Fatality involving ocfentanil documented by identification of metabolites

Allibe, Nathalie; Richeval, Camille; Phanithavong, Mélodie; Faure, Amandine; Allorge, Delphine; Paysant, F.; Stanke‐Labesque, Françoise; Eysseric-Guerin, Hélène; Gaulier, Jean‐Michel

doi:10.1002/dta.2326

Cited by 37 publications

(28 citation statements)

References 25 publications

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“…Although the utility of metabolite determination in biological samples is known, its application to authentic specimens is still scarce in the case of synthetic opioids due to the limited data available about their metabolism (Poklis et al, 2015 ; Staeheli et al, 2016 ; Martucci et al, 2017 ; Allibe et al, 2018 ). Recent publications about the identification of new metabolites of the synthetic opioids in vivo and in vitro are available (Wohlfarth et al, 2016 ; Steuer et al, 2017 ; Watanabe et al, 2017 ; Krotulski et al, 2018a ).…”

Section: Metabolismmentioning

confidence: 99%

“…The analysis of metabolites in the different biological matrices may improve the interpretation of the results, extending the detection window and indicating if it was an acute or a delayed-death evaluating the metabolite-to-parent ratios. Recent publications about the identification of new metabolites of the synthetic opioids are available (Wohlfarth et al, 2016 ; Steuer et al, 2017 ; Watanabe et al, 2017 ; Krotulski et al, 2018a ); however, its application to authentic samples is still scarce (Poklis et al, 2015 ; Staeheli et al, 2016 ; Martucci et al, 2017 ; Allibe et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

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Postmortem Toxicology of New Synthetic Opioids

et al. 2018

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One hundred fifteen Americans die every day from opioid overdose. These overdose fatalities have been augmented by the increased availability of potent synthetic opioids, such as fentanyl and its derivatives. The death rate of synthetic opioids, other than methadone, increased by 72.2% from 2014 to 2015, and doubled from 2015 to 2016, situating the USA in the midst of an opioid overdose epidemic. The analytical identification of these opioids in postmortem samples and the correct toxicological data interpretation is critical to identify and implement preventive strategies. This article reviews the current knowledge of postmortem toxicology of synthetic opioids and the chemical and pharmacological factors that may affect drug concentrations in the different postmortem matrices and therefore, their interpretation. These factors include key chemical properties, essential pharmacokinetics parameters (metabolism), postmortem redistribution and stability data in postmortem samples. Range and ratios of concentrations reported in traditional and non-traditional postmortem specimens, blood, urine, vitreous humor, liver and brain, are summarized in tables. The review is focused on fentanyl and derivatives (e.g., acetyl fentanyl, butyryl fentanyl, carfentanil, furanyl fentanyl, 4-methoxybutyrylfentanyl, 4-fluorobutyrylfentanyl, ocfentanil) and non-traditional opioid agonists (e.g., AH-7921, MT-45, U-47700). All of these data are critically compared to postmortem data, and chemical and pharmacological properties of natural opioids (morphine), semi-synthetic (oxycodone, hydrocodone, hydromorphone, and oxymorphone), and synthetic opioids (methadone and buprenorphine). The interpretation of drug intoxication in death investigation is based on the available published literature. This review serves to facilitate the evaluation of cases where synthetic opioids may be implicated in a fatality through the critical review of peer reviewed published case reports and research articles.

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Section: Metabolismmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Postmortem Toxicology of New Synthetic Opioids

et al. 2018

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“…Metabolites were identified in a two‐step investigative process; first with FS accurate mass analysis of the in vitro incubate and data mining for postulated metabolites, followed by targeted MS 2 analysis for any metabolites identified. Examination of the metabolism of fentanyl and other fentanyl‐analogues allowed the postulation of potential metabolites of CycP‐F . The possible pathways included N ‐dealkylation, amide hydrolysis, hydroxylation and potential sequential transformations.…”

Section: Methodsmentioning

confidence: 99%

“…Identification of target metabolites can therefore greatly increase the chances of detection of these drugs, as well as potentially extending the detection windows in biological matrices. In vitro metabolism studies, particularly followed up with analysis by liquid chromatography‐high resolution accurate mass analysis (LC‐HRAM) have been shown to be excellent tools for identifying potential target metabolites for analysis, with multiple NSOs already being subjected to such experiments . In vitro studies of NPS and addition of identified metabolites to a comprehensive accurate mass screening database allows for a rapid analytical response to the ever‐expanding problem of NPS.…”

