CNS Drugs 2005; 19 (9): 785-803

ADIS DRUG EVALUATION 1172-7047/05/0009-0785/$34.95/0

 2005 Adis Data Information BV. All rights reserved.

Modafinil
A Review of its Use in Excessive Sleepiness Associated With
Obstructive Sleep Apnoea/Hypopnoea Syndrome and Shift
Work Sleep Disorder
Gillian M. Keating and Michael J. Raffin
Adis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by:

M. Billiard, School of Medicine, Gui de Chauliac Hospital, Montpellier, France; J.E. Black, Stanford Sleep
Disorder Clinic, Stanford University, Stanford, California, USA; D.F. Dinges, Division of Sleep and
Chronobiology, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia,
Pennsylvania, USA; R.B. Fogel, Harvard Medical School and Division of Sleep Medicine, Brigham and
Women’s Hospital, Boston, Massachusetts, USA; A.I. Pack, Center for Sleep and Respiratory Neurobiology,
Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA; T. Roehrs, Sleep Disorders and
Research Center, Henry Ford Hospital, Detroit, Michigan, USA; T. Roth, Sleep Disorders and Research
Center, Henry Ford Hospital, Detroit, Michigan, USA; W. Schmidt-Nowara, Sleep Medicine Associates of
Texas, Plano, Texas, USA; J.R.L. Schwartz, Integris Sleep Disorders Center of Oklahoma, Integris Southwest
and Baptist Medical Centers, Oklahoma City, Oklahoma, USA; M.J. Thorpy, Sleep-Wake Disorders Center,
Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York, USA; K.P. Wright Jr,
Sleep and Chronobiology Laboratory, Department of Integrative Physiology, University of Colorado,
Boulder, Colorado, USA.

Data Selection
Sources: Medical literature published in any language since 1980 on modafinil, identified using MEDLINE and EMBASE, supplemented by
AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles.
Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: MEDLINE search terms were ‘modafinil’ and (‘shift work’ or ‘obstructive sleep apnea/apnoea’ or ‘sleep apnea syndromes’
or ‘sleepiness’). EMBASE search terms were ‘modafinil’ and (‘sleep apnea disorder’ or ‘sleepiness’). AdisBase search terms were
‘modafinil’ and (‘shift work’ or ‘obstructive sleep apnoea’ or ‘sleepiness’). Searches were last updated 8 August 2005.
Selection: Studies in patients with excessive sleepiness associated with obstructive sleep apnoea/hypopnoea syndrome or shift work sleep
disorder who received modafinil. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well
controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also
included.
Index terms: Modafinil, shift work sleep disorder, obstructive sleep apnoea/hypopnoea syndrome, excessive sleepiness,
pharmacodynamics, pharmacokinetics, therapeutic use.

Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 786
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 788
2. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 788
2.1 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 788
2.2 Effects on Wakefulness and Locomotor Activity in Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 789
2.3 Effects on Wakefulness, Sleep and Cognition in Human Volunteers . . . . . . . . . . . . . . . . . . . . . . . 789
2.4 Other Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 790
3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 790
786 Keating & Raffin

3.1 Absorption and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 790

3.2 Metabolism and Excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791
3.3 Special Patient Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791
3.4 Potential Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791
4. Clinical Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 792
4.1 In Patients with Obstructive Sleep Apnoea/Hypopnoea Syndrome (OSA/HS) Using Nasal
Continuous Positive Airway Pressure Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 792
4.1.1 Effects on Wakefulness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 793
4.1.2 Other Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794
4.1.3 Health-Related Quality-of-Life (HR-QOL) Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794
4.2 In Patients with Shift Work Sleep Disorder (SWSD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 795
4.2.1 Effects on Wakefulness and Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 795
4.2.2 HR-QOL Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 796
5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 796
5.1 In Patients with OSA/HS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 796
5.2 In Patients with SWSD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 797
6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 798
7. Place of Modafinil in the Management of Excessive Sleepiness Associated With OSA/HS and
SWSD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 798

