Challenges Related to Three Cases of Fatal Intoxication to Multiple Novel Synthetic Opioids

Garneau, Béatrice; Desharnais, Brigitte; Beauchamp-Doré, Audrey; Lavallée, Catherine; Mireault, Pascal; Lajeunesse, André

doi:10.1093/jat/bkz018

Cited by 11 publications

(10 citation statements)

References 23 publications

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“…Examples of sedative designer drugs and reference substances for comparison. Full names of the substances are provided in the supplementary information either designer opioids alone or designer opioids combined with other psychoactive substances (Coopman et al 2016a, b;Cunningham et al 2016;Dussy et al 2016;Dwyer et al 2018;Elliott et al 2016;Fels et al 2017Fels et al , 2019Fort et al 2016;Garneau et al 2019;Gillespie et al 1982;Guerrieri et al 2017;Helander et al 2017a;Karinen et al 2014;Koch et al 2018;Kriikku et al 2019;Kronstrand et al 2014;Krotulski et al 2018;Martucci et al 2018;McIntyre et al 2015bMcIntyre et al , 2016McIntyre et al , 2017Mohr et al 2016;Nash et al 2019;Ojanperä et al 2006;Papsun et al 2016;Partridge et al 2018;Poklis et al 2016;Richeval et al 2019;Ruan et al 2016;Sofalvi et al 2017;Staeheli et al 2016;Swanson et al 2017;Takase et al 2016;Vorce et al 2014;Yonemitsu et al 2016). Frisoni and colleagues recently published an overview of opioid-related fatalities that were attributed to synthetic opioids (Frisoni et al 2018).…”

Section: Adverse Effects Of Synthetic Opioidsmentioning

confidence: 99%

Designer drugs: mechanism of action and adverse effects

2020

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Psychoactive substances with chemical structures or pharmacological profiles that are similar to traditional drugs of abuse continue to emerge on the recreational drug market. Internet vendors may at least temporarily sell these so-called designer drugs without adhering to legal statutes or facing legal consequences. Overall, the mechanism of action and adverse effects of designer drugs are similar to traditional drugs of abuse. Stimulants, such as amphetamines and cathinones, primarily interact with monoamine transporters and mostly induce sympathomimetic adverse effects. Agonism at l-opioid receptors and c-aminobutyric acid-A (GABA A) or GABA B receptors mediates the pharmacological effects of sedatives, which may induce cardiorespiratory depression. Dissociative designer drugs primarily act as N-methyl-D-aspartate receptor antagonists and pose similar health risks as the medically approved dissociative anesthetic ketamine. The cannabinoid type 1 (CB 1) receptor is thought to drive the psychoactive effects of synthetic cannabinoids, which are associated with a less desirable effect profile and more severe adverse effects compared with cannabis. Serotonergic 5-hydroxytryptamine-2A (5-HT 2A) receptors mediate alterations of perception and cognition that are induced by serotonergic psychedelics. Because of their novelty, designer drugs may remain undetected by routine drug screening, thus hampering evaluations of adverse effects. Intoxication reports suggest that several designer drugs are used concurrently, posing a high risk for severe adverse effects and even death.

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Section: Adverse Effects Of Synthetic Opioidsmentioning

confidence: 99%

Designer drugs: mechanism of action and adverse effects

2020

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“…reported the average postmortem NSO blood concentrations for cyclopropylfentanyl ( n = 8) at 7.8 ± 7.2 ng/mL, methoxyacetylfentanyl ( n = 4) at 4.1 ± 2.3 ng/mL and furanylfentanyl ( n = 1) at 3.6 ng/mL ( 269 ). Identifying multiple NSO in a single case is not uncommon; in fact, one case report mentioned that 17 different NSO had been detected ( 237 ). Findings in overdose cases related to fentanyl analogues include miosis, respiratory depression and coma, which is a common occurrence.…”

Section: Nps Opioidsmentioning

confidence: 99%

Reports of Adverse Events Associated with Use of Novel Psychoactive Substances, 2017–2020: A Review

Mohr

Logan

Fogarty

et al. 2022

Journal of Analytical Toxicology

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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 2013-2016, 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,” “novel psychoactive substances”), drug classes (e.g., “designer stimulants,”), and outcome-based terms (e.g., “overdose,” “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 to include 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 four 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 four-year period. This review will increase awareness of adverse events associated with NPS use to better characterize international emerging drug threats.

