Treatment of nonrespiratory
sleep disorders
Dirk Pevernagie
Because of their diverse nature, there is no
generic approach to the treatment of
nonrespiratory sleep disorders. Various
medical and nonmedical conditions are
implicated in disturbed sleep. The
Key points
N Due to the heterogeneous nature of
the various sleep disorders, no
generic approach to treatment can be
proposed. In each of the major
nosological categories,
pharmacological and
nonpharmacological treatment
modalities are available.
N The mainstay of treatment of
insomnia is nonpharmacological. A
stepwise treatment plan is proposed.
Treatment with hypnotic drugs is
appropriate as a primary step in
situational insomnia. In chronic
insomnia, hypnotics may be added as
adjuvant treatment to cognitive
behavioural therapy.
N The mainstay of treatment of
hypersomnia of central origin is based
on prescription of stimulant drugs.
Other medications are available for
cataplexy, one of the core symptoms
of narcolepsy.
N RLS and PLMD are responsive to
treatment with medications belonging
to various pharmacological classes.
Currently, DA agents are the first-line
of treatment. Opioids may be used in
severe cases of RLS.
176
International Classification of Sleep
Disorders 2nd Edition (ICSD-2) lists .70
nonrespiratory nosological items in various
sections, including insomnia, hypersomnia
of central origin, circadian rhythm sleep
disorders, parasomnias, sleep-related
movement disorders and other categories of
impaired sleep. Treatment of this
heterogeneous group of sleep disorders is
based on nonpharmacological approaches
as well as the prescription of agents
belonging to particular drug classes. Since
therapy must be tailored to the individual
patient’s needs, choices between different
pharmacological and nonpharmacological
treatment options, or combinations of
these, are to be made. Pharmacological
therapy requires adjustment of the choice,
dose and regimen of drugs in keeping with
the treatment response. Finally, patients may
suffer from a combination of sleep disorders.
Concurrent sleep disorders call for an
integrated therapeutic approach based on
combining different treatment modalities.
Proficient management of sleep disorders is
based on detailed knowledge of sleep and its
disturbances. The scope of this chapter is
not to elaborate on the intricacies of the
entire spectrum of pathological sleep, as
this would require a thorough review of all
the nosological items listed in the ICSD-2.
The aim is, rather, to provide a general
overview of treatment principles in
nonrespiratory sleep medicine. The
respiratory physician should have a broad
knowledge of the available treatment
options and strategies, but is not compelled
to take the lead in the management of
nonrespiratory sleep problems.
Nevertheless, the respiratory physician must
ERS Handbook: Respiratory Sleep Medicine
be able to handle comorbid issues (e.g. sleep
apnoea complicated by insomnia). Treatment
of sleep patients requires a multidisciplinary
setting. In sleep medicine, diagnostic and
therapeutic management is founded on
cooperation between professionals with a
different specialty background. As respiratory
disturbances are among the most prevalent
sleep disorders, there is a prominent role for
the respiratory physician in this
multidisciplinary process. This role, however,
implies appropriate knowledge of the relevant
respiratory and nonrespiratory aspects of
sleep and its disorders.
Rather than split this chapter into sections
on pharmacological and
nonpharmacological therapy, both
treatment aspects will be discussed under
four main themes, namely insomnia,
hypersomnia of central origin, sleep-related
movement disorders and miscellaneous
conditions. The content and relative role of
either treatment option will be discussed in
each of these categories. Where appropriate,
the special interest for the respiratory
physician will be indicated.
Insomnia
In line with the many components that play
a role in the causation and maintenance of
insomnia, several treatment methods have
emerged. The various factors that play a role
in the pathogenesis of insomnia are
reviewed in chapter 3. The usefulness of
different therapeutic modalities depends on
the contributing factors and the time course
of the illness. Whether insomnia is acute or
chronic and whether insomnia is associated
with medical or psychiatric comorbidities
will influence the management strategy. The
treatment may be general in scope or
targeted to specific adverse factors, such as
socioprofessional stressors, environmental
triggers, maladaptive behaviour or
underlying disease. Prescription of
hypnotics is common and accepted practice
for acute insomnia. For chronic insomnia,
the emphasis is on a nonpharmacological
approach. The use of hypnotic drugs is
adjuvant in this setting. Diagnosis and
treatment of underlying causes is pertinent
and should be considered whenever
ERS Handbook: Respiratory Sleep Medicine
appropriate. The treatment goals are to
improve duration and quality of sleep,
and to improve daytime dysfunction due
to insomnia.
Nonpharmacological treatment
Nonpharmacological treatment of insomnia
comprises a stepped care approach. The
incremental steps include general
recommendations, specific (tailored)
recommendations, and structured
psychological and behavioural interventions
(e.g. cognitive behavioural therapy (CBT)).
Furthermore, the level of support may be
scaled up progressively, starting with self-
support, then group therapy at the nursing
level and individual treatment administered
by specifically trained professionals
(medical psychologists).
At all times, irrespective of whether
insomnia is primary, secondary or
comorbid, the patient should be provided
with proper general information. Explaining
the nature of insomnia and the principles of
its management is a starting point.
Recommendations on good sleep hygiene
are a default step in the treatment plan
(table 1). Adherence to these instructions
often results in better coping with the
problem, and in some patients, no additional
therapeutic measures are required.
For unremitting chronic insomnia,
psychological and behavioural approaches
are the treatment of choice. Some of the basic
methods are briefly explained here; for more
detailed information, see Further Reading.
Stimulus control is a structural behavioural
approach aimed at turning the negative
feelings associated with going to bed into a
positive anticipation. Patients are taught to
break with habits that are adverse to sleep.
The sleeping environment is re-established
as a stimulus for good sleep.
Sleep restriction is based on curtailing time
in bed. Opportunities for sleep such as
napping are limited. This intervention first
induces additional sleep deprivation. The
drive to sleep will thus increase and,
eventually, sleep will be more consolidated.
When sleep continuity improves, time in bed
is progressively extended. Ultimately, there
177
 Table 1. Principles of sleep hygiene: recommendations for the insomnia patient.

