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PubMed1995

The detection of opiate drugs in nontraditional specimens (clothing): a report of ten cases.

We present a series of 10 fatalities involving opiate overdosage, in which morphine, codeine, and 6-monoacetylmorphine were identified and quantified, not only in postmortem biological samples, but also in pieces of underwear taken from the bodies. Small tissue samples (about 1 g) were cut off from several parts of the underwear, stored at ambient temperature until analysis, then extracted by agitation in a mixture of chloroform/2-propanol/n-heptane (60:14:26, v/v/v) and assayed using GC/MS in the single ion monitoring mode. Morphine, codeine and 6-monoacetylmorphine concentrations were in the range 0.02 to 9.27 micrograms/g. These results indicate that the impregnation of underwear by sweat and sebaceous secretions and/or urine provides detectable levels of the drugs excreted by these ways. Even in the absence of biological samples, assaying pieces of clothing may bring some evidence about the drug abuser status of their owner.

Adult↗
PubMed1994

Drug dependence study of the new cognition-enhancing agent nefiracetam in rats.

The new cognition-enhancing agent nefiracetam (N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, DM-9384, CAS 77191-36-7) was assessed for dependence liability in rats using the DAF (drug admixed food) method and an intravenous self-administration system. In the physical dependence test, nefiracetam and codeine phosphate were administered to rats mixed with food for 43 days in a gradually increasing dosage schedule, followed by feeding a drug-free normal diet to detect signs of withdrawal. After the withdrawal, rats in the nefiracetam treated groups showed no withdrawal symptoms (e.g. body weight loss) and exhibited greater body weight gains than control. On the other hand, rats in the codeine phosphate treated group showed overt withdrawal symptoms (e. g. soft stool, diarrhea, vocalization) and a significant body weight loss, suggesting development of physical dependence on the drug. It was concluded that nefiracetam did not possess physical dependence liability in rats. In the reinforcement liability test, through an indwelling cannula implanted into the right jugular vein rats were allowed to self-administer nefiracetam, morphine hydrochloride or pentobarbital for 14 days. Saline was administered to negative control animals for the same period. The daily frequency of self-administration increased progressively with time in rats of the morphine hydrochloride and pentobarbital groups. In the nefiracetam groups, it remained comparable to or was even lower than that in the saline control group. When compared with the saline control, the group mean frequency of self-administration showed a tendency to be small for nefiracetam, whereas the morphine hydrochloride and pentobarbital showed greater frequencies.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

[Detection of morphine after ingestion of poppy seeds].

The aim of this study was to investigate whether morphine can be detected in urine after the ingestion of poppy seeds bought in Denmark. Morphine and codeine were determined in 10 different poppy seed specimens bought in Denmark. Ten and 25 g of the specimens containing the highest amount of morphine and codeine were consumed by respectively six and seven volunteers. Urine samples were collected for analysis at intervals up to 24 h. All samples were found positive by radioimmunoassay up to 24 h after ingestion. Using the less sensitive thin layer chromatography method, one of six and two of seven were positive, two to four hours after intake of respectively 10 and 25 g of the specimens. We conclude that the detection of morphine in urine does not necessarily indicate an illegal drug use.

Codeine↗
PubMedDate not supplied

Clinical trial examining effectiveness of three cough syrups.

BACKGROUND: Cough is one of the most common symptoms of respiratory infections for which patients seek relief. This study was done to assess the effectiveness of three commonly prescribed cough syrups. METHODS: In this multipractice, office-based, randomized clinical trial, guaifenesin was compared with guaifenesin plus codeine or guaifenesin plus dextromethorphan in patients with uncomplicated respiratory tract infections. Family physicians enrolled 97 patients between February 1988 and April 1990. Patients were randomly assigned to treatment and were interviewed by telephone at 2, 4, and 10 days to assess cough relief, treatment adherence, and side effects. There were no statistically significant differences among treatment groups at base line. RESULTS: At day 2 there were no statistically significant differences among treatment groups for any of the outcome measures. At day 4 five of the outcome measures of cough quality, frequency, sleep disturbances, and absenteeism were not statistically significantly different among groups. The only statistically significant difference was the ability to keep up with usual activities, which improved least in patients assigned to dextromethorphan than in patients in other groups. There were no statistically significant differences among the three groups at day 10 for any of the outcomes. CONCLUSION: It appears that codeine, dextromethorphan, and guaifenesin are equally effective in relieving cough symptoms.

