Identification of characteristic heroin metabolites in urine based on data-mining technology and multivariate statistics analysis combined with a targeted verification approach for distinguishing heroin abusers.

A common phenomenon shows that ingestion of opium poppy shell-containing drugs can result in a "false-positive" urinalysis test result for mandatory or workplace heroin abuse screening. Owing to the short detection window (8 h in urine) of the characteristic heroin metabolite 6-monoacetylmorphine (6-MAM) confirmation or exclusion of heroin abusers still presents major challenges for toxicologists. In this work, we developed an ultra-performance liquid chromatography-time-of-flight mass spectrometry method (UPLC-TOF-MS) with online data acquisition and multiple post-data-mining technologies combined with a multivariate statistical and batch validation analysis workflow to assess the characteristic urine metabolites of heroin abusers. Based on the proposed methods, 28 characteristic metabolites were structurally identified, and their fragmentation patterns and metabolite pathways were also summarized. Correlation analysis was used to investigate the internal relationship and similarities among the identified metabolites, and seven representative metabolites were selected as "Target-metabolites". Multi-batch urine of samples of heroin abusers were certified based on the UPLC-MS/MS method for further validation of the practicability of using this method for routine analysis. Overall, the target-metabolites can be utilized as assistant "biomarkers" in workplace or mandatory drug screenings. This approach encourages further studies on the development of the "false-positive" identification system.

Effect of positive urine fentanyl screen on attitudes toward heroin use.

BACKGROUND: It is unknown if targeted risk reduction counseling in the health care setting, after documented exposure to fentanyl, can affect behavior change to reduce risks and increase utilization of evidence-based overdose prevention strategies. METHODS: We conducted a retrospective analysis of results (7/2018-6/2019) from questionnaire-facilitated counseling by recovery coaches in the emergency department (ED) and primary care settings following disclosure of a urine toxicology positive for fentanyl. RESULTS: Seventy-five percent of N = 101 respondents were neither aware of nor expecting fentanyl in their substances of use. Fifty-three (70 %) of those initially unaware answered that learning about exposure to and the risks from fentanyl changed their thoughts about reducing or abstaining from use. A greater proportion of patients seen in the ED expressed desire to stop or reduce opioid use as compared to ambulatory clinic patients (91 % vs. 46 %, p < 0.001). Of those not already engaged in treatment, 18 % and 15 % were interested in medication and behavioural health treatment, respectively, and each of them indicated a change in thought based on the counseling. Forty-five percent of individuals not yet receiving naloxone endorsed interest in receiving it, and 22 % of all respondents were somewhat or very interested in access to safe consumption sites. CONCLUSION: This study suggests a novel clinical utility in toxicology screens to inform behavior in the setting of illicit fentanyl exposure. In addition to linkages to evidence-based treatment, linkages to harm-mitigating strategies associated with ongoing substance use may be critical to a comprehensive overdose prevention strategy in the clinical setting.

Clinical and Forensic Diagnosis of Very Recent Heroin Intake by 6-acetylmorphine Immunoassay Test and LC-MS/MS Analysis in Urine and Blood.