N Limit time in bed for sleeping; lying awake in bed weakens sleep
N Get out of bed when you are not feeling sleepy
N Improve environmental conditions of the bedroom (noise, light and temperature)
N Take a light snack before going to bed but avoid consuming large beverages
N Avoid too much alcohol and stimulants (e.g. nicotine and caffeine)
N Schedule stressful activities so that they occur a long time before bedtime; unwind and
relax in the hours prior to going to sleep
N Do not check your alarm clock at night
N Restrict the use of sleeping pills

should be sufficient sleep time for the
patient to feel rested during the day.
As insomnia is associated with increased
somatised tension, relaxation training is
indicated in some patients. Several
techniques have been described, including
alternating tensing and relaxing of muscle
groups, concentrating on abdominal
breathing, and guided imagery.
CBT for insomnia (CBT-I) is the collective
name for a combination of the
aforementioned techniques with a
psychotherapeutic method to restore
appropriate cognitive pathways. The aim is
to identify disbeliefs about sleep and to turn
these cognitions into positive and realistic
concepts. There is ample scientific evidence
that CBT-I is beneficial, and that the positive
effects on sleep quality are durable.
Pharmacological treatment In contrast to
nonpharmacological treatment, there are no
established guidelines on pharmacotherapy
for chronic insomnia. While effectiveness of
hypnotic medications has been confirmed in
randomised controlled trials (RCTs), none of
these studies has been designed to assess
the superiority of one medication over
another in terms of efficacy and safety.
Neither is there any systematic study
comparing hypnotics with
nonpharmacological interventions.
Hypnotic drugs are the first-line treatment in
the acute setting, i.e. in patients with
situational insomnia. For this indication,
hypnotics are prescribed to be taken nightly
for a couple of weeks. Some caveats must be
borne in mind when hypnotics are
considered for treatment of chronic
insomnia. While successful in the short
term, the effect of hypnotic drugs may wear
off over time. As habituation takes effect,
incremental doses may be necessary to keep
up the initial pharmacotherapeutic results.
Therefore, hypnotics carry an intrinsic risk of
tolerance, and physical and psychological
dependence. The latter problem may occur
especially in patients with a history of drug
or alcohol abuse. Increased sleeplessness is
a frequent complaint following abrupt
discontinuation of hypnotic treatment. This
condition, known as rebound insomnia, may
be accompanied by other symptoms of
withdrawal, e.g. anxiety and agitation. These
drawbacks are the prime reasons why
hypnotics may not be suitable for long-term
use. One way to circumvent the problem of
tolerance is to prescribe hypnotics for
intermittent use, and to restrict intake to
three times per week, at maximum.
Many hypnotics, especially those with long
elimination half-lives, may have a carry-over
effect and cause unwanted sedation in the
morning. Long-acting hypnotics should not
be prescribed in patients who drive motor
vehicles. Short-acting drugs avoid this
complication but may be inefficacious at
controlling sleep maintenance insomnia.
There are several accounts of inappropriate