Section: Introductionmentioning

confidence: 99%

In vitro metabolism of the novel synthetic opioid agonist cyclopropylfentanyl and subsequent confirmation in authentic human samples using liquid chromatography‐high resolution mass spectrometry

Cutler¹,

Hudson²

2019

Drug Testing and Analysis

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Novel synthetic opioids (NSOs) are a class of novel psychoactive substances (NPS) that are growing in popularity and presenting a significant public health risk. Included in this class are derivatives of the highly potent analgesic, fentanyl. Cyclopropylfentanyl (CycP‐F) was first reported to the EU Early Warning System in August 2017, and was subsequently linked to more than 100 deaths in the US alone. Limited pharmacological, pharmacokinetic or toxicological data is available for many emerging NSOs; however we can expect novel fentanyl analogues to present limited detection windows, short onset, narrow therapeutic indices and the potential for very high potency. Knowledge of the metabolism of these drugs is essential for the identification of analytical targets for their detection. Therefore in vitro metabolites of CycP‐F were produced using human liver microsomal incubations. Metabolites formed were elucidated using liquid chromatography‐high resolution accurate mass analysis (LC‐HRAM). Identified metabolites were added to our accurate mass screening database for NPS which was utilised for subsequent screening analysis. CycP‐F and metabolites were identified in two human blood case samples. Eleven metabolites were identified in vitro, with the major metabolites produced via N‐dealkylation, monohydroxylation and N‐oxidation. Analysis of the positive case samples identified four in vivo metabolites, all of which were observed in vitro. The major metabolite identified in vitro and in vivo was the N‐dealkylated nor‐metabolite; two further mono‐hydroxylated and one dihydroxylated metabolite were detected in vivo.

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“…For example, in Ohio, more than 4000 deaths were linked to opioids in 2016, with a 36% increase attributed to heroin and carfentanil abuse [11]. Since 2016, a number of deaths involving NSO have been reported in Europe: six fatalities involving ocfentanil have been reported in Belgium, Switzerland and France, and several cases of death due to carfentanil or another fentanyl analog have recently been described in the United Kingdom and Belgium [12][13][14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Norcarfentanil: carfentanil misuse or remifentanil treatment?

et al. 2019

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Purpose Since the early 2010s, deaths due to the use of new synthetic opioids (NSO) including fentanyl and its analogs have been increasing dramatically. As fentanyl analogs bear strong structural similarities, they can share common metabolites. In some clinical or forensic cases, it can be important to demonstrate the presence of both the metabolite and the parent product to confirm that the compound is responsible for the intoxication. Norcarfentanil is a common metabolite of carfentanil (NSO) and remifentanil (widely used in medical care). This article reported the investigation of norcarfentanil origin in three cases. Methods Comprehensive screenings were performed using gas chromatography coupled to mass spectrometry and liquid chromatography coupled to a diode array detection, whereas targeted screening of NSO were performed using liquid chromatography coupled to tandem mass spectrometry. Results Norcarfentanil was detected at concentrations ranging from 0.05 to 15.8 ng/mL in plasma and from 8.8 to 1820 ng/ mL in urine, but carfentanil was detected in two out of the three cases. The presence of norcarfentanil has been supposed to be due to the treatment with remifentanil during the medical care of the patient. Conclusions In the first two cases, norcarfentanil was present as the metabolite of carfentanil, whereas in the last case, norcarfentanil was the metabolite of remifentanil. Without the identification of remifentanil, confusion could occur, and norcarfentanil could be attributed to carfentanil misuse.

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Fatality involving ocfentanil documented by identification of metabolites

Cited by 37 publications

References 25 publications

Postmortem Toxicology of New Synthetic Opioids

Postmortem Toxicology of New Synthetic Opioids

In vitro metabolism of the novel synthetic opioid agonist cyclopropylfentanyl and subsequent confirmation in authentic human samples using liquid chromatography‐high resolution mass spectrometry

Norcarfentanil: carfentanil misuse or remifentanil treatment?

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