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Treatment of Narcolepsy and other Hypersomnias of Central Origin

An American Academy of Sleep Medicine Review
Merrill S. Wise, MD1; Donna L. Arand, PhD2; R. Robert Auger, MD3; Stephen N. Brooks, MD4; Nathaniel F. Watson, MD5

Methodist Healthcare Sleep Disorders Center, Memphis, Tennessee; 2Wright State University, Dayton, OH; 3Mayo Clinic College of Medicine,

Rochester, MN; 4Stanford Sleep Disorders Clinic, Stanford, CA; 5University of Washington, Seattle, WA

Objective: The purpose of this paper is to summarize current knowledge ies demonstrate that sodium oxybate is effective for treatment of cata-
about treatment of narcolepsy and other hypersomnias of central origin. plexy associated with narcolepsy, and earlier studies provide limited data
Methods: The task force performed a systematic and comprehensive to support the effectiveness of fluoxetine and tricyclic antidepressants for
review of the relevant literature and graded the evidence using the Ox- treatment of cataplexy. Our findings indicate that very few reports provide
ford grading system. This paper discusses the strengths and limitations information regarding treatment of special populations such as children,
of the available evidence regarding treatment of these conditions, and older adults, and pregnant or breastfeeding women. The available litera-
summarizes key information about safety of these medications. Our find- ture provides a modest amount of information about improvement in qual-
ings provide the foundation for development of evidence-based practice ity of life in association with treatment, patient preferences among the
parameters on this topic by the Standards of Practice Committee of the different medications, or patient compliance.
American Academy of Sleep Medicine. Conclusion: Several recent studies provide evidence that modafinil
Results: The majority of recent papers in this field provide information and sodium oxybate are effective for treatment of hypersomnia due to
about use of modafinil or sodium oxybate for treatment of sleepiness as- narcolepsy. No studies were identified that report direct comparison of
sociated with narcolepsy. Several large randomized, placebo-controlled these newer medications with traditional stimulants. Despite significant
studies indicate that modafinil and sodium oxybate are effective for treat- advances in understanding the pathophysiology of narcolepsy, we do not
ment of hypersomnia due to narcolepsy. We identified no studies that have an ideal treatment to restore full and sustained alertness. Future
report direct comparison of these newer medications versus traditional investigations should be directed toward development of more effective
stimulants, or that indicate what proportion of patients treated initially with and better tolerated therapies, and primary prevention.
these medications require transition to traditional stimulants or to com- Keywords: Hypersomnia, narcolepsy, cataplexy, modafinil, sodium oxy-
bination therapy to achieve adequate alertness. As with the traditional bate, stimulants
stimulants, modafinil and sodium oxybate provide, at best, only moderate Citation: Wise MS; Arand DL; Auger RR; Brooks SN; Watson NF. Treat-
improvement in alertness rather than full restoration of alertness in pa- ment of Narcolepsy and other Hypersomnias of Central Origin. SLEEP
tients with narcolepsy. Several large randomized placebo-controlled stud- 2007;30(12):1712-1727.

TABLE OF CONTENTS Amphetamine, methamphetamine, dextro-

amphetamine methylphenidate, and related
1.0 Introduction preparations
1.1 Purpose Modafinil and armodafinil
1.2 Causes of excessive sleepiness Sodium oxybate
2.0 Background Selegiline
3.0 Methods Reboxetine
3.1 Literature search strategy Ritanserin
3.2 Evidence review Pemoline
4.0 Results 4.1.2 Scheduled naps plus stimulants versus stimulants
4.1 Treatment of hypersomnia due to narcolepsy with or alone
without cataplexy 4.2 Treatment of cataplexy
4.1.1 Medications 4.2.1 Sodium oxybate
4.2.2 Medications other than sodium oxybate
4.3 Treatment of disrupted nocturnal sleep associated with
Disclosure Statement narcolepsy
This is not an industry supported study. Dr. Brooks has worked for Pacific Sleep 4.3.1 Sodium oxybate
Medicine a company that contracts to participate in industry sponsored clinical 4.3.2 Hypnotic medications
trials. The other authors have indicated no financial conflicts of interest. 4.4 Treatment of hypnagogic hallucinations and sleep pa-
ralysis associated with narcolepsy
Submitted for publication September, 2007
4.4.1 Sodium oxybate
Accepted for publication September, 2007
4.4.2 Antidepressant medications
Address correspondence to: Standards of Practice Committee, American
Academy of Sleep Medicine, One Westbrook Corporate Center, Suite 920, 4.5 Studies with quality of life data
Westchester IL 60154, Tel: (708) 492-0930, Fax: (780) 492-0943, E-mail: 4.6 Treatment of hypersomnia associated with narcolepsy due to medical conditions
4.7 Treatment of hypersomnia due to recurrent hypersomnia
SLEEP, Vol. 30, No. 12, 2007 1712 Treatment of Narcolepsy and other Hypersomnias—Wise et al
4.8 Treatment of hypersomnia due to idiopathic hypersomnia
Table 1—Outline of the Hypersomnias of Central Origin not due to
4.9 Treatment of hypersomnia due to medical conditions a Circadian Rhythm Sleep Disorder, Sleep Related Breathing Disor-
4.10 Comprehensive management approach for narcolepsy der, or Other Cause of Disturbed Nocturnal Sleep20
and other hypersomnias
5.0 Adverse Side Effects and Safety Considerations Narcolepsy with cataplexy
5.1 Alerting agents Narcolepsy without cataplexy
5.1.1 Modafinil Narcolepsy due to medical condition
5.1.2 Armodafinil Narcolepsy, unspecified
5.1.3 Methylphenidate, amphetamines, and pemoline Recurrent Hypersomnia
Kleine-Levin Syndrome
5.1.4 Selegeline hydrochloride
Menstrual-related Hypersomnia
5.1.5 Ritanserin Idiopathic Hypersomnia with Long Sleep Time
5.1.6 Reboxetine Idiopathic Hypersomnia without Long Sleep Time
5.2 Anticataplectics Behaviorally Induced Insufficient Sleep Syndrome
5.2.1 Sodium oxybate Hypersomnia Due to Medical Condition
5.2.2 Antidepressants Hypersomnia Due to Drug or Substance
6.0 Discussion Hypersomnia Not Due to Substance or Known Physiological Condi-
7.0 Summary and Future Directions tion (Nonorganic Hypersomnia, NOS)
Physiological (Organic) Hypersomnia, Unspecified (Organic Hyper-
somnia, NOS)

Alertness is essential for overall well-being, and it impacts current evidence, including evidence grading using a standard-
learning, performance and safety. Sustained alertness is especially ized approach.
important for individuals employed in high risk occupations and
in areas involving public safety such as transportation, healthcare, 1.1 Purpose
the military, and law enforcement.1-6 Individuals with sleep disor-
ders associated with hypersomnia experience impaired alertness The purpose of this paper is to summarize current knowledge
and decrements in performance across many areas of life.7-9 Ef- about treatment of hypersomnias of central origin. The specific
fective treatment of hypersomnia improves alertness and helps re- objectives are: 1) to provide a systematic and comprehensive re-
store performance and productivity, improves quality of life, and view of the relevant medical literature regarding treatment of the
decreases risk of injury to the individual and to others.10-14 hypersomnias, 2) to grade the evidence contained in the literature
Epidemiological studies of excessive sleepiness reveal wide using the Oxford evidence grading system, 3) to discuss safety
variations in incidence and prevalence depending upon the popu- issues regarding use of medications for hypersomnia, and 4) to
lations studied. Excessive sleepiness is reported by approximately discuss the strengths and limitations of the available evidence.
10%-25% of the general population.15-19 These figures emphasize Findings from this paper will provide the foundation for develop-
the serious public health implications of untreated hypersomnia ment of evidence-based practice parameters by the Standards of
and the importance of clinical diagnosis and treatment of underly- Practice Committee (SPC) of the AASM.
ing sleep disorders that cause sleepiness.
Daytime sleepiness is defined by the International Classifica- 1.2 Causes of Excessive Sleepiness
tion of Sleep Disorders, Second Edition (ICSD-2)20 as “the inabil-
ity to stay awake and alert during the major waking episodes of The most common cause of excessive daytime sleepiness
the day, resulting in unintended lapses into drowsiness or sleep.” (EDS) in modern society is probably due to some combination
Excessive sleepiness varies in severity, and it becomes manifest of insufficient sleep, inadequate sleep hygiene, and work sched-
most commonly during monotonous situations that require little ules.19 A variety of sleep disorders are associated with excessive
interaction. Mild sleepiness can be overcome by activity or shift daytime sleepiness. Examples include sleep-related breathing
to a more stimulating activity. Severe sleepiness is characterized disorders, circadian rhythm sleep disorders, medication-induced
by an overwhelming need to sleep, unintended lapses into sleep, sleepiness, periodic limb movement disorder, and sleepiness as-
amnesia, and automatic behavior (the semiconscious continuation sociated with insomnia.20 Treatment of these underlying sleep dis-
of activity while drowsy). Chronic pathological sleepiness is de- orders generally results in resolution or significant improvement
fined in the ICSD-2 as sleepiness that is present for at least three in daytime sleepiness.
months prior to diagnosis.20 Individuals with hypersomnia of central origin usually experi-
Recent advances in sleep medicine have increased our under- ence daytime sleepiness despite an apparently adequate quantity
standing of conditions associated with hypersomnia and have of nocturnal sleep. The ICSD-2 organizes sleep disorders into
produced more options for treatment. In order to help physicians eight categories based on a common complaint, a presumed basic
synthesize new information to support optimal clinical decision- etiology, or according to the organ system involved.20 The sleep
making, the American Academy of Sleep Medicine (AASM) ap- disorders contained within the Hypersomnias of Central Origin
pointed a task force charged with reviewing available evidence category are listed in Table 1. This category does not include
regarding the treatment of narcolepsy and other hypersomnias of circadian rhythm sleep disorders, sleep related breathing disor-
central origin. This paper updates the previous review paper on ders, or other causes of disturbed nocturnal sleep. The scope of
treatment of narcolepsy,21 expands the scope of review to include this review includes treatment of hypersomnia due to narcolepsy
other hypersomnias of central origin and provides a summary of with cataplexy, narcolepsy without cataplexy, narcolepsy due to
SLEEP, Vol. 30, No. 12, 2007 1713 Treatment of Narcolepsy and other Hypersomnias—Wise et al
Table 2—Summary of Hypersomnia Literature Search Strategy Table 3—Summary of Safety Literature Search Strategy