178 ERS Handbook: Respiratory Sleep Medicine

behaviour in individuals who were awakened
at night after taking sleeping pills. In the
elderly, confusional arousals and falls are
serious side-effects. Inability to rapidly
regain consciousness upon awakening is an
intrinsic disadvantage of hypnotic
treatment. Moreover, hypnotics may cause
anterograde amnesia, rendering some
individuals unable to recall their nocturnal
behaviour. There are concerns over impaired
cognition and a tendency towards
developing depression with chronic use.
Some hypnosedative drugs inhibit
respiratory neurons in the brainstem and
thereby suppress the drive to breathe. This
is especially relevant in OSA patients, in
whom hypnotics increase the incidence and
duration of disturbed breathing events.
Unless these patients are adequately treated
with CPAP, the use of hypnotics (particularly
benzodiazepines (BZDs)) is
contraindicated. Finally, hypnotics should
not be used in pregnancy, during lactation
or by patients with hepatic failure.
As a rule of thumb, in insomnia, the lowest
effective dose of a single hypnotic drug
should be prescribed for the shortest
amount of time. Indeed, the primary
intention of prescribing hypnotic medication
is to achieve symptomatic control. In
contrast with nonpharmacological treatment
modalities, drug treatment fails to address
the causative mechanisms of insomnia,
including precipitating factors, dysfunctional
beliefs and maladaptive behaviour patterns
that tend to sustain the insomnia process.
Therefore, hypnotic drug prescription is to
be considered an adjuvant treatment to
other therapeutic interventions. In all
instances where hypnotics are prescribed for
long-term use, the option to taper and
discontinue the sleep medication should be
reassessed on a regular basis.
Hypnotic agents have several effects on
sleep structure. Most often, there is a
decrease of sleep latency (SL) and number
of nocturnal awakenings (#A) versus an
increase in total sleep time (TST) and sleep
efficiency (SEF). Often, stage 2 NREM sleep
(N2) is increased. Effects on deep sleep
ERS Handbook: Respiratory Sleep Medicine
(N3) and REM sleep may be variable and
depend on the class of drugs selected.
When choosing a specific drug among the
different available medications, the
prescriber should take into account the key
characteristics of that particular agent,
including drug class, mode of action, and
pharmacokinetic and pharmacodynamic
properties. In this chapter, hypnotics are
classified into two general categories: BZD
receptor ligands and non-BZD sedative drugs.
BZDs are a group of compounds that share
a common structure of a benzene ring fused
with a diazepine ring. These drugs bind to a
specific locus of the c-aminobutyric acid
(GABAA) receptor complex, called the BZD
receptor. Activation of the BZD receptors
increases the effect of GABA-ergic
neurotransmission. BZDs have anxiolytic,
hypnosedative, anticonvulsant, amnesic and
muscle-relaxant properties. They may be
prescribed for various medical and
psychiatric indications. While a sedating
effect is a prominent and common feature,
not all BZDs are labelled for the specific
treatment of insomnia. Based on their
pharmacokinetic profiles, BZDs are divided
into three categories pertaining to duration
of action: long-, intermediate- and short-
acting (table 2). BZDs decrease SL and #A,
increase TST, SEF and N2, and tend to
decrease N3 and REM. In general, BZDs are
safe and efficacious in the treatment of
situational insomnia. When prescribed
cautiously and restrictively, BZDs also have
a place in the treatment of chronic insomnia
(e.g. on an intermittent prescription basis).
BZD receptor ligands that lack a BZD
chemical structure have been introduced in
the last two decades. These agents are
called non-BZD BZD receptor agonists
(NBBRAs) or ‘Z drugs’, because their
generic names begin with a ‘Z’ (zolpidem,
zopiclone and zaleplon; table 2). They are,
to date, the most extensively studied
hypnotics. They have a similar effect on
sleep architecture as the classical BZDs. The
combination of efficacy with reasonable
safety promotes this class of drugs as a
plausible first-line pharmacotherapy for
insomnia. However, despite acceptable
179
180
Table 2. Hypnotics.
Compound Class Mode of action Hypnotic tmax min t1/2 h Duration of Metabolism Side-effects
dose mg action
Amitriptyline TCA Inhibition of NA and 25–100 .120 10–28 Long Hepatic; active Cardiac arrhythmias;
5HT reuptake; a1, M1 and metabolite(s) anticholinergic and
H1 receptor antagonism antihistaminic effects;
aggravation of RLS
Flurazepam BZD GABA-ergic 15–30 47–100 Long Hepatic; active Generic side-effects of BZD
metabolite(s)
Gabapentin Structural analogue of Probably GABA-ergic 300–600 180 5–9 Intermediate Renal clearance Residual effects in the
GABA morning; dizziness; ataxia;
headache; rarely leukopenia
Lormetazepam BZD GABA-ergic 1–2 120 12 Intermediate Hepatic; inactive Generic side-effects of BZD
metabolite(s)
Midazolam BZD GABA-ergic 7.5–15 30–90 2–3 Short Hepatic; active Generic side-effects of BZD
metabolite(s)
Mirtazapine Noradrenergic and a1, a2, 5HT1, 5HT2 and 15–30 60–190 13–40 Long Hepatic; active Residual effects in the
specific serotoninergic H1 receptor antagonism metabolite(s) morning; weight gain;
antidepressant aggravation of RLS
Nitrazepam BZD GABA-ergic 5–10 120 30–40 Long Hepatic; inactive Generic side-effects of BZD
metabolite(s)
Ramelteon Melatonin I and II Unknown 8 45 1–3 Short Hepatic; active Nonspecific
receptor agonist metabolite(s)
Quetiapine Dibenzothiazepine a1, M1, H1, 5HT2 and D2 25–50 60–120 7 Intermediate Hepatic; inactive Sedation; aggravation of RLS
antipsychotic receptor antagonism metabolite(s)
Temazepam BZD GABA-ergic 10–30 50 7–11 Intermediate Hepatic; inactive Generic side-effects of BZD
metabolite(s)
Trazodone HCA 5HT2 and a1 receptor 50–100 60–120 5–9 Long Hepatic; active Residual effects in the
antagonism metabolite(s) morning; cardiac arrhythmias;
orthostatic hypotension; rarely
priapism (not dose related)
Triazolam BZD GABA-ergic 0.125–0.250 120 2–6 Short Hepatic; inactive Generic side-effects of BZD
metabolite(s)

ERS Handbook: Respiratory Sleep Medicine

 overall safety, anterograde amnesia,

Dose to be reduced in the elderly and those with hepatic or renal failure; pregnancy and lactation are contraindications. tmax: time to maximum concentration of the drug; t1/2: half-life; TCA:
Generic side-effects of BZD

Generic side-effects of BZD

Generic side-effects of BZD

confusional nocturnal behaviour and
dependency have been reported with some
NBBRAs in some susceptible patients. The
NBBRAs are less likely than the usual BZDs
to cause rebound phenomena after
Side-effects

discontinuation. These advantages are

counterbalanced by the higher cost of
treatment in comparison with the older BZDs.

