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PubMedDate not supplied

In vitro forecasting of drugs that may interfere with codeine bioactivation.

The O-demethylation of codeine (methylmorphine) into morphine is mediated by the polymorphic cytochrome P450 DB1 (P450 IID6). By means of in vitro screening in human liver microsomes we have studied the effect on codeine bioactivation of several drugs used as analgesics or as adjuvants for pain control. In microsomes from an extensive metabolizer subject, paracetamol (acetaminophen) and NSAIDs (acetylsalicylic acid, diclofenac, indomethacin, piroxicam, and pirprofen), benzodiazepines (chlordiazepoxide, clonazepam, diazepam, flunitrazepam, and midazolam), and anticonvulsants (carbamazepine and phenytoin) did not alter the reaction. There was marked inhibition of in vitro morphine production by neuroleptics (chlorpromazine, haloperidol, levomepromazine, and thioridazine), metoclopramide, and tricyclic antidepressants (amitriptyline, clomipramine, desipramine, imipramine, and nortriptyline). Enzyme kinetics showed competitive inhibition by neuroleptics (chlorpromazine Ki = 0.5 microM) and antidepressants (clomipramine Ki = 6.8 microM), which are substrates of the polymorphic monooxygenase. Due to the low affinity of codeine for P450 DB1 (Km = 100-200 microM), its bioactivation in extensive metabolizers, and thus its analgesic efficacy, is liable to vary greatly when it is combined with any drug that has a high affinity for the polymorphic isozyme.

Acetaminophen↗

PubMed1998

Analgesic efficacy of ibuprofen alone and in combination with codeine or caffeine in post-surgical pain: a meta-analysis.

OBJECTIVE: To estimate the analgesic effect of ibuprofen and to test whether codeine and caffeine enhance its effect on post-surgical pain. METHOD: Systematic overview of the literature and meta-analysis of published randomised, controlled trials. RESULTS: Ibuprofen is effective in dental pain, episiotomy pain and other post-operative pain. There is a dose response relationship over the range 50-400 mg. The difference in total pain-relief score relative to placebo was 19-31%. On average, patients were over three times more likely to obtain moderate to excellent pain relief with ibuprofen than with placebo (response-rate ratio = 3.45) and the number needed to treat was 2.44. Codeine 60 mg enhanced the analgesic effect of ibuprofen 400 mg by about 8% in the total pain-relief scale, but it also increased its adverse effects. The additive effect of caffeine was inconsistent. CONCLUSION: Ibuprofen is an effective analgesic in post-operative pain. Codeine 60 mg adds to the analgesic effect of ibuprofen 400 mg. Any additive caffeine effect requires validation.

Adult↗

PubMed1996

Evaluation of multicomponent fluorimetric analytical data by use of partial least-squares calibration. Application to the determination of codeine and ephedrine in urine.

A partial least-squares calibration (PLS) method for the simultaneous spectrofluorimetric determination of acetylsalicylic acid, codeine and ephedrine is proposed. The use of PLS for the multicomponent spectrofluorimetric determination is demonstrated by analysing synthetic mixtures. Analyte mixtures can be resolved even in the presence of strongly overlapped fluorescence signals. The method was validated by subjecting experimental data to exhaustive statistical analysis. The proposed method was applied to the simultaneous determination of the three drugs in synthetic mixtures with a urine matrix. The concentration ranges considered are 1.56-10.92 and 25-100 micrograms/ml for the codeine-ephedrine mixture, and 0.8-3.2, 0.1-0.5 and 1.6-4.8 micrograms/ml for the acetylsalicylic acid-codeine-ephedrine mixture. The analytical results were quite good in all cases.

Calibration↗

PubMed1993

Endogenous morphine and codeine in mice--effect of muramyl dipeptide.

Administration of morphine exerts many effects on the immune system. On the other hand little attention has been paid to the fact, that endogenous morphine and codeine exists in mammals, including man. This raises the question, whether or not endogenous opiate alkaloids play some role in immunoregulation. In addition muramyl-dipeptide (MDP), product of bacterial cell wall degradation and a potent immunomodulatory agent exhibits a broad spectrum of effects including effects on CNS functions. The present study investigated whether or not the endogenous levels of morphine and codeine are affected by administration of MDP in mice. Marked variation was found in spleen, brain, small intestine and heart in morphine and codeine concentrations. The intraperitoneal administration of MDP produced a significant increase in tissue morphine levels 30 minutes after injection.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1993

Endogenous morphine and codeine: release by the chromaffin cells of the eel.

