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Evidence of Designer Benzodiazepine Use in Routine Healthcare Urine Drug Specimens

Garland, Jeneva M. MEd, PharmD; Hull, Jason D. MS; Bender, Chantel L. BS; Marshall, Lucas MS; Holt, Andrew C. PharmD

Author Information
Journal of Addiction Medicine: 5/6 2022 - Volume 16 - Issue 3 - p 354-356
doi: 10.1097/ADM.0000000000000884
  • Open

Abstract

Many practitioners are familiar with the addictive nature of novel psychoactive substances (NPS) such as synthetic cannabinoids (K2, spice) and cathinones (bath salts), but less is known of the NPS related to the benzodiazepines, informally referred to as “designer benzodiazepines” (DBZD).1 While the synthetic cannabinoids and cathinones have traditionally been the most studied NPS, recent focus has been placed on designer opioids, such as illicitly manufactured fentanyl and related analogs, due to their apparent role in overdoses. Within this same timeframe, DBZD have been introduced into the illicit drug marketplace.

NPS are produced by clandestine laboratories to circumvent regulation or detection, often labeling them as “research chemicals” or “not for human use.” Individuals either knowingly purchase NPS via clandestine marketplaces on the internet, or unknowingly ingest them in counterfeit medications.2,3 DBZD are used for the same reasons as prescription benzodiazepines: to increase sociability, to induce relaxation or euphoria, or to alleviate symptoms of withdrawal.3 A person with opioid use disorder may take DBZD to increase the opioid high and/or to blunt the effects of the descent phase, while individuals with stimulant use disorder may take DBZD to come down from a large dose.4

Within the prescribing realm, the risks associated with the co-ingestion of benzodiazepines and opioids are well- documented.4,5 Recently, the FDA strengthened a boxed warning on the benzodiazepine drug class, outlining the risks of nonmedical use, addiction, physical dependence, and withdrawal reactions.6 Understanding these risks, knowledge of DBZD use may be important due to the unknown potency and toxicity profiles of these substances when compared to prescription benzodiazepines.3 Adverse effects of DBZD are wide-ranging, from minor impaired thinking and fatigue to hallucinations, seizures, and coma at high doses.4 In this study, we describe the detection of DBZD in routine healthcare urine samples.

METHODS

To perform a high-level surveillance across many samples in a high-throughput toxicology laboratory, a commonly performed benzodiazepine assay was enhanced to evaluate all processed samples for presence of DBZD. Detection limits were not optimized for each target compound, as the goal of the study was for general prevalence detection. Within the study period in March 2019, 38,073 urine specimens, which had routine benzodiazepine testing ordered by providers, were diluted, subjected to enzymatic hydrolysis, and then analyzed using liquid chromatography-tandem mass spectrometry (LC- MS/MS). Results were evaluated for the presence of the following DBZD and available metabolites: etizolam, alphahydroxy-etizolam, diclazepam, delorazepam, lormetazepam, flubromazepam, 3-hydroxy-flubromazepam, flubromazolam, phenazepam, and 3-hydroxy-phenazepam. Analytes were chosen based on research from surveillance resources, including the United States Drug Enforcement Agency’s Special Testing and Research Laboratory and online drug forums. As part of the study, depending on requested analyses, samples were also evaluated for co-positivity with pharmaceuticals and routine addictive drugs. The study was approved by the Pearl IRB institutional review board and the cost of enhanced DBZD testing was covered as part of the research and therefore, not charged to patients.

RESULTS

Of 38,073 evaluated samples, 40 contained the DBZD etizolam (and/or its metabolite), delorazepam, lormetazepam, and/or flubromazolam (Fig. 1). Testing ordered on each of the 40 positive samples was reviewed to determine co-positivity with opioids and benzodiazepines. Nineteen of 40 samples tested for a traditional benzodiazepine marker contained at least 1, which may either represent a terminal metabolite of a DBZD or a separate ingestion. For instance, 4 samples were positive for lorazepam along with potential upstream intermediary metabolites lormetazepam and delorazepam, which are available illicitly or detectable after controlled studies of diclazepam ingestion.7 Twenty-one samples did not test positive for a traditional benzodiazepine marker, meaning benzodiazepine use would likely go undetected when using traditional definitive testing methodologies. Thirty-three of 40 samples contained an opioid, including 22 with either buprenorphine or methadone detected.

F1
FIGURE 1:
Opioid and benzodiazepine co-positive results in samples positive for designer benzodiazepines.

DBZD geographic distribution was widespread, as positive samples originated from 19 states during this very brief study period (Fig. 2). Samples analyzed were from multiple practice specialties, with positive results occurring for patients of clinics specializing in addiction, psychiatry, general/internal medicine, pain management, neurology, and obstetrics/gynecology.

