Download An update on sleep disorders and their treatment

CMHP Review Sleep_Layout 1 26/09/2013 11:19 Page 1
Sleep disorders
z Review
An update on sleep disorders and their
treatment
Michele Sie GPhC, MCMHP
In the third of this series of updated reviews on the major psychiatric drug groups,
produced in association with the College of Mental Health Pharmacy (CMHP;
www.cmhp.org.uk), Michele Sie describes the main types of sleep disorder and their
features, and provides an overview of their treatment.
S
leep is a fundamental necessity that is required by
all of us. Sleep requirements vary with age and
between individuals but in general the average
requirement for a healthy adult is between seven and
eight hours of sleep per night.1
Sleep is divided into two types. Rapid eye movement (REM) sleep and non-rapid eye movement
(non-REM) sleep. REM sleep, as the name suggests,
is characterised by rapid movements of the eyes, while
in non-REM sleep there is little or no movement of
the eyes and any eye movement is slow.2
The five stages of sleep
There are five stages of sleep.3 Stage 1 is superficial
sleep and only lasts for about five to ten minutes. It is
the transition from being awake to going to sleep. Body
movement slows down, there is some loss of muscle
tone and there may be twitching or sudden myoclonic
jerks. During this time it is easy to be aroused.
Stage 2 is light sleep and accounts for around 50
per cent of sleep in adults. Muscle movement
decreases, eye movements stop, heart rate slows and
the body temperature can drop. This stage lasts about
20 minutes.
Stage 3 is the start of deep or slow wave sleep. Stage
4 is also deep or slow wave sleep, lasts for around 30
minutes and is the restorative period of sleep. During
this stage it is hard to be aroused and if woken then
a period of disorientation and sedation often occur.
Stage 5 is REM sleep. It occurs rapidly after stage
4 and accounts for around 25 per cent of sleep in
adults. During REM sleep, there is increased brain
activity and dreaming occurs. It is believed that processing and consolidating of information and emotions occur while in REM sleep. During this time,
heart rate and respiration increase and atonia occurs
causing a temporary paralysis.
These five stages of sleep make up the sleep cycle,
which lasts for about 90 minutes. This cycle is generally repeated five to six times each night.
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• Have a good bedtime routine, go to bed and get up
at the same time every day and avoid daytime naps
• Avoid stimulants such as caffeine, nicotine, chocolate
and alcohol six hours before bedtime
• Take regular exercise during the day, but avoid
strenuous exercise within four hours of bedtime
• Avoid large meals close to bedtime
• Associate your bed with sleep. Do not watch TV or
listen to music when retiring to bed
• The bedroom should be a quiet, relaxing place to
sleep; make sure the room is not too hot or too cold
• If after 30 minutes you cannot get off to sleep then
get up. Leave the bedroom and try to do something
else, return to bed when sleepy. This can be
repeated as often as necessary until you are asleep
Table 1. Sleep hygiene advice for patients
Neurotransmitter involvement
There are a number of neurotransmitters that have
been implicated in the sleep-wake cycle. During wakefulness there is high activity of histaminergic, noradrenergic and serotonergic neurones. This activity
slows down during non-REM sleep and nearly stops
during REM sleep, suggesting that these neurotransmitters have a role to play in promoting an awake
state. Cholinergic activity is also high in wakefulness,
and although it slows during non-REM sleep, it
increases in activity during REM sleep, suggesting a
role in not only maintaining an awake state but also
possibly in dreaming. Adenosine is considered to be
a mediator of non-REM sleep, and dopamine may
play a role in the transition from sleep to wakefulness. 4 Gamma-aminobutyric acid (GABA), the
inhibitory neurotransmitter, helps induce relaxation
and sleep.5 Melatonin is a naturally occurring hormone, produced by the pineal gland, which regulates
the circadian rhythm of sleep. It starts being released
once it becomes dark, and continues to be released
until the first light of day. It has been shown that melatonin release decreases with age.6 Orexins, produced
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Review z Sleep disorders
in hypothalamic neurones, also have an important
role in regulating the sleep-wake cycle and deficiencies have been identified in narcolepsy.7
Types of sleep disorder
Sleep disorders are defined as conditions characterised
by disturbances of usual sleep patterns or behaviours,
that cause distress and impair daytime functioning.
