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At least 19 recordsLinked to original sources
PubMed1978

Plasma codeine and morphine concentrations after therapeutic oral doses of codeine-containing analgesics.

Plasma concentrations of codeine and morphine were determined by specific radioimmunoassays in healthy human subjects at various times following oral administration of analgesic preparations containing therapeutic doses of codeine phosphate. Following administration of codeine phosphate (60 mg) in combination with aspirin (650 mg) or acetaminophen (600 mg) to two separate groups, mean peak codeine plasma concentrations and beta-phase elimination half-lives were 159 ng/ml and 2.9 hr or 138 ng/ml and 2.4 hr, respectively. Mean maximum concentrations of metabolically produced morphine were 6.8 ng/ml (aspirin-codeine phosphate administration) and 7.4 ng/ml (acetaminophen-codeine phosphate). Following drug administration, the mean ratio of the areas under the respective plasma concentration-time curves for morphine and codeine was 0.095 for the aspirin-codeine phosphate study and 0.12 for the acetaminophen-codeine phosphate study. Thus, free morphine represented about 10% of the free codeine area in each case. These results support the hypothesis that metabolically produced morphine may influence or be responsible for the analgesic efficacy of codeine.

Acetaminophen↗
PubMed1991

Urinary concentrations of codeine and morphine after the administration of different codeine preparations in relation to doping analysis.

A capillary GC method with nitrogen-specific detection is described for the analysis of codeine and morphine in urine. Both drugs were determined after enzymatic hydrolysis of the urine. Morphine was derivatized with trifluoroacetic anhydride. For 5-ml samples of urine, the lower detection limits for accurate quantitation were 50 ng ml-1 and 100 ng ml-1 for morphine and codeine, respectively. Both codeine and morphine were already detectable in urine 1 h after the intake of the analgesic preparation Perdolan. Codeine excretion and concentration peaked 2 h after administration of a dose. The percentage of the dose excreted as codeine was 3.0-6.2%. Administration of the antitussive preparation Bisolvon Griblettes resulted in detectable codeine and morphine levels for at least one day; 5.6-9% was excreted as total codeine over 24 h, the conjugated metabolite morphine accounting for 1.7-7.4% of the dose. Nearly the same amounts of codeine and morphine were excreted after administration of the antitussive syrup Bronchodine. The maximum excretion rate of codeine occurred after 1 h. Generally codeine and morphine remained detectable for 12 h. The results of these administration studies are discussed in relation to the codeine and morphine threshold levels recently introduced by the International Cyclist Union.

Chromatography, Gas↗
PubMed1990

Double-blind comparison of meclofenamate sodium plus codeine, meclofenamate sodium, codeine, and placebo for relief of pain following surgical removal of third molars.

A single-dose, randomized, double-blind, parallel-treatment study was performed in 200 outpatients with acute pain caused by the surgical removal of impacted third molars. Meclofenamate 100 mg plus codeine 60 mg, meclofenamate 50 mg plus codeine 30 mg, meclofenamate 100 mg, codeine 60 mg, and placebo treatment groups were compared for sum of pain intensity differences, peak pain intensity difference, sum of pain relief scores, peak pain relief, number of observations at which pain was half relieved, overall evaluation of effectiveness, and time to remedication with a backup analgesic. Meclofenamate 100 mg plus codeine 60 mg was significantly more effective (P less than .005) than codeine 60 mg for all variables except number of observations at which pain was half relieved. Both meclofenamate-codeine combinations and meclofenamate 100 mg alone were significantly more effective (P less than .005) than placebo for all variables. Eleven adverse experiences were reported in 7 patients (3.5%); the most common was somnolence in 1 patient receiving meclofenamate 100 mg plus codeine 60 mg, in 2 treated with meclofenamate 50 mg plus codeine 30 mg, and in 1 treated with codeine 60 mg.

Adolescent↗
PubMed1990

Plasma codeine and morphine concentrations after a single oral dose of codeine phosphate.

Plasma concentrations of codeine and its O-demethylated metabolite morphine were determined, by a sensitive and specific high performance liquid chromatography (HPLC) method, following a single oral dose of 60 mg codeine phosphate. Ten healthy volunteers received a single dose of 60 mg codeine phosphate. The plasma concentrations were analyzed for codeine and morphine at the 0.5, 1, 3, and 6 hours postdosing. The mean peak codeine plasma concentrations and tmax (time to reach maximum plasma codeine concentrations) were 88.1 ng/mL and 1.2 hours. Mean maximum concentrations of metabolically produced morphine was 2.7 +/- 0.6 ng/mL. The mean ratio of areas under the plasma concentration-time curves for morphine and codeine was 0.027. Thus, free morphine represented only about 2.7 +/- 1.8% of the free codeine area in each case.

