The evidence for the use of long-term benzodiazepines in the setting of treatment-refractory anxiety disorders

Anxiety disorders are an important public health issue because they are highly prevalent and approximately 40% are treatment-refractory (Bystritsky, 2006). In a recent commentary, we suggested that the benefits of benzodiazepines for treatment-refractory anxiety disorders have been underestimated and their risks overestimated (Tibrewal et al., 2021a). Carefully prescribed in discussion with patients, benzodiazepines might be a safer option than some alternative agents, such as quetiapine, for long-term treatment.

Lugg’s (2022) response to our commentary (Tibrewal et al., 2021a) questions the strength of the evidence for the long-term use of benzodiazepines in anxiety disorders, citing an unsystematic PubMed search and outdated historical sources. In fact, this crucial debate was discussed following a Lancet seminar article on anxiety disorders (Penninx et al., 2021). These authors also initially strongly cautioned against the long-term use of benzodiazepines for anxiety disorders. They asserted that benzodiazepines ‘only act acutely, lead to relapse after discontinuation, and are associated with dependency’. However, after our critique of this position (Tibrewal et al., 2021b), Penninx et al. (2021) responded the following: ‘We agree with Tibrewal and colleagues that benzodiazepines can be useful treatments in specialised settings, in which more patients may suffer from refractory anxiety disorders’. Importantly, they did not ‘question the overall efficacy of benzodiazepines for reducing anxiety symptoms’.

A recent systematic review and network meta-analysis published in the Lancet showed that benzodiazepine monotherapy for generalised anxiety disorder (GAD) was effective with a mean difference of −2.29 in favour of benzodiazepines on Hamilton anxiety scale (HAM-A) compared to placebo (Slee et al., 2019). Similarly, a recent systematic review and network meta-analysis of panic disorder pharmacological treatment found that benzo‑diazepines were highly efficacious (remission rate 1.47 compared to 1.38 for selective serotonin reuptake inhibitors (SSRIs)), had the lowest drop-out rates of all agents studied (relative risk ratio of 0.51 compared to SSRI), with the caveat of increased risk of adverse events compared to all other agents (Chawla et al., 2022). These recent studies indicate there may be a role for careful benzodiazepine usage, in selected treatment-refractory anxiety disorders.

The Royal Australian and New Zealand College of Psychiatrists (RANZCP) have also developed a professional practice guideline for the use of benzodiazepines (https://www.ranzcp.org/files/resources/college_statements/practice_guidelines/ppg5-use-of-benzodiazepines.aspx) which notes that ‘Clinical experience indicates that there are a small number of patients, such as those with severe GAD, who are helped by long-term benzodiazepine use, who do not escalate the dose, and for whom no other treatments prove as effective’. Furthermore, the RANZCP guidelines for panic disorder, social anxiety and GAD recommend the following:

benzodiazepines should not be used as first-line agents but reserved for patients whose symptoms have not responded to other treatments. Benzodiazepines may have a favourable adverse effect profile in the management of treatment-refractory anxiety disorders, compared with atypical antipsychotic agents. (Andrews et al., 2018)

These guidelines caution about the risk of dependence: ‘while it is difficult to predict which patients will develop long-term problems, benzodiazepines should be avoided in those with a previous or current history of substance abuse’ (Andrews et al., 2018).

Regarding benzodiazepine dependence, Lugg cites a 42-year-old report by the UK Committee on the Review of Medicines (CRM, 1980). A more contemporaneous review on benzodiazepines and the development of tolerance published in 2012 found that benzodiazepine tolerance develops relatively quickly for the sedative, hypnotic and anticonvulsant actions, while tolerance to anxiolytic effects does not develop at all, based on an analysis of 11 studies (Vinkers and Olivier, 2012). The clinical trials that Vinkers and Olivier (2012) reviewed included both short-acting and long-acting benzodiazepines. They concluded that tolerance is a heterogeneous process, and different adaptive mechanisms might be at play depending on the brain region involved and the Gamma-Aminobutyric Acid (GABA) receptor subtype.

Head-to-head long-term clinical trials are needed, comparing benzodiazepines with SSRIs and agents like quetiapine for treatment-refractory anxiety disorders (panic disorder, social anxiety disorder, GAD) specifically assessing for both the short- and long-term outcomes for anxiety levels, adverse-effects and importantly the development of tolerance. With the advent of electronic health record systems and machine learning technology, we may be able to naturalistically study the long-term benefits and risks of benzodiazepines compared with other agents for patients with treatment-refractory anxiety disorders (Rosenbaum, 2020).

Our focus is not on promoting benzodiazepines as a first-line treatment. However, after a careful risk-benefit analysis by clinical experts in collaborative discussion with patients, benzodiazepines remain an important evidence-based option for reducing suffering in those with treatment-refractory anxiety disorders. Such use has been overly stigmatised to the detriment of patients, and the views expressed by Lugg (2022) are not based on contemporary scientific evidence.