1. INSOMNIA

2. Definitions and epidemiology Insomnia refers to difficulty in falling asleep or staying asleep, or to lack of refreshment from sleep Complains of poor sleep increase with increasing age and are twice as common in women as in men By the age of 50 years 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

3. SLEEP SYSTEM The phenomenon of sleep is actively induced and maintained by neural mechanisms in several brain areas: The lower brainstem Pons Parts of the limbic system These mechanisms have reciprocal inhibitory connections with arousal systems Activation of sleep systems at the same time inhibits waking, and vice versa Normal sleep includes two distinct levels of consciousness: Orthodox sleep Paradoxical sleep They are promoted from separate neural centers

4. Cortex Somatic (hypothalamus pituitary) Emotional (limbic system) General (reticular formation, thalamic and other nuclei SWS REMS (Brainstem, basal forebrain, pons, etc) Arousal systems Inhibition Excitation Inhib or excit motor, autonomic, endocrine Incoming sensory stimuli

5. Orthodox sleep normally takes up about 75% of sleeping time It is divided into four stages (1-4) which merge into each other, forming a continuum of decreasing cortical and behavioral arousal Stages 3 and 4 are associated with increasing amounts of high-voltages δ slow waves (1-3 Hz) shown on electroencephalograph (EEG) These later stages represent the deepest level of sleep and are also termed slow-wave sleep (SWS)

6. Paradoxical sleep (rapid eye movement sleep, REMS) normally takes up 25% of sleeping time and has quite different characteristics. The EEG shows unsynchronized fast activity similar to that found in the alert conscious state, and the eyes show rapid jerky movements. Peripheral autonomic activity is increased during REMS, and there is an increased output of catecholamines and free fatty acids. Vivid dreams and nightmares most often occur in REMS Brief frightening dreams (hypnagogic hallucinations) can occur in orthodox sleep, especially at the transition between sleeping and waking

7. Stage 4 sleep occurs mostly in the first few hours, while REMS is most prominent towards the morning Brief awaking during the night are normal Both SWS and REMS are thought to be essential for brain function.

8. Etiology 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. Increased sensory stimulation activates arousal systems, resulting in difficulty in falling asleep. Common causes include pain or discomfort 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.

9. Drugs are an important cause of insomnia. Difficulty in falling asleep may result directly from the action of stimulants, including caffeine, theophylline, sympathomimetic amines and some antidepressants. Drugs withdrawal after chronic use of CNS depressants, including hypnotics, anxiolytics and alcohol, commonly cause rebound insomnia with delayed or interrupted sleep, increases REMS and nightmares. With rapidly metabolized drugs, such as alcohol or short- acting BZDs, this rebound may occur in the latter part of the night, resulting in early waking. Certain drugs, including neuroleptics, TCAs and propranolol, may occasionally cause nightmares.

10. Difficulty in staying asleep is characteristic of depression. Alteration of sleep stages, increased dreaming and nightmares may also occur in schizophrenia, while recurring nightmares are a feature of PTSD. Interference with circadian rhythms, as in shift work or rapid travel across time zones, can cause difficulty in falling asleep or early waking. Reversal of the sleep pattern, with a tendency to 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.

11. Investigations, differential diagnosis Many patients complaining of insomnia overestimate their sleep requirements. Although most people sleep for 7-8 hours daily, some healthy subjects require as little as 3 hours of sleep, and sleep requirements decline with age. Such ‘physiological insomnia’ does not usually cause daytime fatigue, although the elderly may take daytime naps.

12. If insomnia is causing distress, primary causes such as pain, drugs which disturb sleep, psychiatric disturbance including anxiety and depression, organic causes such as sleep apnea should be identified and treated before hypnotic therapy is prescribed. There is growing concern that sleepiness resulting from insomnia increases the risk of industrial, traffic and other accidents.

13. Treatment 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. The ideal hypnotic would gently suppress all arousal systems while simultaneously stimulating the systems for deep and satisfying sleep. It would allow a natural return of normal sleep patterns and would be suitable for long-term use.