Several psychotropic drugs outside the class

Hepatic; inactive

Hepatic; inactive

Hepatic; inactive

of BZD receptor agonists have potent

metabolite(s)

metabolite(s)

metabolite(s)

sedating side-effects. Among these agents

Metabolism

tricyclic antidepressant; HCA: heterocyclic antidepressant; NA: noradrenaline; 5HT: 5-hydroxytrypamine (serotonin); M: muscarinic; H: histamine.

are antidepressants, neuroleptics,

antiepileptics, melatonin receptor agonists,
antihistaminics and nonprescription
substances. Depending on the clinical
Intermediate
Duration of

context, the sedative action may be adverse

or beneficial. Sedation is an undesirable
Short

Short
action

side-effect when treatment is aimed at

mobilising and stimulating the patient.
When given in nightly dose, sedation may
t1/2 h

2–3

5–7

improve sleep and may be helpful to

1

manage comorbid insomnia. Therefore, a

single psychotropic agent may serve a dual
tmax min

30–180

45–120

purpose of treating the underlying disorder

120

and controlling insomnia as a symptom at

the same time. However, the dosage needed
to improve sleep is generally much lower
than the dosage required to observe any
Hypnotic
dose mg

treatment effect on the disorder for which

5–10

7.5
10

the medication is registered. In depression,

for instance, a low-dose sedative
antidepressant at bedtime is not sufficient
to improve depressive symptoms. To
Mode of action

achieve this goal, the low-dose hypnotic

GABA-ergic

GABA-ergic

GABA-ergic

antidepressant should be combined with

therapeutic dosages of other antidepressants
administered during the daytime. It is
increasingly common practice, however, to
prescribe some of these agents for the
symptomatic treatment of chronic insomnia
irrespective of its cause. While there is
insufficient medical evidence to support the
NBBRA

NBBRA

NBBRA

off-label use of non-BZD psychotropic agents,

Class

empirical results provide no motive to

discourage this practice. Moreover, these
Table 2. Continued

agents are not prone to tolerance to the same

extent as classical BZDs. Some of the
Compound

Zopiclone
Zolpidem
Zaleplon

commonly used medications are described

below. Their pharmacological profiles are
shown in table 2.

