Opiate Metabolites Research Articles

Methamphetamine use among people who inject heroin in Hanoi, Vietnam

The pattern of drug use in Vietnam has changed rapidly over the past decade, and a large number of people who have a history of heroin injection reportedly use methamphetamine. This paper describes factors associated with methamphetamine use among people who inject heroin in Hanoi, the capital of Vietnam. This is a cross-sectional survey among 521 heroin injectors who were recruited through chain referral and outreach at community and clinic settings. Eligibility criteria included: (1) male aged 18 or older; (2) reported heroin injecting during the 12 months before the survey; (3) agreed for a urine test to detect methamphetamine and opiate metabolites. The primary outcome, methamphetamine use, was defined as self-reported methamphetamine use during the 30 days before the survey and/or having a urine test positive for methamphetamine. Structural Equation Model was used to evaluate associated factors for methamphetamine use. One third of participants qualified as methamphetamine users as defined in this study. A longer history of heroin use (β=0.126, p<0.001), using MDMA and/or cannabis (β=0.28, p<0.001) and not using condom during sex (β=0.139, p<0.001) were positively associated with methamphetamine use. Family functioning (β=-0.141; p<0.001) was protective. The goodness-of-fit of Structural Equation Model was excellent (CFI=0.934; TLI=0.912; RMSEA=0.033; WRMR=0.98). Methamphetamine use among people who inject heroin is a substantial issue in Hanoi. Family functioning has made a critical contribution on reducing methamphetamine use. Future studies should pay attention to address the role of factors at the family level in addition to individual-level factors towards the pattern of drug use.

The mechanism of the selective binding ability between opiate metabolites and acyclic cucurbit[4]uril: an MD/DFT study.

Subtle changes in molecular structure often lead to significant differences in host-guest interactions, which result in different host-guest recognition capabilities and dynamics behaviours in complex formation. Herein, we reveal the influence of the guest substituents on host-guest molecular recognition by molecular dynamics (MD) simulation and density functional theory (DFT) approaches. The results suggest that the binding energy barrier of acyclic cucurbit[4]uril (ACB[4]) with opiate metabolites gradually decreases. The methyl group in morphine (MOR) and morphine-3-glucuronide (M3G) strengthens the hydrophobicity of the guest, while depressing the energy loss of the desolvation of polar groups (e.g. hydroxyl) inside the ACB[4] cavity. However, in M3G, the 3-glucuronide group located outside the ACB[4] host cavity effectively alleviates the unfavourable desolvation effect of the hydroxyl and increases the binding constant by two orders of magnitude (compared with normorphine (NMOR)). Our findings stressed the essentiality of the binding mode and intermolecular noncovalent interactions in the host-guest selective binding ability.

A Study of Opiate, Opiate Metabolites and Antihistamines in Urine after Consumption of Cold Syrups by LC-MS/MS.

Studying the origin of opiate and/or opiate metabolites in individual urine specimens after consumption of cold syrups is vital for patients, doctors, and law enforcement. A rapid liquid chromatography–tandem mass spectrometry method using “dilute-and-shoot” analysis without the need for extraction, hydrolysis and/or derivatization has been developed and validated. The approach provides linear ranges of 2.5–1000 ng mL−1 for 6-acetylmorphine, codeine, chlorpheniramine, and carbinoxamine, 2.5–800 ng mL−1 for morphine and morphine-3-β-d-glucuronide, and 2.5–600 ng mL−1 for morphine-6-β-d-glucuronide and codeine-6-β-d-glucuronide, with excellent correlation coefficients (R2 > 0.995) and matrix effects (< 5%). Urine samples collected from the ten participants orally administered cold syrups were analyzed. The results concluded that participants consuming codeine-containing cold syrups did not routinely pass urine tests for opiates, and their morphine–codeine concentration ratios (M/C) were not always < 1. In addition, the distribution map of the clinical total concentration of the sum of morphine and codeine against the antihistamines (chlorpheniramine or carbinoxamine) were plotted for discrimination of people who used cold syrups. The 15 real cases have been studied by using M/C rule, cutoff value, and distribution map, further revealing a potential approach to determine opiate metabolite in urine originating from cold syrups.

