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PubMedDate not supplied

Comparison of derivatives for determination of codeine and morphine by gas chromatography/mass spectrometry.

Pentafluoropropionic anhydride (PFPA) and heptafluorobutyric anhydride (HFBA) derivatives of morphine and codeine demonstrated poor spectra due to low abundances of secondary and tertiary ions. Trifluoroacetamide (MBTFA) has been a widely used derivative; however, the internal standard, nalorphine, displayed very poor stability and this resulted in split peaks by gas chromatography making MBTFA unsuitable for quantitative methods. Quantitation of codeine and morphine using bis-trimethylsilyltrifluoroacetamide (BSTFA/1%TMS) revealed a significant gradual decrease (p less than 0.05) of peak area ratio (PAR) of codeine and morphine compared to the internal standard using selected ion monitoring (SIM). The acetic anhydride derivative showed no significant differences in the peak area ratios for codeine/IS over a period of 24 hours, although the coefficient of variation (CV) was higher for the acetyl derivative than for the TMS derivative of codeine. There was a significant difference associated with the acetyl derivative of morphine at 4 h post derivatization compared to the initial injection (p less than 0.05); however, the acetyl derivative was stable for 24 hours and had a CV of less than 10% at a cutoff of 300 ng/mL.

Acetamides↗

PubMed1998

Laboratory validation study of drug evaluation and classification program: alprazolam, d-amphetamine, codeine, and marijuana.

The Drug Evaluation and Classification (DEC) program is used by police agencies to identify drivers impaired because of drug use and to determine the class(es) of drug causing the impairment. The primary goal of this study was to determine the validity of the DEC evaluation in predicting whether research volunteers were administered alprazolam, d-amphetamine, codeine, or marijuana. A secondary goal was to determine the accuracy of Drug Recognition Examiners (DREs) in detecting if subjects were dosed with these drugs. Community volunteers (n = 48) were administered alprazolam (0, 1, 2 mg), d-amphetamine (0, 12.5, 25 mg), codeine (0, 60, 120 mg), or marijuana (0, 3.58% THC) in a double-blind, randomized, between-subject design. A single drug dose or placebo was administered at each experimental session, and blood samples were obtained before and after dosing. With the exception of marijuana, plasma drug concentration was at or near maximum during the DEC evaluation. The ability of the DEC evaluation to predict the intake of alprazolam, d-amphetamine, codeine, or marijuana was optimal when using 2-7 variables from the evaluation. DREs' decisions of impairment were consistent with the administration of any active drug in 76% of cases, and their drug class decisions were consistent with toxicology in 32% of cases, according to standards of the International Association of Chiefs of Police. These findings suggest that the DEC evaluation can be used to predict accurately acute administration of alprazolam, d-amphetamine, codeine, and marijuana and that predictions of drug use may be improved by focusing on a subset of variables.

Adult↗

PubMed2001

Analysis of morphine and codeine in samples adulterated with Stealth.

Stealth is an adulterant used to avoid detection of drug abuse. The product does have an effect on the ability to detect several drugs of abuse, including the opiates morphine and codeine. It has previously been shown that low concentration (2500 ng/mL morphine) samples adulterated with Stealth tested negative by both Roche OnLine and Microgenics CEDIA immunoassays, but those spiked with higher concentrations (6000 ng/mL of codeine and morphine glucuronide) were positive. Initial results showed confirmation analysis was also sometimes negatively impacted by this adulterant. Urine samples were spiked with 6000 ng/mL of codeine and/or morphine glucuronide to assess the effect of Stealth. Each individual sample was split into separate aliquots. One aliquot of each was adulterated with Stealth following package directions. The samples were then tested by immunoassay and gas chromatography-mass spectrometry (GC-MS). The control and adulterated aliquots were positive by both immunoassays. Results of GC-MS analysis of the Stealth-adulterated aliquots following standard procedures using deuterated internal standards proved unsuccessful in several cases. In 4 of 12 cases (33%), neither the drugs nor internal standards were recovered despite repeated attempts. In one other sample, recovery was dramatically reduced, making accurate quantitation impossible, whereas the unadulterated aliquots of the same samples posed no problem with recovery. Addition of sodium disulfite to the aliquots prior to extraction allowed recovery of the drugs and internal standards from all samples. Analysis of the samples showed the concentration of morphine and codeine decreased in some by as much as 17 and 30%, respectively. In other cases, there was essentially no difference in the concentration seen before and after adulteration, with or without disulfite treatment. Unless the initial concentration of opiate is near the cutoff, samples containing opiates are likely to be immunoassay positive, it is important to consider this procedure as an option for samples that screen positive but the opiates and their respective internal standards are not recovered for GC-MS analysis.