The International Classification of Diseases version 10
(ICD-10)8 has two main diagnostic categories – sleep
disorders and non-organic sleep disorders. Further
classification includes insomnias (disorders of initiatMedication
ing and maintaining sleep), hyersomnias (disorders of
excessive somnolence), sleep apnoea, narcolepsy and
cataplexy, restless legs syndrome, sleep walking, sleep
terrors and nightmare disorder.8
The prevalence of sleep disorders is hard to quantify, as problems with sleep may be a symptom of
another condition. It has been estimated that the
prevalence of sleep disorders in the general population could be as high as 37 per cent,9 with sleep disorders of clinical significance and public health
importance occurring in 10 per cent of the population.10 Insomnia is the most commonly reported sleep
Available
as
Form
available
Half-life,
Licensed indication
hrs (adults)
Tolerance Dependence
Diazepam
Generic
21-50
Insomnia (short-term use)
Yes
Yes
Loprazolam
Lorazepam
Lormetazepam
Nitrazepam
Generic
Generic
Generic
Generic
10
12-16
10
18-36
Insomnia (short-term use)
Insomnia (short-term use)
Insomnia (short-term use)
Insomnia (short-term use)
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Temazepam
(Schedule 3
controlled drug)
Generic
Tablets,
solution
Tablets
Tablets
Tablets
Tablets,
suspension
Tablets,
oral
solution
5-11
Insomnia (short-term use)
Yes
Yes
Insomnia (short-term use
up to 2 weeks)
Insomnia (short-term use
up to 4 weeks)
Insomnia (short-term use
up to 4 weeks)
Yes
Yes
Yes
Yes
Yes
Yes
Benzodiazepines
Z-hypnotics
Zaleplon
Sonata
Capsules
2
Zolpidem
Generic
Tablets
2-3
Zopiclone
Generic
Tablets
3.5-6
Generic
Welldorm
Mixture
Tablets,
elixir
8-10
7-10
Insomnia (short-term use)
Insomnia (short-term use)
Yes
Yes
Yes
Yes
Circadin
Modifiedrelease
tablets
Capsules,
3.5-4
Insomnia in adults over
55 years (short-term use)
No
No
4-5
Severe insomnia in elderly Yes
(short-term use)
Sedation and insomnia
Yes
(short-term use)
Yes
Chloral and derivatives
Chloral hydrate
Cloral betaine
Others
Melatonin
Clomethiazole
Promethazine
(antihistamine)
Phenergan
Tablets,
elixir
10-19
No
*Refers to the active metabolite
Table 2. Treatments for insomnia and their licensed indications25
16
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Sleep disorders
disorder, followed by sleep apnoea and then restless
legs syndrome.10 Sleep disorders have been associated with a number of adverse effects including
increased risk of road traffic accidents,11 medical
errors,12 industrial accidents,13 obesity, type 2 diabetes, 14 hypertension, 15 heart disease 16 and a
decrease in performance and functioning.17
Insomnias
Insomnias are disorders of initiating and maintaining
sleep, leading to an inadequate quantity or quality of
sleep or both. Problems can include difficulty falling
asleep, difficulty staying asleep, or early morning wakening, which can lead to fatigue and impairment of
cognitive function during waking hours.13 Insomnia is
a common symptom of many mental disorders (nonorganic) including mania and depression18 and can
also present in physical conditions (organic) such as
pain and asthma.19,20 Insomnia affects around 20 per
cent of the adult population and can be either transient, occurring in those who normally sleep well, as
a result of exceptional circumstances such as shift
work; short term, caused by emotional problems or a
serious medical condition; or chronic, relating to an
enduring physical or mental health condition.18 It can
lead to a significant impairment in quality of life and
affects the functioning and mental health of those
affected. 21 Economic implications of insomnia
include costs relating to absenteeism and decreased
productivity, as well as increased use of the GP.22
Treatment of insomnias
Non-pharmacological approaches are recommended
as first-line treatment of insomnia23 including sleep
hygiene18,24 (see Table 1), encouraging the use of
techniques to promote and maintain sleep. For
chronic insomnia, cognitive behavioural therapy
(CBT), stimulus control therapy, sleep restriction and
progressive muscle relaxation are recommended first
line as they have been shown to be as effective as pharmacotherapy and, unlike medication, the beneficial
effects of CBT may last beyond the active treatment
phase.23 If insomnia is a symptom of a mental or physical condition then the precipitating cause should be
treated effectively – this often leads to a resolution of
the insomnia. If these techniques are ineffective then
