Insomnia

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27 Insomnia

S. Bleakley, M. Sie

Key points

• Hypnotic drugs do not cure insomnia but can provide useful short-term symptomatic treatment.
• Before starting medication, the primary cause of insomnia should be investigated and treated appropriately where possible.
• Hypnotic drugs should only be used short-term (2–4 weeks); long-term regular use leads to tolerance, dependence and other adverse effects.
• Sleep hygiene, relaxation techniques and psychological methods are more appropriate than hypnotics as long-term treatment for patients with insomnia.
• Non-benzodiazepine hypnotics such as zopiclone, zolpidem and zaleplon have similar pharmacological and adverse effects to benzodiazepines, offer few advantages and are more expensive.
• A melatonin preparation is available for primary insomnia. Its place in therapy is yet to be determined but it does not cause tolerance or dependence.

Definitions and epidemiology

Insomnia refers to difficulty in either falling asleep, remaining asleep or feeling refreshed from sleep. Complaints of poor sleep increase with increasing age and are twice as common in women as in men (Sateia and Nowell, 2004). Thus, by the age of 50, a quarter of the population are dissatisfied with their sleep, the proportion rising to 30–40% (two-thirds of them women) among individuals over 65 years.

Pathophysiology

Insomnia reflects a disturbance of arousal and/or sleep systems in the brain. These systems are functionally interrelated and their activity determines the degree and type of alertness during wakefulness and the depth and quality of sleep.

Sleep systems

The phenomenon of sleep is actively induced and maintained by neural mechanisms in several brain areas, including the lower brainstem, pons and parts of the limbic system. These mechanisms have reciprocal inhibitory connections with arousal systems, so that the activation of sleep systems inhibits waking and vice versa. Normal sleep includes two distinct levels of consciousness, orthodox sleep and paradoxical sleep, which are promoted from separate neural centres.

Orthodox sleep normally takes up about 75% of sleeping time. It is somewhat arbitrarily divided into four stages (1–4) which merge into each other, forming a continuum of decreasing cortical and behavioural arousal (see Fig. 27.1). Stages 3 and 4 represent the deepest phase of sleep and are also termed slow-wave sleep (SWS).

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Fig. 27.1 The five stages of sleep. REM, rapid eye movement.

Paradoxical sleep, rapid eye movement (REM) sleep, normally takes up about 25% of sleeping time and has quite different characteristics to non-rapid eye movement (NREM) sleep. The EEG shows unsynchronised fast activity similar to that found in the alert conscious state and the eyes show rapid jerky movements. Peripheral autonomic activity is increased during REM sleep and there is an increased output of catecholamines and free fatty acids. Vivid dreams and nightmares most often occur during REM sleep, although brief frightening dreams (hypnagogic hallucinations) can occur in orthodox sleep, especially at the transition between sleeping and waking. Normally, stage 4 sleep occurs primarily in the first few hours of the night, while REM sleep is most prominent towards the morning. Brief awakenings during the night are normal. Both SWS and REM sleep are thought to be essential for brain function and both show a rebound after a period of deprivation, usually at the expense of lighter (stage 1 and 2) sleep which appears to be expendable. Many drugs can affect the different stages of sleep. Benzodiazepines suppress stages 3 and 4 of sleep, but only cause a slight decrease in REM sleep. Z-hypnotics shorten stage 1 of sleep and prolong stage 2 of sleep but have little effect on stages 3, 4 and REM sleep. Chloral derivatives do not affect sleep architecture.

Aetiology and clinical manifestations

Insomnia may be caused by any factor which increases activity in arousal systems or decreases activity in sleep systems. Many causes act on both systems (Morin, 2003). Increased sensory stimulation activates arousal systems, resulting in difficulty in falling asleep. Common causes include chronic pain, gastric reflux, uncontrolled asthma and external stimuli such as noise, bright lights and extremes of temperature. Anxiety may also delay sleep onset as a result of increased emotional arousal.