Inclusion criteria General safety topics for the medications of interest were searched
article deemed to be clinically relevant to topic, published within using the Physicians’ Desk Reference31 including adverse effects,
the acceptable time frame, does not meet an exclusion criterion pregnancy and breast-feeding issues, and pediatric issues. A specific
Exclusion criteria search was performed to identify articles about individuals with
editorials, letters to the editor, review papers, books and book sleep disorders who were receiving medications of interest.
chapters, abstracts from professional meetings, publications in
languages other than English, studies involving non-human sub- Medications of interest
jects, case reports with fewer than 10 subjects (adult narcolepsy Amphetamines and related preparations
topics) or fewer than 5 subjects (non-narcolepsy topics) Methylphenidate and related preparations
Search dates Modafinil
● Narcolepsy and cataplexy: 1999 through April, 2006 Armodafinil
● Non-narcolepsy topics: no start date limit through April, 2006 Sodium oxybate
● Repeat (final) search: January, 2006 through October, 2006 Selegiline
Selective serotonin reuptake inhibitors
medical conditions, narcolepsy unspecified, recurrent hypersom- Tricyclic antidepressants
nia (Kleine-Levin syndrome and menstrual-related hypersomnia), Venlafaxine
idiopathic hypersomnia with long sleep time, idiopathic hyper-
somnia without long sleep time, and hypersomnia due to medical nia is not better explained by another sleep disorder, mental dis-
conditions. The decision was reached by the Standards of Practice order, medication use, or substance use disorder.
Committee (SPC) to exclude treatment of behaviorally induced in- Recurrent hypersomnia is characterized by periodic hy-
sufficient sleep syndrome, hypersomnia due to drugs or substanc- persomnia episodes that last a few days to several weeks, and
es, hypersomnia not due to substances or known physiological which recur weeks or months apart.20 Cognitive and behavioral
conditions (nonorganic hypersomnia NOS) and physiological (or- disturbances are common, including confusion, feelings of un-
ganic) hypersomnia, unspecified, from consideration. The AASM reality, hallucinations, binge eating, hypersexuality, irritability
Task Force Report on Use of Stimulants to Modify Performance and aggressive behavior. The best characterized form of recurrent
during Sleep Loss22 is a useful resource regarding treatment of the hypersomnia is the Kleine-Levin syndrome, but other less well
behaviorally induced insufficient sleep syndrome. The decision defined clinical subtypes have been described also. Menstrual-
was reached by the SPC and the task force to exclude from con- related hypersomnia occurs in association with the menstrual
sideration hypersomnia due to psychiatric disorders such as major cycle, often within the first few months after menarche.20
depression, conversion or somatoform disorder, and seasonal af- Idiopathic hypersomnia with long sleep time is character-
fective disorder. ized by excessive sleepiness with prolonged and unrefreshing
Narcolepsy with cataplexy is the most widely recognized and naps of up to three or four hours. The major sleep time is pro-
best characterized disorder in this category. Narcolepsy is charac- longed (at least 10 hours and often 12-14 hours) with few or no
terized by excessive daytime sleepiness and inappropriate transi- awakenings. Patients with idiopathic hypersomnia without long
tion from wakefulness to REM sleep. Many of the features of nar- sleep time experience chronic daytime sleepiness and the major
colepsy, including cataplexy, hypnagogic hallucinations and sleep sleep episode is either normal in duration or slightly prolonged
paralysis, are due to abnormal regulation of rapid eye movement (less than 10 hours).20
(REM) sleep and dissociated REM sleep phenomena.20,23 Disrupt- Hypersomnia due to medical condition is characterized by
ed nocturnal sleep may also be a prominent symptom. Current hypersomnia secondary to a coexisting medical or neurological
evidence strongly supports the pathogenic role of selective loss of disorder that causes hypersomnia. A variety of medical and neu-
hypocretin-containing neurons in the hypothalamus of individuals rological conditions are associated with hypersomnia, including
with narcolepsy with cataplexy.23-26 Narcolepsy (with or without Parkinson disease and other neurodegenerative conditions, head
cataplexy) is a chronic and potentially disabling disorder that af- trauma, stroke, encephalitis, inflammatory conditions, metabolic
fects approximately 1 in 2000 individuals.27,28 and toxic conditions, tumors and other lesions of the central ner-
Narcolepsy without cataplexy is characterized by excessive vous system, and genetic disorders. Examples of genetic disor-
daytime sleepiness, naps which are typically refreshing, normal or ders associated with hypersomnia include myotonic dystrophy,
moderately disturbed nocturnal sleep, and an abnormal tendency Prader-Willi syndrome, Niemann Pick type C disease, and fragile
for inappropriate transition into REM sleep.20 Cases of narcolepsy X syndrome.20
without cataplexy are thought to represent between 10% and 50% Patients with Parkinson disease and hypersomnia may be a
of all narcolepsy cases, but the precise incidence is not known. challenge to classify. When patients with Parkinson disease expe-
Narcolepsy due to a medical condition, also known as sec- rience hypersomnia due to insufficient sleep (due to suboptimal
ondary or symptomatic narcolepsy, is diagnosed when the direct control of symptoms), the diagnosis should be insomnia due to
cause of narcolepsy symptoms is a medical or neurological disor- medical condition. When the hypersomnia is caused by side ef-
der.20 In patients with sleep related breathing disorders (SRBD) fects of dopaminergic agents, the diagnosis should be hypersom-
plus hypersomnia of central origin and sleep-onset REM periods nia due to drug or substance. When hypersomnia is of central
(SOREMPs) on the multiple sleep latency test (MSLT), this dis- origin and the patient does not meet criteria for narcolepsy due to
order should be diagnosed only if SOREMPs on the MSLT persist medical condition, the diagnosis is hypersomnia due to medical
after adequate treatment of the SRBD. In addition, the hypersom- condition.20
SLEEP, Vol. 30, No. 12, 2007 1714 Treatment of Narcolepsy and other Hypersomnias—Wise et al
Table 4—Oxford Centre Evidence-Based Medicine Levels of Evi-
dence32 (Abbreviated; full table available on AASM website at aas-
The AASM (formerly the American Sleep Disorders Associa-
tion) first sponsored a review paper on narcolepsy and its treatment
with stimulants in 1994.29 This paper helped form the basis for the Evidence Level Study Design or Description
first comprehensive practice parameters for use of stimulants in the I Randomized controlled trial (RCT) with nar-
treatment of narcolepsy.30 The review paper addressed appropriate row confidence intervals
medication doses, development of tolerance, potential for side ef-
II Randomized trials without narrow confidence
fects, adverse reactions and abuse, and medication use in children
intervals, or with methodological problems,
and pregnant or breast-feeding women. The second review and
or cohort studies of low quality
practice parameters were published by the AASM in 2001.21 This
paper provided updated and expanded evidence-based recommen- III Nonrandomized concurrently controlled
dations, including coverage of medications used for treatment of studies or case-control studies
cataplexy, therapeutic use of scheduled naps, driving and quality
of life issues, toxicity and side effect issues, pregnancy and nursing IV Case-control or cohort studies with method-
issues, and consideration of relative cost of medications. ological problems, or case series
In the six years since publication of the 2001 paper, several
V Expert opinion, or studies based on physiol-
new developments have occurred that are relevant to this topic:
ogy or bench research
1) availability of newer pharmacologic agents for treatment of
hypersomnia and cataplexy, 2) expansion of the medical litera-
ture regarding treatment of hypersomnia with medications and studies involving non-human subjects were excluded.
behavioral interventions, and 3) creation of the ICSD-2, which Searches involving narcolepsy and cataplexy were performed
formalized the concept of grouping the hypersomnias of central for the period from 1999 through April 26, 2006, since the search
origin not due to a circadian rhythm sleep disorder, sleep related performed for the previous treatment of narcolepsy paper in 2001
breathing disorder, or other cause of disturbed nocturnal sleep, included citations through 2000. Searches involving non-narco-
and created diagnostic criteria for each entity. lepsy topics were performed on April 28, 2006 with no date limit,
The SPC decided to align evidence reviews and practice pa- since non-narcolepsy topics were not covered in the previous pa-
rameters with the organizational structure of the ICSD-2 when- pers. A second and final search using the same search strategy
ever possible. For this reason the scope of this review has been was performed in October, 2006 in order to identify new articles
expanded beyond narcolepsy to include treatment of other hyper- published after the initial search.
somnias of central origin, as discussed above. A separate search was performed to query the medical literature
In 2006 the SPC established the Treatment of Hypersomnia with regard to medication safety issues, including adverse effects,
task force and identified SPC liaisons. The task force conducted pregnancy and breast-feeding issues, and pediatric issues. This
its work through a combination of regularly scheduled telephone search involved a dual strategy in which the Physicians’ Desk Ref-
conference calls, one face-to-face meeting in June, 2006, numer- erence31 was used to identify general information about the medica-
ous email communications, and through use of a web-based direc- tions of interest without regard to diagnosis. Second, the task force
tory and an electronic forum developed by the AASM. performed a more specific Medline search to identify articles re-
garding individuals who received the medications of interest, and
3.0 METHODS the majority of these reports involved subjects with sleep disorders.
In contrast to the strategy employed for the literature search regard-
The SPC developed a list of specific questions and issues to be ing treatment a less restrictive approach was utilized, allowing for
addressed in the review. This resulted in creation of Population, review of case reports and articles with small numbers of subjects.
Intervention, Comparison, and Outcome (PICO) tables, which Our review also included all treatment articles extracted above that
were used to guide the task force and to focus the review process reported adverse events. Extractions were performed on articles
on clinically relevant issues. The PICO tables for this project are that were otherwise excluded from consideration for the regular
available on the AASM website directory at review, including those that addressed hypersomnia and fatigue in
The task force reviewed prior AASM publications relevant to this the setting of psychiatric illness and other medical conditions. The
topic. Safety search strategy is summarized in Table 3.
The initial Medline search performed on April 26, 2006, yield-
3.1 Literature Search Strategy ed 1073 citations. Task force members reviewed each citation by
title and abstract to ascertain whether the article was relevant and
The task force developed search terms and search strategies whether inclusion or exclusion criteria were met. Additional ar-
suitable for queries of the medical literature using Medline. Ex- ticles were considered for inclusion by searching the bibliogra-
plicit inclusion and exclusion criteria were established to guide phies of previously identified articles (a process known as pearl-
selection of relevant citations. Inclusion and exclusion criteria, ing). The task force accepted thirty-three treatment articles for
publication dates, and other limitations of the searches are summa- review and the remainder were rejected because the article was
rized in Table 2. Search terms included the names of each disorder deemed not relevant (did not address issues in the PICO tables)
and each medication of interest. Editorials, letters to the editor, or because the article contained exclusionary features. The task
books and book chapters, abstracts from professional meetings, force identified 48 articles for the Safety search; this group in-
review articles, publications in languages other than English, and cludes all medication-related articles from the treatment search.
SLEEP, Vol. 30, No. 12, 2007 1715 Treatment of Narcolepsy and other Hypersomnias—Wise et al
3.2 Evidence Review ficacy of traditional stimulants for treatment of sleepiness in nar-
colepsy.21 Our updated search from 1999 through October, 2006
Relevant articles that met inclusion criteria were obtained by identified no new studies of traditional stimulants for this indica-
the AASM and the full length article was made available to mem- tion that met inclusion criteria.
bers of the task force using a website directory. The task force
developed data extraction forms customized for this project and Modafinil and Armodafinil
these forms were used to record and summarize key findings from
each article identified. The task force piloted the data extraction Modafinil is a non-amphetamine wakefulness-promoting med-
forms on a subset of articles to identify problems with the format ication, and armodafinil is the (R)- enantiomer of modafinil with
or content of the forms, and appropriate revisions were made. a longer half-life. Our search regarding treatment of sleepiness in
Review of the articles and completion of the data extraction patients with narcolepsy using modafinil or armodafinil identified
forms were performed in a two step process. Primary reviewers (in- 14 articles. Four studies provide level 1 evidence, two provide
dividuals with doctoral level education) were identified and trained level 2 evidence, and seven provide level 3 or 4 evidence regard-
by the AASM using a standardized training module regarding use ing the efficacy of modafinil for treatment of sleepiness associ-
of evidence-based medicine techniques for data extraction and ated with narcolepsy. One study involving armodafinil provided
evidence grading. Following the initial review and data extraction level 1 evidence.
process, members of the task force (secondary reviewers) reviewed The study by Black et al.33 involved subjects with narcolepsy
each citation and data extraction form, and made corrections when who received modafinil for treatment of excessive sleepiness due
necessary. Discrepancies between the primary and secondary re- to narcolepsy. After completing a two week single-blind phase in
viewers were discussed and resolved by the task force chairman. which subjects received their usual doses of modafinil, subjects
This process is identical to that used by the AASM Standards of were randomized into four groups: modafinil placebo plus sodium
Practice Committee and sponsored task forces for reviewing and oxybate placebo (placebo group), modafinil placebo plus sodium
grading medical evidence. The task force used the Oxford Cen- oxybate (sodium oxybate group), modafinil plus sodium oxybate
tre for Evidence-based Medicine Levels of Evidence32 in order to placebo (modafinil group), and modafinil plus sodium oxybate
grade the strength of evidence for each citation. This system for evi- (sodium oxybate/modafinil group). The primary efficacy mea-
dence grading is summarized in Table 4. Evidence grading was not sure was the mean sleep latency on the 20-minute Maintenance
performed for those extractions used solely for assessing adverse of Wakefulness Test (MWT), and secondary measures included
effects of the medications of interest. the Epworth Sleepiness Scale (ESS), diary recordings, and the
An Evidence Table–Table 5–was developed to summarize key Clinical Global Impression-change scale. The modafinil group
findings from each citation. Information extracted from the safety displayed an average mean sleep latency of 9.86 minutes, which
review is provided in Table 6 and general safety information from represents a significant difference compared with the placebo
the Physicians’ Desk Reference31 is provided in Table 7. Tables 5 group (6.87 minutes). Also, when subjects where transitioned
and 6 are available online at appended to the end from their baseline modafinil dosages to the placebo group, the
of this review in PDF format. All statements that indicate significant average mean sleep latency decreased from 9.74 minutes to 6.87
changes in measurements mean statistically significant differences minutes. This finding is also consistent with therapeutic effect
exist, unless stated otherwise in the text or Evidence Table. from modafinil. However, ESS scores were not significantly dif-
After completion of literature review, data extraction, and evi- ferent between the placebo and modafinil groups. Findings also
dence grading, the task force developed successive drafts of the demonstrated improvement in objective and subjective sleepi-
review paper through a series of communications via conference ness as measured by the MWT and ESS in subjects who received
calls and e-mail correspondence. The review paper was produced modafinil plus sodium oxybate, which indicates evidence of an
in consultation with the SPC liaisons, and with commentary by additive effect of modafinil and sodium oxybate.
outside reviewers with expertise in this field. The paper was re- The level I study by Schwartz et al.34 is a double-blind, ran-
vised to incorporate comments from each reviewer. The final doc- domized controlled trial comparing single daily dose treatment
ument was reviewed and approved by the SPC, and by the Board (modafinil 200 mg or 400 mg in the morning) versus a multi-dose
of Directors of the AASM. strategy (200 mg twice per day or 400 mg plus 200 mg). There
was improvement in daytime alertness as measured by the MWT
4.0 RESULTS in all intervention groups compared to baseline, and subjects who
received a split dose composed of modafinil 200 mg or 400 mg in
4.1 Treatment of Hypersomnia due to Narcolepsy with or without the morning plus 200 mg at midday experienced more alertness
Cataplexy than subjects who received only 200 mg in the morning. Although
results support the conclusion that a split dose strategy is associ-
4.1.1 Medications ated with better control of daytime sleepiness than a single daily
dose in patients with residual afternoon or evening sleepiness, Amphetamine, Methamphetamine, Dextroamphetamine, this study does not provide information supporting the efficacy
Methylphenidate, and Related Preparations of modafinil for treatment of excessive sleepiness compared with
placebo or traditional stimulants. In a level 1 double-blind, ran-
The traditional stimulants are considered mainstays for treat- domized trial by Schwartz et al.35 comparing a single daily dose
ment of sleepiness associated with narcolepsy.21 The previous of modafinil 400 mg per day with a split dose of 400 mg plus
practice parameters published in 2001 by the AASM identified 200 mg, subjects in the latter group experienced improvement
three level 2 studies and four level 5 studies that support the ef- in objective and subjective sleepiness in the afternoon and eve-
SLEEP, Vol. 30, No. 12, 2007 1716 Treatment of Narcolepsy and other Hypersomnias—Wise et al
Table 7—General Medication Information and Key Safety Issues

Medication Usual FDA Breastfeeding Pediatric Issues Contraindications Special Comments

daily dose Prenancy Issues
Amphetamine 5-60 mg C Drug excreted in Not recommended Not recommended for “Black box warning” regard-
(Adderall) milk; rec no breast in pts < 3 years children with known ing high potential for abuse
feeding structural cardiac de-
fects; contraindicated in
patients with advanced
arteriosclerosis, symp-
tomatic CV disease,
moderate to severe
hypertension, hyperthy-
roidism, h/o drug abuse,
during or within 14
days of administration
of MAO inhibitors
Methyphenidate 20-40 mg C Excretion not well Not recommended Use with caution in
(Ritalin) in adults; characterized; exer- in pts < 6 years; pts with h/o drug
5-20 mg cise caution with BF some data suggest dependence; pts being
in chil- slowing of growth considered for treat-
dren rate; height and ment should have a
weight should careful cardiac history
be monitored in and physical exam to
children assess for the presence
of cardiac disease
Modafinil 100-400 C Excretion in milk not Pediatric use not Generally low abuse poten-
mg characterized; exer- systematically tial; Schedule IV Controlled
cise caution with BF studied Substances
Sodium oxybate 4.5-9 g B Excretion in milk not Safety and ef- “Black box”warning regard-
per night characterized; exer- fectiveness in pts < ing abuse potential; should
cise caution with BF 16 years of age not not be used with alcohol or
established other CNS depressants
Selegiline 5-10 mg C Excretion in milk not safety and effec- MAO inhibitor; use with
characterized; exer- tiveness in children caution
cise caution with BF not established
Fluoxetine 10-40 mg C Excreted in Safety and effec- “Black box” warning regard-
milk; nursing not tiveness assessed ing increased risk of suicidal
recommended in children aged thinking and behavior in
8-18 yrs with major short term studies of children
depressive disorder and adolescents with major
and 7-18 yrs with depressive disorder and
OCD other psychiatric disorders;
families should be advised of
the need for close observa-
tion and communication with
the prescriber; avoid abrupt
discontinuation of drug due to
possible adverse events
Venlafaxine 75-375 C Excreted in milk; re- Safety and effec- Co-administration with “Black box” warning regard-
mg quires individualized tiveness not estab- MAO inhibitors is ing increased risk of suicidal
decision regarding lished in children contraindicated thinking and behavior in
nursing short term studies of children
and adolescents with major
depressive disorder and other
psychiatric disorders; families
should be advised of the need
for close observation
Protriptyline 10 mg Not estab- Excretion in milk Safety and effec-
lished not known tiveness not estab-
lished in children