AIM: The study evaluates the suitability of a specific immunoassay screening test for 6-acetylmorphine (6-AM) in the setting of suspected very recent heroin consumption for forensic and clinical purposes. MATERIAL AND METHOD: The EMIT® II Plus 6-AM immunoassay was applied in 65 cases that had already tested positive for morphine in urine or blood. Biological samples (n.65 urine and n.53 blood) were obtained from workplace drug tests (WDT n. 5), tests for driving under the influence of drugs (DUID n. 30), vehicle accidents (n. 10), overdoses (n. 12) and heroin-related deaths (n. 8) cases. The 6-AM screening assay results were confirmed with the LC-MS/MS analysis in relation to the cut-off set at 10 ng/mL for both urine and blood. RESULTS: Among the 65 urine samples (all morphine-positive), 38 samples were 6-AM-positive and 27 were 6-AM-negative with 100% agreement between the positive/negative results of the two assays. Among the 53 blood samples (34 positive and 19 negative for the morphine), 16 were 6-AM positive and 37 were negative. Only one of the blood samples, positive for 6-AM by LC-MS/MS at 10.3 ng/mL, was negative by the immunoassay test. Based on the concordance between the results of the 6-AM immunoassay versus the LC-MS/MS, the sensitivity of the 6-AM assay was calculated as 100% and 95% for urine and blood respectively, with a specificity and accuracy of 100% for both biological samples. In addition, the study demonstrated that the 6-AM assay test, originally developed for urine, is also sufficiently sensitive to identify 6-AM in blood. Therefore, it could be applied in cases of vehicle accidents or overdose to distinguish rapidly between very recent heroin use and the intake of other opiates for therapeutic purposes.

Aberrant default-mode functional and structural connectivity in heroin-dependent individuals.

BACKGROUND: Little is known about connectivity within the default mode network (DMN) in heroin-dependent individuals (HDIs). In the current study, diffusion-tensor imaging (DTI) and resting-state functional MRI (rs-fMRI) were combined to investigate both structural and functional connectivity within the DMN in HDIs. METHODS: Fourteen HDIs and 14 controls participated in the study. Structural (path length, tracts count, (fractional anisotropy) FA and (mean diffusivity) MD derived from DTI tractography)and functional (temporal correlation coefficient derived from rs-fMRI) DMN connectivity changes were examined in HDIs. Pearson correlation analysis was performed to compare the structural/functional indices and duration of heroin use/Iowa gambling task(IGT) performance in HDIs. RESULTS: HDIs had lower FA and higher MD in the tract connecting the posterior cingulate cortex/precuneus (PCC/PCUN) to right parahippocampal gyrus (PHG), compared to the controls. HDIs also had decreased FA and track count in the tract connecting the PCC/PCUN and medial prefrontal cortex (MPFC), as well as decreased functional connectivity between the PCC/PCUN and bilateral PHG and MPFC, compared to controls. FA values for the tract connecting PCC/PCUN to the right PHG and connecting PCC/PCUN to the MPFC were negatively correlated to the duration of heroin use. The temporal correlation coefficients between the PCC/PCUN and the MPFC, and the FA values for the tract connecting the PCC/PCUN to the MPFC were positively correlated to IGT performance in HDIs. CONCLUSIONS: Structural and functional connectivity within the DMN are both disturbed in HDIs. This disturbance progresses as duration of heroin use increases and is related to deficits in decision making in HDIs.

Prevalence of heroin markers in urine for pain management patients.

Surveys of current trends indicate heroin abuse is associated with nonmedical use of pain relievers. Consequently, there is an interest in evaluating the presence of heroin-specific markers in chronic pain patients who are prescribed controlled substances. A total of 926,084 urine specimens from chronic pain patients were tested for heroin/diacetylmorphine (DAM), 6-acetylmorphine (6AM), 6-acetylcodeine (6AC), codeine (COD), and morphine (MOR). Heroin and markers were analyzed using liquid chromatography tandem mass spectrometry (LC-MS-MS). Opiates were analyzed following hydrolysis using LC-MS-MS. The prevalence of heroin use was 0.31%, as 2871 were positive for one or more heroin-specific markers including DAM, 6AM, or 6AC (a known contaminant of illicit heroin). Of these, 1884 were additionally tested for the following markers of illicit drug use: 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), methamphetamine (MAMP), 11-nor-9-carboxy-Δ(9)-tetracannabinol (THCCOOH), and benzoylecgonine (BZE); 654 (34.7%) had positive findings for one or more of these analytes. The overall prevalence of heroin markers were as follows: DAM 1203 (41.9%), 6AM 2570 (89.5%), 6AC 1082 (37.7%). MOR was present in 2194 (76.4%) and absent (

Distinguishing heroin abuse from codeine administration in the urine of Chinese people by UPLC-MS-MS.