ERS Handbook: Respiratory Sleep Medicine 181

 Trazodone is a heterocyclic antidepressant,
with weak antidepressive but strong
sedative effects. This agent increases TST,
SEF and N3, and has variable effects on
REM sleep. Trazodone has little potential for
tolerance or dependence.
Amitriptyline is a classical tricyclic
antidepressant with sleep-enhancing
properties. This agent increases TST, SEF
and REM latency, and has variable effects on
N3. Cardiac, antihistaminic and
anticholinergic side-effects limit the use of
amitriptyline and other tricyclic
antidepressants. In low doses, however,
these side-effects are minimal, whereas
sleep-promoting effects are still present.
Mirtazapine is a noradrenergic and specific
serotoninergic antidepressant. Effects on
sleep are similar as those observed with
trazodone. Due to a substantial
antihistaminic action, weight gain is a
common side-effect.
Ramelteon is a potent melatonin agonist.
The hypnotic action is limited to decreasing
SL and probably results from an effect on
the suprachiasmatic nucleus. This agent is
not commercialised in Europe.
In the class of neuroleptics (antipsychotics),
among other agents, quetiapine is a drug
that can be used for treating insomnia
outside the context of psychotic and bipolar
disorders. It is known to increase TST, SEF,
N2 and N3, whereas SL and #A are decreased.
Gabapentin belongs to a class of
anticonvulsant medications. This agent also
has hypnotic and analgesic properties.
Effects on sleep include an increase in N3
and a reduction of #A. In addition, beneficial
effects have been observed on restless legs
syndrome, periodic limb movements
(PLMs) and parasomnias of N2.
Other agents are available to treat insomnia.
This group of miscellaneous
nonprescription drugs includes melatonin,
valerian, antihistaminics and chloral
hydrate. Prescription of melatonin is
discussed later. Use of valerian,
antihistaminics and chloral hydrate is not
182
recommended and they are not further
reviewed in this chapter.
Special interest for the respiratory physician
Comorbid insomnia in OSA is a prevalent
clinical problem that presents a particular
therapeutic challenge to the patient and
physician. The prescription of sleep-
promoting drugs may worsen SDB and the
application of nasal CPAP may worsen
insomnia. The resolution of this enigma
requires a multidisciplinary approach.
Depending on the relative severity of either
of the components, treatment for insomnia
and OSA may be initiated simultaneously or
sequentially. In this category of patients,
there is a prominent role for
nonpharmacological treatment of insomnia
and for intensive nursing support to
optimise adherence to CPAP treatment.
Prescribing hypnotics without CPAP
treatment is considered unsafe.
Hypersomnia of central origin
Sleepiness is a natural phenomenon. It may
be a normal physiological manifestation (e.g.
occurring at bedtime), or it may be induced in
certain conditions (e.g. sleep deprivation) or
in the context of certain diseases (e.g. sleep
apnoea and narcolepsy). Excessive daytime
sleepiness (EDS), also known as
hypersomnia, is a term reserved for a clinical
condition in which a subject experiences
recurrent, abnormal lapses of alertness and
has a strong tendency to fall asleep
involuntarily. This condition entails secondary
problems due to impaired performance in
private, professional and social areas of life.
Lost productivity, increased risk of causing
personal injury and public damage, and
significantly decreased quality of life are
sequelae that are regularly observed in
patients suffering from EDS. Hypersomnia is
a common symptom in several sleep
disorders, including sleep disturbances due
to medical or psychiatric causes, sleep
apnoea syndromes and hypersomnias of
central origin. In this chapter, the discussion
of treatment of excessive sleepiness will be
limited to the latter group of disorders.
Hypersomnias of central origin are listed in
the third section of the ICSD-2 and are
ERS Handbook: Respiratory Sleep Medicine
reviewed in chapter 3 of this handbook. It is
a collective name for disorders in which EDS
is a primary complaint that is not
attributable to disturbed nocturnal sleep or
a circadian rhythm misalignment. Other
sleep disorders may co-exist, but must be
treated appropriately prior to establishing a
diagnosis in this category.
Narcolepsy is one of the main entities in the
category of the central nervous system
(CNS) hypersomnias. This disease is known
to result from the loss of hypocretin-
producing neurons in the hypothalamus.
Most often, narcolepsy is associated with
paroxysmal episodes of muscle atonia,
called cataplexy. Cataplexy is typically
elicited by sudden emotion. Some variants
of narcolepsy lack this symptom. Cataplexy
is a disabling manifestation that requires
special therapeutic attention.
In contrast with narcolepsy, the
pathogenesis of other disorders in this
group is still unknown. Recurrent
hypersomnias and idiopathic hypersomnia
(IHS) are believed to be caused by a
temporary or permanent dysfunction of the
sleep/wake regulating mechanisms in the
CNS. Behaviourally induced insufficient
sleep syndrome and hypersomnias due to
medical causes constitute a miscellaneous
group of conditions that are primarily
related to the effect of external factors on
nocturnal sleep and, as a consequence, on
daytime alertness.
The principles of treating hypersomnia of
central origin encompass improvement of
daytime alertness and the control of
associated features such as cataplexy.
Stimulants are the cornerstone in the
treatment of EDS. Nonstimulating drugs are
used for the treatment of cataplexy. This
symptom may fully remit with proper
treatment. In contrast, it proves very
difficult, if not impossible, to restore a
normal level of alertness in hypersomnia
patients with the administration of the
currently available stimulating agents.
Nonpharmacological treatment Behaviourally
induced insufficient sleep is the most
pertinent differential diagnosis in
ERS Handbook: Respiratory Sleep Medicine
hypersomnia of central origin, especially in
young people. It may prove difficult to
estimate the extent of sleep deprivation in
these patients. Nevertheless, sleep
extension (i.e. prolonging the nocturnal
sleep period) should be recommended
whenever this diagnosis is suspected. With
a successful outcome, the need for treatment
with stimulating drugs may be obviated.
While nonpharmacological treatment for
narcolepsy and other CNS hypersomnias is
part of an integrative therapeutic approach,
evidence of its effectiveness is limited.
Patients are advised to adhere to regular
bedtimes, to take care to get sufficient night-
time sleep and to schedule ‘strategic’ naps
during the daytime, at least when short
bouts of sleep have a restorative effect. In
IHS, for instance, naps are often not
refreshing and may even cause additional
drowsiness. These patients should abstain
from napping during the daytime. Neither is
there strong evidence to recommend
behavioural treatment for cataplexy. Patients
should avoid circumstances that elicit
strong emotions, as cataplexy is precipitated
by these conditions. Avoiding situational
emotions will certainly reduce the number of
attacks, but the downside of this ‘remedy’ is
that patients tend to withdraw from social
life. This is obviously an undesirable
outcome. Therefore, lifestyle issues seem to
have minimal impact and pharmacological
treatment is mandatory in most of the patients.
Pharmacological treatment Stimulating
agents are key to the treatment of EDS
associated with narcolepsy and IHS.
Amphetamines and methylphenidate
increase the release and block the reuptake
of monoamines and, thus, produce central
and peripheral sympathomimetic effects. At
the cognitive level, they increase alertness
and psychomotor activity. Modafinil is an
atypical nootropic and stimulant agent that
is chemically different from the
amphetamines and has a weaker wake-
promoting effect. This substance has an as
yet undisclosed mode of action. While RCTs
are lacking regarding the use of
methylphenidate and amphetamines in
narcolepsy and IHS, available evidence
183
 suggests that these agents are capable of
enhancing alertness to at least two-thirds of

Headache most frequently;

Dose to be reduced in the elderly and those with hepatic or renal failure; pregnancy and lactation are contraindications. tmax: time to maximum concentration of the drug; t1/2: half-life.
drowsiness, confusional
normal levels, whereas with modafinil, this

Generic side-effects of

Generic side-effects of

rarely toxic epidermal

arousal, constipation
effect is less pronounced. Side effects are

Nausea, headache,
psychostimulants

psychostimulants
highly variable among patients and are dose-
dependent. Methylphenidate and

Side-effects

necrolysis
amphetamines are associated with classical
monoaminergic side-effects, including
insomnia, loss of appetite, tremor,
irritability, headache, palpitations and

inactive metabolite(s)
Hepatic and minimal
Hepatic and variable
elevated blood pressure. Within the

Hepatic; inactive
recommended dose range, the risk of

renal clearance;
renal clearance

metabolite(s)
tolerance and dependence is low in

Metabolism
narcolepsy and IHS, and there is no need to

Hepatic
schedule ‘drug-free holidays’. In higher than
recommended dose ranges, patients should
be monitored carefully with respect to

Intermediate
developing mental problems and
Duration of
hypertension. Modafinil has been studied action

Short

Short
Long
more extensively than the other stimulants.
It has a good benefit-to-risk ratio with fewer
and milder side-effects. Because of its safety

10–12

0.5–1
t1/2 h

7–14

2–4
and long-acting profile, modafinil has been
recommended by the American Academy of
tmax h

Sleep Medicine as first-line treatment for

0.5–2
2–3
narcolepsy. Therapeutic efficacy is usually
2
3

preserved in the long term. The higher cost

of treatment, however, is an obvious
doses per
Posology

disadvantage. The aforementioned agents

3–4
2–3
day

1–2

are listed in table 3.

