An Expanding World of Novel Psychoactive Substances: Opioids

Novel synthetic opioids and benzodiazepines are an emerging trend on the narcotic drugs market. We present a lethal case of U-47700 and flubromazepam poisoning. A 24-year-old man suffered apnoea after the consumption of the synthetic opioid U-47700 in combination with the benzodiazepine flubromazepam. After reanimation and hospital admission, hypoxic cerebral damage and severe brain oedema were stated. Six days after admission, mechanical ventilation was discontinued, and the patient died. Seven blood serum samples and one urine sample collected during the hospitalisation were analysed by liquid chromatography-tandem mass spectrometry. In the sample collected 42 minutes after admission, the concentrations of U-47700 and flubromazepam were 370 and 830 ng/mL, respectively. Three days later, the concentrations of U-47700 and flubromazepam dropped to 4.2 and 280 ng/mL, respectively. The resulting concentration-time-curves allowed calculating a U-47700 elimination half-life of approximately six hours and confirmed the previously reported flubromazepam elimination half-life of around 100 hours. In the presented case, intoxication by the synthetic opioid U-47700 with a contribution of flubromazepam can be assumed as the cause of death. The concentration-time curves allow an estimation of the clinical course of similar cases. Flubromazepam may lead to prolonged central-nervous depressant effects.

Section: Introductionmentioning

confidence: 99%

Mixed intoxication by the synthetic opioid U‐47700 and the benzodiazepine flubromazepam with lethal outcome: Pharmacokinetic data

Koch

Auwärter

Hermanns-Clausen

et al. 2018

“…The threat of novel psychoactive substances (NPS) has been an ongoing concern over recent years, with the number of new compounds reported continuing to rise . Synthetic cannabinoids and cathinone type compounds remain the most popular NPS compounds to be abused . However, another group, novel synthetic opioids (NSOs), is growing in popularity and is presenting a significant public health risk.…”

Section: Introductionmentioning

confidence: 99%

“…1 Synthetic cannabinoids and cathinone type compounds remain the most popular NPS compounds to be abused. 1,2 However, another group, novel synthetic opioids (NSOs), is growing in popularity and is presenting a significant public health risk. While they only make up about 4% of NPS reported up to 2017, 3 NSOs are fast becoming one of the most dangerous groups of novel substances available.…”

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

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.

“…In the last 5 years, an increasing number of NPS have been detected on the illegal drug market in Europe: 98 new substances were detected in 2015 (2/week) for the first time in the Europe, bringing the number of NPS monitored by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) to more than 560, of which 70% were detected in the last 5 years . Among these NPS, new synthetic opioids, such as fentanyl analogues and derivatives, have rapidly increased in popularity and notoriety in recent years . Eighteen European countries reported that more than 10% of all opioid users presented for problems primarily related to opioids other than heroin in 2014 .…”

Section: Introductionmentioning

confidence: 99%

“…Many fentanyl derivatives are highly potent and can be sold as heroin to unaware users, thus standing a high risk of overdose and death, as illustrated with acetylfentanyl, which was subject to an EMCDDA–Europol joint report in 2015 . Today, the recreational abuse of fentanyl‐like substances is of significant concern, as these substances often exhibit unexpected and severe side effects . Ocfentanil (OcF) is one of these potent and non‐controlled fentanyl analogues.…”

Section: Introductionmentioning

confidence: 99%

Fatality involving ocfentanil documented by identification of metabolites

Allibe

Richeval

Phanithavong

et al. 2017

The use of new psychoactive substances (NPS) has rapidly increased over the last decade. In the last 4 years, producers increasingly appear to be targeting non-controlled synthetic opioids, involving fentanyl derivatives such as ocfentanil (OcF). Identification of metabolites is of major importance in the context of NPS use, as it could improve the detection window in biological matrices in clinical and forensic intoxication cases. Hence, this work aims to report a fatality involving OcF documented by the identification of metabolites. A 30-year-old woman was found dead at home: an unidentified powder was found near her body and some injection sites were found at the autopsy. Toxicological analyses allowed to determine the presence of OcF in the powder, blood (3.7/3.9 μg/L, peripheral/cardiac) and in other post-mortem samples. The most relevant potential CYP- and UGT-dependent metabolites of OcF were investigated in vitro using human liver microsome incubation and liquid chromatography coupled with high resolution mass spectrometry, and subsequently confirmed in post-mortem samples. Four OcF metabolites were produced in vitro (a mono-hydroxylated OcF, O-desmethylOcF, a hydroxylated desmethylOcF and a glucuronidated form of the O-desmethylOcF), and all except the glucuronide were observed in blood and bile post-mortem samples. Considering the relative intensity of the chromatographic peak areas, O-desmethylOcF can be suggested to be an abundant metabolite of OcF. Nevertheless, the relevance of O-desmethylOcF as being a complementary analytical target of OcF for OcF use detection needs further in vivo confirmation, especially through analysis of urines from users.