Heroin is a highly addictive drug, and heroin abuse is considered to be a serious criminal act. The major metabolite of heroin, morphine, can usually be detected as evidence of heroin abuse. However, it is difficult to determine heroin use when morphine and codeine are both detected, because codeine use will also result in the presence of morphine in urine. Therefore, it is important to distinguish heroin abuse from codeine administration. In this study, urine samples from 21 volunteers with various ingestion patterns of a compound codeine phosphate oral solution were used as negative controls, and urine samples from 89 alleged heroin users were used as positive controls. Urine from single and multiple doses of codeine administration were collected at different time points for a systematic comparison. After protein precipitation, the urine samples were analyzed for the presence of free morphine, free codeine and their metabolites by ultra-performance liquid chromatography-tandem mass spectrometry. The method of percentiles, with median and standard interquartile ranges, was used to describe and analyze the data based on the normality of the distribution. The ratios of concentration of morphine and morphine to codeine were found to be the possible criteria to distinguish heroin users from codeine users in Chinese people.

Retrospective study of outcomes, for patients admitted to a drug treatment centre board.

Retrospective study of urinary heroin outcomes of a cohort (123) of patients commenced on a methadone treatment program. Significantly poorer outcomes were associated with urines positive for cocaine (OR 0.69 CI 0.59-0.81) benzodiazepines (OR 0.7 CI 0.53-0.93) with prescribing of low dose methadone (OR 0.65 CI 0.48-0.87), with urines positive for heroin at time of admission (OR 0.74 CI 0.56-0.97) and with behavioural sanctions (OR 0.8, CI 0.65-0.98). Improved outcomes were associated with granting of take away methadone (OR 1.34 CI 1.1-1.62). with an indication of improved outcomes associated with alcohol positive urines (OR 1.34 CI 0.95-1.9) and increased duration of clinic attendance (OR 1.21 CI 0.99-1.47). On multiple regression analysis low dose methadone (0.07 CI 0.01-0.33) prescribing remained negatively associated with urine heroin outcomes.

Tetrodotoxin alleviates acute heroin withdrawal syndrome: a multicentre, randomized, double-blind, placebo-controlled study.

1. Tetrodotoxin (TTX) is a powerful sodium channel blocker extracted from the puffer fish. The efficacy and safety of TTX as monotherapy for the treatment of acute heroin withdrawal syndrome were evaluated in the present study. This 7-day, multicentre, randomized, double-blind, placebo-controlled study was carried out between December 2008 and October 2009. In total, 216 patients who met the Diagnostic and Statistical Manual of Mental Disorders IV diagnosis of heroin addiction were recruited. After providing written informed consent, subjects were randomly assigned to double-blind treatment in one of the following groups: 5 µg TTX group (group 1), 10 µg TTX group (group 2) or the placebo group (group 3). 2. Evidence suggests that both 5 and 10 µg TTX significantly reduced withdrawal symptoms by day 3 compared with placebo, and there was no significant difference in the incidence of adverse events in the three groups. 3. In conclusion, this clinical trial shows that TTX (5 and 10 µg given t.i.d.) is effective in alleviating opiate withdrawal symptoms with few side-effects.

Evaluation of prooxidant-antioxidant balance in chronic heroin users in a single assay: an identification criterion for antioxidant supplementation.

BACKGROUND: Opiate abuse has been linked to oxidative stress, through the separate evaluation of oxidants and antioxidants. OBJECTIVES: To determine prooxidant-antioxidant balance (PAB) in chronic heroin users in a single assay, easily applied in a clinical setting. Specifically, to examine whether PAB values correlate with the duration of abuse or with the presence of anti-HCV antibodies. METHODS: Sixty-four chronic heroin users - 34 cases and 30 controls - participated in this study. PAB was determined by an Enzyme-linked immunosorbent assay (ELISA) method, developed by members of the study group. RESULTS: In heroin users, oxidative balance was disrupted in favor of prooxidants. There was no correlation of PAB values with the duration of abuse or with the presence of anti-Hepatitis C virus (HCV) antibodies. CONCLUSIONS: Chronic heroin users can benefit from an antioxidant therapy, and the method currently presented can be used as an identification criterion.

