Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 21C) docx

19 treatment is justified if it has significantly improved their wellbeing and function. A combination of medication with psychological techniques is likely to be most beneficial, especially for resistant cases. Sleep disorders NORMAL SLEEP Humans spend about a third of the time asleep but why we sleep is not yet fully understood. Sleep is a state of inactivity accompanied by loss of awareness and a markedly reduced responsiveness to environ- mental stimuli. When a recording is made of the electroencephalogram (EEG) and other physiolo- gical variables such as muscle activity and eye movements during sleep (a technique called poly- somnography), a pattern of sleep emerges, consisting of five different stages. This pattern varies from person to person, but usually consists of four or five cycles of quiet sleep alternating with paradoxical, or active, rapid eye movement (REM) sleep, with longer periods of paradoxical sleep in the latter half of the night. A representation of these stages and cycles over time is known as a hypnogram, and one derived from a normal subject appears in Figure 19.6, with paradoxical sleep depicted as the shaded areas. SLEEP DISORDERS Quiet sleep is further divided into four stages, each with a characteristic EEG appearance, during which there is progressive relaxation of the muscles and slower, more regular breathing as the deeper stages are reached. Most sleep in these deeper stages occurs in the first half of the night. During paradoxical sleep, the EEG appearance is similar to that of waking or drowsiness. There is irregular breathing, complete loss of tone of the skeletal muscles, and frequent phasic movements particularly of the eyes, consisting of conjugate movements which are mostly lateral but can also be vertical (hence the term rapid eye movement sleep); most dreaming takes place in this stage. The length of total sleep in a day varies between 3 and 10 hours in normal subjects with an average in the 20-45 year age group of 7-8 h. Sleep time is decreased in older subjects, to about 6 h in the over 70 year age group, with increased daytime napping reducing the actual night time sleep even more. The amount of time spent in each of the five stages varies between subjects and particularly with age, with much less slow wave sleep in older people. The number of awakenings after the onset of sleep also increases with advancing age. A normal subject has several short awakenings during the night, most of which are not perceived as awakenings unless they last more than about 2 minutes. Probably there will not be clear consciousness but subject may have occasional brief thoughts of how comfortable Fig. 19.6 Normal hypnogram 397 19 PSYCHOTROPIC DRUGS they feel or how pleased that it's not time to get up yet, with an immediate return to sleep. If during the short period of waking some factor causes anxiety or anger, e.g. aircraft noise, partner's snores or dread of being awake, progress to full awakening and being remembered is much more likely. The more times this happens the more subjects complain of an unrefreshing sleep. The time spent asleep as a percentage of the time in bed is used as a measure of sleep efficiency (96% in the case shown in Figure 19.6). One of the most common ways in which insomnia develops is by 'clock watching'; subjects check the time on awakening, remember it and repeat this cycle many times during the night. Remembering the time of a transient awakening reinforces the subject's perception of sleeping poorly (periods of sleep in between are neglected) and also produces anger and frustration which in turn delay their return to sleep and may promote subsequent awakenings. TYPES OF SLEEP DISORDER Several types of sleep disorder are recognised and their differentiation is important; a simplified summary is given below but reference to DSM, ICD or ICD 4 will clarify the exact diagnostic criteria • insomnia: not enough sleep or sleep of poor quality; problems of falling asleep (initial insomnia) or staying asleep (maintenance insomnia), or waking too early • hypersomnia: excessive daytime sleepiness • parasomnia: unusual happenings in the night nightmares night terrors sleep walking REM behaviour disorder 4 DSM-IV American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders (DSM IV), 1st edition. American Psychiatric Association, Washington DC. ICSD American Sleep Disorders Association (1992) International Classification of Sleep Disorders: Diagnostic and Coding Manual. ICD-10 WHO (1994) Classification of Mental and Behavioural Disorders. • other sleep scheduling disorders (circadian rhythm disorder) restless legs syndrome periodic leg movements of sleep. Insomnia Insomnia is characterised by the complaint of poor sleep, with difficulty either in initiating sleep or maintaining sleep throughout the night. It can occur exclusively in the course of another physical disorder such as pain, mental disorder, e.g. depres- sion, or sleep disorder, e.g. sleep apnoea. In a large proportion of patients it is a primary sleep disorder and causes significant impairment in social, occu- pational or other important areas of functioning. One survey showed similar deficits in quality of life in insomniacs as in patients with long-term disorders such