Emerging Characteristics of Isotonitazene-Involved Overdose Deaths: A Case-Control Study.
01 Sep 2021-Journal of Addiction Medicine (Ovid Technologies (Wolters Kluwer Health))-Vol. 15, Iss: 5, pp 429-431
TL;DR: Isotonitazene was involved in a substantial minority of synthetic opioid overdose deaths in the first 7 months of 2020, and was significantly more likely to involve the designer benzodiazepine flualprazolam.
Abstract: OBJECTIVES Case reports of fatal overdoses involving the novel synthetic opioid isotonitazene have prompted the U.S. Drug Enforcement Administration to consider an emergency scheduling of the drug in June 2020. We aimed to epidemiologically characterize deaths involving isotonitazene. METHODS We conducted a case control study using publicly available mortality records from January 1, 2020 to July 31, 2020 in Cook County, IL and Milwaukee County, WI. Cases (all deaths involving isotonitazene) and controls (all deaths involving other synthetic opioids) were compared on demographic characteristics, number of substances involved in fatal overdose, and co-involvement of other substances. RESULTS We identified 40 fatal overdoses involving isotonitazene and 981 fatal overdoses involving other synthetic opioids. Isotonitazene deaths involved a significantly greater number of substances, and were significantly more likely to involve the designer benzodiazepine flualprazolam. DISCUSSION Isotonitazene was involved in a substantial minority of synthetic opioid overdose deaths in the first 7 months of 2020. Future studies characterizing its prevalence in other markets are warranted. Emergence of highly potent novel synthetic opioids underscore the need for comprehensive health services for people with opioid use disorder.
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TL;DR: The Stanford-Lancet Commission on the North American Opioid Crisis was formed in response to soaring opioid-related morbidity and mortality in the USA and Canada over the past 25 years as discussed by the authors .
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TL;DR: A review of 2-benzylbenzimidazolone derivatives can be found in this paper, where the authors provide an overview on the chemistry, pharmacological profiles, adverse effects, addiction liability, regulatory status, and the impact on chemical neuroscience.
Abstract: Etonitazene and related 2-benzylbenzimidazoles are potent analgetics invented in the research laboratories of the Swiss pharmaceutical giant CIBA in the late 1950s. Though the unprecedented structure distinguishes this class of compounds from poppy-derived and other synthetic analgetics, a range of studies indicate that these drugs are selective μ opioid receptor agonists possessing morphine-like pharmacotoxicological properties in animals as well as humans. Several unscheduled members of this synthetically readily accessible class of opioids that are not controlled under the international and national drug control systems have recently emerged on the illicit drug market. Among them, isotonitazene has been implicated in at least 200 fatalities in Europe and North America. None of the 2-benzylbenzimidazole derivatives have been developed into medicines, but etonitazene and some of its derivatives have been used as receptor probes and in addiction behavior studies in animals. The unique structure has inspired research on such benzimidazoles and related benzimidazolones of which "brorphine" made its debut as one of the newest psychoactive substance to emerge on the illicit opioid drug market in mid-2019. This in-depth review provides a historical introduction, an overview on the chemistry, pharmacological profiles, adverse effects, addiction liability, regulatory status, and the impact on chemical neuroscience of the 2-benzylbenzimidazoles. Structurally related benzimidazoles with opioid and/or analgesic properties are also discussed briefly.
43 citations
TL;DR: Insight and context of case findings described in the literature and in digital government surveillance databases and websites during a recent 4-year period are provided to increase the awareness of adverse events associated with NPS use to better characterize international emerging drug threats.
Abstract: Abstract An important role of modern forensic and clinical toxicologists is to monitor the adverse events of novel psychoactive substances (NPS). Following a prior review from 2013 to 2016, this critical literature review analyzes and evaluates published case reports for NPS from January 2017 through December 2020. The primary objective of this study is to assist in the assessment and interpretation of these cases as well as provide references for confirmation methods. Chemistry, pharmacology, adverse events and user profiles (e.g., polypharmacy) for NPS are provided including case history, clinical symptoms, autopsy findings and analytical results. Literature reviews were performed in PubMed and Google Scholar for publications using search terms such as NPS specific names, general terms (e.g., ‘designer drugs’ and ‘novel psychoactive substances’), drug classes (e.g., ‘designer stimulants’) and outcome-based terms (e.g., ‘overdose’ and ‘death’). Government and website drug surveillance databases and abstracts published by professional forensic science organizations were also searched. Toxicological data and detailed case information were extracted, tabulated, analyzed and organized by drug category. Case reports included overdose fatalities (378 cases), clinical treatment and hospitalization (771 cases) and driving under the influence of drugs (170 cases) for a total of 1,319 cases providing details of adverse events associated with NPS. Confirmed adverse events with associated toxidromes of more than 60 NPS were reported including synthetic cannabinoid, NPS stimulant, NPS hallucinogen, NPS benzodiazepine and NPS opioid cases. Fifty of these NPS were reported for the first time in January 2017 through December 2020 as compared to the previous 4 years surveyed. This study provides insight and context of case findings described in the literature and in digital government surveillance databases and websites during a recent 4-year period. This review will increase the awareness of adverse events associated with NPS use to better characterize international emerging drug threats.