2

The only drug that is labelled for the

Dose mg

100–400

4.5–9.0

treatment of cataplexy is sodium oxybate

20–60

10–60

(pharmaceutical name for c-

hydroxybutyrate; GHB). It is administered in
Increases the release and

Increases the release and

two doses: at bedtime and once again after

inhibits the reuptake of

inhibits the reuptake of

3–4 h of sleep. With chronic administration,

NA and dopamine

NA and dopamine

sodium oxybate improves sleep continuity

Mode of action

and reduces cataplectic attacks as well as

Unknown

Unknown

EDS. Because sodium oxybate has powerful

CNS depressant effects, it should not be
used in combination with alcohol or
sedative drugs, and is contraindicated in
Indication

SDB and respiratory failure. Elimination of

Cataplexy
and EDS

this agent involves conversion to succinic

EDS

EDS

EDS

semialdehyde that is subsequently

transformed to succinate. Following
Dextroamphetamine
Table 3. Stimulants.

metabolisation of succinate in the Krebs

Methylphenidate

Sodium oxybate

cycle, the end product is carbon dioxide. The

mode of action is unknown. GHB belongs to
Compound

Modafinil

the class of hypnotics. It can be abused,

however, as a recreational drug. GHB as an
illicit compound is known for significant

184 ERS Handbook: Respiratory Sleep Medicine

associated morbidity and mortality. While
sodium oxybate should be prescribed
cautiously and its use should be monitored,
the abuse potential in narcolepsy seems to
be low.
Tricyclic antidepressants and selective
serotonin reuptake inhibitors are effective
(but prescribed off label) in the treatment of
cataplexy and other manifestations of
narcolepsy, including sleep paralysis and
hypnagogic hallucinations. Inhibition of
noradrenaline (NA) reuptake presumably
mediates the effect of antidepressants on
cataplexy. At present, there is no evidence to
accept that particular antidepressants are
more powerful than others in controlling
cataplexy, despite different properties
regarding NA reuptake inhibition. A review
of antidepressants prescribed for cataplexy
is outside the scope of this chapter.
A disturbance of maintaining sleep is a
frequent complaint in narcoleptic patients.
Sleep disruption in narcolepsy may require
treatment with hypnotic drugs. When
cataplexy is also present, sodium oxybate is
the treatment of choice.
Special interest for the respiratory physician
Residual hypersomnia is a problem that is
encountered in 5–10% of well-treated OSA
patients. Hypersomnias of central origin, as
described above, should be considered in
the differential diagnosis. If this condition
remains unexplained after appropriate
clinical investigation, symptomatic
treatment with stimulants should be
considered. In the USA and some European
countries, modafinil is approved for treating
OSA patients with persistent EDS despite
adequate CPAP treatment. However, careful
monitoring is required and modafinil use is
not recommended in individuals with
uncontrolled hypertension, ischaemic heart
disease or epilepsy.
Sleep-related movement disorders
The most prominent nosological items in the
ICSD-2 section on sleep-related movement
disorders are restless legs syndrome (RLS)
and PLM disorder (PLMD). While these
entities often co-occur, it is uncertain
whether they share a common
ERS Handbook: Respiratory Sleep Medicine
pathophysiological background. RLS is a
neurological disorder with sensory and motor
manifestations. The diagnosis is based on a
tetrad of symptoms: there is an irresistible
urge to move the legs due to an unpleasant
‘creepy’ sensation, this urge increases upon
resting, movement temporarily relieves the
unpleasant sensation and these symptoms
are worse in the evening and in the initial part
of the night. RLS is relevant for sleep, as it
may be associated with difficulties initiating
sleep (DIS) or difficulties maintaining sleep
(DMS). PLMD is associated with recurrent
stereotyped leg movements that may induce
arousals and, thus, disrupt sleep. Treatment
of PLMD is largely empirical, as well-
designed RCTs are lacking. At present, it is
not clear whether PLMD outside the context
of RLS is clinically relevant, and whether there
is an indication to treat. Neither are there any
guidelines with respect to choosing the
primary outcomes that should guide the
treatment strategy. In contrast, the treatment
of RLS is well documented, as many RCTs are
now available. Guidelines for the treatment
and follow-up of RLS have been published.
Therefore, the therapeutic options that follow
deal mainly with the management of RLS.
Nonpharmacological treatment RLS patients
should avoid smoking and consuming food
and beverages that contain CNS-stimulating
substances, such as alcohol, caffeine and
chocolate. Some patients may benefit from
aerobic exercise, manipulating the legs, or
applying warm or cold water to the legs. In
addition, good sleep hygiene should be
maintained to avoid the development of
insomnia as a comorbid factor. These
measures are often insufficient and cannot
replace pharmacological treatment in
moderate-to-severe RLS.
Pharmacological treatment Several classes of
drugs are available for the treatment of RLS,
including mineral supplements, BZD
receptor agonists, dopaminergic (DA)
agents, opiate agonists and anticonvulsants.
Only DA agonists have been the subject of
extensive RCTs.
RLS may be a clinical manifestation of iron
deficiency. When serum ferritin levels are
