Qualitative identification of fentanyl and other synthetic opioids using ambient ionization high resolution time-of-flight mass spectrometry

The Centers for Disease Control and Prevention deemed the increase in overdose fatalities, due to the use of opioids, an “opioid epidemic” in the United States. Heroin, fentanyl, and other synthetic opioids are commonly abused and are contributing to the opioid epidemic. In 2016, the Drug Enforcement Administration temporarily placed three fentanyl analogs (beta-hydroxythiofentanyl, butyryl fentanyl, and furanyl fentanyl) under Schedule I due to their imminent threat to public health. These drugs elicit analgesic effects similar to heroin making them desirable drugs to abuse. Novel fentanyl analogs and designer opioids are expected to become more prominent in forensic casework in the near future as the opioid epidemic continues. These drugs can be seen in forensic seized drug and urine casework samples either alone or mixed with other drugs of abuse. It is therefore necessary to have an efficient methodology to identify these new compounds. Currently, gas chromatography-mass spectrometry (GC/MS) is used to identify drugs of abuse and is considered the “gold standard” in forensic casework. However, analysis times can often range from 15 to 60 minutes in length. Another drawback is the need for spectral library matching, which requires analytical reference materials for identification. Therefore, the identification of novel fentanyl analogs and designer drugs is limited until a reference material becomes available. In this study, direct sample analysis time-of-flight mass spectrometry (DSA-TOFMS) was evaluated to provide rapid identification of fentanyl and other synthetic opioids in seized drug and urine casework samples. DSA is a direct ambient ionization source, which requires no chromatography and minimal sample preparation. TOFMS is a high resolution mass spectrometer that uses collision-induced dissociation (CID) to produce precursor ion and characteristic fragmentation ions, which provide additional structural and molecular formula information, allowing for the identification of compounds without a reference material. The analytes explored in this study include: heroin, 6-monoacetylmorphine (6-MAM), morphine, fentanyl, norfentanyl, 4-anilino-N-phenethylpiperidine (4-ANPP), acetyl fentanyl, beta-hydroxythiofentanyl, butyryl fentanyl, furanyl fentanyl, valeryl fentanyl, AH-7921, U-47700, buprenorphine, norbuprenorphine, desomorphine, MT-45, W-15, and W-18. Direct sample analysis time-of flight mass spectrometry (DSA-TOFMS) is a novel instrumentation that could be utilized in the forensic sciences field to qualitatively identify illicit substances in casework samples. In this study, 19 compounds of interest containing heroin, fentanyl, fentanyl analogs, and other synthetic opioids were evaluated using DSA-TOFMS. DSA-TOFMS abbreviated the workload of the analysis and was utilized to provide precursor ion and characteristic fragmentation ions within an analysis time of 20 seconds. Certified reference standards were used to optimize instrumentation settings, to determine precursor ions and characteristic fragmentation ions, and to determine the limit of detection of the instrument. A carryover study determined there were no persisting ions present when entering the capillary inlet between runs. A repeatability study revealed the DSA-TOFMS repeated results within the acceptable criteria range of above 500 counts and within 10ppm error 93% (10ppm) and 83% (1ppm). Forensic seized drug casework samples were evaluated with DSA-TOFMS and qualitatively identified. Out of the 64 samples, 89% were qualitatively identified as heroin, 4% were qualitatively identified as fentanyl, 1% was qualitatively identified as heroin and fentanyl, 3% were qualitatively identified as acetyl fentanyl, and 3% were qualitatively identified as furanyl fentanyl. The casework samples containing furanyl fentanyl were considered “true unknown unknown samples,” as the Maine Health and Environmental Testing Laboratory gas chromatography-mass spectrometry library did not have a spectrum to use for the identification of these samples. Forensic urine casework samples were evaluated with DSA-TOFMS. Samples previously confirmed to contain compounds of interest were prepared using minimal sample preparation technique (filtered using 0.45 microns syringe filters and diluted (1:10) with LC/MS grade water). Analysis displayed the limitations of DSA-TOFMS as only twelve of the forty compounds of interest were present and only three of the twelve were within the acceptable criteria range. DSA-TOFMS is a fast and reliable technique with minimal sample preparation for forensic seized drug samples. However, the concentration in complex matrixes, such as urine and blood, were unable to be qualitatively identified using this sample preparation method by DSA-TOFMS