Drugs are an important cause of insomnia. Difficulty in falling asleep may result directly from the action of stimulants, including caffeine, nicotine, theophylline, sympathomimetic amines, some antidepressants, levothyroxine and antimuscarinics. Some illicit substances, cocaine, amphetamines and anabolic steroids can also cause insomnia. Drug withdrawal after chronic use of central nervous system depressants, including hypnotics, anxiolytics and alcohol, commonly causes rebound insomnia with delayed or interrupted sleep, increased REM sleep and nightmares. With rapidly metabolised drugs, such as alcohol or short acting benzodiazepines, this rebound may occur in the latter part of the night, resulting in early waking. Certain drugs, including antipsychotics, tricyclic antidepressants and propranolol, may occasionally cause nightmares.

Difficulty in staying asleep is characteristic of depression. Patients typically complain of early waking but sleep records show frequent awakenings, early onset of REM sleep and reduced NREM sleep. Alteration of sleep stages, increased dreaming and nightmares may also occur in schizophrenia, while recurring nightmares are a feature of post-traumatic stress disorder (PTSD). Interference with circadian rhythms, as in shift work or rapid travel across time zones, can cause difficulty in falling asleep or early waking.

Frequent arousals from sleep are associated with myoclonus, ‘restless legs syndrome’, muscle cramps, bruxism (tooth grinding), head banging and sleep apnoea syndromes. Reversal of the sleep pattern, with a tendency for poor nocturnal sleep but a need for daytime naps, is common in the elderly, in whom it may be associated with cerebrovascular disease or dementia. In general, decreased duration of sleep has been shown to increase the risk of obesity (Kripke et al., 2002) and hypertension (Gangwisch et al., 2006). Sleep disturbances in the elderly are also associated with increased falls, cognitive decline and a higher rate of mortality (Cochen et al., 2009). There is growing concern that daytime sleepiness resulting from insomnia increases the risk of industrial, traffic and other accidents.

Investigations and differential diagnosis

Many patients complaining of insomnia overestimate their sleep requirements. Although most people sleep for 7–8 h daily, some healthy subjects require as little as 3 h of sleep and sleep requirements decline with age. Such ‘physiological insomnia’ does not usually cause daytime fatigue, although the elderly may take daytime naps. If insomnia is causing distress, primary causes such as pain, drugs which disturb sleep, psychiatric disturbance including anxiety and depression and organic causes such as sleep apnoea should be identified and treated before hypnotic therapy is prescribed.

Treatment

Non-drug therapies

Explanation of sleep requirements, attention to sleep hygiene (see Box 27.1), reduction in caffeine or alcohol intake and the use of analgesics where indicated may obviate the need for hypnotics (Anon, 2004). Medications that cause insomnia should also be avoided if possible. Psychological techniques such as relaxation therapy and cognitive behavioural therapy (CBT) are also helpful (Kierlin, 2008). However, studies comparing psychological approaches to hypnotics are scarce (Riemann and Perlis, 2009).

Box 27.1 Principles of typical advice for good sleep hygiene (Anon, 2004)

• Have a good bed time routine, go to bed and get up at the same time every day and avoid daytime naps.
• Avoid stimulants such as caffeine, nicotine, chocolate and alcohol 6 h before bedtime.
• Take regular exercise during the day, but avoid strenuous exercise within 4 h of bedtime.
• Avoid large meals close to bedtime.
• Associate bed with sleep. Do not watch TV or listen to music when retiring to bed.
• The bedroom should be a quiet, relaxing place to sleep; make sure the room is not too hot or too cold.
• If after 30 min you cannot get off to sleep, then get up. Leave the bedroom and try to do something else, return to bed when sleepy. This can be repeated as often as necessary until you are asleep.

Hypnotic drugs

Hypnotic drugs provide only symptomatic treatment for insomnia. Although often efficacious in the short-term, they do little to alter the underlying cause which should be sought and treated where possible. About 20 million prescriptions for hypnotics are issued each year in the UK and these drugs can improve the quality of life if used rationally.

The ideal hypnotic would

• gently suppress brain arousal systems while activating systems that promote deep and satisfying sleep,
• have a rapid onset of action with a duration of less than 8 h,
• have no hangover effect the next day,
• not induce tolerance or dependence if used long-term,
• not cause withdrawal effects when stopped,
• not depress respiration,
• be safe for use in the elderly patient.

Unfortunately, no such hypnotic exists; most available hypnotics are general central nervous system depressants which inhibit both arousal and sleep mechanisms. Thus, they do not induce normal sleep and often have adverse effects, including daytime sedation (‘hangover’) and rebound insomnia on withdrawal. They are unsuitable for long-term use because of the development of tolerance and dependence.