Codeine↗

PubMed2006

Urinary excretion of morphine and codeine following the administration of single and multiple doses of opium preparations prescribed in Taiwan as "brown mixture".

Parallel to the "poppy-seed defense" strategy commonly reported in the United States, donors of urine samples tested positive for opiates in Taiwan often claimed the consumption of Brown Mixture (BM) as the source of the observed morphine and codeine. Because BM contains opium powder (10.0-10.5% morphine), opium tincture (0.9-1.1% morphine), or camphorated opium tincture (0.045-0.055% morphine) and is a popular remedy, and heroin use is considered a serious criminal act, the claim of BM use has to be adequately addressed. In this study, BM from seven different manufacturers (5 tablets and 2 solutions) and urine samples from alleged heroin users and volunteers with various ingestion patterns and were analyzed for their morphine and codeine contents. The analytical procedure included hydrolysis, trimethylsilylation, and gas chromatography-mass spectrometry analysis. The contents of morphine and codeine in the tablets were found to be very consistent, but with significant differences in the two BM solutions. Morphine concentrations found in urine specimens collected from volunteers ingesting BM tablets (or solutions) were always < 4000 ng/mL. The following morphine-to-codeine ([M]/[C]) ratios were observed for urine specimens with morphine concentration > or = 300 ng/mL: (A) < 3.0 for volunteers ingesting BM solution and (B) > 3.0 (mostly > 5.0) for volunteers ingesting BM tablets and alleged heroin users. It appeared that (A) BM ingestion (tablet or solution) was unlikely to result in a morphine concentration > 4000 ng/mL; and (B) [M]/[C] ratio might not be an effective parameter to differentiate heroin use from BM tablet ingestion.

Codeine↗

PubMedDate not supplied

Simultaneous identification and quantitation of codeine and morphine in urine by capillary gas chromatography and mass spectroscopy.

An analytical procedure for simultaneous determination of codeine and morphine in urine is described. The detection of codeine and morphine is based on liquid-liquid extraction and derivatization to the acetylated compounds. The acetylated codeine and morphine are separated by capillary gas chromatography and identified mass spectrometrically by selected ion monitoring (SIM). Quantitative determination was carried out by SIM using nalorphine as internal standard. Excellent linearity was obtained over a concentration range of 25 to 800 ng/mL. The overall recovery for codeine and morphine in the extraction was found to be 58% and 40%, respectively. The on-column sensitivity for both compounds was 2 ng at a peak-to-noise ratio of 5:1. The derivatives, acetylcodeine, diacetylmorphine, and diacetylnalorphine were stable at room temperature for 72 hr.

Codeine↗

PubMed2003

Comparative analysis of apoptosis-inducing activity of codeine and codeinone.

BACKGROUND: There are relatively few studies about the antiproliferative effects of codeine-related compounds on human cancer cell lines, compared with those of morphine-related compounds. The authors previously found that codeinone, an oxidation metabolite of codeine, among 10 opioids, showed the highest cytotoxic activity (DNA fragmentation-inducing activity) against human promyelocytic leukemic cell lines (HL-60). This was counteracted by an antioxidant, N-acetyl-L-cysteine (NAC). These findings prompted us to perform a more detailed study of apoptosis induction after codeinone treatment. METHODS: Apoptosis was induced by treating HL-60 cells for 1-6 h with codeine or codeinone. DNA fragmentation was assessed by both agarose gel electrophoresis and fluorometric determination of the fragmented DNA after staining with diamidinophenylindole (DAPI). The appearance of apoptotic cells was monitored by microscopic observation after staining with Hoechst (H)-33342, and fluorescence activated cell sorter (FACS) after staining with Annexin. The release of cytochrome c and cytochrome oxidase from mitochondria and activation of caspase 3 were monitored by Western blot analysis. Intracellular caspase 3-like activity was confirmed by FACS, using cell permeable substrate. Mitochondrial manganese-containing superoxide dismutase (MnSOD) activity and mRNA expression were assayed by activity staining after separation on the polyacrylamide gel electrophoresis, and reverse transcriptase-polymerase chain reaction (RT-PCR), respectively. RESULTS: Codeinone induced internucleosomal DNA fragmentation and production of Annexin-positive apoptotic cells more potently than codeine in HL-60 cells. Codeinone stimulated the release of both cytochrome c and cytochrome oxidase, and cleavage of procaspase 3 without significant changes in both the activity and expression of MnSOD. CONCLUSIONS: Codeinone was found to possess both apoptosis and necrosis-inducing activity, in addition to the reported antinociceptive activity, further substantiating its antitumor potential.

