Chemical profile of counterfeit buprenorphine vials seized in Tehran, Iran

Buprenorphine, commonly known by the trademark Temgesic, is one of the most popular drugs of abuse among the opioid-addicted young individuals in Iran. Temgesic, Bungesic, etc. are the most popular and important illicit opioid drugs in Tehran's illicit drugs black market, and are now among the most widely abused by opioid addicts. Because of this, counterfeiting of this drug has increased in Tehran. In this study, the qualitative analysis of counterfeit buprenorphine by gas chromatography-mass spectrometry (GC-MS) and high performance liquid chromatography (HPLC) demonstrates the presence of diacetylmorphine, acetylcodeine and pheniramine, as well as the absence of buprenorphine. In conclusion, due to the absence of quality control and difficulties in differentiating counterfeit buprenorphine from genuine products, the use of counterfeit buprenorphine leads the opioid abusers to health risks.     

A survey of buprenorphine related deaths in Singapore

Buprenorphine is available in Singapore as substitution treatment for opioid dependence since 2002. This study surveys buprenorphine related deaths in Singapore between September 2003 and December 2004. The aims are to establish the autopsy prevalence of buprenorphine related deaths and the demographical and toxicological profile of the cases. Toxicological screening was performed for all unnatural deaths, deaths involving known drug addicts, as well as when autopsy revealed no obvious cause of death. Twenty-one cases had buprenorphine detected in post-mortem blood and/or urine samples. Eighteen were sudden deaths. There were two fatal falls from height and one death by hanging. All subjects were male. The age range was 24-48 years. Fourteen subjects were between 30 and 39 years of age. The mean age was 35 years. The majority (62%) were Chinese. Eleven (52%) were known drug abusers. For sudden deaths, two groups were identified. Six cases died from natural causes. Blood buprenorphine levels ranged from undetected (detected in urine) to 3.2 ng/mL (mean 1.4 ng/mL). Twelve cases were attributed directly and indirectly to mixed drug poisoning. Blood buprenorphine levels ranged from undetected (detected in urine) to 17 ng/mL (mean 3.2 ng/mL). Nineteen cases showed concurrent abuse of buprenorphine and benzodiazepine, diazepam being the most frequently detected, followed by nitrazepam and midazolam. The availability of buprenorphine as substitution therapy is associated with an increase in buprenorphine related deaths. The danger of co-abuse of buprenorphine and benzodiazepines is highlighted.     

Current and Promising Pharmacotherapies for Substance Use Disorders among Justice-Involved Populations

Growing recognition of the biological underpinnings of substance use disorders (SUDs) has led to increased acceptance of pharmacotherapy-based treatments for general populations and, more recently, for individuals under criminal justice supervision, including those in correctional settings. This paper focuses on pharmacotherapies that have been approved by the United States Food and Drug Administration (FDA) for treatment of alcohol use disorder and opioid use disorder. For alcohol use disorder, these medications are disulfiram, naltrexone, and acamprosate; for opioid use disorder, these are methadone, buprenorphine, and naltrexone. Promising pharmacotherapies for stimulant use disorder are also briefly summarized. The paper concludes with three “lessons learned,” specifically: (1) treatment and policy should reflect the fact that substance misuse and addiction is a medical disorder, (2) interventions for SUDs should be integrated into primary care, and (3) reductions in substance use among pharmacotherapy-treated patients do not necessarily lead to concomitant reductions in crime (nor should this be the primary rationale for providing such treatment).     

Evaluation and applicability of Alere iCup DX 14 for rapid postmortem urine drug screening at autopsy

Performing point‐of‐care urine drug screen testing at autopsy by a forensic pathologist may provide an early indication of the presence of analytes of interest during autopsy. An evaluation for the screening of 14 classes of common drugs of abuse in postmortem urine by the point‐of‐care screening device, Alere iCup DX 14, is presented. One hundred ninety postmortem urine samples were screened with the iCup occurring at autopsy by the forensic pathologist. Positive and negative results obtained from the screening kit were evaluated against confirmatory test results obtained using routine forensic toxicology analyses that employed LC‐MS/MS and GC‐MS to detect a combination of over 85 common drugs of abuse and medications. Sensitivity for each respective iCup drug class ranged from 66% (buprenorphine) to 100% (methadone, tricyclic antidepressants). Specificity for each respective iCup drug class ranged from 89% (benzodiazepines) to 100% (amphetamines, barbiturates, buprenorphine, 3,4‐methylenedioxymethamphetamine, methadone). Positive predictive values ranged from 44% (benzodiazepines) to 100% (amphetamines, barbiturates, buprenorphine, methylenedioxymethamphetamine, methadone), while negative predictive values ranged from 96% (methamphetamine) to 100% (barbiturates, methadone, tricyclic antidepressants). A high false‐positive rate was yielded by the benzodiazepine class. The lack of fentanyl screening in the point‐of‐care device is a significant limitation considering its prolific prevalence in forensic casework. The results obtained in the study should be acknowledged when considering the use of the Alere iCup DX 14 in the context of postmortem casework to help indicate potential drug use contemporaneously with autopsy and when requiring such preliminary results prior to the release of a final forensic toxicology report.     