Summary
Abstract Modafinil (Provigil) is a wake-promoting agent that is pharmacologically dis-
tinct from CNS stimulants, such as amfetamine, dexamfetamine and methylpheni-
date. Modafinil is approved for use in the US and certain European countries for
use in patients with excessive sleepiness associated with narcolepsy, obstructive
sleep apnoea/hypopnoea syndrome (OSA/HS) or shift work sleep disorder
(SWSD).
Oral modafinil promotes wakefulness in patients with OSA/HS and SWSD. It
is an effective adjunctive therapy in patients with residual excessive sleepiness
associated with OSA/HS who are receiving nasal continuous positive airway
pressure (nCPAP) therapy. In SWSD, the drug improves night-time wakefulness
without disrupting daytime sleep. Modafinil is generally well tolerated in patients
with OSA/HS or SWSD and has a low abuse potential. Thus, modafinil is a
valuable new treatment option for use in patients with excessive sleepiness
associated with OSA/HS (as an adjunct to nCPAP) or SWSD.

Pharmacological The exact mechanism by which modafinil promotes wakefulness is unknown,

Properties although it appears that it primarily affects areas of the brain involved in
controlling wakefulness.
Modafinil increased wakefulness in numerous animal models, including mod-
els of sleep deprivation and narcolepsy. Modafinil did not have detrimental effects
on subjective and objective measures of nocturnal sleep in healthy volunteers. In
sleep-deprived volunteers, modafinil significantly improved mood, fatigue, sleep-
iness and alertness/vigilance, compared with placebo. In addition, modafinil
attenuated the cognitive impairment associated with sleep deprivation and, during
laboratory night-shifts, significantly attenuated the decline in cognitive tests
versus placebo. Modafinil appears to have a low potential for abuse.
Modafinil is rapidly absorbed; at steady state, a peak plasma concentration of
6.4 µg/mL was reached in 2.7 hours with modafinil 200mg once daily. Approxi-

 2005 Adis Data Information BV. All rights reserved. CNS Drugs 2005; 19 (9)
Modafinil: A Review 787

mately 90% of a modafinil dose is metabolised, primarily to two inactive metabo-

lites. The pharmacokinetics of modafinil were altered in older versus younger men
and in patients with chronic hepatic impairment versus healthy volunteers.

Clinical Efficacy Five randomised, double-blind, placebo-controlled trials examined the efficacy of
oral modafinil 200–400mg once daily in patients with excessive sleepiness
associated with OSA/HS or SWSD. Two of the OSA/HS trials were of paral-
lel-group design (n = 157 and 309; treatment duration 4 and 12 weeks) and the
third was a crossover trial (n = 30; treatment duration 2 weeks). Two studies in
SWSD (n = 204 and 278) were of parallel-group design and of 12 weeks’ duration.
In patients with excessive sleepiness associated with OSA/HS who were
receiving nCPAP, modafinil 200 or 400 mg/day improved wakefulness, as
assessed by Epworth Sleepiness Scale (ESS) scores, to a significantly greater
extent than placebo in the parallel-group studies, but not in the smaller crossover
study. At study end, sleep-onset latency, assessed by the Maintenance of Wakeful-
ness Test (MWT) or Multiple Sleep Latency Test (MSLT), improved to a
significantly greater extent with modafinil 200 or 400 mg/day versus placebo in
the parallel-group studies. In the crossover study, sleep-onset latency improved to
a significantly greater extent with modafinil 400 mg/day than with placebo
according to the MWT, but not the MSLT. Additional analysis of the 4-week
parallel-group study found that performance on Psychomotor Vigilance Task
(PVT) testing was improved to a significantly greater extent with modafinil 400
mg/day than with placebo.
In the parallel-group studies in patients with OSA/HS, significantly more
modafinil 200 or 400 mg/day recipients than placebo recipients experienced
clinical improvement. However, in the crossover study, there was no significant
between-treatment difference in the proportion of patients whose condition was
rated as ‘better’. No reduction in nCPAP use occurred in the parallel-group
studies, although a significant reduction in nCPAP use was seen with modafinil
400 mg/day versus placebo in the crossover study. Modafinil did not have an
adverse impact on night-time sleep in any of the studies. Moreover, aspects of
functional status and health-related quality of life (HR-QOL) were improved to a
significantly greater extent with modafinil 200 or 400 mg/day than with placebo in
the parallel-group studies, although no such between-treatment difference was
seen in the crossover study.
In night-shift workers with SWSD, a significantly greater proportion of
modafinil 200 mg/day than placebo recipients experienced clinical improvement
according to Clinical Global Impression of Change ratings at the final visit.
Improvements in night-time wakefulness (assessed using MSLT sleep-onset
latency and Karolinska Sleepiness Scale scores) and performance (PVT testing)
were significantly greater in modafinil 200 mg/day than placebo recipients at
study end. Modafinil did not have an adverse impact on daytime sleep. Signifi-
cantly greater improvements in functional status and HR-QOL occurred with
modafinil 200 or 300 mg/day than with placebo.