Safety of opioid patch initiation in Australian residential aged care

Explores opioid use by aged care facility residents before and after initiation of transdermal opioid patches. Abstract Objective: To explore opioid use by aged care facility residents before and after initiation of transdermal opioid patches. Design: A cross-sectional cohort study, analysing pharmacy data on individual patient supply between 1 July 2008 and 30 September 2013. Setting: Sixty residential aged care facilities in New South Wales. Participants: Residents receiving an initial opioid patch during the study period Main outcome measure: The proportion of residents who were opioid-naive in the 4 weeks prior to patch initiation was determined. In addition, the patch strength at initiation and the daily dose of transdermal patches and of additional opioids 1 month after initiation were determined. Results: An opioid patch was initiated in 596 of 5297 residents (11.3%: 2.6% fentanyl, 8.7% buprenorphine) in the 60 residential aged care facilities. The mean age at initiation was 87 years, and 74% of the recipients were women. The proportion of recipients who were opioid-naive before patch initiation was 34% for fentanyl and 49% for buprenorphine. Most were initiated at the lowest available patch strength, and the dose was up-titrated after initiation. Around 15% of fentanyl users and 10% of buprenorphine users needed additional regular opioids after patch initiation. Conclusions: The results suggest some inappropriate initiation of opioid patches in Australian residential aged care facilities. Contrary to best practice, a third of residents initiated on fentanyl patches were opioid-naive in the 4 weeks before initiation. &nbsp

Assessing the 2004-2018 fentanyl misusing issues reported to an international range of adverse reporting systems

© 2019 Schifano, Chiappini, Corkery and Guirguis. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Submitted 2 October 2018, Accepted 14 January 2019, published 1 February 2019.Objective: A recent, global, increase in the use of opioids including the prescribing, highly potent, fentanyl has been recorded. Due its current popularity and the potential lethal consequences of its intake, we aimed here at analyzing the fentanyl misuse, abuse, dependence and withdrawal-related adverse drug reactions (ADRs) identified within the European Medicines Agency (EMA), the United Kingdom Yellow Card Scheme (YCS), and the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) databases. Methods: Descriptive analysis of both ADRs and related cases. Results: The analysis of fentanyl-related misuse, abuse, dependence and withdrawal cases reported during years 2004-2018 to the EMA, the YCS, and the FAERS showed increasing levels overtime, specifically, EMA-related data presented two peaks (e.g., in 2008 and 2015), whilst the FAERS dataset was characterized by a dramatic increase of the ADRs collected over the last 18 months, and particularly from 2016. Some 127,313 ADRs (referring to n = 6,161 patients/single cases) related to fentanyl's misuse/abuse/dependence/withdrawal issues were reported to EMA, with 14,287 being judged by the reporter as "suspect." The most represented ADRs were: "drug dependence "(76.87%), "intentional product misuse" (13.06%), and "drug abuse" (7.45%). Most cases involved adult males and the concomitant use of other prescribing/illicit drugs. A range of idiosyncratic (i.e., ingestion/injection of transdermal patches' fentanyl) and very high-dosage intake cases were here identified. Significant numbers of cases required either a prolonged hospitalization (192/559 = 34.35%) or resulted in death (185/559 = 33.09%). Within the same time frame, YCS collected some 3,566 misuse/abuse/dependence/withdrawal ADRs, corresponding to 1,165 single patients/cases, with those most frequently reported being "withdrawal," "intentional product misuse," and "overdose" ADRs. Finally, FAERS identified a total of 19,145 misuse/abuse/dependence/withdrawal-related cases, being "overdose," withdrawal, and "drug use disorder/drug abuse/drug diversion" the most represented ADRs (respectively, 43.11, 20.80, and 20.29%). Conclusion: Fentanyl abuse may be considered a public health issue with significant implications for clinical practice. Spontaneous pharmacovigilance reporting systems should be considered for mapping new trends of drug abuse.Peer reviewe

