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Last year saw a worrisome spike in drug overdoses involving benzodiazepines, and an even bigger one in those where unapproved and illegally manufactured agents such as etizolam and flubromazolam played a role, officials said.

While absolute numbers of fatal benzodiazepine-involved overdoses remained small (less than 3,000 in 2020), according to a in Morbidity and Mortality Weekly Report (MMWR), the percentage increase from April to June 2019 to the same period in 2020 was not: 42.9%.

Total overdoses treated in emergency departments (EDs) with benzodiazepines detected also increased sharply. The proportion of all ED visits involving such cases rose 23.7% in 2020 over the previous year, and for those also involving opioids, it increased 34.4%, reported Stephen Liu, PhD, of the CDC's National Center for Injury Prevention and Control, and colleagues.

Benzodiazepines are widely prescribed for anxiety and insomnia. They are also widely misused, and in recent years have been seen with increasing regularity in drug cocktails taken by abusers. Moreover, made in basement laboratories, sometimes called "designer benzodiazepines," have . A published Thursday, authored by members of a special toxicology research consortium, examined the presence of such compounds in ED patients treated for suspected opioid overdoses.

Led by Kim Aldy, DO, of the American College of Medical Toxicology in Phoenix, the group analyzed 141 samples collected in four states from October 2020 to March 2021. A shocking 15% were positive for at least one illicit benzodiazepine agent, including clonazolam, etizolam, and flubromazolam.

The pharmacologic properties of these agents aren't fully known, the group noted, particularly how they might interact with opioids -- themselves a heterogeneous drug class that includes many homebrew compounds.

In fact, naloxone was not always fully effective in relieving overdose symptoms in these cases. In 13 patients given the opioid reversal agent, "five showed no improvement after the first dose," Aldy and colleagues said. One patient showed some improvement after the first dose but ultimately needed another nine doses and finally a naloxone infusion.

"The growing use of illicit benzodiazepines requires a better understanding of the synergistic toxicity when these drugs are used along with opioids," the researchers wrote. "Raising awareness among clinical, public safety, and community partners about dangers associated with the use of illicit benzodiazepines, including co-use with opioids, is critical."

In the other study, Liu and colleagues analyzed data from the Drug Overdose Surveillance and Epidemiology (DOSE) system, which tracks nonfatal cases in 32 states and the District of Columbia, as well as records of fatal overdoses in 23 states participating in the State Unintentional Drug Overdose Reporting System (SUDORS).

DOSE data showed a total of 15,830 cases in all of 2020 that involved benzodiazepines, of which some 23% also involved opioids. Notably, during the second quarter of 2020, when total ED visits for any reason plummeted on account of the COVID-19 pandemic, visits for benzodiazepine-involved overdoses increased, and continued to rise in the third quarter as well.

The SUDORS data on fatal benzodiazepine-involved overdoses counted a total of 2,721 for the full 2020 calendar year, including 532 in which illicit agents were found.

Perhaps most alarming was a rapid, continual increase in the number of such cases during 2019 and 2020. In the first quarter of 2019, only about 20 fatal overdoses involving illicit benzodiazepines were recorded; the number hit 100 by year end and had topped 300 in the second quarter of 2020. (It should be noted, however, that these data were subject to numerous limitations, including that "postmortem toxicology testing and drug involvement determination vary over time and across states," as Liu and colleagues put it.)

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