WITHDRAWN: Ratio of Morphine and Codeine over Antihistamines in Urine by LC-MS/MS for Determining Opiate Metabolites from Cold Syrups

Abstract Determining the origin of opiate and/or opiate metabolites from cold syrups in individual urine specimens is vital for patients, doctors and law enforcement. Ten participants were orally administered cold syrups with three different formulations. The results revealed that people consuming cold syrups containing codeine did not routinely pass urine tests for opiates (cutoff value: 2000 ng mL−1) and did not have a morphine–codeine ratio

Linking opiate metabolites to heroin through gas chromatography-combustion-isotope ratio mass spectrometry

A practical gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS) technique was developed for tracing seized heroin through heroin abusers' opiate metabolites.

Predictors of correspondence between self-reported substance use and urinalysis screening among a racially diverse cohort of young men who have sex with men and transgender women

It is unknown if estimates of illicit drug use among young men who have sex with men and transgender women (YMSM/TW) may be biased due to historical distrust of research or reliable due to more accepting norms for use. Research is needed to examine the validity of drug use self-reports among YMSM/TW.Data came from an ongoing longitudinal study of YMSM/TW aged 16–29 living in Chicago (analytic N = 1029). Baseline urinalysis screens for marijuana, ecstasy, amphetamine, methamphetamine, cocaine, benzodiazepine, and opiate metabolites were compared to self-reported use within different recall periods using measures of concordance. Generalized estimating equations logistic regressions were conducted on three waves of data to identify predictors of disclosing past-6-month use of marijuana and non-marijuana drugs.Past-6-month self-reported use of all non-marijuana substances was <15%. There was excellent agreement between self-reported and drug-tested marijuana use. For other substances, sensitivities within the urinalysis detection window were <0.5 but increased with longer recall periods. Black participants had lower odds of disclosing non-marijuana drug use. Gender minority participants had lower odds of disclosing marijuana use. Participants with a history of arrest had higher odds of disclosing both marijuana and non-marijuana drug use. Wave and year of first research participation were non-significant, suggesting no systematic bias or increasing honesty associated with longer research participation.Programs that rely on self-identification of non-marijuana illicit substance use may be missing a substantial portion of drug-using YMSM/TW. Future epidemiological studies should work to reduce social desirability biases and include biomarker-based drug screenings to increase validity.

LC-MS-MS Method Development and Analysis of Stimulants, Opiates, Synthetic Opiates, PCP, and Benzodiazepines in Wastewater. Preponderance of these Drugs During Football Games.

A method was developed for the analysis of stimulant drugs, opiates, synthetic opiates, PCP, and benzodiazepines in wastewater samples using liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS). A total of 33 compounds (stimulant-type drugs and metabolites of opiates, synthetic opiates, PCP, and benzodiazepines) were analyzed. These drugs included amphetamine (Amp) (1), methamphetamine (Meth) (2), methylenedioxyamphetamine (MDA) (3), methylenedioxymethamphetamine (MDMA) (4), methylenedioxyethylamphetamine (MDEA) (5), benzoylecgonine (BE, the major metabolite of Coc) (6), cocaine (Coc) (7), 6-monoacetylmorphine (6-MAM, the primary urinary metabolite of heroin) (8), codeine (9), hydrocodone (10), hydromorphone (11), morphine (12), norhydrocodone (the primary urinary metabolite of hydrocodone) (13), oxycodone (14), oxymorphone (15), 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrolidine (EDDP, the primary urinary metabolite of methadone) (16), fentanyl (17), meperidine (18), methadone (19), norfentanyl (the primary urinary metabolite of fentanyl) (20), normeperidine (the primary urinary metabolite of meperidine) (21), phencyclidine (PCP) (22), tramadol (23), alprazolam (24), temazepam (25), nordiazepam (26), chlordiazepoxide (27), flurazepam (28), oxazepam (29), α-OH-alprazolam (the primary urinary metabolite of alprazolam) (30), α-OH-triazolam (the primary urinary metabolite of triazolam) (31), 2-OH-ethylflurazepam (the primary urinary metabolite of flurazepam) (32), and 7-NH2-flunitrazepam (the primary urinary metabolite of flunitrazepam) (33). These drugs were chosen because of their widespread abuse. Wastewater samples were collected at both the Oxford Wastewater Treatment Plant in Oxford, Mississippi (MS), and the University Wastewater Treatment Plant in University, MS. Samples were collected on weekends on which the Ole Miss Rebel football team held home games (Vaught-Hemingway Stadium, University, MS 38677). The collected samples were analyzed using a validated method and found to contain Amp, Meth, MDMA, MDA, Coc, BE, codeine, hydrocodone, hydromorphone, morphine, norhydrocodone, oxycodone, oxymorphone, tramadol, EDDP, meperidine, normeperidine, methadone, alprazolam, α-OH-alprazolam, nordiazepam, oxazepam, and temazepam. None of the samples contained MDEA, 6-MAM, fentanyl, norfentanyl, PCP, chlordiazepoxide, flurazepam, 2-OH-ethylflurazepam, 7-NH2-flunitrazepam, and α-OH-triazolam.

