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 p
Trang 1treatment 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
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
Trang 2they 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 ICD4 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
Trang 3A 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
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.
Trang 4bedroom 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 GABAA-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
Trang 5TABLE 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 pre-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
Trang 6it 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
Trang 7im-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 (t1/2 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 tl / 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
Trang 8(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
(t1/2 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
5HT2-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 5HT2-receptor, o1-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
Trang 9Sleep-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
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
Trang 10Night-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 bereturn-ing 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 movemove-ments, 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's6
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