Pharmacologic

Management of Excessive
D a y t i m e Sl e e p i n e s s
Shinichi Takenoshita, MD, MPH, Seiji Nishino, MD, PhD*

KEYWORDS
 Stimulants  Excessive daytime sleepiness  Narcolepsy  Idiopathic hypersomnia

KEY POINTS
 Excessive daytime sleepiness (EDS) is related to medical and social problems, including mental
disorders, physical diseases, poor quality of life, and so forth.
 Several different types of stimulants (or wake-promoting compounds) are available to treat EDS,
and a variety of new drugs are under development.
 The side effects of some of the stimulants are potent, and careful selection and management is
required.

INTRODUCTION in World War II. Currently, preventing sleepiness

caused by sleep deprivation is still a major
EDS is defined as “irresistible sleepiness in a situ- research project by the Defense Advanced
ation when an individual would be expected to be Research Projects Agency in the United States.
awake, and alert.”1 EDS has been a big concern In 1931, the first stimulant (ie, amphetamine)
not only from a medical but also from a public was applied to treat EDS associated with narco-
health point of view. According to recently pub- lepsy.10 Since then, many new stimulants have
lished articles, the prevalence of patients who suf- developed to treat EDS, and many patients
fer from EDS is approximately 20% in the world.2–4 received benefits. Stimulants, however, are drugs
Patients with EDS have the possibility of falling with strong side effects (ie, sympathomimetic)
asleep even when they should wake up and and addiction potential and these treatments are
concentrate, for example, when they drive, play mostly symptomatic; they improve the level of
sports, or walk outside. Subjects who have EDS alertness by simply suppressing sleepiness.
encounter a lower quality of life and have a higher Abuse potential of stimulants is a problem espe-
odds ratio of developing a mental disorder, cogni- cially when diagnoses of hypersomomnias are
tive impairment, and motor vehicle accidents.5–8 loosely made, and this is particularly true for nar-
Although nonpharmacologic treatments (ie, colepsy, where stimulant abuse is rare among pa-
napping and work accommodations) are often tients with well-defined narcolepsy.11–14 In
helpful, a large majority of the diagnosed patients this article, clinical characteristics of common
reported using pharmacologic therapies, mostly hypersomnias and pharmacologic treatments of
stimulant medications.9 each hypersomnia are described. New treatment
Historically, EDS was also a large concern in the options under development for treating EDS asso-
military. Many countries let soldiers take stimu- ciated with these hypersomnias are also
lants when they were engaged in military service

This article originally appeared in September, 2017 issue of Sleep Medicine Clinics (Volume 12, Issue 3).
[Link]

Disclosure Statement: S. Nishino had a sponsored research contract (SPO#50970) with Ono Pharmacutical Co.
Ltd.
Sleep and Circadian Neurobiology Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford
University School of Medicine, Stanford University, Palo Alto, CA, USA
* Corresponding author. 3155 Porter Drive, Room 2141, Palo Alto, CA 94304.
E-mail address: nishino@[Link]

Sleep Med Clin 15 (2020) 177–194

[Link]
1556-407X/20/Ó 2020 Elsevier Inc. All rights reserved.
178 Takenoshita & Nishino

discussed. The hypersomnias focused on in this narcolepsy type 2, idiopathic hypersomnia, and
article are narcolepsy type 1, narcolepsy type 2, hypersomnia due to a medical disorder, because
idiopathic hypersomnia, and hypersomnia due to relatively consistent guidelines for the pharmaco-
a medical disorder, defined in the International therapy of these diseases are available. The
Classification of Sleep Disorders, Third Edition ICSD-3 diagnostic criteria of these hypersomnias
(ICSD-3). are summarized in Table 1. For the treatment of
Kleine-Levin syndrome and other hypersomnias,
see the article by Arnulf.16
TYPES OF HYPERSOMNIAS
NARCOLEPSY
According to the ICDS-3, published in 2014, dis-
Symptoms of Narcolepsy
eases that result from EDS are listed as narcolepsy
type 1, narcolepsy type 2, idiopathic hypersomnia, Narcolepsy is a syndrome characterized by “EDS
Kleine-Levin syndrome, hypersomnia due to a that is typically associated with cataplexy and
medical disorder, hypersomnia due to a medication other [rapid eye movement] REM sleep phenom-
or substance, hypersomnia associated with a psy- ena such as sleep paralysis and hypnagogic hallu-
chiatric disorder, and insufficient sleep syndrome.15 cinations.”17 The prevalence of narcolepsy with
This review covers the pharmacologic treat- cataplexy has been examined in many studies
ments of EDS associated with narcolepsy type 1, and falls between 25 and 50 per 100,000 people

Table 1
Diagnostic criteria, International Classification of Sleep Disorders, Third Edition

Hypersomnia due to a
Narcolepsy Type 1 Narcolepsy Type 2 Idiopathic Hypersomnia Medical Disorder
Criteria A and B All Criteria A–E All Criteria A–F All Criteria A–D
A. Daily periods of A. Daily periods of irre- A. Daily periods of irre- A. Daily periods of irre-
irrepressible need pressible need to pressible need to pressible need to
to sleep or daytime sleep or daytime sleep or daytime sleep or daytime
lapses into sleep, lapses into sleep, lapses into sleep, lapses into sleep,
present for at least present for at least present for at least present for at least
3 mo 3 mo 3 mo 3 mo
B. Either 1 or 2 B. Mean sleep latency B. Fewer than 2 SOREM B. The daytime sleepi-
or both 8 min and 2 or periods on MSLT (or ness occurs as a
1. Cataplexy and more SOREM periods fewer than one of consequence of a
mean sleep on MSLT. REM within nocturnal REM la- significant underly-
latency 8 min 15 min of sleep onset tency was 15 min) ing medical or
and 2 or more on the preceding C. No cataplexy neurologic
SOREM periods nocturnal polysom- D. Either 1 or 2 or both condition.
on MSLT. REM nogram may replace 1. Mean sleep la- C. Mean sleep latency
within 15 min one of the SOREM tency 8 min on is 8 min, and fewer
of sleep onset periods. MSLT than 2 SOREM pe-
on the preceding C. No cataplexy 2. Total 24-h sleep riods are observed.
nocturnal D. CSF hypocretin-1 time 660 min on D. The symptoms are
polysomnogram concentration has 24-h polysomno- not better explained
may replace one not been measured graphic moni- by another un-
of SOREM or CSF hypocretin-1 toring or wrist treated sleep disor-
periods. concentration actigraphy (aver- der, a mental
2. Low CSF is 110 pg/mL or aged over 7 d) disorder, or the ef-
hypocretin-1 greater than one- E. Insufficient sleep fects of medications
concentration third of control syndrome is or drugs.
(<110 pg/mL or values. ruled out.
less than one- E. The hypersomno- F. The hypersomno-
third of control lence and/or MSLT lence and/or MSLT
values) findings are not bet- findings are not bet-
ter explained by ter explained by
other causes. other causes.
From International classification of sleep disorders: diagnostic and coding manual, 3rd edition. Westchester (IL): American
Academy of Sleep Medicine; 2014; with permission.
 Management of Excessive Daytime Sleepiness 179