as diabetes. About 60% of patients with insomnia have abnormal sleep when measured objectively but the rest have no sleep abnormality which can be measured at present, yet are as disabled by their perceived symptoms as those with measurable sleep. Insomnia may or may not be accompanied by daytime fatigue but is not usually accompanied by subjective sleepiness during the day. When sleep propensity in the daytime is measured by objective means (time to EEG sleep) these patients are in fact less sleepy than normal subjects. The time of falling asleep is determined by three factors, which in normal sleepers occur at bedtime. These are (a) circadian rhythm, i.e. the body's natural clock in the hypothalamus triggers the rest/ sleep part of the sleep-wake cycle, (b) 'tiredness', i.e. time since last sleep, usually about 16 hours and (c) lowered mental and physical arousal. If one of these processes is disrupted then sleep initiation is difficult, and it is these three factors that are addressed by a standard sleep hygiene program (see below). Early in the course of insomnia rigo- rous adherence to sleep hygiene principles alone may restore the premorbid sleep pattern but in some patients the circadian process is less stable and they are less susceptible to these measures. 398 INSOMNIA A summary of precipitating factors for insomnia is shown in Table 19.7. TREATMENT OF INSOMNIA Timely treatment of short-term insomnia is valu- able, as it may prevent progression to a chronic condition, which is much harder to alleviate. Psy- chological treatments are effective and pharmaco- therapy may be either unnecessary or used as a short-term adjunct. The approaches are to: • treat any precipitating cause (above) • educate about trigger factors for sleep and reassure that sleep will improve • establish good sleep hygiene • consider hypnotic medication. 19 Sleep hygiene • keep regular bedtimes and rising times • reduce daytime napping • daytime (but not evening) exercise and exposure to daylight • avoid stimulants, alcohol and cigarettes in evening • establish bedtime routine — 'wind down' — milk drink may be helpful • avoid dwelling on problems in bed • bed should be comfortable and not too warm or too cold. In the treatment of long-term insomnia the most important factor is anxiety about sleep, arising from conditioning behaviours that predispose to heigh- tened arousal and tension at bedtime. Thus the TABLE 19.7 Precipitating factors for insomnia Pharmacological • nonprescription drugs such as caffeine or alcohol. Alcohol reduces the time to onset of sleep but disrupts sleep later in the night. Regular and excessive consumption disrupts sleep continuity; insomnia is a key feature of alcohol withdrawal. Excessive intake of caffeine and theophylline, either in tea, coffee or cola drinks, also contributes to sleeplessness. • starting treatment with certain antidepressants, especially seroton in reuptake inhibitors (e.g. fluoxetine.fluvoxamine), or monoamine uptake inhibitors; sleep disruption is likely to resolve after 3—4 weeks. • other drugs which increase central noradrenergic and serotonergic activity include stimulants such as amphetamine, cocaine and methylphenidate and sympathomimetics such as the 3-adrenergic agonist salbutamol and associated compounds. • withdrawal from hypnotic drugs: this is usually short-lived. • treatment with 3-adrenoceptor blockers may disrupt sleep, perhaps because of their serotonergic action; a 3-blocking drug which crosses blood-brain barrier less readily is preferred, e.g. atenolol. Psychological: hyperarousal due to • stress • the need to be vigilant at night e.g. because of sick relatives or young children • being 'on-call'. Physical • pain, in which case adequate analgesia will improve sleep • pregnancy • coughing or wheezing: adequate control of asthma with stimulating drugs as above, may paradoxically improve sleep by reducing waking due to breathlessness • respiratory and cardiovascular disorders • need to urinate; this may be affected by timing of diuretic medication • neurological disorders, e.g. stroke, movement disorders • periodic leg movements of sleep (frequent jerks or twitches during the descent into deeper sleep), rarely reduce subjective sleep quality but are more likely to cause them in the subject's sleeping partner. Psychiatric • Patients with depressive illnesses often have difficulty falling asleep at night and complain of restless, disturbed and unrefreshing sleep, and early morning waking. When their sleep is analysed by polysomnography.time to sleep onset is indeed prolonged, and there is a tendency for more REM sleep to occur in the first part of the night, with reduced deep quiet sleep in the first hour or so after sleep onset and increased awakenings during the night.They may wake early in the morning and fail to get back to sleep again. • Anxiety disorders may cause patients to complain about their sleep, either because there is a reduction in sleep continuity or because normal periods of nocturnal waking are somehow less well tolerated. Nocturnal panic attacks can make patients fearful of going off to sleep. • Bipolar patients in the hypomanic or manic phase will sleep less than usual and sometimes changes in sleep pattern can be an early warning that an episode is imminent. Disruption of circadian