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PubMed1987

Pharmacokinetics of codeine after single- and multiple-oral-dose administration to normal volunteers.

The pharmacokinetics of codeine, codeine glucuronide, morphine, and morphine glucuronide were assessed after single- (60 mg) and multiple-dose (60 mg every six hours for nine doses) oral administration of codeine sulfate to six normal volunteers. Multiple blood and urine samples were collected after administration of the single- and last multiple-oral doses. Drug concentrations were analyzed using radioimmunoassay techniques. No significant alterations in codeine pharmacokinetics were noted after multiple-dose oral administration. However, accumulation of morphine during multiple dosing was significant (AUC24 = 102 +/- 33 ng/mL/hr after single dose versus 212 +/- 118 ng/mL/hr after the last multiple dose). Peak concentration and AUC24 data for morphine glucuronide indicated that significant accumulation of this compound occurs upon multiple-dose administration. These data indicate that morphine and morphine glucuronide serum concentrations are significantly increased during chronic oral codeine therapy and suggest that morphine, and perhaps morphine glucuronide, contribute significantly to the analgesic activity of chronic oral codeine therapy.

Adult↗
PubMed1988

Double-blind parallel comparison of ketoprofen (Orudis), acetaminophen plus codeine, and placebo in postoperative pain.

One hundred sixty-one patients with postoperative pain were treated at a single center in a double-blind, randomized, parallel study designed to compare the efficacy and safety of single oral doses of ketoprofen (50 and 150 mg), an acetaminophen (650 mg) plus codeine (60 mg) combination, and placebo. From 1 through 4 hours after administration of the study drugs, the mean summed pain intensity difference (SPID) and time-weighted total pain relief (TOPAR) scores for the three active treatments generally were significantly (P less than 0.05) higher than those for placebo but not significantly different from each other. At the 6-hour evaluation, the ketoprofen groups, but not the acetaminophen-codeine group, had higher (P less than 0.05) mean SPID and TOPAR scores than the placebo group, as a result of a shorter duration of pain relief in the acetaminophen-codeine group. The 6-hour TOPAR scores were significantly (P less than 0.05) higher for both ketoprofen groups than for the acetaminophen-codeine group; the ketoprofen 150 mg group also had significantly (P less than 0.05) higher mean 6-hour SPID and global subjective assessment scores. As a result of a higher frequency of somnolence, there was a significantly (P less than 0.05) greater incidence of central nervous system adverse drug reactions among patients treated with acetaminophen plus codeine than among those treated with 150 mg of ketoprofen. These results indicate that the analgesic efficacy of both 50 and 150 mg doses of ketoprofen equals that of acetaminophen 650 mg plus codeine 60 mg and the duration of the analgesic effect of ketoprofen is significantly longer.

Acetaminophen↗
PubMed1977

Evaluation of teratogenic potential codeine sulfate in CF-1 mice.

The most prominent defect of codeine sulfate, 100 mg/kg sc, was delayed ossification of the supraoccipital bone, paws, xiphoid, and sternebrae as well as other sternebral defects such as checkerboard sternebrae and polysternebrae. Although these anomalies were similar to the minor defects seen in the fetuses of morphine sulfate-treated mice, the major anomalies such as exencephaly, cryptorchid testes, and rib and vertebral fusions produced by morphine were not present in the fetuses of mice challenged with codeine. Thus, codeine sulfate appears to be less teratogenic than morphine sulfate. A review of the incidences of the various defects in mice treated on a single day with codeine showed that there was a range of days on which the mouse fetus was susceptible to codeine's teratogenic effects, with the most critical days of gestation being Days 8-10. Furthermore, a comparison of the defects that occurred in those treated on both Days 8 and 9 with the defects that occurred in those treated on a single day of gestation reveals an additive or cumulative teratogenic response to codeine.

Animals↗
PubMed1987

Solid-state esterification of codeine phosphate by the acid constituent of effervescent tablets.