a hypnotic medication may be considered.18 A short
course of a z-hypnotic (zaleplon, zolpidem, zopiclone) is recommended first line for the management
of insomnia precipitated by a life stressor that is
expected to resolve in the near future.23
A number of different classes of medication are
licensed as hypnotics. These include benzodiazepines,
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z Review
Mild
• rebound anxiety and insomnia
• sleep disturbance
• irritability
• panic attacks
• tremor
• sweating
• poor concentration
• dry retching and nausea
• palpitations
• headache
• muscular pain and stiffness
Moderate
• perceptual changes, eg hypersensitivity to light or
sound
• generalised feelings of distress
• flu-like symptoms
• sore eyes
• decreased appetite and weight loss
• depression
• depersonalisation
• abnormal sensations of movements
Severe (rare)
• seizures
• psychotic symptoms
Table 3. Symptoms of benzodiazepine withdrawal syndrome36
z-hypnotics, chloral derivatives, clomethiazole, antihistamines and melatonin.25 Benzodiazepines, z-hypnotics, chloral derivatives and clomethiazole all act
by binding to the GABAA receptor and enhancing the
effect of GABA.26,27 Activation of this receptor leads
to an influx of chloride ions into the neurone reducing its excitability, thereby reducing activity in the
brain. This results in sedation, helping to induce
sleep. Antihistamines that act as antagonists at the H1receptor and cross the blood-brain barrier cause sedation. 28 Melatonin, as previously discussed, is a
naturally occurring hormone, produced by the pineal
gland, which regulates the circadian rhythm of sleep.6
Hypnotics decrease time to sleep onset and
episodes of waking in sleep as well as increasing total
sleep time.29 They can also affect the architecture
(length of stages) of sleep. Benzodiazepines suppress
stages 3 and 4 of sleep, but only cause a slight decrease
in REM sleep. Z-hypnotics shorten stage 1 of sleep
and prolong stage 2 of sleep but have little effect on
stages 3, 4 and REM sleep. Chloral derivatives do not
affect sleep architecture.26,27 Melatonin promotes
sleep initiation and helps to reset the circadian clock,
allowing uninterrupted sleep. It has also been shown
to improve next day functioning.30
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Review z Sleep disorders
Most medications used to treat insomnia can cause
tolerance and dependence (see Table 2).25 Tolerance
occurs following continued administration of a medication and is characterised by a decrease in susceptibility to the medicinal effects.31 Tolerance has been
observed with all currently licensed hypnotics with the
exception of melatonin. Dependence occurs when
there is a need to take repeated doses of a medication
to maintain wellbeing or to prevent withdrawal symptoms and can be psychological, physical or both.32
Psychological dependence is a craving or compulsion
to continue using the medication to maintain a feeling of wellbeing. Physical dependence is the need to
continue taking medication to prevent physical withdrawal effects. Withdrawal syndrome is most often associated with the benzodiazepines33 (see Table 3), but
withdrawal symptoms have also been documented with
chloral derivatives, clomethiazole and z-hypnotics.34,35
To reduce the risk of dependence and tolerance, it
is recommended that hypnotics are only used in severe
and disabling insomnia, which is causing extreme distress. For transient insomnia, only one or two doses
should be given and for short-term insomnia, hypnotics
should only be used for a limited course of up to three
weeks, preferably intermittently. In chronic insomnia,
hypnotics are rarely beneficial and the underlying illness needs to be managed.25 If hypnotics that cause a
withdrawal syndrome are used for more than three
weeks they should be withdrawn slowly. For those wishing to withdraw from long-term, short-acting benzodiazepines, switching to diazepam, a long-acting
benzodiazepine, can be useful (see Table 4). Diazepam
can then be reduced slowly, for example by one-eighth
of the daily dose every fortnight.25,33,36
NICE carried out a Technology Appraisal on the
newer hypnotics in 200424 and reported that there was
a lack of compelling evidence to distinguish between
the z-hypnotics and the shorter-acting benzodiazepine
hypnotics and concluded that prescribing decisions
should be made on a cost basis. They recommended
that patients who had not responded to either a benzoBenzodiazepine