(0.025%–0.05%).18,19 The onset of the disease is trigger cataplexy than negative emotions; howev-
most often seen during adolescence around pu- er, any strong emotion is a potential trigger.29
berty.20 As with the sleepiness of other sleep dis- Hypnagogic or hypnopompic hallucinations
orders, sleepiness or EDS of narcolepsy presents may be visual, tactile, auditory, or multisensory
with an increased propensity to fall asleep, events, usually brief but occasionally continuing
nodding, or easily dozing in relaxed or sedentary for a few minutes, that occur at transitions from
situations or a need to exert extra effort to avoid wakefulness to sleep (hypnagogic) or from sleep
sleeping in these situations.21 Additionally, irresist- to wakefulness (hypnopompic).21 Hallucinations
ible or overwhelming urges to sleep commonly may contain combined elements of dream sleep
occur from time to time during wakeful periods in and consciousness and are often bizarre or dis-
untreated narcolepsy patients. These so-called turbing to patients.
sleep attacks are not instantaneous lapses into Sleep paralysis is the inability to move, lasting
sleep, as is often thought by the general public, from a few seconds to a few minutes, during the
but represent episodes of profound sleepiness transition from sleep to wakefulness or from wake-
experienced by those with marked sleep depriva- fulness to sleep. Episodes of sleep paralysis may
tion or other severe sleep disorders. This feeling is alarm patients, particularly those who experience
most often relieved by short naps (15–30 minutes), the sensation of being unable to breathe. Although
but in most cases the refreshed sensation only accessory respiratory muscles may not be active
lasts a short time after awaking. The refreshing during these episodes, diaphragmatic activity
value of short naps is of considerable diagnostic continues, and air exchange remains adequate.
value for EDS associated with narcolepsy. One of the most frequently associated symp-
EDS can be objectively measured with the stan- toms is insomnia, best characterized as a difficulty
dardized multiple sleep latency test (MSLT), and to maintain nighttime sleep. Typically, narcoleptic
the MSLT findings (mean sleep latency <8 minutes) patients fall asleep easily, only to wake up after a
were included in the diagnostic criteria of EDS short nap and are unable to return to sleep for
associated with narcolepsy and other hypersom- another hour or so. Narcoleptic patients do not
nias (see Table 1).17 The maintenance of wakeful- usually sleep more than normal individuals over
ness test (MWT) was also developed to measure the 24-hour cycle30–32 but frequently have disrup-
how alert patients are when they are set in a boring ted nighttime sleep.30–32 Frequently associated
situation during the day.22 Although the MWT is problems are periodic leg movements,33,34 REM
not included in the diagnostic criteria of any hyper- behavior disorder, other parasomnias,35,36 and
somnias, many researchers believe that the MWT obstructive sleep apnea.34,37,38
is more sensitive in evaluating effects of treat- Other commonly reported symptoms include
ments, such as by pharmacotherapy with wake- automatic behavior — absent-minded behavior
promoting compounds. One of the reasons for or speech that is often nonsensical that the patient
this is the floor effects seen with MSLT; when the does not remember. Hypnagogic hallucinations,
EDS is sever, it is often difficult to detect the ther- sleep paralysis, and automatic behavior are
apeutic effects (to sleep vs to stay awake with nonspecific to narcolepsy and occur in other sleep
MWT) with the MSLT protocol. Therefore, the disorders (as well as in healthy individuals); howev-
MWT is often used to examine the therapeutic ef- er, these symptoms are far more common
fects of wake-promoting compounds. There is not and occur with much greater frequency in
enough evidence, however, to set the cutoff value narcolepsy.39
even when the MWT is used to measure the effect
of the treatment of diseases.23,24
Hypocretin/Orexin Deficiency in Type 1
In addition to EDS, narcoleptic patients exhibit
Narcolepsy
cataplexy and other abnormal manifestations of
REM sleep, such as hypnagogic hallucinations In most patients with cataplexy, a deficiency in the
and sleep paralysis.25 Cataplexy, the sudden hypocretin neuropeptide system is involved in
occurrence of muscle weakness in association the pathophysiology of human narcolepsy.40
with emotions, such as laughing, joking, or anger, The observation that cerebrospinal fluid (CSF)
has long been considered a pathognomonic hypocretin-1 levels are decreased in patients
symptom of the syndrome.21,26,27 Cataplectic with narcolepsy provides a new diagnostic tool
events usually last from a few seconds to 2 or and refines the nosologic considerations for
3 minutes but occasionally continue longer.28 Pa- narcolepsy.
tients are usually alert and oriented during the Using a large sample of patients and controls,
event despite their inability to respond. Positive the authors determined that 110 pg/mL (30% of
emotions, such as laughter, more commonly mean control values) was the most specific and
180 Takenoshita & Nishino