Both the adrenomedullary equivalent and the plasma of the American eel (Anguilla rostrata) contain endogenous morphine and codeine. The opiate concentrations are similar to those found in the rat adrenal and human plasma, respectively. The adrenal medulla equivalent of the eel was perifused in vitro and the levels of catecholamines and endogenous opiate alkaloids in the perfusate were measured. A strong correlation between the release of morphine and codeine and between the release of norepinephrine (NE) and epinephrine (E) was found. On the other hand, there was no significant correlation between the release of dopamine (DA) and that of the other catecholamines or opiate alkaloids, suggesting three different ways of release of these components of the secretory cocktail of the chromaffin cells. The plasma of eels stressed by urethane anesthesia showed a substantial increase in DA, NE, and E levels but there was no clear stress response of plasma morphine and codeine.

Adrenal Medulla↗

PubMed1988

Codeine produces a cholinergically mediated analeptic effect in rats and rabbits.

The intravenous administration of codeine to diazepam-narcotized rabbits resulted in a shortened duration of loss of righting reflex. Coadministration of naltrexone plus codeine enhanced this analeptic effect and was also effective in shortening the duration of pentobarbital narcosis. The analeptic effect was blocked by atropine, but not by methylatropine, indicating involvement of a central cholinergic mechanism. In rats the analeptic activity correlated with the reversal of the diazepam-induced fall in sodium dependent high affinity choline uptake in hippocampal and cortical synaptosomes. These findings may represent the pharmacological basis of the recently reported antinarcoleptic action of codeine in man.

Animals↗

PubMed1989

Double-blind evaluation of analgesic efficacy of orally administered diclofenac, nefopam, and acetylsalicylic acid (ASA) plus codeine in chronic cancer pain.

The analgesic efficacy and toxicity of oral diclofenac sodium 50 mg (q.i.d.) vs. nefopam 60 mg (q.i.d.) and a combination of 640 mg ASA and 40 mg codeine (q.i.d.) in cancer patients with moderate to severe chronic pain has been evaluated in a randomized double-blind study. Planned duration of treatment was 10 days. Pain intensity was evaluated by a visual analog scale. The length of patient participation in the trial, the patient's final global evaluation and the incidence of side effects were also evaluated. Ninety-nine patients were enrolled in the study. All treatments produced a statistically significant pain relief (P less than 0.01) without differences among groups but only 26 of 99 patients (26.3%) completed the planned treatment period. Mean time in the study was 4.65 days. Inefficacy and side effects were the main reasons for premature treatment interruption. Patients treated with nefopam had a significantly shorter period in the study than patients treated with the other 2 treatments. Adverse effects were slightly more frequent with the nefopam and ASA + codeine regimens. The 3 therapeutic regimens appear to be similar as to analgesic efficacy, but diclofenac presents the advantage of a slightly better safety profile than nefopam and the ASA + codeine combination.

Administration, Oral↗

PubMed1994

Determination of codeine and its metabolites in microsomal incubates by high-performance liquid chromatography.

A rapid and sensitive HPLC method has been developed for the determination of codeine, norcodeine and morphine in small volumes of a biological matrix, using a cyanopropyl column and a combination of coulometric and UV detection. The compounds were isolated using C18 solid-phase extraction cartridges prior to quantitative analysis. The limit of detection was 250 pg/ml for morphine and 5 ng/ml for both norcodeine and codeine. Recovery of each compound was greater than 90% and intra- and inter-assay precision was better than 10%. The method has been used to study the metabolism of codeine in microsomal incubations.

Animals↗

PubMed1991

Evaluation of a method for simultaneous quantification of codeine, ethylmorphine and morphine in blood.

Codeine, ethylmorphine and morphine are the most commonly detected opiates in forensic blood samples in Norway. A method for the simultaneous quantification of these opiates utilizing solid phase extraction and gas chromatography-mass spectrometry has been evaluated. The detection limits were 0.026 mumol/l for codeine, 0.025 mumol/l for ethylmorphine and 0.032 mumol/l for morphine (corresponding to 7.8, 7.8 and 9.1 micrograms/l, respectively). The analytical variations at concentrations of 1.0 mumol/l codeine, 1.0 mumol/l ethylmorphine and 0.5 mumol/l morphine were less than 5%.

Codeine↗

PubMed1990

Determination of morphine and codeine in urine by gas chromatography-mass spectrometry.