Activities of Daily Living↗
PubMed1993

Automated solid-phase extraction of opiates from urine (I).

The extraction of morphine and codeine in urine by C18 bonded-phase columns was studied using a fully automated solid-phase extraction system. Extracts of urine were analysed by a high-performance liquid chromatographic method. Recovery of the opiates depends on the urine pH, and the choice of washing solvents and eluent. Studies were carried out on the optimisation of eluent volume by establishing a recovery-time profile for the elution process. Regenerated C18 bonded-phase columns could be re-used with negligible carry-over and insignificant recovery loss. An automated extraction procedure was developed for morphine and codeine in urine with absolute recoveries exceeding 80%.

Chromatography, Liquid↗
PubMed1995

Post-operative analgesia for craniotomy patients: current attitudes among neuroanaesthetists.

As part of an evaluation of post-operative analgesia for craniotomy patients, a postal questionnaire was sent to 183 consultant members of the Neuroanaesthesia Society of Great Britain and Ireland, inquiring about their current practices for post-operative neurosurgical analgesia. Replies were received from 110 neuroanaesthetists in 37 different neurosurgical centres. Intramuscular codeine phosphate or dihydrocodeine was the mainstay of post-operative analgesia for 97% of neuroanaesthetists despite the fact that over half of them thought that analgesia was inadequate. Only four neuroanaesthetists would ever consider using opioids post-operatively because of fears about respiratory depression and sedation, yet all except one used opioids per-operatively. Post-operative analgesia for craniotomy patients is perceived as inadequate by most neuroanaesthetists, yet traditional prejudice against opioid use prevents this being remedied. We suggest that patient-controlled analgesia with morphine could be a safe alternative to codeine phosphate.

Analgesia↗
PubMed1996

[Reduced prescription of benzodiazepine preparations in general practice. Much to gain with little effort].

Many patients experience side effects from prolonged use of benzodiazepines and analgesics containing codeine. Therefore 66 daily users of these drugs (average dose before intervention 34 DDD/month) were encouraged to take part in a cessation experiment. They were told that a large share of their symptoms which were the indication for benzodiazepines and analgesics might be side effects from this medication. They were also given a cessation plan. Over two years the prescriptions (measured in DDD) for this group were reduced by 57%, and 26% of the patients stopped taking these medicines. A strategy is proposed for cessation of use of benzodiazepines and codeine-containing analgesics in general practice.

Adult↗
PubMed1996

Inhalation exposure to volatilized opioids produces antinociception in mice.

The goal of this study was to determine whether opioids of varying potencies are pharmacologically active via the inhalation route of administration in mice. The opioids evaluated included heroin, morphine, codeine, fentanyl and meperidine; each of these drugs has the potential for abuse in humans. Inhalation exposure to each of these compounds produced antinociception in a dose-dependent manner as assessed in the tall-flick test. No pyrolysis products were detected after heating either morphine or codeine at 250 degrees C for 5 min. Although 6-acetylmorphine was found after heating heroin, it accounted for less than 5% of the recovered sample. Heroin was somewhat less potent by inhalation administration than i.v. injection, with ED50 values of 1.6 and 0.69 mumol/kg, respectively. In contrast, the relative potency of morphine was substantially greater when inhaled than when injected, with respective ED50 values of 0.77 and 3.9 mumol/kg. Whereas the body to brain ratios of [3H]morphine were approximately 8 and 20 for inhalation exposure and i.v. injection, respectively, the ratio for heroin was approximately 5 regardless of administration route. This pattern of results suggests that the increase in morphine potency upon inhalation may have resulted from an increased accessibility to the brain compared with i.v. injection. Finally, naloxone reversed the antinociceptive effects of volatilized heroin, but neither the kappa selective antagonist nor-binaltorphimine nor the delta selective antagonist naltrindole blocked this antinociception, which suggests the involvement of mu opioid receptors. These findings taken together suggest the potential for the abuse of a variety of opioids, in addition to heroin, through the inhalation route of administration by humans.