Multiple-drug toxicity caused by the coadministration of 4-methylmethcathinone (mephedrone) and heroin.

An accidental death caused by the combined use of a new designer drug, 4-methylmethcathinone (mephedrone), and heroin is reported. A 22-year-old Caucasian male was found unresponsive in his living quarters and was transported to the hospital where he died. During autopsy, needle marks were found along the decedent's lower legs and ankles. Investigators discovered the decedent and his roommate had been using "Black Tar" heroin and mephedrone. Routine toxicological analysis detected morphine in the decedent's blood at 0.06 mg/L. Additionally, 6-acetylmorphine, morphine, codeine, and doxylamine were detected in his urine. A designer drug screen, employing a basic liquid-liquid extraction followed by pentafluropropionic anhydride derivatization, was used to isolate mephedrone from both blood and urine specimens. The derivatized extracts were analyzed by gas chromatography- mass spectrometry (GC-MS) operating in full-scan mode. Quantitative analysis of mephedrone was performed by GC-MS operating in selective ion monitoring mode using methamphetamine-d(14) as an internal standard. Mephedrone was confirmed in the decedent's blood and urine at 0.50 and 198 mg/L, respectively. The physiological and pharmacological effects of mephedrone and any associated toxicity have not been reported. However, because of its structural similarities with methcathinone and the high concentration in the decedent's blood, the overall contribution of mephedrone to the death could not be minimized. Therefore, the medical examiner reported the cause of death as multiple-drug toxicity and the manner of death as accidental.

Validation of meconin as a marker for illicit opiate use.

The detection of markers for illicit opiate misuse is important both in the management of substance misuse and in the postmortem identification of illicit opiate use. In addition to 6-monoacetylmorphine and acetyl codeine, other markers, such as papaverine, noscapine, and their metabolites, have been proposed as markers of illicit opiate use. Urine samples (362) from individuals attending substance misuse services and 26 postmortem cases were analyzed for meconin, a noscapine metabolite by gas chromatography-mass spectrometry. Three hundred of the substance misuse service samples and 14 of the postmortem samples had morphine present as the major opiate. Meconin was detected in 284 (94.7%) of these substance misuse samples and 11 (78%) of the postmortem samples. There was a specificity of 100% in both groups. In the 62 substance misuse cases where morphine was not the major opiate detected and four separate cases in which medicinal diamorphine was known to have been administered, meconin was not detected. The use of meconin as a useful adjunct in detecting illicit opiate use is recommended.

Urine drug test interpretation: what do physicians know?

OBJECTIVE: To determine the level of urine drug test (UDT) interpretive knowledge of physicians who use these instruments to monitor adherence in their patients on chronic opioid therapy. METHODS: A seven-question instrument consisting of six five-option, single-best-answer multiple choice questions and one yes/no question was completed by 114 physicians (77 who employ UDT and 37 who do not) attending one of three regional opioid education conferences. We calculated frequencies and performed chi2 analyses to examine bivariate associations between UDT utilization and interpretive knowledge. RESULTS: The instrument was completed by 80 percent of eligible respondents. None of the physicians who employ UDT answered all seven questions correctly, and only 30 percent answered more than half correctly. Physicians who employ UDT performed no better on any of the questions than physicians who do not employ UDT. CONCLUSIONS: Physicians who employ UDT to monitor patients receiving chronic opioid therapy are not proficient in test interpretation. This study highlights the need for improved physician education; it is imperative for physicians to work closely with certified laboratory professionals when ordering and interpreting these tests.

