codeine-6-glucuronide and norcodeine

Acute and chronic pain often requires a multimodal approach. Combination therapy reduces the number of individual daily administrations and improves patient's compliance with the prescribed analgesic treatment. Despite the association codeine/paracetamol is one of the most widely used central analgesic, the exact mechanism of action, particularly of paracetamol, is still object of pharmacological research. Recent findings showed that paracetamol may act through cerebral cyclo-oxygenase, descending opioidergic inhibitory pathways, serotonin pathway, and the endocannabinoid system; while codeine activity seems to related not only to its conversion to morphine, as previously known, but also by itself and through its metabolites, such as norcodeine (NORC) and codeine-6-glucuronide (C-6-G). The addition of codeine to paracetamol significantly improves the analgesic action and reduces the number needed to treat (NNT) from 5 to 2.3-3.1. Recent warnings about the risk of its metabolism related to CYP450 and its genetic variability in general population should be mainly considered when the association is used in paediatric patients undergoing tonsillectomy and/or adenoidectomy procedures for obstructive sleep apnoea syndrome (OSAS). In adults, the association codeine/paracetamol has been shown to be effective and safe in different settings: acute pain, trauma patients, and chronic nociceptive pain.

Topics: Acetaminophen; Analgesics; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Codeine; Drug Combinations; Drug Therapy, Combination; Humans; Morphine; Pain; Treatment Outcome

Our objective was to investigate whether codeine or one of its metabolites contributes substantially to central nervous effects independent from the cytochrome P450 (CYP) 2D6-mediated O-demethylation to morphine.. After oral administration of codeine, plasma concentrations of codeine and its metabolites, as well as pupil size as a measure of central nervous effects, were measured in 11 healthy volunteers representing poor, intermediate, extensive, and ultrarapid metabolizers for CYP2D6. Subsequently, the observed plasma morphine concentrations were mimicked by use of computerized morphine infusion, and the miotic effects were compared with those observed after codeine administration. The contribution of codeine, codeine-6-glucuronide, norcodeine, morphine, morphine-6-glucuronide, and normorphine to the miotic effects was analyzed by means of pharmacokinetic-pharmacodynamic modeling.. The areas under the curve of the miotic effects after codeine were 1.7 +/- 2 times greater than after morphine (P <0.01). This contrasted to similar or even lower morphine concentrations after codeine than after morphine (area under the curve ratio, 0.5 +/- 0.4; P =.21). A pharmacokinetic-pharmacodynamic fit of the miotic effects by use of morphine as the only active moiety was most significantly (P <.0001) improved when codeine-6-glucuronide as a second active moiety was added.. CYP2D6-dependent formation of morphine does not explain exclusively the central nervous effects of codeine. Codeine-6-glucuronide is the most likely additional active moiety.

Topics: Adult; Algorithms; Analgesics, Opioid; Area Under Curve; Central Nervous System; Codeine; Cytochrome P-450 CYP2D6; Data Interpretation, Statistical; Dealkylation; Female; Humans; Infusions, Intravenous; Male; Models, Statistical; Morphine; Morphine Derivatives; Pupil

This article presents levels and tissue distribution of codeine, codeine-6-glucuronide (C6G), norcodeine, morphine and the morphine metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in post-mortem blood (peripheral and heart blood), vitreous fluid, muscle, fat and brain tissue in a series of 23 codeine-related fatalities. CYP2D6 genotype is also determined and taken into account. Quantification of codeine, C6G, norcodeine, morphine, M3G and M6G was performed with a validated solid phase extraction LC-MS method. The series comprise 19 deaths (83%) attributed to mixed drug intoxication, 4 deaths (17%) attributed to other causes of death, and no cases of unambiguous monointoxication with codeine. The typical peripheral blood concentration pattern in individual cases was C6G≫codeine≫norcodeine>morphine, and M3G>M6G>morphine. In matrices other than blood, the concentration pattern was similar, although in a less systematic fashion. Measured concentrations were generally lower in matrices other than blood, especially in brain and fat, and in particular for the glucuronides (C6G, M3G and M6G) and, to some extent, morphine. In brain tissue, the presumed active moieties morphine and M6G were both below the LLOQ (0.0080mg/L and 0.058mg/L, respectively) in a majority of cases. In general, there was a large variability in both measured concentrations and calculated blood/tissue concentration ratios. There was also a large variability in calculated ratios of morphine to codeine, C6G to codeine and norcodeine to codeine in all matrices, and CYP2D6 genotype was not a reliable predictor of these ratios. The different blood/tissue concentration ratios showed no systematic relationship with the post-mortem interval. No coherent degradation or formation patterns for codeine, morphine, M3G and M6G were observed upon reanalysis in peripheral blood after storage.