Benzodiazepines

By far the most commonly prescribed hypnotics are the benzodiazepines. A number of different benzodiazepines are available (see Table 27.1). These drugs differ considerably in potency (equivalent dosage) and in rate of elimination but only slightly in clinical effects. All benzodiazepines have sedative/hypnotic, anxiolytic, amnesic, muscular relaxant and anticonvulsant actions with minor differences in the relative potency of these effects.

Table 27.1 Overview of the medication used for insomnia

image

Pharmacokinetics

Most benzodiazepines marketed as hypnotics are well absorbed and rapidly penetrate the brain, producing hypnotic effects within half an hour after oral administration. Rates of elimination vary, however, with elimination half-lives from 6 to 100 h (see Table 27.1). These drugs undergo hepatic metabolism via oxidation or conjugation and some form pharmacologically active metabolites with even longer elimination half-lives. Oxidation of benzodiazepines is decreased in the elderly, in patients with hepatic impairment and in the presence of some drugs, including alcohol.

Pharmacokinetic characteristics are important in selecting a hypnotic drug. A rapid onset of action combined with a medium duration of action (elimination half-life about 6–8 h) is usually desirable. Too short a duration of action may lead to, or fail to control, early morning waking, while a long duration of action (e.g. nitrazepam) may produce residual effects the next day and may lead to accumulation if the drug is used regularly. However, frequency of use and dosage are also important. For example, diazepam (5–10 mg) produces few residual effects when used occasionally, despite its slow elimination, although chronic use impairs daytime performance. Large doses of short acting drugs may produce hangover effects, while small doses of longer acting drugs may cause little or no hangover.

Mechanism of action

Most of the effects of benzodiazepines result from their interaction with specific binding sites associated with postsynaptic GABAA receptors in the brain. All benzodiazepines bind to these sites, although with varying degrees of affinity, and potentiate the inhibitory actions of GABA at these sites.

GABAA receptors are multi-molecular complexes (see Figs. 27.2 and 27.3) that control a chloride ion channel and contain specific binding sites for GABA, benzodiazepines and several other drugs, including many non- benzodiazepine hypnotics and some anticonvulsant drugs (Haefely, 1990). The various effects of benzodiazepines (hypnotic, anxiolytic, anticonvulsant, amnesic, muscle relaxant) result from GABA potentiation in specific brain sites and at different types of GABAA receptor. There are multiple subtypes of GABAA receptor which may contain different combinations of at least 18 sub-units (including α1–6, β1–3, γ1–3 and others) and the subtypes are differentially distributed in the brain.

image

Fig. 27.2 The GABAA receptor and sub-units. The GABAA receptor is a heteropentameric glycoprotein. A total of five distinct polypeptide sub-units have been cloned to date; α, β, γ, d and r, and multiple isoforms of these sub-units are reported in the literature. Different confirmations of the GABAA receptor are found throughout the brain, and the most common mammalian arrangements of sub-units is (α1)2(β2)2(γ1). The specific sub-units in the GABAA receptor confer functional diversity on the receptor. For example, the γ sub-unit needs to be co-expressed with the α and β sub-units to observe the potentiation of the GABAA receptor by benzodiazepines.

image

Fig. 27.3 Schematic representation of the GABAA receptor. GABA is the major inhibitory neurotransmitter in the central nervous system. The GABAA receptor is composed of five sub-units – two α, two β and one γ sub-unit. Two molecules of GABA activate the receptor by binding to the α sub-units. Once activated the receptor allows the passage of negatively charged ions (Cl-) into the cytoplasm, which results in hyper-polarisation and the inhibition of neurotransmission.

Source: www.CNSforum.com.

Benzodiazepines bind to three or more subtypes and it appears that their combination with α2-containing subtypes mediates their anxiolytic effects, α1-containing subtypes their sedative and amnesic effects, and α1 as well as α2 and α5 their anticonvulsant effects (Rudolph et al., 2001).