Administration, Oral↗
PubMed1979

Ratios of total morphine to total codeine in urine of subjects consuming medicinal preparations containing morphine or codeine and in drug abusers.

Urinary total morphine: total codeine ratios were studied in two groups of people. Group A consisted of 76 subjects receiving three different medicinal preparations containing morphine or codeine, while Group B consisted of 33 drug abusers detected at urinary mass screening. Distinct differences in these ratios were observed. In Group A, total morphine: codeine ratios of 1:2.6 and below were obtained for subjects consuming either Tablet Codeine Co or Syrup Phensedyl. Subjects consuming Kaolin et Morphine mixture did not excrete any codeine in the urine. In Group B, total morphine: total codeine ratios of 1.9:1 and above were obtained. In addition all subjects in Group B excreted both morphine and codeine. The clear separation of the morphine: codeine ratios makes this a possible index to differentiate between these groups.

Codeine↗
PubMedDate not supplied

Forensic drug testing for opiates, III. Urinary excretion rates of morphine and codeine following codeine administration.

The urinary excretion profile of free and conjugated codeine and morphine was determined by GC/MS for four healthy male subjects after intramuscular administration of 60- and 120-mg doses of codeine. Codeine and metabolites were rapidly excreted with the majority of drug appearing in the first 24 h. No dose-related differences in metabolism were observed. The initial ratio of total codeine to total morphine was substantially greater than 1.0 but declined over time. For two of the four subjects, the codeine-morphine ratio declined below 1.0 late in the elimination phase. With a 300-ng/mL cutoff, one subject tested positive on more than one occasion for total morphine and negative for codeine during the terminal elimination phase. The data indicate that urine codeine-morphine ratios are not reliable indices of the type of opiate exposure.

Codeine↗
PubMed1978

Analgesic studies of codeine and oxycodone in patients with cancer. II. Comparisons of intramuscular oxycodone with intramuscular morphine and codeine.

The relative analgesic potency of single graded intramuscular doses of oxycodone and morphine was evaluated in a double-blind study in patients with chronic pain due to cancer. When both intensity and duration of analgesia are considered (total analgesic effect), oxycodone was 2/3 to 3/4 as potent as morphine, while in terms of peak analgesia, it was 8/10 to equipotent. In doses producing equivalent peak effect, oxycodone had a shorter duration of action than morphine. Intramuscular oxycodone was also compared to intramuscular codeine in a similar patient group. In terms of total analgesic effect, oxycodone was 10 times as potent as codeine, while in terms of peak analgesia it was 12 times as potent. These relative potency relationships of oxycodone, taken in conjunction with the oral/parenteral potency ratios of codeine and oxycodone established in the previous paper and several previous relative potency assays involving morphine, oxymorphone and codeine, demonstrate a highly consistent pattern of analgesic structure-activity relationships encompassing morphine, oxymorphone, codeine and oxycodone. The results of these studies do not appear to support the hypothesis that, in man, the analgesic activity of codeine is due to its O-demethylation to morphine.

Adult↗
PubMed1978

Analgesic studies of codeine and oxycodone in patients with cancer. I. Comparisons of oral with intramuscular codeine and of oral with intramuscular oxycodone.

The relative analgesic potency of oral and intramuscular codeine was evaluated in a double-blind crossover comparison of graded single doses in patients with chronic pain due to cancer. When both duration and intensity of analgesia are considered (total effect), oral codeine was 6/10 as potent as the intramuscular form. This is a high oral/parenteral analgesic relative potency ratio compared with morphine, metopon and oxymorphone and correlates well with the results of recent studies which have determined the oral vs. intramuscular bioavailability of codeine in man. Oral and intramuscular oxycodone were also compared in a similar patient group. Like codeine, oxycodone retained at least 1/2 of its analgesic activity when administered orally. We hypothesize that the high oral/parenteral relative potency ratios of codeine and oxycodone relative to morphine and its congeners are not due to more efficient absorption after oral administration, but rather that methylation at position 3 in codeine and oxycodone protects these drugs from rapid first-pass metabolism.

