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PubMedDate not supplied

Determination of morphine and codeine in blood and bile by gas chromatography with a derivatization procedure.

Two gas chromatographic methods for the simultaneous quantitation of morphine and codeine in blood and bile from cases of opiate-related deaths are described. Both methods employ simple solvent extraction followed by hexane-ethanol partitioning clean-up and use nalorphine as the internal standard. The first method relies on the formation of trimethylsilyl derivatives and detection with a nitrogen-phosphorous detector. The second method involves the formation of heptafluorobutyryl derivatives and detection with an electron capture detector. Both methods are sensitive, able to detect down to 0.04 microgram/mL of morphine and 0.1 microgram/mL of codeine. Their wide linear dynamic ranges cover from low therapeutic to lethal levels for both morphine and codeine. The methods are amenable to batchwise operation and each analysis can be completed within three hours. The results of both methods correlate very well. The trimethylsilyl derivatives can be hydrolyzed and rederivatized for form heptafluorobutyryl derivatives for the second method, which then serves to confirm the results of the first method. Pholcodine, another common opiate, can likewise be determined. Average recovery was 80% for blood morphine and codeine and 60% for bile morphine and codeine.

Bile↗

PubMed1978

Appraisal of codeine as an analgesic in older patients.

In an investigation of a new oral analgesic agent, codeine was chosen as the reference drug because of its established reputation as an effective agent for the relief of pain. Thirty-five patients with cancer pain were studied. Their average age was 58 years, During a 5-day hospital stay they received, on each of three days, either codeine (120 mg or 60 mg) or placebo. At hourly intervals after ingestion the nurse observer collected data on pain intensity and the degree of pain relief, and the patients independently charted the hourly intensity. Statistical analysis failed to show any significant superiority of either dose of codeine over placebo. Moreover, codeine is known to have a constipating effect. Re-appraisal of the value of codeine as an analgesic agent in elderly patients seems justified.

Adult↗

PubMed1985

Identification of transformation products arising from bacterial oxidation of codeine by Streptomyces griseus.

14-Hydroxycodeine and norcodeine were rigorously identified as products arising from codeine oxidation by Streptomyces griseus ATCC 10137. Both products were routinely detected in extracted culture filtrates after growth of cells in the presence of codeine for 1 week. Under these conditions, about 4 mol% of the codeine starting material was consumed, with norcodeine and 14-hydroxycodeine representing the only identifiable transformation products (molar ratio, 4:1, respectively). Extraction of a series of culture filtrates and purification of the pooled metabolites by thin-layer and high-pressure liquid chromatography led to the isolation of both biological products, the structures of which were verified by high-resolution mass spectrometry and proton nuclear magnetic resonance spectroscopy. The identities of both biological products were further confirmed by comparison of their spectral properties with those of authentic standards. This is the first report providing structural evidence for the biological formation of 14-hydroxycodeine from codeine and of codeine oxidation by S. griseus.

Biotransformation↗

PubMed1991

Safe use of codeine in the recovering alcoholic or addict.

The effect that codeine has on the process of addiction and recovery is unclear. Confusion about definitions, study endpoints, and a lack of well-controlled clinical studies has led to this uncertainty. Codeine addiction is uncommon in people who do not have existing vulnerability to addiction, including alcoholism. Codeine use can sustain addiction or increase the risk of relapse in patients afflicted with addiction. The risk of relapse must be considered when treating conditions such as pain or cough in a person recovering from addiction. Codeine use may be circumvented with the appropriate use of alternative treatments for pain or cough. If codeine use becomes necessary, cautious prescribing and reliance on the patient's recovery support network become imperative.

Alcoholism↗

PubMed1990

Species difference in codeine uridine diphosphate-glucuronyltransferase activity of liver microsomes.

Species difference in codeine uridine diphosphate-glucuronyltransferase (UDPGT) activity was studied in liver microsomes of mice, rats, guinea pigs and rabbits. Codeine UDPGT activity was the highest in guinea pigs, followed by that in rabbits, and the lowest in mice and rats among these four animal species. The specific activities of codeine UDPGT in liver microsomes were not correlated well with those toward morphine, 4-nitrophenol, and 4-hydroxybiphenyl in liver microsomes of each of the species. Inducibility of liver microsomal codeine UDPGT activity in rats was examined by pretreatment with phenobarbital and 3-methylcholanthrene and compared with those of other UDPGT activities. The activity was inducible by phenobarbital pretreatment as the activity toward morphine and 4-hydroxybiphenyl. The inducibility of codeine UDPGT activity by phenobarbital pretreatment was not as high as that of morphine UDPGT activity.