Zopiclone

In 1988, zopiclone, a cyclopyrrolone, was the first non-benzodiazepine to be approved for the treatment of insomnia in the European market. Although classed as a non-benzodiazepine, it still binds to benzodiazepine receptors but is said to be more selective for the α1 subtype. It has hypnotic effects similar to benzodiazepines and carries a similar potential for adverse effects including tolerance, dependence and abstinence effects on withdrawal. Psychiatric reactions, including hallucinations, behavioural disturbances and nightmares, have been reported to occur shortly after the first dose. Other common adverse reactions include a bitter taste, a dry mouth and difficulty arising in the morning (Zammit, 2009). This drug appears to have no particular advantages over benzodiazepines, although it may cause less alteration of sleep stages and does not have the controlled drug requirements of the benzodiazepines. Eszopiclone the S- (+) isomer of zopiclone is available in the USA but there are no current plans to launch in the UK. What advantage, if any, the isomer incurs over zopiclone is unclear.

Zolpidem

Zolpidem is an imidazopyridine that binds preferentially to the α1 benzodiazepine receptor sub-unit thought to mediate hypnotic effects. It is an effective hypnotic with only weak anticonvulsant and muscle relaxant properties. As it has a short elimination half-life (2 h) hangover effects are rare but rebound effects may occur in the later part of the night, causing early morning waking and daytime anxiety. High doses have been reported to cause brief psychotic episodes, tolerance and withdrawal effects. Anecdotal case reports (mainly from the USA) have associated zolpidem with complex sleep related behaviours. These have included ‘sleep-driving’, making phone calls, preparing food and eating while asleep. The majority of these cases also involved ingestion of alcohol and should be interpreted with caution because they are not replicated in the wider medical literature (Zammit, 2009). A controlled release version of zolpidem (zolpidem-CR) is available in some countries.

Zaleplon

Zaleplon is a pyrazolopyrimidine which, like zolpidem, binds selectively to the α1 benzodiazepine receptor. It is an effective hypnotic, has a very short elimination half-life (1 h) and appears to cause minimal residual effects on psychomotor or cognitive function after 5 h. There is little evidence of tolerance or withdrawal effects in short-term use and the drug appears suitable for use in the elderly (Doble et al., 2004).

All the ‘Z-hypnotics’ are recommended for short-term use only (2–4 weeks) and are more expensive than benzodiazepines. There is no compelling evidence to distinguish them from the shorter acting benzodiazepine hypnotics (National Institute of Health and Clinical Excellence, 2004). Patients who do not respond to either a benzodiazepine or z-hypnotic should not be prescribed the other.

Melatonin

Melatonin is a naturally occurring hormone, produced by the pineal gland, which regulates the circadian rhythm of sleep. It begins to be released once it becomes dark, and continues to be released until the first light of day. Melatonin release decreases with age which may in-part explain why older adults require less sleep. Melatonin supplementation promotes sleep initiation and helps to reset the circadian clock allowing uninterrupted sleep. It has also been shown to improve next day functioning. Contrary to most other hypnotics melatonin shows no abuse or tolerance potential and appears to have no next day sedation problems. Prolonged release melatonin (Circadin®) was launched in June 2008 and is available at a dose of 2 mg at night for up to 3 weeks. It is licensed as monotherapy in primary insomnia for adults over 55 years old. Whilst the adverse effect profile looks advantageous there are currently no trials comparing melatonin against psychological or other hypnotic treatments. Circadin® is also much more expensive than other currently prescribed hypnotics (Anon, 2009).

Other hypnotic drugs

The risk of adverse effects, including dependence and dangerous respiratory depression in overdose, generally outweighs the potential benefits of the older hypnotics, chloral derivatives, clomethiazole and barbiturate. Therefore, these drugs are best avoided. Antidepressants with sedative properties, such as amitriptyline, mirtazapine, trazodone and agomelatine may be helpful if sleep disturbance is secondary to depression. Sedative antihistamines, such as promethazine, diphenhydramine and chlorphenamine, which can be purchased over-the-counter, have mild-to-moderate hypnotic efficacy but commonly produce hangover effects and rebound insomnia can occur after prolonged use (Anon, 2004).

Potential adverse effects of hypnotic use

Tolerance and dependence

Tolerance to the hypnotic effects of benzodiazepines and probably z-hypnotics develops rapidly and may lead to dosage escalation. Nevertheless, poor sleepers may report continued efficacy and the drugs are often used long-term because of difficulties on withdrawal.