Frequency of Hepatitis B and C Viruses, and HIV Among Drug Addicts in the Eastern Anatolia, Turkey.

Background:Hepatitis B, hepatitis C and HIV infections constitute serious healthcare problems worldwide.Objectives:There are a limited number of studies regarding the prevalence of hepatitis B, hepatitis C and HIV infections among the drug addicts in Turkey; hence, the current study aimed to determine the frequency of these infections among 235 drug addicts treated in a drug addiction treatment centre/Elazig, Turkey.Patients and Methods:HBsAg, anti-HBs, anti-HCV and anti-HIV tests in 235 drug addicts were studied by ELISA technique. Urine samples obtained from drug addicts were analyzed for cannabis, opiate and cocaine metabolites.Results:All the 235 drug users were males, and their mean age was 30.69 ± 9.494 years; 112 (47.7%) of them were in the age group ranging 20 - 29 years (P < 0.05). Of 235 drug addicts, 113 (48.1%) and 115 (48.9%) were only cannabis and opiate users, respectively. In urine samples of seven (3%) drug addicts both cannabis and opiate metabolites were detected. Cocaine was detected in none of the urine samples. The frequencies of HBsAg, anti-HBs and anti-HCV among drug addicts were 2.6%, 38.3%, and 9.4%, respectively. None of the drug addicts was positive for HIV. Anti-HCV was more prevalent in opiate users than in cannabis users: 15.7% vs. 1.8% (P < 0.001).Conclusions:The obtained results showed that HCV infection was an alarming problem among opiate users in the eastern part of Turkey. It is suggested to rapidly diagnose the infected persons; thus preventive measures and appropriate control may limit further transmission of these infections.

Drug Testing in the Workplace

Congress passed the Drug-Free Workplace Act in April 1988, which resulted in the Mandatory Guidelines for Federal Workplace Drug Testing Programs. The intent was to establish a substance-free work environment for all federal workers by requiring that all federal employees pass a urine drug test before employment. These guidelines specifically, and exclusively, focus on testing urine specimens for metabolites of marijuana, cocaine, phencyclidine, opiates (focusing on heroin metabolites), and amphetamines (including Ecstasy). Since then, there have been many scientific, technical, and legal challenges to the validity of urine drug testing. In response, the Substance Abuse and Mental Health Services Administration, a division operating under the executive branch of the United States Department of Health and Human Services, put forth, through many revisions, strict procedural guidelines and specimen validity-testing criteria to manage suspicious or adulterated samples during and after urine collection. This review focuses on the legal ramifications, the procedural process, and the sensitivity and specificity of the two urine drug tests used for workplace drug testing: immunoassay and gas chromatography-mass spectrometry. Moreover, we dissect the problematic issue of cross-sensitivity between illicit and prescription drugs, and how this affects the validity of future urine drug testing.

Differences in depression severity and frequency of relapses in opiate addicts treated with methadone or opiate blocker after detoxification

