrochloride (dilaudid): To completely eliminate the movements of rats in the device described above, dilaudid was 10 times as potent as morphine. Complete tranquilization was obtained with dilaudid in one-tenth of the dosage necessary with morphine. When daily doses of equal tranquilizing potency were given, no significant difference in addiction liability could be found between dilaudid and morphine.