Schedules of controlled substances: rescheduling of buprenorphine from schedule V to schedule III. Final rule

This final rule is issued by the Deputy Administrator of the Drug Enforcement Administration (DEA) to reschedule buprenorphine from a Schedule V narcotic to a Schedule III narcotic under the Controlled Substances Act (CSA). This action is based on a rescheduling recommendation by the Department of Health and Human Services (DHHS) and a DEA review indicating that buprenorphine meets the criteria of a Schedule III narcotic. The DEA published a proposed rule to reschedule buprenorphine on March 21, 2002 (67 FR 13114). The comment period was extended for an additional 30 days until May 22, 2002 (67 FR 20072). The DEA received ten comments but no requests for hearings. This final action will impose the regulatory controls and criminal sanctions of a Schedule III narcotic on those persons who handle buprenorphine or products containing buprenorphine     

An Unusual Case of Death Probably Triggered by the Association of Buprenorphine at Therapeutic Dose with Ethanol and Benzodiazepines and with Very Low Norbuprenorphine Level

Buprenorphine is largely prescribed for maintenance treatment in opioid dependence due to its safety profile. Nevertheless, fatalities at therapeutic dose have been described when associated with other central nervous system depressants, such as ethanol or benzodiazepines. Here, we report a case of death due to association of buprenorphine at therapeutic dose with benzodiazepines and ethanol. Although toxicity has been often attributed to its metabolite norbuprenorphine rather than to buprenorphine itself, in our case, norbuprenorphine was not detected in urine and bile and only in traces in blood. Moreover, the presence in blood of free buprenorphine but not of glucuronide metabolites argues for an unusual early death, at the beginning of buprenorphine metabolism. We propose that in the context of prior toxic impregnation, buprenorphine directly (and not via its metabolite norbuprenorphine) acted as a triggering factor by blocking the ventilatory response, rapidly leading to fatal respiratory depression.     

Methadone-related deaths in Norway

IntroductionThe use of methadone in opioid maintenance treatment (OMT) is potentially associated with a number of adverse effects and the risk of fatal toxicity. Increased methadone availability may lead to an increase in methadone-related deaths. We have investigated methadone-related deaths in Norway over the period 2000–2006.Materials and methodsMethadone-positive samples over the period 2000–2006 were identified from forensic toxicological investigations, and demographic and toxicological data were retrieved. The cases were cross-linked with the Norwegian Cause of Death Registry and regional OMT registers.ResultsA total of 312 individuals had died after taking methadone over the period 2000–2006, predominantly men with a mean age of 36. In 85% of cases (n = 264), the deceased had died of a methadone-related intoxication, most often in combination with other drugs, including benzodiazepines, cannabis and other opioids. Only 22% of the deceased had been in OMT at the time of death. A larger proportion of OMT patients had died of causes other than intoxications compared to those not in OMT (30% vs. 8%, respectively), most commonly related to disease.ConclusionsOne methadone-related death occurred, on average, every week over the time period investigated. Only 22% of the deceased were registered in opioid maintenance treatment (OMT) programs. The findings underline the need to control diversion of medication from OMT programs.     

Evaluation of the One-Step ELISA kit for the detection of buprenorphine in urine, blood, and hair specimens