Tolerability Modafinil was generally well tolerated in patients with excessive sleepiness
associated with OSA/HS or SWSD in randomised, double-blind, placebo-control-
led studies. Adverse events were generally of mild-to-moderate severity.

 2005 Adis Data Information BV. All rights reserved. CNS Drugs 2005; 19 (9)
788 Keating & Raffin

In three studies in patients with OSA/HS, the most commonly reported adverse
events (i.e. occurring in ≥5% of patients) included headache, infection, nausea,
anxiety, accidental injury, diarrhoea, hypertension, nervousness, dizziness,
insomnia, rhinitis and dry mouth. Headache, nausea and nervousness occurred
significantly more frequently in modafinil than in placebo recipients.
In a study in SWSD, the most commonly reported adverse events (i.e. occur-
ring in ≥5% of patients) in modafinil recipients included headache, nausea,
infection, accidental injury, abdominal pain, nervousness, insomnia, dry mouth
and tooth disorder; only insomnia occurred in a significantly greater proportion of
modafinil than placebo recipients.

1. Introduction properties of modafinil most relevant to OSA/HS

The dyssomnias are a group of sleep disorders
characterised by difficulty in initiating or maintain-
ing sleep, or excessive sleepiness.[1] Both obstruc-
tive sleep apnoea/hypopnoea syndrome (OSA/HS)
and shift work sleep disorder (SWSD) are examples
of dyssomnias.[1] OSA/HS is an intrinsic sleep disor-
der; excessive sleepiness arises out of the sleep
disruption that occurs in patients with this syn-
drome. SWSD is a circadian rhythm sleep disorder;
it comprises symptoms of excessive sleepiness or
insomnia that occur transiently in relation to work
schedules.[1]
Modafinil (Provigil)1 is an orally administered
benzhydrylsulfinylacetamide derivative with docu-
mented efficacy in narcolepsy (reviewed by Mc-
Clellan and Spencer[2]). It is indicated in the US and
certain European countries to improve wakefulness
in patients with excessive sleepiness associated with
narcolepsy, OSA/HS (as an adjunct to standard
treatment with nasal continuous positive airway
pressure [nCPAP] therapy) or SWSD. This article
reviews the use of modafinil in patients with exces-
sive sleepiness associated with OSA/HS or SWSD.
2. Pharmacodynamic Properties
The pharmacodynamic profile of modafinil has
been reviewed previously.[2] This section provides a
brief overview, updating the pharmacodynamic
and SWSD.
2.1 Mechanism of Action
Modafinil is a centrally acting agent that is struc-
turally and pharmacologically distinct from CNS
stimulants such as amfetamine, dexamfetamine and
methylphenidate.[3]
The exact mechanism by which modafinil pro-
motes wakefulness is not known.[4] It appears that
the drug primarily affects areas of the brain thought
to be involved in controlling wakefulness. A study
in rats found that compared with vehicle, modafinil
increased Fos expression (an indicator of neuronal
activation) in the tuberomammillary nucleus and in
orexin neurons in the perifornical area, cell groups
in the hypothalamus implicated in the control of
wakefulness.[5] Modafinil also decreased Fos activi-
ty in the ventrolateral preoptic area, an area that
contains sleep-promoting neurons.[5] In this study,
modafinil did not substantially increase Fos expres-
sion in the anterior hypothalamic area (AHA) or
suprachiasmatic nuclei (SCN),[5] although in other
animal studies,[6,7] the drug induced Fos expression
in both these areas (the SCN are implicated in the
regulation of circadian rhythms). This relatively se-
lective effect for the hypothalamus is in contrast to
the action of stimulants such as methylphenidate and
amfetamine, which promote neuronal activation
throughout the brain.[6,7]