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“…Following equations were used according to Baranczewski and Obach:

t_{1 / 2} = \frac{\ln 2}{k ((), \min)}

\ln {[peak area ratio]}_{remaining} = \ln {[peak area ratio]}_{initial} - k \times t

{CL}_{int} = \frac{\ln 2}{t_{1 / 2} ((), \min)} \times \frac{{[normalV]}_{incubation} ((), ml)}{{[normalP]}_{incubation} ((), mg)} \times \frac{([], Liver) ((), g)}{([], BW) ((), kg)} \times SF ((), \frac{mg}{normalg})

{CL}_{h} = \frac{normalQ \times f_{u} \times {CL}_{int}}{normalQ + f_{u} \times {CL}_{int}}

{CL}_{h} = \frac{normalQ \times {CL}_{int}}{normalQ + {CL}_{int}}

(well‐stirred model with and without free fraction in plasma)

{CL}_{h} = normalQ \times ((), 1 - e^{(\frac{- f_{u} \times {CL}_{int}}{normalQ})})

…”

Section: Methodsmentioning

confidence: 99%

“…They are usually sold via the Internet and only limited pharmacological and toxicological data are available. Several cases of acute intoxications and deaths were described recently and clearly underline the health risks associate with an NSO abuse . Investigations on the toxicokinetic characteristics of NSOs are of great importance regarding analytical questions but also for a thorough general risk assessment, particularly in terms of simultaneous drug intake.…”

Section: Introductionmentioning

confidence: 99%

Toxicokinetics and analytical toxicology of the abused opioid U‐48800 — in vitro metabolism, metabolic stability, isozyme mapping, and plasma protein binding

Gampfer

Richter

Schäper³

et al. 2019

Drug Testing and Analysis

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Due to the risk of new synthetic opioids (NSOs) for human health, the knowledge of their toxicokinetic characteristics is important for clinical and forensic toxicology. U‐48800 is an NSO structurally non‐related to classical opioids such as morphine or fentanyl and offered for abuse. As toxicokinetic data of U‐48800 is not currently available, the aims of this study were to identify the in vitro metabolites of U‐48800 in pooled human liver S9 fraction (pS9), to map the isozymes involved in the initial metabolic steps, and to determine further toxicokinetic data such as metabolic stability, including the in vitro half‐life (t1/2), and the intrinsic (CLint) and hepatic clearance (CLh). Furthermore, drug detectability studies in rat urine should be done using hyphenated mass spectrometry. In total, 13 phase I metabolites and one phase II metabolite were identified. N‐Dealkylation, hydroxylation, and their combinations were the predominant metabolic reactions. The isozymes CYP2C19 and CYP3A4 were mainly involved in these initial steps. CYP2C19 poor metabolizers may suffer from an increased U‐48800 toxicity. The in vitro t1/2 and CLint could be rated as moderate, compared to structural related compounds. After administration of an assumed consumer dose to rats, the unchanged parent compound was found only in very low abundance but three metabolites were detected additionally. Due to species differences, metabolites found in rats might be different from those in humans. However, phase I metabolites found in rat urine, the parent compound, and additionally the N‐demethyl metabolite should be used as main targets in toxicological urine screening approaches.

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Challenges Related to Three Cases of Fatal Intoxication to Multiple Novel Synthetic Opioids

Cited by 11 publications

References 23 publications

Designer drugs: mechanism of action and adverse effects

Designer drugs: mechanism of action and adverse effects

Reports of Adverse Events Associated with Use of Novel Psychoactive Substances, 2017–2020: A Review

Toxicokinetics and analytical toxicology of the abused opioid U‐48800 — in vitro metabolism, metabolic stability, isozyme mapping, and plasma protein binding

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