A solid-phase enzyme immunoassay involving microtiter plates was recently proposed by International Diagnostic Systems corporation (IDS) to screen for buprenorphine in human serum. The performance of the kit led us to investigate its applicability in other biological matrices such as urine or blood, and also hair specimens. Low concentrations of buprenorphine were detected with the ELISA test and confirmed by HPLC/MS (buprenorphine concentrations measured by HPLC/MS: 0.3 ng/mL in urine, 0.2 ng/mL in blood, and 40 pg/mg in hair). The intra-assay precision values were 8.7% at 1 ng/mL of urine (n = 8), 11.5% at 2 ng/mL in serum (n = 8), and 11.5% at 250 pg/mg of hair (n = 8), respectively. The immunoassay had no cross-reactivity with dihydrocodeine, ethylmorphine, 6-monoacetylmorphine, pholcodine, propoxyphene, dextromoramide, dextrometorphan at 1 and 10 mg/L, or codeine, morphine, methadone, and its metabolite EDDP. A 1% cross-reactivity was measured for a norbuprenorphine concentration of 50 ng/mL. Finally, the immunoassay was validated by comparing authentic specimens results with those of a validated HPLC/MS method. From the 136 urine samples tested, 93 were positive (68.4%) after the ELISA screening test (cutoff: 0.5 ng/mL) and confirmed by HPLC/MS (buprenorphine concentrations: 0.3-2036 ng/mL). From the 108 blood or serum samples screened, 27 were positive (25%) after the ELISA test with a cutoff value of 0.5 ng/mL (buprenorphine concentrations: 0.2-13.3 ng/mL). Eighteen hair specimens were positive (72%) after the screening (cutoff: 10 pg/mg) and confirmed by LC/MS (buprenorphine concentrations: 40-360 pg/mg). The ELISA method produced false positive results in less than 21% of the cases, but no false negative results were observed with the immunological test. Four potential adulterants (hypochloride 50 mL/L, sodium nitrite 50 g/L, liquid soap 50 mL/L, and sodium chloride 50 g/L) that were added to 10 positive urine specimens (buprenorphine concentrations in the range 5.3-15.6 ng/mL), did not cause a false negative response by the immunoassay.     

The U.S. Mandatory Guidelines for Federal Workplace Drug Testing Programs: current status and future considerations

The U.S. Department of Health and Human Services (HHS) drug testing standards were published in 1988 and revised in 1994, 1998, and 2004. In 2004, significant revisions defining, standardizing, and requiring specimen validity testing on Federal employee donor urine specimens were included. In a separate notice, HHS proposed to establish scientific and technical guidelines for the Federal Workplace Drug Testing Program to: (1) permit laboratory testing of hair, oral fluid, and sweat patch specimens in addition to urine specimens for marijuana, cocaine, phencyclidine, opiates (with focus on heroin), and amphetamines [including methylenedioxymethamphetamine (MDMA), methylenedioxyethamphetamine (MDEA), methylenedioxyamphetamine (MDA)]; (2) permit use of on-site point of collection test (POCT) devices to test urine and oral fluid at collection sites; (3) permit use of instrumented initial test (screening only) facilities [IITF] to quickly identify negative specimens; and (4) add training requirement for collectors, on-site testers, and MROs. This proposal was published in the Federal Register on 13 April 2004, with a 90-day public comment period. The Substance Abuse and Mental Health Services Administration, HHS, reviewed those comments and is preparing the Final Notice that will define the requirements for such testing, including: specimen collection procedures, custody and control procedures that ensure donor specimen identity and integrity, testing facility, initial and confirmatory test cutoff concentrations, analytical testing methods, result review and reporting, evaluation of alternative medical explanations for presence of drug or metabolite in the donor's specimen, and laboratory certification issues. Voluntary pilot performance testing (PT) programs for each specimen type are on-going since April 2000 to determine how to prepare PT materials for specimens other than urine to evaluate laboratories' ability to routinely achieve accuracy and precision required. Certification programs will be developed using the current urine drug testing National Laboratory Certification Program model. The addition of accurate and reliable workplace drug testing using hair, oral fluid, and sweat patch specimens will complement urine drug testing, and aid in combating industries devoted to suborning drug testing through adulteration, substitution, and dilution. For example, hair testing may detect chronic drug use for up to 90 days and be useful in pre-employment situations; oral fluid testing may detect drug use in past hours and be useful in post-accident situations; sweat patch testing may be useful in follow-up drug testing and treatment programs; POCTs and IITFs may be most useful for quickly identifying specimens that are negative for drugs and indicate that the specimen is valid.     

The development and application of a rapid gas chromatography-mass spectrometry method to monitor buprenorphine withdrawal protocols

There are several drug therapies that can be used to treat opiate abuse. One such treatment that is currently gaining wide acceptance is the use of the combined agonist/antagonist drug buprenorphine. As with all long-term treatments, there is a potential for compliance issues to arise, which establishes the need for a technique to facilitate the monitoring of individuals prescribed buprenorphine. One such method has been developed and applied to the routine monitoring of buprenorphine and its primary metabolite in urine. The method was found to be sensitive (limits of detection of 1.0 ng/mL for both buprenorphine and norbuprenorphine), reproducible and linear up to 2000 ng/mL. This article describes the application of this method to the analysis of specimens collected from subjects prescribed a reducing low-dose buprenorphine regimen (10.0-0.4 mg per day) for acute opiate detoxification. A significant relationship between the daily dose and the mean creatinine-corrected concentration of buprenorphine in the urine was observed, together with a relatively stable relationship between the ratio of the urinary concentrations of norbuprenorphine to buprenorphine across the dose range studied.     