Analgesics, Opioid↗

PubMed1999

Long-term codeine use is associated with depressive symptoms.

A community survey was conducted among long-term (>6 months) users of codeine-containing products to characterize chronic use of these extensively consumed medications. Respondents recruited through newspaper advertisements completed a mailed questionnaire. Three hundred thirty-nine completed questionnaires were obtained, yielding a response rate of 70%. Codeine dependence/abuse as defined by DSM-IV criteria was present in 41% of the respondents. Two thirds of the subjects had sought help for mental health problems, most often depression (70%). Scores on the Symptom Checklist-90 subscales were modestly elevated, particularly on the Depression subscale (1.2 +/- 0.9). Long-term codeine use is strongly associated with dependence. Depression and depressive symptoms are common. These data suggest that dysphoric mood states may be significant in maintaining long-term codeine use.

Adolescent↗

PubMed2000

Cytochrome P450 2D6 and treatment of codeine dependence.

Oral opioid analgesics such as codeine are used extensively worldwide and are frequently misused. Codeine is a substrate of CYP2D6, a genetically polymorphic P450 enzyme, and is metabolized to the more potent drug morphine. CYP2D6 activity can be inhibited by fluoxetine, and the inhibition of morphine formation may help individuals reduce their use of codeine. Fourteen long-term users of oral opiates (principally codeine) were assessed for an open-label pilot treatment study of fluoxetine 20 mg/day combined with a brief behavioral intervention and structured tapering of the opiate. Eight subjects entered and completed the 8-week treatment. Opiate use decreased by 30% to 100% of baseline use (p < 0.0001) in parallel with a decrease in CYP2D6 activity. Fluoxetine may have a role in the treatment of opiate dependence by decreasing opiate-reinforcing properties.

Adult↗

PubMed1990

The effects of codeine on human aggressive responding.

Ten healthy male research subjects received placebo, 25, 50 and 75 mg/70 kg of codeine in a controlled laboratory setting. During each session subjects had two response options. The non-aggressive response option was maintained by points exchangeable for ten cents. The aggressive response option ostensibly subtracted a point from the subject's fictitious partner. Aggressive responding was engendered by point subtractions attributed to a fictitious partner. Codeine did not significantly alter the frequency of monetarily reinforced, nonaggressive, responding. Aggressive responding was significantly increased at the 50 mg/70 kg dose of codeine. The frequency of aggressive responses during the placebo sessions preceding administration of the first codeine dose were significantly and positively correlated with scores on the Buss-Durkee Hostility Scale. Aggressive responding increased for four of five subjects scoring below the median on the Buss-Durkee Hostility Scale at the 50 mg/70 kg dose; while administration of 50 mg/70 kg increased aggressive responding of one subject who scored above the median. Aggressive responding for both groups of subjects was unaffected by the 75 mg/70 kg dose.

Administration, Oral↗

PubMed2000

Acetaminophen versus acetaminophen with codeine after pediatric tonsillectomy.

OBJECTIVE: To compare the effectiveness of acetaminophen versus acetaminophen with codeine after pediatric tonsillectomy and adenoidectomy. STUDY DESIGN: Prospective, randomized, double-blind study. METHODS: Fifty-one children ages 3 to 12 years scheduled for outpatient tonsillectomy and adenoidectomy were studied. Patients were randomly assigned to receive acetaminophen or acetaminophen with codeine in unlabeled bottles for postoperative pain control. The Wong-Baker FACES pain rating scale was used to help children quantify their level of pain after surgery. The level of pain, quantity of pain medication required, presence of side effects, and the percentage of a normal diet consumed was recorded for 10 postoperative days. RESULTS: There was no difference (P > .05, all time points) in the level of postoperative pain reported by the parents and children in the two groups. The acetaminophen with codeine group tended to have increased problems with nausea, emesis, and constipation, but these differences did not reach statistical significance. Children in the acetaminophen group consumed a significantly higher percentage of a normal diet on the first 6 postoperative days (P < .05, all time points). CONCLUSION: There was no difference in the level of pain control provided by acetaminophen and acetaminophen with codeine as measured by the Wong-Baker FACES pain rating scale. Postoperative oral intake was significantly higher in children treated with acetaminophen alone.

