Background

The term 'insomnia' is used loosely to describe many symptoms, including difficulty getting to sleep, frequent nocturnal awakenings, early morning waking, and waking unrefreshed.8^,9 Depending exactly how insomnia is defined, its reported prevalence in the general population has ranged from 6% to 48%.8–10 Up to 15% of adults report persistent and/or severe symptoms (i.e. on at least 3 nights per week, for at least 1 month), and the rate is higher in women, older people and those with medical or psychiatric disorders.9^,11 Such symptoms may be associated with daytime tiredness, functional impairment, susceptibility to accidents, and medical and psychiatric morbidity.8

Potential causes of insomnia include external stimuli (e.g. light, noise) or somatic stimuli (e.g. pain, heartburn, dyspnoea, restless legs); physiological disturbance (e.g. effects of shift work or jet lag); psychological disorders (e.g. anxiety, depression, substance misuse); and sleep-disturbing effects of caffeine, alcohol and prescribed or over-the-counter medicines (e.g. sympathomimetic drugs, beta-blockers, diuretics, selective serotonin re-uptake inhibitors).8^,9 Primary insomnia is a diagnosis of exclusion, and accounts for around 30% of chronic insomnia.12

Principles of management

General measures

The patient should be asked about the pattern, duration and severity of their insomnia symptoms. Underlying causes should be sought through a careful medical, psychiatric and drug history and examination and, wherever possible, corrected before considering specific treatment for insomnia. Sometimes the likely cause will be obvious to the patient. Patients should be asked specifically about their use of alcohol, which is often drunk inappropriately to aid sleep. Such use often aggravates insomnia and has many other potential problems.13 A diary of sleep (including daytime naps) and daytime activities (e.g. recording mealtimes, work, exercise and intake of coffee, tea and alcohol) may reveal behaviour patterns unconductive to sound sleep, and can provide a clearer picture of exactly how much sleep the patient is getting.8 All patients should be advised about lifestyle adjustments to promote restful sleep ('sleep hygiene'), including moderating caffeine and alcohol consumption; limiting daytime naps; avoiding large meals, vigorous exercise and stimulating activities late in the evening; keeping regular hours, ideally going to bed and rising at the same times each day; and ensuring that the bedroom is comfortable and quiet.8^,12^,13 For many patients, such measures may be all that is required to restore a better sleep pattern.

Psychological treatments

Several types of brief cognitive and behavioural intervention and relaxation therapy can help to regulate the sleep-wake cycle, curtail sleep-incompatible behaviour, and re-establish normal sleep patterns in patients with insomnia.14 Evidence suggests that benefit from such interventions is comparable to that with current hypnotic therapy in the short term (although slower in onset),11 is well maintained in the 6 months following therapy,14^,15 and could be delivered cost-effectively in primary care.15 Currently, however, a lack of trained staff limits the scope for many of these treatments in NHS primary care.

The role of hypnotic drugs

Currently marketed hypnotics are effective in promoting sleep in the short term, but there is little evidence to support their efficacy during long-term use.8^,12^,16–18 Because of concerns about adverse effects, including the risk of dependence, a hypnotic should only be used when sleep disturbance markedly affects the life of the individual or his or her family, and when other approaches have failed.13 Even then, it should be used in the lowest effective dose for the shortest possible period, preferably intermittently (e.g. one night in three) rather than regularly.7^,8^,12^,13^,17 For example, for a distressed patient with insomnia following an acute traumatic event, 2-3 nights is probably the longest for which a hypnotic should be prescribed. For insomnia associated with a predictably limited illness or upset, intermittent treatment, say for up to 2-3 weeks at the most, is reasonable.12

Treatment with a hypnotic drug is not usually appropriate for chronic insomnia. Here, it is particularly crucial that treatment is primarily aimed at alleviating the underlying cause, such as depression. A hypnotic should be offered only as an adjunct to non-drug treatment of insomnia, and should be reserved for patients with the most severe symptoms. It should be given intermittently, not continuously, again, for at most 2-3 weeks.8^,12

Benzodiazepines and Z-drugs

While annual prescriptions for benzodiazepine hypnotics fell from 10 million to around 6 million in England between 1993 and 2003, those for the Z-drugs, zaleplon, zolpidem and zopiclone, rose from 0.3 million to over 4 million over the same period4 (1993 data available from the Prescription Pricing Authority). This suggests that prescribers may believe that changing to a Z-drug can avoid the problems associated with regular hypnotic use. However, in reality, the precautions needed are just as stringent as those for benzodiazepines.