rhythm Shift work, jet lag and irregular routine can cause insomnia, in that patients cannot sleep when they wish to. 399 19 PSYCHOTROPIC DRUGS bedroom is associated with not sleeping and auto- matic negative thoughts about the sleeping process occur in the evening. Cognitive behavioural therapy is helpful in dealing with 'psychophysiological' insomnia and together with education and sleep hygiene measures as above is the treatment of choice for long-term primary insomnia. Cognitive behavioural therapists are specially trained in changing behaviour and thoughts about sleep, parti- cularly concentrating on learned sleep-incompatible behaviours and automatic negative thoughts at bedtime. The availability of these therapies is often limited and some patients are unwilling or unable to engage with them. Drug therapy may: • relieve short-term insomnia when precipitating causes cannot be improved • prevent progression to a long-term problem by establishing a sleep habit • interrupt the vicious cycle of anxiety about sleep itself. DRUGS FOR INSOMNIA Most drugs used in insomnia act as agonists (see GABA receptor above) at the GABA A -benzodiazepine receptor and have effects other than their direct sedating action, including muscle relaxation, memory impairment, and ataxia, which can impair performance of skills such as driving. Clearly those drugs with onset and duration of action confined to the night period will be most effective in insomnia and less prone to unwanted effects during the day. Those with longer duration of action are likely to affect psychomotor performance, memory and con- centration; they will also have enduring anxiolytic and muscle-relaxing effects. Benzodiazepines A general account of the benzodiazepines is appropriate here, although their indications clearly extend beyond use as hypnotics. All benzodiazepines and newer benzodiazepine- like drugs are safe and effective for insomnia, if the compound with the right timing of onset of action and elimination is chosen. However, care should be taken in prescribing them to patients with co-morbid sleep-related breathing disorders such as obstructive sleep apnoea syndrome (see below) which is exacerbated by benzodiazepines. Objective measures of sleep show that benzodiazepines decrease time to sleep onset and waking during the night; subjective effects of improved sleep are usually greater than the objective changes, probably because of their anxiolytic effects (selectivity between anxiolytic and sedative effect is low). Other changes in sleep architecture are to some extent dependent on duration of action, with the very short-acting compounds having the least effect. Most commonly very light (stage 1) sleep is decreased, and stage 2 sleep is increased. Higher doses of longer-acting drugs partially suppress slow wave sleep. Occasionally the agonist (sedative) compounds in current use cause paradoxical effects, e.g. excite- ment, aggression and antisocial acts. Alteration of dose, up or down, may eliminate these (as may chlorpromazine in an acute severe situation). Pharmacokinetics. Benzodiazepines are effective after administration by mouth but enter the circula- tion at very different rates that are reflected in the speed of onset of action, e.g. alprazolam is rapid, oxazepam is slow (Table 19.8). The liver metabolises them, usually to inactive metabolites but some compounds produce active metabolites, some with long t l / 2 which greatly extends drug action, e.g. chlordiazepoxide, clorazepate and diazepam all form desmethyldiazepam (t l / 2 80 h). Uses. Benzodiazepines are used for: insomnia, anxiety, alcohol withdrawal states, muscle spasm due to a variety of causes, including tetanus and cerebral spasticity, epilepsy (clonazepam, see p. 421), anaesthesia and sedation for endoscopies and cardioversion. The choice of drug as hypnotic and anxiolytic is determined by pharmacokinetic properties (see before, and Table 19.8). Doses. Oral doses as anxiolytics are given with their indications (see before) and those for hypno- tics appear in Table 19.8. Injectable preparations: • Intravenous formulations, e.g. diazepam 10-20 mg, given at 5 mg/min into a large vein (antecubital fossa) to minimise thrombosis: the 400 INSOMNIA 19 TABLE 19.8 Properties of drugs used for insomnia Works selectively Rapid 1/2t Usual dose Daytime Safety to enhance onset (hours) (P.o.) (hangover) GABA effects Zopiclone Zolpidem Zaleplon* Temazepam Loprazolam Lormetazepam Nitrazepam Lorazepam Diazepam Oxazepam Alprazolam Clonazepam Chloral hydrate/chloral betaine Clomethiazole Barbiturates Promethazine / / / / / / / / / / / / X X X X + ++ ++ + + + + + + + + + 3.5-6 1.5-3 1-2 5-12 5-13 8-10 20-48 10-20 20-60 5-20 9-20 18-50 8-12 4-8 7-14 7.5 mg 10mg 10mg 20 mg 1 mg 1 mg 5-10 mg 0.5-1 mg 5-10 mg 15-30 mg 0.5 mg 0.5-1 mg 0.7-1 g 192mg 25 mg ?Yes No No ?Yes ?Yes ?Yes Yes Yes Yes Yes Yes Yes ?Yes ?Yes Yes ?Yes / / / / / / / / / / / / X X X x// * Can be taken during the night, up to 5 h before vehicle driving. dose may be repeated once in 10 min for status epilepticus or in 4 h for severe acute anxiety or agitation: midazolam is a shorter-acting alternative, e.g. for endoscopies. The dose should be titrated according to response, e.g. drooping eyelids, speech, response to commands. • Intramuscular injection of diazepam is