17 citations
TL;DR: A systematic literature search was conducted according to the PRISMA guidelines as mentioned in this paper to identify BO use trends and gather toxicological data from BO-related cases to assist in clinical and forensic investigations.
Abstract: Synthetic benzimidazole opioids (BOs) are highly potent µ-opioid receptor agonists with heroin-like effects. Isotonitazene was first available in 2019 in the drug market, although new analogs have multiplied recently. The authors aimed to identify BO use trends and gather toxicological data from BO-related cases to assist in clinical and forensic investigations.A systematic literature search was conducted according to the PRISMA guidelines. PubMed and Scopus databases were accessed in October 2021 to identify scientific reports of BO-related intoxication and fatalities. Publication dates, case descriptions, symptoms, autopsy findings, and concentrations of BOs and metabolites in biological matrices were compiled.Data from 8 case reports with 93 fatalities involving isotonitazene ( n = 65), metonitazene ( n = 20), etonitazepyne ( N -pyrrolidino etonitazene) ( n = 8), flunitazene ( n = 4), and/or butonitazene ( n = 1), and 1 acute intoxication involving etonitazepyne were collected. Autopsy findings included pulmonary congestion/high lung weight (66%), cardiomegaly/high cardiac weight (39%), cerebral edema (22%), gastric contents in the airways (22%), and organ congestion (22%). Median peripheral blood concentrations were 1.7 ng/mL for isotonitazene (0.4-9.5 ng/mL, n = 13), 5.4 ng/mL for metonitazene (0.52-33 ng/mL, n = 17), 5.4 ng/mL for etonitazepyne (2.4-8.3 ng/mL, n = 2), 1.3 ng/mL for flunitazene (0.58-2.1 ng/mL, n = 2), and 3.2 ng/mL for butonitazene ( n = 1). Central nervous system depressants were almost always coadministered.Isotonitazene was predominant in cases from 2019 to mid-2020 and was replaced by metonitazene after scheduling in the United States. Typical findings on opioid overdoses have been reported. Peripheral blood concentrations were consistent with a potency similar to that of fentanyl. These results must be interpreted carefully, considering the scarcity of reports on BO-related cases and drug co-exposures.
16 citations
References
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05 Dec 2014
TL;DR: The EMCDDA Programme 2, 'Analysis of responses', set out to identify how social reintegration is understood in each Member State and to map the availability of social reIntegration facilities in Member States according to these national perceptions.
Abstract: INTRODUCTION The issue of social rehabilitation and reintegration (hereafter social reintegration2) is mentioned under the third strategy target of the EU Action Plan 2000–2004. The third EU strategy target is to 'substantially increase the number of successfully treated addicts', and point 3.1.3.4 instructs that 'Member States [are] to ensure that adequate attention is paid to social and professional rehabilitation and reintegration of former addicts'. However, social reintegration is also linked to social exclusion, which is mentioned in chapter 2 of the EU Action Plan, where it is stated that 'the EMCDDA [is] to develop indicators on drug-related crime, the availability of illicit drugs (including at street level) and drug-related social exclusion'. For the EMCDDA, social reintegration comes under strategy target four – that is, as a response to social exclusion – however, target two is clearly also relevant. Social exclusion is often perceived as a cause of problem drug use, although many see it as a consequence of problem drug use. We will not elaborate on this further here, except to note that social exclusion and problem drug use are two phenomena that are very closely interlinked and that social reintegration is a possible response to both. The EMCDDA Programme 2, 'Analysis of responses', set out to identify how social reintegration is understood in each Member State and to map the availability of social reintegration facilities in Member States according to these national perceptions. It became evident at an early stage that this would be a complex task, involving extensive data collection, as national reports generally provided insufficient data on this specific subject. eight countries turned out to be difficult to map and so, in February 2002, the EMCDDA launched a call for tender for a project, 'Mapping social reintegration services in EU countries'. 3 The aim of this project was to describe the state of the art of social reintegration in the following eight countries: The research specifications, to investigate 'the state of the art of social reintegration', suggested that the following should be identified for each of the eight countries: 1 Other contributors will be mentioned in the respective chapters. 2 Our country studies so far have shown that the term 'rehabilitation' is used ambiguously across Europe – from low-threshold refuges, to normal treatment, to actual reintegration into society. For this reason, we shall use the term 'social reintegration' in this report, as this is used much more …
2,183 citations
TL;DR: Comprehensive surveillance and prevention measures are critical to reducing opioid-involved deaths, including continued surveillance of evolving drug use and overdose, polysubstance use, and the changing illicit drug market.