Relapse of opiate dependence is a common occurrence after detoxification and introduction of opiate addicts in abstinence from opiates. Clinical evaluation showed that over 90% of opiate addicts exhibit depressive manifestations during detoxification, or develop post-detoxification depression. The aim of this study was to determine differences in the frequency of relapses, severity and course of depression during a of 6-month period, and previous patterns of use of opioids in the two groups of opiate addicts treated by two different therapeutic modalities. The results of the two groups of opiate addicts were compared: the patients on substitution methadone treatment (M) and the patients treated with opiate blocker naltrexone (B). In all the patients, clinical and instrumental evaluations confirmed depressive syndrome. Opioid relapses were diagnosed by the panel test for rapid detection of metabolites of opiates in urine. Then they were brought in connection with scores of depression and addiction variables. The Hamilton Depression Scale (HAMD) and Zunge Depression Scale were the applied instruments for measuring the level of depression. All the subjects completed a questionnaire Pompidou (short version). Psychological measurements were carried out during a 6-month follow-up on three occasions. The presence of opiate metabolites in urine was controlled every two weeks. Both groups of patients (M and B) had high scores on HAMD during the study. The group on methadone had a strong depression in all three measurements. There was a drop in the level of depression in both experimental groups over time, which was accompanied by a decrease in the incidence of recurrence. In both tested groups the frequency of relapses was positively correlated with earlier addiction variables - intravenous application of opioids, the experience of overdose, the absence of immunization against hepatitis C and hepatitis C virus carriers. The opioid relapse behavior is associated with a marked depression in post-detoxification period. The tested group M had a more expressed depression which is consistent with the literature data. In both tested groups the frequency of relapses was positively correlated with individual addiction variables associated with latent suicidal behavior. Diagnosing and monitoring depression of opiate addicts as well as timely remediation of post-detoxification depression symtoms, could help in prevention of opiate relapse.

Monitoring Pregnant Women's Illicit Opiate and Cocaine Use With Sweat Testing

Dependence on illicit drugs during pregnancy is a major public health concern as there may be associated adverse maternal, fetal, and neonatal consequences. Sweat patches (n = 389) were collected from 39 pregnant volunteers who provided written informed consent for this Institutional Review Board-approved protocol and wore patches, replaced approximately weekly, from study entry until delivery. Patches were analyzed for opiates (heroin, 6-acetylmorphine, 6-acetylcodeine, morphine and codeine) and cocaine (cocaine, benzoylecgonine, ecgonine methyl ester, anhydroecgonine methyl ester) by solid phase extraction and gas chromatography mass spectrometry. Seventy-one percent (276) of collected sweat patches were > or =5 ng per patch (limit of quantification) for one or more analytes. Cocaine was present in 254 (65.3%) patches in concentrations ranging from 5.2 to 11,835 ng per patch with 154 of these high enough to satisfy the proposed Substance Abuse and Mental Health Services Administration guidelines for a confirmatory drug test (25 ng per patch). Interestingly, 6-acetylmorphine was the most prominent opiate analyte documented in 134 patches (34.4%) with 11.3% exceeding the proposed opiate Substance Abuse and Mental Health Services Administration cut-off (25 ng per patch). Heroin was identified in fewer patches (77), but in a similar concentration range (5.3-345.4 ng per patch). Polydrug use was evident by the presence of both cocaine and opiate metabolites in 136 (35.0%) patches. Sweat testing is an effective method for monitoring abstinence or illicit drug use relapse in this high-risk population of pregnant opiate- and/or cocaine-dependent women.

Tests for Drugs of Abuse

Tests for Drugs of Abuse

The Maternal Lifestyle Study: Drug exposure during pregnancy and short-term maternal outcomes