absorbed erratically and may be slower in acting than an oral dose: lorazepam and midazolam i.m. are absorbed rapidly. Tolerance to the anxiolytic effects does not seem to be a problem. In sleep disorders the situation is not so clear; studies of subjective sleep quality show enduring efficacy but about half of the objective (EEG) studies indicate decreased effects after 4-8 weeks, implying that some tolerance develops. That said, the necessity for dose escalation in sleep disorders is rare. Dependence. Both animal and human research has shown that brain receptors do change in character in response to chronic treatment with benzodiaze- pines and therefore will take time to return to pre- medication levels after cessation of medication. Features of withdrawal and dependence vary. Commonly there is a kind of psychological depend- ence based on the fact that the treatment works to reduce patients' anxiety or sleep disturbance and therefore they are unwilling to stop. If they do stop, there can be relapse, where original symptoms return. There can be a rebound of symptoms, particularly after stopping hypnotics, where there is a worsen- ing of sleep disturbance for one or two nights, with longer sleep onset latency and increased waking during sleep—this is common. In anxiety disorders there may be a few days of increased anxiety and edginess which then resolves, probably in 10-20% of patients. More rarely, there is a longer withdrawal syndrome characterised by the emergence of symp- toms not previously experienced, e.g. agitation, headache, dizziness, dysphoria, irritability, fatigue, depersonalisation, hypersensitivity to noise and visual stimuli. Physical symptoms include nausea, vomiting, muscle cramps, sweating, weakness, muscle pain or twitching and ataxia. After pro- longed high doses abrupt withdrawal may cause confusion, delirium, psychosis and convulsions. The syndrome is ameliorated by resuming medica- tion but resolves in weeks; in a very few patients it persists, and these people have been the subject of much research, mainly focusing on their per- sonality and cognitive factors. Withdrawal of benzodiazepines should be gradual after as little as 3 weeks' use but for long-term users 401 19 PSYCHOTROPIC DRUGS it should be very slow, e.g. about 0.125 (1/8) of the dose every 2 weeks, aiming to complete it in 6-12 weeks. Withdrawal should be slowed if marked symptoms occur and it may be useful to substitute a long t l / 2 drug (diazepam) to minimise rapid fluctuations in plasma concentrations. Abandonment of the final dose may be particularly distressing. In difficult cases withdrawal may be assisted by concomitant use of an antidepressant. Adverse effects. In addition to those given above, benzodiazepines can affect memory and balance. Hazards with car driving or operating any machinery can arise from amnesia and impaired psychomotor function, in addition to sleepiness (warn the patient). Amnesia for events subsequent to administration occurs with i.v. high doses, for endoscopy, dental surgery (with local anaesthetic), cardioversion, and in these situations it can be regarded as a blessing. 5 Women, perhaps as many as 1 in 200, may expe- rience sexual fantasies, including sexual assault, after large doses of benzodiazepine as used in some dental surgery, and have brought charges in law against male staff. Plainly a court of law has, in the absence of a witness, great difficulty in deciding whom to believe. No such charges have yet been brought, it seems, by a man against a woman. Paradoxical behaviour effects (see above) and perceptual disorders, e.g. hallucinations, occur occasionally. Headache, giddiness, alimentary tract upset, skin rashes and reduced libido can occur. Extrapyramidal reactions, reversible by flumazenil, are rare. Benzodiazepines in pregnancy. The drugs are not certainly known to be safe and indeed diazepam is teratogenic in mice. The drugs should be avoided in early pregnancy as far as possible. It should be remembered that safety in pregnancy is not only a matter of avoiding prescription after a pregnancy has occurred but that individuals on long-term 5 Although one patient, normally a gentle man, believed he was being lied to when told his endoscopy had been performed. 'He assaulted his physician and was calmed only by a second endoscopy.' Later he was very embarrassed and apologised repeatedly (Lurie Y et al 1990 Lancet 336: 576). Another post-dental surgery patient purchased a bone china teaset and later condemned his wife for extravagance. therapy may become pregnant. Benzodiazepines cross the placenta and can cause fetal cardiac arrhythmia, and muscular hypotonia, poor suck- ling, hypothermia and respiratory depression in the newborn. Interactions. All potentiate the effects of alcohol and other central depressants, and all are likely to exacerbate breathing difficulties where this is already compromised, e.g. in obstructive sleep apnoea. Overdose. Benzodiazepines are remarkably safe in acute overdose and the therapeutic dose x 10 induces sleep from which the subject is easily aroused. It is said that there is no reliably recorded case of death from a benzodiazepine taken alone by a person in good physical (particularly respiratory) health, which is a remarkable tribute to their safety (high therapeutic index); even