Acetaminophen↗

PubMed2007

Codeine and cough: an ineffective gold standard.

PURPOSE OF REVIEW: Cough is one of the most common reasons why patients visit physicians. The opioid codeine has been a mainstay in the treatment of cough for decades and this drug is widely regarded as the 'gold standard' cough suppressant. RECENT FINDINGS: Recent placebo-controlled studies have shown that codeine is no more effective than placebo in suppressing cough caused by either upper respiratory disorders or chronic obstructive pulmonary disease. These recent reports are not consistent with several older placebo-controlled studies that demonstrated the efficacy of codeine. The reasons for this difference are not fully understood. SUMMARY: We propose that these differences, as well as results from animal models, can be explained by the existence of a complex hierarchical control system that regulates the expression of coughing. This system, known as a holarchy, is composed of regulatory elements known as 'holons' that interact with one another to regulate cough. Based on work in animal models, codeine is proposed to act on an intermediate order holon that may not be critical for coughing under some situations in humans. Testing of this hypothesis and further elucidation of the control system for cough will represent an important direction for future research in this area.

Animals↗

PubMed1983

Adverse reactions to intravenous codeine phosphate in children. A report of three cases.

Adverse reactions ranging from tachycardia and cutaneous vasodilatation to severe hypotension and apnoea occurred in three children who were given codeine phosphate intravenously. The cause of these reactions is discussed and a review of the literature on the parenteral use of codeine phosphate is presented. The findings indicate that the standard reference formularies and pharmacopeoiae, with one exception, deal inadequately with the parenteral use of codeine phosphate. On the evidence of the cases presented we would support the conclusion of the American Medical Association's drug evaluations, that codeine phosphate should not be used intravenously in children.

Anesthesia, General↗

PubMed1975

The effect of codeine phosphate on the absorption of ethyl alcohol.

The effect of syrup, B.P. and codeine phosphate syrup, B.P.C. on blood alcohol levels was determined in six normal subjects. 2 Treatment with syrup alone had little or no influence on the concentration of ethanol in blood. 3 In contrast, pretreatment with codeine phosphate syrup significantly reduced alcohol absorption, as assessed by the maximum blood levels achieved or the area subtended by the blood concentration-time curve. It is suggested that the diminished absorption of ethanol is related to the pharmacological action of codeine on the stomach. 4 It was considered that the concentration of ethanol in linctuses or syrups containing codeine was unlikely to have any significant effect on the central nervous system.

Codeine↗

PubMed1982

Codeine added to paracetamol induced adverse effects but did not increase analgesia.

1 In a double-blind crossover study identical oral surgical procedures were performed on two separate occasions in 24 outpatients. 2 At one operation they were given tablets containing paracetamol + codeine phosphate (400 mg + 30 mg), and at the other plain paracetamol (400 mg). The day of operation 2 tablets were taken 3, 6 and 9 h after surgery, the following two days 1 tablet four times daily. 3 Several measurements/assessments were recorded for a paired comparison of the postoperative courses. 4 No increase In the analgesic effect could be demonstrated by addition of codeine to paracetamol. 5 On the day of operation 18 patients reported adverse effects like nausea, dizziness and drowsiness with paracetamol + codeine, while only 3 patients experienced side effects with paracetamol alone (P less than 0.001). 6 Measurements revealed almost identical swelling after the two operations. 7 Compared with results obtained in previous studies, the present findings indicate that paracetamol may exert anti-inflammatory activity and reduce postoperative swelling, even when given 3 h after surgery. 8 On the day of operation and the following two days 20 patients preferred the treatment with plain paracetamol, while only 4 favoured paracetamol + codeine (P less than 0.001).

Acetaminophen↗

PubMed1982

Double-blind comparison of the respiratory and sedative effects of codeine phosphate and (+/-)-glaucine phosphate in human volunteers.

1 Two antitussive agents (+/-)-glaucine phosphate and codeine phosphate have been compared with placebo with respect to ventilation, ventilatory response to carbon dioxide, pulse, blood pressure, digit symbol substitution, sedation score and the Zahlen-Verbindung test performance in ten healthy volunteers (22-36 years). The study was double-blind and the two doses of each antitussive agent and the placebo were administered as a syrup. 2 Both codeine phosphate and (+/-)-glaucine phosphate displaced the ventilatory response to carbon dioxide to the right. 3 The effect of codeine phosphate on the ventilatory response to carbon dioxide was not dose dependent: 30 mg produced greater effects than the 60 mg dose. 4 Only the highest dose of (+/-)-glaucine phosphate (60 mg) caused respiratory depression and this was associated with sedation and decreased performance in the digit symbol substitution test. 5 Neither antitussive agent had significant effects upon pulse or blood pressure and codeine phosphate had no detectable sedative activity.