OBJECTIVE: Reports of maternal effects resulting from drug exposure during pregnancy are inconsistent. The Maternal Lifestyle Study (MLS) is a multicenter, prospective, observational study that was initiated to better define the effects of exposure to illicit drugs during pregnancy on the mother, fetus, and infant. METHODS: Between May 1993 and May 1995, of 19,079 mother-infant dyads that were screened after delivery for cocaine and opiate exposure at four clinical centers (Brown University, University of Miami, University of Tennessee, Memphis, and Wayne State University), 16,988 (89%) met eligibility criteria and 11,811 (70%) of those eligible agreed to participate in the study. Exposure was defined as an admission of use of cocaine or opiates or both or the presence of cocaine or opiate metabolites in meconium as determined by use of gas chromatography–mass spectroscopy assay. Nonexposure was defined as a negative drug use history by interview and a negative immunoassay screen. When exposure could not be confirmed, such as when meconium was not obtained or was inadequate for confirmatory analysis, the mother-infant dyad was excluded (n = 3184). RESULTS: Of the mothers who consented to participate, 50% were African American, 38% were married, 64% were Medicaid recipients, and 95% had at least one prenatal care visit (median, 10 visits). Significant differences (P <.01) between cocaine-opiate exposed (n = 1185) and nonexposed (n = 7442) mothers included race (African American: 74.6% and 47.0%, respectively), mean age (29.6 and 26.1 years, respectively), and polydrug use including any combination of alcohol, tobacco, and/or marijuana (93% and 42%, respectively). Odds ratios (99% CI) indicate that exposed mothers had a significantly higher risk(P <.001) of medical complications including syphilis 6.7 (4.8-9.6), gonorrhea 1.9 (1.3-3.0), and hepatitis 4.8 (2.6-8.91); psychiatric, nervous, and emotional disorders 4.0 (2.2-7.4); and abruptio placenta 2.3 (1.4-3.9). The odds of a positive test for human immunodeficiency virus were higher (available on 28% of the cohort) in the exposed group 8.2 (14.3-15.4). Seventeen cases of maternal acquired immunodeficiency syndrome (AIDS) were identified. Opiate exposure with its attendant needle use significantly increased the risk of hepatitis and AIDS. The number of hospitalizations during pregnancy did not differ between the exposure groups because 11% of patients in each group were hospitalized at least once. However, violence as a cause of hospitalization was more common in the cocaine-exposed group, 19.6 (2.7-144.7). CONCLUSION: This observational study confirmed many of the reported adverse social and serious medical perinatal complications of mothers exposed to cocaine or opiates during pregnancy. The overall prevalence of these risk outcomes was lower than has been reported previously. (Am J Obstet Gynecol 2002;186:487-95.)

The Maternal Lifestyle Study: drug use by meconium toxicology and maternal self-report.

The objective of this study was to describe drug use by pregnant women participating in the 4-site Maternal Lifestyle Study of in utero cocaine and/or opiate exposure. Meconium specimens of 8527 newborns were analyzed by immunoassay with GC/MS confirmation for metabolites of cocaine, opiates, cannabinoids, amphetamines, and phencyclidine. Maternal self-report of drug use was determined by hospital interview. The prevalence of cocaine/opiate exposure in the 4 sites was 10.7% with the majority (9.5%) exposed to cocaine based on the combination of meconium analysis and maternal self-report. However, exposure status varied by site and was higher in low birth weight infants (18.6% for very low birth weight and 21.1% for low birth weight). Gas chromatography/mass spectrometry (GC/MS) confirmation of presumptive positive cocaine screens was 75.5%. In the cocaine/opiate-exposed group, 38% were cases in which the mother denied use but the meconium was positive. There was 66% agreement between positive meconium results and positive maternal report. Only 2% of mothers reported that they used only cocaine during pregnancy and mothers were 49 times more likely to use another drug if they used cocaine. Accurate identification of prenatal drug exposure is improved with GC/MS confirmation and when the meconium assay is coupled with a maternal hospital interview. However, the use of GC/MS may have different implications for research than for public policy. We caution against the use of quantitative analysis of drugs in meconium to estimate the degree of exposure. Our study also highlights the polydrug nature of what used to be thought of as a cocaine problem.

Predictors and risk-taking consequences of drug use among HIV-infected women.

To determine rates of drug use among women with HIV, and to examine associations between drug use, health, risk behavior, and sexually transmitted diseases (STD). A longitudinal cohort study of 260 women with confirmed HIV-positive serostatus. Each participant contributed a self-report interview, a clinical examination, laboratory testing of cultures for Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, and urinalysis for the presence of metabolites of cocaine and opiates. Data were examined on 140 women at 1-year follow-up. Women were defined as drug users if they reported crack, cocaine, or heroin use in the 6 months before the interview or if they had a positive toxicologic test result for cocaine or opiates. 34% of those in the sample were classified as positive for drug use. Drug use was associated with the number of sexual partners, age at first intercourse, prevalence of STDs, and lower quality of life. STDs were present at baseline in 33.7% and 15.5% of drug users and nonusers, respectively. Drug use among this population was also associated at both baseline and follow-up with the likelihood of having a Karnofsky score below 80, and with overall perceived general health. Drug users in this cohort were more likely to engage in behaviors that place them at risk for STDs, to have elevated STD prevalence, and to have lower perceived health across several indices. Identification of drug use and treatment for it need to be a central component of HIV care for women.

The role of liquid chromatography-mass spectrometry in the determination of heroin and related opioids in biological fluids.

