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We have examined cerebrospinal fluid (CSF) from twelve patients who were not on any medication and found them to contain both morphine and codeine in concentrations of 2 to 339 fmol/ml. These are comparable to the concentration of opioid peptides in spinal fluid. Both morphine and codeine are present mainly in conjugated form from which the free alkaloids can be released by acid hydrolysis.
The affinity of morphine, codeine, dihydrocodeine and their glucuronides for mu-, delta-, and kappa-opioid receptors was investigated. Binding was studied on guinea-pig brain homogenates with [3H]DAMGO, [3H]DPDPE, and [3H]U69593. The substitution of the free phenolic group of morphine caused a decrease in binding at opioid receptors without affecting the mu/delta-ratio nor that of mu/kappa. Glucuronidation of the 6-hydroxyl group of morphine, codeine or dihydrocodeine did not affect the affinity to mu-receptors, slightly increased the affinity for delta-receptors and reduced the affinity for kappa-receptors. The 6-glucuronides possess a decreased selectivity for mu-receptors over delta-receptors whereas that for mu- over kappa-receptors was increased. It is concluded that chemical variations at 3- and 6-position of morphine independently affect the affinity to opioid receptor subtypes.
The literature indicates that morphine can inhibit the growth of both small cell and non small cell lung cancer cell lines and that nicotine can reverse this inhibition. In this report we present data showing that mammalian lung tissue contain the opiate alkaloids morphine and codeine and that these alkaloids are also to be found in normal lung cell lines. However, analysis of both small cell and non small cell lung cancer cells indicate that they do not contain these opiate alkaloids endogenously. If morphine exerts an inhibitory effect on proliferation of these cells it is interesting that the lung cancer cell lines lack the opiate alkaloids endogenously. Our studies also present data indicating that the circulating levels of morphine and codeine are elevated in smokers as compared to non smokers which we hypothesize to reflect the invocation of a compensatory mechanism.
To understand better the mechanism of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema, we studied the effects of ACE-inhibitor treatment on wheal-and-flare responses to histamine, codeine, and bradykinin in 10 normal subjects. No change in the size of wheal-and-flare reactions to histamine occurred, but the size of wheal reactions to codeine and bradykinin increased in all study subjects after ingesting the ACE inhibitor, captopril. Five of 10 study subjects developed flushing reactions after ACE-inhibitor treatment. We conclude that inhibition of bradykinin metabolism by ACE inhibitors is the probable cause of ACE inhibitor-related angioedema and that substance P is not the predominant mediator in this process.
1. The paper describes the mental disturbances of 44 abusive cases of "BRON," an over-the-counter (OTC) cough suppressant solution containing methylephedrine, codeine, caffeine, and chlorpheniramine. 2. Major psychiatric symptoms observed included hallucinatory-paranoid state and affective disorder. There also were groups which exhibited a combination of the two states and abuse only. 3. The hallucinatory-paranoid state group had a relatively small BRON usage amount, short usage term and few withdrawal symptoms. The affective disorder group, in contrast, had large usage amount, longer usage term, and showed significant autonomic nerve disorders during withdrawal. These tendencies were seen more clearly in the mixed state group. 4. The hallucinatory-paranoid state group showed little or no physical dependence, while that of the affective disorder group was thought to be firmly established. Thus, in the former group, methylephedrine was considered the major behavior modifying drug, while in the latter, it was thought to be codeine.
Thirteen-week toxicity studies in F344/N rats and B6C3F1 mice were conducted to determine general toxicity and target organ toxicity with amphetamine sulfate, ampicillin trihydrate, codeine, 8-methoxypsoralen, alpha-methyldopa sesquihydrate, penicillin VK, and propantheline bromide. This paper discusses the toxicity observed; use of the toxicity data to set dose levels for subsequent 2-year studies; and comparison of dose levels administered to rodents with doses used in the treatment of human disease. Drugs were administered orally in the feed or by gavage. The lowest doses in the 13-week studies were comparable to therapeutic doses in man on a mg/m2 (body surface area) basis or 5-10 times doses used in man on a mg/kg body weight basis. Little toxicity was seen at the low dose level with ampicillin, penicillin VK, 8-methoxypsoralen or propantheline bromide. At higher doses, target organ toxicity seen included the urinary bladder in male rats after propantheline bromide; the glandular stomach in rats and mice after penicillin VK; the liver and adrenals in rats after 8-methoxypsoralen; and the kidney in mice and rats after alpha-methyldopa. After amphetamine, codeine, or ampicillin administration, no target organ toxicity was seen in rats or mice, even at doses which caused body weight gain depression. The high doses chosen for subsequent 2-year studies were within 10 times human dose levels when compared on a mg/m2 body surface area.
