Detection of novel benzodiazepines in post-mortem cases

Abstract

The global prevalence of novel benzodiazepines (BZDs) has increased significantly in recent years with the predominant BZDs constantly changing to evade bans pertaining to specific chemical structures. As of 2020 the European Union Early Warning System (EWS) was monitoring 30 novel BZDs, 16 of which have been reported since 2016. Evidence of novel BZD-associated harms is growing and there is concern regarding their prevalence in drug-related deaths. We therefore analysed deaths in England, Wales, and Northern Ireland where novel BZDs, i.e., those that are not available on prescription via the National Health Service (NHS) in the United Kingdom, were detected at post-mortem in order to determine the circumstances surrounding novel BZD-associated fatalities. The National Programme on Substance Abuse Deaths (NPSAD) receives voluntary reports on drug-related deaths from coroners across England, Wales, and Northern Ireland that covers approximately 80% of all coronial jurisdictions. Deaths that occurred between 1999-2020 and were reported to NPSAD by the 1st of November 2021 where a novel BZD was detected at post-mortem were extracted for analysis. Qualifying cases contained toxicological evidence of novel BZDs and/or their metabolites in post-mortem tissue(s). Analysis and statistical tests were performed using the IBM® SPSS software (Version 26). 971 deaths were extracted from NPSAD where a novel BZD was detected at post-mortem, with the first post-mortem detection occurring in 1999 with flunitrazepam. A sharp increase in deaths has been reported since 2016 and a total of 16 different novel BZDs detected in submitted toxicology reports. Five of these novel BZDs were detected for the first time in 2019 and 2020 (flualprazolam, delorazepam, flubroalprazolam, cinolazepam, meclonazepam), but nevertheless represent 20% of total novel BZD detections ( n = 211/1,064 [note: in some cases multiple novel BZDs were detected]). The most commonly detected novel BZDs were alprazolam and phenazepam until 2018, after which etizolam, flubromazolam and flualprazolam detections prevail. The cause of death in 95% of cases ( n = 926/971) was due to drug toxicity in which novel BZDs were directly implicated in causing death in 34% ( n = 319/926). Polydrug use was evident in 99% of cases ( n = 964/971) and the majority involved the co-administration of at least one additional central nervous system (CNS) depressant (98%, n = 943/964), namely opioids (84%, n = 812/964). Most deaths were deemed to be accidental in nature (92%, n = 894/971), with small proportions due to suicide (4%, n = 42/971), natural causes (1%, n = 12/971), and those where intent could not be determined (2%, n = 23/971). Decedents were mainly male (83% of cases, n = 801/971), had a known history of illicit substance use (71%, n = 687/971) and lived in the most deprived areas of the country (deciles 1-3, 59% of cases; n = 541/971). The results of this study document a startling increase in novel BZD detections in post-mortem toxicology, with a shift in the predominant novel BZDs over time. As novel BZDs are sold on the Internet as ‘research chemicals’ or the illicit market at a low cost, there is greater access and less oversight which can lead to dosing errors and unintended adverse effects. The concomitant use with other CNS depressants furthers the likelihood of a fatal outcome through increased sedation and respiratory depression, as shown here with the majority of fatalities resulting from mixed drug toxicity. To our knowledge this is the largest dataset on novel BZD-related fatalities to date. Reporting of novel BZD deaths has increased considerably in England, Wales, and Northern Ireland with specific concerns relating to polydrug use. The wide availability of novel BZDs combined with the lack of complete understanding regarding their pharmacology is likely contributing to the exponential rise in novel BZD-associated fatalities.