Randomized controlled trial proves effectiveness of methadone maintenance treatment in prison

A study on methadone maintenance treatment (MMT) undertaken by the Correctional Service of Canada in 2001 demonstrated that MMT has a positive impact on release outcome and on institutional behaviour. Now, a new study undertaken in an Australian prison system has demonstrated that MMT also reduces drug use and injection in prisons. The implications of this study are far reaching. They suggest that in all jurisdictions where community-based programs operate, prison-based methadone programs should be introduced or expanded.     

Parent and Metabolite Opioid Drug Concentrations in Unintentional Deaths Involving Opioid and Benzodiazepine Combinations,,

Effects of benzodiazepines on postmortem opioid parent and parent/metabolite blood concentration ratios were determined for fentanyl‐, hydrocodone‐, methadone‐, or oxycodone‐related accidental deaths. These opioids are partially metabolized by the CYP3A4 enzyme system, which is also affected by diazepam and alprazolam. Opioid/metabolite combinations examined were as follows: fentanyl/norfentanyl, hydrocodone/dihydrocodeine, methadone/EDDP, and oxycodone/oxymorphone. Parent opioid concentrations were analyzed for 877 deaths. Parent/metabolite concentration ratios were analyzed for 349 deaths, excluding cases with co‐intoxicants present known to interfere with opioid elimination. Alprazolam in combination with diazepam significantly decreased median hydrocodone concentrations by 48% (p = 0.01) compared to hydrocodone alone. The methadone parent/metabolite concentration ratio was reduced by 35% in the presence of diazepam compared to methadone alone (p = 0.03). Benzodiazepines did not statistically significantly affect fentanyl or oxycodone concentrations. Possible factors affecting opioid concentrations and possible toxicity development, including any differential effects on specific opioids, should continue to be explored.     

Deaths involving buprenorphine: a compendium of French cases

Buprenorphine at high dosage became available in France in 1996, as a substitution treatment for heroin addicts. Since this date, numerous deaths were attributed to this drug. This paper reports two original series of 39 and 78 fatalities involving buprenorphine observed at the Institute of Legal Medicine of Strasbourg and at 13 other French forensic centers, respectively. The files were recorded from January 1996-May 2000. The first 20 fatalities that were previously published were excluded from this epidemiological study. From these 117 subjects, 96 were male (82%). Buprenorphine and its primary metabolite norbuprenophine were assayed in post-mortem blood by HPLC/MS (n=11 labs) or by GC/MS (n=3 labs). Blood levels for buprenorphine ranged from 0.5 to 51.0ng/ml (mean 10.2ng/ml) and 0.1 to 76ng/ml (mean 12.6ng/ml) in Strasbourg and the other centers, respectively. Blood levels for norbuprenorphine ranged from 0.2 to 47.1ng/ml (mean 8.2ng/ml) and <0.1 to 65ng/ml (mean 10.6ng/ml) in Strasbourg and the other centers, respectively. The mean values appear to be within the therapeutic range. Buprenorphine was identified in 24 of the 26 hair samples assayed in Strasbourg, at concentrations ranging from 10 to 1080pg/mg. Intravenous injection of crushed tablets, a concomitant intake of psychotropics (especially benzodiazepines and neuroleptics) and the high dosage of the buprenorphine formulation available in France appear as the major risk factors for such fatalities. In addition, two suicide-related deaths were also observed, with blood buprenorphine concentrations at 144 and 3276ng/ml.     