sensitive cutoff value for diagnosing narcolepsy.41 REM sleep abnormalities (ie, sleep-onset REMs
Most samples had undetectable levels (<40 pg/ [SOREMs]). Furthermore, even if the strict criteria
mL), and a few had detectable but very diminished for narcolepsy-cataplexy are applied, up to 10%
levels. None of the patients with idiopathic hyper- of patients with narcolepsy-cataplexy show
somnia, sleep apnea, restless legs syndrome, or normal CSF hypocretin levels. Considering that
insomnia had abnormal hypocretin levels. occurrence of cataplexy is tightly associated with
Because the specificity of the CSF finding is also hypocretin deficiency, impaired hypocretin neuro-
high, low CSF hypocretin-1 levels were included transmission is still likely involved in narcolepsy-
in the International Classifications of Sleep Disor- cataplexy with normal CSF hypocretin levels.
der, Second Edition, as a positive diagnosis for Conceptually, there are 2 possibilities to explain
narcolepsy-cataplexy.42 In the most recent revi- these mechanisms: (1) specific impairment of
sion of the ICSD, ICSD-3, published in 2014,15 hypocretin receptor and their downstream
narcolepsy-cataplexy was renamed narcolepsy pathway and (2) partial/localized loss of hypocretin
type 1, or hypocretin deficiency syndrome, ligand (yet normal CSF levels exhibited). A good
whereas narcolepsy without cataplexy was example for the former is Hcrtr 2-mutated narco-
renamed narcolepsy type 2 (hypocretin nondefi- leptic dogs; they exhibit normal CSF hypocretin-
cient) to emphasize the pathophysiologic basis of 1 levels45 while having full-blown narcolepsy.
the diseases. Thannickal and colleagues46 reported 1 narco-
lepsy without cataplexy patient (HLA typing was
Immune System and Narcolepsy unknown) who had an overall loss of 33% of hypo-
cretin cells compared with normal, with maximal
It has been reported that a large majority people
cell loss in the posterior hypothalamus. This result
with narcolepsy have the tissue-type HLA
favors the second hypothesis, but studies with
DR2.21,28 High-resolution typing revealed that nar-
more cases are needed.
colepsy has the closest association with HLA-
DQB1*0602, which is found in 95% of narcoleptic
patients with cataplexy and 41% of patients with Treatment of Excessive Daytime Sleepiness
narcolepsy without cataplexy but only 18% to Associated with Narcolepsy Types 1 and 2
35% of the general population.21,43 The tight asso-
Nonpharmacologic treatments (ie, behavioral
ciation between narcolepsy and an antigen-
modification, such as regular napping and work
presenting class II HLA type suggests that autoim-
accommodations) are often helpful. In a survey
mune processes may play a critical role in type 1
by a patient group organization,47–49 however,
narcolepsy because many autoimmune diseases
94% of all patients reported using pharmacologic
exhibit tight associations with class II HLA haplo-
therapies, mostly stimulant medications.50
types. Type 1 narcolepsy cases could thus involve
Sleepiness is usually treated using
an autoimmune alteration of hypocretin-containing
amphetamine-like CNS stimulants (ie, methylphe-
cells in the central nervous system (CNS), but the
nidate) or modafinil (ie, 2-[(diphenylmethy)sulfinyl]
antigen for this pathologic process has not yet
acetamide) and its R-enantiomer, armodafinil,
been identified. Dauvilliers and colleagues44 re-
which are wake-promoting compounds unrelated
ported an HLA-DQB1*0602–positive monozygotic
to amphetamines (Table 251). More recently, the
twin pair discordant for narcolepsy and CSF
American Academy of Sleep Medicine (AASM)
hypocretin-1 (only the affected subject had a low
recommended the use of sodium oxybate, a
hypocretin-1 level), suggesting that altered CSF
short-lasting sedative of unknown mechanisms,
hypocretin levels are state dependent and not trait
as first-line treatment of EDS and cataplexy, The
dependent and likely an acquired deficit. In other
most commonly used amphetamine-like com-
words, the genetic background is likely not suffi-
pounds are methylphenidate, methamphetamine,
cient to develop an abnormality in the hypocretin
D-amphetamine (all schedule II compounds), and
system. This finding is also complementary to
mazindol (a schedule IV compound) (Fig. 1; see
the autoimmune hypothesis.
Table 2). The clinical use of stimulants in narco-
lepsy often has been the subject of standards of
Considerations for the Pathophysiology of
practice published by AASM.52 Typically, a patient
Type 2 Narcolepsy
is started on a low dose, which is then increased
There are debates about the pathophysiology of progressively to obtain satisfactory results.
narcolepsy with normal hypocretin levels (ie, type Studies have shown that daytime sleepiness can
2 narcolepsy). More than 90% of the patients be greatly improved subjectively, but sleep vari-
with narcolepsy without cataplexy show normal ables are never completely normalized by stimu-
CSF hypocretin levels, yet they show apparent lant treatments.53 Milder stimulants with low
 Management of Excessive Daytime Sleepiness 181

Table 2
Current pharmacologic treatment of excessive daytime sleepiness associated with narcolepsy

Scheduled
Compound Classa Usual Daily Doses Half-Life (h) Side Effects/Notes
b
Modafinil IV 100–400 mg 9–14 No peripheral
sympathomimetic action,
headaches, nausea
Armodafinil IV 100–300 mg 10–15b Similar to those of modafinil
Mazindol IV 2–8 mg 10–13 Reduction of appetite or
increase in blood pressure
Methylphenidate II 80 mg 2–4 Same as amphetamines; less
hydrochloride reduction of appetite or
increase in blood pressure
Methamphetamine II 5–80 mg 9–12 Irritability, mood changes,
headache, palpitations,
tremors, excessive sweating,
insomnia
D-Amphetamine II 60 mg 10–28 Irritability, mood changes,
sulfate headache, palpitations,
tremors, excessive sweating,
insomnia
Sodium oxybate III 4.5–9 g 0.5–1 Overdoses (a single dose of
60–100 mg/kg) induce
dizziness, nausea, vomiting,
confusion, agitation,
epileptic seizures,
hallucinations, coma with
bradycardia, and respiratory
depression; evidence of
withdrawal syndrome
a
All compounds in the list are scheduled and the class is listed.
b
The half-life of the S-enantiomer of modafinil is short (approximately 3–4 h), so the half-life of racemic modafinil mostly
reflects the R-enantiomer (armodafinil).