GC-MS is one of the recommended analytical techniques for the identification and confirmation of opiates in urine. A method for the qualitative detection and quantitation of codeine and morphine in urine samples by this technique has been developed. This method is also suitable for the detection of their main metabolites in urine: norcodeine and normorphine. It also allows the identification of 6-monoacetylmorphine in urine, which can be used as a confirmatory marker of heroine abuse. The derivatized compounds are separated by capillary gas chromatography (GC) and identified by mass spectrometry (MS) in the selective ion monitoring acquisition mode (SIM). The recoveries from urine at concentrations of 1000 ng ml-1 are 72% for codeine and 80% for morphine. The method is linear in the range studied (0-1000 ng ml-1) for codeine and morphine.

Codeine↗

PubMed1984

Naloxone treatment for codeine-induced gastrointestinal symptoms.

Codeine often causes gastrointestinal cramping and pain. Treatment for such symptoms is usually symptomatic and supportive. Although naloxone is commonly used to treat other medical problems due to opiates, its use in treating such cramping has not been previously reported. The authors present four cases in which naloxone (Narcan) was used with success in relieving gastrointestinal side effects that were apparently due to codeine. It is suggested that patients with gastrointestinal symptoms and a history that strongly implicates codeine as the etiology be treated with naloxone.

Adult↗

PubMed2004

Evaluation of the mass spectrometric fragmentation of codeine and morphine after 13C-isotope biosynthetic labeling.

All major fragment ions of codeine and morphine were elucidated using LC-electrospray MS/MS and high resolution FT-ICR-MS combined with an IRMPD system. Nanogram quantities of labeled codeine were isolated and purified from Papaver somniferum seedlings, which were grown for up to 9 days in the presence of [ring-13C6]-l-tyrosine, [ring-13C6]-tyramine and [1,2-13C2], [6-O-methyl 13C]-(R,S)-coclaurine. The labeling degree of codeine up to 57% into morphinans was observed.

Carbon Isotopes↗

PubMed1988

Bioactivation of the narcotic drug codeine in human liver is mediated by the polymorphic monooxygenase catalyzing debrisoquine 4-hydroxylation (cytochrome P-450 dbl/bufI).

Codeine O-demethylation to its active moiety morphine was investigated in human liver microsomes from 1 poor and 5 extensive metabolizer subjects (debrisoquine-type of oxidation polymorphism). Apparent Km of the reaction in one extensive metabolizer's microsomes was 149 microM and Vmax 17.6 nmol X mg P-1 X hour-1 versus greater than 1 mM and 1.6 nmol X mg P-1 X hour-1 respectively in one poor metabolizer. In vitro morphine production was competitively inhibited by quinidine (Ki 15 nM), the selective inhibitor of cytochrome P-450 dbl/bufI. There was also an excellent correlation between dextromethorphan O-demethylation, a prototype reaction for cytochrome P-450 dbl/bufI activity, and codeine O-demethylation. These data allow to conclude that codeine bioactivation to morphine is dependent on the polymorphic monooxygenase known as cytochrome db1/bufI.

Biotransformation↗

PubMed1986

Simultaneous high-performance liquid chromatographic stability-indicating analysis of acetaminophen, codeine phosphate, and sodium benzoate in elixirs.

A stability-indicating high-performance liquid chromatographic method has been developed for the simultaneous determination of acetaminophen, codeine phosphate and sodium benzoate in an elixir formulation. The reversed-phase paired-ion method utilizes UV detection at 214 nm, a C18 column at 50 degrees C and requires ca. 10 min per analysis. The method has been validated for use with elixirs containing 120 mg of acetaminophen, 12 mg of codeine phosphate and 7.5 mg sodium benzoate preservative per 5 ml. The known potential degradation products p-aminophenol, codeine N-oxide and codeinone are separated for quantitation simultaneous with the parent compounds. The method has been shown to be linear, reproducible, specific, sensitive and rugged.

Acetaminophen↗

PubMed1985

Simultaneous high-performance liquid chromatographic stability-indicating analysis of acetaminophen and codeine phosphate in tablets and capsules.

A high-performance liquid chromatographic method has been developed for the simultaneous determination of acetaminophen and codeine phosphate for product stability studies, and release and dissolution testing of tablets and capsules. The reversed-phase method utilizes UV detection at 214 nm, a C18 column and requires a maximum of 10 min per analysis. The method has been validated for use with products containing as much as 500 mg of acetaminophen and as little as 7.5 mg of codeine phosphate. The known potential degradation products, p-aminophenol, codeine N-oxide, and codeinone are separated for quantitation simultaneous with the parent compounds. The method has been shown to be linear, reproducible, specific, sensitive and rugged.