14. Unfortunately, no such hypnotic exists; All presently available hypnotics are general CNS depressants which inhibit both arousal and sleep mechanism. 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.

15. Benzodiazepines By far the most commonly prescribed hypnotics are the BZDs. Theses drug differ considerably in potency (equivalent dosage) and in rate of elimination but only slightly in clinical effects. All BZDs have sedative/hypnotic, anxiolytic, amnesic, muscular relaxant and anticonvulsant actions with minor differences in the relative potency of these effects.

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

17. Pharmacokinetics 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 hours) is usually desirable (temazepam, loprazolam). Too short a duration of action may lead to, or fail to control, early morning waking While a long duration of action (nitrazepam) may produce residual effects the next day and may lead to cumulation if the drug used regularly. However, frequency of use and dosage are important.

18. 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.

19. Effects on sleep A major site of the hypnotic action of BZDs is the brainstem reticular formation which, is of central importance in arousal The reticular formation is extremely sensitive to depression by BZDs which decrease both spontaneous activity and responses to afferent stimuli. Similar depression of limbic arousal systems adds to hypnotic efficacy in patients with insomnia due to anxiety. Active sleep mechanisms are also suppressed, and this effects lead to disruption of the normal sleep patterns.

20. BZDs are effective hypnotics: they hasten sleep onset; decrease nocturnal awakenings; increase total sleeping time; and often impart a sense of deep, refreshing sleep. They produce changes in the relative proportion of different sleep stages. Stage 2 (light sleep) is prolonged and mainly accounts for the increased sleeping time. By contrast, the duration of SWS and REMS are decreased. The latency to the first REMS episode is prolonged and dreaming is diminished.

21. This abnormal sleep profile probably arises because of the unselective depression of both arousal and sleep mechanisms. The suppression of REMS may be an important factor in determining rebound effects on drug withdrawal. Mechanism of action Most of the effects of BZDs result from their interaction with specific binding sites associated with postsynaptic GABA A receptors in the brain.

22. Profile of some hypnotic drugs

23. Adverse effect of hypnotic use Tolerance: Tolerance to the hypnotic effects of BZDs develops rapidly. Sleep latency, Stage 2 sleep, SWS, REMS, Dreaming and Intrasleep awakenings All tend to return to pretreatment levels after few weeks of regular use.

24. Rebound insomnia: It is common on withdrawal of BZDs Sleep is poorer than before drug treatment Sleep latency is prolonged Intrasleep wakenings become more frequent REMS duration and intensity is increased, with vivid dreams or nightmares which may add to frequent awakening. These symptoms are most marked when the drugs have been taken in high doses or for long periods But can occur after only a weak of low dose administration. They are conspicuous with moderately rapidly eliminated BZDs (temazepam, lorazepam) and may last for several weeks.

25. Oversedation, hangover effects: Many BZDs used as hypnotics can give rise to a subjective ‘hangover’. After most of them, even those with short elimination half- lives, psychomotor performance and memory may be impaired on the following day. Oversedation is most likely with slowly eliminated BZDs, especially if used chronically. 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.

26. Some BZDs 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.

27. Drug interactions: BZDs have additive effects with other CNS depressants. Combinations of BZDs with alcohol, other hypnotics, sedative TCAs, anti-histamines or opioids can cause marked sedation and may lead to accidents or severe respiratory depression.

28. Pregnancy and lactation: The regular use of BZDs is contraindicated in pregnancy The drugs are concentrated in fetal tissues where hepatic metabolism is minimal. They also enter breast milk Long-acting BZDs are contraindicated during lactation, Short to medium-acting BZDs appear to be safe.

29. Zopiclone Zopiclone is a cyclopyrrolone It is a non- BZD that binds to BZD receptors. It has hypnotic effects similar to BZDs and carries the same potential for adverse effects including dependence and abstinence effects on withdrawal. Psychiatric reactions, including hallucinations and behavioral disturbances, have been reported to occur shortly after the first dose. This drug appears to have no particular advantages over BZDs, although it may cause less alteration of sleep stages.