Approximate equivalent
dose to diazepam 5mg
Chlordiazepoxide
Loprazolam
Lorazepam
Lormetazepam
Nitrazepam
Oxazepam
Temazepam
15mg
0.5-1mg
0.5-1mg
0.5-1mg
5mg
15mg
10mg
Table 4. Diazepam equivalent doses25,36
18
diazepine or a z-hypnotic should not be prescribed the
other. Switching between these two classes of hypnotics
should only occur if the adverse effects experienced
could be directly related to a specific agent.24
The therapeutic use of some older hypnotics has
also been questioned. Chloral derivatives are now considered less suitable for prescribing due to their adverse
effects and abuse potential and clomethiazole is only
recommended for use in insomnia in those over 55
years of age.25 Clomethiazole only has evidence to support its use in this age group when other hypnotics have
failed, although it is rarely used now due to the risk of
accidental overdose and respiratory depression.25
Some hypnotics cause a hangover effect, i.e. sedation and impairment of psychomotor performance,
including driving ability and memory on the following
day. To avoid this, it is recommended that medications
with a short half-life of between four and six hours
should be used. Medications with shorter half-lives than
this can give rise to early morning wakening.36
Excessive daytime sleepiness, hypersomnia and
narcolepsy
Excessive daytime sleepiness occurs in about 3-5 per
cent of the population and can be caused by poor
sleep quality and duration due to either a concurrent
sleep, mental health or medical disorder.
Hypersomnia is characterised by excessive daytime
sleepiness or daytime sleep episodes that cause severe
distress or impairment in functioning and occur
almost daily but are not part of a concurrent sleep,
mental health or medical disorder. It is hard to quantify the prevalence of hypersomnia as symptoms of
excessive daytime sleepiness can occur with any sleep
disorder that causes a loss of night-time sleep.18
Narcolepsy, a condition that normally presents with
excessive daytime sleepiness, can be distinguished from
other sleep disorders by the presence of cataplexy (a
sudden and transient loss of muscle tone, while awake,
usually triggered by strong emotions such as laughing),
sleep paralysis and sleep-related hallucinations. These
symptoms are believed to be characteristics of REM
sleep, which do not normally occur during the awake
state. Narcolepsy is reported to affect around 0.05 per
cent of the population and normally begins between
the ages of 10 and 20 years.18,37 Recent evidence has
suggested a strong correlation between decreased levels of orexins (also called hypocretins) and narcolepsy.38
Treatment of excessive daytime sleepiness, hypersomnia and
narcolepsy
Excessive daytime sleepiness should be managed by
treating the underlying cause.37 Guidance from the
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Sleep disorders
Treatment
Modafinil
Sodium oxybate
Methylphenidate
Dexamfetamine
Selegiline
Tricyclic
antidepressants†
SSRIs
Venlafaxine
Reboxetine
Licensed for
narcolepsy
z Review
Shown to be effective in: *
Daytime
sleepiness
Disrupted
sleep
Cataplexy
Sleep-related
hallucinations
Sleep paralysis
Yes
Yes
No
Yes
No
No
Yes
Yes
Yes
Yes
Maybe
No
No
Yes
No
No
No
No
No
Yes
No
No
Maybe
Maybe
No
Maybe
No
No
Maybe
Maybe
No
Maybe
No
No
Maybe
Maybe
No
No
No
No
No
No
No
No
No
Maybe
Maybe
Maybe
Maybe
Maybe
Maybe
Maybe
Maybe
Maybe
* Yes = there is evidence provided by randomised trials or meta-analysis of randomised controlled trials; maybe = there is
evidence provided by poorly conducted case-control or cohort studies, case series or expert opinion
† Clomipramine is licensed for the adjuctive treatment of cataplexy associated with narcolepsy
Table 5. Treatment options for the symptoms of narcolepsy39
American Academy of Sleep Medicine39 recommends
treatment options for hypersomnia and narcolepsy
based on the current evidence available. For hypersomnia, modafinil may be effective for the treatment
of daytime sleepiness due to idiopathic hypersomnia,
Parkinson’s disease, multiple sclerosis or myotonic
dystrophy. Methylphenidate may also be effective for
the treatment of daytime sleepiness due to myotonic
dystrophy. Lithium carbonate may be effective for
treatment of recurrent hypersomnia. None of these
treatments are licensed for hypersomnia and their
use would be off-label. The American Academy of
Sleep Medicine also recommends a number of treatment options for the different symptoms experienced
in narcolepsy (see Table 5).