Mode, speed and duration of action

While the Z-drugs are chemically distinct from benzodiazepines, both classes of drug work in the same way. Both enhance neuronal inhibition by gamma-aminobutyric acid (GABA), by binding to specific sites (benzodiazepine receptors) on GABA_A receptors in the brain.19^,20 Various benzodiazepine receptor subtypes are thought to mediate different functional effects (e.g. α₁ subtypes have been linked to sedative, hypnotic and amnesic effects; α₂ and α₃ to anxiolytic effects).20 Benzodiazepines and zopiclone are non-selective agonists at these sites,19^,20 while zolpidem and zaleplon are more selective for α₁ subtypes (which, in theory, should minimise non-hypnotic effects).21^,22 However, the clinical relevance of such selectivity is unproven.

Both benzodiazepine hypnotics and Z-drugs have a rapid onset of action (between 30 and 90 minutes), but Z-drugs are shorter-acting than any currently licensed benzodiazepine hypnotic.20 Among the latter, the duration of action of loprazolam (elimination half-life 6-12 hours) and lormetazepam (half-life 10-12 hours) is relatively short, and that of lorazepam (half-life 10-20 hours) and temazepam (half-life 8-22 hours) intermediate.7 Nitrazepam (half-life 15-38 hours) and diazepam and its active metabolites (half-life 20-200 hours) are long-acting.7 The elimination half-life of zopiclone, following a usual adult dose (7.5mg), is 3.5-6 hours.19 For zolpidem (10mg), it is around 2.5 hours.21 Zaleplon is very short-acting: plasma concentration peaks around 1 hour after ingestion (of 10mg), and the elimination half-life is also around 1 hour.22

Hypnotic efficacy

In the short term, benzodiazepine hypnotics hasten sleep onset, decrease nocturnal awakenings, and increase total sleep time in patients with insomnia.18 However, tolerance to the hypnotic effects may develop within a few weeks of regular use.7^,17 Abrupt cessation of benzodiazepine hypnotics (particularly short-acting drugs) may be followed by rebound insomnia.17^,23

Zolpidem and zopiclone appear to have short-term efficacy similar to that of benzodiazepine hypnotics.16^,18^,21 However, data comparing zaleplon with currently used benzodiazepine hypnotics are sparse. Zaleplon reduces sleep latency compared with placebo,22 and so might help people who have difficulty falling asleep. However, it does not seem consistently to improve the quality or duration of sleep or reduce nocturnal awakenings.22

Studies of varying design and duration have reported that tolerance occurs infrequently with Z-drugs in healthy adults and patients with insomnia.21^,22^,24 Nevertheless, the summaries of product characteristics (SPCs) for all three Z-drugs warn that tolerance can occur after repeated use for a few weeks, and none of the drugs is licensed for treatment for longer than 4 weeks (2 weeks for zaleplon), including tapering of the dose.25–27 Rebound insomnia is reported to be uncommon on cessation of Z-drugs.21^,22^,24 However, in general, published randomised comparisons with benzodiazepines have not given data on the frequency of symptoms associated with withdrawal of the drugs.10

Adverse effects

Hypnotics can cause dose-related over-sedation and cognitive impairment, which may manifest as residual, next-day hangover effects. The problems are best minimised by use of a drug with a short or medium duration of action (less than 8 hours) given only intermittently in the lowest effective dose.20 Elderly people are especially vulnerable to over-sedation because they eliminate the drugs more slowly, are more susceptible to CNS depression, and are more likely to be on potentially interacting drugs.5 These are compelling reasons for trying to avoid use of hypnotics completely in elderly people. If a hypnotic is given, the dose for people aged over 65 years should be no more than half the usual adult dose.