efficacy and potency, such as modafinil or armo- Exceptionally, psychotic complications may be
dafinil, are usually tried first (see Fig. 1). More observed, most often when the medications are
effective amphetamine-like stimulants (methyl- used at high doses and chronically disrupt
phenidate, D-amphetamine, and methamphet- nocturnal sleep.55
amine) are then used if needed (see Fig. 1).
Stimulant compounds are generally well tolerated Modafinil/armodafinil
in patients with narcolepsy. Minor adverse effects, Modafinil (2-[(diphenylmethyl)sulfinyl]acetamide) is
such as headaches, irritability, nervousness, a chemically unique compound developed in
tremors, anorexia, palpitations, sweating, and France. Modafinil has been available in France
gastric discomfort, are common. Cardiovascular since 1984 on a compassionate mode and was
impact, such as increased blood pressure, is officially approved in France in 1992. Modafinil
possible, considering that sympathomimetic ef- (and its R-enantiomer) has been approved in
fects of these classes of compounds have been 1998 in the United States for the treatment of nar-
established in animals, although they have been colepsy, shift-work disorder, and residual sleepi-
remarkably difficult to document in human studies. ness in treated patients with sleep apnea
Surprisingly, tolerance rarely occurs in this patient syndrome.
population and drug holidays are not recommen- Armodafinil, the R-enantiomer of racemic moda-
ded by the AASM.52 Stimulant abuse is rare finil, with a longer half-life, was also recently
among patients with well-defined narcolepsy.11–14 approved by the Food and Drug Administration
A compliance study has shown that approximately (FDA) for EDS associated with narcolepsy as well
50% of patients who receive stimulants reduce or as for residual sleepiness in nasal continuous pos-
withdraw stimulant medications by themselves.54 itive airway pressure–treated individuals and
182 Takenoshita & Nishino

Fig. 1. The most commonly used amphetamine-like compounds.

sleepiness in shift work sleep disorder. Impor- In clinical practice, modafinil is given once a
tantly, the R-enantiomer of modafinil has a half- day in the morning on an empty stomach in
life of 10 hours to 15 hours, which is longer than bed to maximize the effect of the drug. The start-
that of the S-enantiomer of modafinil (3–4 hours).56 ing dose is usually 200 mg, and the dose range
The dual pharmacokinetic properties of the can vary between 100 mg and 400 mg, as
racemic mixture may explain why modafinil is needed, depending on the effect.64 If the
often more potent when taken twice per day at maximum dose (400 mg/d) is not sufficient to
the beginning of therapy, during the period of treat EDS among narcolepsy patients, then it is
drug accumulation. In terms of plasma concentra- recommended to increase the dose up to
tions, armodafinil is higher than modafinil late in 600 mg per day.
the day on a milligram-to-milligram basis.57 That As discussed previously, armodafinil is usually
is the reason why modafinil is given twice a day given once a day in the early morning, and the
at the beginning of therapy, and armodafinil is dose range of armodafinil is 100 mg to 300 mg
given once a day. each morning.
Several randomized trials have shown that mod- The mechanism of action of modafinil/armodafi-
afinil is effective against EDS in narcolepsy nil is highly debated. There are few studies
compared with placebo.58,59 Armodafinil improves addressing the mode of action of armodafinil,
the MWT compared with placebo among narco- and this review mostly discusses the action of
lepsy patients.60 Both modafinil and armodafinil racemic modafinil. Modafinil/armodafinil has
are classified as schedule IV (defined as drugs not been shown to bind to or inhibit any receptors
with low potential for abuse and low risk of depen- or enzymes of known neurotransmitters.65,66
dence) (see Table 2).61 In vitro, modafinil/armodafinil binds to the dopa-
The prevalence of side effects of modafinil/ mine transporter [DAT] and inhibits dopamine
armodafinil is not high, and headache, nausea, (DA) reuptake.66,67 These binding inhibitory effects
dry mouth, and anorexia are the known side ef- have been shown associated with increased extra-
fects.62 Modafinil can cause a serious rash in chil- cellular DA levels in the striatum in rats and dog
dren, although rarely.63 brain.68,69
 Management of Excessive Daytime Sleepiness 183

The most striking finding was that DAT knockout Molecular targets mediating amphetamine-like
mice were completely unresponsive to the wake- stimulant effects are complex and vary depending
promoting effects of methamphetamine, on the specific analog/isomer and the dose admin-
GBR12909 (a selective DAT blocker), and modafi- istered. Amphetamine per se increases catechol-
nil. These results further confirm the critical role of amine (DA and norepinephrine [NE]) release and
DAT in mediating the wake-promoting effects inhibits reuptake. These effects are mediated by
of amphetamines and modafinil and that an intact specific catecholamine transporters (ie, DAT and
DAT molecule is required for mediating the arousal NE transporter).73 Amphetamine derivatives inhibit
effects of these compounds.69 Qu and col- the uptake and enhance the release of DA, NE, or
leagues70 further demonstrated that wake- both by interacting with these molecules. These
promoting effects of modafinil were attenuated in mechanisms, as well as the reverse transport (ie,
D2 receptor knockout mice and were completely exchange diffusion) and the blocking of reuptake
abolished in D2 receptor knockout mice with D1 of DA/NE by amphetamine, all lead to an increase
antagonist, confirming the importance of dopami- in NE and DA synaptic concentrations.73
nergic neurotransmission for the modes of the ac- Methylphenidate is now recommended for use
tion of modafinil. as one of the second-line options. Because there
Furthermore, a recent human PET study in 10 are new medicines available, like sodium oxybate
healthy humans with [11C] cocaine (DAT radioli- and modafinil/armodafinil, methylphenidate is
gand) and [11C] raclopride (D2/D3 radioligand sen- used when patients do not response to these
sitive to changes in endogenous DA) also new classes of drugs.
demonstrated that modafinil (200 mg and The mechanism of action of methylphenidate is
400 mg given orally) decreased [11C] cocaine bind- similar to that of amphetamines and mainly in-
ing potential in the caudate (53.8%), putamen creases the extracellular concentration of DA by
(47.2%), and nucleus accumbens (39.3%).71 In blockage of the DAT and also, to a lesser degree,
addition, modafinil also reduced binding potential increases DA release.74,75
of [11C] raclopride in these structures, suggesting The side effects of methylphenidate are reduced
the increases in extracellular DA were caused by appetite, nausea, headache, insomnia, and psy-
DAT blockades.71 These results are highly consis- chosis, which are similar to that of amphetamine.74
tent with the results of the animal studies, dis- It has been said that methylphenidate increases
cussed previously; modafinil’s effects on the risk of cardiovascular events in children and
alertness are entirely abolished in mice without adults76; however, a large cohort, including
the DAT protein69 and in animals lacking D1 and more than 1 million children and young adults,
D2 receptor functions.70 has shown that the cardiovascular events risk is
not strongly associated with attention deficit-
Methylphenidate and amphetamines hyperactivity disorder drugs, which is mainly
In 1935, amphetamine was used for the first time methylphenidate.77
for the treatment of narcolepsy. Narcolepsy was In clinical practice, methylphenidate is initially
possibly the first condition for which amphet- prescribed 10 mg per day at first. The recommen-
amine was used clinically. It revolutionized ther- ded maximum dose is up to 80 mg per day.
apy for the condition, even though it was not
curative. Methylphenidate, the piperazine deriva- Sodium oxybate
tive of amphetamine, was introduced for the Sodium oxybate, the sodium salt of g-hydroxybu-
treatment of narcolepsy in 1959, and both com- tyrate (GHB), taken in the evening and once again
pounds share similar pharmacologic proper- during the night, reduces daytime sleepiness, cat-
ties.72 Phenylisopropylamine (amphetamine) has aplectic attacks, and other manifestations of
a simple chemical structure resembling endoge- REM sleep.78–82 GHB has been used in Canada
nous catecholamines. and European countries for the treatment of
Amphetamine-like compounds, such as methyl- narcolepsy-cataplexy. The administration of GHB
phenidate, pemoline, and fencamfamine, are struc- was followed by a significant decrease in number
turally similar to amphetamines; all compounds of stage shifts and awakenings, wakefulness after
include a benzene core with an ethylamine group sleep onset, and percentage of sleep stage 1.
side chain (phenethylamine derivatives). Methyl- Sleep efficiency and slow-wave sleep percentage
phenidate has been commonly used for the treat- increased REM latency decreased significantly.83
ment of EDS in narcolepsy, and a racemic mixture Although improvement in sleepiness occurs rela-
of both the D-enantiomer and L-enantiomer is tively quickly, anticataplectic effects appear 1
used, but D-methylphenidate mainly contributes to week to 2 weeks after the initiation of the treat-
clinical effects, especially after oral administration. ment. Due to its positive effects on mood and
184 Takenoshita & Nishino