1 Also registered as Alertec, Modasomil, Modiodal, Modavigil and Vigil. The use of trade names is for product
identification purposes only and does not imply endorsement.

 2005 Adis Data Information BV. All rights reserved. CNS Drugs 2005; 19 (9)
Modafinil: A Review
Modafinil did not bind to adenosine, dopamine,
GABA, serotonin, benzodiazepine, noradrenaline
(norepinephrine), histamine H3 or melatonin recep-
tors in vitro.[4,8] The results of animal studies
demonstrate that modafinil interacts with several
neurotransmitters and neuropeptide pathways (e.g.
glutamatergic,[9] GABA-ergic,[9-13] ser-
[14-16] histaminergic[17] and orexinergic[5]).
otonergic,
In particular, it is thought that the activity of
modafinil may be related to a reduction in GABA-
ergic transmission in areas of the brain involved in
the regulation of wakefulness.[9,12]
The role of dopamine in modafinil-induced
wakefulness remains uncertain. Modafinil increased
striatal extracellular dopamine in narcoleptic dogs,
and the wake-promoting effects of the drug were
abolished in dopamine transporter knockout mice,
suggesting that modafinil needs dopamine transport-
ers to achieve its wake-promoting action.[18] Also,
modafinil demonstrated weak affinity for the
dopamine uptake carrier site in vitro,[8] and in-
creased dopamine release was seen in the rat
prefrontal cortex with modafinil administration.[16]
However, other studies suggest that modafinil does
not have direct effects on dopamine transmis-
sion,[13,19] and demonstrated that the wakefulness
induced by modafinil was not antagonised by
haloperidol (a dopamine receptor antagonist).[20-22]
Recent data indicate that modafinil potentiates
the inhibitory effect of noradrenaline on sleep-pro-
moting neurons in the ventrolateral preoptic nucle-
us.[23] Earlier data suggested that modafinil is
neither a direct nor indirect α1-adrenoceptor ago-
nist, although its mechanism of promoting wakeful-
ness appears to require an intact α1-adrenergic sys-
tem.[8,11,20,21,24] Modafinil does not inhibit the ac-
tivity of monoamine oxidase B[25] or phospho-
diesterases II–V.[4]
2.2 Effects on Wakefulness and Locomotor
Activity in Animals
Modafinil increased wakefulness in numerous
animal models,[26-33] including models of sleep dep-
rivation[27,31] and narcolepsy.[32] Modafinil also re-
 2005 Adis Data Information BV. All rights reserved.
789
duced hypersomnolence in an animal model of
sleep-disordered breathing.[34]
Modafinil increased locomotor activity in several
animal models,[21,26,35] although in one study this
increase was shown to reflect the increased amount
of time spent awake, as there was no increase in the
intensity of locomotor activity (i.e. locomotor activ-
ity count per minute of wakefulness).[26] Moreover,
no increase in locomotor activity was seen with
increasing doses of modafinil (from 125 to 8000 µg/
kg) in narcoleptic dogs.[32]
2.3 Effects on Wakefulness, Sleep and
Cognition in Human Volunteers
Numerous trials have examined the effects of
modafinil in human volunteers. Some studies en-
rolled healthy volunteers (n = 10–60) who were not
sleep deprived,[36-41] some used sleep-deprivation
protocols (n = 6–50)[42-48] and two, one of which is
available as an abstract,[49] used laboratory night-
shift protocols (n = 16[49] and 32[50]). All trials were
double-blind[36-50] and used active[37,38,43,44,46,48] and/