SLEEP, Vol. 30, No. 12, 2007 1717 Treatment of Narcolepsy and other Hypersomnias—Wise et al
ning compared with subjects who received 400 mg per day in a A small open label study with level 4 evidence reported by
single dose. Subjects who received the split dose also exhibited Ivanenko et al.41 provides data regarding response to modafinil
improvements in executive function compared with those who in children with sleepiness due to narcolepsy or idiopathic hy-
received a single daily dose. The level 1 study by Schwartz 36 persomnia. The study assessed the effects of modafinil on day-
is a double-blind, placebo-controlled study that assessed subjects time sleepiness, mood, and academic performance in 13 children
previously exposed to modafinil who reported dissatisfaction with (mean age 11.0 ± 5.3 yrs) with narcolepsy or idiopathic hyper-
late afternoon or evening sleepiness. Subjects who received 400 somnia. Treatment with modafinil was associated with subjective
mg per day in a divided dosage experienced improvement in sub- improvement in sleepiness as reported by parents, and objective
jective and objective measures of sleepiness in the afternoon or improvement as measured by the MSLT (6.6 ± 3.7 min at baseline
evening compared with those on a single dosage. versus 10.2 ± 4.8 min on modafinil). The children also showed
Level 1 evidence was presented by Harsh et al. in a large, multi- improvement in mood and academic performance, and modafinil
center double-blind, randomized controlled trial of armodafinil.37 was generally well tolerated.
Subjects who received 150 mg or 250 mg as a single dose ex- A large multicenter open label study with level 4 evidence42
perienced improvement in subjective and objective sleepiness compared the efficacy and safety of modafinil in narcolepsy pa-
compared with placebo during the 12 week trial. Efficacy was tients previously treated with stimulant medications following a
assessed with the MWT using six 20-minute tests, the Clinical two-week “washout” period. Treatment with modafinil 200 mg or
Global Impression of Change (CGI-C), the ESS, patient diaries, 400 mg was associated with significant subjective improvement
and evaluation of cognitive performance and fatigue. Compared in daytime alertness versus baseline (no medication), regardless
with baseline measurements, subjects experienced an average of which stimulant was taken prior to administration of modafinil.
change in mean sleep latency on the MWT of 1.3, 2.6, and 1.9 Treatment benefit was maintained throughout six weeks of treat-
minutes in the 150 mg, 250 mg, and combined groups, respec- ment.
tively, compared with a decrease of 1.9 minutes for placebo (P An open label study with level 4 evidence by Becker et al.43 as-
<0.01). These measurements involved MWT tests at 09:00-15:00. sessed changes in fatigue, mood, and health-related quality of life
Late-day MWT scores (15:00-19:00) also improved significantly in narcolepsy patients. After a 14-day “washout” period, subjects
in both treatment groups compared with placebo (2.8 minute im- received 200-400 mg of modafinil per day (>70% received 400
provement in combined group versus placebo). Although subjects mg per day) during a six-week trial. Treatment with modafinil
who received armodafinil showed evidence of sustained improve- was associated with improvement in health-related quality of life
ments in alertness across the entire day, this study did not provide using the SF-36 and improved mood using the Profile of Mood
a direct comparison of modafinil and armodafinil. States (POMS) in comparison with no medication treatment. In-
In a study with level 2 evidence,38 narcolepsy patients were com- clusion criteria for this study included patient dissatisfaction with
pared with control subjects in a three-week titration of modafinil traditional stimulants.
(200 mg, 300 mg, and 400 mg) versus placebo. Changes in alert- A novel study by Dauvilliers et al.44 compared subjective re-
ness were assessed using the ESS (decrease in median score from sponse to modafinil in men and women with narcolepsy, includ-
14.5 to 12.5) and the MSLT (mean sleep latency change from 3.2 ing subjects with catechol-O-methyltransferase (COMT) gene
min to 6.6 min) following introduction of modafinil. The primary sexual dimorphism. Results indicate that COMT genotype dis-
objective in this study was assessment of changes in low reso- tribution between men and women with narcolepsy is associated
lution brain electromagnetic tomography (LORETA) to identify with response to modafinil. The optimal daily dose of modafinil
brain regions associated with vigilance in controls and subjects was lower in subjects with low activity COMT genotype, and op-
with narcolepsy, and not assessment of response to treatment with timal daily dose was approximately 100 mg lower in women than
modafinil. In a study with level 2 evidence,39 subjects who had men. Ninety-one percent of subjects experienced a moderate to
participated in a 16-week open label study with modafinil en- good response to modafinil as measured by the Global Clinical
tered a two-week randomized placebo-controlled trial to evaluate Impression Scale.
continued efficacy and safety of modafinil. There was sustained A long-term (40 week) open label trial with level 4 evidence
improvement in subjective and objective sleepiness in subjects by Mitler et al.45 assessed the efficacy and safety of modafinil in
receiving modafinil (200-500 mg per day), with return of exces- subjects who were studied previously in two double-blind pla-
sive sleepiness in subjects who received placebo. cebo-controlled studies. Subjects received modafinil 200 mg to
A level 3 study by Guilleminault et al40 evaluated the response 400 mg per day (approximately 75% received 400 mg per day).
of 60 subjects with narcolepsy with cataplexy who were begun on Subjects demonstrated sustained subjective improvement in ex-
treatment with modafinil in an open label study. The trial included cessive sleepiness as measured by the ESS and quality of life
four groups of patients: 1) drug naïve subjects, 2) subjects who measures, and modafinil was generally well tolerated across the
were previously treated with traditional stimulants, 3) subjects period of study.
who were previously treated with anti-cataplexy medication, and
4) subjects treated with stimulants and anti-cataplexy medication. Sodium Oxybate
Subjects were treated with modafinil at a dosage of 100 to 600 mg
per day and clinical response was assessed using the ESS and a Sodium oxybate is a rapidly acting sedative/hypnotic medica-
visual analog scale of subjective sleepiness. Drug naïve subjects tion. Our search identified three studies with level 1 evidence, and
demonstrated the best clinical response to modafinil, while pa- two studies with level 4 evidence regarding the effectiveness of
tients treated previously with traditional stimulants experienced sodium oxybate for treatment of sleepiness associated with nar-
the most difficulty with transition to modafinil. Eight of 14 sub- colepsy. We identified several older studies that reported clinical
jects requested a return to traditional stimulants. trials using a related drug, gammahydroxybutyrate (GHB). The
SLEEP, Vol. 30, No. 12, 2007 1718 Treatment of Narcolepsy and other Hypersomnias—Wise et al
GHB studies were not reviewed because sodium oxybate, which Selegiline
is the sodium salt of GHB, is the only regulated and marketed
form of GHB in the United States. Selegiline is an MAO-B inhibitor that is metabolized to am-
In a large placebo-controlled randomized trial with level 1 evi- phetamine and methylamphetamine. Our search identified no
dence,46 sodium oxybate was evaluated using 3 g, 6 g, and 9 g per studies that met inclusion criteria regarding treatment of sleepi-
night in a divided dosage. Subjective sleepiness was improved ness due to narcolepsy with selegiline. The previous AASM
at 6 g and 9 g doses as measured by the ESS and by reduction in practice parameters paper on treatment of narcolepsy identified
the number of inadvertent naps or sleep attacks, with the greatest two level 2 studies and one level 4 study which provided limited
improvement at the 9 g/night dose. This study involved 136 sub- evidence of effective treatment of hypersomnia associated with
jects with narcolepsy with cataplexy who were allowed to con- narcolepsy using selegiline.
tinue receiving stable doses of stimulant medications. In a level 1
study47 that involved a large double-blind, placebo-controlled trial Reboxetine
of sodium oxybate at 4.5-9 g/night, subjective (ESS) and objec-
tive (MWT) measures of sleepiness were improved in a dose-re- Our search identified one small open-label study with level
lated fashion. Subjects were allowed to continue use of traditional 4 evidence regarding treatment of sleepiness and cataplexy as-
stimulants at a stable dosage. sociated with narcolepsy using reboxetine, a new selective nor-
The study by Black et al.33 involved subjects with narco- adrenaline reuptake inhibitor with antidepressant efficacy.50 This
lepsy who previously received modafinil for treatment of ex- preliminary study suggests that reboxetine exerts stimulant and
cessive sleepiness due to narcolepsy. Results from this study anti-cataplectic effects in narcolepsy patients. Subjective (ESS)
were reviewed previously in Section (modafinil and ar- and objective (MSLT) measures of sleepiness were employed.
modafinil). Following a two-week single-blind baseline phase Following treatment for two weeks, a significant improvement in
during which they received their customary dosage of modafinil daytime sleepiness was observed as measured by a mean decrease
(200 mg to 600 mg per day), subjects were randomized into four of 48.6% on the ESS, and a mean increase of 54.7% in sleep la-
groups: modafinil placebo plus sodium oxybate placebo (place- tency on the MSLT.
bo group), modafinil placebo plus sodium oxybate (sodium oxy-
bate group), modafinil plus sodium oxybate placebo (modafinil Ritanserin
group), and modafinil plus sodium oxybate (modafinil/sodium
oxybate group). After eight weeks of treatment, findings indicat- We identified two papers with level 2 evidence that assessed
ed improvement in objective (MWT) and subjective sleepiness the effectiveness of ritanserin, a 5-HT2 antagonist, for treatment
(ESS) in the sodium oxybate group compared with the placebo of excessive sleepiness associated with narcolepsy. The study by
group. The average mean sleep latency on MWT for the pla- Lammers et al.51 was a double-blind, placebo-controlled trial in-
cebo group was 6.87 minutes compared with 11.97 minutes in volving 28 subjects with narcolepsy. Ritanserin 5 mg per day was
the sodium oxybate group (P <0.001), and 13.15 minutes in the added to the subjects’ usual medication during a four-week trial.
combined sodium oxybate/modafinil group (P <0.001). This lat- There was improvement in subjective daytime sleepiness but no
ter finding is consistent with an additive effect in subjects who significant change in mean sleep latency was demonstrated on
received both modafinil and sodium oxybate. This paper repre- the MSLT. A second study by Mayer et al.52 reported results from
sents the only study identified that allows comparison between a double-blind, placebo-controlled study in which 134 subjects
subjects with narcolepsy who received sodium oxybate versus with narcolepsy received ritanserin 5 mg or 10 mg, or placebo
modafinil. In this study, the degree of improvement in alertness in addition to their usual medication regimes. This study showed
as measured by the MWT is greater in the sodium oxybate group some improvement in subjective quality of sleep, but in contrast
than in the modafinil group (average mean sleep latency 11.97 to the previous study, there was no significant improvement in
minutes for sodium oxybate; 9.86 minutes for modafinil group; daytime alertness as measured by a 40-hour polygraphic record-
6.87 minutes for placebo group). Subjective sleepiness as mea- ing performed at baseline and after four weeks of treatment.
sured by the ESS after eight weeks of treatment also demonstrat-
ed greater improvement in the sodium oxybate group than the Pemoline
modafinil group or the placebo group (ESS 12.0 for sodium oxy-
bate group; 15.0 for modafinil group; 16.0 for placebo group). Pemoline was identified as an effective option for treatment of
The difference between sodium oxybate and placebo was statis- sleepiness associated with narcolepsy in the AASM 2001 prac-
tically significant (P <0.001), whereas the difference between tice parameters paper.21 However, the rare but potentially fatal
modafinil and placebo was not (P <0.767). hepatic toxicity associated with pemoline has severely limited
A small open-label pilot study with level IV evidence was clinical use of this medication, and pemoline is no longer being
reported by Mamelak et al48 in which subjects with narcolepsy produced in the United States. Our updated search revealed no
with cataplexy were given 4.5 g, 6 g, 7.5 g, and 9 g of sodium new studies regarding use of pemoline for treatment of sleepiness
oxybate in a divided dosage at night. Subjects demonstrated im- in narcolepsy.
provements in subjective (ESS) and objective (MWT) measures
of sleepiness. A 12-month, open-label extension trial with level 4 4.1.2 Scheduled Naps Plus Stimulants Versus Stimulants Alone
evidence49 demonstrated improvement in subjective sleepiness as
measured by the ESS following administration of 3-9 g per night Previous AASM papers have indicated that scheduled naps can
of sodium oxybate. be beneficial to combat sleepiness associated with narcolepsy, but
naps are seldom effective as a primary therapy.21 Our updated
SLEEP, Vol. 30, No. 12, 2007 1719 Treatment of Narcolepsy and other Hypersomnias—Wise et al
search identified one level 2 study by Rogers et al.53 that compared The paucity of formal clinical trials involving treatment of
three different sleep schedules for reducing daytime sleepiness cataplexy may reflect, at least in part, the widespread “off-label”
in narcolepsy. In 29 subjects with narcolepsy receiving treatment clinical use of antidepressants for treating cataplexy. The litera-
with medication, the addition of two 15-minute naps did not alter ture regarding treatment of cataplexy consists primarily of case
the severity of daytime sleepiness or the duration of unscheduled reports and small open-label studies. A paper by Houghton et al,56
daytime sleep. The combination of scheduled naps and regular provides a review of the medical treatment options for cataplexy.
nocturnal sleep times produced significant reduction in severity
of sleepiness and duration of daytime sleep in treated narcolep- 4.3 Treatment of Disrupted Nocturnal Sleep Associated with
tics. The authors conclude that scheduled sleep periods are helpful Narcolepsy
only for those narcolepsy patients who remain profoundly sleepy
despite treatment with stimulant medications. 4.3.1 Sodium Oxybate