libido, its slow-wave sleep–enhancing properties, action of wake-promoting effects of sodium oxy-
and a subsequent increase in growth hormone bate is unknown. Patients first need to take liquid
release, GHB is widely abused by athletes and sodium oxybate before they go to bed, and then
other populations.84,85 In addition, because of its they need to take the second dose 2.5 hours to
euphorigenic, behavioral disinhibitive, and amnes- 4 hours after the first dose. This is because of
tic properties, coupled with simple administration the short half-life (0.5–1 hour in the body) and short
(ie, high solubility, colorlessness, and tasteless- duration of action (2–4 hours) of sodium oxybate.90
ness when mixed with a drink), the abuse/misuse The recommended starting dose is 4.5 g a night
of GHB as a recreational substance and as a divided into 2 equal doses of 2.25 g, which may
date rape drug has risen sharply in recent years, be adjusted up to a maximum of 9 g per night in in-
leading to an increased number of overdoses crements of 1.5 g per night with 1-week to 2-week
and intoxications for which no specific antidote ex- intervals. The benefit was significant after 4 weeks,
ists.81,86 GHB was classified as a schedule I drug highest after 8 weeks, and maintained during long-
that currently has no accepted medical use for term therapy.91 The side effects of sodium oxybate
treatment in the United States. Recent large- are nausea, insomnia, headache, dizziness, vomit-
scale, double-blind, placebo-controlled clinical tri- ing, weight loss, psychiatric complications, and
als in the United States, however, led to reestab- sleep apnea92 (see Table 2).
lish sodium oxybate (the sodium salt of GHB) as Because of the abuse potency of the com-
a first-line treatment of narcolepsy-cata- pound, the Risk Evaluation and Mitigation Strate-
plexy.79–81,87 In the United States, sodium oxybate gies program operated by the US FDA mandates
is the approved formula of GHB and is classified as prescriber/patient education for safe use and
a schedule III compound. The compound is espe- registration to prescribe sodium oxybate.93 There
cially useful in patients with severe insomnia and are also economic drawbacks to using sodium
cataplexy who do not tolerate antidepressant oxybate for the treatment of narcolepsy. The cost
medication well because of its side effects on sex- of sodium oxybate is expensive, at up to
ual potency. Although improvement in sleepiness $143,604 per 1 year.94 The patent will expire in
occurs quickly, anticataplectic effects appeared 2024, and the cost of sodium oxybate is likely to
1 week to 2 weeks after the initiation of the treat- be more economical after 2024.
ment. Sodium oxybate has demonstrated statisti- The mechanism of how sodium oxybate works
cally significant improvements in both symptoms, has not been fully understood and it may have
EDS and cataplexy, either as a monotherapy or multiple mechanisms of action in the brain. A se-
in combination with modafinil, in clinical trials.88 ries of experimental evidence suggests that so-
According to the meta-analysis, sodium oxybate dium oxybate may work as an agonist on g-
was superior to placebo in increasing MWT aminobutryic acid (GABA)B receptors.95 Sodium
(5.18 minutes; 95% CI, 2.59–7.78) and reducing oxybate is one of the precursors of GABA, and a
weekly sleep attacks ( 9.65 times; 95% CI, portion of it may be converted to GABA and stim-
17.72–1.59).89 From these wake-promoting ef- ulate GABA receptors.96 Several researchers also
fects (on the day after the intake of compound at claimed that sodium oxybate has its own receptor
night), some researchers try to classify sodium (GHB receptor),97 but functional roles of this re-
oxybate as a CNS stimulant, but the mode of ceptor are still largely unknown (Fig. 2).

Fig. 2. The GHB receptor.

 Management of Excessive Daytime Sleepiness 185

Despite these new findings, the physiologic sig- Pitolisant is currently only available in Europe.
nificance of the brain GHB signaling pathway, The side effects are gastrointestinal pain,
especially for the therapeutic effects against EDS increased appetite, weight gain, headache,
and cataplexy, is still unknown. One of the insomnia, and anxiety.106 The initial dose of pitoli-
possible modes of action is mediating the regula- sant is 9 mg, taken as a single dose in the morning.
tion of activities of adrenergic locus coeruleus The maximum dose is up to 36 mg.
(LC) neurons. The activity of the LC is essential
for the maintenance of muscle tone, and the LC Combination strategy
ceases to fire during cataplectic attacks.98 GHB Combination therapy of some stimulants is also
may prevent a cataplectic attack by dampening recommended when the administration of a single
the tone of LC neurons via the stimulation of inhib- type of stimulant is not effective against EDS of
itory extrasynaptic GABA receptors in the LC, thus narcolepsy patients.
increasing the threshold for autoinhibition.99 Wors- The recommended combinations of stimulants
ening of periodic leg movements in narcoleptic pa- are sodium oxybate 1 modafinil/armodafinil, pito-
tients by sodium oxybate may suggest lisant, or methylphenidate 1 sodium oxybate, and
dopaminergic involvements in the drug action. modafinil or methylphenidate 1 pitolisant.