Elevated urinary aluminium in current and past users of illicit heroin.

The use of illicit heroin is associated with aberrant neurology of unknown aetiology and various psychiatric illnesses. Aluminium, which is a proven neurotoxin, is present in significant amounts in illicit heroin and may also be volatilized and inhaled following the vaporization of heroin off aluminium foil ('Chasing the Dragon'). The purpose of this study was to establish if the use of illicit heroin was associated with an increase in the body burden of aluminium. We have used graphite furnace atomic absorption spectrometry to measure the aluminium and iron contents of the urine of current and past users of illicit heroin and used these data to estimate body burdens of aluminium. Urinary excretion of aluminium is the most effective non-invasive indicator of the body burden of aluminium and was found to be significantly (P < 0.001) higher in users of illicit heroin, range 14-3382 nmol/mmol creatinine (mean +/- SD; 222 +/- 491 nmol/mmol creatinine), than in a normal non-drug abusing control population, range 23-74 nmol/mmol creatinine (mean +/- SD; 43 +/- 19 nmol/mmol creatinine). Exposure to aluminium from the use of illicit heroin may be of particular significance because the urinary excretion of iron, another major contaminant of illicit heroin, in users (mean +/- SD; 53 +/- 63 nmol/mmol creatinine) was not significantly different (P > 0.05) from the control population (mean +/- SD; 38 +/- 18 nmol/mmol creatinine). We have shown for the first time that the use of illicit heroin may be a significant contributor to the body burden of aluminium. Further research will be required to determine if adventitious aluminium has a role in heroin use-related neuropathology and neurology.

A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence: a randomized controlled trial.

OBJECTIVE: Both methadone and buprenorphine are effective therapy for heroin dependence. Efficacy is best documented for methadone maintenance therapy, but safety concerns limit its use. Buprenorphine offers lower overdose risk and improved access, but efficacy may be lower. The authors compared adaptive, buprenorphine-based stepped care to optimal methadone maintenance treatment. METHOD: This randomized controlled trial was undertaken 2004-2006. It consisted of a 24-day uniform double-blind induction phase followed by single-blind flexible dosing based on structured clinical criteria, for a total of 6 months. Ninety-six self-referred subjects with heroin dependence were randomly assigned to methadone or to stepped treatment initiated with buprenorphine/naloxone and escalated to methadone if needed. All subjects received intensive behavioral treatment. Primary outcome was retention in treatment. Secondary outcomes were completer analyses of problem severity (Addiction Severity Index) and proportion of urine samples free of illicit drugs. RESULTS: Overall, 6-month retention was 78%. Stepped treatment and methadone maintenance therapy outcomes were virtually identical. Among completers of stepped therapy, 46% remained on buprenorphine/naloxone. Proportion of urine samples free of illicit opiates increased over time and ultimately reached approximately 80% in both arms. Problem severity decreased significantly and uniformly in both arms. CONCLUSIONS: A stepped treatment of heroin dependence as described here appears equally efficacious compared to optimally delivered methadone maintenance therapy. Together with prior data on the advantageous safety of buprenorphine, this suggests that broad implementation of strategies using buprenorphine as first-line treatment should be considered.

The significance of putative urinary markers of illicit heroin use after consumption of poppy seed products.