Administration, Inhalation↗
PubMed1996

A double-blind, randomized, parallel-group study of the pharmacokinetics and onset of action of Naprelan in patients following oral surgery.

Naprelan (Wyeth-Ayerst Laboratories, Philadelphia, Pennsylvania) is a novel formulation of naproxen sodium designed to offer both a rapid onset and a sustained duration of analgesia. Its onset of action was assessed in a double-blind, double-dummy, randomized, parallel-group study of 129 patients who had just undergone oral surgery to remove impacted third molars. Patients received Naprelan (500 mg or 1,000 mg), naproxen (500 mg), codeine (30 mg), or placebo. Both doses of Naprelan compared favorably with the established Naprosyn (formulation of naproxen; Syntex Laboratories, Inc., Palo Alto, California) with respect to onset of action, which occurred within 30 minutes in the majority of patients. The relative adverse effect profile showed that both Naprelan doses were as well tolerated as Naprosyn, codeine, and placebo. Pharmacokinetic and pharmacodynamic analysis confirmed the findings of previous Phase I studies in healthy subjects.

Adolescent↗
PubMed1998

[Acral erythema and HIV infection].

BACKGROUND: Acral erythema is a non specific skin condition observed in connective tissue diseases, viral infections and toxic skin reactions. More recently, this symptom has been reported in HIV-infected patients. CASE REPORT: We observed two cases of acral erythema in HIV seropositive patients. Both patients were drug abusers. Erythema was limited to the limbs with no clinical manifestation of connective tissue disease. Both consumed approximately 40 tablets of codeine daily and had hepatitis C without cirrhosis. DISCUSSION: Our 2 cases of acral erythema in HIV-infected patients can be added to 32 cases of digital erythema in HIV patients reported in the literature. The common features in most of these patients was intravenous opiate abuse and hepatitis C without cirrhosis. The degree of immunodeficiency, the nature of opportunistic infections and antiretroviral treatments do not appear to affect the development of skin signs. HIV infection, simultaneous HIV-HCV infection and codeine suggest they might have a pathogenic role in the development of distal vascularization disorders.

Acrodermatitis↗
PubMed1996

The use of controlled analgesics in a general population (15-59 years)--the influence of age, gender, morbidity, lifestyle and sociodemographic factors.

The use of controlled analgesics (codeine, buprenorphine and pentazocine preparations) was studied through drugs dispensed (prescriptions) over a one-year period in the municipality of Tromsø, Norway. Drug use was linked to information from the Tromsø Health Survey, a cross-sectional survey where the population was invited to a health screening. The study sample comprised 9640 women and 9141 men between 15 and 59 years of age. About 9% of the population had obtained one or more prescriptions. Combined codeine preparations dominated, and the average amount purchased was 25 defined daily doses/year. The use was mainly sporadic, but regular use did occur. Low self-evaluated health, headache suffering and former use of analgesics and psychotropics were the most significant predictors. However, daily smoking and low education level were also significant predictors. Drug use increased significantly with age, but only a minor gender difference was observed. After adjustment for differences in health problems the gender difference became insignificant.

Journal Article↗
PubMed2000

Field-amplified sample stacking capillary zone electrophoresis applied to the analysis of opiate drugs in hair.