or placebo[36-50] controls; some studies were
randomised.[36,39-42,47,49,50] Modafinil was adminis-
tered as a single dose in the morning,[36,39-41] as a
single dose in the evening,[37,38,42,48] as nightly doses
for 4 nights,[49,50] at different timepoints (night,
morning and afternoon) over 3 days[43,44,46] or at
8-hour intervals for up to 3 days.[45,47]
Unlike dexamfetamine, single doses of modafinil
100 or 200mg did not have detrimental effects on
subjective and objective measures of nocturnal sleep
in young (mean age 30 years)[37] or elderly (mean
age 68 years)[38] healthy volunteers. Among
healthy volunteers, single doses of modafinil
100–200mg[36,39,41] or 4 mg/kg[40] had no significant
effects on cognition in one study,[36] but improved
cognitive function to a significantly greater extent
than placebo (p < 0.05) in three others.[39-41] Detri-
mental mood changes (e.g. increased somatic anxie-
ty) occurred with modafinil in one study,[36] but not
in another study.[40]
Compared with placebo, modafinil 200–400 mg/
day significantly (p < 0.05) improved mood,[46] fa-
tigue[46] and sleepiness[46,48] in sleep-deprived volun-
CNS Drugs 2005; 19 (9)
790
teers. With modafinil 200–600 mg/day, sleep-
deprived volunteers experienced significant im-
provements in alertness/vigilance versus placebo
(p < 0.05).[44,45,48] Following sleep deprivation,
modafinil 300 mg/day recipients experienced signif-
icantly (p < 0.05) less sleep disturbance during the
first recovery night than dexamfetamine recipi-
ents.[43]
Modafinil 200–400 mg/day attenuated the cogni-
tive impairment associated with sleep depriva-
tion.[42,46-48] Compared with placebo, modafinil
ameliorated deterioration in several parameters, in-
cluding attentional processes,[47] logical reason-
ing,[46] reaction time[42,46,48] and short-term memo-
ry.[42,46]
Compared with placebo, modafinil 200mg signif-
icantly improved alertness and performance during
a laboratory night-shift.[49,50] The increase in
Karolinska Sleepiness Scale (KSS) scores (a subjec-
tive measure of sleepiness) was significantly smaller
with modafinil than with placebo (p < 0.05), as was
the increase in the number of attention lapses (p <
0.05).[49] Moreover, modafinil 200 mg/day signifi-
cantly (p < 0.05) attenuated the decline in certain
cognitive tests (Wisconsin Card Sorting Test, Hayl-
ings Sentence Completion Test and Torrance Test of
Creative Thinking-Verbal) compared with place-
bo.[50]
2.4 Other Effects
No deterioration in blood pressure (BP) control
occurred with modafinil 200 or 400mg once daily in
a pooled analysis, available as an abstract, of pa-
tients (n = 274) with OSA and a current or past
history of hypertension.[51] There was also no signif-
icant change from baseline in heart rate. The pooled
analysis included data from three randomised,
double-blind, placebo-controlled studies in patients
with OSA.
In patients with OSA/HS, no significant differ-
ence between modafinil and placebo administration
was observed with regards to BP in one study.[52] In
another study,[53] there was a statistically significant
increase in sitting systolic BP with modafinil
(+1.0mm Hg vs –2.6mm Hg in placebo recipients;
 2005 Adis Data Information BV. All rights reserved.
Keating & Raffin
p = 0.035); however, it was not deemed clinically
meaningful (see section 4.1 for study details).
Modafinil 300mg increased body temperature in