Three drugs that affect the neuroendocrine system (amphetamine, methylphenidate, and codeine) caused decreases in body weights and in the incidence of spontaneously occurring mammary gland neoplasms in the female F344/N rat in 2-year carcinogenicity studies. Using a mathematical model that relates body weight changes to the incidence of mammary gland neoplasms, we find that the decrease in mammary gland tumours seen in female rats cannot be fully explained by body weight decreases relative to control animals. Further, the observed decreases in body weight in treated female rats were not a function of differences in feed consumption between treated and control groups. These pharmaceuticals are thought to affect the biologic system through interaction with membrane receptors. This interaction and/or subsequent cell signaling events may play a role in the observed decrease in spontaneously occurring mammary gland neoplasms in the female rat treated with amphetamine, methylphenidate, or codeine.
1. Monoamine turnover and neuropeptide Y (NPY) levels were investigated in the central and peripheral nervous systems in adult male rats chronically treated with codeine. 2. An increase in the dopaminergic turnover was observed in the striatum and cortex. The norepinephrine levels and the serotoninergic turnover were unchanged in all the brain areas. 3. Epinephrine levels were decreased in the adrenal glands. 4. In addition, we observed a significant decrease of NPY levels in the hypothalamus, the striatum and the adrenal glands. These observed changes were not found when assessing NPY level in plasma fluid. 5. The implication of these modifications in the induction of codeine dependence are discussed in view of previous results obtained with morphine.
A method is described for the simultaneous determination of 6-monoacetylmorphine (6-MAM), morphine and codeine in post-mortem urine specimens using reversed-phase high-performance liquid chromatography with dual ultraviolet spectrophotometric and electrochemical detection. The limits of detection for a 1-ml urine sample were 0.04 mg/l for 6-MAM and 0.05 mg/l for both morphine and codeine. The presence of 6-MAM in urine indicates prior use of heroin and enables differentiation between morphine- and heroin-related deaths.
Since 1983 a large number of small-scale illicit laboratories producing morphine and heroin from commercially available, codeine-based pharmaceutical products have been encountered in New Zealand. The codeine demethylation procedure is based on the use of pyridine hydrochloride. Very simple laboratory equipment and reagents are required and these can be utilised by people with little or no chemical background, following a recipe-like procedure. The process yields a characteristic product known as 'homebake'. This process is fully described.
A sensitive method for the analysis of unconjugated morphine, codeine, normorphine and total morphine after hydrolysis of glucuronide conjugates is described. The method was applicable to 50-microliters volumes of plasma. The analytes were converted to heptafluorobutyryl (HFB) derivatives before analysis by gas chromatography-negative ion chemical ionization mass spectrometry. Morphine and codeine were quantified against their [2H3]-isotopomers. Linearity, precision and accuracy were quite acceptable (in the 10(-10)-10(-9) g range), and the absolute limits of detection were < 1 pg.
This paper presents evidence of studies on the effects of the narcotic alkaloids, cocaine hydrochloride, morphine sulfate, and codeine phosphate, on nonenzymatic lipid peroxidation in rat brain mitochondria. These organelles abound in polyunsaturated fatty acids and are thus susceptible to oxidative attack. Lipid peroxidation was indexed mainly by assaying the extent of malonaldehyle (MDA) production and also the formation of fluorescent products in the course of the reaction. We found that morphine sulfate lowered fluorescence while the other two alkaloids showed no effect on lipid peroxidation in the absence of the inducers, 1.0 mM ascorbic acid or 0.1 mM ferrous sulfate. The apparent antioxidative nature of morphine sulfate was also observed in its effects on induced and noninduced MDA production, both cocaine hydrochloride and codeine phosphate stimulated MDA production by about 20% in the absence of any inducers. This paper also attempts to draw a structure-activity relationship for the antioxidative action of opium alkaloids, which we postulated to be due to the chelating capability of the alkaloid molecule.