After consumption of poppy seeds various substances were detected in urine or blood samples using an immunoassay and a sophisticated liquid chromatographic-tandem mass spectrometric procedure. These compounds are widely considered to be putative markers of heroin (HER) abuse whereas acetylcodeine was regarded as a marker for illicit preparations ("street HER"). Besides positive urinary opiate immunoassay results during a 48 hours monitoring period, peak concentrations of morphine (MOR), codeine and their glucuronides appeared 4 to 8 hours after ingestion of poppy seeds, and concentrations of total MOR higher than 10 microg/mL were observed. Also, in serum samples taken up to 6 hours after consumption, MOR glucuronides were found. Free MOR was only detected in traces (1 to 3 ng/mL) within 2 hours of consumption. In addition, 3 of 6 onsite opiate sweat tests revealed positive results 6.5 hours after ingestion. Furthermore, it was demonstrated that neither noscapine (NOS) nor papaverine (PAP) was detectable in urine or blood samples after the consumption of poppy seeds containing up to 94 microg NOS and up to 3.3 mug PAP. NOS and PAP were rapidly metabolized, whereas desmethylpapaverine and, especially, its glucuronide were found in urine samples of poppy seed consumers even 48 hours after consumption. According to these results PAP metabolites should not be regarded as markers of illicit HER abuse. In conclusion, only acetylcodeine can be regarded as a specific marker but has the problem of a short half-life. Therefore, we suggest that NOS and PAP, but not their metabolites, might be used cautiously as additional markers of illicit HER abuse as they have not been detected after oral intake of poppy seeds in normal doses. But it must be kept in mind that in some cases poppy seeds with an unusually high content of these alkaloids could be available, and that these substances are also agents in some pharmaceuticals.

Validation of techniques to detect illicit heroin use in patients prescribed pharmaceutical heroin for the management of opioid dependence.

BACKGROUND: The clinical implementation and evaluation of heroin substitution programmes have been confounded by the lack of objective and validated biomarkers for illicit heroin use in patients prescribed pharmaceutical heroin. This study examined the capacity to detect illicit heroin use by gas chromatography-mass spectrometry (GC-MS) analysis of urine samples for the presence of opium impurities common to illicit, but not pharmaceutical heroin. AIMS: To characterize the diagnostic properties of the metabolites of noscapine and papaverine in comparison to morphine as a gold-standard marker of illicit heroin use; and to examine the relationships between the self-reported time since most recent heroin use and the detection of these opioids in urine. DESIGN: A cross-sectional study of 52 opioid-dependent patients in treatment (not prescribed heroin), who self-reported illicit heroin use within the preceding 2 weeks. Self-report data regarding recent drug use and a urine sample were collected. GC-MS analyses of urines were conducted and reported by laboratory staff blinded to self-report data. FINDINGS: The metabolites of papaverine (hydroxypapaverine and dihydroxypapeverine) were found to have high sensitivity, specificity and negative predictive values as markers for illicit heroin use compared to the 'gold-standard' morphine. Other opioids, including 6-mono-acetylmorphine (6-MAM), codeine and noscapine metabolites (e.g. meconine) were less adequate in detecting heroin use. CONCLUSIONS: GC-MS detection of papaverine metabolites in urine appears to be suitable method of identifying illicit heroin use for clinical and research purposes.

Changes to methadone clearance during pregnancy.

OBJECTIVE: Measurement of plasma methadone concentration to investigate the rate of clearance of methadone prescribed for heroin dependence in the first, second and third trimesters of pregnancy. A secondary objective was to evaluate the outcome of pregnancy. METHODS: Longitudinal within subject study of nine pregnant opioid dependent subjects prescribed methadone at the Leeds Addiction Unit, an outpatient community based treatment centre. Plasma concentration versus time data for methadone was collected during each trimester and post-partum for our subjects. Data was available for the first and second trimesters for 4/9 cases. All but one of the subjects provided data during the third trimester and data post-partum was collected from three respondents. Measurements of methadone levels in plasma were carried out using high performance liquid chromatography (HPLC). RESULTS: Trough mean plasma methadone concentrations reduced as the pregnancies progressed from 0.12 mg/L (first trimester) to 0.07 mg/L (third trimester). The weight-adjusted clearance rates gradually increased from a mean of 0.17 to 0.21 L/hr/kg during pregnancy, although patterns differed substantially between the nine women. An assessment of relative clearance of methadone using two patients for whom we have had all three CL values (trimester 1-3) demonstrated notable change of CL (P = 0.056) over time. Eight of our subjects delivered (3 males), within two weeks of their due date the ninth (male) was premature (21 days). The mean length of gestation was 39.7 weeks (SD = 10 days) and none of the neonates met criterion for 'low birth weight' mean = 3094, SD = 368 g). Five neonates spent time (0.5-28 days) in a special care baby unit (SCUBU) and 4 of these displayed signs of methadone withdrawal. CONCLUSIONS: General Practitioners and hospital doctors should recognise the significant benefits of prescribing methadone for heroin-dependent women during pregnancy. We recommend that if a pregnant opioid user complains of methadone withdrawal symptoms (i.e. that the methadone dose does not "hold" them) the prescribing clinician takes this observation seriously and considers a more detailed assessment. Further work on key factors undergoing changes during pregnancy accounting for differences in methadone metabolism in the mother, fetus and neonate are required.