if the statement is not absolutely true, death must be extremely rare. But deaths have occurred in combination with alcohol (which combination is quite usual in those seeking to end their own lives) and from complications of prolonged unconsciousness. Flumazenil selectively reverses benzodiazepine effects and is useful in diagnosis and in treatment (see below). Temazepam is a benzodiazepine that was until recently the most popular hypnotic in the form of a soft gel liquid-filled capsule but, being readily injected, it was widely also abused and the formula- tion was withdrawn. Temazepam is now classed as a controlled drug; it is available as a tablet, with a much longer absorption time and duration of action making daytime hangover effect more likely. Con- sequently it is much less often prescribed. Benzodiazepine antagonist: flumazenil is a com- petitive antagonist at benzodiazepine receptors and it may have some agonist actions, i.e. it is a partial agonist. Clinical uses include reversal of benzo- diazepine sedation after endoscopies, dentistry and in intensive care. Heavily sedated patients become alert within 5 minutes. The t l / 2 of 1 h is much shorter than that of most benzodiazepines (see Table 19.8), so that repeated i.v. administration may be needed. Thus the recovery period needs supervision lest sedation recurs; if used in day surgery it is im- 402 19 INSOMNIA portant to tell patients that they may not drive a car home. The dose is 200 micrograms by i.v. injection given over 15 seconds, followed by 100 micrograms over 60 seconds if necessary, to a maximum of 300-600 micrograms. Flumazemil is useful for diagnosis of self-poisoning and also for treatment, when 100-400 micrograms are given by continuous i.v. infusion and adjusted to the degree of wakefulness. Adverse effects of flumazenil can include brief anxiety, seizures in epileptics treated with a benzo- diazepine and precipitation of withdrawal syn- drome in dependent subjects. Rarely, vomiting is induced. Buspirone (see p. 396). Nonbenzodiazepine hypnotics that act at the GABA A -benzodiazepine receptor Although structurally unrelated to the benzodiaze- pines, these drugs act on the same macromolecular receptor complex but at different sites from the benzodiazepines; their effects can be blocked by flumazenil, the receptor antagonist. Those described below are all effective in insomnia, have low pro- pensity for tolerance, rebound insomnia, withdrawal symptoms and abuse potential but there are few data of their effects in long-term studies. Zopiclone is a cyclopyrrolone in structure. It has a fairly fast (about 1 hour) onset of action which lasts for 6-8 hours, making it an effective drug both for initial and maintenance insomnia. It may cause fewer problems on withdrawal than benzodiazepines. Its duration of action is prolonged in the elderly and in hepatic insufficiency. About 40% of patients experience a metallic aftertaste. Care should be taken with concomitant medication that affects its metabolic pathway (see Table 19.2a). The dose is 3.75-7.5 mg p.o. Zolpidem is an imidazopyridine in structure and has a fast onset (30-60 min) and short duration of action. Patients over 80 years have slower clearance of this drug. Zaleplon is a pyrazolopyrimidine. It has a fast onset and short duration of action. Studies of psycho- motor performance in volunteers have shown that it has no effect on psychomotor skills, including driving skills, when taken at least 5 hours before testing. This means that it can be taken during the night (either when patients have tried getting off to sleep for a long time, or if they wake during the night and cannot return to sleep) without hangover effect. OTHER DRUGSTHAT ACT ONTHE GABA A -BENZODIAZEPINE RECEPTOR Chloral hydrate, clomethiazole and barbiturates also enhance GABA function but at high doses have the additional capacity directly to open the membrane chloride channel (see Figure 19.4); this may lead to potentially lethal respiratory depres- sion and explains their low therapeutic ratio. These drugs also have a propensity for abuse/misuse and are very much second-line treatments. Chloral hydrate has a fast (30-60 min) onset of action and duration of action 6-8 h. It is a prodrug, being rapidly metabolised by alcohol dehydrogenase into the active hypnotic trichloroethanol (t 1 / 2 8h). Chloral is dangerous in serious hepatic or renal failure and aggravates peptic ulcer. Interaction with ethanol is to be expected since both are metabolised by alcohol dehydrogenase. Ethanol also appears to induce the formation of trichloroethanol which attains higher plasma concentrations if alcohol is co-administered, increasing sedation. Triclofos (Tricloryl) and cloral betaine (Welldorm) are related compounds. Clomethiazole is structurally related to vitamin B 1 (thiamine) and is a hypnotic, sedative and anti- convulsant. It is comparatively free from hangover; it can cause nasal irritation and sneezing. Depend- ence occurs and use should always be brief. When taken orally, it is subject to extensive hepatic first- pass metabolism (which is defective in the elderly and in liver damaged alcoholics who get higher peak plasma concentrations), and the usual t l / 2 is 4 h (with more variation in the old than the young); it may also be given i.v. Barbiturates