Codeine phosphate in a paracetamol:codeine effervescent tablet was found to react at room temperature and 37 degrees C with the citric acid constituent to form citrate esters of codeine. The esterification was confirmed in a solid-state reaction at elevated temperature. The structures of the three possible monosubstituted esters (1-3) were elucidated from spectroscopic data (nuclear magnetic resonance and mass spectrometry) and by selective hydrolysis of the dimethyl esters to give symmetrical and asymmetrical dimethyl citrates. In the degradation reaction, formation of the symmetrically substituted citrate ester of codeine, 1, was found to predominate. Tartaric acid, which can be used in effervescent tablet formulations, was also found to give an ester with codeine phosphate in a similar nonsolvolytic reaction. A liquid chromatographic method was developed for the separation of the citrate esters of codeine.

Chemical Phenomena↗
PubMed1991

A dose-ranging study of the pharmacokinetics of codeine phosphate following intravenous administration to rats.

The linearity of the pharmacokinetics of codeine was examined in male Sprague-Dawley rats given iv bolus doses of 1, 1.5, 3, and 4 mg/kg of codeine phosphate. Codeine and morphine were determined in serial blood samples utilizing HPLC with electrochemical detection. Codeine exhibits characteristics consistent with a two-compartment pharmacokinetic model. The kinetics of codeine are linear in the iv dose range 1-4 mg/kg. The ratio AUCmorphine:AUCcodeine increases disproportionately with increasing doses of codeine.

Animals↗
PubMed1991

Impact of environmental and genetic factors on codeine analgesia.

The polymorphic cytochrome P-450 DB1 (P-450 IID6) is responsible for the O-demethylation of codeine to morphine by human liver microsomes. The influence of P-450 DB1 variable activity on the bioactivation of codeine in vivo to morphine and on its analgesic effect was investigated in phenotyped healthy volunteers--7 extensive [EM] and 1 poor [PM] metabolizer of debrisoquine. After pretreatment with oral placebo or quinidine sulphate 50 mg, codeine phosphate 100 mg or placebo were administered orally according to a double-blind randomized crossover design. In EM subjects the plasma morphine Cmax was 17.9 nmol/l, whereas virtually no morphine was detectable after quinidine pretreatment (1.5 nmol/l), and in the PM subject (0.60 nmol/l). In EM codeine significantly increased subjective (VAS) and objective (R-III reflex) pain thresholds in response to selective transcutaneous nerve stimulation, whereas no significant analgesia was detected after placebo, or after codeine with quinidine pretreatment, or in the PM. In PM of genetic origin, or due to environmental alteration of the phenotypic expression (i.e. drug interaction), codeine is not activated into morphine and is an inefficient analgesic.

Administration, Oral↗
PubMed1981

Codeine-induced memory changes: nature and relationship to opiate system.

Learning and recall processes were studied in three experiments with 33 subjects, 1 and 3 h after oral administration of codeine phosphate 25 mg, 50 mg and 100 mg. Recall was measured 3 and 24 h after drug administration. Nine subjects received naloxone i.m. with the 50 mg dose of codeine. Learning and memory were assessed by using associative, serial and concept learning tasks. Flicker fusion frequency was measured to assess the general vigilance level of the subjects. Learning performance in the serial learning task was improved 3 h after administration of codeine 100 mg. Recall in the serial learning task was also improved after codeine 25 mg, but only when the material was learnt after 1 hour and was recalled 24 h after drug intake. To demonstrate the enhanced recall both learning and recall had to take place under the same drug condition. The same test showed a tendency to enhanced recall after codeine 50 mg of material learnt 1 hour after drug intake and recalled 24 h later. This effect was counteracted by naloxone. The data are consistent with the hypothesis that codeine may exert its action via opiate receptors and that this system participates in memory functions.

Adult↗
PubMed1982

Paracetamol plus supplementary doses of codeine. An analgesic study of repeated doses.

A double-blind, multicentre analgesic trial was carried out in patients suffering from pain after removal of an impacted lower wisdom tooth. 266 patients were evaluated after random allocation to treatment with paracetamol 500 mg, paracetamol 500 mg plus codeine 20 mg, paracetamol 500 mg plus codeine 30 mg, or paracetamol 500 mg plus codeine 40 mg. On the day of surgery the patients assessed their own pain intensity hourly on a visual analogue scale. The analysis of the results was carried out according to the method which considered repeated dose intake. A statiscally significant dose-response relationship was obtained between the supplementary doses of codeine and analgesic efficacy. In the comparison of side effects, their frequency increased with increasing amounts of codeine. In clinical practice codeine 30 mg appeared to be the optimal supplement for paracetamol 500 mg.