,50 mg?L-1, the patient should be checked
185
 for concealed loss of blood and iron
supplementation should be commenced.
Magnesium sulfate can temporarily relieve
symptoms of RLS, but there are no data on
long-term benefits.
Clonazepam, a long-acting BZD, is cited in
the older literature as effective for treating
RLS. There are no convincing studies to
show that clonazepam and other BZDs
sufficiently control RLS symptoms. BZDs
shorten sleep onset and suppress the
arousals resulting from movements rather
than the movements themselves. Symptoms
of discomfort as well as PLMs usually
persist despite the use of these agents.
Therefore, BZDs are not considered first-line
treatment of RLS.
DA agents are the best studied and most
successful drugs for treatment of RLS (and
PLMD). Levodopa improves the symptoms
of RLS and reduces the number of PLMs.
The use of this medication is limited
because of rapid emergence of worsening
symptoms in the hours prior to
administration (augmentation; see later).
Dopamine agonists are now considered the
first-line treatment for RLS. The older ergot
medications (e.g. pergolide) have been
abandoned because of rare but serious
adverse effects, including the development
of pleuropulmonary fibrosis or cardiac
valvulopathy.
Nonergot preparations are preferred and
currently three dopamine agonists have a
label for RLS in this category. Pramipexole is
a full dopamine agonist with high affinity for
the D3 receptor subtype. This agent is very
effective in controlling RLS and PLM.
Ropinirole has a similar pharmacodynamic
and clinical profile. Rotigotine is a D3 and D2
dopamine agonist that has been developed
for transdermal administration. It may be
used to treat night-time and daytime
symptoms of RLS. Mild skin reactions may
be seen at the application site of the patch.
These compounds are highly effective and
have mild (mostly transient) side-effects,
including nausea and drowsiness. Recent
evidence suggests that these dopamine
agonists are also safe and efficacious in the
long term. However, this optimistic
186
expectation needs confirmation by
appropriately designed prospective RCTs.
Rarely, RLS patients on DA agents develop
disturbances of impulse control, and show
an increased desire for gambling and sexual
interactions. In up to one-third of the
patients, the use of DA agonists may be
limited by augmentation. This dose-
dependent phenomenon is characterised by
the unpleasant sensation and urge to move
occurring earlier during the day, being more
severe and spreading to the upper limbs. In
cases of severe augmentation, treatment
with DA agonists should be discontinued
and agents from another class of drugs
should be prescribed temporarily.
Opioids have also proven therapeutic
efficacy and durability, but are restricted to
the treatment of severe RLS. Patients who
are unresponsive to other medications or
who have developed augmentation are
candidates for opioid therapy. While there is
a low risk of tolerance in RLS patients,
opioids should not be prescribed to
individuals with a previous history of alcohol
or substance abuse. These agents carry a
risk for respiratory depression during sleep
in susceptible patients.
Gabapentin improves RLS symptoms at
doses between 300 and 2,400 mg a day.
This medicine is an alternative choice for
patients with mild symptoms or for
replacement of DA agents when
augmentation becomes an issue. Moreover,
gabapentin may be prescribed as an add-on
when night-time symptoms are severe or
pain is a prominent complaint.
Some frequently used agents from the four
drug classes described here are presented
in table 4.
Special interest for the respiratory physician
When reading PSG recordings, it may prove
difficult to distinguish hypopnoeas from
PLM events. Hypopnoeas are temporary
reductions in airflow terminated by a few
hyperpnoeic breaths. In PLMD, the limb
movements are often accompanied by a
temporary increase in amplitude of tidal
breathing. The (normal) breathing between
PLM events may be mistakenly identified as
ERS Handbook: Respiratory Sleep Medicine
 hypopnoeas. Careful reading of the

Residual effects in the morning; dizziness;

Generic side-effects of dopamine agonists

Generic side-effects of dopamine agonists

Generic side-effects of dopamine agonists

polysomnogram is of prime

Dose to be reduced in the elderly and those with hepatic or renal failure; pregnancy and lactation are contraindications. tmax: time to maximum concentration of the drug; t1/2: half-life.
importance for making the correct

ataxia; headache; rarely leukopenia

Generic side-effects of opioids diagnosis of SDB versus PLMD

Generic side-effects of opioids

and, therefore, for choosing
Generic side-effects of BZDs

appropriate treatment.
Miscellaneous sleep disorders
Parasomnias Parasomnias are
Side-effects

subdivided into disorders of NREM

and REM sleep. NREM parasomnias
are primarily disorders of arousal:
patients awaken partially from deep
sleep and demonstrate strange
Hepatic; inactive

Hepatic; inactive
Renal clearance

Renal clearance
Hepatic; active

Hepatic; active

Hepatic; active

behaviours before returning to sleep.

metabolite(s)

metabolite(s)

metabolite(s)

metabolite(s)

metabolite(s)
Metabolism

Conservative measures are the

mainstay of managing these
disorders. Patients should avoid a
stressful lifestyle and should secure
the bedroom environment against
30–40

