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4.3.1 History

Benzodiazepine is the chemical name for a group of drugs discovered in the 1960s, otherwise known as (minor) tranquilisers. The individual drugs are often more familiar by their trade names. One of the most commonly used benzodiazepines is diazepam, whose trade name is Valium. They also include chlordiazepoxide (librium), lorazepam and temazepam.

From the 1960s onwards, benzodiazepines were widely prescribed to people with sleeping difficulties and people with anxiety and ‘neurotic’ disorders, especially women, often for long periods of time. In the 1980s it became apparent that many people who take benzodiazepines for more than a few weeks become physically dependent on them and experience significant withdrawal symptoms when they stop. Recommendations were then made that they should not be prescribed routinely other than for short periods.

Starting in the late 1980s, the Z-drugs (zopiclone, zolpidem and zaleplon) were introduced. These are chemically different from benzodiazepines but have similar effects and are now widely prescribed for insomnia. The drugs pregabalin and gabapentin also bear some similarities to benzodiazepines in terms of their pharmacological actions. In psychiatry, they are prescribed for anxiety. They are also used for epilepsy and nerve pain. In 2013, a UK study reported that pregabalin and gabapentin prescribing had increased by 350% and 150% respectively in just five years1. Withdrawal reactions have been described following discontinuation, which are similar to benzodiazepine withdrawal reactions.2,3

4.3.2 Theories of action

Benzodiazepines act by enhancing the activity of the brain chemical known as gamma aminobutyric acid (GABA). GABA has an inhibitory effect and benzodiazepines increase this. Therefore, they lower the activity of the brain, causing sedation and relaxation at lower doses, progressing to sleep and then coma and death at very high doses. Z-drugs also work by stimulating the GABA system.

In most situations benzodiazepines are regarded as non-specific treatments. In other words, they are thought to work according to a drug-centred model by producing an artificial drug-induced sedative state, rather than reversing an underlying disease. Since it is well known that they induce similar effects in everyone, regardless of whether or not they suffer from a psychiatric problem, it is difficult to deny the impact of their drug-induced effects. An exception to this is the case of anxiety. It has been suggested that anxiety is caused by abnormalities of GABA activity, which can be specifically reversed by the action of benzodiazepines on the GABA system. However, there is limited evidence of this.4

4.3.3 Drug effects

Benzodiazepines and similar drugs have sedative properties, similar in nature to alcohol. They cause a sensation of relaxation, which is both mental and physical, and they are recognised muscle relaxants. Like alcohol they may occasionally lead to disinhibited or aggressive behaviour, although there is little robust evidence in clinical or help-seeking populations.4a The alterations they produce are usually experienced as pleasurable, and they are used for recreational purposes, especially by those who prefer sedative drugs or ‘downers’.

4.3.4 Evidence of efficacy

Short-term studies of benzodiazepines show that they reduce anxiety more than a placebo and are slightly more effective than other common drugs treatments for anxiety such as SSRIs.5 However, studies generally only last a few weeks, so it is not certain whether this effect persists, since the body adapts to counteract their effects. This is the mechanism of dependence. The body’s arousal mechanisms are stepped up to counteract the effects of the drugs, leading to the need for greater doses to produce the same effects and causing unpleasant withdrawal symptoms when they are stopped.

Randomised controlled trials of benzodiazepines for insomnia show that they increase duration of sleep by around an hour on average, but do not improve the time it takes to get to sleep (sleep latency).6 In contrast, a recent meta-analysis of Z-drugs found that sleep latency was reduced by an average of 22 minutes compared to placebo, a difference which the authors concluded may not be clinically meaningful, and there was no evidence of improvement of sleep duration, although there was insufficient evidence on this particular outcome.7

4.3.5 Common uses

Benzodiazepines are recommended for the short-term treatment of anxiety and Z-drugs for the short-term treatment of insomnia. Benzodiazepines are also prescribed for the treatment of alcohol withdrawal and are frequently prescribed to people with severe psychiatric problems because of their sedative properties. As such, they are prescribed extensively to psychiatric inpatients with various diagnoses.

Within psychiatric hospitals, benzodiazepines are commonly used in emergency situations to sedate people who are behaving in a disturbed or aggressive way. Studies show that benzodiazepines are effective and comparable to other sedative agents (such as antipsychotics) in this situation.8 However, evidence about whether they can reduce disturbed behaviour over a long period is lacking.