Topics: Adipose Tissue; Adult; Aged; Brain Chemistry; Chromatography, Liquid; Codeine; Cytochrome P-450 CYP2D6; Female; Forensic Toxicology; Genotype; Humans; Male; Mass Spectrometry; Middle Aged; Morphine; Morphine Derivatives; Muscle, Skeletal; Norway; Postmortem Changes; Solid Phase Extraction; Substance-Related Disorders; Tissue Distribution; Vitreous Body; Young Adult

The toxicodynamics and, to a lesser degree, toxicokinetics of the widely used opiate codeine remain a matter of controversy. To address this issue, analytical methods capable of providing reliable quantification of codeine metabolites alongside codeine concentrations are required. This article presents a validated method for simultaneous determination of codeine, codeine metabolites codeine-6-glucuronide (C6G), norcodeine and morphine, and morphine metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in post-mortem whole blood, vitreous fluid, muscle, fat and brain tissue by high-performance liquid chromatography mass spectrometry. Samples were prepared by solid-phase extraction. The validated ranges were 1.5-300 ng/mL for codeine, norcodeine and morphine, and 23-4,600 ng/mL for C6G, M3G and M6G, with exceptions for norcodeine in muscle (3-300 ng/mL), morphine in muscle, fat and brain (3-300 ng/mL) and M6G in fat (46-4,600 ng/mL). Within-run and between-run accuracy (88.1-114.1%) and precision (CV 0.6-12.7%), matrix effects (CV 0.3-13.5%) and recovery (57.8-94.1%) were validated at two concentration levels; 3 and 150 ng/mL for codeine, norcodeine and morphine, and 46 and 2,300 ng/mL for C6G, M3G and M6G. Freeze-thaw and long-term stability (6 months at -80°C) was assessed, showing no significant changes in analyte concentrations (-12 to +8%). The method was applied in two authentic forensic autopsy cases implicating codeine in both therapeutic and presumably lethal concentration levels.

Topics: Adipose Tissue; Autopsy; Brain; Calibration; Cause of Death; Chromatography, High Pressure Liquid; Codeine; Forensic Toxicology; Humans; Limit of Detection; Mass Spectrometry; Morphine Derivatives; Muscle, Skeletal; Opioid-Related Disorders; Reference Standards; Reproducibility of Results; Solid Phase Extraction; Substance Abuse Detection; Vitreous Body

Compared to morphine and morphine-6-glucuronide (M6G), codeine and its other major metabolites codeine-6-glucuronide and norcodeine have weak affinity to opioid μ-receptors. Analgesic effects of codeine are thus largely dependent on metabolic conversion to morphine by the polymorphic cytochrome P450 isoenzyme 2D6 (CYP2D6). How this relates to toxicity and post-mortem whole blood levels is not known. This paper presents a case series of codeine-related deaths where concentrations of morphine, M6G and morphine-3-glucuronide (M3G), as well as CYP2D6 genotype, are taken into account. Post-mortem toxicological specimens from a total of 1444 consecutive forensic autopsy cases in Central Norway were analyzed. Among these, 111 cases with detectable amounts of codeine in femoral blood were identified, of which 34 had femoral blood concentrations exceeding the TIAFT toxicity threshold of 0.3mg/L. Autopsy records of these 34 cases were retrieved and reviewed. In the 34 reviewed cases, there was a large variability in individual morphine to codeine concentration ratios (M/C ratios), and morphine levels could not be predicted from codeine concentrations, even when CYP2D6 genotype was known. 13 cases had codeine concentrations exceeding the TIAFT threshold for possibly lethal serum concentrations (1.6 mg/L). Among these, 8 individuals had morphine concentrations below the toxic threshold according to TIAFT (0.15 mg/L). In one case, morphine as well as M6G and M3G concentrations were below the limit of detection. A comprehensive investigation of codeine-related fatalities should, in addition to a detailed case history, include quantification of morphine and morphine metabolites. CYP2D6 genotyping may be of interest in cases with unexpectedly high or low M/C ratios.