19–55
t1/2 h

8–12

self-inflicted injury. Drug treatment is

5–9
3–4

5–7
6

empirical. REM sleep parasomnias are

characterised by vivid dream
tmax h

experiences or unusual dream

1.5–3
1–4

1–2

1–3

1–3
1.5

enactment (see section on REM sleep

3

behaviour disorder). Antidepressants

Doses per day

may be indicated for these disorders,

Transdermal

because of their REM sleep-

suppressive properties. There is a
1–2

1–2

special interest for the respiratory

1

physician, because some parasomnia

manifestations may be triggered by
0.125–0.500

disturbed breathing events. In this

0.25–1.00
Dose mg

300–600

case, the underlying respiratory

10–30
0.5–2

5–40

disorder should be treated before

1–3

considering other treatment options.

D2 dopamine agonist (affinity for D3

D2 dopamine agonist (affinity for D3

Delayed sleep phase syndrome Among

the different circadian rhythm sleep
disorders, jet lag disorder, shift work
Table 4. Drugs used to treat RLS and PLMD.

D3, D2 dopamine agonist

Opioid receptor agonist

Opioid receptor agonist

disorder and delayed sleep phase

syndrome (DSPS) are the most
receptor subtype)

receptor subtype)

prevalent clinical entities. DSPS is a

Mode of action

Anticonvulsant

condition in which the patients have

difficulties in falling asleep at normal
bedtimes and waking up in the
BZD

morning: the nocturnal sleep phase is

shifted by o2 h relative to
conventional or socially accepted
Pramipexole
Clonazepam

Gabapentin

times. Because the patients tend to

Methadone
Compound

Rotigotine
Ropinirole
Codeine

oversleep, significant sociofamilial

disharmony may ensue. The
treatment is based on a combination

ERS Handbook: Respiratory Sleep Medicine 187

 of nonpharmacological measures and
prescription of melatonin. An intervention
whereby a shifting sleep schedule is
prescribed is called chronotherapy: sleep
may either be systematically delayed or
advanced, until sleep is synchronised with
the desired bedtime. Light therapy in the
morning (10,000 lux for 30 min) may be
supplemented with formulations of
melatonin, which is a natural hormone
secreted by the pineal gland. In a dose range
of 0.5–3 mg, administered o3 h before the
endogenous dim-light melatonin onset,
melatonin may advance sleep. In addition,
melatonin has weak hypnotic properties but
is not often powerful enough to be
prescribed as a hypnotic drug.
Sleep in somatoform disorders Many
psychosomatic and somatoform disorders
(chronic fatigue syndrome, fibromyalgia,
burn-out, etc.) are accompanied by sleep
complaints, including insomnia,
hypersomnia and nonrestorative sleep. In
some patients, a primary sleep disorder can
be diagnosed. Appropriate treatment of the
underlying sleep disturbance should result
in an improvement of the psychosomatic
complaints. Often, however, the findings
from the diagnostic work-up are nonspecific
or no obvious sleep disturbance can be
demonstrated. In this case, no therapeutic
recommendations can be made. At present,
there are no compounds available that
would improve the ‘intrinsic quality’ of sleep.
Further reading
N American Academy of Sleep Medicine.
(2005). The International Classification of
Sleep Disorders. 2nd Edn. Westchester,
American Academy of Sleep Medicine.
188
N Billiard M, et al. (2006). EFNS guidelines
on management of narcolepsy. Eur J
Neurol; 13: 1035–1048.
N Buysse D. (2011). Clinical pharmacology
of other drugs used as hypnotics. In:
Kryger MH, et al., eds. Principles and
Practice of Sleep Medicine. 5th Edn. St
Louis, Elsevier-Saunders; pp. 492–509.
N Espie CA. (2009). ‘‘Stepped care’’: a
health technology solution for delivering
cognitive behavioral therapy as a first line
insomnia treatment. Sleep; 32: 1549–1558.
N Hening WA, et al. (2004). An update on
the dopaminergic treatment of restless
legs syndrome and periodic limb move-
ment disorder. Sleep; 27: 560–583.
N Mendelson W. (2011). Hypnotic medica-
tions: mechanisms of action and phar-
macologic effects. In: Kryger MH, et al,
eds. Principles and Practice of Sleep
Medicine. 5th Edn. St Louis, Elsevier-
Saunders; pp. 483–491.
N Montplaisir J, et al. (2011). Restless legs
syndrome and periodic limb movements
during sleep. In: Kryger MH, et al, eds.
Principles and Practice of Sleep Medicine.
5th Edn. St Louis, Elsevier-Saunders;
pp. 1026–1037.
N Morgenthaler T, et al. (2006). Practice
parameters for the psychological and
behavioral treatment of insomnia: an
update. An American Academy of Sleep
Medicine report. Sleep; 29: 1415–1419.
N Morin CM, et al. (2006). Psychological
and behavioral treatment of insomnia:
update of the recent evidence (1998-
2004). Sleep; 29: 1398–1414.
N Schutte-Rodin S, et al. (2008). Clinical
guideline for the evaluation and manage-
ment of chronic insomnia in adults. J Clin
Sleep Med; 4: 487–504.
N Wise MS, et al. (2007). Treatment of
narcolepsy and other hypersomnias of
central origin. Sleep; 30: 1712–1727.
ERS Handbook: Respiratory Sleep Medicine