sleep-deprived volunteers, whereas a physiological
decline in body temperature was observed in place-
bo recipients between approximately 2200 and
0800h.[46,54] Modafinil 200mg was also shown to
have a thermogenic effect during a sweating test in
healthy volunteers who were not sleep deprived.[55]
The potential for modafinil to be associated with
abuse and dependency appears to be much lower
than that of amfetamine-like stimulants.[56]
Modafinil 200–800mg produced no or minimal
stimulant-like subjective effects (e.g. euphoria) in
small studies (n = 6–24) in healthy volunteers[57] and
volunteers with recent histories of cocaine use.[58-60]
Postmarketing surveillance data also indicate a low
abuse potential for modafinil.[61]
3. Pharmacokinetic Properties
This section provides a brief overview of the
pharmacokinetics of modafinil, focusing on the dos-
age recommended in OSA/HS and SWSD (200 mg/
day) [section 6]. Most of the data concerning the
pharmacokinetics of the drug were obtained from a
study in healthy men (section 3.1 and section 3.2),[3]
supplemented by data from the prescribing informa-
tion[4,62] and a review article.[63] The use of
modafinil in special patient populations (section 3.3)
and its drug interaction potential (section 3.4) are
also discussed.
3.1 Absorption and Distribution
Repeat administration of oral modafinil
200–800mg once daily to healthy volunteers was
associated with dose-proportional increases in the
modafinil peak plasma concentration (Cmax) and
area under the plasma concentration-time curve
(AUC).[3] Steady-state is reached after 2–4 days of
drug administration.[4] Once-daily administration of
modafinil was associated with an accumulation ratio
of ≈1.5 at day 7.[3]
Modafinil is rapidly absorbed. At day 7, mean
Cmax was 6.4 µg/mL with modafinil 200mg once
daily, with a corresponding mean time to Cmax
CNS Drugs 2005; 19 (9)
Modafinil: A Review
Table I. Pharmacokinetics (mean values) of oral modafinil 200mg in
six healthy men following a single dose (day 1) and once-daily
administration for 7 days[3]
Parameter Day 1
Cmax (µg/mL) 4.8
tmax (h) 2.3
AUC∞ (µg • h/mL) 74.0
AUCτ (µg • h/mL)
V/F (L/kg) 0.8
t1/2 (h)
CL/F (mL/min) 46.0
CLR (mL/min) 2.3
AUC∞ = area under the plasma concentration-time curve from time
zero to infinity; AUCτ = AUC across one dosing interval; Cmax =
peak plasma concentration; CL/F = apparent oral plasma
clearance; CLR = renal clearance; t1/2 = elimination half-life; tmax =
time to Cmax; V/F = apparent volume of distribution.
(tmax) of 2.7 hours (table I).[3] The modafinil tmax
may be delayed by ≈1 hour when taken with food.[4]
The mean AUC for modafinil across one dosing
interval (AUCτ) was 79 µg • h/mL at a dosage of
200mg once daily (table I).[3] Modafinil is a racemic
compound whose enantiomers do not interconvert.[4]
At steady-state, exposure to l-modafinil was approx-
imately 3-fold higher than exposure to d-modafinil
(AUCτ of 60 vs 17 µg • h/mL with modafinil 200
mg/day).[3]
The apparent volume of distribution of modafinil
is 0.8 L/kg,[3] suggesting that there is tissue penetra-
tion. Plasma protein binding is ≈60%.[63]
3.2 Metabolism and Excretion
Metabolism (primarily hepatic) accounts for
≈90% of the elimination of modafinil, with <10% of
the administered dose excreted in the urine as un-
changed drug.[4] Metabolism occurs via hydrolytic