Rebound insomnia

Rebound insomnia, in which sleep is poorer than before drug treatment, is common on withdrawal of benzodiazepines. Sleep latency (time to onset of sleep) is prolonged, intra-sleep wakenings become more frequent and REM sleep duration and intensity are increased, with vivid dreams or nightmares which may add to frequent awakenings. These symptoms are most marked when the drugs have been taken in high doses or for long periods, but can occur after only a week of low dose administration. They are prominent with moderately, rapidly eliminated benzodiazepines (temazepam, lorazepam) and may last for many weeks. With slowly eliminated benzodiazepines (diazepam), SWS and REM sleep may remain depressed for some weeks and then slowly return to the baseline, sometimes without a rebound effect. Tolerance and rebound effects are reflections of a complex homeostatic response to regular drug use, involving desensitisation, uncoupling and internalisation of certain GABA/benzodiazepine receptors and sensitisation of receptors for excitatory neurotransmitters (Allison and Pratt, 2003). These changes encourage continued hypnotic usage and contribute to the development of drug dependence.

Oversedation and hangover effects

Many benzodiazepines used as hypnotics can give rise to a subjective ‘hangover’ effect and after most of them, even those with short elimination half-lives, psychomotor performance, including driving ability and memory, may be impaired on the following day. Over sedation is most likely with slowly eliminated benzodiazepines, especially if used chronically, and is most marked in the elderly in whom drowsiness, incoordination and ataxia, leading to falls and fractures, and acute confusional states may result even from small doses. Chronic use can cause considerable cognitive impairment, sometimes suggesting dementia. Paradoxical excitement may occasionally occur.

Some benzodiazepines in hypnotic doses may decrease alveolar ventilation and depress the respiratory response to hypercapnia, increasing the risk of cerebral hypoxia, especially in the elderly and in patients with chronic respiratory disease.

Drug interactions

Benzodiazepines have additive effects with other central nervous system depressants. Combinations of benzodiazepines with alcohol, other hypnotics, sedative tricyclic antidepressants, antihistamines or opioids can cause marked sedation and may lead to accidents or severe respiratory depression.

Rational drug treatment of insomnia

A hypnotic drug may be indicated for insomnia when it is severe, disabling, unresponsive to other measures or likely to be temporary. In choosing an appropriate agent, individual variables relating to the patient and to the drug need to be considered (see Table 27.1).

Patient care

Type of insomnia

The duration of insomnia is important in deciding on a hypnotic regimen. Transient insomnia may be caused by changes of routine such as overnight travel, change in time zone, alteration of shift work or temporary admission to hospital. In these circumstances, a hypnotic with a rapid onset, medium duration of action and few residual effects could be used on one or two occasions.

Short-term insomnia may result from temporary environmental stress. In this case, a hypnotic may occasionally be indicated but should be prescribed in low dosage for 1 or 2 weeks only, preferably intermittently, on alternate nights or one night in three.

Chronic insomnia presents a much greater therapeutic problem. It is usually secondary to other conditions (organic or psychiatric) at which treatment should initially be aimed. In selected cases, a hypnotic may be helpful but it is recommended that such drugs should be prescribed at the minimal effective dosage and administered intermittently (one night in three) or temporarily (not more than 2 or 3 weeks). Occasionally it is necessary to repeat short, intermittent courses at intervals of a few months.

The elderly

The elderly are especially vulnerable both to insomnia and to adverse effects from hypnotic drugs. They may have reduced metabolism of some drugs and may be at risk of cumulative effects. They are also more susceptible than younger people to central nervous system depression, including cognitive impairment and ataxia (which may lead to falls and fractures). They are sensitive to respiratory depression, prone to sleep apnoea and other sleep disorders and are more likely to have ‘sociological’, psychiatric and somatic illnesses which both disturb sleep and may be aggravated by hypnotics. For some of these elderly patients, hypnotics can improve the quality of life but the dosage should be adjusted (usually half the recommended adult dose) and hypnotics with long elimination half-lives or active metabolites should be avoided.

