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This guide, describes how benzodiazepines act, and provides evidence of the advantages and disadvantages associated with their use. These aspects are those more specifically highlighted in this summary.
It was initially published as guidelines in order to provide assistance to general practitioners in the appropriate prescribing of benzodiazepines. Evidence-based recommendations are collated, and on basis of further information in the body of the guide, key principles of accountable prescribing, practice systems of care, and patient-focused care are provided.
Benzodiazepines are a group of prescription-only medicines that have a sedating/hypnotic and calming effects on the nervous system. Examples of benzodiazepines active ingredients are diazepam, lorazepam, oxazepam, temazepam and alprazolam. Most are now generics (no more under patent), but still widely recognizable under brand names such as Valium® or Xanax®. They come in tablet and capsule forms and some are available for intravenous use in hospital settings.
The arrival of benzodiazepines into clinical practice in the 1960s allowed doctors to offer this medication at a time when few effective therapeutic alternatives were available. Benzodiazepines appeared safe in comparison to barbiturates, chloral hydrate and other drugs, which were problematic due to toxicity and overdose.
Due to the apparent low level of side effects and rapid onset of effect, and together with a pressing mental health need, benzodiazepines were commonly used and prescribed short- and long-term for anxiety, depression, insomnia, mental illness, and neuromuscular conditions. By the 1970s, they were among the most prescribed drugs in the world.
Benzodiazepines have four basic properties that give rise to their clinical use:
These properties are the result of an enhancement of the activity of the major natural inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the central nervous system (CNS). Benzodiazepines bind to GABA receptors of neurons and cause the same inhibition of activity of the brain as the GABA neurotransmitter. This results in drowsiness and cognitive impairment (at the level of the cerebral cortex), dampening of emotions such as fear and anxiety (at the level of the mesolimbic dopamine system), memory impairment and anticonvulsant actions (at the level of the hippocampus), and impairment of balance, motor control, muscle tone and coordination (at the level of the cerebellum and other motor areas).
On this basis, benzodiazepines are prescribed for a broad range of conditions including:
In particular, benzodiazepines have been shown to be one of the most effective drug classes in the management of alcohol withdrawal syndrome. The rationale for the use of benzodiazepines is that they modulate the hyperactivity of the central nervous system due to the alcohol withdrawal, by interacting with GABA receptors.
The pharmacological effects are non-selective, and benzodiazepines are short-, medium- or long-acting, depending on the speed (kinetic) and mechanisms by which they are eliminated from the body, which vary greatly. Accordingly, equivalence among different benzodiazepines is difficult to establish.
Newer drugs also to bind the same GABA receptor are marketed for insomnia due to their kinetic profile. However, high doses are required to produce the other effects such as decreased anxiety, and these drugs have similar risks than benzodiazepines.
Depending on the indication, guidelines and formularies give durations of 1–4 weeks for benzodiazepine therapy. But these drugs may continue to exert subtle effects longer than the duration of intended clinical action. Indeed, with repeated dosing, accumulation within the fatty tissue occurs and a steady state of blood concentration can be reached in approximately five half-lives. Due to slow leaching from fatty tissue, benzodiazepines may be detected in urine tests weeks to months after cessation of benzodiazepine use.
Benzodiazepines may also have significant interactions with other drugs that are eliminated by the same way via the liver.
Benzodiazepines should be not prescribed, or only with extreme caution, to:
Also, benzodiazepines are generally not recommended for use in children and have little place in the management of chronic musculoskeletal pain. There is sparse evidence that they are clinically effective as muscle relaxants.
Tolerance to all drugs of dependence develops with repeated use. The development of tolerance is associated with escalation in dose, binge dosing, and is one of the criteria for dependence. Due to a range of neuroadaptive and physiological mechanisms, within a few days of reaching a steady state of plasma concentration, patients may start to experience a loss of effect from benzodiazepines at different speeds and different degrees, and may never be complete. Steady state plasma concentrations of benzodiazepines and their metabolites are usually reached between a few days and 2 weeks after starting therapy.
If a high proportion of patients with epilepsy develop tolerance to the anticonvulsant effects within a few weeks, tolerance to the hypnotic effects is less clear. Tolerance to the anxiolytic and amnesic effects of benzodiazepines probably does not occur at all, even if there is some evidence that a slow (years) tolerance may develop. There is also a high degree of cross-tolerance between benzodiazepines and other sedative/hypnotic medications and alcohol.
