Study, May/19:Flubromazolam overdose: new designer benzo/role of flumazenil

The full title of this American study is "Flubromazolam overdose: A review of a new designer benzodiazepine and the role of flumazenil".

https://www.ncbi.nlm.nih.gov/pubmed/31123661 

Abstract:

Designer products, a term referring to analogs of known chemical compounds with no established medical use, represent an easily accessible alternative to prescription-only products. During the past decade, designer benzodiazepines have become widely available on the online forums. Although these agents offer individuals an inexpensive and accessible alternative to prescription-only products, they are not without risk. Because of the lack of federally enforced quality standards, these designer products come with an intrinsic risk of unpredictable and potentially toxic adverse effects. This article presents a 36-year-old male with prolonged bradycardia resulting from the use of flubromazolam, a designer benzodiazepine purchased from the Internet. A PubMed search was conducted for flubromazolam, designer benzodiazepine, and flumazenil. This article will summarize the available literature regarding flubromazolam and the role of flumazenil in managing these overdoses.

Full Study:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513059/

A few excerpts from the full study:

Flubromazolam is just one example of a designer benzodiazepine marketed on Internet shops as a research chemical.2-4 Although it is available for purchase, it is not a prescription product regulated by the US Food and Drug Administration. Flubromazolam has yet to be classified as a controlled substance in the United States at the federal level. The only state to classify it as a Schedule I controlled substance is Virginia.4,6 Unlike the United States, European countries have federally regulated flubromazolam since 2015. It was classified as a narcotic substance in Switzerland in 2015 and has been illegal to produce, supply, or consume in the United Kingdom since 2016.4 Prescription benzodiazepines are generally regarded as having a more favorable safety profile than their barbiturate predecessors and undergo extensive premarket testing. Designer benzodiazepines, however, do not undergo the same safety and toxicity testing and therefore have indeterminate potency and the potential to cause unforeseen clinical manifestations (eg, uncharacteristic signs/symptoms, unintentional overdose).3

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Although they exist within a legal gray area, designer benzodiazepines are readily available for purchase on the Internet despite the limited information known about them. A PubMed search limited to the English language and human data was conducted using the keywords flubromazolam, designer benzodiazepine, and flumazenil. Diclazepam, flubromazepam, flubromazolam, and clonazolam are some designer benzodiazepines reported in the literature.3 Powders, injectable solutions, and blotters are a few examples of the many formulations available to online consumers.3 The individual in this case reported using flubromazolam. Flubromazolam is the triazolo-analog of another designer benzodiazepine, flubromazepam, and is structurally related to the prescription triazole benzodiazepines alprazolam and triazolam.2,4

Because flubromazolam has not been extensively tested, the exact dose at which clinical effects manifest following ingestion is unknown. On Internet forums mild anxiolytic and skeletal muscle relaxant effects have been reported with doses as low as 0.1 mg and significant sedation at doses of 0.5 mg.3-5 Flubromazolam has been described as “hard to dose” because of its unpredictable dose-response effects.5 Other clinical manifestations described in online forums include cognitive impairment, memory loss, ataxia, sleep paralysis, visual disturbances, heart palpitations, rapid onset of tolerance, and severe withdrawal lasting more than a month.5 A summary of the symptoms reported in the medical literature can be found in the Table.

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Based on its pharmacology, flumazenil theoretically remains an option for managing designer benzodiazepine overdoses. Flumazenil reverses the effects of benzodiazepines via antagonism of their binding site on the GABA-A receptor.8 It is intended to be used as an adjunct to proper airway management and circulatory support for benzodiazepine overdose.8 Typical doses for this indication start at 0.2 mg given intravenously, with repeat doses administered as clinically indicated. The onset of reversal occurs within 1 to 2 minutes of administration, with a peak effect in 6 to 10 minutes. Following extensive distribution to the extravascular space, flumazenil has a terminal half-life of 40 to 80 minutes.8 Although initially considered to be a safe antidote lacking intrinsic activity, serious adverse events, such as seizures, cardiac arrest, and death, have been reported following the use of flumazenil.9-13 Despite these risks, flumazenil has been used following one reported flubromazolam overdose. In the case by Łukasik-Głębocka et al,4 respiratory insufficiency returned 30 minutes after receiving flumazenil. Because the half-life of flubromazolam far exceeds that of flumazenil, the reemergence of symptoms once flumazenil is eliminated can be expected.

The risk-benefit ratio of using flumazenil in benzodiazepine overdose is influenced by the presence of an underlying risk of seizures and the dose used. Administering flumazenil in the presence of proconvulsant coingestants (eg, anticholinergics, stimulants, cyclic antidepressants) can be potentially harmful because it will reverse the seizure protective effects of benzodiazepines.14 In a retrospective review14 of 904 benzodiazepine overdoses reported to the California Poison Control System, the authors found a significant association between exposure to proconvulsant drugs and seizures with flumazenil use (odds ratio, 3.41; 95% confidence interval, 1.13-10.72). In clinical practice flumazenil is avoided in patients who have or are suspected to have coingested a proconvulsive substance, are chronically taking benzodiazepines, and/or have a known history of seizures.14,15

Unlike the case presented by Łukasik-Głębocka et al,4 flumazenil was not administered in this case because of multiple concomitant proconvulsant medications (eg, tramadol, baclofen), a history of seizures (on lamotrigine), and chronic use of clonazepam. Additionally, bradycardia lasting nearly 72 hours suggests a prolonged half-life of flubromazolam consistent with the literature. Considering the short half-life of flumazenil, comparatively, multiple repeat doses would have been necessary to elicit only a temporary effect.