02. Do Benzodiazepine Users Escalate Doses Over Time?

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Benzodiazepines and Z-drugs: Questioning Conventional Wisdom

A recent Danish registry study published in the American Journal of Psychiatry challenges the commonly held belief that long-term users of benzodiazepines and related drugs tend to escalate their use due to tolerance.

The study followed nearly one million incident prescriptions for benzodiazepine receptor agonists over a 20-year period, including both benzodiazepines and Z-drugs.

The eight most prescribed agents in the study were alprazolam, diazepam, midazolam, nitrazepam, oxazepam, triazolam, zopiclone, and zolpidem. The medications were divided into three groups:

• Hypnotic benzodiazepines (midazolam, nitrazepam, and triazolam)
• Anxiolytic benzodiazepines (alprazolam, diazepam, and oxazepam)
• Z-drugs (zolpidem and zopiclone)

Long-term Use and Dose Escalation: Surprising Findings

Surprisingly, only 15% of patients prescribed these medications used them for longer than a year, with the highest rates for Z-drugs and the lowest for anxiolytic benzodiazepines. Nearly half of the patients only filled their prescription once, suggesting that physicians may be deprescribing benzodiazepines after initiating them.

Of the 5% of individuals who remained on the medications for at least three years, there was no indication of dose escalation based on median dose. Most users actually de-escalated their dose over time.

Substance Use Disorders: A Predictor of Dose Escalation

However, 7% of individuals remaining on the medication for at least three years did escalate doses above the recommended level, with psychiatric comorbidity and substance use disorders representing the main predictors of dose escalation. This serves as a reminder that caution should be exercised when deciding whether to start a benzodiazepine for patients with a history of substance use disorders, especially alcohol use disorder.

Challenging Guidelines and Boxed Warnings

Many countries, including Denmark and the US, have established guidelines intended to restrict prescription of benzodiazepine-related medications to short-term use due to concerns about tolerance and dependence. In 2020, the FDA issued a boxed warning for all benzodiazepines highlighting the risk for misuse, abuse, and dependence.

However, this study suggests that these concerns might be overblown. The authors argue that such guidelines are outdated and unlikely to apply to patients across the board.

A Return to Evidence-Based Prescribing

The authors advocate for a return to the evidence base and suggest that guidelines should focus on relative and absolute contraindications for specific groups of patients rather than on an outright ban of classes. They point out that when benzodiazepines and Z-drugs are restricted, prescriptions for other sedating agents, such as quetiapine, increase, despite their significant side effects and lack of rigorous evidence for the prescribed indication.

Implications for Prescribers: Individualized Risk-Benefit Analysis

This study suggests that benzodiazepines and Z-drugs can be used safely and represent a reasonable aspect of our armamentarium for anxiety and sleep. For most patients, benzodiazepines should be used as a short-term strategy, such as during SSRI initiation for panic disorder.

However, there may be a small subset of patients for whom long-term benzodiazepine use may make sense, such as those with panic disorder who cannot tolerate antidepressants and have limited access to CBT. Provided they don’t have other contraindications, prescribers shouldn’t feel compelled to repeatedly try to taper their benzodiazepine just because of a theoretical concern about tolerance or dose escalation.

Ultimately, each prescribing decision should be based on an individualized risk-benefit analysis rather than dogmatic approaches to certain medications or classes.

Abstract

Long-Term Use of Benzodiazepines and Benzodiazepine-Related Drugs: A Register-Based Danish Cohort Study on Determinants and Risk of Dose Escalation

Thomas Wolff Rosenqvist, M.D., Marie Kim Wium-Andersen, M.D., D.M.Sc., Ida Kim Wium-Andersen, M.D., Ph.D., Martin Balslev Jørgensen, M.D., D.M.Sc., and Merete Osler, M.D., D.M.Sc. American Journal of Psychiatry, Volume 181, Number 3.
 

Objective:

The authors investigated the frequency and determinants of long-term use and risk of dose escalation of benzodiazepines and benzodiazepine-related drugs (benzodiazepine receptor agonists, or BZRAs).

Methods:

All adults ages 20–80 years living in Denmark on January 1, 2000 (N=4,297,045) were followed for redeemed prescriptions of BZRAs in the Danish National Prescription Registry from January 1, 2000, to December 31, 2020. For each drug class, we calculated long-term use for more than 1 or 7 years, and dose escalation measured as increase in dose to a level above the recommended level. Associations were examined using logistic regression.

Results:

The authors identified 950,767 incident BZRA users, of whom 15% and 3% became long-term users for more than 1 or 7 years, respectively. These percentages were highest for individuals who initiated Z-drugs (17.8% and 4%). Among the 5% of BZRA users who had at least 3 years of continuous use, there was no indication of dose escalation, as the median dose remained relatively stable. However, 7% (N=3,545) of BZRA users escalated to doses above the recommended level. Psychiatric comorbidity, especially substance use disorder, was associated with higher risk of long-term use and dose escalation.

Conclusions:

A limited portion of the population that received BZRA prescriptions were classified as continuous users, and only a small proportion of this group escalated to doses higher than those recommended in clinical guidelines. Thus, this study does not, under the current regulations, support the belief that BZRA use frequently results in long-term use or dose escalation.

Reference

Rosenqvist, T., Wium-Andersen, M., Wium-Andersen, I., Jørgensen, M., & Osler, M. (2023). 

Long-Term Use of Benzodiazepines and Benzodiazepine-Related Drugs: A Register-Based Danish Cohort Study on Determinants and Risk of Dose Escalation.

American Journal of Psychiatry

. Volume 181, Number 3.