Other stimulants
Pitolisant (H3 inverse agonist) Amphetamine and dextroamphetamine (amphet-
Histamine has long been implicated in the control amines, dose 5–60 mg/d), mazindol (a weak DA
of vigilance, and H1 antagonists are strongly seda- releaser with DA and NE reuptake inhibitor, dose
tive. The downstream effects of hypocretins on the 2–8 mg/d), pemoline (amphetamine-like stimulant,
histaminergic system (hcrtr2 excitatory effects) are dose 37.5–112.5 mg/d), and bupropion (DA uptake
likely important in mediating the wake-promoting inhibitor with wake-promotion, dose 150–300 mg/
properties of hypocretin.100 Although centrally d) are occasionally used if the first-line and
injected histamine or histaminergic H1 agonists second-line medications turn out to be insufficient.
promote wakefulness, systemic administrations
of these compounds induce various unacceptable Pharmacotherapy of Rapid Eye Movement
side effects via peripheral H1 receptor stimulation. Sleep–Related Symptoms in Narcolepsy
In contrast, the histaminergic H3 receptors are
regarded as inhibitory autoreceptors and are The pharmacotherapy of REM sleep–related
enriched in the CNS. H3 antagonists or inverse symptoms in narcolepsy is briefly discussed. Be-
agonist enhance wakefulness in normal rats and sides sodium oxybate, tricyclic antidepressants;
cats101 and in narcoleptic mice models.102 Hista- serotonin–NE reuptake inhibitors, such as milnaci-
minergic H3 antagonists might be a useful as pran; and selective serotonin reuptake inhibitors,
wake-promoting compounds for the treatment of such as paroxetine and fluvoxamine, are recom-
EDS or as cognitive enhancers,103 and several his- mended for patients suffering from cataplexy, hyp-
taminergic H3 receptor antagonists/inverse ago- nagogic hallucinations, and sleep paralysis.107
nists are currently being investigated. Pitolisant Side effects of these antidepressants include
(previously called BF2.649 and tiprolisant; Bio- dry mouth, obesity, sexual dysfunction, type 2 dia-
projet, Wakix, Paris, France) was the first clinically betes, and suicidal tendencies.108 Antidepres-
used inverse agonist of the histamine H3 autore- sants suppress cataplexy, hypnagogic
ceptor and increases histamine release in the hy- hallucinations, and sleep paralysis, and this effect
pothalamus and cortex. In a pilot single-blind seems due to suppression of REM sleep or prolon-
study on 22 patients with narcolepsy/cataplexy, gation of REM sleep latency.21,109
pitolisant (40 mg in the morning) reduced EDS.104
Idiopathic Hypersomnia
Recent double-blind phase III trials on 95 narco-
leptic subjects in 32 sleep disorder centers in 5 Eu- With the clear definition of narcolepsy (cataplexy
ropean countries revealed that pitolisant (10 mg, and dissociated manifestations of REM sleep), it
20 mg, or 40 mg) once a day was efficacious on became apparent that some patients with hyper-
the 2 major symptoms of narcolepsy, EDS and somnia suffer from a different disorder. In the late
cataplexy, compared with placebo and was better 1950s and early 1960s, Bedrich Roth110 first
tolerated compared with twice-a-day modafinil described a syndrome characterized by EDS, pro-
(100 mg, 200 mg, or 400 mg).105 If these findings longed sleep, and sleep drunkenness, and by the
are substantiated in further ongoing studies, H3- absence of sleep attacks, cataplexy, sleep paraly-
receptor inverse agonists, including pitolisant, sis, and hallucinations. The terms, independent
could offer a new treatment option for patients sleep drunkenness and hypersomnia with sleep
with narcolepsy. drunkenness were initially suggested, but now
186 Takenoshita & Nishino