Topics: Adult; Aged; Codeine; Cytochrome P-450 Enzyme System; Female; Forensic Toxicology; Gas Chromatography-Mass Spectrometry; Genotype; Humans; Isoenzymes; Male; Middle Aged; Morphine; Morphine Derivatives; Narcotics; Polymerase Chain Reaction

Codeine (30 mg phosphate) was metabolized by eight human volunteers to the following six metabolites: codeine-6-glucuronide 81.0 +/- 9.3 per cent, norcodeine 2.16 +/- 1.44 per cent, morphine 0.56 +/- 0.39 per cent, morphine-3-glucuronide 2.10 +/- 1.24 per cent, morphine-6-glucuronide 0.80 +/- 0.63 per cent, and normorphine 2.44 +/- 2.42 per cent. Two out of eight volunteers were unable to O-dealkylate codeine into morphine and lack therefore the cytochrome P450 IID6 isoenzyme. The half-life of codeine was 1.47 +/- 0.32 h, that of codeine-6-glucuronide 2.75 +/- 0.79 h, and that of morphine-3-glucuronide 1.71 +/- 0.51 h. The systemic clearance of codeine was 2280 +/- 840 ml min-1, the renal clearance of codeine was 93.8 +/- 29.8 ml min-1, and that of codeine-6-glucuronide was 122 +/- 39.2 ml min-1. The plasma AUC of codeine-6-glucuronide is approximately 10 times higher than that of codeine. Protein binding of codeine and codeine-6-glucuronide in vivo was 56.1 +/- 2.5 per cent and 34.0 +/- 3.6 per cent, respectively. The in vitro protein binding of norcodeine was 23.5 +/- 2.9 per cent; of morphine, 46.5 +/- 2.4 per cent; of normorphine, 23.5 +/- 3.5 per cent; of morphine-3-glucuronide, 27.0 +/- 0.8 per cent; and of morphine-6-glucuronide, 36.7 +/- 3.8 per cent.

Topics: Adult; Codeine; Female; Half-Life; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Protein Binding

A high-performance liquid chromatographic method has been developed for the detection, separation and measurement of codeine and its metabolites norcodeine, morphine and normorphine, with their glucuronide conjugates. The glucuronidase Escherichia coli type VIIA hydrolyses codeine-6-glucuronide completely and is used for the construction of the calibration curves of codeine-6-glucuronide. Enzymic hydrolysis of codeine-6-glucuronide depends on the specific activity of the glucuronidase applied. Examples are shown of a volunteer who is able to form morphine from codeine and one who is unable to do so.

Topics: Chromatography, High Pressure Liquid; Codeine; Electrochemistry; Glucuronates; Humans; Hydrolysis; Morphine; Morphine Derivatives; Reproducibility of Results

Plasma and urine concentrations of codeine and its measurable metabolites were determined by HPLC in six healthy subjects after a single 30 mg oral dose of codeine either alone or after 7 doses of 1 g paracetamol 8 hourly. After codeine alone, the t1/2 (h), AUC (mumol.l-1.h) and CLR (ml.min-1) for codeine were 2.2, 0.81, and 252 respectively. These were not significantly altered by paracetamol: 2.2, 0.84, and 291 respectively. For codeine-6-glucuronide the values were 2.4, 22.0, and 29.7 respectively. These were not significantly different from those after codeine plus paracetamol: 2.4, 21.9, and 39.6. There were no significant differences between the two treatments in the apparent partial clearances (ml.min-1) of codeine to morphine (88 codeine alone, 70 codeine plus paracetamol), to norcodeine (71 codeine alone, 88 codeine plus paracetamol), and to codeine-6-glucuronide (820 codeine alone, 1022 codeine plus paracetamol). The urinary excretion of codeine-6-glucuronide, morphine, norcodeine, and codeine were not significantly different between the two treatments.

Topics: Acetaminophen; Administration, Oral; Adolescent; Adult; Codeine; Drug Interactions; Female; Humans; Male; Metabolic Clearance Rate; Morphine; Time Factors

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.

Topics: Animals; Chromatography, High Pressure Liquid; Codeine; Guinea Pigs; Male; Mice; Morphine; Morphine Derivatives; Rabbits; Rats; Rats, Inbred Strains; Species Specificity