have a low therapeutic index, i.e. relatively small overdose may endanger life; they also cause dependence and have been popular drugs of abuse. The use of intermediate-acting drugs 403 19 PSYCHOTROPIC DRUGS (amylobarbital, butobarbital, secobarbital) is now limited to severe intractable insomnia in patients already taking barbiturates (they should be avoided in the elderly). The long-acting phenobarbital is used for epilepsy (see Chapter 20), and very short-acting thiopental for anaesthesia (see p. 353). Overdose following self-poisoning by hypnotic barbiturates may have severe features including hypotension (may lead to renal failure), hypothermia, respira- tory depression and coma. Supportive measures may suffice with i.v. fluid to restore central venous pressure and so cardiac output and, if that fails, using a drug with cardiac inotropic effect (see p. 457). A good urine volume (e.g. 200 ml/h) promotes elimination of the drug. Urine alkalinisation accele- rates removal of phenobarbital (an acid, pKa 7.2) as do repeated doses of activated charcoal. Active elimination by haemoperfusion or dialysis may be needed in particularly severe and complicated cases. Other drugs used in insomnia Antihistamines. Most proprietary (over the counter) sleep remedies contain antihistamines. Prometha- zine (Phenergan) has a slow (1-2 h) onset and long (t 1 / 2 12 h) duration of action. It reduces sleep onset latency and awakenings during the night after a single dose but there have been no studies showing enduring action. It is sometimes used as a hypnotic in children. There are no controlled studies showing improvements in sleep after other antihistamines. Trimeprazine (alimemazine) is used for short-term sedation in children. Most antihistamine sedatives have a relatively long action and may cause day- time sedation. Antidepressants. In the depressed patient, improve- ment in mood is almost always accompanied by improvement in subjective sleep and therefore choice of antidepressant should not usually involve additional consideration of sleep effects. Never- theless, some patients are more likely to continue with medication if there is a short-term improve- ment, in which case mirtazapine or nefazodone provide an effective antidepressant together with sleep-promoting effects. Antidepressant drugs, particularly those with 5HT 2 -blocking effects, may occasionally be effective in long-term insomnia (but see Table 19.6). Antipsychotics have been used to promote sleep in resistant insomnia occurring as part of another psychiatric disorder, probably due to a combination of 5HT 2 -receptor, o 1 -adrenoceptor and histamine Hj-receptor antagonism, in addition to their primary dopamine antagonist effects. Their long action leads to daytime sedation and extrapyra- midal movement disorders may result from dopa- mine receptor blockade (see p. 380, Antipsychotics). Nevertheless, modern antipsychotics, e.g. quetia- pine, have been occasionally used for intractable insomnia. Melatonin, the hormone produced by the pineal gland during darkness, has been investigated for insomnia but it appears to be ineffective. The impressive nature of the diurnal rhythm in mela- tonin secretion has stimulated interest in its use therapeutically to reset circadian rhythm to prevent jet-lag on long-haul flights and for blind or partially sighted people who cannot use daylight to synch- ronise their natural rhythm. There is controversy about dose and timing of treatment and in most countries pharmaceutical preparations are not generally available. Herbal preparations. Randomised clinical trials have shown some effect of valerian in mild to moderate insomnia, and hops, lavender and other herbal compounds show promise in pilot studies that are presently being pursued more fully. Summary of pharmacotherapy for insomnia • Drug treatment may be effective for a short period (2-4 weeks). • Some patients may need long-term medication. • Intermittent medication, i.e. taken only on nights that symptoms occur, is preferable and may often be possible with modern, short-acting, compounds. • Discontinuing hypnotic drugs is usually not a problem if the patient knows what to expect. There will be a short period (usually 1-2 nights) of rebound insomnia on stopping hypnotic drugs which can be ameliorated by phased withdrawal. 404 19 HYPERSOMNIA Sleep-related breathing disorders causing excessive daytime sleepiness are rarely treated with drugs. Sleepiness caused by the night-time disruption of obstructive sleep apnoea syndrome is sometimes not completely abolished by the standard treatment of continuous positive airway pressure overnight, and the use of wake-promoting drugs, e.g. modafinil, is being evaluated in these patients. Narcolepsy is a chronic neurological disorder and is characterised by excessive daytime sleepiness (EDS), usually accompanied by cataplexy (attacks of weakness on emotional arousal). These symptoms are often associated with the intrusion into wake- fulness of other elements of rapid eye movement (REM) sleep, such as sleep paralysis and hypnagogic hallucinations, i.e. in a transient state preceding sleep. Stimulants are effective in the treatment of EDS due to narcolepsy. Suitable agents include dexamfe- tamine, methylphenidate, and modafinil. Amfetamines release stored neurotransmitters, primarily