Animals↗

PubMed1988

Genetic differences in preferences for morphine and codeine in Lewis and Fischer 344 inbred rat strains.

Preferences for morphine and codeine in two inbred strains of rats, Lewis and Fischer 344 (F344), were systematically investigated using the drug-admixed food (DAF) procedure. Rats were allowed access to food only between 10:00 a.m.-4:00 p.m., but allowed free access to water. The rats were allowed to choose either DAF (0.5 mg/g) or normal food on the first day and then were allowed access only to DAF on the second and third days. After this schedule was repeated 10 times, they were again allowed to choose either DAF or normal food for a successive 8 days. In both strains, preferences for morphine and codeine rapidly increased; the preferences in Lewis rats were significantly higher than those in F344 rats during the daily choice trials. In the range of 0.25 to 1 mg/g for the DAF concentration, there was a negative correlation between the preference and concentration in Lewis and F344 rats, except in the codeine group of F344 rats. When a test dose (60 mg/kg and 30 mg/kg, s.c., in Lewis and F344 rats, respectively) of morphine or codeine was given at 30 min before the beginning of the choice trial, Lewis rats, but not F344 rats, showed a significantly lower preference for the respective drug. The above results indicate that genotype is an important determinant of the degree of preferences for morphine and codeine.

Animals↗

PubMedDate not supplied

Blood concentrations and clinical findings in nonfatal and fatal intoxications involving glutethimide and codeine.

Blood concentrations and clinical findings were evaluated in twenty-six nonfatal and twelve fatal intoxications involving the combination of glutethimide and codeine ("loads"). The mean glutethimide concentration was 10 +/- 5 mg/L for nonfatal cases (range 2-18 mg/L) and 13.9 +/- 6.6 mg/L for fatal cases (range 4.6-26.4 mg/L). The mean codeine concentration for fatal intoxications was 1.21 +/- 1.17 mg/L (range 0.13-4.32 mg/L). Codeine concentrations were not measured in cases of nonfatal intoxication. Nine nonfatal cases required hospitalization on a medical ward (mean length of stay 3 +/- 3 days). Depressed level of consciousness was the most common abnormal physical finding (24 cases); 18 patients were lethargic but arousable with nonpainful stimulation and 6 patients with serum glutethimide concentrations of 10 mg/L or greater were comatose. The level of consciousness showed statistically significant correlation with the glutethimide concentration (P less than 0.01). Twenty-four nonfatal intoxications involved at least one other drug in addition to glutethimide and codeine (salicylates in 12 and acetaminophen in 4), while only 7 fatal cases involved at least one additional drug (acetaminophen and diazepam in 3 each). The finding of glutethimide should prompt a search for codeine and vice versa, especially when the presence of either does not in and of itself explain the clinical condition of the patient.

Adult↗

PubMed1992

Further metabolic studies of codeine and morphine in mice pretreated with sympathomimetics.

The effects of ephedrine and phenylpropanolamine (PPA) on the 24 h urinary excretion of morphine, codeine and their metabolites, and on the plasma and brain disposition of morphine and codeine at steady state in mice were studied. Morphine-3-glucuronide was the major urinary metabolite in morphine treated animals, while for codeine treated animals norcodeine and morphine-3-glucuronide were the major metabolites. In all cases percentage of drug excreted unchanged was 10-15% of the administered dose. Ephedrine or PPA pretreatment had no apparent effect on these parameters. The metabolic ratios for the different pathways were comparable in all treatment groups. Steady-state plasma and brain concentration-time profiles of codeine and morphine also showed marked similarity in all treatment groups. Apparently, ephedrine or PPA pretreatment has no effect on the disposition of morphine and codeine in mice. The results are discussed from the perspective of our earlier findings of dependence on cough mixtures containing opioids and sympathomimetics.

Animals↗

PubMed1991

Screening of Candida sp. for N-dealkylation of codeine.