Adult↗

PubMed1983

Effects of codeine on the respiratory responses to exercise in healthy subjects.

In six healthy subjects, respiration and the sensation of breathlessness were assessed during submaximal exercise and the subsequent recovery. The overall responses were expressed by the relationship of breathlessness to minute volume. Because of the high subjective component in the assessments, validation of the method in these particular subjects was an integral part of the study. The relationship of breathlessness to ventilation during identical periods of exercise was highly reproducible and sensitivity was demonstrated by an alteration in this relationship in the presence of an inspiratory resistance. Codeine at a dose of 60 mg by mouth was compared with placebo, each treatment being given on two occasions. The study was conducted in a double-blind fashion with randomization of the order of treatments. Codeine at this dose allowed higher levels of carbon dioxide to be tolerated during breath-holding; oxygen uptakes at rest and during exercise were unaffected. Ventilation and breathlessness at the end of exercise were each slightly but significantly reduced by codeine but the relationship between breathlessness and ventilation was not changed. Codeine did not prevent detection of an inspiratory resistance.

Adult↗

PubMed1989

Interindividual and interethnic differences in the demethylation and glucuronidation of codeine.

1. The 8 h urinary excretion of codeine and seven of its metabolites was compared in 149 healthy Swedish Caucasians and 133 healthy Chinese following a single oral dose of 25 mg codeine phosphate. 2. The total 8 h urinary recovery of drug-related material was 74 +/- 24% in the Caucasians and 60 +/- 14% in the Chinese (P less than 0.001). The excretion of unchanged codeine was significantly higher in the Chinese (7.2%) compared with the Caucasians (4.3%, P less than 0.001). 3. The Caucasians excreted significantly greater proportions of codeine-6-glucuronide (C6G) (62%) than the Chinese (44%) (P less than 0.001). The frequency distribution of the log metabolic ratio (MR) for glucuronidation (codeine/C6G) was shifted towards higher values in the Chinese population. Males in both groups and Chinese smokers had significantly lower glucuronidation MRs than females and non-smokers in the respective populations (P less than 0.001). 4. The frequency distribution of the MR for O-demethylation (codeine/morphine (M) + M-3 and M-6-glucuronide (M3G and M6G) + normorphine (NM) was highly skewed in the Caucasians, suggestive of a bimodal distribution. There was a 160-fold interindividual variation in this MR. A unimodal distribution of the log O-demethylation MR was observed in Chinese. The Caucasians excreted less M and more M6G than did the Chinese (P less than 0.001). 5. Significantly more norcodeine (NC) and less NC-glucuronide (NCG) were excreted in the Chinese compared with the Caucasians (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed2007

Reaction pattern to histamine and codeine in a human intradermal skin test model.

BACKGROUND: Skin prick and intradermal skin tests (IDT) are useful tools in evaluating IgE-mediated allergic disorders. In the literature, many variations of the techniques used are described. No general agreement exists on test procedures and reading of test results. OBJECTIVE: To analyse test conditions for IDT to facilitate comparability between different study protocols. METHODS: We tested 24 healthy volunteers with three concentrations of histamine and codeine each on the upper back, lateral upper arm and volar forearm, with/without addition of ethylene diamine tetra-acetic acid. Reading of the resulting weal was performed by taking a digital image of the weal, later outlining the weal perimeter in triplicate and calculating the weal area using the NIH Image J software version 1.3. RESULTS: Weal size was dose dependent for both substances, generally larger on the upper back than on the forearm and upper arm, and larger after codeine than after histamine. Addition of the Ca2+ -chelator ethylene diamine tetra-acetic acid did not significantly affect weal size. Weal size induced by histamine showed better consistency than that induced by codeine. CONCLUSIONS: The results and our technique provide valuable tools for the daily routine as well as for the ability to compare information of intradermal tests from different studies or clinical reports. When assessing skin reactivity, we recommend the use of 1 mg/mL codeine as well as 0.1 mg/mL histamine to reflect aspects of mast-cell releasability and of vascular reactivity. The involvement of local factors influencing the vascular reactivity or differences in opiate receptor density on mast cells surfaces needs to be addressed in future studies.

Adult↗