Dose-related over-sedation with benzodiazepine hypnotics may manifest as ataxia, motor inco-ordination and mental confusion, and may contribute to falls and fractures in the elderly,28^,29 and to accidents in the home, at work or while driving.20^,30 In elderly patients, even small doses can cause acute confusional states, night-time wandering and, occasionally, paradoxical excitement;3 also, treatment-related impairment of memory and cognitive function may be wrongly diagnosed as features of dementia.5^,7^,17

Because Z-drugs are shorter-acting than benzodiazepine hypnotics, they might be expected to cause fewer residual daytime effects. However, few randomised trials have directly compared Z-drugs with equivalent doses of currently available short- or intermediate-acting benzodiazepines, such as temazepam, and these have not shown consistent differences in safety or tolerability in people with insomnia.10 The SPCs for all the Z-drugs caution that, like other sedative and hypnotic drugs, they may cause daytime drowsiness, impaired concentration, confusion and amnesia.25–27

Published studies have shown that zopiclone, in a usual night-time dose, can impair memory and driving ability for up to 11 hours in healthy adults, and taking the drug may increase the likelihood of being involved in a road accident.20^,30 Next-day impairment has also been shown with higher doses of zolpidem, or doses taken during the night,20^,21 and use of the drug has been associated with an increased risk of hip fracture in older patients.29 In usual dose (10mg), zaleplon appears to have no detectable effects on psychomotor performance or driving when taken late in the night, up to 2 hours before scheduled waking time.20 Nevertheless, the company advises that patients "should not use or undertake activities requiring full psychomotor co-ordination for 4 hours or more" after taking zaleplon.27 Like benzodiazepines, Z-drugs occasionally produce paradoxical stimulant effects and adverse psychiatric reactions. Other effects include gastrointestinal disturbance (nausea, dyspepsia) and, with zopiclone, a bitter or metallic taste.

All patients (and especially those who drive or operate machinery) must be warned about the risks of hangover effects if prescribed any hypnotic drug. All hypnotics can depress respiration, so should be avoided in patients with respiratory failure and obstructive sleep apnoea; all have additive effects with alcohol and other CNS depressants. Prescribers must check that the patient is not using potentially interacting prescribed or over-the counter medicines or herbal remedies.

Risk of dependence and misuse

All currently marketed hypnotics have been associated with at least some features of physical and/or psychological dependence, and have demonstrated a potential for misuse and dose escalation in at least a minority of patients.7^,17^,19

Dependence on benzodiazepines can develop within a few weeks or months of regular use, and may manifest as chronic reliance on regular prescriptions; unsuccessful efforts to cut down or stop; and rebound insomnia or other withdrawal symptoms on stopping treatment.7 Withdrawal effects occur in around 30-45% of patients taking regular therapeutic doses long term.7 They may include acute anxiety symptoms, perceptual distortions, hallucinations, depression and, uncommonly, seizures and delirium.7^,17

Misuse of benzodiazepines is common among people with alcohol dependence and in polysubstance misuse.31^,32 Also, very high doses of benzodiazepines (often temazepam) are sometimes swallowed, 'snorted' or injected intravenously as euphoriants in their own right.17 Such misuse can cause severe problems, including fatal overdose and, in those who inject, tissue necrosis, gangrene and transmission of hepatitis and HIV.31^,32

Although tolerance and rebound insomnia are reported to be uncommon phenomena with Z-drugs, the SPCs for all three warn of the possibility of physical and psychological dependence and withdrawal effects. Dependence on Z-drugs is a recognised risk for some patients and its incidence may be increasing.33 Misuse of zopiclone or zolpidem, characterised by massive dose escalation and withdrawal symptoms, has mainly been reported in patients with a history of drug or alcohol misuse or other psychiatric disorder.19 However, misuse of zolpidem for anxiolytic and stimulant actions has also been reported in patients without these characteristics.34

Although the worldwide number of reports of dependence and misuse of Z-drugs is low, there is a clear need for vigilance, particularly given the slowness, historically, in recognising problems with psychoactive drugs. Importantly, studies designed to test comparative risks of dependence with benzodiazepines and Z-drugs have not been carried out - a major gap in knowledge. As with other hypnotic drugs, Z-drugs are best avoided in people with a history of alcohol or drug misuse, and should only be used in strict accordance with their SPCs.

Other drugs

The risk of adverse effects (e.g. dependence, dangerous respiratory depression in overdose) generally outweigh potential benefits of the older hypnotics, clomethiazole* and chloral hydrate, and these drugs are best avoided.13 Barbiturates too are obsolete as hypnotics, because of the dangers of dependence and overdose.