A number of Candida species were selected in order to test their ability to N- or O-demethylate codeine. Complex media and chemically defined media used in our experiments. Transformation products were analysed by reversed phase HPLC and TLC methods. N- and O-demethylation of codeine was performed by C. tropicalis NCYC 997, NCYC 405, NCYC 470 and C. albicans LSHTM 3153. Transformation by C. tropicalis NCYC 997 had better results. N- and O-demethylation occurred in the chemically defined medium. Change in the colour of the transformation mixture, in cultures containing more than 5 mmol.l-1 codeine, was attributed to codeine N-oxide, but its presence was not confirmed by HPLC. N- and O-demethylation of codeine by Candida sp. was compared to that occurred in mammals.

Candida↗

PubMed1990

Evaluation of ketorolac, aspirin, and an acetaminophen-codeine combination in postoperative oral surgery pain.

One-hundred twenty-eight outpatients with postoperative pain after the surgical removal of impacted third molars were randomly assigned, on a double-blind basis, to receive oral doses of ketorolac tromethamine 10 mg, aspirin 650 mg, a combination of acetaminophen 600 mg plus codeine 60 mg, or placebo. Using a self-rating record, subjects rated their pain and its relief hourly for 6 hours after medicating. All active medications were significantly superior to placebo. The acetaminophen-codeine combination was significantly superior to aspirin for peak analgesia. Ketorolac was significantly superior to aspirin for every measure of total and peak analgesia, and significantly superior to acetaminophen-codeine for measures of total effect. The analgesic effect of ketorolac was significant by hour 1 and persisted for 6 hours. Repeat-dose data also suggested that ketorolac 10 mg was superior to aspirin 650 mg and acetaminophen-codeine on the day of surgery. Differences among the active medications were trivial for the postoperative days 1-6 analyses. The frequency of adverse effects was over 4 times greater for acetaminophen-codeine than for ketorolac or aspirin.

Acetaminophen↗

PubMed1990

A multiinstitutional evaluation of the analgesic efficacy and safety of ketorolac tromethamine, acetaminophen plus codeine, and placebo in cancer pain.

Seventy-five patients with moderate to severe cancer pain were randomly assigned in a double-blind fashion to receive first-dose ketorolac tromethamine 10 mg orally, acetaminophen 600 mg plus codeine 60 mg orally, or placebo, followed by subsequent doses of ketorolac or acetaminophen plus codeine four times daily for 7 days. Patient characteristics were similar among the treatment groups. The first-dose observation documented that both ketorolac and acetaminophen plus codeine produced an equivalent reduction in cancer pain and were superior to placebo as measured by pain intensity differences and pain relief. Multidose comparison documented a small but statistically significant advantage in mean daily pain relief favoring acetaminophen plus codeine, although there were no differences in mean daily ratings of overall effects for either study medication. Adverse symptoms were acceptable with both ketorolac and acetaminophen plus codeine. We conclude that ketorolac has significant analgesic activity in patients with cancer pain, although its precise role in the treatment regimen of these patients remains undefined.

Acetaminophen↗

PubMed1988

Effects of lidocaine, codeine and vadocaine hydrochloride on platelet aggregation in human platelet-rich plasma.

Lidocaine and vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl)propionanilide+ ++ hydrochloride, OR K-242-HCl; INN: vadocaine), which is structurally related to lidocaine, inhibited the second phases of human platelet aggregation induced by adenosine diphosphate (ADP, 10 mumol/l) or epinephrine (10 mumol/l) and partly aggregation induced by collagen (2.5 micrograms) at concentration relevant to local anesthetic action (0.1-1.0 mmol/l). Codeine was effective at slightly higher concentrations. The concomitant formation of thromboxane B2 (TXB2) was inhibited at similar concentrations. The aggregation induced by arachidonic acid (200 mumol/l) and the first phases of ADP (10 mumol/l)- or epinephrine (10 mumol/l)-induced aggregations were inhibited by all the compounds at the concentrations 1-10 mmol/l, codeine being the most potent inhibitor. The only exception was vadocaine, which inhibited the first phase of epinephrine-induced aggregation at concentrations greater than or equal to 0.25 mmol/l. Vadocaine may possess a2-adrenergic blocking activity. At low concentrations (less than or equal to 0.1 mmol/l), all the compounds stimulated/tended to stimulate the second phase of ADP-induced aggregation and concomitant formation of TXB2. They strongly stimulated TXB2 formation induced by exogenous arachidonic acid even at concentrations causing inhibition of aggregation. Codeine was the most and vadocaine the least potent in this respect. Lidocaine as well as vadocaine (0.1 mmol/l) and codeine (1.0 mmol/l) potentiated the antiaggregatory effect of dibutyryl-cyclic AMP (dB-cAMP) on the ADP-induced aggregation. Lidocaine (0.1 mmol/l) and codeine (1.0 mmol/l) similarly potentiated the effect of the adenylate cyclase stimulator prostaglandin E1 (PGE1).