Administration, Oral↗
PubMed1977

Specific radioimmunoassays for codeine and morphine. Metabolism of codeine to morphine in the rat.

Specific antisera to morphine have been raised in response to immunization with a conjugate of N-carboxypropylnormorphine with bovine serum albumin (BSA). These antisera effectively distinguish changes in substituents at the 3 and 6 positions of the alkaloid, thus reducing cross-reactivity with codeine and morphine-3-glucuronide to negligible levels. The utility of these antisera has been illustrated by their application in radioimmunoassay procedures, along with similarly specific anti-codeine sera (Findlay et al., 1976) to a study of the biotransformation of codeine to morphine in the rat. After oral administration of codeine, serum levels of morphine were low, but significantly higher than codeine levels after 15 min., indicating rapid metabolism of codeine to morphine in this species.

Animals↗
PubMed1975

Blood codeine concentrations in fatalities associated with codeine.

The toxicologic findings in eight cases of death due primarily to codeine overdosage are presented. Blood codeine concentrations ranged from 1.4 to 5.6 mug/ml as determined by gas-liquid chromatography. Morphine was found in only two of the blood samples, at concentrations of 0.2 and 0.6 mug/ml, and may have resulted from heroin usage rather than codeine metabolism. A case of death of a codeine user by violent means is also presented in which the blood codeine concentration was 2.6 mug/ml.

Adult↗
PubMed1990

Morphine formation from codeine in rat brain: a possible mechanism of codeine analgesia.

The O-demethylation of codeine to morphine was demonstrated in rat brain homogenate. Maximal formation occurred at 10 minutes, with a Vmax of 5.93 +/- 0.16 nmol/g brain/h and Km of 37.82 +/- 4.99 microM. The formation was significantly (P less than 0.05) greater in the microvessel-rich brain fraction. Intraperitoneal injection of codeine in the rat resulted in brain concentrations of morphine which could not be solely attributed to transfer of morphine from the blood stream across the blood-brain barrier. Morphine formed in the brain after codeine administration may be an important mechanism for codeine-induced analgesia.

Analgesia↗
PubMed1985

The relative bioavailability of paracetamol and codeine after oral administration of a combination of buclizine, paracetamol and codeine, with or without docusate, and of paracetamol alone in healthy volunteers.

A randomized, double-blind, crossover study was carried out in 10 healthy volunteers to investigate whether the inclusion of the wetting agent docusate sodium (10 mg) in a combined oral formulation ('Migraleve') with buclizine hydrochloride (6.25 mg), codeine phosphate (8 mg) and paracetamol (500 mg) had any effect on the bioavailability of the analgesics. On 3 occasions at weekly intervals, the subjects were given 2 tablets of the standard formulation, the combination without docusate or 500 mg paracetamol alone. Blood samples were taken before and at fixed times during the 4 hours after administration of each preparation for estimation of plasma concentrations of paracetamol, by gas-liquid chromatography, and of codeine, by radioimmunoassay. The results showed that there were no significant differences between the mean paracetamol concentrations achieved after administration of each of the 3 preparations at any of the time points. Peak paracetamol plasma concentrations were 11.25 +/- 1.74 micrograms/ml at 0.5 hours, 9.6 +/- 1.04 micrograms/ml at 0.75 hours, and 9.53 +/- 1.66 micrograms/ml at 0.5 hours, respectively, after the standard formulation, the combination without docusate, and paracetamol alone. Mean elimination half-lives for paracetamol were 2.83 +/- 0.51, 1.92 +/- 0.20 and 2.49 +/- 0.46 hours, respectively, and the differences were not significant. The difference between mean plasma concentrations of codeine after the two preparations including this analgesic bordered on significance at 3 hours and was significant at 4 hours, but the areas under the curve were not significantly different. Peak codeine plasma concentrations after the standard formulation were 42.1 +/- 9.4 ng/ml at 0.75 hours compared with 36.9 +/- 3.4 ng/ml at 1.5 hours after the combination without docusate.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed1990

Species differences in metabolism of codeine: urinary excretion of codeine glucuronide, morphine-3-glucuronide and morphine-6-glucuronide in mice, rats, guinea pigs and rabbits.