4.2 Treatment of Cataplexy Sodium oxybate was associated with improved sleep archi-
tecture in two studies, including a reduction in nocturnal awak-
4.2.1 Sodium Oxybate enings.46,48 One level 4 study reported a subjective decrease in
nocturnal awakenings at 7.5 and 9 g/night doses,48 while the sec-
Our search identified four studies that examined the effective- ond study with level 1 evidence reported this finding at the 9 g/
ness of sodium oxybate for treatment of cataplexy. One level 1 night dose only.46 Sodium oxybate was associated with increased
study54 reported results of a large randomized double-blind, pla- nighttime delta sleep in a dose-dependent manner in the study by
cebo-controlled trial of sodium oxybate using 4.5 g, 6 g, 7.5 g, Mamelak et al.48
and 9 g/night doses. Significant dose-dependent reductions in
cataplexy were reported for 4.5 g, 6 g, and 9 g doses, with reduc- 4.3.2 Hypnotic Medications
tions in median number of cataplectic attacks of 57%, 65%, and
87.7%, respectively, compared with placebo. Another study with Our review yielded no studies that met inclusion criteria using
level 1 evidence reported significant improvement in cataplexy traditional hypnotic medications for treatment of disrupted noc-
frequency at a dosage of 9 g/night only compared with placebo.46 turnal sleep associated with narcolepsy.
A level 1 study55 reported results from a double-blind controlled
trial with abrupt discontinuation of sodium oxybate during a two 4.4 Treatment of Hypnagogic Hallucinations and Sleep Paralysis in
week period with continuation of subjects’ usual stimulant medi- Patients with Narcolepsy
cation. Subjects experienced a median increase of 21 cataplexy
attacks during the withdrawal period compared to subjects who 4.4.1 Sodium Oxybate
continued to receive medication. An open-label 12-month study
with level 4 evidence48 demonstrated sustained reduction of cata- We identified two studies that provide data on the effects of
plexy frequency over the period of study when subjects received sodium oxybate on self-reported incidence of hypnagogic hallu-
sodium oxybate doses of 3 to 9 g per night. cinations (HH) and sleep paralysis (SP).46,48 In one study, when
subjects with narcolepsy received 4.5 to 9 g per night doses, the
4.2.2 Medications other than sodium oxybate proportion of patients reporting a decrease in HH ranged from
29%-76%, and the proportion of patients reporting a decrease in
In the previous AASM practice parameters paper on treatment SP ranged from 38%-76%.48 However, the second study46 with
of narcolepsy,21 a recommendation was included indicating that sodium oxybate revealed no significant differences in HH and SP
tricyclic antidepressants and fluoxetine may be effective treatment when compared with placebo.
for cataplexy (Guideline). The recommendation for tricyclic anti-
depressants was based on a single level 5 study as well as clinical 4.4.2 Antidepressant Medications
experience and committee consensus. The recommendation for
fluoxetine was based on one level 2 and one level 5 study. Our review identified no studies that reported changes in hyp-
Our review identified only two additional studies involving nagogic hallucinations or sleep paralysis in association with anti-
treatment of cataplexy with medications other than sodium oxy- depressant medications.
bate published since 2000 which met inclusion criteria. Lammers
et al.51 reported results from a double-blind controlled trial with 4.5 Studies with Quality of Life Data
level 2 evidence using ritanserin, a long acting 5-HT2 receptor
blocker. Subjects received 5 mg per day of ritanserin or placebo We identified three studies that provide information regard-
plus their usual medications for narcolepsy. There was no signifi- ing changes in quality of life measures in response to treat-
cant change in the frequency of cataplexy in subjects who received ment with medication.14,43,45 Two studies involve treatment with
ritanserin. In an open-label study with level 4 evidence, Larrosa et modafinil,43,45 and one study involves sodium oxybate.14 The
al.50 evaluated 12 subjects with narcolepsy with cataplexy treated study by Weaver et al.14 was designed to assess changes in func-
with reboxetine, a selective norepinephrine reuptake inhibitor tional status following treatment with sodium oxybate. There was
with demonstrated antidepressant effects. In this brief study, sub- significant improvement in functional status as measured by the
jects were assessed before and two weeks after initiation of treat- Functional Outcomes of Sleep Questionnaire (FOSQ) in subjects
ment, and a significant reduction in the cataplexy subscore of the who received 6 and 9 g per night of sodium oxybate compared
Ullanlinna Narcolepsy Scale was present.50 with placebo. The study by Mitler et al.45 showed improvement in
SLEEP, Vol. 30, No. 12, 2007 1720 Treatment of Narcolepsy and other Hypersomnias—Wise et al
quality of life scores in six of eight domains following treatment Hogl et al.61 performed a double-blind, placebo-controlled
with modafinil. In the study by Becker et al.43 there was signifi- crossover study (level 2 evidence) involving modafinil for
cant improvement in functional status as measured by the SF-36 treatment of sleepiness in 12 PD subjects. Subjects were given
instrument in subjects treated with modafinil. modafinil 100 mg/day during week 1 and 200 mg/day during week
2. There was improvement in subjective sleepiness as measured
4.6 Treatment of Hypersomnia Associated with Narcolepsy due to by the ESS, but no significant improvement was demonstrated
Medical Conditions in objective sleepiness as measured by the MWT. A small four
week open-label study with level 4 evidence involving modafinil
Our search identified no studies that met inclusion criteria re- in PD (10 subjects) demonstrated similar subjective improve-
garding treatment of hypersomnia associated with narcolepsy due ment in EDS as measured by the ESS.62 Ondo et al.63 performed
to medical conditions. a randomized, double-blind, placebo-controlled trial with level
2 evidence involving modafinil (200 mg or 400 mg/day) in 40
4.7 Treatment of hypersomnia due to Recurrent Hypersomnia subjects with PD. In contrast to the previous findings, there were
no somnolytic effects associated with modafinil using objective
Our search identified one small case series with level 4 evi- (MSLT) or subjective (ESS) measures of sleepiness. The Unified
dence involving five adolescents with Kleine-Levin syndrome Parkinson’s Disease Rating Scale showed no significant changes
treated with lithium carbonate.57 Although all patients experienced with modafinil in the Ondo or the Nieves studies.
relapses while receiving lithium carbonate, the duration of hyper- Rammohan et al.64 performed a single-blind, placebo-con-
somnia episodes was shorter and there were no behavioral symp- trolled pilot study of modafinil for treatment of fatigue and sleepi-
toms during episodes in which subjects were treated with lithium ness in 72 subjects with MS (level 2 evidence). Subjects were
carbonate. Several small case reports indicate varying degrees of given modafinil (200 and 400 mg/day) or placebo, and assess-
improvement or lack of improvement associated with treatment ments using the ESS and several fatigue measures revealed im-
with a variety of medications including stimulants, anti-epileptic provement in sleepiness at both doses, but interestingly, fatigue
medications, antidepressants, and neuroleptics. A systematic re- improved only with 200 mg/day. An open-label study with level 4
view of Kleine-Levin syndrome patients by Arnulf, et al.58 reports evidence involving 50 subjects with MS given up to 300 mg/day
that sleepiness decreased in 40% of 75 treated patients, using of modafinil demonstrated improvement in sleepiness and fatigue
stimulants (primarily amphetamines). We identified no controlled based on self-reports.65
studies that report results of treatment of recurrent hypersomnia Talbot et al.66 reported results of a randomized, double-blind,
with medications. placebo-controlled crossover study involving 20 subjects with
myotonic dystrophy who were given modafinil. This study pro-
4.8 Treatment of Hypersomnia due to Idiopathic Hypersomnia vided level 1 evidence. Following four weeks of treatment, im-
provement in sleepiness was evident as measured by prolongation
Our search identified one study59 that met inclusion criteria in- of the mean sleep latency on the MWT. There was a nonsignifi-
volving treatment of idiopathic hypersomnia with or without long cant reduction in subjective sleepiness using the ESS. A small
sleep time. This small open-label level 4 study included 18 subjects open-label study with level 4 evidence involving methylpheni-
with idiopathic hypersomnia and 24 subjects with narcolepsy. Fol- date for treatment of sleepiness associated with myotonic dystro-
lowing treatment with modafinil at 200 to 500 mg/day in two divid- phy demonstrated improvement in subjective sleepiness in 7 of 11
ed doses, subjects with idiopathic hypersomnia experienced a sig- subjects at doses up to 40 mg/day. Two subjects developed signs
nificant improvement in subjective drowsiness and number of sleep of tolerance at the maximum dose.67
attacks per day. The small open-label study by Ivenenko41 involv-
ing treatment of 13 children with modafinil includes three children 4.10 Comprehensive Management Approach for Narcolepsy and
with idiopathic hypersomnia and 10 children with narcolepsy. The other Hypersomnias
small sample size of subjects with idiopathic hypersomnia makes
it difficult to draw conclusions regarding modafinil treatment for Previous AASM review papers and practice parameters have
idiopathic hypersomnia in children. Anecdotal clinical experience emphasized the importance of providing a comprehensive ap-
with treatment of idiopathic hypersomnia with traditional stimu- proach to management of narcolepsy.21 General strategies include
lants has suggested variable and often only modest improvement patient and family education, counseling regarding the importance
in sleepiness.60 A variety of other medications have been prescribed of good sleep hygiene and medication compliance, discussion of
for treatment of idiopathic hypersomnia, including antidepressants, safety issues including driving recommendations individualized
clonidine, levodopa, bromocriptine, selegiline, and amantadine.60 for each patient’s circumstances, discussion of potential adverse
However, there are no reports that describe a consistent response to side effects of medication, and vocational counseling. Regular
these medications for this condition. follow-up is useful in order to monitor response to treatment, to
assess presence of co-morbid sleep disorders such as obstructive
4.9 Treatment of Hypersomnia due to Medical Conditions sleep apnea or periodic limb movement disorder, and to address
psychosocial issues that often arise.
Our search revealed seven studies related to the treatment of No new articles since the prior review were identified in the lit-
hypersomnia due to medical conditions61-67: three studies involve erature regarding the use of a comprehensive approach for man-
Parkinson disease, two involve multiple sclerosis (MS), and two agement of hypersomnia due to narcolepsy or the other hyper-
involve myotonic dystrophy. All but one of these studies investi- somnias covered in this paper. However, continued application
gated the impact of modafinil on EDS in these conditions. of the same comprehensive approach as that outlined previously
SLEEP, Vol. 30, No. 12, 2007 1721 Treatment of Narcolepsy and other Hypersomnias—Wise et al
for narcolepsy appears reasonable for the care of patients with volving residual sleepiness in patients with obstructive sleep ap-
hypersomnia. nea reported hypertension that was felt to be related to modafinil
in approximately 4% of the patients, suggesting that this sub-
5.0 ADVERSE SIDE EFFECTS AND SAFETY CONSIDERATIONS group of hypersomnolent patients may be more susceptible to
this effect.68 In a study of modafinil in patients with MS, 3 of
Information about safety and adverse effects of these medications 71 subjects (4%) reported worsening of MS symptoms while re-
was obtained from a variety of sources, including the articles iden- ceiving the medication. None of the affected individuals required
tified in our literature search regarding treatment efficacy, articles further treatment, and symptoms resolved without adjustment of
identified in an independent safety search, and from the Physicians’ modafinil dosage.64 Exacerbation of MS symptoms was also de-
Desk Reference.31 Because of our search strategy and publication scribed in 1 patient in an open-label study, necessitating discon-
patterns in this area over the past several years, the majority of arti- tinuation of treatment for 5 days.68
cles reviewed contain information about adverse effects from stud- In 3 placebo-controlled studies that investigated the use of
ies regarding modafinil and sodium oxybate. Information regard- modafinil in Parkinson’s disease-associated hypersomnia,61,63,72
ing adverse effects of traditional stimulants is available in previous side effects were never reported as severe. In one study,72 the
AASM publications, and limited information is presented based on occurrence of side effects did not differ significantly from pla-
our review of the Physician’s Desk Reference.21,29-31 We have sum- cebo. In an open-label study with modafinil, no patients experi-
marized information from these sources in Table 6 (provided on the enced worsening of parkinsonian symptoms but one of 10 sub-
AASM website,, and Table 7 provided in the jects experienced visual hallucinations while receiving 100 mg
text. Although our review is systematic and clinically focused, it is of modafinil. Hallucinations persisted despite discontinuation of
not exhaustive and the reader may need to seek additional sources the drug, and the patient eventually required treatment with anti-
for certain types of information. The scope of our search involved psychotic medication.62 A case report of pramipexole-associated
identification of adverse side effects, pediatric issues, and risks as- hypersomnia in a Parkinson disease patient described successful
sociated with use of these medications in pregnant or breastfeeding treatment with modafinil, with no adverse side effects.73
women. We identified no information regarding pregnant or breast- Although one study of modafinil (maximum 200 mg daily)71
feeding women other than that contained in the PDR.31 The follow- for the treatment of fatigue in association with depression demon-
ing discussion of safety issues is organized by medication. strated a relatively high dropout rate due to adverse events (10%), 2
case series demonstrated no reports of adverse events among adult
5.1 Alerting Agents patients treated with modafinil for hypersomnia in association with
depression (bipolar and unipolar).74,75 High-dose modafinil (800
5.1.1 Modafinil mg total daily dose) was associated with exacerbation of psychotic
symptoms in an adult patient with schizophrenia.76
Twenty-eight articles were identified and reviewed for discus- A case report highlighted the importance of medication inter-
sion of safety issues. The majority of adverse events were mild or actions when modafinil is prescribed with other medications. The
moderate in severity. Beginning at doses of 100 mg daily, the most author describes a young woman receiving modafinil, methylphe-
commonly reported side effects were headache (10%-26%), ner- nidate, and hypnotics who overdosed and eventually died.77 How-
vousness and/or anxiety (3%-20%), nausea (5%-11%), dry mouth ever, a separate report described a patient who ingested 4500 mg
(3%-7%), diarrhea (4%-6%), asthenia (4%-6%), and insomnia (3%- of modafinil in a suicide attempt followed by full recovery in 24
6%), all of which occurred at an incidence that was statistically sig- hours. This observation suggests that overdose of modafinil alone
nificant as compared to placebo.63,64,68-70 Only one study indicated a is not likely to have serious consequences.59 A case report also de-
clearly defined dose relationship with respect to severity of adverse scribes the successful continuation of modafinil with concomitant
effects (involving patients with MS).64 One study showed no signif- amphetamine and clomipramine with general anesthesia.78
icant differences in the incidence of adverse effects between active There were limited opportunities to assess adverse effects of
treatment and placebo.38 The adverse effect profile was similar for modafinil in children. A retrospective study by Ivenenko41 re-
the controlled and uncontrolled studies that were reviewed. ported the response of children (mean age 11 yrs [range 2-18]),
In general, when investigators reported that subjects withdrew with narcolepsy and idiopathic hypersomnia with follow-up for
from a study due to adverse effects, withdrawal occurred at a rate a mean duration of 16 months.41 While modafinil was generally
ranging from 3%-10%.64,68-70 Reasons for drug-related discon- well-tolerated, 2 of 13 (15%) patients experienced exacerbations
tinuation included dry mouth (33%-50%), headache (29%-50%), of preexisting seizures and psychotic symptoms, respectively.
heart palpitations (25%-33%), anxiety or agitation (25%), nau- The medication was ultimately continued in both instances, with
sea (25%), dizziness (25%), insomnia (25%), depersonalization adjunctive anticonvulsants and psychotropic medication. There is
(25%), and sexual dysfunction (25%).61,63,64,66,68-70 The open-label one case report of de novo manic symptoms in a 17-year-old boy
study incidence of drug-related discontinuation was identical to with narcolepsy treated with modafinil 400 mg daily, ultimately
that reported above, and reasons for discontinuation were gener- requiring discontinuation of modafinil.79
ally similar. However, complaints in open-label studies included
more cognitive and psychiatric concerns, such as difficulty con- 5.1.2 Armodafinil
centrating (33%), abnormal thinking (20%-40%), and depression
(20%-40%).36,43,62,65,71 Two reports were identified in the literature relating to side
Several reports describe unique adverse effects in specific pa- effects of armodafinil and both of these were placebo-controlled
tient populations. Although clinically significant changes in vital trials. As with modafinil, most adverse effects appear to be mild
signs were not described by any of the other studies, a study in- or moderate in severity.37,80 With doses of 150 mg or 250 mg daily,
SLEEP, Vol. 30, No. 12, 2007 1722 Treatment of Narcolepsy and other Hypersomnias—Wise et al
headaches were described in 16%-28% (dose-related), nausea in subjects were using high-dose stimulants, as defined by the orig-
7%-14%, dizziness in 2%-8%, insomnia in 7%, and anorexia in inal American Sleep Disorders Association criteria.30 No statis-
3%-6% of patients. In the study involving patients with OSA,80 tically significant change in systolic or diastolic blood pressure
clinically significant increases in specific liver function tests oc- was observed during the study period in subjects receiving ei-
curred in 1%-3% of subjects. Also reported in this study were ther the low dose or high dose. Preexisting hypertension did not