Acetaminophen↗
PubMed1996

The effect of cetirizine and loratadine on codeine-induced histamine release in human skin in vivo assessed by cutaneous microdialysis.

OBJECTIVE AND DESIGN: To determine whether or not cetirizine and loratadine inhibit codeine- induced histamine release in human skin in vivo, we conducted a placebo-controlled double-blind trial in which histamine release was assessed by dermal microdialysis. SUBJECTS: A group of ten normal volunteers were studied, each subject visiting the laboratory on three occasions with intervals of at least 2 weeks between visits. TREATMENT: Cetirizine, loratadine (both 10 mg) or placebo was given orally 4 h before provocation of weal and flare responses in the skin by intradermal injection of 25 microliters of 3 or 10 mg/ml codeine 1 mm from the centre of individual 216 microns diameter microdialysis fibres inserted in the dermis. METHODS: Dialysate was collected at 2 min intervals for 4 min before and 20 min after codeine injection and histamine assayed spectrofluorometrically. Weal and flare responses to codeine were assessed in the opposite arm. RESULTS: Histamine concentrations in the microdialysis fibre outflow with 3 and 10 mg/ml codeine were maximal at 2-4 min when 910 +/- 156 and 1194 +/- 304 nM respectively were found in the placebo group. Cetirizine and loratadine did not modify either the kinetics or total histamine release while significantly (p < 0.01) inhibiting weal and flare responses. CONCLUSIONS: Neither cetirizine nor loratadine inhibited codeine-induced histamine release or modified the time course of its release in human skin in vivo when given in clinically used doses which are sufficient to significantly reduce weal and flare responses.

Adult↗
PubMed2005

The GC-MS detection and characterization of neopine resulting from opium use and codeine metabolism and its potential as an opiate-product-use marker.

Neopine, a minor opium alkaloid and an isomer of codeine (also known as beta-codeine), has been detected in both the urine of opium users and pharmaceutical codeine users. The characterization of neopine was achieved by comparison of the mass spectra and GC retention times of the trimethylsilyl derivative. The presence of neopine in the urine of pharmaceutical codeine users was attributed to the metabolism of codeine through a double bond migration in ring C, from the 7-8 to the 8-14 position. The potential use of the alkaloid as a confirmation marker of opium and/or pharmaceutical codeine use and the ability to differentiate these from heroin use has been discussed.

Biomarkers↗
PubMed1998

Codeine in post-operative pain. Study of the influence of sparteine phenotype and serum concentrations of morphine and morphine-6-glucuronide.

OBJECTIVE: Within the past decade, human experimental pain studies have supported the 50-year-old hypothesis that codeine is a prodrug, which has to be converted to morphine to exert an analgesic effect. This study aimed at evaluating the impact of sparteine phenotype and serum concentrations of morphine on the efficacy of codeine in post-operative pain. METHODS: Eighty-one patients with a pain rating of 3 or more on a 0-10 numerical rating scale 0.5 h after surgery were included in the study. The patients were given an oral dose of 100 mg codeine and rated pain with the numerical rating scale 0.5 h and 1 h after medication. Blood for determination of serum concentration of codeine and its metabolites was collected 1 h after medication, and a 12-h urine sample after administration of 100 mg sparteine was used to determine the sparteine phenotype. RESULTS: Eight patients were poor metabolizers and 66 were extensive metabolizers of sparteine, while the urine samples for the remaining seven patients were lost. In 22 patients, including the eight poor metabolizers, the serum concentrations of both morphine and morphine-6-glucuronide (M6G) were below the limit of determination of the assay, i.e. 1.5 nmol x l(-1) and 2 nmol x l(-1), respectively. A sum of the concentration of these two substances below 10 nmol x l(-1) was found in an additional eight patients. The sum of differences between pre- and post-operative pain ratings did not differ between the two phenotypes (P = 0.60), whereas the 30 patients with serum concentrations of morphine plus M6G below 10 nmol x l(-1) had a marginally significant lower sum than the 51 patients with higher levels of these substances (median 1.5 vs 2.5, P = 0.058). CONCLUSION: A low serum concentration of morphine and M6G seems to be common in patients treated with codeine for post-operative pain, and low concentrations of these active substances may be related to decreased efficacy of codeine.

