Benzodiazepines

By Marcello Cherchi, MD PhD

For patients

Benzodiazepines are a group of medications originally developed for treating several psychiatric and neurologic disorders. A few of these medications are sometimes used for certain diseases that cause dizziness. You must be very careful with these medications because they are addictive and can make you drive a car badly.

For clinicians

Overview

Benzodiazepines enhance the activity of the inhibitory neurotransmitter GABA (gamma aminobutyric acid) at various subsets of GABA receptors which are distributed throughout the central nervous system. Their original indications included several neurological, psychiatric and neuromuscular diseases, but they have also come to be used off-label for a range of disorders, including several vestibular disorders. Benzodiazepines carry the risk of developing physiologic dependence, and discontinuation can cause withdrawal. Benzodiazepines impair driving through their effects on cognition (wakefulness, attention, processing speed, reaction time).

Introduction

The first benzodiazepine, chlordiazepoxide, was synthesized in 1955 (Wick 2013). This was followed by diazepam in 1963, and numerous analogues thereafter. Benzodiazepines have a depressant effect in the sense that they potentiate an inhibitory neurotransmitter (GABA, gamma amino-butyric acid). Benzodiazepines have had various clinical indications, including management of insomnia, alcohol withdrawal, psychiatric disorders (e.g., anxiety, panic disorder,) and neurological disorders (e.g., seizures, myoclonus, and other muscle spasms). They are also used off-label for a variety of purposes.

Pharmacology

All benzodiazepines act at receptors that bind GABA (gamma amino-butyric acid). Different benzodiazepines have different pharmacologic profiles in terms of their half-lives, the particular subset of GABA receptors that they influence, and binding affinities (Bailey et al. 1994).

Relevance in otoneurology

GABA receptors are present at numerous levels in the peripheral and central vestibular system (Soto et al. 2013), so benzodiazepines have the potential to influence vestibular function, with the usual effect being one of vestibular suppression.

Some benzodiazepines are used off-label in the acute management of vestibular disease. For example, some practitioners advocate the use of alprazolam, clonazepam or diazepam for attacks of Ménière’s disease. Patients whose episodes are associated with retching may be able to ingest the orally disintegrating tablet formulation of clonazepam. Patients who are entirely unable to take anything by mouth may benefit from a diazepam suppository.

Clonazepam is sometimes attempted for long-term management of mal de debarquement syndrome.

Cautions and contraindications

All benzodiazepines have the potential for a patient to develop physiologic dependence on the drug, and to suffer withdrawal when the drug is discontinued (O’Brien C 2005). These risks must be balanced against their possible benefits.

Since GABA receptors are expressed throughout the central nervous system, it is unsurprising that benzodiazepines can have undesired effects, particularly on cognitive factors such as wakefulness, attention, processing speed and reaction time (Vinckenbosch et al. 2021). These characteristics make benzodiazepines problematic for driving. With a few exceptions of dissenting opinions (Hindmarch et al. 1977; van der Sluiszen et al. 2017; van der Sluiszen et al. 2019), there is considerable literature regarding driving risks incurred by any benzodiazepine (Dassanayake et al. 2011; Dubois et al. 2008; Hemmelgarn et al. 1997; Leung 2011; Rapoport et al. 2009; Smink et al. 2010; Stone et al. 2015; Verster et al. 2004; Vinckenbosch et al. 2021), including alprazolam (Verster et al. 2002), clobazam (Biehl 1979), clonazepam (van der Meyden et al. 1989), diazepam (Boucart et al. 2007; de Gier et al. 1981; Moskowitz and Smiley 1982; O’Hanlon et al. 1982; O’Hanlon et al. 1995; Seppala et al. 1976; Takahashi et al. 2010), etizolam (Rohrig et al. 2021), flualprazolam (Youso et al. 2022), flubromazolam (Rohrig et al. 2021), lorazepam (Clarkson et al. 2004; Daurat et al. 2013; Hindmarch and Gudgeon 1980; O’Hanlon et al. 1995; Seppala et al. 1976), medazepam (Seppala et al. 1976) and phenazepam (Stephenson et al. 2013).

The degree of driving impairment appears to correlate poorly with serum concentration of benzodiazepines (Verster and Roth 2013), suggesting that there are longer-term effects of these medications that are independent of their presence in the bloodstream at a particular moment.

There is also evidence that benzodiazepines have longer-term consequences, in the sense that their effects last beyond the presence of these drugs in the bloodstream (Ritvo et al. 2023).

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