statistically significant mean changes (from baseline to final visit) appear to be a significant variable in predicting blood pressure
in morning diastolic blood pressure and evening heart rate, but changes.
the proportion of patients with clinically significant changes in In contrast, a case report describes a young man who developed
either parameter were comparable to the placebo group. Subjects a lacunar stroke during methylphenidate use (prescribed 60 mg
withdrew from the study due to adverse effects potentially attrib- daily), without a concurrent history of substance misuse or known
uted to medication in 5%-9% of subjects. Reasons for withdrawal cardiovascular risk factors.83 In a case-control study comparing
(with some subjects reporting 2 reasons simultaneously) included patients receiving high-dose stimulants to those receiving stan-
headache (20%-29%), insomnia (14%), diarrhea (14%), disori- dard dosages (methylphenidate was most commonly prescribed),
entation (14%), dizziness (14%), abnormal behavior (14%), and the odds for developing tachyarrhythmias were approximately 3-
nausea (10%). fold in the high-dose group.84
The most worrisome adverse effects among those receiving
5.1.3 Methylphenidate, Amphetamines, and Pemoline high-dose stimulants appear to be psychiatric, as demonstrated
by the higher frequency of psychosis, substance misuse, and
A recent “black box” warning emphasized that amphetamines psychiatric hospitalization compared to those receiving standard
have a high potential for abuse.31 The warning indicated that ad- doses.84 The odds ratio for psychosis when comparing the two
ministration for prolonged periods of time may lead to drug de- groups was 12.0. Anorexia or weight loss was also more common
pendence and must be avoided. Prescribing physicians should be in this group.
aware of the possibility of subjects obtaining amphetamines for
non-therapeutic use or for distribution to others. The warning also 5.1.4 Selegeline Hydrochloride
indicated that misuse of amphetamines may cause sudden death
and serious cardiovascular adverse events. The AASM issued a One placebo-controlled study using selegeline was identified
statement in August, 2006 that addressed the “black box” warning in patients with narcolepsy.85 One of thirty patients (3%) discon-
( The statement reviewed that amphetamine tinued the protocol due to severe headache attributed to the drug.
preparations are effective agents for the treatment of sleepiness No other side effects were reported.
associated with narcolepsy, and should not be withheld from ap-
propriate patients. They are generally used in patients with more 5.1.5 Ritanserin
severe sleepiness and when other medications have proven inef-
fective. The statement also indicated that physicians who pre- One placebo-controlled study was identified that utilized this
scribe amphetamines should be knowledgeable about the drugs medication in patients with narcolepsy.52 Although specific details
and should carefully assess the risk-benefit ratio for each patient. were not reported, 6% of patients dropped out of the study due to
The statement recommended that a clinical assessment for cardiac adverse events (constipation, confusion, somnolence, broncho-
disease should be performed, and that patients should be informed spasm, dry mouth, tongue paralysis). However, the proportion of
about the possibility of adverse side effects. subjects receiving active drug versus placebo was not reported.
Pemoline has been associated with potentially fatal hepatotox-
city and is no longer being manufactured or marketed in the Unit- 5.1.6 Reboxetine
ed States. During the period from 1975 until June 1999, thirteen
cases of acute liver failure in patients receiving pemoline were One open-label pilot study assessed both stimulant and an-
reported to the FDA.81 Although this represents a relatively small ticataplectic effects of reboxetine in patients with narcolepsy.50
number of cases, the reported rate ranged from 4 to 17 times the Specific descriptions of the incidence of side effects were not re-
rate expected in the general population.81 ported, but all patients successfully completed the protocol. Only
Review of the literature reveals several recent additions re- minor side effects were reported, including dry mouth, hyperhi-
garding adverse effects associated with traditional stimulants and drosis, constipation, and restlessness.
pemoline. In a study that assessed myotonic dystrophy patients
with hypersomnia,67 2 of 11 patients (18%) discontinued the med- 5.2 Anticataplectics
ication because of the development of tolerance, and because of
intolerable feelings of “personality change.” 5.2.1 Sodium Oxybate
Despite concerns among practitioners regarding the risk of
hypertension with long-term use of these medications, systemat- Nine articles were reviewed for safety issues, including 4 pla-
ic studies have yet to demonstrate a consistent positive associa- cebo-controlled studies. Most reports indicated that adverse ef-
tion. Wallin and Mahowald retrospectively studied 54 subjects fects were of mild or moderate severity, but 4 studies reported
with narcolepsy or idiopathic hypersomnia who had received serious effects potentially related to the drug.46,54,86 One study
uninterrupted stimulant treatment (methylphenidate, pemoline, suggested that the incidence of adverse effects may be higher in
and dextroamphetamine) for a minimum of 2 years and a mean females, due to a higher mg/kg ratio as compared to males. How-
of nearly 4 years.82 Methylphenidate, either alone or in combi- ever, these events were observed primarily in an experimental
nation with pemoline, was used in 80% of patients, and 30% of state of relative starvation. Dosage adjustments based on gender
SLEEP, Vol. 30, No. 12, 2007 1723 Treatment of Narcolepsy and other Hypersomnias—Wise et al
were not felt to be warranted in the usual setting.87 performing the multiple sleep latency test. Symptoms resolved
At doses ranging from 3-9 g nightly, adverse effects were dose- upon resumption of the medication.90
related and included dizziness in 12%-34%, nausea in 6%-34%,
enuresis in 6%-14%, and vomiting in 6%-11%.46,54 Among the 6.0 DISCUSSION
open-label studies, some of which allowed for assessments of ex-
tended treatment duration, the side effect profile was similar to that Our review of the literature indicates that the majority of ar-
described above, but also included reports of headaches (23%), ticles that meet inclusion criteria pertain to modafinil or sodium
anorexia (12%), back pain (12%), and edema (12%).48,49,88 oxybate for treatment of narcolepsy, and that most published
One placebo-controlled trial reported in two manuscripts as- studies of modafinil or sodium oxybate were pharmaceutical in-
sessed the effects of abrupt discontinuation of drug after long- dustry supported. Of the 33 articles reviewed and graded, 25 stud-
term therapy.55,89 The occurrence of adverse events in active and ies evaluate subjects with narcolepsy or idiopathic hypersomnia,
placebo treatment groups was insignificant. No symptoms of 7 involve subjects with hypersomnia due to a medical condition
frank withdrawal or serious events were reported, and there was (3 studies regard Parkinson disease, 2 regard multiple sclerosis,
no evidence of rebound cataplexy, in contrast to reports involving and 2 regard myotonic dystrophy), and 1 involves recurrent hy-
abrupt antidepressant withdrawal. persomnia. Twenty studies report results of trials with modafinil
When subjects withdrew as a result of adverse effects poten- or armodafinil, and seven report trials involving sodium oxybate.
tially attributed to drug, this occurred at a rate ranging from 7%- Only one study reports results that involve a traditional stimu-
12%.46,48,49,54 Although the reasons for withdrawal were described lant. This was a small open label study that reported the results
as mild or moderate in severity in most cases, the specific inci- of methylphenidate treatment of sleepiness associated with myo-
dence of each event was not always explicitly stated. Adverse tonic dystrophy.
events included abnormal coordination, amnesia, apathy, asthenia, These findings reflect a clear shift toward investigation and re-
decreased libido, depression, respiratory complaints, hypesthesia, porting of newer therapeutic agents, and as noted, the majority
headache, metallic taste, nervousness, somnolence, stomach up- of newer studies are supported by the pharmaceutical industry.
set, weight loss, and psychosis.46,48,49 The latter event occurred in This observation is in contrast to the widespread use of traditional
a patient with preexisting mental illness.49 stimulants in the United States, presumably due to continuation
Serious adverse events resulting in withdrawal from study in- of prior usage patterns, the view that traditional stimulants are
cluded an acute confusional state in 1 patient,46 an accidental fall generally more potent than the newer medications, and possibly
and ankle fracture in a patient with preexisting vertigo, and el- cost and insurance coverage issues.
evated liver function tests in an additional patient.54 Elevated liver Among studies that involve subjects with narcolepsy or idio-
enzymes were also described in a long-term open-label study, but pathic hypersomnia, nine were graded as level 1, five were level 2,
were not deemed to be of clinical significance.49 A separate open- 1 was level 3, and ten were level 4. In contrast, among studies that
label study also described agitation in response to the medication involve subjects with other forms of hypersomnia, only one study
in an elderly woman. The agitation was deemed serious in nature, provided level 1 evidence, 3 studies had level 2 evidence, and 4
but the patient was ultimately able to resume participation in the had level 4 evidence. Thus, studies of narcolepsy or idiopathic
trial.49 hypersomnia had generally higher evidence levels than studies
Reported laboratory abnormalities included a slight increase in that involve other forms of hypersomnia of central origin.
urine pH at a 9 g per night dosage, attributed to increased sodium Our review identified a number of studies that indicate that
consumption associated with the drug.46 Changes in serum phos- modafinil and sodium oxybate are effective and generally well
phorus and calcium were noted across dose groups in one study, tolerated for treatment of sleepiness associated with narcolepsy.
but these were deemed to be clinically insignificant.49 The same Most studies document optimal therapeutic response with 200
study reported a mild decrease in diastolic blood pressure across mg to 400 mg per day of modafinil, and several studies provide
treatment groups, with a maximum change of 7 mm Hg. evidence of more sustained alertness across the day using a split-
One retrospective study afforded the opportunity to assess dose regime. Optimal therapeutic response to sodium oxybate is
effects of the medication in a pediatric population (mean age generally demonstrated with 6 g to 9 g of medication given in
13.75[9-16]), utilizing doses from 3-7 g nightly, for a mean treat- two divided doses at night. However, we identified no clinical
ment duration of approximately 11 months.86 Among the 8 pa- trials that provide head-to-head comparison of traditional stimu-
tients studied, 2 (25%) described terminal insomnia, 1 (12.5%) lants versus newer agents such as modafinil or sodium oxybate
described constipation, 1 (12.5%) described tremors, and 2 sub- for treatment of narcolepsy. The study by Black et al.33 allowed
jects (25%) required discontinuation of the medication due to ad- for comparison of modafinil and sodium oxybate and the combi-
verse effects. One subject described “dissociated feelings” and the nation of the two in a randomized placebo-controlled trial. This
other (with preexisting mental illness) endorsed increased night- study provides evidence that supports a somewhat better thera-
mares and suicidal ideation. peutic response with sodium oxybate compared with modafinil,
as assessed by objective (MWT) and subjective (ESS) measures.
5.2.2 Antidepressants Two of the large studies using sodium oxybate for treatment of
narcolepsy symptoms allowed subjects to continue receiving
A variety of antidepressants are used in the clinical setting for stimulant medications, indicating possible additive or synergistic
treatment of cataplexy. However, the literature is sparse with re- effects. The absence of comparative studies leaves unanswered
gard to adverse side effects for this indication. A single report de- the question of which medications are the most efficacious and
scribed a case of prolonged rebound cataplexy (one episode last- best tolerated, and whether certain subgroups of patients may re-
ing 25 minutes) after cessation of fluoxetine in preparation for spond better to some medications than others.
SLEEP, Vol. 30, No. 12, 2007 1724 Treatment of Narcolepsy and other Hypersomnias—Wise et al
Clinical practice patterns suggest that modafinil is currently moderate improvement in sleepiness rather than complete resto-
viewed as the initial drug of choice for treatment of sleepiness as- ration (normalization) of alertness in patients with narcolepsy.
sociated with narcolepsy91 (Task Force, personal observations). The literature contains very few studies that involve special
However, there are no data available to indicate what propor- populations with hypersomnia such as children, older adults, or
tion of patients treated initially with modafinil require transition pregnant or breastfeeding women. There is little information re-
to a traditional stimulant, to sodium oxybate, or to combination garding patient preference, patient compliance, or the impact of
therapy. As stated, only one study33 provides data regarding com- cost and drug availability in formularies on decision making re-
parison of modafinil, sodium oxybate, a combination of the two garding medications for treatment of pathological sleepiness or
medications, and placebo. cataplexy.
As with the traditional stimulants, modafinil and sodium oxy- Current treatment options for narcolepsy and other hypersom-
bate provide, at best, only moderate improvement of sleepiness nias of central origin remain symptomatic in nature. Despite sig-
rather than full restoration (normalization) of alertness in patients nificant advances in understanding the pathophysiology of nar-
with narcolepsy. Despite progress in understanding the pathogen- colepsy, we do not have an ideal treatment to completely restore
esis of narcolepsy, the ideal treatment for sleepiness due to narco- full and sustained alertness across the day. Future investigations
lepsy is not yet available. should be directed toward development of more effective and bet-
Our review also revealed no studies that provide a direct head- ter tolerated therapies, and primary prevention.
to-head comparison of antidepressants and sodium oxybate for
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63. Ondo, WG, Fayle, R, Atassi, F, and Jankovic, J. Modafinil for daytime 81. Littner, M. Sleep practitioners need to be aware of new changes in
somnolence in Parkinson’s disease: double-blind, placebo-controlled the labeling of pemoline (CYLERT). Sleep 1999;22:833
parallel trial. J Neurol Neurosurg Psychiatry 2005;76:1636-9 82. Wallin, MT, and Mahowald, MW. Blood pressure effects of long-
64. Rammohan, KW, Rosenberg, JH, Lynn, DJ, Blumenfeld, AM, Pol- term stimulant use in disorders of hypersomnolence. J Sleep Res
lak, CP, and Nagaraja, HN. Efficacy and safety of modafinil (Pro- 1998;7:209-15
vigil) for the treatment of fatigue in multiple sclerosis: a two centre 83. Sadeghian, H. Lacunar stroke associated with methylphenidate
phase 2 study. J Neurol Neurosurg Psychiatry 2002;72:179-83 abuse. Can J Neurol Sci 2004;31:109-11
65. Zifko, UA, Rupp, M, Schwarz, S, Zipko, HT, and Maida, EM. 84. Auger, RR, Goodman, SH, Silber, MH, Krahn, LE, Pankratz, VS,
Modafinil in treatment of fatigue in multiple sclerosis. Results of an and Slocumb, NL. Risks of high-dose stimulants in the treatment
open-label study. J Neurol 2002;249:983-7 of disorders of excessive somnolence: a case-control study. Sleep
66. Talbot, K, Stradling, J, Crosby, J, and Hilton-Jones, D. Reduction 2005;28:667-72
in excess daytime sleepiness by modafinil in patients with myotonic 85. Mayer, G, Ewert Meier, K, and Hephata, K. Selegeline hydrochlo-
dystrophy. Neuromuscul Disord 2003;13:357-64 ride treatment in narcolepsy. A double-blind, placebo-controlled
67. van der Meche, FG, Bogaard, JM, van der Sluys, JC, Schimsheimer, study. Clin Neuropharmacol 1995;18:306-19
RJ, Ververs, CC, and Busch, HF. Daytime sleep in myotonic dystro- 86. Murali, H, and Kotagal, S. Off-label treatment of severe childhood
phy is not caused by sleep apnoea. J Neurol Neurosurg Psychiatry narcolepsy-cataplexy with sodium oxybate. Sleep 2006;29:1025-9
1994;57:626-8 87. Borgen, LA, Okerholm, R, Morrison, D, and Lai, A. The influence
68. Black, JE, and Hirshkowitz, M. Modafinil for treatment of resid- of gender and food on the pharmacokinetics of sodium oxybate oral
ual excessive sleepiness in nasal continuous positive airway pres- solution in healthy subjects. J Clin Pharmacol 2003;43:59-65
sure-treated obstructive sleep apnea/hypopnea syndrome. Sleep 88. Borgen, LA, Okerholm, RA, Lai, A, and Scharf, MB. The phar-
2005;28:464-71 macokinetics of sodium oxybate oral solution following acute and
69. DeBattista, C, Doghramji, K, Menza, MA, Rosenthal, MH, and chronic administration to narcoleptic patients. J Clin Pharmacol
Fieve, RR. Adjunct modafinil for the short-term treatment of fatigue 2004;44:253-7
and sleepiness in patients with major depressive disorder: a pre- 89. U.S Xyrem Multi-Center Study Group. The abrupt cessation of
liminary double-blind, placebo-controlled study. J Clin Psychiatry therapeutically administered sodium oxybate (GHB) does not cause
2003;64:1057-64 withdrawal symptoms. J Toxicol Clin Toxicol 2003;41:131-5
70. Kingshott, RN, Vennelle, M, Coleman, EL, Engleman, HM, Mack- 90. Poryazova, R, Siccoli, M, Werth, E, and Bassetti, CL. Unusually
ay, TW, and Douglas, NJ. Randomized, double-blind, placebo-con- prolonged rebound cataplexy after withdrawal of fluoxetine. Neu-
trolled crossover trial of modafinil in the treatment of residual ex- rology 2005;65:967-8
cessive daytime sleepiness in the sleep apnea/hypopnea syndrome. 91. Guilleminault, C, and Fromherz, S (2005) Narcolepsy: diagnosis
Am J Respir Crit Care Med 2001;163:918-23 and management. In Principles and Practice of Sleep Medicine, 4th
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tive modafinil at initiation of treatment with a selective serotonin ders, Philadelphia
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72. Adler, CH, Caviness, JN, Hentz, JG, Lind, M, and Tiede, J. Ran-
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in patients with Parkinson’s disease. Mov Disord 2003;18:287-93
73. Hauser, RA, Wahba, MN, Zesiewicz, TA, and McDowell Anderson,
W. Modafinil treatment of pramipexole-associated somnolence.
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74. Fernandes, PP, and Petty, F. Modafinil for remitted bipolar depres-
sion with hypersomnia. Ann Pharmacother 2003;37:1807-9
75. Menza, MA, Kaufman, KR, and Castellanos, A. Modafinil augmen-