1. Metabolites of codeine were determined by use of h.p.l.c. in urine of male mice, rats, guinea pigs and rabbits injected with 10 mg codeine/kg subcutaneously. 2. In 24 h urines of these species, unchanged codeine, codeine glucuronide, free morphine, and morphine-3-glucuronide were as follows: mice, 6.8, 1.6, 0.8 and 7.6% dose; rats, 1.6, 0.2, 4.3 and 23.9% dose; guinea pigs, 1.6, 39.8, 0.2 and 1.6% dose; rabbits, 2.2, 24.5, 1.3 and 17.9% dose. Urinary excretion of morphine-6-glucuronide was 0.7% dose in guinea pigs, 1.9% in rabbits, and not detectable in mice and rats. Norcodeine was found only in the urine of mice. 3. These results indicate that codeine is metabolized in all four species by glucuronidation and by oxidative N- and O-demethylation, but the quantitative excretions of metabolites were quite different in different species.

Animals↗
PubMed1979

Urinary excretion levels of morphine and codeine in subjects consuming medicinal preparations containing morphine or codeine and in drug abusers.

Urinary levels of morphine and codeine were studied in two groups of people: Group A--urine samples of 76 subjects receiving three different medicinal preparations containing morphine or codeine. Group B--urine samples of 67 drug abusers detected at urinary mass screening. Distinct differences in these levels were observed. In Group A, UPPER 99% Confidence limits of morphine concentrations of 2.56 microgram/ml, 2.40 microgram/ml and 2.29 microgram/ml were reached after consumption of prescribed doses of Syrup Phensedyl, Tablet Codeine Co and Kaolin et Morphine mixture respectively. In Group B, the LOWER 99% Confidence limit of morphine concentration was 3 microgram/ml. In contrast, the codeine levels obtained for both groups were similar. The clear separation of the ranges of morphine values for the two groups shows that the urinary morphine level forms a reliable index for the differentiation between these two groups.

Adolescent↗
PubMedDate not supplied

The human urinary excretion pattern of morphine and codeine following the consumption of morphine, opium, codeine and heroin.

The urinary excretion patterns of morphine and codeine in a number of individuals following consumption of morphine-based narcotic drugs have been studied. From the data collected the relative amounts of codeine and morphine in urine specimens were compared and certain trends, consistencies and irregularities were revealed. To a certain extent, the ratio of the proportion of codeine to morphine excretion in urine may be used to determine the nature of the drugs consumed. This correlation is useful in the interpretation of the results of urine analysis which is the basis of effective control and rehabilitation of drug addiction.

Codeine↗
PubMed1978

[The behaviour of codeine and codeine-6-glucuronide in hydrolysis with hydrochloric acid (author's transl)].

The behaviour of codeine and codeine-6-glucuronide with hydrochloric acid has been investigated. Three methods of hydrolysis were selected; they are often used in routine identification of drugs in urine. With method I (12--13% HCl; 30 min at 100 degrees C) about 53% of codeine-6-glucuronide were not hydrolized. The corresponding values: with method II (20% HCl; 6 min heated azeotrope in open vessel) about 8% and with method III (nearly 5% HCl; 30 min at 100 degrees C) about 83%.

Chemical Phenomena↗
PubMed1992

A multiple dose comparison of combinations of ibuprofen and codeine and paracetamol, codeine and caffeine after third molar surgery.

In a randomised, double-blind, double-dummy, multiple dose, crossover study in 30 patients we compared an ibuprofen/codeine combination (400 mg ibuprofen/25.6 mg codeine phosphate) with a paracetamol/codeine/caffeine combination (1 g paracetamol/16 mg codeine phosphate/60 mg caffeine) for pain relief over 6 days after two-stage bilateral lower third molar removal. The ibuprofen combination produced significantly greater analgesia than the paracetamol combination, both on single-dose analysis of the first and second days and on multiple-dose measures for days 1, 2, 3 and 4. The mean incidence of adverse effects over the 6 days was 20% for both combinations. This trial design (crossover with multiple dosing in outpatients) is a sensitive way of testing for analgesia, and is potentially more predictive of adverse effect problems than single-dose studies. It confirms that multiple dosing may show increased efficacy.

Acetaminophen↗
PubMed1975

Acute codeine overdose: correspondence between clinical course and codeine metabolism.

A patient presented with clinical features of drug overdose. Although heroin was suspected, codeine was identified by drug analysis. The clinical course was complicated by shock, respiratory arrest and laboratory evidence of acute hepatic insufficiency. An inital slow rate of codeine metaboism, possibly related to the hepatic damage, corresponded to prolonged respiratory depression.

Adult↗