The opioid most commonly sold in the illicit market is heroin. This substance, classified as an analgesic narcotic drug, has an extremely short half-life, and it is rapidly metabolized to 6-monoacetyl-morphine and further to morphine. Morphine is principally metabolized by conjugation to morphine-3 and morphine-6 glucuronides. Morphine itself is a potent analgesic that is frequently used in the pharmacological intervention of cancer pain. The toxicological and clinical evaluation of heroin and morphine have stimulated pharmacokinetic studies in human and animal models. Although a number of methods exist to determine opiates and their metabolites, liquid chromatography (LC) appears to be the technique that can separate without any pretreatment the lipophilic and the hydrophilic analytes of the complete metabolic profile of heroin and/or morphine. Moreover, mass spectrometry (MS) used as a detector for liquid chromatography is unique, because it offers universality and selectivity. Furthermore, efforts have been made to develop LC/MS interfaces that could overcome the previous problem of poor sensitivity. For this reason, in recent years LC combined with MS has been applied to the analysis of opiates--parent drugs and metabolites--in biological fluids. This article reviews the existing literature on the determination, using liquid chromatography coupled to mass spectrometry, of opiate metabolites found in different biological matrices after the administration of the parent compounds.

Formation and clearance of active and inactive metabolites of opiates in humans.

The results of recent investigations of the analgesic and the nonanalgesic effects of opioid glucuronides are relevant to the research on drug abuse in forensic toxicology. As has been shown for heroin, knowledge of the state of distribution and elimination of active and inactive metabolites and glucuronides offers new possibilities in forensic interpretation of analytic results. Because of similar metabolic degradation, calculation of the time-dependent ratio of the concentration of morphine and its glucuronide metabolites in blood or serum allows a rough estimation of increased dosage and of time elapsed since the last application. Drug effects can be examined with respect to individual case histories, including overdose and survival time if the patient died. However, different methods of administration and the strong influence of different volumes or compartments of distribution of parent compounds and metabolites on concentrations in human body tissues require careful use of glucuronide concentration data. In Germany, dihydrocodeine (DHC) is prescribed as a heroin substitute, and relative overdoses are needed to be effective. DHC metabolism was studied in three patients who died from overdoses. All metabolites (dihydrocodeine-6-glucuronide [DHC6], nor-DHC [NDHC], dihydromorphine [DHM], nor-DHM [NDHM], and DHM-3- and 6-glucuronide [DHM3G, DHM6G]) were determined using HPLC and fluorescence detection. Concentrations of DHM (0.16 mg/L to 0.22 mg/L serum) were found. The DHM glucuronide ratios were similar to those of morphine. Receptor binding studies showed that the binding affinity of DHM to porcine mu-receptor was higher than that of morphine, and DHM6G's binding affinity was as high as that of morphine-6-glucuronide (M6G). Metabolites may play an important role in the effectiveness of DHC in substitution and toxicity. Because of enzyme polymorphism, the formation of DHC poses a risk for proper dosage in patients who are either poor or extensive metabolizers. The distribution of opioid glucuronides in cerebral spinal fluid in relation to transcellular transport in central nervous tissue is discussed with respect to the receptor binding of opiates and drug effect.

Determination of morphine in urine by solid-phase immunoextraction and high-performance liquid chromatography with electrochemical detection

The analysis of morphine in biological fluids is of vital interest in monitoring opiate abuse and in drug abuse research. Although methods for analysis of morphine and its metabolites are well established, studies are still being carried out to improve sample preparation procedures as well as detection levels of morphine in biological samples. In this study, morphine-specific immunosorbents were developed to concentrate morphine prior to HPLC analysis. Urine (0.1 ml) was diluted 10-fold with phosphate-buffered saline, pH 7.4 (PBS), loaded onto a solid-phase immunoextraction column and washed with 15 ml PBS followed by elution with 2 ml of elution buffer (40% ethanol in PBS, pH 4). The eluted fraction was analysed for morphine by HPLC–electrochemical detection using a cyanopropyl (CN) analytical column with 25% acetonitrile in phosphate buffer–sodium lauryl sulphate, pH 2.4 as the mobile phase. Duration of the extraction procedure was approximately 40 min. Calibration graphs were linear from 100 ngml−1 to 500 ngml−1 in urine. The inter-assay R.S.D. was <10% and the recovery of morphine from urine was >98%. Immunocolumns demonstrated remarkably high specificity towards morphine showing minimal binding with other opiate metabolites such as codeine, normorphine, norcodeine, morphine-3-glucuronide, morphine-6-glucuronide.