The pharmacology of narcolepsy treatments4,39-42
The stimulants dexamfetamine and methylphenidate
block the reuptake of, and enhance the release of,
noradrenaIine, dopamine and serotonin, all of which
could be responsible for their wake-promoting effects.
These stimulants have been shown to increase arousal,
decrease sleepiness, increase latency to sleep and produce a severe decrease in REM sleep. The mode of
action of sodium oxybate (the sodium salt of gamma
hydroxybutyrate) is unclear. It has been shown to
reduce the number of episodes of cataplexy and daytime napping, to improve excessive daytime sedation,
with restoration of fragmented sleep, as well as increase
the duration of stage 3 and 4 non-REM sleep. Although
the mode of action of modafinil is unclear, it may act
by blocking dopamine and noradrenaline reuptake as
well as increasing dopamine, serotonin, glutamate and
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histamine release. It may also activate orexin neurones
and reduce GABA. Modafinil increases wakefulness
and latency to sleep, as well as reducing non-REM and
REM sleep. Dexamfetamine, methylphenidate and
sodium oxybate all have abuse potential and this has
led to modafinil (which has less abuse potential) being
the first-line treatment for narcolepsy.
Obstructive sleep apnoea
The most common sleep-related breathing disorder is
obstructive sleep apnoea, occurring in approximately
3-7 per cent of men and 2-5 per cent of women. It is
more likely to occur in patients with cardiac or metabolic disorders. Risk factors include obesity, upper airway abnormalities, male gender, menopause and age.
It is characterised by loud snoring, followed by apnoea
(a period of silence, when breathing ceases due to complete airway obstruction), which can last up to 90 seconds. Following each apnoea there is a wakening
episode and these episodes occur many times during
the night, although those affected do not normally
recall these arousals. This interrupted night-time sleep
leads to excessive daytime sleepiness, which in turn
affects quality of life and alters social, familial and professional performance.43 Treatment for this condition
includes lifestyle changes such as weight loss, smoking
cessation and avoidance of alcohol. Sedatives and sleeping tablets at night are not recommended as these can
decrease dilation of the airways, thus worsening the
condition. Obstructive sleep apnoea may also be treated
with continuous positive airway pressure (CPAP), which
forces air into the lungs via a face mask, keeping the
airways open and preventing the apnoea.44
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Restless legs syndrome
Restless legs syndrome is a neurological disorder associated with pain or paraesthesia in the legs that is temporarily relieved by movement; it is often
accompanied by periodic limb movements during
sleep. The prevalence of the disorder has been
reported to be up to 10 per cent and it occurs more
frequently in women and those over 65 years of age.
Restless legs syndrome expresses a circadian rhythm,
being worse in the evening and at night and easing
in the morning. It is caused by a decrease in
dopamine function in the CNS.13,45
As expected, dopaminergic agonists have been
shown to alleviate the symptoms of restless legs syndrome in 70 to 100 per cent of patients and are the
first-line treatment option. Ropinirole, pramipexole
and rotigotine are all licensed for the treatment of
moderate to severe restless legs syndrome. 46
Bromocriptine, cabergoline and pergolide are not
recommended due to the risk of heart valve damage.45 Levodopa has also been shown to be effective
but around 80 per cent of patients develop rebound,
in which symptoms return within a few hours following administration, or augmentation, in which symptoms occur earlier in the evening, prior to treatment.
