Synthetic opioids – threats, solutions and perspectives

Актуальність. На сьогодні в Україні гострі отруєння наркотичними та психотропними речовинами є вкрай актуальною медико-соціальною проблемою, далекою від вирішення. Мета дослідження — аналіз випадків смертельних отруєнь наркотичними та психотропними речовинами, спрямований на пошук заходів з підвищення ефективності системи охорони здоров’я з надання медичної допомоги при гострих побутових отруєннях. Матеріали та методи. Досліджено медичні дані пацієнтів з діагнозом «гостре наркотичне отруєння» (Міжнародна класифікація хвороб 10-го перегляду: Т40.0–Т40.3); дані Державної служби статистики України та Центру медичної статистики Міністерства охорони здоров’я України; звіти бюро судово-медичних експертиз. Лабораторні дослідження здійснено за допомогою імунохроматографічного аналізу і хромато-мас-спектрометрії (прилад — Aligent 6850/5973N, колонка — HP-5MS). Використана програма Statistica 12.6 (Windows 10/7). Результати. За 2015–2019 рр. в лабораторії Київського токсикологічного центру було виявлено більше 40 груп речовин, що призвели до гострих отруєнь, а кількість позитивних тестів зросла в 2,3 раза. Лідерами в структурі наркотиків визначені метадон, героїн і морфін. За 2014–2018 рр. в Україні зареєстровано 1365 смертей внаслідок отруєнь наркотичними та психотропними речовинами, зокрема у 2018 році — 399 випадків, 90,5 % становили чоловіки (361 випадок) та 9,5 % — жінки (38 випадків). Серед 355 випадків смертей отруєння опіоїдами становили 153 (кодеїн та морфін — 54 випадки (43,1 %), метадон — 76 випадків (21,4 %), опій — 15 випадків (4,2 %), синтетичні опіоїди — 8 випадків (2,3 %)). Серед 144 випадків смертей від отруєнь іншими наркотиками 31 (21,5 %) — отруєння психодислептиками (галюциногенами), 2 (1,4 %) — отруєння кокаїном та 5 (3,5 %) — отруєння психостимуляторами. Кількість смертей у 2018 році порівняно з даними 2017 року зросла в 1,5 раза, отруєння метадоном — у 2,5 раза, а отруєння неідентифікованими наркотиками — у 3 рази. В Україні у 2018 році частота смертей, пов’язаних зі вживанням наркотичних та психотропних речовин, та отруєнь ними серед населення віком від 15 до 64 років становила 10 осіб на кожен 1 000 000 населення. Висновки. Результати досліджень, здійснених різними державними установами в період 2014–2019 рр., свідчать про загрозливу динаміку збільшення як числа випадків отруєнь наркотичними та психотропними речовинами, так і збільшення їх різноманіття, наслідком чого є прогресивне зростання показників летальності і смертності, переважно серед населення чоловічої статі віком 25–44 років.

Background: New Psychoactive Substances (NPS) constitute a broad range of hundreds of natural and synthetic drugs, including synthetic opioids, synthetic cannabinoids, synthetic cathinones, and other NPS classes, which were not controlled from 1961 to 1971 by the United Nations drug control conventions. Among these, synthetic opioids represent a major threat to public health. Methods: A literature search was carried out using public databases (such as PubMed, Google Scholar, and Scopus) to survey fentanyl-, fentanyl analogs-, and other synthetic opioid-related deaths. Keywords including “fentanyl”, “fentanyl analogs”, “death”, “overdose”, “intoxication”, “synthetic opioids”, “Novel Psychoactive Substances”, “MT-45”, “AH-7921”, and “U-47700” were used for the inquiry. Results: From our literature examination, we inferred the frequent implication of fentanyls and synthetic opioids in side effects, which primarily affected the central nervous system and the cardiovascular and pulmonary systems. The data showed a great variety of substances and lethal concentrations. Multidrug-related deaths appeared very common, in most reported cases. Conclusions: The investigation of the contribution of novel synthetic opioid intoxication to death should be based on a multidisciplinary approach aimed at framing each case and directing the investigation towards targeted toxicological analyses.