Deuterodiacetylmorphine as a marker for use of illicit heroin by addicts in a heroin-assisted treatment program.

In preparation for a treatment program concerning the medical coprescription of heroin and methadone to treatment-resistant addicts in the Netherlands, we studied a novel strategy for monitoring co-use of illicit (nonprescribed) heroin. A deuterated analogue of heroin was added (1:20) to pharmaceutical, smokable heroin (a powder mixture of 75% w/w diacetylmorphine base and 25% w/w caffeine anhydrate), to be used by inhalation after volatilization ("chasing the dragon"). Plasma and urine samples were collected from nine male patients who had used pharmaceutical, smokable heroin during a four-day stay in a closed clinical research unit, and these samples were analyzed by liquid chromatography coupled with tandem mass spectrometry. Ratios of deuterated and undeuterated diacetylmorphine and 6-acetylmorphine (MAM/MAM-d3) in plasma and urine were calculated from peak areas of these substances in the respective chromatograms. The MAM/MAM-d3 ratios in plasma and urine were normally distributed (with small standard deviations) and independent from concentrations of 6-acetylmorphine and from time after use of pharmaceutical heroin. A MAM/MAM-d3 ratio in urine above 32.8 was considered indicative of co-use of illicit heroin, and this value was associated with a false-positive rate of only 1% (95% confidence interval: -1 to 3%). The MAM/MAM-d3 ratio was detectable in urine for 4-9.5 h after use of pharmaceutical, smokable heroin. Addition of stable, isotopically labelled heroin to pharmaceutical, smokable heroin is considered to be a feasible strategy for the detection of co-use of illicit heroin by patients in heroin-assisted treatment.

Excretion profile of opiates in dependent patients in relation to route of administration and type of drug measured in urine with immunoassay.

It is accepted that opiates are detectable in urine within three days from the last dose at a cut-off value of 300 ng/mL. In our clinical practice, some patients tested positive for morphine even after a week of detoxification. The present study evaluates the time course of opiate excretion in urine of dependent subjects (F11.25 according to ICD-10) in relation to route of administration and a kind of street heroin. The group comprised 71 men treated for opiate dependency: 33 of them used heroin exclusively by inhalation; 26 i.v.; 12 used i.v. homemade poppy straw decoctions. Opiate levels were measured once a day by fluorescence polarization immunoassay (TDx Abbott). Detection time ranged from 3 to 10 days for cut-off value 300 ng/mL and from less than one up to seven days for cut-off value 2000 ng/mL. The increases in urine drug concentration that result from changes in urinary output may be mistakenly interpreted as a new drug use. Normalization of drug excretion to urine creatinine concentration reduces the variability of drug measurement attributable to urine dilution. The time function of creatinine normalized opiate concentration has a log-linear character, and decreases at a rate of 2.5 per day on average. New "normalized" cut-off values were proposed: 225 ng/mg creatinine, 1500 ng/mg creatinine, and 3750 ng/mg creatinine that corresponds to 300 ng/mL urine, 2000 ng/mL urine, and 5000 ng/mL urine.