The dopaminergic agonists may also cause rebound
and augmentation but to a lesser extent than levodopa.47 There is limited evidence for the use of opioids, gabapentin, pregabalin, carbamazepine and
clonidine, but it is unclear if the benefit/harm balance is advantageous. 45
Medicines associated with causing or exacerbating restless legs syndrome include some antidepressants, antipsychotics and sedating antihistamines. If
these medicines are prescribed in those presenting
with symptoms of restless legs syndrome, consideration should be made to reducing and stopping where
possible or switching to an alternative agent.45,48
Sleep walking, sleep terrors and nightmare disorder
Sleep walking, sleep terrors and nightmare disorder
are all types of parasomnias. Parasomnias are
described as abnormal behavioural or physiological
events occurring in association with sleep, specific
sleep stages or sleep-wake transitions.18 They are classified into two groups: disorders of REM sleep or disorders of non-REM sleep, as outlined below.
Disorders of REM sleep
Nightmare disorder is characterised by repetitive, frightening dreams, occurring during REM sleep, which
lead to the patient waking and becoming fully alert.
Those affected often have a lingering sense of fear or
20
anxiety that can cause difficulty in returning to sleep,
leading to significant distress that may or may not
affect daytime functioning.18 Between 2 and 5 per cent
of the adult population suffer from frequent nightmares and these may be idiopathic or part of posttraumatic stress disorder (PTSD).49 Some medications
may be associated with nightmares including baclofen,
clarithromycin, beta-blockers and corticosteroids, and
these should be avoided.25,36 For nightmares related
to PTSD, prazosin, an alpha-adrenoceptor blocker, has
been shown to be effective in reducing nightmare frequency, although it must be taken long-term as on cessation nightmares commonly recur. Clonidine, an
alpha2-adrenergic receptor agonist, has a small evidence base for reducing nightmares in refugees at a
dose of 0.2-0.6mg daily in divided doses and may be
an option if prazosin is not effective.50
For idiopathic nightmares, CBT, including systematic desensitisation, lucid dreaming techniques and
image rehearsal therapy have been shown to be effective in reducing nightmare frequency.49,50 There is
no effective pharmacological treatment for idiopathic
nightmares.
REM sleep behaviour disorder occurs when there is a
loss of the muscle atonia that normally occurs in REM
sleep. This leads to motor activity, generally in response
to a nightmare of being attacked or chased, which can
often be of an unexpected and violent nature. If
awoken, there is vivid recall of the dream.18 It can lead
to accidental injury to oneself or one’s partner. The
prevalence is estimated to be around 0.5 per cent of the
population. It is more common in older males and may
be a prodromal symptom of a neurological disease such
as Parkinson’s disease or Lewy body dementia. It has
been reported as an adverse effect of paroxetine, fluoxetine and impipramine in combination, venlafaxine,
mirtazapine and beta-blockers.51 Clonazepam, 0.52.0mg at bedtime, has been shown to resolve or substantially reduce symptoms in up to 90 per cent of those
treated, but long-term treatment is required as symptoms often return on cessation of clonazepam.52 It
should be used with caution in patients with dementia,
gait disorders or concomitant obstructive sleep apnoea.