Acetaminophen↗

PubMed1996

Histamine release in intact human skin by monocyte chemoattractant factor-1, RANTES, macrophage inflammatory protein-1 alpha, stem cell factor, anti-IgE, and codeine as determined by an ex vivo skin microdialysis technique.

BACKGROUND: The chemokines monocyte chemoattractant factor-1, RANTES, and macrophage inflammatory protein-1 alpha release histamine from human basophils, as well as rat and mouse mast cells. The purpose of this investigation was to determine whether these chemokines release histamine from human skin mast cells in situ. METHODS: A microdialysis technique was used to measure histamine release in skin. First, the model was validated by using anti-IgE, codeine, and stem cell factor (SCF); then the histamine-releasing effects of the chemokines were investigated. A total of 47 skin specimens from 41 donors were investigated. Hollow microdialysis fibers were inserted intradermally, and each fiber was slowly perfused (3 microliters/min). Anti-IgE, codeine, SCF, or chemokines were injected intradermally above individual fibers, and dialysate was collected at 2-minute intervals for 20 minutes. Each series of investigations comprised five to eight single experiments. RESULTS: Anti-IgE (4 to 4000 U/ml), codeine (0.001 to 1 mg/ml), and SCF (5.4 x (10(-11) to 10(-8) mol/L)) released histamine in a dose-dependent manner; maximum histamine release was 97.4, 116.3, and 9.5 pmol/20 min, respectively. Monocyte chemoattractant factor-1, RANTES, and macrophage inflammatory protein-1 alpha in concentrations of 10(-10) to 10(-6) mol/L did not release histamine; histamine release by 10(-6) mol/L chemokine was less than 0.2 pmol/20 min. None of the chemokines modulated anti-IgE-induced histamine release. In contrast, SCF significantly potentiated anti-IgE-induced histamine release by 33%. All chemokines, but not SCF, released histamine from human basophils. CONCLUSION: We conclude that the chemokines monocyte chemoattractant factor-1, RANTES, and macrophage inflammatory protein-1 alpha do not release histamine from human skin mast cells.

Aged↗

PubMed1999

A comparison of ketorolac tromethamine and acetaminophen codeine in the management of acute apical periodontitis.

Effective management of severe endodontic pain is often a major problem. The analgesic effect of ketorolac tromethamine (Toradol, 10 mg p.o.) was compared with acetaminophen codeine (325 mg/15 mg p.o.) in patients with severe pain due to acute apical periodontitis in a double-blind clinical study. A total of 66 patients presenting with severe pain (defined as 7 cm and more using a visual analog scale) were randomly assigned to receive either ketorolac tromethamine or acetaminophen codeine (33 patients in each group), and recorded their pain score once every 10 min for 90 min after administration. Results indicate that patients in the ketorolac group had significantly less pain than those who received acetaminophen codeine (p = 0.005).

Acetaminophen↗

PubMed1993

The effect of an ibuprofen-codeine combination for the treatment of patients with pain after removal of lower third molars.

A double-blind randomized crossover analgesic trial was carried out on 70 patients undergoing surgical removal of one lower third molar at each visit. The analgesic efficacy of a two-dose regimen of the combination ibuprofen-codeine, 400 to 60 mg, was compared with ibuprofen, 400 mg. Each of the two doses was taken when the patient needed pain relief and the pain intensity was measured on a visual analog scale during the 10-hour period after the first medication. Because of carryover effects between periods 1 and 2, the analysis was carried out only for period 1 according to a parallel group design. Of the 60 patients who were evaluated for analgesic effect, the mean pain reduction of dose 1 was 63% for the 29 patients given ibuprofen-codeine and 50% for the 31 patients given ibuprofen; the mean duration of effect was 7.5 and 6.3 hours, respectively. The difference in pain reduction index (pain reduction X duration of effect) between the two treatments was significant in favor of the combination, whereas the separate variables of pain reduction and duration of effect were not significantly different. The mean pain reduction was 67% after doses 1 and 2 for patients on ibuprofen-codeine and 52% for those on ibuprofen; the mean duration of effect was 9.4 and 9.2 hours, respectively. For doses 1 and 2, the difference in pain reduction index per dose between the two treatments was significant but not the difference for the separate variables, pain reduction, and duration of effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