this syndrome is categorized as idiopathic hyper- have been reported in the literature in the past
somnia with and without long sleep time.42 30 years.118 The prevalence of symptomatic (ie,
In the absence of systematic studies, the preva- hypersomnia due to a medical disorder) hyper-
lence of idiopathic hypersomnia is unknown. somnia, however, may be much higher. For
Nosologic uncertainty causes difficulty in deter- example, several million subjects in the United
mining the epidemiology of the disorder. Recent States suffer from chronic brain injury; 75% of
reports from large sleep centers reported the ratio these patients have sleep problems and approxi-
of idiopathic hypersomnia to narcolepsy to be mately half of them claim sleepiness.119 Patients
1:10.111 The age of onset of symptoms varies, with hypersomnia due to a medical disorder have
but it is frequently between 10 years and 30 years. EDS caused by coexisting medical or neurologic
The condition usually develops progressively over disorders. Daytime sleepiness of this disorder
several weeks or months. Once established, may be similar to that of narcolepsy or idiopathic
symptoms are generally stable and long lasting, hypersomnia.15,114 Common disorders are dis-
but spontaneous improvement in EDS may be cussed later, and in any secondary hypersomnia,
observed in up to one-quarter of patients.111 it is important to treat the underlying disease be-
The pathogenesis of idiopathic hypersomnia is sides providing symptomatic therapies.
unknown. Hypersomnia usually starts insidiously.
Occasionally, EDS is first experienced after tran- Posttraumatic Hypersomnia
sient insomnia, abrupt changes in sleep-wake According to a meta-analysis research, the preva-
habits, overexertion, general anesthesia, viral lence of EDS among posttraumatic brain injury pa-
illness, or mild head trauma.111 Despite reports tients is 27%.120 CSF hypocretin-1 levels are low
of an increase in HLA-DQ1, DQ11, DR5, Cw2, in most of patients with moderate to severe trau-
and DQ3 and decrease in Cw3, no consistent find- matic brain injury in their acute injury phase.121
ings have emerged.111 Regarding treatment, the effectiveness of modafi-
The most recent attempts to understand nil is still under controversy. A randomized
the pathophysiology of idiopathic hypersomnia controlled trial (RCT) has shown that modafinil im-
relate to the investigation of potential role of the proves the Epworth Sleepiness Scale (ESS) score
hypocretins. Most studies suggest, however, significantly compared with placebo at 6 treatment
normal CSF levels of hypocretin-1 in idiopathic weeks.122 Another RCT shows, however, that
hypersomnia.41,112 modafinil did not consistently improve the ESS
Patients of idiopathic hypersomnia have less score compared with the placebo at 10 treatment
sleep paralysis (20% of patients with idiopathic weeks.123 Another RCT has demonstrated that
hypersomnia) and sleep hallucinations (25%) armodafinil do not improve the ESS score
than narcolepsy. Among idiopathic hypersomnia compared with placebo at 12 treatment weeks.124
patients, sleep drunkenness and long nocturnal
sleep times without fragmentation are common, Hypersomnia Secondary to Parkinson Disease
and the effects and duration of naps are unrefresh-
ing and long compared with narcolepsy Like narcolepsy and idiopathic hypersomnia, day-
patients.15,113,114 time sleepiness is measured by ESS and MSLT.
There is no FDA-approved medicine to treat Among Parkinson disease patients, 20% to 50%
EDS caused by idiopathic hypersomnia. In the are said to have EDS.125–127
clinical setting, modafinil is used off-label to The effect of modafinil on this disorder is still
treat EDS in idiopathic hypersomnia, as in narco- controversial. There are some studies that have
lepsy.115,116 If EDS is irresistible and resistant to shown that modafinil improves the EDS in Parkin-
modafinil, methylphenidate and amphetamine- son disease patients,128,129 whereas there are
like compounds are also used. A recent article other articles that have shown that modafinil
has shown that sodium oxybate improves does not improve the EDS in Parkinson disease
the sleepiness of idiopathic patients as much as patients.129,130 An article has also shown that so-
it improves sleepiness in narcolepsy type 1; how- dium oxybate can improve the EDS in Parkinson
ever, sodium oxybate has strong side effects and disease patients.131
dependency, as discussed preivously.116,117
Common Stimulants in Daily Life
Caffeine is probably the most popular and widely
Hypersomnia due to a Medical Disorder
consumed CNS stimulant in the world. Caffeine
The prevalence of symptomatic narcolepsy (ie, is digested from foods, drinks, and sometimes
narcolepsy due to a medical disorder) is likely chocolate, coffee, energy drinks, soft drinks, and
small, and only approximately 120 of such cases so forth. Caffeine is a xanthine derivative and
 Management of Excessive Daytime Sleepiness 187

acts as an adenosine A1 and adenosine A2A recep- peptides do not cross the blood-brain barrier
tor agonist.132 Adenosine content is increased in (BBB) well. Intranasal delivery is a noninvasive
the basal forebrain after sleep deprivation. Adeno- method of bypassing the BBB to deliver therapeu-
sine has thus been proposed as a sleep-inducing tic agents to the brain and spinal cord. Although
substance accumulating in the brain during pro- developments of small molecule nonpeptide
longed wakefulness.133 Side effects of caffeine hypocretin receptor agonists are in progress and
are often overlooked; however, sometimes they shown effective in mouse models,140 these are still
are crucial. A variety of side effects of caffeine not available for clinical use. The toxicity/side ef-
are well known, which are headache, stomach up- fects of systemic administration of hypocretin re-
set, nervousness, and so forth. For the common ceptor agonists are also unknown.
side effects of caffeine in terms of sleep, caffeine Recent reports in both rhesus monkeys and
typically prolongs sleep latency, reduces total humans show some effects using intranasal
sleep time and sleep efficiency, and worsens hypocretin-1 administration.141,142 A recent
perceived sleep quality.132 An average cup of cof- double-blind, randomized, placebo-controlled
fee contains 50 mg to 150 mg of caffeine. Caffeine crossover design study on 7 patients with narco-
is also available over the counter (NoDoz, 200 mg lepsy/cataplexy and matched healthy controls
caffeine [GlaxoSmithKline plc, Middlesex, United showed that intranasal hypocretin-1 restores ol-
Kingdom]; Vivarin, 200 mg caffeine [Meda Con- factory function in narcolepsy/cataplexy pa-
sumer Healthcare Inc, NJ]). This suggests that tients.141 But unfortunately, no data exist
stimulant effects of caffeine tablets are not strong concerning potential effects on daytime sleepi-
enough to manage pathologic sleepiness, but ness and cataplexy at this time.
narcoleptic patients often take caffeine before
they are diagnosed. According to a recent review, Immune-Based Treatments
moderate caffeine intake (400 mg/d) is not associ-
Type 1 narcolepsy is currently thought to be an
ated with adverse effects.134 The average cup of
autoimmune disorder targeting hypothalamus
ground roasted coffee contains 85 mg of caffeing,
hypocretin neurons. An autoimmune basis for the
and instant coffee contains 60 mg of caffeing.135
hypocretin cell loss in narcolepsy has been sus-
Drinking fewer than 5 cups of ground roasted cof-
pected due to its strong DQB1*0602 association
fee per day is better for health.
and association with T-cell receptor polymor-
phisms.143 Based on the autoimmune hypothesis
FUTURE TREATMENT OPTIONS of narcolepsy, immune-based therapy, such as
Hypocertin-Based Treatments steroids (in 1 patient), intravenous immunoglobu-
lins, and plasmapheresis have been proposed,
Because a large majority of human narcolepsy pa-
with some promising results in a few cases.144,145
tients are hypocretin ligand deficient, hypocretin
Recently, a case of narcolepsy with cataplexy with
replacement therapy may be a new therapeutic
undetectable CSF hypocretin-1 level that
option. This may be effective for both sleepiness
completely reversed shortly after disease onset
(ie, fragmented sleep/wake pattern) and cata-
was reported.144 Although needing replication in
plexy. Animal experiments using ligand-deficient
well-designed trials, these results suggest that
narcoleptic dogs suggest that stable and centrally
immune-based therapy could become a new
active hypocretin analogs (possibly nonpeptide
treatment option for patients with narcolepsy/cat-
synthetic hypocretin ligands) need to be devel-
aplexy at disease onset.
oped to be peripherally effective.136,137 This is
also substantiated by a mice study that found
Other Possible Treatments of Interests (Non–
normalization of sleep/wake patterns and behav-
Hypocretin-Based Treatments)
ioral arrest episodes (equivalent to cataplexy and
REM sleep onset) in hypocretin-deficient mice In addition to hypocretin replacement, preclinical
knockout models supplemented by central admin- and clinical trials for new classes of compounds
istration of hypocretin-1.138 In addition, orexin are also in progress.
gene therapy (injection of an aden-oassociated More than a decade ago, Osamu Hayaishi146
viral vector coding for prepro-orexin plus a red and his group claimed that prostaglandin (PG) D2
fluorescence protein into the mediobasal hypo- is an endogenous sleep substance, and a series
thalamus) markedly improved the MWT in orexin/ of animal studies by his group reported that
ataxin-3 narcoleptic mice.139 These results PGD2 or PGD2 receptor (DP1) agonists promote
demonstrate that cell transplantations and gene sleep in animals (see Huang and colleagues147).
therapy may be developed in the future. One of The same research group also reported that
the concerns for this option is that the hypocretin PG DP1 potently promotes wakefulness. This
188 Takenoshita & Nishino