Cholecystokinin and morphine pharmacological intervention during 99mTc-HIDA cholescintigraphy: A rational approach

Pharmacological intervention with either cholecystokinin-8 (CCK-8) or morphine during 99mTc- hepatoiminodiacetic acid (HIDA) cholescintigraphy is required primarily for the assessment of the diseases affecting the gallbladder, the common bile duct, or the sphincter of Oddi. For imaging, the patient should be prepared by an overnight fast, or with 4 hours of minimum fast. Pre-emptying with CCK-8 is probably undesirable and should either be avoided or one should wait for at least 4 hours after CCK-8 to begin the 99mTc-HIDA study to achieve higher specificity of the test for acute cholecystitis. When he gallbladder is not observed by 60 mins in a clinical setting of acute cholecystitis, a dose of 0.04 mg/kg of morphine is administered intravenously and imaging continued for an additional 30 mins. Nonvisualization of the gallbladder by 90 mins with morphine in an appropriate clinical setting is diagnostic for acute cholecystitis. When the gallbladder is not observed by 60 min but is seen with morphine administered after 60 mins, a positive diagnosis of abnormal gallbladder function can be made. When the gallbladder is observed in a clinical setting of biliary pain or chronic calculous or acalculous cholecystitis, CCK-8 at a dose rate of 3.3 ng/kg/min is infused intravenously for 3 mins (10 ng/kg/3 min) for the measurement of the ejection fraction. An ejection fraction value of less than 35% is indicative of calculous or acalculous chronic cholecystitis. The gallbladder emptying is directly related to the total number of cholecystokinin receptors in the smooth muscle. The ejection fraction can be controlled to any desired level simply by controlling the dose rate or the duration of infusion of CCK-8. Morphine and other opiate metabolites circulate for many hours in blood and act on the sphincter of Oddi and decrease the gallbladder ejection fraction. Careful drug history, especially that of opiates, is very critical in all subjects with a low ejection fraction before assigning an abnormality to the gallbladder motor function.

Morphine-3-glucuronide: hyperglycemic and neuroendocrine potentiating effects

The greater potency of morphine-6-glucuronide (M6G) as well as the inactivity of morphine-3-glucuronide (M3G) with respect to the antinociceptive effects of the parent molecule, morphine (MOR), have been well established. It has been suggested that M3G is an antagonist of MOR's antinociceptive and respiratory depressive effects. The present study addressed the central nervous system (CNS) interaction of these opiate metabolites on their metabolic and hormonal effects. Whole body glucose kinetics were assessed on conscious, chronically catheterized, unrestrained rats. M3G (5 μg) or H 2O (5 μl) was injected intracerebroventricularly (i.c.v.) 15 min prior to the bolus administration of H 2O (5 μl), M6G (1 μg), or MOR (80 μg). i.c.v. M3G (5 μg) resulted in behavioral excitation, hyperglycemia (+50%), stimulation of glucose rate of appearance ( R a; +100%), glucose rate of disappeaance ( R d; +70%), and metabolic clearance rate (MCR; +33%) within 30 min after injection with no alterations in hormone concentrations. i.c.v. M6G and MOR produced progressive hyperglycemia with significantly high catecholamine and corticosterone levels. M3G pretreatment resulted in enhanced elevations in plasma glucose levels (+52% and +18%), plasma lactate (+138% and +108%), norepinephrine (+96% and +30%), and epinephrine (+62% and +67%) in response to both i.c.v. MOR and M6G administration. These findings suggest a non-opiate and non-hormonal mechanism for M3G-induced hyperglycemia. In contrast, the metabolic and hormonal responses to i.c.v. M6G and MOR are associated with elevations in catecholamine and corticosterone levels, which are remarkably enhanced by M3G pretreatment, most likely through accelerated catecholamine release. Our findings suggest a modulatory role for MOR glucuronidation, not only by rendering it inactive, as in the case of M3G, but by an interplay of the metabolic effects of the parent molecule and its metabolite