Melatonin, at a dose of 3-12mg at bedtime, has also
been shown to be effective in treating this disorder.51
Disorders of non-REM sleep
Sleep terror disorder (night terrors) is characterised by
episodes of disruption of sleep that usually begin with
a fearful scream or cry. There may be signs of arousal
such as sitting up in bed with the eyes open, increased
heart rate, rapid breathing and sweating, but the individual remains in a deep sleep and is hard to awaken
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Sleep disorders
Medication
Common side-effects
Treatments for insomnia
Benzodiazepines
Drowsiness, sedation, blurred vision, unsteadiness and ataxia all of which may persist the
following day
Clomethiazole
Sedation, nasal congestion and irritation, gastrointestinal disturbances
Cloral and derivatives
Gastric irritation, nausea and vomiting, abdominal distention, flatulence, headache,
tolerance, dependence, excitement, delirium, ketonuria, rash
Melatonin
Headache, pharyngitis, back pain, asthenia
Promethazine
Drowsiness, dizziness, restlessness, headaches, nightmares, tiredness, disorientation, blurred
vision, dry mouth, urinary retention
Z-hypnotics
Drowsiness, mild bitter or metallic after-taste (with zopiclone only), gastrointestinal
disturbances, nausea and vomiting, dizziness, headache, dry mouth
Treatments for hypersomnia and narcolepsy
Dexamfetamine
Palpitations, tachycardia, increased blood pressure, overstimulation, restlessness, dizziness,
insomnia, euphoria, dyskinesia, dysphoria, tremor, headache, dry mouth, unpleasant taste,
diarrhoea, constipation, anorexia and weight loss, growth retardation in children
Methylphenidate
Abdominal pain, nausea, vomiting, dyspepsia, dry mouth, anorexia, reduced weight gain,
tachycardia, palpitation, arrhythmias, changes in blood pressure, cough, tics, insomnia,
nervousness, weakness, depression, irritability, aggression, headache, drowsiness, dizziness,
fever, arthralgia, rash, pruritus, alopecia
Modafinil
Headache, dizziness, somnolence, paraesthesia, blurred vision, constipation, dry mouth,
decreased appetite, abdominal pain, nausea, diarrhoea, dyspepsia, nervousness, insomnia,
anxiety, depression, abnormal thinking, confusion, weakness, tachycardia, palpitations, chest
pain, vasodilatation, abnormal liver function tests
Reboxetine
Constipation, dizziness, dry mouth, insomnia, sweating
SSRIs
Anxiety or restlessness, insomnia, diarrhoea, nausea and vomiting, loss of appetite
Selegiline
Nausea, constipation, diarrhoea, dry mouth, postural hypotension, dyskinesia, vertigo,
sleeping disorders, confusion, hallucinations, arthralgia, myalgia, mouth ulcers
Sodium oxybate
Nausea, vomiting, diarrhoea, abdominal pain, anorexia, hypertension, peripheral oedema,
fainting, sleep disorders, confusion, disorientation, paraesthesia, hypoesthesia, impaired
attention, depression, drowsiness, anxiety, dizziness, headache, tremor, asthenia, fatigue,
urinary incontinence, nocturnal enuresis, arthralgia, muscle cramps, blurred vision and
sweating.
Requires re-titration if a treatment interval of 14 days or more
Tricyclic antidepressants
Drowsiness, blurred vision, dry mouth, constipation, urinary retention, weight gain
Venlafaxine
Gastrointestinal disturbances, constipation, diarrhoea, nausea, headache, dizziness,
insomnia, sweating, anxiety
Treatment for restless leg syndrome
Dopamine agonists
Abnormal dreams, insomnia, dizziness, headache, somnolence, constipation, nausea and
vomiting
Treatment for PTSD-related nightmares
Prazosin
Dizziness, drowsiness, headache, fainting, depression, nervousness, vertigo, palpitations,
oedema, nasal congestion, blurred vision, constipation, diarrhoea, dry mouth, urinary
frequency, nausea, vomiting, rash, lack of energy, weakness
Table 6. Common side-effects of medications used to treat sleep disorders25
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Review z Sleep disorders
or comfort. The episodes occur during stage 3 and 4
of non-REM sleep and can last up to 10 minutes,
before the individual calms down and returns to sleep.
Unlike nightmares, there is no recall of the episode
the following morning. In childhood, the prevalence
of sleep terrors is between 1 and 6 per cent, and it is
more common in boys. In children, the disorder usually resolves spontaneously by adolescence. In adults,
the prevalence is less than 1 per cent, with episodes
generally beginning between the ages of 20 and 30
years, and the disorder being of a chronic nature.