suggests the possibility use of PG DP1 antago- SUMMARY

nists as wake-promoting compounds. This may
also be clinically important because it is reported This article overviews pharmacotherapy of EDS
that increased serum lipocalin-type PGD synthase associated with narcolepsy type 1, narcolepsy
(beta-trace) levels correlate with EDS associated type 2, idiopathic hypersomnia, and hypersomnia
with narcolepsy.148 Wake-promoting effects of a due to a medical disorder.
DP1 antagonist, ONO-4127, were evaluated in a Narcolepsy-cataplexy is most commonly
mouse model of narcolepsy (ie, orexin/ataxin-3 caused by a loss of hypocretin-producing cells in
transgenic mice) and compared with effects of the hypothalamus (ie, type 1 narcolepsy). Low
modafinil.149 ONO-4127 perfused in the basal CSF hypocretin-1 levels can be used to diagnose
forebrain area potently promoted wakefulness in the condition. The disorder is tightly associated
both wild-type and narcoleptic mice, and the with HLA-DQB1*0602, suggesting that the
wake-promoting effects of ONO-4127 at cause in most patients may be autoimmune
2.93  10 4 M approximately corresponded to destruction of these cells. The treatment of EDS in-
those of modafinil at 100 mg/kg, orally; ONO- cludes the use of amphetamine-like CNS stimu-
4127 reduced DREM (direct transitions from lants, modafinil and its R-enantiomer armodafinil.
wake to REM sleep), an electroencephalogram/ Methylphenidate is the most commonly pre-
electromyogram assessment of behavioral cata- scribed amphetamine-like stimulant in the United
plexy, in narcoleptic mice, suggesting ONO-4127 States, and this compound is efficacious and
is likely to have anticataplectic effects; DP1 antag- well tolerated by most narcoleptic patients.
onists may be a new class of compounds for the Because of its safety and low side-effect profile,
treatment of narcolepsy-cataplexy. modafinil became the first-line treatment of choice
Another possible area that currently gathers less for EDS associated with narcolepsy. These wake-
pharmaceutical interest is the use of thyrotropin- promoting compounds, however, do not improve
releasing hormone (TRH) direct or indirect agonists. cataplexy and dissociated manifestations of REM
TRH itself is a small peptide, which penetrates the sleep, so antidepressants (monoamine uptake in-
BBB at very high doses. Small molecules with hibitors) are additionally used to treat these as-
agonistic properties and increased BBB penetration pects. Sodium oxybate (a sodium salt of GHB,
(ie, CG3703, CG3509, or TA0910) have been devel- available in the United States), when given at night,
oped, partially thanks to the small nature of the start- improves EDS and cataplexy, Therefore, the num-
ing peptide.150 TRH (at a high dose of several ber of US patients treated with sodium oxybate is
milligrams/kilogram) and TRH agonists increase increasing, and it has become the first-line treat-
alertness and have been shown to be wake promot- ment of narcolepsy. Combination therapy with
ing and anticataplectic in the narcoleptic canine some stimulants is also recommended when the
model,151,152 and these effects might be related to administration of single stimulant type is not effec-
the excitatory effects of TRH on motoneurons.153 tive against EDS of narcolepsy patients.
Initial studies had demonstrated that TRH enhances There is no FDA-approved medicine to treat EDS
DA and NE neurotransmission,154,155 and these associated with idiopathic hypersomnia. In the clin-
properties may partially contribute to the wake- ical setting, modafinil is used off-label to treat EDS
promoting and anticataplectic effects of TRH. in idiopathic hypersomnia. If EDS is irresistible and
Recent studies have suggested that TRH may pro- resistant to modafinil, methylphenidate and
mote wakefulness by directly interacting with the amphaemine-like compounds are also used.
thalamocortical network; TRH itself and TRH recep- Treatments of EDS associated with symptom-
tor type 2 are abundant in the reticular thalamic nu- atic hypersomnia (ie, hypersomnias due to a med-
cleus.156 Local application of TRH in the thalamus ical disorder) are more complex because these
abolishes spindle wave activity,157 and in the slice conditions are heterogeneous, and hypocretin in-
preparations, TRH depolarized thalamocortical volvements are seen in some disease conditions
and reticular/perigenuculate neurons by inhibition but not in all. Specific brain structures that have
of leak K1 conductance.157 been damaged and mechanisms involved in the
Other pathways with possible applications in the EDS are likely varied. Unresponsiveness to stimu-
development of novel stimulant medications lant treatments may occur depending on the un-
include the adenosinergic system (more selective derlying pathophysiologic mechanism. In this
receptor antagonists than caffeine), the dopami- regard, development of new types of wake-
nergic/adrenergic system (for example, DA/NE- promoting compounds would likely benefit these
reuptake inhibitors), the GABAergic system (for patients.
example, inverse benzodiazepine agonists), and Emerging treatments undergoing investigation
the glutamatergic system (ampakines).158 include histaminergic compounds (pitolisant, an
 Management of Excessive Daytime Sleepiness 189

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