LC-MS-MS analysis of buprenorphine and norbuprenorphine in whole blood from suspected drug users

A liquid chromatography tandem mass spectrometry method is described for the analysis of buprenorphine and norbuprenorphine in whole blood. Linearity was achieved between 0.2-5 ng/g for buprenorphine and 0.5-5 ng/g for norbuprenorphine. Stability studies on spiked whole blood and an authentic sample showed no degradation of buprenorphine- and norbuprenorphine-glucuronide to their respective aglycones. Buprenorphine and norbuprenorphine showed some degradation when stored at 4°C for three weeks, but was stable when stored at -20°C for 4 weeks. The method was applied to forensic cases of driving under the influence of drugs (DUID) and petty drug offences (PDO) during 2007-2009. Out of 2459 cases analyzed, 322 were positive for both buprenorphine and norbuprenorphine (13%), 219 for buprenorphine only (9%), and 12 for norbuprenorphine only (0.5%). The mean and median concentrations (N=322) were 1.7 and 1.0 ng/g, respectively, for buprenorphine and norbuprenorphine. The mean and median norbuprenorphine/buprenorphine ratios were 1.5 and 1.1, respectively. There was no significant difference in concentration ratios for DUID and PDO cases (p>0.05). We conclude that the described method for analysis of buprenorphine and norbuprenorphine in whole blood could be used to investigate use or misuse of buprenorphine but that many of the cases presented with very low concentrations of buprenorphine. We also conclude that analysis should be performed within two weeks unless samples are stored frozen prior to analysis.     

Analysis of buprenorphine in urine specimens.

The simultaneous determination of buprenorphine (Temgesic) and its major metabolite, N-desalkylbuprenorphine, in urine samples has been studied. By using reversed-phase high-performance liquid chromatography (HPLC) with electrochemical detection, therapeutic concentrations of unconjugated buprenorphine down to 0.2 ng/mL, and 0.15 ng/mL for the metabolite, can be detected in urine samples. This method has been applied to a variety of urine samples from drug users. The possible analytical interference from several other regulated drugs has been studied. The results were also compared with those obtained from a commercial radioimmunoassay (RIA) test. This test is only capable of detecting buprenorphine concentrations higher than 1 ng/mL.     

Medicare and Medicaid programs; quarterly listing of program issuances--fourth quarter 1997--HCFA. Notice

This notice lists HCFA manual instructions, substantive and interpretive regulations, and other Federal Register notices that were published during October, November, and December of 1997 that relate to the Medicare and Medicaid programs. It also identifies certain devices with investigational device exemption numbers approved by the Food and Drug Administration that may be potentially covered under Medicare. Section 1871(c) of the Social Security Act requires that we publish a list of Medicare issuances in the Federal Register at least every 3 months. Although we are not mandated to do so by statute, for the sake of completeness of the listing, we are including all Medicaid issuances and Medicare and Medicaid substantive and interpretive regulations (proposed and final) published during this timeframe.     

Medicare and Medicaid programs; quarterly listing of program issuances--third quarter 1996--HCFA. Notice

This notice lists HCFA manual instructions, substantive and interpretive regulations, and other Federal Register notices that were published during July, August, and September of 1996 that relate to the Medicare and Medicaid programs. It also identifies certain devices with investigational device exemption numbers approved by the Food and Drug Administration that may be potentially covered under Medicare. Section 1871(c) of the Social Security Act requires that we publish a list of Medicare issuances in the Federal Register at least every 3 months. Although we are not mandated to do so by statute, for the sake of completeness of the listing, we are including all Medicaid issuances and Medicare and Medicaid substantive and interpretive regulations (proposed and final) published during this time frame.     

Medicare and Medicaid programs; quarterly listing of program issuances; fourth quarter 1996--HCFA. Notice

This notice lists HCFA manual instructions, substantive and interpretive regulations, and other Federal Register notices that were published during October, November, and December of 1996 that relate to the Medicare and Medicaid programs. It also indicates certain devices with investigational device exemption numbers approved by the Food and Drug Administration that may be potentially covered under Medicare. Section 1871(c) of the Social Security Act requires that we publish a list of Medicare issuances in the Federal Register at least every 3 months. Although we are not mandated to do so by statute, for the sake of completeness of the listing, we are including all Medicaid issuances and Medicare and Medicaid substantive and interpretive regulations (proposed and final) published during this time frame.     

Medicare and Medicaid programs; quarterly listing of program issuances--first quarter, 1998--HCFA. Notice

This notice lists HCFA manual instructions, substantive and interpretive regulations, and other Federal Register notices that were published during January, February, and March of 1998 that relate to the Medicare and Medicaid programs. It also identifies certain devices with investigational device exemption numbers approved by the Food and Drug Administration that may be potentially covered under Medicare. Section 1871(c) of the Social Security Act requires that we publish a list of Medicare issuances in the Federal Register at least every 3 months. Although we are not mandated to do so by statute, for the sake of completeness of the listing, we are including all Medicaid issuances and Medicare and Medicaid substantive and interpretive regulations (proposed and final) published during this timeframe.