Adult↗
PubMed1998

Codeine testing in sweat and saliva with the Drugwipe.

With the growing interest in drug testing within different sectors of society, there has become a need for drug assays that can be performed immediately at the site of specimen collection. Recently, Securetec (Ottobrunn, Germany) has introduced the Drugwipe, a non instrument-based, on-site immunodiagnostic assay for the detection of drugs on surfaces. Different tests are available for opiates, cocaine and cannabis. To document the applications of the Drugwipe "opiate" on human biological fluids, 60 mg codeine phosphate were orally administered to 6 subjects. First, sweat testing with the Drugwipe was studied. The wiping section of the kit was used to swab the forehead of the subjects for 10 s, at 1, 4, 9 and 24 h after codeine administration. At the same time, for each period, a sweat patch (Pharmchek, USA) was applied to the outer portion of the upper arm. Codeine was then quantified in the patch by GC/MS and the measured concentrations used as reference. In all subjects except one the Drugwipe tested positive for opiates, however with few false negative results. In the second part of the study, results of the Drugwipe were compared with those obtained by GC/MS for saliva. The tongue of the subjects was carefully wiped over a period 24 h, and at the same time a specimen of saliva collected. Although codeine could be detected using the Drugwipe, numerous false negative results were observed. Codeine tested positive by GC/MS but remained negative using the Drugwipe in several cases. This can be explained by a codeine concentration which was too low to show positive with the Drugwipe, interfering substances may be present in saliva or the sampling procedure is inadequate.

Adult↗
PubMed1991

Codeine O-demethylation: rat strain differences and the effects of inhibitors.

The oxidative metabolism of more than 20 drugs (e.g. sparteine, debrisoquine, dextromethorphan) is mediated by cytochrome P450IID6. Codeine O-demethylation to morphine was recently demonstrated to co-segregate with the polymorphic metabolism of debrisoquine and dextromethorphan. The female Dark-Agouti rat (DA) is an animal model for the poor metabolizer phenotype (PM) using debrisoquine or dextromethorphan as substrates. Studies were carried out to evaluate codeine metabolism in liver microsomes from female DA and Sprague-Dawley (SD) rats. The intrinsic clearance of codeine to morphine was 10-fold lower in DA rats due to a 5-fold higher Km (287 vs 49 microM) and a 2-fold lower Vmax (48 vs 94 nmol/mg/hr). Nineteen drugs were tested for inhibition of codeine O-demethylation. The four most potent competitive inhibitors were dextromethorphan (Ki = 2.53 microM), propafenone (Ki = 0.58 microM), racemic methadone (Ki = 0.3 microM) and quinine (Ki = 0.07 microM). The differences in morphine formation from codeine between SD and DA rats and the inhibition results show that this animal model appears to be a suitable model for the human EM and PM phenotypes, respectively. These strains could be used to study the pharmacodynamic consequences of the genetic polymorphism in codeine O-demethylation, and the effects of metabolic inhibitors. The outcome of these studies could impact on the therapy of pain control.

Animals↗
PubMed1994

Endogenous codeine: autocrine regulator of catecholamine release from chromaffin cells.

In addition to the catecholamines (CAs) dopamine (DA), norepinephrine (NE) and epinephrine (E), perifused chromaffin cells of the eel secrete codeine and morphine. In controls, the release of NE and E is strongly correlated, while there is no correlation with DA. Low, physiological concentrations of codeine (500 pg/ml) reduce the release of NE and E, while 8-fold higher concentrations stimulate an instant, transitory release of all three CAs. Much higher concentration of codeine (100 ng/ml), corresponding to the therapeutically effective range in the human, again reduce the release of NE and E. Physiological and very high concentrations of morphine have no clear effect on CA release, while an intermediate concentration (38 ng/ml) increases the secretion of all three CAs. The opiate antagonist naloxone lowers the basal CA secretion and prevents the morphine-induced CA increase. During naloxone perifusion, a normally non-effective concentration (40 ng/ml) of codeine reduces the CA release. It appears that codeine is an autocrine regulator which suppresses CA release via naloxone-insensitive receptors, and stimulates CA release via opiate receptor(s). Co-released morphine may modulate the action of codeine.

Anguilla↗
PubMed1978

Tolerance and evidence of physical dependence to daily codeine injections in the rat.