A considerable number of elderly patients give a history of regular hypnotic use going back for 20 or 30 years. In many of these patients, gradual reduction of hypnotic dosage or even withdrawal may be indicated and can be carried out successfully, resulting in improved cognition and general health with no impairment of sleep or escalation of other symptoms (Curran et al., 2003).

The young

Traditional benzodiazepine-like are generally contraindicated for children. Where sedation is required, sedative antihistamines or melatonin are usually recommended.

Disease states

Hypnotics are contraindicated in patients with acute pulmonary insufficiency, significant respiratory depression, obstructive sleep apnoea or severe hepatic impairment. In patients with chronic pain or terminal conditions, suitable analgesics including non-steroidal anti-inflammatory agents or opiates, sometimes combined with neuroleptics, usually provide satisfactory sedation. In such patients, the possibility of drug dependence becomes a less important issue and regular use of hypnotics with a medium duration of action should not be denied if they provide symptomatic relief of insomnia.

Choice of drug

There is little difference in hypnotic efficacy between most of the available agents. The main factors to consider in the rational choice of a hypnotic regimen are duration of action and the risk of adverse effects, especially over sedation and the development of tolerance and dependence. Cost may also be a factor when prescribing melatonin.

Rate of elimination

Slowly eliminated drugs should be avoided because of the risk of over sedation and hangover effects. Very short acting drugs such as zaleplon carry the risk of late night rebound insomnia and daytime anxiety. Drugs with a medium elimination half-life (6–8 h) appear to have the most suitable profile for hypnotic use. These may include temazepam and loprazolam, as these are the drugs of first choice in most situations where hypnotics are indicated. Zopiclone is a reasonable second choice and sedative antihistamine such as promethazine is a safe third choice. These are useful in children, although sedative antihistamine may produce daytime drowsiness.

Duration and timing of administration

To prevent the development of tolerance and dependence, the maximum duration of treatment should be limited to 2 or 3 weeks and treatment should, where possible, be intermittent (one night in two or three). Dosage should be tapered slowly if hypnotics have been taken regularly for more than a few weeks. Doses should be taken 20 min before retiring in order to allow dissolution in the stomach and absorption to commence before the patient lies down in bed.

Case studies

Case 27.1

Mr PH, aged 24, was hospitalised for 3 months after a serious motorcycle injury followed by painful complications. While in hospital he developed panic attacks and insomnia. He received no psychological support but was prescribed temazepam, initially in 20 mg doses but later increased to 60 mg because of continued insomnia. After discharge from hospital Mr PH continued to receive temazepam from his primary care doctor and the dosage was increased over a period of years until he was taking 80 mg temazepam each night and 40–80 mg during the day. At the age of 30, Mr PH was removed from the practice list of his doctor after he altered a prescription. He later attended several different primary care doctors, obtaining multiple temazepam prescriptions. When he could no longer satisfy his need from prescriptions he took to obtaining temazepam on the street, taking large and irregular doses by mouth. All this time, his anxiety levels increased. His behaviour became chaotic and he was twice imprisoned for credit card fraud but he was able to obtain temazepam and other drugs from his co-prisoners. When last heard of, Mr PH, aged 35, was again buying temazepam illicitly, as well as other addictive drugs, had started injecting intravenously and was involved in a court case for obtaining money under false pretences.

Question

How could this tragedy have been prevented?

Answer

Mr PH’s downfall could have been averted at several stages.

• The hospital staff should not have allowed the temazepam dosage to escalate and should have provided psychological/psychiatric help for what was probably PTSD or panic disorder.
• An antidepressant drug could have been prescribed, along with psychological measures, instead of prolonged treatment with excessive doses of temazepam.
• On discharge from hospital, Mr PH’s doctor should have been warned of his temazepam intake and a slow withdrawal schedule suggested.
• The series of primary care doctors who gave Mr PH prescriptions should have been aware that he was likely to obtain illicit supplies and should have referred him to a withdrawal clinic or drugs unit.

Case 27.2

Mrs AK, a recently widowed lady aged 65, had difficulty sleeping after her bereavement. She was prescribed nitrazepam in a bedtime dose of 5 mg, which was very effective and was continued for over 4 weeks. Mrs AK lived alone but was visited occasionally by her daughter. On a visit 2 weeks after the nitrazepam was started, Mrs AK seemed calm and said that she was sleeping well but the daughter noticed her mother was unsteady on her feet. A week later the daughter visited again and found her mother lying on the bedroom floor, in pain and unable to move. She said that she had lost her balance on getting out of bed. An ambulance was called and it was found in hospital that Mrs AK had broken her hip.