* This new spelling reflects the use of recommended International Non-proprietary Names (rINNs) instead of former British Approved Names (BANs), as required by European law. For more information, see the British National Formulary, or http://medicines.mhra.gov.uk/inforesources/productinfo/banslist.pdf

In patients in whom sleep disturbance is thought to be a manifestation of underlying depression, treatment with an antidepressant with sedative properties (e.g. amitriptyline, mirtazapine, trazodone), in full therapeutic dose, is reasonable. There is no evidence that such treatment helps to relieve insomnia in patients who do not have depression, and its use risks potentially serious adverse effects (e.g. antimuscarinic effects and cardiotoxicity with amitriptyline).8

Sedative antihistamines, such as promethazine and diphenhydramine, are widely purchased over-the-counter as 'sleep aids'. However, sound evidence for their efficacy is lacking, hangover effects are common, and rebound insomnia can occur after prolonged use. Other products used include herbal preparations, such as valerian (which occasionally causes cardiotoxicity or hepatotoxicity) and the hormone melatonin. Melatonin is not licensed in the UK, so products are not subject to the usual statutory safety testing or quality-control checks. Evidence for its hypnotic efficacy is weak and no large-scale studies have been published.

Withdrawing hypnotics

There is little justification for repeat prescribing of hypnotics. Although patients often insist that their sleeping tablet is helping them, for many, if not most, of those on long-term hypnotics, gradual withdrawal is desirable and achievable. In a recent study, 81 of 104 patients (mean age 77 years), who wished to stop benzodiazepine hypnotics after many years of use, were able to withdraw successfully with blinded tapering of the dose (i.e. with gradual substitution of placebo), plus psychological support, over 8-9 weeks.5 In the study group as a whole, cognitive function improved, without detrimental effects on sleep or an increase in anxiety, when compared with a control group who opted to stay on hypnotics. In a recent randomised trial, involving 284 patients on long-term benzodiazepines (mainly hypnotics), 39% of those receiving either of two brief interventions (a short consultation or a letter from their GP advising gradual reduction in benzodiazepine intake) achieved at least a 25% reduction in their use of benzodiazepines;35 24% of a control group who completed an assessment and were randomised to "usual GP care" also reduced their benzodiazepine intake by at least 25%.

These studies excluded several categories of patients (e.g. because of psychiatric illness, or because withdrawal of hypnotics was considered inappropriate), and other patients declined to take part. Nevertheless, the findings, together with those of earlier studies36^,37 demonstrate that, in selected patients, a high rate of success can be achieved, even after many years of benzodiazepine use, using fairly simple interventions. The key strategies are gradual tapering of dosage plus, when necessary, psychological support.38 The same approach seems reasonable for long-term users of other hypnotics. For those who have difficulty withdrawing, switching to an equivalent dose of a long-acting benzodiazepine, such as diazepam, followed by dosage reductions in small steps, is suggested.3

Cost considerations

The National Institute for Clinical Excellence (NICE) recently recommended that "because of lack of compelling evidence to distinguish between zaleplon, zolpidem, zopiclone or the shorter-acting benzodiazepine hypnotics, the drug with the lowest purchase cost (taking into account daily required dose and product price per dose) should be prescribed".33 Only if the patient experiences adverse effects specifically related to that drug does NICE recommend switching to a different hypnotic.

The cost of commonly used licensed hypnotic drugs, given at usual adult doses for 14 days, ranges from around £0.50-£0.80 for temazepan to around £3.40-£4.00 for zaleplon.

Conclusion

The current and long-standing high level of prescribing of hypnotic drugs, mostly in older people, represents a risk to individual and public health and cannot be justified. A change in culture, and education about sleep and 'sleeping tablets', is needed. Hypnotic drugs should, in general, be given only for very short periods (ideally, intermittently and for no more than a few days) to alleviate acute distressing insomnia caused by short-lasting events, illnesses or upsets. They should only be given after careful assessment, and after education and appropriate non-drug measures have proved insufficient. To minimise residual next-day sedative effects, a shorter-acting drug, given in the lowest effective dose, is a better choice than a longer-acting drug. However, in elderly people, it is safer to avoid hypnotics altogether, wherever possible.

Long-term use of hypnotic drugs has not been proven to be effective for patients with chronic insomnia, and should generally be avoided. In such individuals, first-line management should be directed at identifying and treating any underlying cause (such as depression); alongside this, psychological and/or behavioural treatments are a more suitable approach than hypnotic drugs. To enable full implementation of this approach, there should be an increase in the number of appropriately trained staff in the NHS.

All currently available drugs appear capable of causing dependence with regular use, and should be treated as such. Patients should be advised of this risk, and should not be issued with repeat prescriptions without reassessment. Many long-term users of benzodiazepine hypnotics are able to reduce or stop their use of these medications, with benefit to their health and without detriment to their sleep, if given simple advice and support during dose-tapering.