F2
FIGURE 2:
States from which designer benzodiazepine positive samples were collected. States with positive results indicated in dark blue.

DISCUSSION

According to recent statistics from the National Survey on Drug Use and Health, 5.4 million people 12 years of age or older reported nonmedical use of a prescription benzodiazepine in 2018.8 In part, this is because prescription benzodiazepines are readily available, as illustrated by 1 study involving 65,912 patients who visited primary care facilities. The authors concluded that 15% of patients were written at least 1 benzodiazepine prescription, and those with a substance use disorder were even more likely to be prescribed a benzodiazepine (27%).5 In addition, the number of deaths involving benzodiazepines has increased from 1135 in 1999 to 10,724 in 2018, with over 80% of these deaths involving an opioid.9

The recreational drug market has shown an increase in the number of DBZD introduced over the last decade.3,4 One illustration of this trend was highlighted in a study of the National Poison Data System, which reported a 330% increase in DBZD exposures from January 1, 2014 to December 31, 2017.1 This nonmedical use is of great concern, as DBZD may be detected by immunoassay testing, but evade detection if sent for confirmation by traditional definitive testing methodologies, which would likely be incorrectly characterized as a false-positive immunoassay test. Those at risk of adverse events from prescription benzodiazepines may be at similar, lesser, or even greater risk if ingesting DBZD, as much is unknown concerning their potency, duration of action, and adverse effect profile.3,4 Although providers routinely identify cases of prescription opioid and benzodiazepine combinations through traditional methodologies, such as prescription drug monitoring programs, our results show evidence of DBZD use, which goes undetected by prescription monitoring programs.

CONCLUSIONS

In this article, we describe the detection of DBZD in 40 patient samples collected from clinics specializing in addiction, psychiatry, general/internal medicine, pain management, neurology, and obstetrics/gynecology. The detected DBZD were found to be co-positive with an opioid in over 82% of samples, and a prescription benzodiazepine in 47.5% of samples, meaning benzodiazepine use would likely go undetected in 52.5% of these patients when using traditional definitive testing methodology alone. With the unknown potency of NPS, DBZD may pose a greater risk of adverse events than prescription benzodiazepines, and practitioners may benefit from this knowledge when assessing their patients’ substance use history.

REFERENCES

1. Carpenter JE, Murray BP, Dunkley C, et al. Designer benzodiazepines: A report of exposures recorded in the National Poison Data System, 2014 – 2017. Clin Toxicol. 2018;57(4):282–286.
2. United Nations Office on Drugs and Crime. Global Smart Update Volume 18: Non-medical Use of Benzodiazepines: A Growing Threat to Public Health? United Nations Office on Drugs and Crime; 2017. Available at: https://www.unodc.org/documents/scientific/Global_SMART_Update_2017_Vol_18.pdf. Accessed November 20, 2020.
3. Orsolini L, Corkery JM, Chiappini S, et al. ‘New/Designer Benzodiazepines’: An analysis of the literature and psychonauts’ trip reports. Curr Neuropharmacol. 2020;18(9):809–837.
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5. Kroll DS, Nieva HR, Barsky AJ, et al. Benzodiazepines are prescribed more frequently to patients already at risk for benzodiazepine-related adverse events in primary care. J Gen Intern Med. 2016;31(9):1027–1034.
6. United States Food and Drug Administration. FDA Drug Safety Communication: FDA requiring Boxed Warning update to improve safe use of benzodiazepine drug class. United States Food and Drug Administration; September 23, 2020. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-requiring-boxed-warning-updated-improve-safe-use-benzodiazepine-drug-class#:∼:text=Particular%20caution%20should%20-:text = Particular%20caution%20should%20be%20taken,severe%20respira-tory%20depression%20and%20death. Accessed November 20, 2020.
7. Moosmann B, Bisel P, Auwärter V. Characterization of the designer benzodiazepine diclazepam and preliminary data on its metabolism and pharmacokinetics. Drug Test Anal. 2014;6(7–8):757–763.
8. Substance Abuse and Mental Health Services Administration. Key substance use and mental health indicators in the United States: Results from the 2018 National Survey on Drug Use and Health. 2019. HHS Publication No. PEP19-5068. Available at: https://www.samhsa.gov/data/. Accessed November 20, 2020.
9. United States Dept of Health and Human Services, Centers for Disease Control and Prevention. Multiple Cause of Death 1999-2018 on CDC WONDER Online Database. National Center for Health Statistics; 2020. Available at: https://wonder.cdc.gov/mcd.html. Accessed November 20, 2020.
Keywords:

designer benzodiazepines; nonmedical benzodiazepine use; novel psychoactive substances; substance use disorder

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Addiction Medicine.