There is often a family history of sleep terrors or sleep
walking. Fever and lack of sleep have been shown to
increase the frequency of sleep terror episodes.53
Sleep walking disorder is characterised by episodes of
complex motor behaviour initiated during sleep,
including rising from bed, walking about, eating and
talking. An episode is accompanied by reduced alertness and responsiveness and the individual can be hard
to awaken. An episode can either spontaneously end in
arousal with brief confusion, or the individual returns
to bed and sleeps until morning with no recall of the
episode on awakening. Episodes also occur during
stage 3 and 4 of non-REM sleep and can last from a few
minutes to half an hour. The prevalence in children is
between 1 and 5 per cent and, like sleep terrors, the
disorder normally resolves during adolescence. It is
rare for episodes to occur for the first time in adults,
and if they do this may be associated with a sleeprelated breathing disorder, hyperthyroidism, personality disorder, mood disorder or anxiety disorder.53
Sleep terrors and sleep walking are more likely to
occur near the beginning of sleep whereas nightmares are more likely to occur later in the night.53
Treatment of sleep terror and sleep walking disorders
Non-pharmacological treatments are the first-line
option for these conditions, including reduction of
trigger factors such as stress, fever and sleep deprivation.53 Some medications may cause sleep disorders as an adverse effect. An association between
z-hypnotics and sleep walking has been documented
and dexamfetamine, oxybutynin and ethosuximide
may cause night terrors.25 It is also important to
ensure a safe environment to reduce the risk of causing injury during an episode, including secure locks
on doors and windows, and heavy curtains to protect
windows. A consistent bedtime routine should be
maintained to reduce the risk of sleep deprivation,
which may further worsen episodes.53
Medication is rarely indicated, particularly in children, unless the disorder is of a severe nature causing distress and loss of daytime functioning. There
are reports of imipramine, nortriptyline, sertraline,
22
paroxetine, carbamazapine, diazepam and valproate
semisodium, all at low doses, being successful at managing both sleep terror and sleep walking disorders,
but there is a lack of controlled studies to confirm
their effectiveness.53
Other sleep disorders
Sleep disorders may also relate to either another mental health disorder or general medical condition, or may
be substance-induced. These sleep disorders are mainly
managed by optimising the treatment of the underlying mental health or physical health condition, or withdrawing the substance causing the sleep disorder.18
Future developments
There are a number of treatments currently being
investigated in phase 2 and 3 clinical trials including: pitolisant, a histamine H3- receptor inverse agonist, for the treatment of narcolepsy, cataplexy and
excessive daytime sleepiness, and ‘ADX-N05’ also for
the treatment of narcolepsy and excessive daytime
sleepiness. Tasimelteon, a melatonin MT1 and MT2receptor agonist, is currently waiting approval of
FDA for the treatment of non-24-hour sleep-wake
disorder, a circadian rhythm disorder that affects the
majority of totally blind individuals who lack light
perception and who therefore cannot entrain their
master body clock to the 24-hour day. Armodafinil,
the r-enantiomer of modafinil, a stimulant for the
management of narcolepsy and shift work sleep disorder, has been approved in the USA. Development
of almorexant, an orexin OX1 and OX2-receptor
antagonist, for the treatment of primary insomnia
has ceased as a result of its side-effect profile.54
Conclusion
There are a large number of different sleep disorders,
ranging from disorders affecting the induction of
sleep to disorders that cause disturbance during sleep.
Insomnia is the most prevalent disorder and should
initially be managed with sleep hygiene techniques. If
hypnotics are necessary, they should only be used
short term to avoid dependence and tolerance. Sleep
disorders that occur in childhood generally resolve
spontaneously around adolescence and often do not
require psychological or pharmacological treatment.
Most medications for sleep disorders other than
insomnia are not licensed and their use would be ‘offlabel’, so consent issues need to be considered and
clearly documented.
Declaration of interests
None declared.
Progress in Neurology and Psychiatry September/October 2013
www.progressnp.com
CMHP Review Sleep_Layout 1 26/09/2013 11:19 Page 9
Sleep disorders
Michele Sie is Chief Pharmacist, West London Mental
Health Trust, St. Bernards Hospital, West London
Mental Health NHS Trust, Southall
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