SLEEP, Vol. 30, No. 12, 2007 1727 Treatment of Narcolepsy and other Hypersomnias—Wise et al
Evidence Table—Practice Parameters for the Treatment of Narcolepsy and other Hypersomnias of Central Origin An American Academy of Sleep Medicine Report

Author (yr); Intervention/ Outcomes Study Description/ Recruitment # patients # controls enrolled/ Dose/Dosing Strategy Primary Study Outcomes Conclusions
Oxford Comparison Measures Study type/Blinding Source/ Funding enrolled/ completed/Controls’
Grade; Patient Intervention Method Source/ completed/ Age + SD [range]/
Group. Recruitment Patients’ Age %male
+ SD [range]/
Bastuji (1988); Modafinil EDS (subj) Pre and 1-2 months NR/NR/Expert- 24/22 with N/ 40 NA 200 mg-500 mg/ day in There were significant decreases Modafinil was effective for reducing EDS in pts.
4; N, IH post treatment Assigned or Selected ±17 yrs/ 70.8%, divided doses/BID (in am and in the mean number of drowsy with N or IH.
comparison of number Grps 17/14 with IH, 45 at noon) episodes and number of sleep
of drowsiness and ±15 yrs/52.9% attacks reported by both pt.
sleepiness attacks per groups; no effect on C.
day reported in a diary
using Modafinil /cohort
study/no blinding
Becker, P. M. Modafinil Mood/Quality A 6-week open label Clinic population/ 151/123/39 [18- NA 200 or 400 mg, optimal dose Modafinil significantly Treatment with Modafinil significantly improved
et al. (2004); of Life, safety/ multicenter trial to Pharmaceutical/ 68]/46% determined at end of second improved health related quality health related quality of life as assessed by SF-36
4; N. AE determine if Modafinil Expert-Assigned or week and participant remained of life component summary and all POMS-associated factors, in comparison to
reduced fatigue, Selected Grps on that dose for duration of the scores on the SF-36, and abstinence from treatment.
improved mood and trial/q day, 1 hour before or significantly improved, scores in
health related quality after first meal all domains of the POMS.
of life compared to
baseline/cohort study/
no blinding
Black 2006; Modafinil, sodium Daytime Characterization 44 sites in the 278/222/Sodium Crossover Usual modafinil dose between EDS as defined by the MWT Sodium oxybate and modafinil are both effective
1; N. oxybate/Placebo Sleepiness of the efficacy of United States, oxybate group: study/41.0+/- 200-600 mg/day. Sodium which was performed following for treating EDS in narcolepsy, producing additive
(Subjective), sodium oxybate as Canada, the 35.1 +/- 12.9/52%; 13.4/43.6% oxybate 6 g nightly for the nocturnal PSG at visits 2, 3, 4, effects when used together. Sodium oxybate is
Daytime a single agent, or in Czech Republic, modafinil initial 4-weeks of the double- and 5 according to validated beneficial as both monotherapy and adjunctive
Sleepiness combination with France, Germany, group: 38.9+/- blind study then increased to standards (Four 20 min tests 2 therapy for the treatment of EDS in narcolepsy.
(Objective), modafinil, for the the Netherlands, 15.6/50.8%; 9g nightly for the duration hours apart).
Mood/Quality treatment of EDS in Switzerland, and the sodium oxybate/ of the study./Following a
of Life narcolepsy. United Kingdom/ modafinil 2-week single-blind baseline
Pharmaceutical/ group: 38.9+/- period during which patients
Expert-Assigned or 15.9/46.3%. took their customary doses of
Selected Grps modafinil (200 to 600 mg/day)
and nightly placebo sodium
oxybate solution (equally
divided doses at bedtime
and then 2.5-4 hours later),
patients were randomized in
a double-blind fashon to 1 of
4 groups: Group 1: placebo
sodium oxybate + placebo
modafinil, Group 2: sodium
oxybate + placebo modafinil,
Group 3: placebo sodium
oxybate + modafinil, Group 4:
sodium oxybate + modafinil.
Dauvilliers, Y. Modafinil EDS (subj) To determine if the NR/private 84/84/ 48.21 NA W 262.5 ± 16.65 mg M 343.34 52/84 classified as good 91% of narcolepsy patients showed moderate to
et al. (2002); GCIS COMT genotype foundation, Univ +19.25 [14- ± 16.17mg responders; 25/84 classified good response to Modafinil; response to Modafinil
4; N. affects the response Hospital of Geneva/ 80]/61.9% as moderate responders; 7/84 is affected by COMT genotypes, which suggests
to treatment with Expert-Assigned or classified as non responders to that Modafinil affects dopaminergic transmission.
Modafinil and if the Selected Grps Modafinil;An equal number
differences in COMT of men and women were
genotype distribution categorized as good responders;
between men and optimal daily dosage of
women is associated Modafinil was significantly
with response to lower in women than men
Modafinil/cohort (262 mg compared to 343 mg);
study/single blind optimal daily dose somewhat
affected by COMT genotype.

SLEEP, Vol. 30, No. 12, 2007 S1

Author (yr); Intervention/ Outcomes Study Description/ Recruitment # patients # controls enrolled/ Dose/Dosing Strategy Primary Study Outcomes Conclusions
Oxford Comparison Measures Study type/Blinding Source/ Funding enrolled/ completed/Controls’
Grade; Patient Intervention Method Source/ completed/ Age + SD [range]/
Group. Recruitment Patients’ Age %male
+ SD [range]/
Group (2005); Sodium oxybate/ Improve 8 week DB PC trial 42 sleep clinics/ 228/209/40.5 [16- NA 4.5 g, 6.0 g, 9.0 g (all in Significant reduction in weekly Sodium oxybate highly effective in treating
1; N, C. Placebo Cataplexy to evaluate sodium Pharmaceutical/ 75]/34.6% 2 divided doses) after cataplexy with nightly doses cataplexy in a time and dose-dependent manner;
oxybate in the Expert-Assigned or washout from anticataplectic of 4.5, 6.0 and 9.0 g sodium weekly titration appears to be well-tolerated.
treatment of cataplexy/ Selected Grps medications/All patients oxybate for 8 weeks, with
Randomized Control on active drug started with median decreases of 57.0, 65.0
Trial/Double-Blind 4.5 g per night; one group and 87.7%, respectively; overall
Testing continued this dose for reduction of cataplexy greater at
duration of study; a second 8 weeks than at 4 weeks.
group increased to 6.0 g after a
week and continued this dose
for duration of study ; a third
group increased to 6.0 g after a
week, then 7.5 g after a week,
then 9.0 g and continued this
dose for duration of study
Group, 2005; Sodium oxybate/ Daytime A multi-center Subset of narcolepsy 228/209 (401 pts NA 4.5, 6 or 9g/Two equally ESS and CGI showed dose Sodium oxybate when taken with other traditional
1; N. Placebo Sleepiness randomized, double subjects in a mulit- originally entered divided doses taken related significant improvement stimulants significantly decreases daytime
(Subjective), blind, placebo center drug trial/ a larger ongoing immediately before bed and at all doses. MWT latencies sleepiness in a dose related manner as measured by
Daytime controlled study Expert-Assigned or trial but only 228 2.5-4 hours later; all pts in showed significant increases ESS and number of sleep attacks. MWT scores are
Sleepiness evaluating the Selected Grps/ entered the double treatment groups started at 4.5 only at 4.5 and 9 g dose (1.75 also significantly improved for the 4.5 and 9g dose
(Objective), effectiveness of sodium Pharmaceutical blind phase)/40.5 but 2/3 were then titrated up to and 10 min respectively). with 9g showing a robust increase.
Mood/Quality oxybate on sleepiness (16-75) 34.6% either their assigned group of Inadvertent sleep attacks
of Life, Safety/ in narcolepsy pts 6g or 9g showed dose related decrease
Adverse with cataplexy over but only significant for 6 and 9g
Events 8 weeks/Randomized
Control Trial/Double-
Blind Testing
Guilleminault, Modafinil EDS (subj) Four groups of N Three sleep clinics, 60/60; 31 from NA 100-600mg/after withdrawal, Naive pts. accepted Modafinil Modafinil is an appropriate medication to al (2000); pts. with EDS were two in Europe and USA; 29 from pts. were switched to 100 best; pts. withdrawn counteract daytime sleepiness, but caution is
3; N with C. switched to Modafinil one in the United Europe/ 41±18 mg of Modafinil; dosage was from amphetamine had the warranted in switching from amphetamine to
from their current States/NR/Expert- [19-68]/55% increased by 100-mg every 3 most problems and failure to Modafinil in some pts., and presence of C may
medication: 1) no Assigned or Selected days; most common dosage withdraw; use of a progressive warrant both Modafinil in combination with
medication regimen Grps was 400-mg divided into two withdrawal protocol may anticataplectic agent.
(naïve); 2) only dosages given morning and reduce problems; Venlafaxine
stimulant medications; noon hydrochloride combined well
3) only anticataplectic with Modafinil to control
medications; 4) cataplectic attacks.
both stimulant and
study/no blinding