Tolerance also makes it difficult to calculate equivalence between various benzodiazepines.
Benzodiazepines are associated with a number of side effects including:
More specifically, the main recognized side effects of benzodiazepine use are:
Despite their familiarity and ubiquitous use, the concepts of addiction and dependence are complex. The definition of benzodiazepine dependence changed to include benzodiazepine addiction and abuse. Historically, dependence has been defined in pharmacological terms, as a state that develops during chronic drug treatment in which cessation elicits an abstinence reaction (withdrawal). This is time limited and reversible by renewed administration of the drug. Slow discontinuation of benzodiazepines is recommended to avoid withdrawal symptoms (e.g. rebound anxiety, agitation, insomnia or seizures) particularly when use exceeds 8 weeks.
The World Health Organization (WHO) and leading authors describe dependance as a cluster of complex behavioural, cognitive and physiological phenomena that may develop after repeated substance use that involves variable combinations of interacting patient and drug factors, including reinforcement, tolerance and withdrawal.
This has created difficulties in determining incidence and prevalence of benzodiazepine dependence. Based on the available epidemiological data, the prevalence of benzodiazepine abuse is generally low in the therapeutic setting (i.e. where the drug is adequately medically prescribed). A 2013 study found most patients used benzodiazepines according to guidelines, and only 0.9% ended up as excessive users after 3 years.
Some authors argued however that based on the incidence of withdrawal symptoms, evidence of benzodiazepine dependence can be quite high. In the 1980s, the addictive nature of benzodiazepines was progressively evidenced and it became generally accepted that benzodiazepines brought their own problems. In 1988, the Committee on Safety of Medicines (UK) published the first guideline for benzodiazepine use, and recommended limiting the length of treatment to 2–4 weeks1. Since then, many international guidelines have advocated for the reduction in prescribing benzodiazepines, particularly short-acting benzodiazepines for long-term disorders such as anxiety.
However, there has been – and still is – a wide divergence between recommendations and clinical practice, and the conditions where benzodiazepines are most commonly prescribed (i.e. anxiety and insomnia) remain sources of debate. Good clinical governance and an evidence-based approach remain key to safe and appropriate prescription.
By alleviating anxiety and withdrawal symptoms, treatment can encourage continued use. Used alone and at therapeutic doses, benzodiazepines have not been associated with significant positive reinforcement for most patients (i.e. the drug itself does not encourage further use or dose escalation). Patients with a history of alcohol abuse, or even those with moderate alcohol consumption, appear to experience the greater reinforcement effects when taking benzodiazepines.
1 Committee on Safety of Medicines. Current problems – Benzodiazepines, dependence and withdrawal symptoms. London: Committee on Safety of Medicines, 1988. Available at:
webarchive.nationalarchives.gov.uk/20141205150130
Benzodiazepine withdrawal syndrome is highly variable and related to high dosage and long-term use. It remains unclear why some long-term users can withdraw without difficulty, even after years of continuous use, while others undergo protracted agonies.
The symptoms of withdrawal usually appear within 2–3 half-lives of the benzodiazepines being withdrawn, which usually lessen and then disappear within a few weeks. Sudden withdrawal of benzodiazepines can be associated with seizures.
The mildest form of withdrawal is rebound of the original symptoms, such as anxiety and insomnia, recurring transiently at a greater intensity. Withdrawal symptoms include irritability, paraesthesia, tinnitus, headaches, dizziness, poor memory, poor concentration, perceptual distortions, menstrual disturbances and sensory hypersensitivity. Withdrawal symptoms can usually be minimised by gradual reduction.
Withdrawal symptoms from benzodiazepines prescribed for insomnia can ensue after 4–6 weeks of use in approximately 15–30% of patients, while other studies suggest much higher incidences of withdrawal: in the order of 30–45% of patients who have used regular therapeutic doses of benzodiazepines for more than a few months.
For example, it has been suggested that in the absence of substance use disorder, the risk of addiction to benzodiazepines during long-term treatment of anxiety and related disorders has been exaggerated, and that the pharmacological dependence that develops when benzodiazepines are used long-term does not create compulsive or uncontrollable benzodiazepine-seeking behaviour, and adverse health and/or social consequences.
Among the key points in this matter, the report highlighted:
The responsibilities of any patient taking benzodiazepines should include:
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