The present paper describes the methodological optimization and validation of capillary zone electrophoresis (CZE) for the determination of major opiates (morphine, codeine, 6-monoacetylmorphine, acetylcodeine, heroin) in hair samples by using a field-amplified sample stacking injection before the separation in a binary running buffer (0.1 M sodium phosphate, pH 2.5, with 40% ethylene glycol). The applied potential was 20 kV, at 25 degrees C. Detection was by UV absorption at the fixed wavelength of 214 nm or by recording the full spectrum between 190-400 nm, thus improving the analytical selectivity and identification power of CZE. Hair samples were liquid/liquid extracted; dried extracts, reconstituted with a low-conductivity solvent (0.1 mM phosphoric acid, with 80% 1-propanol), were injected by electromigration at 10 kV for 99 s, after a 0.5 mm plug of water. Under the described conditions, the limit of detection (with a signal-to-noise ratio of 3) in hair extracts was 100 pg/mL for codeine, 75 pg/mL for morphine and 6-monoacetylmorphine (6-MAM), 150 pg/mL for ethylmorphine, and 0.75 ng/mL for acetylcodeine and heroin. The precision of the method was validated for standards in pure solution by using internal standardization, providing for intraday and day-to-day assays, in terms of migration times, relative standard deviation (RSD) values < or = 0.2%, and in terms of peak areas, RSD values <5.71%.

Electrophoresis, Capillary↗
PubMed2001

Selective antibodies to methadone enantiomers: synthesis of (R)- and (R,S)-methadone conjugates and determination by an immunoenzymatic method in human serum.

Selective antibodies to (R)-methadone (Mtd) and to its racemate were produced in rabbits by immunization with conjugates of (R)- or (R,S)-hemisuccinyl-methadol-bovine serum albumin, respectively. A hapten was first prepared by reduction of (R)- or (R,S)-Mtd with sodium borohydride, followed by esterification with succinic anhydride. The conjugation of hapten with albumin was achieved by the mixed anhydride method. After immunization of rabbits, the titers and specificity of each antibody were determined by ELISA. The antibodies obtained were tested with (R)-, (S)-, (R,S)-Mtd, its major metabolite (EDDP), and some drugs of abuse (morphine, codeine, cocaine). The sensitivities of antibodies to (R)- and (R,S)-Mtd were about 1 and 2 ng/ml, respectively. Selective (R)-antibodies recognized (R)-Mtd about 40 times more avidly than the (S)-isomer, while an antiserum against (R,S)-Mtd recognized (R)- and (S)-isomers to about the same degree. Both selective antibodies showed little interference (about 0.5%) with EDDP metabolite and no crossreactivity with morphine, codeine, and cocaine. These two selective antibodies were used to develop an immunoenzymatic method (ELISA) for the determination of (R)- and (R,S)-Mtd in serum samples of patients under maintenance treatment for narcotic addiction.

Animals↗
PubMedDate not supplied

Analysis of opiates, cocaine and metabolites in urine by high-performance liquid chromatography with diode array detection (HPLC-DAD).

An analytical method is proposed for the simultaneous determination of morphine, codeine, 6-acetyl-morphine (MAM), cocaine, benzoylecgonine (BEG), cocaethylene, methadone and 2-ethylen-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in urine using high performance liquid chromatography coupled to a diode array detector (HPLC-DAD). The selection of working wavelengths is based on the highest chromatographic response for each component: 233 nm for cocaine, BEG and cocaethylene; 285 nm for morphine, codeine and MAM; and 292 nm for methadone and EDDP. The mobile phase, which is a mixture of acetonitrile and 0.02 M phosphate buffer at pH 6.53, was eluted in gradient mode through an XTerra RP-8 column (250 mm x 4.6 mm i.d., 5 microm particle size). After applying a solid-phase extraction procedure with Bond Elut Certify cartridges, the recoveries obtained were between 60% (EDDP) and 97% (cocaethylene). A good linearity of the method in the 0.1-10 microg mL(-1) range of urinary concentrations was obtained because the coefficient of correlation exceeded 0.99 for each drug. The precision and accuracy were quite good, with values of <7% and within the range +/- 6%, respectively. Finally, the proposed method was applied to 23 urine samples from fatal intoxications related to methadone, heroin and[sol ]or cocaine.

Chromatography, High Pressure Liquid↗
PubMed1991

In vitro interaction between psychotropic drugs and alcohol dehydrogenase activity.