PurposeThe number of new synthetic opioids, especially fentanyl analogs, on the illicit market is increasing each year and becoming a disturbing phenomenon. Due to the very high potency, ease of addiction and high risk of overdose with the fatal effect, they pose a serious threat to public health. The ever-changing drug market, lack of reference standards and low doses make this class of new psychoactive substances (NPS) a continual analytical challenge in terms of detection and identification. Structure elucidations of five synthetic opioids are described in this paper.MethodsUnequivocal identifications were performed using liquid chromatography–high resolution tandem mass spectrometry with quadrupole time-of-flight analyzer (LC–QTOF-MS/MS) and nuclear magnetic resonance (NMR) spectroscopy with prior chromatographic purification of the sample in each case.ResultsIdentified NPS included one non-fentanyl opioid belonging to “U-compounds group”—3,4-methylenedioxy-U-47700 and four fentanyl analogs: o-methyl-acetylfentanyl, benzoylfentanyl, 2-thiophenefentanyl and benzoylbenzylfentanyl.ConclusionsComplementary LC–QTOF-MS/MS and NMR techniques enabled the unambiguous identification of new synthetic opioids. To the best of our knowledge, this is the first comprehensive characterization of these five NPS with complete data which are published to facilitate their detection and identification by forensic and clinical laboratories.

In January 2020, the World Health Organization (WHO) issued a Public Health Emergency of International Concern, declaring the COVID-19 outbreak a pandemic in March 2020. Stringent measures decreased consumption of some drugs, moving the illicit market to alternative substances, such as New Psychoactive Substances (NPS). A systematic literature search was performed, using scientific databases such as PubMed, Scopus, Web of Science and institutional and government websites, to identify reported intoxications and fatalities from NPS during the COVID-19 pandemic. The search terms were: COVID-19, SARS-CoV-2, severe acute respiratory syndrome coronavirus 2, coronavirus disease 2019, intox*, fatal*, new psychoactive substance, novel psychoactive substance, smart drugs, new psychoactive substance, novel synthetic opioid, synthetic opioid, synthetic cathinone, bath salts, legal highs, nitazene, bath salt, legal high, synthetic cannabinoid, phenethylamine, phencyclidine, piperazine, novel benzodiazepine, benzodiazepine analogue, designer benzodiazepines, tryptamine and psychostimulant. From January 2020 to March 2022, 215 NPS exposures were reported in Europe, UK, Japan and USA. Single NPS class intoxications accounted for 25, while mixed NPS class intoxications represented only 3 cases. A total of 130 NPS single class fatalities and 56 fatalities involving mixed NPS classes were published during the pandemic. Synthetic opioids were the NPS class most abused, followed by synthetic cathinones and synthetic cannabinoids. Notably, designer benzodiazepines were frequently found in combination with fentalogues. Considering the stress to communities and healthcare systems generated by the pandemic, NPS-related information may be underestimated. However, we could not define the exact impacts of COVID-19 on processing of toxicological data, autopsy and death investigations.

New Psychoactive Substances (NPS), and particularly synthetic opioids, are constantly growing in the illicit market, and represent a particular danger due to their high potency and the fact that they're often not covered by legislation yet. Thus, there is the constant need for sensitive, reliable and reproducible techniques to detect and identify these substances in a variety of different matrices, both for clinical and forensic purposes. In particular, hair analysis can provide important information on past and/or continuative use of different substances such as psychoactive drugs.In this study, we report a review of the existing literature on synthetic opioids analysis in hair, in order to summarize the analytical methods currently used for synthetic and semi-synthetic opioids and NPS hair testing. Methanol with addition of diluted acidic solution represents the most frequently extraction solution. Purification procedures, either carried out through solid phase or liquid/liquid are still needed in order to achieve an adequate sensitivity; in particular, several methods provided a limit of detection lower than 1 pg/mg for most of the monitored substances. Chromatographic techniques coupled with mass spectrometric systems confirmed to be the best choice among the available analytical techniques for monitoring psychoactive substances and metabolites in keratin matrices. Though high-resolution mass spectrometric instruments, such as Time of Flight, are gaining interest, triple quad still guarantees better sensitivity. Beside common synthetic and semi-synthetic opioids, such as hydromorphone, hydrocodone and tramadol, the most frequently detected compounds in hair samples, among fentanyl derivatives, are furanyl fentanyl, sufentanil and butyryl fentanyl.