dopamine and noradrenaline, in the brain. This causes a behavioural excitation, with increased alertness, elevation of mood, increase in physical activity. Dexamfetamine, the dextrorotatory isomer of amfetamine, is about twice as active in humans as the laevo isomer and is the main prescribed amfetamine. It is rapidly absorbed and its duration of action varies among individuals; most people with narcolepsy find twice daily dosing optimal to maintain alertness during the day. About 40% of narcoleptic patients find it neces- sary to increase their dose, indicating tolerance. Although physical dependence does not occur, there is mental and physical depression on withdrawal. Unwanted effects include edginess, restlessness, insomnia and appetite suppression, weight loss, and increase in blood pressure and heart rate. Amphetamines are commonly abused because of their stimulant effect but this is rare in narcolepsy. Methylphenidate releases stored dopamine but most of its action is to inhibit uptake of central neurotransmitters. Its effects and adverse effects are very similar to amphetamines. Methylphenidate has a low systemic availability and slow onset of INSOMNIA action, making it less liable to abuse. Its duration of effect is quite short (3—4 h) so patients with narcolepsy need to plan the timing of their tablets to fit with daily activities. It is also used in attention deficit/hyperactivity disorder (see below). Modafinil is a wake-promoting agent whose specific biochemical mechanism of action is obscure. It increases brain concentrations of dopamine after chronic administration in animals but has no overtly stimulant effect like amphetamines. It appears to have a slow onset and its action lasts 8-12 h; abuse potential is very low. Modafinil is used in narcolepsy and other hypersomnias and has also been studied in normal people who need to stay awake for long periods and function well. In narcolepsy, patients usually need a stimulant for their hypersomnia and a TCA or SSRI for their cataplexy, so care should be taken when combining these. Dexamfetamine and methylphenidate must not be given with MAOIs. There is potential for interaction between methylphenidate and TCAs (hypertension) and SSRI antidepressants. It appears that modafinil, methylphenidate and dexamfeta- mine may themselves be combined without adverse outcome (modafinil is occasionally used regularly and dexamfetamine added intermittently when peak alertness is particularly critical). Modafinil accelerates the metabolism of oral contraceptives, reducing their efficacy. Cataplexy is most effectively treated with 5HT uptake-blocking drugs such as domipmmine or fluoxetine, or some other antidepressant drugs, e.g. reboxetine. PARASOMNIAS Nightmares arise out of REM sleep and are reported by the patient as structured, often stereo- typed dreams that are very distressing. Usually the patient wakes up fully and remembers the dream. Psychological methods of treatment may be appro- priate, e.g. a program of rehearsing the dream, inventing different endings. In a small number of cases where adverse events such as angina have been provoked by recurrent nightmares it may be appropriate to consider drug treatment with an antidepressant with a marked suppressing effect on REM sleep, such as the MAOI, phenelzine. Night- 405 19 PSYCHOTROPIC DRUGS mares of a particularly distressing kind are a feature of post-traumatic stress disorder. Case reports indi- cate benefit from various pharmacological agents but no particular drug emerges as superior. Many prefer to use a 5HT-blocker such as trazodone or nefazodone. Night terrors and sleep-walking arise from slow wave sleep and they are often coexistent. There is usually a history dating from childhood and often a family history. Exacerbations commonly coincide with periods of stress and alcohol will increase their likelihood. In a night terror patients usually sit or jump up from deep sleep (mostly early in the night) with a loud cry, look terrified and move violently, sometimes injuring themselves or others. They appear asleep and uncommunicative, often return- ing to sleep without being aware of the event. These terrors are thought to be a welling-up of anxiety from deep centres in the brain which is normally inhibited by cortical mechanisms. They can occur in up to 30% of normal children but become trouble- some and often dangerous in adults. They can be successfully treated with the benzodiazepine, clonazepam or the SSRI, paroxetine. Nocturnal panic attacks may be distinguished from night terrors by the fact that the patient will wake fully before panic symptoms have reached a peak and is fully aware. REM behaviour disorder, first described by in 1988, consists of lack of paralysis during REM sleep which results in acting out of dreams, often vigorously with injury to self or others. It can occur acutely as a result of drug or alcohol withdrawal but its chronic manifestation can be idiopathic or associated with neurological disorder (about 50% of each). It is much commoner among older patients. Successful treatment has been described with clonazepam or clonidine which decrease REM sleep without increasing awakenings. OTHER SLEEP DISORDERS Restless legs syndrome (RLS) is a disorder that usually occurs prior to sleep onset and is character- ised