A series of CNS-stimulating and -depressant drugs have been studied for their in vitro interaction with horse liver alcohol dehydrogenase (ADH) activity. The depressant drugs studied included barbital, phenobarbital, thiopental, nitrazepam, chlorpromazine, sulpiride, clomethiazole, Li2CO3, diazepam, phenytoin, ethosuximide, morphine, and codeine. The stimulant drugs were theophylline, caffeine, amphetamine, imipramine, chlorimipramine, amitriptyline, and tranylcypromine. The results were as follows. First, ADH activity was inhibited by the action of chlorpromazine, tranylcypromine, imipramine, chlorimipramine, amitriptyline, sulpiride, amphetamine, codeine, ethosuximide, morphine, clomethiazole, nitrazepam, Li2CO3, theophylline, and phenobarbital, in descending order of inhibitory effect. Second, inhibition followed by activation of ADH activity was observed for imipramine and chlorimipramine. Third, activation of ADH activity was observed for phenytoin. Finally, the following drugs were not seen to exert any effect on ADH activity: barbital, thiopental, diazepam, and caffeine.

Alcohol Dehydrogenase↗
PubMed1992

Interaction of opiate molecules with lipid monolayers and liposomes.

The interaction of opiate molecules (buprenorphine, codeine, dextromethorphan, diprenorphine, etorphine, meperidine, methadone, morphine, and naloxone) with lipids (phosphatidylcholine, phosphatidylinositol, phatidylinositol, phosphatidylserine, and cholesterol) by using liposomes and monomolecular layers as membrane models is described. The ability of opiates to induce leakage of carboxyfluorescin from liposomes is highly dependent on the hydrophobicity of the opiate molecules. Buprenorphine and etorphine increased the membrane permeability in all the experiments. On the contrary, naloxone, morphine, and codeine only caused a slight release of the entrapped dye in the presence of acidic phospholipids. Moreover, the leakage of carboxyfluorescein is directly related to the concentration of drug in the incubation media. Studies of the kinetics of the surface penetration of these molecules into monolayers of phospholipids were performed. Again, in this system, buprenorphine and etorphine exhibited stronger interactions than the most hydrophilic opiates. Nevertheless, in these experiments, differences among the opiate molecules are not so high as in the liposomes. The time course of the penetration of all of these molecules in the monolayers fits the Lineweaver-Burk equation. This fact suggests a lack of specific interactions and the predominance of hydrophobic factors. Moreover, the high percentage of release of entrapped dye caused by some opiate molecules suggests a possible toxic side-effect for these agents.

Chemical Phenomena↗
PubMed2003

Antitussive activity of Abies webbiana Lindl. leaf extract against sulphur dioxide-induced cough reflex in mice.

The methanol extract of A. webbiana Lindl was evaluated for its effect on a cough model induced by sulphur dioxide gas in mice. When administered orally it exhibited significant antitussive activity compared with the control in a dose dependent manner. The antitussive activity of the extract was compared with that of codeine phosphate, a prototype antitussive agent. The A. webbiana leaf extract (400 and 600 mg/kg) showed maximum inhibition of cough frequency by 71.69% and 78.67%, respectively, when compared with the control group and was comparable in effect to codeine phosphate.

Abies↗
PubMed2002

Antitussive effect of nociceptin/orphanin FQ in experimental cough models.

Cough is an important defensive pulmonary reflex that removes irritants, fluids or foreign materials from the airways. However, often cough is non-productive and requires suppression. Opioid mu receptor agonists, such as codeine are commonly used as antitussive agents and are among the most widely administered drugs in the world. Codeine suppresses the responsiveness of one or more components of the central reflex pathway for cough and is an efficacious antitussive drug for cough due to diverse aetiologies. However, opioids produce side effects that include sedation, addiction potential and constipation. Therefore, novel cough suppressant therapies should maintain or improve upon the antitussive efficacy profile of opioids. Moreover, these novel therapies should have a safety profile significantly better than current antitussive therapies. Presently, we discuss preclinical findings showing that activation of the 'opioid-like' receptor (NOP(1)) inhibits cough in the guinea pig and cat.

Animals↗