Hair samples are frequently analyzed in order to characterize consumption patterns of drugs. However, the interpretation of new psychoactive substance (NPS) findings in hair remains difficult because of lacking data for comparison. In this study, selected postmortem hair samples (n = 1203) from 2008 to 2020 were reanalyzed for synthetic cathinones, piperazines, phenethylamines, hallucinogens, benzodiazepines and opioids to evaluate prevalence data and concentration ranges. Hair samples were extracted using a two-step extraction procedure and analyzed using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Overall NPSs were detected in 381 cases (31.6%). Many cases were tested positive for more than one NPS in the same time span. A variety of NPS with a large range of concentrations was observed. For better comparability and interpretation of positive cases in routine work, quantitation data for 13 NPS were calculated as percentiles. The most frequently detected NPS in this study were N-ethylamphetamine, α-pyrrolidinovalerophenone, mephedrone, benzedrone, metamfepramone, and 4-fluoroamphetamine. In conclusion, a high prevalence of these drugs was observed from postmortem hair samples. The results show a growing use of many different NPSs by mainly young drug-using adults. Consequently, NPS screening procedures should be included in forensic toxicology. Our quantitative data may support other toxicologists in their assessment of NPS hair concentrations.

Background and Objectives: Over the past twenty years a large number of new psychoactive substances (NPS) have entered and modified the recreational drug scene. Their intake has been associated with health-related risks, especially so for vulnerable populations such as people with severe mental illness, who might be at higher risk of suicidality or self-injurious behavior. This paper aims at providing an overview of NPS abuse and the effects on mental health and suicidality issues, by performing a literature review of the current related knowledge, thereby identifying those substances that, more than others, are linked to suicidal behaviors. Materials and Methods: A comprehensive and updated overview of the literature regarding suicidality and NPS categories has been undertaken. An electronic search was performed, including all papers published up to March 2021, using the following keywords “NPS” OR “new psychoactive substances” OR “novel psychoactive substances” OR “synthetic cannabinoids” OR “phenethylamines” OR “synthetic cathinones” OR “tryptamines” OR “piperazines” OR “new synthetic opioids” OR “designer benzodiazepines” AND (“suicide” OR “suicidality”) NOT review NOT animal on the PubMed, Cochrane Library, and Web of Science online databases. Results: Suicidality and self-injurious behavior appear to be frequently associated with some NPS such as cathinones, synthetic cannabinoids, and new synthetic opioids. The results are organized according to the substances recorded. Conclusion: The growing use of NPS has become a significant clinical issue, causing increasing concern and challenges for clinicians working in both mental health and emergency departments. Thus, considering the associations between NPS and suicidality or self-injurious behaviors, areas where suicide-prevention efforts and strategies might be focused are the early detection, monitoring, and restriction of NPS.

Synthetic illicit opioids in Brazil: Nitazenes arrival

The new drug phenomenon

Investigation of the μ and κ-opioid receptor activation by eight new synthetic opioids using the [35S]-GTPγS assay: U-47700, isopropyl U 47700, U-49900, U-47931E, N-methyl U-47931E, U-51754, U-48520 and U-48800

The role of analytical pharmacotoxicology in adressing the main functions of the National Early Warning System on NPS

