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).

image

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

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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.

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