Hypnotics and Triazolobenzodiazepines - Best Predictors of High-Dose Benzodiazepine Use: Results from the Luxembourg National Health Insurance Registry
Abstract
Background: Benzodiazepines are not all the same concerning their risk of high-dose use. Methods: We studied benzodiazepine use from the Luxembourg national records of all insured. We calculated the 12-year prevalence from 1995 to 2007. Benzodiazepine users were divided into 3 groups, short-term with no longer than 3-month intake, intermediate with multiple administration with at least a 1-year interruption, and continuous who never stopped. A high-dose user (HDU) was defined as a patient who received a higher dose than the yearly maximum usual therapeutic dose. Results: An average of 16.0% of the adult insured population received at least 1 benzodiazepine annually, 42.9% were older than 50, 55.9% were women, and 5.4% were HDUs. We found that 32.6% were short-term users, 49.0% intermediate and 18.4% continuous. Compared to diazepam, hypnotics had higher risks for high-dose use in at least 1 age group at first-benzodiazepine intake, the risks being greater in elderly subjects and women, the highest risks being with triazolam (adjusted odds ratio = 215.85; 95% confidence interval = 133.75-348.35) in the 69- to 105-year-old group at first-benzodiazepine intake. Anxiolytics had a low risk except for alprazolam and prazepam in the 69- to 105-year-old group at first-benzodiazepine intake, clonazepam and clobazam had the lowest risk in 18- to 43-year-olds at first-benzodiazepine intake. Alprazolam had dispensed volumes increased by threefold over the 12-year period. Conclusion: All hypnotics had higher risks for high-dose use compared to diazepam in continuous users. Two anxiolytics, clonazepam and clobazam, had the lowest risks. Hypnotics and the triazolobenzodiazepines alprazolam and triazolam were most problematic. Elderly subjects and women are at greater risks.
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Short and intermediate elimination half-life benzodiazepines are at greater risk of rebound anxiety compared to long elimination half-life agents.
“Short and intermediate elimination half-life benzodiazepines are at a greater risk of rebound anxiety compared to long elimination half-life agents [20, 44, 70].”
From Acute and Persistent Withdrawal Syndromes Following Discontinuation of Psychotropic Medications (2020) · cites this paper as [44]
Triazolobenzodiazepines (like alprazolam and triazolam) have the greatest withdrawal risk due to their lipophilicity, high potency, and high binding affinity at GABA-A receptors, and are the drugs most likely to be used in high doses for long periods.
“The risk may be particularly high for triazolobenzodiazepines (like alprazolam and triazolam) which have the greatest withdrawal risk due to their lipophilicity, high potency, and high binding affinity at GABA-A receptors, and are the drugs most likely to be used in high doses for long periods (Cloos et al., 2015).”
From Pharmacological principles for safe benzodiazepine and Z-drug dose reduction (2026) · cites this paper as Cloos et al., 2015
Seizure during benzodiazepine withdrawal usually occurs in predisposed subjects (history of brain damage, alcohol addiction, abnormal electroencephalograms) or in those treated with drugs that lower the seizure threshold (TCAs, bupropion, antipsychotics).
“Seizure usually occurs in predisposed subjects (i.e., history of brain damage, alcohol addiction, abnormal electroencephalograms) [44] or in those treated with drugs which lower the seizure threshold (i.e., TCAs, bupropion, antipsychotics) [45].”
From Acute and Persistent Withdrawal Syndromes Following Discontinuation of Psychotropic Medications (2020) · cites this paper as [44]
New withdrawal symptoms appear more frequently and are more severe with high-potency benzodiazepines with short to medium elimination half-life.
“They appear more frequently [37, 44, 48] and are more severe [49] with high-potency benzodiazepines with short to medium elimination half-life.”
From Acute and Persistent Withdrawal Syndromes Following Discontinuation of Psychotropic Medications (2020) · cites this paper as [44]
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“The 1980s and 1990s also saw regulatory restrictions for certain benzodiazepines (triazolam in particular) in Europe, Hong Kong, and the United States (Cloos et al., 2015).”
- Authors
- Cloos, J.-M., Bocquet, V., Rolland-Portal, I., Koch, P., & Chouinard, G.
- Affiliations
- University Hospital Zurich (CH)
- Hôpital Saint-Antoine (FR)
- ORCID
- Cloos, Jean-Marc
- Venue
- Psychotherapy and Psychosomatics
- Publisher
- S. Karger AG
- Published
- 2015
- Volume
- 84
- Issue
- 5
- Pages
- 273-283
- ISSN
- 0033-3190 (ISSN-L)
- 1423-0348
- OpenAlex
- W1904984328
- Cited by
- 57
- References
- 41
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 9 · 2023: 4 · 2022: 3 · 2021: 7 · 2020: 4 · 2019: 6 · 2018: 10 · 2017: 5 · 2016: 4 · 2015: 3
- FWCI
- 3.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Psychotherapy and Psychosomatics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Pharmaceutical Practices and Patient Outcomes
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Opioid Use Disorder Treatment
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Keywords
- benzodiazepine use, hypnotics, triazolobenzodiazepines, triazolam, alprazolam, diazepam, clonazepam, clobazam, anxiolytics, elderly patients, women
- MeSH terms
- Adult, Aged, Aged, 80 and over, Benzodiazepines, Drug Tolerance, Drug Utilization, Female, Humans, Hypnotics and Sedatives, Male, Middle Aged, Registries, Retrospective Studies, Anti-Anxiety Agents
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