Abstract: Of the 70,237 drug overdose deaths in the United States in 2017, approximately two thirds (47,600) involved an opioid (1). In recent years, increases in opioid-involved overdose deaths have been driven primarily by deaths involving synthetic opioids other than methadone (hereafter referred to as synthetic opioids) (1). CDC analyzed changes in age-adjusted death rates from 2017 to 2018 involving all opioids and opioid subcategories* by demographic characteristics, county urbanization levels, U.S. Census region, and state. During 2018, a total of 67,367 drug overdose deaths occurred in the United States, a 4.1% decline from 2017; 46,802 (69.5%) involved an opioid (2). From 2017 to 2018, deaths involving all opioids, prescription opioids, and heroin decreased 2%, 13.5%, and 4.1%, respectively. However, deaths involving synthetic opioids increased 10%, likely driven by illicitly manufactured fentanyl (IMF), including fentanyl analogs (1,3). Efforts related to all opioids, particularly deaths involving synthetic opioids, should be strengthened to sustain and accelerate declines in opioid-involved deaths. Comprehensive surveillance and prevention measures are critical to reducing opioid-involved deaths, including continued surveillance of evolving drug use and overdose, polysubstance use, and the changing illicit drug market; naloxone distribution and outreach to groups at risk for IMF exposure; linkage to evidence-based treatment for persons with substance use disorders; and continued partnerships with public safety.
1,094 citations
"Emerging Characteristics of Isotoni..." refers background in this paper
...J Addict Med Volume 15, Number 5, September/October 2021 D eaths involving synthetic opioids have increased tenfold from 2013 to 2018 in the United States, with 36,509 nationwide in 2019.(1,2) Though the largest share of synthetic opioid deaths involve fentanyl and its analogues, novel synthetic opioids are continuously emerging....
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TL;DR: Fentanyl has spread westward, increasing deaths in the short-term and threatening to dramatically worsen the nation’s already severe opioid epidemic in the long-term, and increasing the standard dose of naloxone, expanding Medicaid, improving coverage of addiction treatment, and public health educational campaigns should be prioritized.
89 citations
"Emerging Characteristics of Isotoni..." refers background in this paper
...counties that have publicly available detailed drug-involved mortality.(10) Of these, none had any cases where isotonitazene was listed as a cause of death....
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TL;DR: It is proposed that higher doses of naloxone are needed to combat the new era of overdoses due to the more potent synthetic opioids such as fentanyl.
Abstract: There has been a dramatic increase of deaths due to illicit fentanyl. We examined the pharmacology of fentanyl and reviewed data on the number of repeat doses of naloxone used to treat fentanyl overdoses. Multiple sequential doses of naloxone have been required in a certain percentage of opioid overdoses due to fentanyl. In addition, fentanyl appears to differ from other opioids as having a very rapid onset with high systemic levels found in overdose victims. A rapid competition is required by naloxone to out-compete large numbers of opioid receptors occupied by fentanyl in the CNS. Taken together, we propose that higher doses of naloxone are needed to combat the new era of overdoses due to the more potent synthetic opioids such as fentanyl.
84 citations
"Emerging Characteristics of Isotoni..." refers background in this paper
...Determining whether isotonitazene-involved overdoses require higher doses of naloxone is also a key priority, and along with the spread of fentanyl, may support increasing the standard dose of naloxone.(7,8)...
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...The naloxone dosing required to reverse an isotonitazene overdose has not been established; however, studies of other potent synthetic opioids suggest a higher standard dose may be required in some cases.(4,8) In June 2020, the U....
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