Question

Should the doctor have prescribed nitrazepam for this lady?

Answers

• Long acting benzodiazepines should be avoided in the elderly. The elimination half-life of nitrazepam is 15–38 h and the recommended dose for the elderly is 2.5–5 mg. Temazepam, loprazolam or lormetazepam would have been a better choice but for short-term use only (preferably only 2 weeks).
• The elderly are particularly prone to ataxia and light-headedness with benzodiazepines and this can lead to falls and fractures.
• Benzodiazepines are not recommended, except acutely, for bereavement. Their amnesic effects may interfere with subsequent psychological adjustment.

References

Allison C., Pratt J.A. Neuroadaptive processes in GABAergic and glutamatergic systems in benzodiazepine dependence. Pharmacol. Ther.. 2003;98:171-195.

Anon. What’s wrong with prescribing hypnotics? Drug Ther. Bull.. 2004;42:89-93. Available at: http://dtb.bmj.com/content/42/12/89.full.pdf Accessed March 2010

Anon. Melatonin for primary insomnia. Drug Ther. Bull.. 2009;47:74-77. Available at: http://dtb.bmj.com/content/47/7/74.full.pdf Accessed March 2010

Cochen V., Arbus C., Soto M.E., et al. Sleep disorders and their impact on healthy, dependent and frail older adults. J. Nutr. Health. Aging. 2009;13:322-330.

Curran H.V., Collins R., Fletcher S. Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life. Psychosom. Med.. 2003;33:1223-1237.

Doble A., Martin I.L., Nutt D. Calming the brain: benzodiazepines and related drugs from laboratory to clinic. London: Martin Dunitz; 2004.

Gangwisch J., Heymsfield S., Boden-Albala B., et al. Short sleep duration as a risk factor for hypertension. Hypertension. 2006;47:833-839.

Haefely W. Benzodiazepine receptor and ligands: structural and functional differences. In: Hindmarch I., Beaumont G., Brandon S., et al, editors. Benzodiazepines: Current Concepts. Chichester: John Wiley; 1990:1-18.

Kierlin L. Sleeping without a pill: non-pharmacologic treatments for insomnia. J. Psychiatr. Pract.. 2008;14:403-407.

Kripke D., Garfinkel L., Wingard D., et al. Mortality associated with sleep duration and insomnia. Arch. Gen. Psychiatry. 2002;59:131-136.

Morin C.M. Treating insomnia with behavioural approaches: evidence for efficacy, effectiveness and practicality. In: Szuba M.P., Kloss J.D., Dinges D.F., editors. Insomnia: Principles and Management. Cambridge: Cambridge University Press; 2003:83-95.

National Institute of Health and Clinical Excellence. Guidance on the use of Zaleplon, Zolpidem and Zopiclone for the short-term management of insomnia, Technology Appraisal 77.. London: NICE. 2004. Available at: http://guidance.nice.org.uk/TA77/Guidance/pdf/English Accessed March 2010

Riemann D., Perlis M.L. The treatments of chronic insomnia: a review of benzodiazepine receptor agonists and psychological and behavioral therapies. Sleep Med. Rev.. 2009;13:205-214.

Rudolph U., Crestani F., Mohler H. GABAA receptor subtypes: dissecting their pharmacological functions. Trends Pharmacol. Sci.. 2001;22:188-194.

Sateia M.J., Nowell P.D. Insomnia. Lancet. 2004;364:1959-1973.

Zammit G. Comparative tolerability of newer agents for insomnia. Drug Saf.. 2009;32:735-738.

Further reading

Bloom H.G., Ahmed I., Alessi C.A., et al. Evidence-based recommendations for the assessment and management of sleep disorders in older persons: supplement. J. Am. Geriatr. Soc.. 2009;57:761-789.

Parish J. Sleep-related problems in common medical conditions. Chest. 2009;135:563-572.

Sullivan S.S., Guilleminault C. Emerging drugs for insomnia: new frontiers for old and novel targets. Expert Opin. Emerg. Drugs. 2009;14:411-422.

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