Adenosine Diphosphate↗

PubMed1988

Gas chromatographic/mass spectrometric analysis of morphine and codeine in human urine of poppy seed eaters.

In this study, poppy seeds were examined for a natural constituent that might serve as a maker for the seeds' ingestion as opposed to opiate abuse. Thebaine was selected as possible marker, since it was found to be a component of all poppy seeds examined and was not a natural component of different heroin samples. During the course of this investigation, a new extraction and cleanup procedure was developed for the gas chromatographic/nitrogen phosphorus detection (GC/NPD) and gas chromatographic/mass spectrometric (GC/MS) analysis of morphine and codeine in urine. A linear response, over a concentration range of 25 to 600 ng/mL, was obtained for codeine and morphine (r = 0.9982 and 0.9947, respectively). The minimum detectable level (LOD) and limit of quantitation (LOQ) for morphine were 10 and 30 ng/mL, respectively; whereas LOD and LOQ for codeine were 2 and 8 ng/mL, respectively. The coefficients of variance (CV, n = 6) for morphine and codeine analyses at the 100-ng/mL level were 13.3 and 4.6%, respectively. This procedure was used for the analysis of urine samples from five poppy seed eaters who each ingested 200 g of poppy seed cake. Results indicated that significant amounts of morphine and codeine are excreted in urine and that in all subjects, at least at one point in time, the apparent morphine concentration as determined by radioimmunoassay (RIA) analysis exceeded the cutoff value (300 ng/mL) established for screening. Thebaine was not detected in urine specimens collected following poppy seeds ingestion and thus could not be used as a marker.

Chromatography, Gas↗

PubMed1988

Comparative studies on the dependence liability of morphine hydrochloride, codeine phosphate and two novel antitussive compounds vadocaine hydrochloride and N-(2',4'-dimethyl-6'-methoxyphenyl)-4-(diethylamine) butanamide hydrochloride in mice.

The effects of two novel antitussive compounds, vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl)propionanilide+ ++ hydrochloride, OR K-242-HCl; INN: vadocaine) and N-(2,4-dimethyl-6-methoxyphenyl)-4-(diethylamine)butanamide hydrochloride (OR K-269-HCl) on the suppression of withdrawal signs (hypothermia and weight loss) induced by repeated morphine administration were compared to those of acute morphine and codeine administrations. Moreover, spontaneous and precipitated withdrawal-induced hypothermia, weight loss and behavioural changes from repeated codeine, vadocaine and OR K-269-HCl administrations were studied. Acute administration of morphine clearly reversed the hypothermia and weight loss induced by spontaneous withdrawal from morphine. Codeine was not able to suppress the hypothermia and weight loss induced by morphine withdrawal. Acute injections of vadocaine and OR K-269-HCl did not alter these withdrawal signs either. Moreover, acute administration of codeine tended to prevent the weight loss induced by codeine withdrawal and caused behavioural changes. Spontaneous or precipitated withdrawal from repeated vadocaine or OR K-269-HCl administration caused neither hypothermia, weight loss nor behavioural changes. These results support the view that compounds vadocaine and OR K-269-HCl are free from morphine-like addictive properties.

Animals↗

PubMed1987

Chemical characterization and regulation of endogenous morphine and codeine in the rat.

Data on the tissue distribution of morphine and codeine in rat are presented. The concentration of these two opiate alkaloids seems to be distributed uniformly in the cortex, midbrain, pons/medulla and cerebellum. The spinal cord and the adrenal gland have high levels of morphine and codeine and the adrenal has more codeine than morphine. The major fraction of the alkaloids reside in a synaptosomal fraction and are present in tissues as the sulfate conjugate. The levels of morphine in the spinal cord and the urinary excretion of morphine are elevated in the arthritic rat model. We used extracted alkaloid samples from arthritic rats spinal cord for analysis by mass spectrometry and found molecular ions identical with morphine and codeine. The results are discussed in the light of possible physiological roles of endogenous morphine and codeine.