Recent years have seen a steady growth in the availability and consumption of novel psychoactive substances (NPS) across the world. NPS are sold as legal, cheap and non-detectable substitutes for controlled drugs of abuse. The consumers are not normally provided with certain information on the composition of the product, or the recommended dosing and possible side effects. According to the EMCDDA, since 2009, tens of new compounds belonging to six major groups of NPS are introduced into the market each year. These major categories include psychostimulants, synthetic cannabimimetics, psychedelic compounds, dissociatives, synthetic opioids and benzodiazepine analogues. The number of compounds belonging to the two most popular groups, psychostimulatory cathinones and synthetic cannabimimetics, makes up to two-thirds of the total number of NPS. The great majority of NPS are synthetic compounds, and some of these were initially designed as potential medicines or pharmacological tools. NPS exert their actions by various pharmacological mechanisms such as the enhancement of central monoaminergic neurotransmission for psychostimulants, activation of cannabinoid receptors by synthetic cannabimimetics, activation of serotonin receptors by psychedelics, antagonism for NMDA receptors for dissociatives, and activation of μ-opioid and GABAA receptors by synthetic opioids and benzodiazepines, respectively. NPS can produce a wide spectrum of life-endangering side effects. Some of these actions are specific to a certain compound or group of compounds, while some can be produced by drugs from different classes of NPS. In general, NPS may impair cognitive functions, exacerbate or trigger mental disorders and cause severe neurological and cardiovascular symptoms. Significantly, there are specific antidotes for only two groups of NPS, opioids and benzodiazepines, and treatment of acute NPS intoxication is therefore usually symptomatic.

The search for synthetic opioids as alternatives to opium-based derivatives has provided an important impulse to drug development around the globe. An important goal in the systematic evaluation of new drug candidates is the identification of compounds that provide a more favorable side-effect profile, which includes reduced dependence-producing properties and abuse liability. A rich source of information about these research efforts can be found in the scientific literature. However, the exploration of these important discoveries has also been increasingly mined by largescale producers of these materials, which are then offered for sale. These so-called ‘research chemicals’ or new psychoactive substances (NPS)[1] have created challenges to policy makers, clinicians, and law enforcement around the world.[2] Recent examples of synthetic opioids that emerged as NPS on the market, and which were associated with severe cases of adverse effects, include 3,4-dichloro-N- {[1-(dimethylamino)cyclohexyl]methyl}benzamide (AH-7921), 1-cyclohexyl-4-(1,2- diphenylethyl)piperazines (MT-45) and N-phenyl-N-[1-(2-phenylethyl)piperidin-4- yl]acetamide (acetylfentanyl), respectively (Figure 1). Following the recommendation provided by the World Health Organization’s Expert Committee on Drug Dependence (ECDD),[3] AH-7921 was placed in Schedule I of the 1961 Single Convention, as amended by the 1972 Protocol in 2015.[4] Furthermore, ECDD’s recommendation to place MT-45 into Schedule I and acetylfentanyl in Schedules I and IV of the same Convention[5] have been recently confirmed by the Commission on Narcotic Drugs.[6] -Dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) (Figure 1) has recently emerged on the market and can be purchased from various Internet retailers and is a structural isomer of AH-7921 (Figure 1). The preparation of U- 47700 and other derivatives was disclosed by the Upjohn Company in the 1970s[7] followed by the recognition that U-47700 showed increased analgesic properties and morphine-like behavioural features in mice compared to morphine itself.[8,9] The presence of two chiral centres gives rise to a cis- and trans- racemic mixture with the trans-form being advertised for sale. Binding studies also revealed that U-47700 displayed an appreciable selectivity for the μ-opioid receptor over the −opioid receptor.[10,11] A variety of cyclohexyl trans-1,2-diamines have been found to be potent analgesics and the vicinal 1,2-diamine pattern has provided access to a large range of substances with diverse biological activities.[12-14] Since U-47700 did not progress to clinical trials, there is no direct clinical information pertaining to its effects. Keeping in mind the various limitations that may be associated with descriptions obtained from self-reporting users, its effects have been described with various positive and negative symptoms but appeared to be essentially comparable to other opioids. Specifically, euphoria was reported in individuals, sometimes being short-lived, as well as general lift in mood with these desired effects being experienced in waves. The negative effects were also opioid based, including nausea with some users describing respiratory depression. For some users, U-47700 had a shorter duration of action and the urge to keep re-dosing was stated as being very high.