Benzodiazepines and Z-drugs have modest effects in insomnia and so they might be useful, temporarily, in someone who is having trouble sleeping. However, this effect will wear off, and if they are taken for more than a few weeks, withdrawing from them will itself produce sleeping difficulties. It is a similar situation with anxiety. Benzodiazepines can have remarkable effects in reducing anxiety initially, but these effects are likely to decline with time. When the drugs are stopped, anxiety will be induced by the process of withdrawal. For this reason, it is recommended that benzodiazepines be reserved for short-term use only.9

Despite benzodiazepines being generally recommended for short-term use only, many people appear to be prescribed benzodiazepines over long periods. Recent research estimates that the current number of people taking benzodiazepines long-term (beyond one year) in England is over 266,000.10

4.3.6 Common adverse effects

Like all sedative drugs, benzodiazepines impair people’s ability to perform simple physical and mental tasks like driving and mental arithmetic. As with alcohol, people are often unaware of their impairment and rate themselves as functioning better than they are. It may only be after they withdraw from the drugs that they realise how impaired they were.11 Other effects that derive from the ability of benzodiazepines to suppress nervous activity include confusion, slurring of speech and loss of balance and usually only occur at higher doses, or if some other factor (like a physical illness of some sort) is present. These effects are more likely to occur in elderly people, and when they do, elderly people can have falls and suffer other accidents because of being over-sedated.

At very high doses, such as when they are taken in an overdose, benzodiazepines can, like other sedative drugs, suppress the respiratory system and cause death.

There has been some concern that benzodiazepines may occasionally lead to disinhibited behaviour and aggression. This mainly seems to occur when high doses are used in people with a prior history of behavioural problems and in people who are more vulnerable to this, like children, the elderly and people with learning disability.12

Pregabalin and gabapentin also suppress the activity of the central nervous system, and their use can result in drowsiness, sedation, and reduced breathing. These risks are raised by higher doses, such as might be taken in an overdose, or when they are used in combination with other drugs that depress the nervous system. Like benzodiazepines, this can lead to respiratory failure and death in extreme cases. They are also associated with weight gain, which is not generally thought to occur with benzodiazepines.

Benzodiazepines are well-recognised recreational drugs, often used alongside other illicit substances like opiates. The agents with the shortest half-life are the most susceptible to abuse, and some, like temazepam, have been added to the schedule for controlled drugs. There have also been calls to make pregabalin and gabapentin-controlled substances, due to their propensity to become drugs of recreational or illicit use.13 Both are reported to produce a ‘high’ in those taking them. The abuse potential may be higher with pregabalin, which is absorbed faster and is more potent than gabapentin.14,15 However, gabapentin can also produce euphoria.16

4.3.7 Long-term harm

A few studies have looked at whether long-term use of benzodiazepines affects the structure of the brain. Two of these studies found a reduction in the amount of brain matter after long-term use of benzodiazepines, similar to findings with antipsychotics.17,18 However, two other studies found no effects.19,20

Some studies have reported an increased incidence of dementia in people taking benzodiazepines compared to those who are not taking them.21,22 However, since people with dementia can often present initially with increased anxiety or depression, for which they may be prescribed benzodiazepines, these studies do not necessarily indicate a causal relationship. However, a meta-analysis found that the risk of dementia was raised in people who had taken benzodiazepines in the past as well as those taking them currently or recently.23 It also found that the risk of dementia was higher in people who took higher doses of benzodiazepines compared to those who took lower doses, and a correlation between increased risk and dose is generally regarded as a likely indicator of causation. A more recent study, however, suggested that the association might be accounted for by other drugs being taken alongside the benzodiazepines.24 Despite remaining uncertainties, the evidence reinforces current recommendations that the drugs should be reserved for short-term use where possible.9 Benzodiazepines are definitely to be avoided during the last part of pregnancy, as they can cause neurological toxicity in the newborn infant.25

Together with drowsiness and confusion caused by their sedative properties, the most pressing concern regarding benzodiazepine use is dependence. The occurrence of withdrawal syndromes after stopping benzodiazepines and Z-drugs is well established and also reported in relation to gabapentin and pregabalin (see section 5 for further information).

4.3.8 Conclusion

Benzodiazepines are effective in reducing feelings of anxiety and have a modest effect in insomnia in the short-term. The main concern with their use is the significant risk of tolerance and dependence, and the associated difficulties that people can experience when trying to withdraw from the drugs.

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