Sprague-Dawley rats from two different vendors, Möllegård, Denmark and B&K Universal, Sweden, have been tested for the antinociceptive effect of morphine, methadone, buprenorphine and codeine on the hot plate. Morphine and methadone had significantly weaker effect in Möllegård rats compare to B&K rats. In contrast, the effect of buprenorphine was stronger in Möllegård rats than in B&K rats and the effect of codeine was similar in the two substrains. Plasma levels of morphine, morphine-6-glucuronide, morphine-3-glucuronide, buprenorphine and norbuprenorphine were determined at two time points after drug injection. Möllegård rats had significantly lower mean plasma level of morphine and significantly higher ratio of morphine-3-glucuronide/morphine at 30 min, compared to B&K rats. No difference was seen for the metabolism of buprenorphine in the two substrains. The results suggest that Möllegård rats metabolize morphine to morphine-3-glucuronide to a greater extent than B&K rats, and this may at least partly underlie the substrain difference in the effect of morphine. It is also suggested that the antinociceptive mechanisms of buprenorphne may be different from those of morphine and methadone.
Oral fluid is an interesting alternative matrix for drug testing in many environments, including law enforcement, workplace drug testing, and drug treatment facilities. Performance characteristics of the FDA-cleared, qualitative, Cozart RapiScan Opiate Oral Fluid Drug Testing System (Opiate Cozart RapiScan System or Opiate CRS) were compared to the semi-quantitative Cozart Microplate EIA Opiate Oral Fluid Kit (Opiate ELISA) and to gas chromatography/mass spectrometry (GC/MS). The following oral fluid opiate cutoffs were evaluated: the GC/MS limit of quantification (LOQ) of 2.5 mg/l; 15 microg/l currently used for oral fluid testing in the United Kingdom (UK); 30 microg/l (Opiate CRS cutoff); and 40 microg/l, the proposed Substance Abuse and Mental Health Services Administration (SAMHSA) cutoff. Subjects provided informed consent to participate in this IRB-approved research and resided on the closed research ward throughout the study. Three oral codeine doses of 60 mg/70 kg were administered over a 7-day period. After a 3-week break, subjects received three doses of 120 mg/70 kg within 7 days. Oral fluid specimens (N = 1273) were analyzed for codeine (COD), norcodeine (NCOD), morphine (MOR) and normorphine (NMOR) by GC/MS with an LOQ of 2.5 microg/l for all analytes. MOR and NMOR were not detected in any sample; 26.5% of the specimens were positive for COD and 13.7% for NCOD. Opiate CRS uses a preset, qualitative cutoff of 10 microg/l; this is equivalent to 30 microg/l in undiluted oral fluid as the oral fluid collection process involves a 1:3 dilution with buffer. Sensitivity, specificity, and efficiency of Opiate CRS compared to Opiate ELISA were 98.6, 98.1, and 98.2% at a 30 microg/l cutoff and 99.0, 96.2, and 96.6% at a 40 microg/l cutoff. Compared to the much lower GC/MS LOQ of 2.5 microg/l, sensitivity, specificity and efficiency were 66.8, 99.3 and 90.7%. Increasing the GC/MS cutoff to the current UK level yielded performance characteristics of 81.5% (sensitivity), 99.3% (specificity), and 95.4% (efficiency). Using a GC/MS cutoff identical to the preset Opiate CRS cutoff yielded sensitivity, specificity, and efficiency of 88.5, 99.2, and 97.5%, respectively. At the proposed SAMSHA confirmation cutoff of 40 microg/l, sensitivity increased with little change in specificity and efficiency (91.3% sensitivity, 98.9% specificity, and 97.5% efficiency). Oral fluid is a suitable matrix for detecting drugs of abuse. Opiate CRS, with a 30 microg/l cutoff, is sufficiently sensitive, specific and efficient for oral fluid opiate analysis, performing similarly to Opiate ELISA at the same cutoff, and having performance characteristics >91% when compared to GC/MS at the proposed SAMHSA cutoff.
A positive chemical ionization gas chromatography-mass spectrometric method was validated to simultaneously quantify drugs and metabolites in skin collected after controlled administration of methamphetamine, cocaine, and codeine. Calibration curves (2.5-100 ng/skin biopsy) for methamphetamine, amphetamine, cocaine, norcocaine, benzoylecgonine, cocaethylene, norcocaethylene, anhydroecgonine methyl ester, morphine, codeine, and 6-acetylmorphine (5-100 ng/skin biopsy for ecgonine methyl ester and ecgonine ethyl ester) exhibited correlation coefficients >0.999 and concentrations +/-20% of target. Intra- and inter-run precisions were <10%. This procedure should be useful for postmortem analysis; data are included on drug concentrations in skin after controlled drug administration.