Due to the increase in the use of novel psychoactive substances (NPS) and their overall prevalence, it is important to have effective and reliable screening technologies to detect NPS in biological matrices. Enzyme-linked immunosorbent assays (ELISA) are among the most popular screening methods. To evaluate the effectiveness of ELISA for NPS detection, five subclasses of NPS (novel synthetic opioids, fentanyl analogs, stimulants, benzodiazepines and hallucinogens) were evaluated in whole blood for their cross-reactivity on commercially available ELISA kits. A variety of novel synthetic opioids were tested at concentrations of 1-80 ng/mL and 50-2000 ng/mL and demonstrated no cross-reactivity to a morphine ELISA plate at either concentration range. Fentanyl analogs were tested at concentrations ranging from 0.01 to 1 ng/mL and had cross-reactivities ranging from 8% to 178% on the fentanyl ELISA kit used. Both para-chloro fentanyl (178%) and acryl fentanyl (164%) showed cross-reactivities well above that of fentanyl. Novel stimulants were tested at concentrations of 0.5-40 ng/mL and 20-2,000 ng/mL. 4-Fluoroamphetamine was the only novel stimulant with cross-reactivity (3,354%) to the amphetamine ELISA plate. Novel benzodiazepines were tested at concentrations of 1-40 ng/mL on a benzodiazepine plate. Cross-reactivities ranged from 36.1% to 263%, with desalkylflurazepam having the highest cross-reactivity. Finally, novel hallucinogens were tested at concentrations of 0.5-10 ng/mL on a phencyclidine (PCP) ELISA plate, which produced no cross-reactivity and then with 10-1,000 ng/mL, which gave results from 56.6% to 151%. Both hydroxy-PCP (151%) and chloro-PCP (137%) showed cross-reactivities above that of PCP. This research has demonstrated the utility of using ELISA-based screening for novel benzodiazepines, hallucinogens and for fentanyl analogs; however, there is limited application and risk of false-negative results for the other drug classes due to low or non-existent cross-reactivities.

Introduction: New synthetic opioids (NSO), a class of new psychoactive substances (NPS), have recently emerged and pose an upcoming global public health challenge. The effects produced by NSO are similar to those from morphine, but they present greater pharmacological potency and abuse potential. Due to the increasing number of fatal overdoses and seizures in which NSO have been detected as heroin substitutes or adulterants, individuals with Opioid Use Disorder (OUD) represent a vulnerable population. The aim of our study was to describe and characterize from a gender perspective a Spanish cohort of potential conscious or unconscious NSO users. Methods: A cross-sectional study was conducted in a cohort of OUD participants under treatment in addiction care services in Barcelona and Badalona, Spain. Clinical evaluation was performed through an ad hoc survey, a scale to evaluate reasons to use an opioid without prescription (range 0–4) and the Wellbeing Index (WHO-5) (range 0–100). Objective consumption of NSO was assessed by urinalysis carried out by two validated methods: high-sensitivity gas chromatography-mass spectrometry (MS) and ultra-high-performance liquid chromatography-high-resolution MS. Results: A total of 154 participants with OUD were enrolled. They were mainly men (72.7%), mean age 47.8 years. Methadone was the predominant medication for opioid agonist treatment (mean dose 61.25 mg/day). A total of 32 (20.8%) participants reported having consumed some opioid to become “high” in the previous 3 months. The principal reasons for consuming illicit opioids were Replacing other drugs (mean 2.03) and Availability (mean 1.62), although Low price, was more highly valued by men (p = 0.045) and Shorter effect duration, most highly rated by women (p = <0.001). In the WHO-5, the mean score was 55 (SD = 30.1) without differences by gender. Fentanyl and derivatives or/and metabolites were detected in 7 (6.1%) participants, but illicit/non-prescribed NSOs were found in 5 out of 114 patients (4.4%), and other non-fentanyl opioids in 36 participants (26 men and 10 women). Conclusion: A non-negligible consumption of NSO-fentanyl’s (positive detection in 6.1% of biological samples) was detected. The reasons for using these substances and also the well-being differed between the genders. There is therefore both voluntary and involuntary NSO consumption in our country which highlights the importance of approaching this potential public health problem.