Animals↗

PubMed1986

Taste preference for cough syrups: a comparative study of three codeine-containing medications.

Unpleasant taste is a common feature of cough syrups, particularly those containing codeine. An antitussive compound of codeine sulfate and chlorpheniramine maleate was formulated in a coated drug-resin complex, which prevents release of the active ingredients until they reach the stomach and small intestine. Thus patients do not taste the bitterness of the codeine. A three-way crossover taste test was conducted in 175 volunteers who tasted each of three cough syrups in random sequence, rated the taste of each, and ranked their preferences. The cough syrups used in the study were the aforementioned formulation (CM), promethazine hydrochloride with codeine (PH), and iodinated glycerol with codeine phosphate (IG). Tastes were rated on a scale from +2 (very good) to -2 (very poor). Mean rating scores for each product were 0.97 for CM, 0.14 for PH, and -1.5 for IG. Pairwise comparisons showed statistically significant differences between CM and PH (P less than 0.01) and CM and IG (P less than 0.001) but no significant difference between PH and IG. CM was ranked as most liked by 115 respondents and as least liked by 27 respondents. Reasons cited for this preference were its sweet rather than medicinal taste and its smooth, thick consistency. Bitterness was a common reason for the lack of preference for PH and IG. CM thus was shown to have greater user acceptability than either of the other two cough syrups tested.

Antitussive Agents↗

PubMed1986

Effect of dextromethorphan on guinea pig ileal contractility in vitro: comparison with levomethorphan, loperamide and codeine.

Dextromethorphan (DM) was tested for its effect on the contractility of the guinea pig ileum in vitro. Comparisons were made with levomethorphan, levorphanol, codeine and loperamide. DM and codeine inhibited the contractions of the electrically stimulated ileum, with IC50 values of 15 and 8 microM, respectively. The inhibitory effect of DM, in contrast to codeine, was not blocked by the opiate antagonist naloxone. Pretreatment (8, 50 and 100 microM) with DM and its I-isomer levomethorphan reduced in a dose-dependent fashion both phasic and tonic contractions produced by maximally effective concentrations of carbachol and 80 mM KCl. Pretreatment (8, 50 and 100 microM) with codeine, dextrorphan or levorphanol, unlike DM, did not reduce carbachol or KCl-induced contractions. The concentration-response curves to calcium in K+ depolarized ileum were shifted to the right in a parallel manner suggesting competitive antagonism for DM (pA2 5.3), levomethorphan (pA2 5.3) and loperamide (pA2 6.6). Codeine and levorphanol (8, 50 and 100 microM) did not antagonize calcium-induced contractions. In two assays of calmodulin-dependent processes DM was inactive (IC50 greater than 1 mM), whereas trifluoperazine and calmidazolium (standard calmodulin antagonists) were active in the micromolar range. In summary, these data suggest that DM, through a nonopiate mechanism, antagonizes gut contractility possibly by "stabilizing" neuronal and/or muscle cell membranes.

Actins↗

PubMed1987

Symptomatic treatment of chronically recurring tension headache: a placebo-controlled, multicenter investigation of Fioricet and acetaminophen with codeine.

A double-blind, randomized, multicenter investigation was conducted to compare the efficacy and safety of Fioricet, acetaminophen with codeine, and placebo for the symptomatic treatment of tension headache. At the onset of a typical headache, the patients took two capsules of their assigned study medication and rated responses over the next four hours in three target symptoms areas: pain, emotional or psychic tension, and muscle contractions or stiffness in the head and neck. Physicians made global assessments of the same symptom responses and of adverse reactions for each patient. One hundred ninety-eight patients were evaluated. Both active analgesic preparations were more effective than placebo in relieving pain and muscle stiffness or contractions. Fioricet, but not acetaminophen with codeine, was significantly better than placebo in alleviating emotional or psychic tension; Fioricet was also significantly better than acetaminophen with codeine in relieving this symptom. Certain analyses suggested the possibility that Fioricet had a faster and more sustained analgesic effect than acetaminophen with codeine. By the end of the four-hour trial, significantly more patients achieved complete pain relief with Fioricet than with acetaminophen with codeine. The quality and quantity of adverse reactions did not differ significantly among the treatment groups. None was serious, and all abated without medical intervention.

Acetaminophen↗