Trends in long-term prescribing of dependence forming medicines

Using patient-level primary care data to estimate the extent to which antidepressant medicines are prescribed to people continuously for long periods of time. Aim This descriptive research used patient-level primary care data to estimate the extent to which antidepressant medicines are prescribed to people continuously for long periods of time. The study also drew on survey data and data on the number of prescriptions dispensed. Findings - The number of antidepressant prescriptions dispensed each year in England doubled between 2008 and 2018 - Survey data show that the proportion of adults reporting use of antidepressants in the past year increased in the 1990s, and again between 2007 and 2014 - The average length of time that antidepressants are continuously prescribed to people for has increased over time. - Some types of antidepressants (for example, tricyclics and other antidepressants) tend to be prescribed for longer periods than other types (such as SSRIs). - In 2014, one in twelve prescribing periods for tricyclics and other antidepressants lasted for three years or more Methods The analyses in this report are descriptive and show the overall prevalence of long-term prescribing in each year. We used a sample of around 50,000 patients prescribed at least one antidepressant medicine between 2000 and 2017. This was drawn from the Clinical Practice Research Datalink (CPRD). The CPRD contains data about prescriptions issued by GPs (including the length and size of prescription) and characteristics of the patients prescribed to (such as their age, sex, and area where they live). Medicines were grouped for analysis into: tricyclics, selective serotonin reuptake inhibitors (SSRIs), and other ADMs. The length of individual prescriptions and continuous prescribing periods were derived using information on consultation dates, the quantity of tablets prescribed, and the numeric daily dose

Postoperative pain management in children: Guidance from the pain committee of the European Society for Paediatric Anaesthesiology (ESPA Pain Management Ladder Initiative)

The main remit of the European Society for Paediatric Anaesthesiology (ESPA) Pain Committee is to improve the quality of pain management in children. The ESPA Pain Management Ladder is a clinical practice advisory based upon expert consensus to help to ensure a basic standard of perioperative pain management for all children. Further steps are suggested to improve pain management once a basic standard has been achieved. The guidance is grouped by the type of surgical procedure and layered to suggest basic, intermediate, and advanced pain management methods. The committee members are aware that there are marked differences in financial and personal resources in different institutions and countries and also considerable variations in the availability of analgesic drugs across Europe. We recommend that the guidance should be used as a framework to guide best practice

Evaluation of the analgesic effect of 4-anilidopiperidine scaffold containing ureas and carbamates

Fentanyl is a powerful opiate analgesic typically used for the treatment of severe and chronic pain, but its prescription is strongly limited by the well-documented side-effects. Different approaches have been applied to develop strong analgesic drugs with reduced pharmacologic side-effects. One of the most promising is the design of multitarget drugs. In this paper we report the synthesis, characterization and biological evaluation of twelve new 4-anilidopiperidine (fentanyl analogues). In vivo hot-Plate test, shows a moderate antinociceptive activity for compounds OMDM585 and OMDM586, despite the weak binding affinity on both μ and δ-opioid receptors. A strong inverse agonist activity in the GTP-binding assay was revealed suggesting the involvement of alternative systems in the brain. Fatty acid amide hydrolase inhibition was evaluated, together with binding assays of cannabinoid receptors. We can conclude that compounds OMDM585 and 586 are capable to elicit antinociception due to their multitarget activity on different systems involved in pain modulation. © 2016 Informa UK Limited, trading as Taylor & Francis Group

Oral transmucosal fentanyl

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