SLEEP, Vol. 30, No. 12, 2007 S2

Author (yr); Intervention/ Outcomes Study Description/ Recruitment # patients # controls enrolled/ Dose/Dosing Strategy Primary Study Outcomes Conclusions
Oxford Comparison Measures Study type/Blinding Source/ Funding enrolled/ completed/Controls’
Grade; Patient Intervention Method Source/ completed/ Age + SD [range]/
Group. Recruitment Patients’ Age %male
+ SD [range]/
Harsh 2006; Armodafinil/Placebo Daytime 12 week DB RCT 47 centers in 132/105 (65/49 64/55/39.2+12.0/51% 150 mg or 250 mg /Once daily At final visit, mean MWT In patients with narcolepsy, armodafinil at doses
1; N. Sleepiness with placebo control 6 countries/ for 150 mg group; for 12 weeks SL increased 1.3, 2.6 and 1.9 of 150 or 250 mg/day significantly improved
(Subjective), to assess efficacy and pharmaceutical 67/56 for 250 min from baseline in the 150 wakefulness during the day, CGI-C and some
Daytime safety of armodafinil industry/Expert- mg group)/40.4 mg, 250 mg and armodafinil measures of memory and attention compared to
Sleepiness in patients with Assigned or Selected +12.5/44% for combined groups, respectively; placebo.
(Objective), narcolepsy Grps 150mg dose group; proportion of patients with at
Safety/ 35.0+12.5/37% for least minimal improvement
Adverse 250 mg dose group in CGI-C was significantly
Events higher for 150 mg, 250 mg and
armodafinil combined groups
compared to placebo at all
time points (p<0.0001); ESS,
global fatigue rating per BFI,
some measures of attention and
memory per CDR improved
with armodafinil compared to
placebo; naps and unintentional
sleep periods were reduced per
diaries in armodafinil groups
compared to placebo; no change
in cataplexy with armodafinil;
no adverse effects on PSG
parameters with armodafinil.
Hogl, (2002); Modafinil/placebo EDS (subj), This cross-over study Clinic population/ 15/12/65.0 NA 100 mg the first week of Although there was significant Modafinil produces significant improvement in
2; PD. EDS (obj) was designed to Pharmaceutical/ ±7.6/75% treatment and 200 mg the improvement of subjective subjective alertness, but not objective alertness in
test the efficacy of Expert-Assigned or second week/q am sleepiness (ESS scores) patients with PD.
Modafinil compared Selected Grps there was no improvement in
to placebo for the objective measures of sleepiness
treatment of increased (MWT).
daytime sleepiness in
pts. with PD/cohort
study/double blind
Ivanenko, A. et Modafinil EDS (subj), The effects of Clinic population/ 13 / 13/ 11.0 + 5.3 NA Mean dose = 346 ± 120 mg/ Parents reported improvements Modafinil produced a modest but significant
al. (2003); 4; EDS (obj), Modafinil on daytime NR/Expert-Assigned years, [2 - 18]/ typically in the morning and in daytime sleep attacks, EDS, decrease in sleepiness in children and appears to be
N, IH. safety/AE sleepiness in children or Selected Grps 46% at noon and daytime naps; Mood and safe and well tolerated in this population.
with IH or N was academic performance also
assessed over 15.6 + improved with Modafinil;
7.8 months./cohort average MSL on the MSLT
study/no blinding increased with treatment
(10.2 + 4.8 min) as compared
to baseline (6.6 + 3.7); one
child failed to improve with
Modafinil and three showed
partial improvement requiring
an additional medication/ 12
children respondeded.
Lammers Ritanserin/Placebo Daytime Randomized double- NS, presumably 28/28 ( 16 received NA 2.5 milligrams/Following a Ritanserin reduced subjective Ritanserin, as “add on” therapy for narcolepsy,
(1991); 2; N. Sleepiness blind placebo expert assigned./ Ritanserin & 12 1-week “baseline” period, EDS and increase feeling of reduces subjective EDS and increases the feeling
(Subjective), controlled trial of Private Foundation/ received placebo)/ Ritanserin was dosed twice a refreshed in morning. There of being refreshed in the morning. There was no
Daytime Ritanserin, a potent Expert-Assigned or 43 (range 16-67) day for 4 weeks in addition to was no effect on MSLT latency, effect on objective sleepiness (MSLT mean sleep
Sleepiness long-acting 5-HT2 Selected Grps their usual medical regimen cataplexy or sleep attacks. latency), frequency of cataplexy or sleep attacks,
(Objective), receptor blocker, in 28 for narcolepsy or the mood rating scale. Ritanserin increased
Improve narcolepsy patients./ slow-wave sleep (stage 3+4), and reduced wake
Cataplexy, Randomized Control after sleep onset.
Mood/Quality Trial/Double-Blind
of Life, Safety/ Testing

SLEEP, Vol. 30, No. 12, 2007 S3

Author (yr); Intervention/ Outcomes Study Description/ Recruitment # patients # controls enrolled/ Dose/Dosing Strategy Primary Study Outcomes Conclusions
Oxford Comparison Measures Study type/Blinding Source/ Funding enrolled/ completed/Controls’
Grade; Patient Intervention Method Source/ completed/ Age + SD [range]/
Group. Recruitment Patients’ Age %male
+ SD [range]/
Larrosa, O. et Reboxetine EDS (subj Pre-post test study to Clinic Population/ 12 enrolled, NA 10 mg per day/6 mg q am, 4 Roboxitine was effective Preliminary results demonstrate improvement of
al. (2001); 4; N and obj) determine if reboxitine Pharmaceutical/ 12 complet- mg at lunchtime in reducing all measures of subjective sleepiness and reduction in C; effect
with C. using ESS, was effective for Expert-Assigned or ed/36.6±11.7/50% subjective sleepiness including on MSLT less consistent in those with mean sleep
VAS, MSLT/ reducing EDS and C Selected Grps ESS, VAS sleepiness as well latency < 6 mins.
Catplexy compared to baseline/ as objective EDS based on
subscale of cohort study/no pre- and post MSLT data as well
Ullanlinna blinding as C subscale of the Ullanlinna
N Scale/ N Scale; Roboxitine increased
Mood (Beck % stage 1 and REM latency
Depression at night, with decreased #
Inventory)/ SOREM’s on MSLT; no change
Quality of in BDI; performance still below
Life, TST, healthy normal controls.
Mamelak, M. Sodium oxybate EDS (subj), The authors 4 clinical trial sites/ 29/25/52.6 + 8.8 NA 4.5 g/night, 6.0 g/night, 7.5 g/ Sodium oxybate produced dose- Sodium oxybate produced dose-related
et al. (2004); EDS (obj), investigated the effects Pharmaceutical years, [range NR]/ night, 9.0 g/night/ One-half of related increases in SWS and improvements in narcolepsy symptoms.
4; N. Safety/AEs, of escalating doses of 28% male total dose taken twice nightly. delta power; daytime SOL on
TST sodium oxybate on Dose escalated every 2 weeks MWT increased; and nocturnal
sleep architecture and following a 4-week period of awakenings decreased. The ESS
daytime functioning/ 4.5 g/night score decreased and all scales
Cohort Study/No of the narcolepsy symptom
Blinding questionnaire improved.
Mayer (2003); Ritanserin/ placebo EDS (subj), The effect of NR 134 enrolled /122 NA Ritanserin 5mg or 10 mg or Subjective symptoms: 5 mg Ritanserin had very little effect on improving
2; N. EDS (obj), ritanserin (a 5-HT2 completed/Placebo placebo was taken once daily improved “refreshed” feeling narcolepsy symptoms. While ritanserin did
Safety/AEs, antagonist) on daytime group: 40.9 + 14.2, after breakfast for 28 days; in am., sleep attacks, daytime improve some parameters of PSG-recorded sleep,
TST sleepiness and 5 mg group: 43.2 + subjects were allowed to sleepiness, work & activities, corresponding subjective improvements were not
daytime functioning 12.5; 10 mg group: continue receiving their usual social life and partners rated found. Ritanserin should not be used as a primary
in narcoleptics was 43.2 + 15.0. range: medication regimes improvements in daytime stimulant or hypnotic.
assessed/RCT/Double- 16 - 65 years; sleepiness and work &
Blind Testing 62.7% male activities. 10 mg improved sleep
quality and sleep attacks.
Mitler (2000); Modafinil/NA Daytime long-term (40 weeks) Patients who had 478/341 (9.0% NA 200, 300, 400 mg; 1st group: CGI-Change: 80% of patients Modafinil (most patients received 400 mg)
4; N. Sleepiness open label efficacy participated in discontinued 200, 300 or 400 mg daily at improved, 10% unchanged, 10% significantly reduced EDS and generally
(Subjective), and safety study of one of two prior treatment due discretion of investigator; 2nd worsened; mean ESS: improved improved QoL in patients with N; the medication
Daytime modafinil/Cohort or clinical studies/ to AE; 11.5% group: 200 mg/day for one from 16.5 to 12.4; QoL scores was generally well-tolerated and there was no
Sleepiness Ecological Studies/No Pharmaceutical/ discontinued week, then 400 mg/day for improved in 6 of 8 SF-36 indication of tolerance.
(Objective), Blinding Expert-Assigned or treatment due to one week, then either 200 mg domains.
Safety/ Selected Grps lack of efficacy)/42 or 400 mg daily for duration
Adverse +/- 13 (18-65)/46% of study at the discretion of
Events the investigator/NR

SLEEP, Vol. 30, No. 12, 2007 S4

Author (yr); Intervention/ Outcomes Study Description/ Recruitment # patients # controls enrolled/ Dose/Dosing Strategy Primary Study Outcomes Conclusions
Oxford Comparison Measures Study type/Blinding Source/ Funding enrolled/ completed/Controls’
Grade; Patient Intervention Method Source/ completed/ Age + SD [range]/
Group. Recruitment Patients’ Age %male
+ SD [range]/
Moldofsky Modafinil/placebo Daytime 16 week open label Subjects who 69/63 for open 33/33 for 2 week 200-400 mg daily for most At end of 2nd week RCT Modafinil continued to be an effective and well-
(2000); 2; N. Sleepiness study with modafinil completed prior label portion; RCT/ns/ns for 2 week patients; 1 patient took 150 portion, MWT mean SL were tolerated drug after 16 weeks of treatement of EDS
Subjective and followed by clinical trial 30/28 for 2 week RCT portion mg daily; 2 patients took 500 70% longer on modafinil in patients with narcolepsy
and Objective, 2 week RCT with with modafinil/ RCT/45 +/- 16 / mg daily/Open label portion: than on placebo (p=0.009);
Mood/Quality placebo control to Pharmaceutical/ 33.3% for open patients started with 200 mg in in patients switched from
of Life, Safety/ evaluate continued Expert-Assigned or label portion a.m. and 100 mg at noon; dose modafinil to placebo MWT SL
Adverse Event efficiacy and safety in Selected Grps then adjusted up or down by decreased by 37% (p=0.006),
narcoleptic patients 100 mg increments based on compared to decrease in 7% in
taking modafinil clinical assessment; patients group remaining on modafinil
(participants had randomized to modafinil arm (p=0.35); 24.3% of MWT
completed a prior 6 during 2 week RCT portion sessions ended without sleep
week RCT crosover continued their individualized on modafinil compared to 6.1%
study)/Randomized dose from open label portion on placebo (p<0.001); few
Control Trial/Double- changes on PSG measures of
Blind Testing - for sleep architecture; compared to
RCT portion and No placebo, modafinil reduced total
Blinding - open label number of reported episodes of
portion severe somnolence plus sleep
attacks plus naps (p=0.017);
ESS scores lower on modafinil
(13.2+/-5.7) compared to
placebo (15.4+/-5.8) at end of
study (p=0.023); no changes in
FCRRT; no changes in POMS
Nieves, A. V. Modafinil/none ESS and a 4-week open-label Movement Disorders 10/9/≥18, [66.9+_ NA Titrated as needed from 100- Mean ESS score at baseline of Modafinil is effective in reducing subjective EDS
et al. (2002); Unified PD trial of Modafinil Center/NR 7]/ 80% 400mg/day, not to exceed patients completing the study in patients with PD treated with dopaminergic
4; PD. Rating Scale in 10 patients with 400mg/day for 4 weeks/1 (n = 9) was 14.22 (± 3.03) and drugs -- it did not seem to worsen parkinsonian
part III PD, who also had dose of 100mg “early in the post-study (on an average dose symptoms and may allow further increase in
EDS and were on morning,” and were allowed of 172 mg/day), mean ESS dopaminergic therapy in patients previously unable
various dopaminergic to increase the dose by 100 mg score was 6.0 (± 4.87). Unified to tolerate certain dosages.
drugs/Cohort Study/No every week up to a maximum PD Rating Scale scores were
Blinding of 400 mg divided in two NOT affected.
Ondo, W. G. et Modafinil/ Placebo EDS (subj), Study designed to Clinic population 40/37[64.8 ± NA 200 mg/day or 400 mg/day/ Modafinil did not reduce EDS Modafinil is not effective for reducing EDS
al. (2005); 2; EDS (obj), test the efficacy of at a tertiary 11.]/3/72-5% half the dosage taken after (subj) or EDS (obj). experienced by patients with PD.
PD. Safety/AEs modafinil in reducing referral center/ waking and the other half at
Mood/Quality the symptoms of Pharmaceutical noon
of Life EDS in patients with
Poppe (2003); Lithium carbonate/NS Frequency and Case series of 5 Children’s Hospital, 5/5/13 to 17 years NA Lithium retard tablet at a dose Influence of lithium therapy on The risk of episodes under treatment with lithium
4; Recurrent duration of patients with Kleine- Technical University old; /60% male that maintained serum levels frequency and/or duration of dropped from 100% to 93% per preceeding month
Hypersomnia. hypersomnic Levin Syndrome Dresden/NA/Expert- between 0.6-0.9 mmol/l./ KLS episodes. of therapy (Odds Ratio =0.09; 95% confidence
episodes (KLS) treated with Assigned or Selected Between 20 and 36 months of interval 0.89-0.96; p<0.001). Quantitatively,
lithium prophylaxis/ Grps therapy lithium therapy reduces the mean duration of
Case Studies/ No episodes by 19% (p=0.012).