by disagreeable sensations, that cause an almost irresistible urge to move the legs. The sensation is described as 'crawling', 'aching', 'tingling' and is partially or completely relieved with leg motion, returning after movement ceases. Most if not all patients with this complaint also have periodic limb movements disorder (PLMD), which may occur independently of RLS. These periodic limb move- ments consist of highly stereotyped movements, usually of the legs, that occur repeatedly (typically every 20-40 seconds) during the night. They may wake the patient, in which case there may be a complaint of daytime sleepiness or occasionally insomnia, but often only awaken the sleeping partner, who is usually kicked. RLS and PLMS are considered to be movement disorders and may respond to formulations of levodopa but dopamine agonists, e.g. ropinirole, and other treatments such as gabapentin are under investigation Sleep scheduling disorders. Circadian rhythm disorders are often confused with insomnia and both can be present in the same patient. With such sleep scheduling disorders, sleep occurs at the 'wrong' time, i.e. at a time that does not fit with work, social or family commitments. A typical pattern may be a difficulty in initiating sleep for a few nights due to stress, whereupon once asleep the subject continues sleeping well into the morning to 'catch up' the lost sleep. Thereafter the 'time since last sleep' cue for sleep initiation is delayed and the sleep period gradually becomes more delayed until the subject is sleeping in the day instead of at night. A behavioural program with strategic light exposure is appropriate, with pharmacological treatment as an adjunct, e.g. melatonin, to help reset the sleep-wake schedule. Drugs for Alzheimer's 6 disease (dementia) Dementia is described as a syndrome 'due to disease of the brain, usually of chronic or progressive nature in which there is disturbance of multiple higher cortical functions, including memory, think- ing, orientation, comprehension, calculation, learn- ing capacity, language and judgement, without clouding of consciousness.' 7 Deterioration in 406 [...]... for Psychopharmacology guidelines Journal of Psychopharmacology 14: 3-20 Ballenger J C et al 1998 Consensus statement on panic disorder from the International Consensus Group on Depression and Anxiety Journal of Clinical Psychiatry 59: 47-54 Ballenger J C et al 1998 Consensus statement on social anxiety disorder from the International Consensus Group on Depression and Anxiety Journal of Clinical Psychiatry... C et al 2000 Consensus statement on posttraumatic stress disorder from the International Consensus Group on Depression and Anxiety Journal of Clinical Psychiatry 61: 60-66 Ballenger J C et al 2001 Consensus statement on generalized anxiety disorder Journal of Clinical Psychiatry 62: 53-58 Davies S J C et al 1999 Association of panic disorder and panic attacks with hypertension American Journal of Medicine... differential effects of serotonin selective reuptake SKILLED TASKS 19 inhibitors on cytochrome P450 enzymes Journal of Psychopharmacology 12: Supp B S89-S97 Roth T et al 2001 Consensus for the pharmacological management of insomnia in the new millennium International Journal of Clinical Practice 55: 42-52 Sack R L et al 1997 Sleep-promoting effects of melatonin: at what dose, in whom, under what conditions... rivastigmine is considered 'pseudo-irreversible' since inhibition lasts several hours Galantamine is associated both with reversible inhibition and with enhanced acetylcholine action on nicotinic receptors.8 Clinical trials show that these agents produce an initial increase in patients' cognitive ability There may be associated global benefits, including improvements in noncognitive aspects such as depressive... in acetylcholine production with decline in cognition 6 Alois Alzheimer (1864-1915) German psychiatrist who studied the brains of demented and senile patients and correlated hisological findings with clinical features 7 ICD-10 diagnostic system 8 Irreversible antagonists exist but, not surprisingly, have no place in therapeutics (sarin nerve gas is an example) 19 The beneficial effects of drugs are... Kryger M H et al (eds) 2000 Principles And Practice Of Sleep Medicine, Third Edition Philadelphia: W B Saunders Kuperberg G R, Murray R 1996 Advances in the treatment of schizophrenia British Journal of Clinical Practice 50: 315-323 Mayeux R, Sano M 1999 Treatment of Alzheimer's disease New England Journal of Medicine 341: 1670-1679 Nelson J C 1997 Treatment of refractory depression Depression and Anxiety... monitor progress Given the limited evidence of overall benefit in relation to cost, the use of these drugs is the subject of debate but there follows a practical position The UK National Institute for Clinical Excellence (NICE) recommends that donepezil, galantamine and rivastigmine should be available as adjuvant therapy for those with a MMSE score above 12 points, subject to the following conditions: . revision of the 1993 British Association for Psychopharmacology guidelines. Journal of Psychopharmacology 14: 3-20 Ballenger J C et al 1998 Consensus . Journal of Clinical Psychiatry 61: 60-66 Ballenger J C et al 2001 Consensus statement on generalized anxiety disorder. Journal of Clinical Psychiatry