Codeine is an analgesic with uses similar to morphines, but it is of much less effect, i.e., it had a mild sedative effect; codeine is usually used as the phosphate form (Cod.P) and is often administrated by mouth with aspirin of paracetamol. Due to its serious use, if it is in large dose, attention is paid in this research to the synthesis and stereochemistry of new iron, cobalt, nickel, copper, and zinc complexes of this drug in both solution and the solid states. The spectra of these complexes in solution and the study of their stoichiometry refer to the formation of 1:1 ratio of metal (M) to ligand (L). The steriochemical structures of the solid complexes were studied on the basis of their analytical, spectroscopic, magnetic, and thermal data. Infrared spectra proved the presence of MO bonds. Magnetic susceptibility and solid reflectance spectral measurements were used to infer the structures. The prepared complexes were found to have the general formulae [ML(OH)(x)(H2O)(y)](H2O)(z)H3PO4, M: Co(II), Ni(II), and Cu(II), x = 1, y = 0, z = 0; M: Fe(II), x = 1, y = 2, z = 1; Fe(III), x = 2, y = 1, z = 0; Co(III), x = 0, y = 2, z = 1; Zn(II), x = 1, y = 0, z = 3; and L: (Cod.P) of the general formula C18H24NO7P (anhydrate). Octahedral, tetrahedral, and square planer structures were proposed for these complexes depending upon the magnetic and reflectance data and were confirmed by detailed mass and thermal analyses comparative studies.
Screening for and confirmation of illicit, abused and banned drugs in human urine is a timely topic in which capillary separation techniques play a key role. Capillary electrophoresis (CE) represents the newest technology employed in this field of analysis. Two rapid competitive binding, electrokinetic capillary-based immunoassays are shown to be capable of recognizing the presence, but not the identity, of urinary opioids, namely codeine (COD), codeine-6-glucuronide, dihydrocodeine (DHC), dihydrocodeine-6-glucuronide, morphine (MOR), morphine-3-glucuronide and ethylmorphine (EMOR). In these approaches, aliquots of urine and immunoreagents of a commercial, broadly cross-reacting fluorescence polarization immunoassay for opiates were combined and analyzed by capillary zone electrophoresis or micellar electrokinetic capillary chromatography with laser induced fluorescence detection. With the fluorescent tracer solution employed, the former method is shown to provide simple electropherograms which are characterized by an opioid concentration dependent magnitude of the free tracer peak. In presence of dodecyl sulfate micelles, however, two tracer peaks with equal opioid concentration sensitivity are monitored. These data suggest the presence of two fluorescent tracers which react competitively with the urinary opioids for the binding sites of the antibody. Assay sensitivities for COD and MOR are comparable (10 ng/ml), whereas those for DHC and EMOR are about four-fold lower. Furthermore, glucuronides are shown to react like the corresponding free opioids. Analysis of urines that were collected after administration of 7 mg COD and 25 mg DHC tested positively in both assay formats. The presence of the free and conjugated codeinoids in these urines and their identification was accomplished by capillary electrophoresis-ion trap mass spectrometry (CE-MS). This confirmatory assay is based upon solid-phase extraction using a mixed-mode polymer cartridge followed by CE hyphenated to the LCQ mass spectrometer with electrospray ionization in the positive ion mode. With this technology, MS2 is employed for proper identification of COD (m/z 300.4) and DHC (m/z 302.4) whereas MS3 provides unambiguous identification of the glucuronides of COD (m/z 476.5) and DHC (m/z 478.5) via their fragmentation to COD and DHC, respectively. MSn (n > or = 2) is shown to be capable of properly identifying the urinary codeinoids on the 100-200 ng/ml concentration level.
Morphine, codeine and O6-acetylmorphine are reacted with heptafluorobutyric anhydride, rendering them suitable for electron capture detection and quantitation. The fluorinated derivatives are extracted from an acetonitrile-sodium bicarbonate solution into light petroleum in a rapid one-step extraction procedure. The derivatives are chromatographed on a stationary phase of 3% OV-17 on Gas-Chrom Q. Morphine, codeine and O6-acetylmorphine can be readily quantitated in heroin at levels as low as 0.001%, 0.01% and 0.01% respectively. Reproducibility, linearity and recovery studies are described.