Core temperatures, measured by telemetry, and acquisition of food pellets on a continuous reinforcement schedule were recorded every 30 min in unrestrained male rats given saline for 5 days before and 5 days after 10 daily SC injections of codeine phosphate (200 mg/kg) at 08:00 hr. After the first codeine injection rats were immobile, slightly catatonic, breathed shallowly and had elevated core temperatures, loss of body weight and inhibition of feeding activity. As injections of codeine were repeated, the initial depressant signs decreased and the period of inhibited feeding was replaced by prolonged (greater than 8 hr) post-injection bouts of feeding activity (stimulated feeding) during daylight hours. Core temperatures remained elevated during this phase of drug-induced feeding activity. Mean body weight and 24-hr food intake remained below control levels over the 10-day codeine period as diurnal feeding patterns became reversed. On the first withdrawal day core temperatures declined and feeding patterns changed from those responses on the last codeine day as the rats lost body weight and were hyperirritable. As withdrawal continued core temperature and feeding patterns began to resemble those of the saline control period, body weights increased and hyperirritability subsided. In this study, tolerance and evidence of physical dependence to daily injections of codeine could be demonstrated in rats by continuous monitoring of their diurnal feeding and temperature responses.

Animals↗
PubMed1990

Codeine analgesic and morphine hyperalgesic effects on thermal nociception in domestic fowl.

The effects of codeine phosphate and morphine sulfate (2.5, 15.0, and 30 mg/ml/kg; IM) on latency of a jump response elicited by a noxious (61 degrees C) thermal stimulus were studied in White Leghorn cockerels at 15-16 days posthatch. Codeine induced a significant dose-dependent increase in jump response latency (analgesic effect), whereas morphine at each dose induced a significant decrease in jump response latency (hyperalgesic effect). Naloxone (5 mg/ml/kg) reversed the hyperalgesic effect of morphine (30 mg/ml/kg) and potentiated codeine analgesic effects. It is unlikely that codeine analgesic effects in domestic fowl reflect demethylation of codeine to morphine. These opposite codeine and morphine effects may reflect the interaction of these opiates at different populations of opioid receptors or at different substrates.

Analgesics↗
PubMed1986

Discrimination between urticaria-prone and other allergic patients by intradermal skin testing with codeine.

To study the ability of cutaneous mast cells to degranulate in urticaria-prone patients, subjects were skin tested with the known mast cell degranulator, codeine sulfate. Sensitivity to codeine as determined by the concentrations of codeine necessary to cause a net wheal of 5 mm was compared between urticaria-prone subjects, allergic subjects, and normal control subjects. Urticaria-prone subjects were more sensitive to codeine at every concentration tested and exhibited a mean reactivity to codeine that was almost 100 times that of the other allergic individuals and normal control subjects. This difference could not be explained by an increased sensitivity to histamine in 71% of urticaria-prone patients nor by any dermatographic tendencies or increased relative allergic reactivity. These findings suggest that codeine skin testing can be used to identify a distinct population of patients with urticaria.

Adult↗
PubMed1993

Fibrin formation during ongoing cutaneous allergic reactions: comparison of responses to antigen and codeine.

BACKGROUND: Fibrin formation, assessed by fibrinopeptide A levels, was evaluated over a 5-hour period at skin chamber sites challenged continuously with pollen antigen or codeine in 10 reactive individuals. METHODS: The levels of fibrinopeptide A at antigen sites were compared with those at sites challenged with buffer diluent alone or with codeine for the first 3 hours, followed by antigen challenge during the subsequent 2 hours. RESULTS: Findings showed: (1) fibrinopeptide A levels were higher at antigen challenge sites than at codeine challenge sites by the third hour, with these levels at both sites greater than those at buffer sites; (2) antigen challenge of the previous codeine sites during the third to fifth hours led to a further increase in fibrinopeptide A levels; (3) fibrinopeptide A levels correlated with chamber fluid immunoglobulin G levels but not with chamber fluid histamine levels. CONCLUSIONS: Because antigen and codeine both activate mast cells prominently, these findings suggest that other factors play a role in the persistent fibrin formation at allergic skin reaction sites. Because antigen activates both basophils and mast cells and codeine only activates mast cells, we conclude that both basophils and mast cells contribute to the persistent fibrin formation at sites of allergic reactions.

Antigens↗