30. Zolpidem Zolpidem is an imidazopyridine It binds preferentially to one BZD receptor subtype (BZD-1) thought to mediate hypnotic effects. It is an effective hypnotic with only weak anticonvulsant and myorelaxant properties. In contrast, BZDs bind to three known subtypes and zopiclone to two. Because of its short elimination half-life (2 hours) hangover effects are rare But rebound effects may occur in the later part of the night, causing early morning waking and daytime anxiety. With high doses, brief psychotic episodes, tolerance and withdrawal effects have been reported.

31. Zaleplon Zaleplon is a pyrazolopyrimidine It binds selectively to BZD-1 receptor. It is an effective hypnotic at a dose of 5-10 mg It has a very short elimination half-life (1 hour), and appears to cause minimal residual effects on psychomotor or cognitive function after 5 hours. No tolerance or rebound insomnia were observed after 4 weeks treatment The drug appears suitable for use in the elderly.

32. Chloral derivatives (chloral hydrate, triclofos, dichloralphenazone) Chloral derivatives still have some use as hypnotics in general practice. They are all metabolized to trichlorethanol, which has an elimination half-life of 8 hours. These drugs are moderately effective as hypnotics and their effects on sleep are similar to those of BZDs. They can produce hangover effects, dependence, and an abstinence syndrome on withdrawal and may cause gastrointestinal disturbance.

33. The mechanism of action (on GABA A receptors) is similar to that of BZDs, But respiratory and cardiovascular depression occurs on overdose. Chloral derivatives (chloral hydrate, triclofos, dichloralphenazone)

34. Clomethiazole Clomethiazole has hypnotic and anticonvulsant properties and a mode of action on GABA A receptors similar to that of BZDs. It is fairly rapidly eliminated (half-life of 4 hours) and produces little respiratory depression at therapeutic doses. For these reasons it has been advocated for use in the elderly and sometimes used in alcohol and narcotic detoxification. It has a low therapeutic index, produces a profound respiratory depression in overdose, and carries an appreciable risk of dependence, especially in combination with alcohol.

35. Promethazine Promethazine is one of the few drugs with useful hypnotic properties which does not act on GABA-BZD receptors. It is a sedative antihistamine with antagonistic effect on H 1 receptors in the brain. Promethazine is related to the phenothiazines, and has additional slight neuroleptic and anticholinergic effects. Hangover effects are common, and it occasionally produces excitement rather than sedation. It is sometimes of value in pediatrics practice and in cases where other hypnotics are contraindicated. Other antihistamines with similar effects include diphenhydramine and chlorpheniramine.

36. Other drugs used as hypnotics TCAs with sedative effects and neuroleptic drugs in low dosage are being increasingly used as hypnotic alternatives to BZDs. Such drugs are not recommended for general hypnotic use since they have potentially serious adverse effects.

37. Rational drug treatment of insomnia A hypnotic drug may be indicated for insomnia when it is Severe Disabling Unresponsive to other measures Likely to be temporary In choosing an appropriate agent, individual variables relating to the patient and to the drug need to be considered

38. Drug treatment in insomnia

39. Patient care 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 rapid onset of action and medium duration of action and few residual effects could be used on one or two occasions.

40. 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.

41. Chronic insomnia 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. Hypnotics should be taken 20 minutes before retiring in order to allow dissolution in the stomach and absorption to commence before the patient lies down in bed.

42. In the elderly: Hypnotics can improve the quality of life but the dosage should be adjusted Usually half the recommended adult dose Hypnotics with long elimination half-lives should be avoided. In the children: Hypnotics are generally contraindicated for children. Where sedation is required, sedative antihistamines are usually recommended. A single dose of a BZD (with appropriate dosage reduction) may be more effective

43. Hypnotics are contraindicated in patients with acute pulmonary insufficiency, significant respiratory depression, obstructive sleep apnea 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.