Some facts about benzodiazepines and their uses

Introduction - the aim of this guide

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.

What are benzodiazepines?

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.

What are the pharmacological properties of benzodiazepines?

Benzodiazepines have four basic properties that give rise to their clinical use:

• anxiolytic 
• sedative/hypnotic 
• anticonvulsant 
• muscle relaxant. 

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:

• insomnia  
• anxiety disorders  
• alcohol withdrawal  
• mania/hypomania  
• epilepsy  
• acute seizures  
• arousal/agitation in the in-patient setting  
• palliative care  
• musculo-skeletal disorders. 

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.

Who should not use benzodiazepines?

Benzodiazepines should be not prescribed, or only with extreme caution, to:

• Women who are, or may be pregnant; 
• Patients with active substance use disorders, including alcohol (unless it is part of an alcohol withdrawal program), and illicit drugs; 
• Patients with medical or mental health conditions that may be worsened by benzodiazepines (e.g. fibromyalgia, chronic fatigue syndrome, depression, bipolar disorder or impulse control disorders); 
• Patients being treated with opioids for chronic pain or addiction; 
• Patients experiencing grief reactions, as benzodiazepines may suppress and prolong the grieving process.  

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.

Is there a progressive tolerance to benzodiazepines?

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.

What are the main side effects of benzodiazepines?

Benzodiazepines are associated with a number of side effects including:

• drowsiness and unsteadiness, potentially increasing the risk of a fall; 
• impairment in judgement and dexterity, making tasks such as driving or using heavy machinery more difficult; 
• forgetfulness, confusion, irritability; 
• paradoxical aggression and excitability (although this is rare, it is the opposite effect to what is expected with these medicines).  

More specifically, the main recognized side effects of benzodiazepine use are:

• Cognitive impairment which encompasses several symptoms of benzodiazepine effects on the central nervous system. These include dose-related sedation, drowsiness, learning impairment, psychomotor slowing and anterograde amnesia after acute administration. Chronic cognitive to some, but not all of the acute effects. A range of cognitive and psychomotor effects may persist after withdrawal.
  Long-term use of benzodiazepines has been associated with significant long-term cognitive impairment effects modified by tolerance but other prospective trials did not show an association between benzodiazepines and accelerated cognitive decline. Benzodiazepines can also produce various forms of amnesia
  An increased risk of dementia appears from various studies but the difficulty with these studies is that the symptoms that often precede dementia, such as anxiety, sleep disorders, are the very indications for which benzodiazepines are commonly prescribed.
  Benzodiazepines have especially been shown to impair vision, attention, information processing, memory, motor coordination and combined-skill tasks, and they are associated with a 60–80% increase in the risk of traffic accidents. Taking alcohol and benzodiazepines together increases accident risk more than seven times. All drivers should be advised of increased crash risk when taking benzodiazepines, and patients who experience any degree of sedation should be cautioned not to drive.
• Anxiety that patients may experience while taking benzodiazepines long term or after stopping long-term use (rebound anxiety); 
• Depression which may be aggravated or that first appears during benzodiazepine use, possibly by reducing the output of neurotransmitters such as serotonin and noradrenaline; 
• Paradoxical stimulation and disinhibition (especially at high doses), leading patients to behave out of character and potentially placing themselves in dangerous situations because of an impaired perception of inherent risk in particular in sexual behaviour and reckless driving. So called ‘benzo binges’ have been associated with shoplifting and other crimes. Patients may also experience paradoxical excitement with increased anxiety, insomnia, talkativeness, restlessness, mania, and occasionally rage and violent behaviour (known as the ‘Rambo effect’).
  Epidemiological studies have demonstrated an excess of consultations for accidents among persons taking benzodiazepines. Patients over 60 years of age have the most significant risk of harm with benzodiazepine use relating to falls, fractures and cognitive decline, particularly if the patient has additional risk factors for cognitive or psychomotor adverse events.
  The harmful effects of benzodiazepines, other than the risk of dependence with long-term use, have been associated (i.e. not proven cause and effect) with a 4–6-fold increased risk of death from all causes. Also, when benzodiazepines are combined with other CNS depressants (e.g. alcohol, opioids), patients are at risk of respiratory depression, heavy sedation, coma and death.  

Are benzodiazepines addictive?

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 
 www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con2024428.pdf

What are the symptoms at withdrawal of a treatment with benzodiazepines?

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.

What would be an accountable prescription of benzodiazepines?

Among the key points in this matter, the report highlighted:

1. Prescribing benzodiazepines, as with any treatment, should be based on a comprehensive medical assessment, a diagnosis, thoughtful consideration of the likely risks and benefits of any medication as well as alternative interventions, and a management plan derived through shared decision-making and continual clinical monitoring. The immediate relief with benzodiazepines is tempting, yet the best outcomes are often achieved with non-drug treatment. 
2. General practitioners should be aware of the concerns associated with benzodiazepines and these risks should be discussed with patients. Care should be exercised when changing from one psychoactive substance to another or when using combination therapies;  
3. Benzodiazepines should be prescribed at the lowest effective dose, for the shortest clinical time frame to minimise risks preferably given intermittently, and regular attempts at reduction should be scheduled. Long-term use, beyond 4 weeks, should be uncommon, made with caution and based on thoughtful consideration of the likely risks and benefits of benzodiazepines; 
4. Prescription should be accompanied with a plan to reduce and cease benzodiazepines as some patients find it hard to stop. There are several behaviours, such as escalating use patterns, drug-seeking behaviour and doctor or prescription shopping, that indicate a patient may have problematic benzodiazepine use; 
5. Significant caution, such as seeking specialist opinion, should be taken in prescribing benzodiazepines to patients with comorbid alcohol/ substance abuse or polydrug use;  
6. Supervised benzodiazepine treatment may remain an acceptable long-term therapeutic option if alternatives to benzodiazepine treatment fail, have limited benefit or are inappropriate (either psychologically or pharmacologically); 
7. To manage inappropriate requests by patients, general practitioners should develop specific strategies for benzodiazepines. 

What should be the responsibilities of a patient using benzodiazepines?

The responsibilities of any patient taking benzodiazepines should include:

• To see one doctor at one practice for all its health needs and prescriptions in this domain;
• To agree that such medication is prescribed as a trial and if it appears that there is no improvement in the daily function or quality of life from the controlled substance, that medication may be discontinued;
• To inform the doctor of all medications he is taking, including herbal remedies and illicit medication as well as pain level and functional activity along with any side effects of the medications;
• To understand the use of alcohol is contraindicated together with benzodiazepines as well as the use any illicit substances (e.g. cocaine, amphetamines or marijuana), and to notify the doctor of any history of alcohol or drug misuse/addiction;
• To not request or accept from any other doctor or individual drugs of dependence while receiving such medication.