SLEEP, Vol. 30, No. 12, 2007 S5

Author (yr); Intervention/ Outcomes Study Description/ Recruitment # patients # controls enrolled/ Dose/Dosing Strategy Primary Study Outcomes Conclusions
Oxford Comparison Measures Study type/Blinding Source/ Funding enrolled/ completed/Controls’
Grade; Patient Intervention Method Source/ completed/ Age + SD [range]/
Group. Recruitment Patients’ Age %male
+ SD [range]/
Rammohan Modafinil/ Placebo Fatigue 9-week, single blind, NS/Pharmaceutical 72/65/44 (23- NA 200mg/day; 400mg/day/All 200 mg/day Dose: compared to 200mg/day of modafinil improves fatigue in MS
(2002); 2; MS. Severity Scale, pilot study designed 61)/75% patients received placebo placebo run-in, sig improvement patients. Mean ESS scores were significantly
modified to assess efficacy and during weeks 1–2, 200 mg/day in fatigue was demonstrated improved with 200mg/day and 400mg/day in
fatigue impact safety of modafinil for modafinil during weeks 3–4, -- mean scores post-treatment comparison with baseline scores.
scale; ESS; the treatment of fatigue 400 mg/day modafinil during were: FSS, 4.7 vs 5.5 for
a visual in patients with (MS)./ weeks 5–6, and placebo during placebo (p<0.001); MFIS,
analogue scale Cohort Study/Single weeks 7–9. 37.7 vs 44.7 (p<0.001); and
for fatigue Blinding VAS-F, 5.4 vs 4.5 (p=0.003).
(VAS-F) 400mg/day Dose: Fatigue scores
not significantly improved
versus placebo run in. Mean
ESS scores were significantly
improved (p<0.001) with 200
mg/day modafinil (7.2) and 400
mg/day (7.0) vs the score at
baseline (9.5).
Rogers, A. E. Naps, regular Narcolepsy To determine if Clinic population/ 29/29/43.7 ±13.9 NA NA Only the combination of naps Although the scheduled naps are often
et al. (2001); schedule,combo Symptom the combination Oxford Medilog Inc [18-64], 41.4% and scheduled bedtimes reduced recommended, they were not more effective than
2; N. naps/regular bedtimes/ Status of scheduled sleep the amount of unscheduled stimulant medications alone. Only the combination
Other Treatment and Questionnaire periods and stimulant daytime sleep compared of scheduled naps and regular bedtimes was more
Schedules (NSSQ); 24 medications was more to stimulant therapy alone effective in reducing unscheduled daytime sleep
hr ambulatory effective than stimulant (baseline). episodes than stimulant stimulant therapy alone.
PSG therapy alone/RCT/No
monitoring Blinding
Saletu, M. et al. Modafinil/ Placebo EDS (subj), This study examined NS/Pharmaceutical 16/15/[39.1±13.3], 16/16[/37.1±13.5]/ 200, 300, 400 mg modafinil (3 The EEG differences between Modafinil is associated with improvement
(2004); 2; N. EDS (obj) narcoleptics and 62.5% 62.5% week fixed titration schedule) groups were characterized by in subjective and objective daytime
normal controls in a significant decrease in alpha-2 sleepiness;LORETA provided evidence of a
crossover study of power, mainly in the frontal, functional deterioration of the
a three-week fixed temporal and parietal areas of fronto-temporo-parietal network of the right-
titration of modafinil the right hemisphere, along with hemispheric vigilance system in narcolepsy
(200, 300, 400 mg) and a global decrease in beta power, and a therapeutic effect of modafinil on the left
placebo to identify also accentuated over the right hemisphere, which is less affected by the disease.
brain regions cortical brain areas. ESS score
associated with decreased from median 14.5
vigilance in after 3 weeks of placebo to 12.5
untreated and after 3 weeks of modafinil. In
modafinil-treated the MSLT latency to sleep stage
narcoleptic patients by S1 significantly increased from
means a median of 3.2 min after three
of low resolution weeks of placebo to 6.6 min
brain electromagnetic after three weeks of modafinil
tomography (p<0.05).
Double-Blind Testing
Schwartz Modafinil/placebo Daytime Double-blind, NR/Pharmaceutical/ 32/NR/43 +/- 12 NR/NR/Crossover 200 mg QD; 400 mg QD; CGI-change improved in all A split-dose 400 mg regimen is superior to once
(2003); 1; N. Sleepiness randomized, Expert-Assigned or [28-61]/27 for 200 study design; one 200 mg BID/All groups took groups compared to baseline; daily dosing for sustaining wakefulness throughout
(Subjective), multicenter study Selected Grps mg QD group; 47 week of modafinil 200 mg at 0700 hrs + placebo ESS scores improved in all the entire waking day.
Daytime of 3 Modafinil +/- 16 [28-71]/64 washout followed by at noon for 1 week; group A groups (trend toward more
Sleepiness dosing regimens in for 400 mg QD randomization to one continued this regimen for 2 improvement in 400 mg QD
(Objective), patients with a prior group; 39 +/- 15 of 3 dosing regimens more weeks; group B took compared to 200 mg QD, but
Safety/ positive response to [19-60]/50 for for a 3 week period 400 mg at 0700 and placebo at not statistically significant);
Adverse the medication who 400 mg split dose noon for 2 more weeks; group mean MWT sleep latency
Events were dissatisfied with group C took 200 mg at 0700 and improved in all groups (more
late-afternoon or 200 mg at noon for 2 more improvement in both 400 mg
evening sleepiness./ weeks groups than in 200 mg group);
Randomized Control improvement in evening
Trial/Double-Blind sleepiness was greater in the
Testing split-dose group.

SLEEP, Vol. 30, No. 12, 2007 S6

Author (yr); Intervention/ Outcomes Study Description/ Recruitment # patients # controls enrolled/ Dose/Dosing Strategy Primary Study Outcomes Conclusions
Oxford Comparison Measures Study type/Blinding Source/ Funding enrolled/ completed/Controls’
Grade; Patient Intervention Method Source/ completed/ Age + SD [range]/
Group. Recruitment Patients’ Age %male
+ SD [range]/
Schwartz, J. R. Modafinil This study was Clinic population/ 56/56/42 years NA 200 mg, 400 mg, and 600 Significantly higher percentages Split dosing regimens for modafinil(≥400mg) are
(2005); 1; N. designed to determine Pharmaceutical [18-70 years, with mg/200 mg q am (0700), 400 of patients receiving the split more effective than 200 mg once daily dosing for
if a split dose of one 14 year old], mg q am (0700), 200 mg BID dosage regimen were able to maintaining alertness in the late afternoon and
modafinil would be 52% male (0700 and 1200), and 400 mg sustain wakefulness on MWT early evening, but significant differences were not
more effective than q am (0700) with 200 mg at during the late afternoon and noted with respect to 400 mg once daily dosing.
a single morning noon evening, as compared only to
dose for reducing the 200mg once daily regimen.
sleepiness in the late
afternoon and evening/
Randomized Control
Schwartz, J. R. Modafinil EDS (subj), Efficacy of 200 20 sleep centers 151 enrolled / 123 NA 200 mg or 400 mg/There was Compared to a post-washout Modafinil was an effective and well-tolerated
et al. (2003); EDS (obj) - 400 mg of modafinil around the completed/Mean a 2 week washout period from baseline, all doses of modafinil treatment for daytime sleepiness in narcoleptics
4; N. was assessed in United States/ age 39, range: 18 all stimulant medications. improved the ESS score and previously treated with and reporting
narcoleptics reporting Pharmaceutical - 68 years; 46% Then, subjects received CGI-C scores. 70% of the dissatisfaction with stimulant medications
dissatisfaction with male modafinil 200 mg for first patients were taking 400 mg
psychostimulant week, then 200 mg or 400 modafinil daily at the end of the
treatment taken to mg for weeks 2 - 6 depending study.
alleviate daytime on best dose for individual
sleepiness/NR/No subject.
Schwartz, J. R. Modafinil (400 mg qam EDS (subj This double-blind Expert assigned or 24/24/400mg NA 400 mg modafinil and 600 A significantly higher Higher, split doses of modafinil were more
et al. (2004); and 200 mg q noon vs. and obj), AE, study assessed if an selected groups from treatment group mg modafinil/400 mg q am percentage of patients receiving effective than single morning doses of modafinil
1; N. 400 mg qam)/placebo and Executive additional afternoon a clinic population/ (40; 18-61), 600 (0700); and split-dose (400mg the higher split dose of for improving alertness in the late afternoon and
Functioning dose of modafinil pharmaceutical mg treatment qam, 200mg qnoon) modafinil were able to remain evening.
using ESS, (600 mg total daily industry group (45; 14-60)/ awake during the late afternoon
CGI, MWT, dose) would be more 58% and evening than patients
and WCST effective than a single on single dosage (either 200
morning dose (400 mg) or 400 mg q am). Executive
for reducing afternoon functioning was also improved.
and evening sleepiness/
randomized control
Talbot (2003); Modafinil/placebo EDS (subj A randomized double- Expert assigned or 20/19/43 [18- Within subject design 100 mg, 200 mg/ 100 mg on Non-significant reduction Modafinil at 100 and 200 mg showed a non-
1; Myotonic and obj) using blind crossover study selected groups from 65]/68% days 1-5, followed by 200 mg in ESS. SL on MWT was significant reduction in median ESS, however
Dystrophy. ESS, SF36, of modafinil versus a clinic population/ on days 6-28 prolonged by treatment (31.7- median SL on MWT score was prolonged by
PSG, MWT placebo for the pharmaceutical 40min, p=.006). treatment.
treatment of EDS in industry
patients with Myotonic
control trial/Double-
Blind Testing
U.S. Xyrem Sodium oxybate/placebo C This double blind Expert assigned 56/55/≥16 NA Sodium oxybate ranging During the 2-week double-blind This randomized controlled trial provides evidence
Multicenter improvement, treatment withdrawal or selected groups [47.7]/42% from 3.0 to 9.0 g nightly/ phase, the abrupt cessation of supporting the long-term efficacy of sodium
Study Group AE using study examining the /pharmaceutical sodium oxybate or placebo sodium oxybate therapy in the oxybate for the treatment of cataplexy. There
(2004); 1; N C. diaries long-term efficacy of industry was administered in equally placebo patients resulted in a appeared to be no evidence of rebound cataplexy
sodium oxybate on divided doses immediately significant increase in the upon abrupt discontinuation of treatment, nor any
cataplexy/randomized upon going to bed and again number of cataplexy attacks symptoms of frank withdrawal.
control trial/Double- 2.5–4 hr later (median change = 21; P 0.001)
Blinding compared to patients who
remained on sodium oxibate.

SLEEP, Vol. 30, No. 12, 2007 S7

Author (yr); Intervention/ Outcomes Study Description/ Recruitment # patients # controls enrolled/ Dose/Dosing Strategy Primary Study Outcomes Conclusions
Oxford Comparison Measures Study type/Blinding Source/ Funding enrolled/ completed/Controls’
Grade; Patient Intervention Method Source/ completed/ Age + SD [range]/
Group. Recruitment Patients’ Age %male
+ SD [range]/
U.S. Xyrem® Sodium oxybate/14-21 EDS (subj), C This study evaluated Expert assigned 118/80/43.7 [18- NA 3 mg, 4.5 mg, 6 mg, 7.5 mg, Cataplexy episodes decreased 3 to 9 g of sodium oxybate produced significant
Multicenter day baseline period improvement, the safety and efficacy or selected groups 79]/43.5% or 9 mg of sodium oxybate signficantly the first month and long-term reductions in cataplexy and
Study Group AE using CGI, of five different doses from clinical nightly/initial dose at bedtime (compared to baseline numbers) subjective daytime sleepiness.
(2003); 4; N C. ESS, logs (3-9 g) of sodium populations ≥ 18 and second dose 2.5-4 hours in all treatment groups, and
oxybate during a yo/pharmaceutical later continued to remain at a lower
multicenter 12-month industry level throughout the 12 month
open-label trial/cohort trial period. ESS decreased at
study/No Blinding 1-month for all tx groups except
4.5 g (n=6).
US Xyrem Sodium oxybate/placebo EDS (subj and This multi-site double- Random selection 136/120/43.1/ NA 3 g, 6 g, 9 g/half at bedtime, The 9 g dose reduced the # of Sodium oxybate is an effective and safe treatment
Multi-center obj)/Catplexy blind trial investigated from sleep disorders 41.9% male the other half 2.5 - 4 hrs later; cataplexy attacks compared for EDS associated with narcolepsy, particularly at
Study Group and AE using the effects of 3 doses centers in the dose was started after an to placebo. CGI exhibited the 9 g dose.
(2002); 1; N. ESS, CGI, and of sodium oxybate United States/ extended washout period of change from baseline at 9 g
logs/number on the treatment of pharnaceutical other anticataplectic drugs (as dose. Inadvertent naps/sleep
of nocturnal narcolepsy symptoms/ industry long as 6 weeks) attacks reduced at both 6 g and
awakenings/ randomized control 9 g doses. 9 g dose decreased
HH and SP trial/Double-Blind nocturnal awakenings.
Van der Meche Methylphenidate/NA EDS (subj) This unblinded study Expert assigned 22/median age for NA 10 mg/10 mg daily increased Methylphenidate produced Methylphenidate is effective in reducing
(1994); 4; using a evaluated if EDS in or selected groups males 36, females to 10-20 mg BID increased daytime alertness hypersomnia associated with Myotonic Distrophy.
Myotonic “standard MD is caused by OSA, /Netherlands 50 [16-67]/63.6% in 7 of 11 patients/3 of the 17
Dystrophy. questionnaire” and if not whether or male patients tested had OSA.
not methylphenidate
would reduce the
series/No Blinding
Weaver (2006); Sodium Oxybate Mood/Quality Randomized, double Outpatient facility 217 68 randomized/47 4.5, 6 or 9 g/day in divided When compared to Compared with placebo-treated patients,
1; N, C. /Placebo of Life blind, placebo- of 42 sleep centers randomnized/181 intent to treat/Placebo doses. First dose QHS, second placebo, the 9 g/day group participants treated with doses of sodium oxybate
controlled parallel- in the United States, intent to treat/4.5 40.8+/- 15.5/28.8 dose 2.5 to 4 hours later./The demonstrated improvement in of 6 g/day and 9g/day experienced significant
group clinical trial Canada, and Europe/ g/day 41.8+/- first 14 days was a lead in all components of the FOSQ improvements in functional status as measured by
of 285 patients with Pharmaceutical/ 16.7/32.8; 6 g/day period, followed by a 21 day except the intimacy and sexual the FOSQ.
narcolepsy treated with Expert-Assigned or 39.2+/- 15.9/37.9; withdrawl from anticataplectic relationships scale. The 6g/day
sodium oxybate (4.5 Selected Grps 9 g/day 39.9+/- therapy, then a 5 to 18 day dose demonstrated improvement
to 9 g/day in divided 12.5/34.6 washout period, concluding in 2 of 5 subscales. A dose
doses) for 4 weeks with randomization to the effect was evident for the total
following withdrawl 2 treatment arms and doses score and all FOSQ subscales
of their baseline anti- of 4.5, 6 or 9 g/day of except the intimacy and sexual
cataplexy medications. sodium oxybate. Participants relationships scale. There was
The effect on quality of randomized to sodium oxybate no significant change at the 4.5
life was assessed with all received 7 days of the 4.5 g/day dose.
Functional Outcomes g dose, followed by titration
of Sleep Questionnaire to their final dose according
(FOSQ)./Randomized to the randomization scheme.
Control Trial/Double- Participants on active
Blind Testing treatment were on study
medication for at least 7 days
before proceeding to the next

SLEEP, Vol. 30, No. 12, 2007 S8

Author (yr); Intervention/ Outcomes Study Description/ Recruitment # patients # controls enrolled/ Dose/Dosing Strategy Primary Study Outcomes Conclusions
Oxford Comparison Measures Study type/Blinding Source/ Funding enrolled/ completed/Controls’
Grade; Patient Intervention Method Source/ completed/ Age + SD [range]/
Group. Recruitment Patients’ Age %male
+ SD [range]/
Zifko (2002); Modafinil/NA EDS (subj), This unblinded Expert assigned 50/47/40.4 +/- NA 50 - 300 mg daily/started at Both the Fatigue Severity Scale Fatigue and sleepiness were significantly improved
4; MS. QOL, AE study assessed the or selected gropus 10.3/40% male 100 mg daily and increased and ESS decreased significantly by modafinil in patients with MS. The drug was
using ESS, tolerability, optimal from 2 centers to 200 mg or 300 mg daily as during the 3 months of study. generally well-tolerated.
Fatigue dose, and efficacy of specializing in MS/ needed. Maximum doses were Both the patients’ self-reported
Severity modafinil in patients governent sources, achieved in 4 weeks or less fatigue and the clinicians’
Scale, clinical with multiple sclerosis pharmaceutical impression of fatigue improved.
outcome and fatigue and industry
rating, and EDS/cohort study/No
patient self- Blinding
appraisal in

N= Narcoplepsy
C= Cataplexy
IH = Idiopathic Hypersomnia
PD = Parkinson disease
MS = Multiple sclerosis

SLEEP, Vol. 30, No. 12, 2007 S9