deamidation, S-oxidation, aromatic ring hydroxyl-
ation and glucuronide conjugation.[4] Modafinil acid
and modafinil sulfone are the two main circulating
metabolites of the drug; neither appears to be phar-
macologically active.[63] The metabolites are excret-
ed renally with 31–40% of the modafinil dose ex-
creted as modafinil acid (the major urinary metabo-
lite).[3]
Mean renal clearance of modafinil following a
single dose of 200mg was 2.3 mL/min (table I).[3]
 2005 Adis Data Information BV. All rights reserved.
791
With repeat administration, the mean plasma elimi-
nation half-life (t1/2) was 17 hours (table I).[3] The t1/2
Day 7
of the d-isomer was approximately 4-fold shorter
6.4 than that of the l-isomer (4.3 vs 16.0 hours at steady
2.7 state with 200mg once daily).[3]
79.0 3.3 Special Patient Populations
0.8
17.0
Elderly healthy men (mean age 63 years; n = 12)
44.0
had mean modafinil AUC values (AUC from time
zero to infinity; AUC∞) that were significantly
higher (68 vs 57 µg • h/mL; p < 0.05) than those in
younger healthy men (mean age 29 years; n = 12)
after a single dose of modafinil 200mg.[64] In addi-
tion, mean apparent clearance was significantly
lower in older versus younger men (0.63 vs 0.72
L/kg; p < 0.05).
The modafinil Cmax at steady-state was 112%
higher and the t1/2 was 104% longer in nine patients
with chronic hepatic impairment (Child class B–C)
than in 12 healthy volunteers.[65] Modafinil 100mg
twice daily was administered to patients with hepat-
ic impairment for 8 days and to healthy volunteers
for 15 days.
The pharmacokinetics of single-dose modafinil
200mg were not altered to a significant extent in
patients with severe renal impairment (creatinine
clearance ≤1.2 L/h [≤20 mL/min]).[4] However, ex-
posure to the metabolite modafinil acid increased
9-fold.
3.4 Potential Drug Interactions
In vitro, modafinil has been shown to inhibit the
cytochrome P450 (CYP) isoenzyme CYP2C19
(moderately potent, reversible inhibition), modestly
induce CYP1A2, CYP3A4/5 and CYP2B6 and sup-
press CYP2C9.[66] This raises the possibility of in-
teractions between modafinil and drugs that inhibit,
induce or are metabolised by CYP enzymes.
Suppression of CYP2C9 was not confirmed clini-
cally. The pharmacokinetics of (S)-warfarin (pre-
dominantly metabolised by CYP2C9) were not sig-
nificantly altered by 4 weeks of pretreatment with
modafinil in healthy volunteers.[67]
In healthy women receiving long-term adminis-
tration of an ethinylestradiol/norgestimate oral con-
CNS Drugs 2005; 19 (9)
792
traceptive, modafinil (200mg once daily for 1 week
then 400mg once daily for 3 weeks) altered the
pharmacokinetics of steady-state ethinylestradiol
and a single dose of triazolam, both CYP3A4/5
substrates.[68] The addition of modafinil versus pla-
cebo resulted in significantly (p < 0.05) greater
decreases in the mean AUCτ (–18% vs –4%) and
mean Cmax (–11% vs –5%) of ethinylestradiol, and
significantly (p < 0.05) greater decreases in the
mean AUC∞ (–59% vs +8%) and mean Cmax (–42%
vs +7%) of triazolam administered with the final
dose of modafinil or placebo.[68] These results also
suggest that induction of CYP3A4/5 activity by
modafinil was primarily gastrointestinal rather than
hepatic. Drugs besides triazolam that undergo sig-
nificant intestinal metabolism mediated by CYP3A
enzymes include ciclosporin, verapamil and lovasta-
tin.[68]
Other drugs that modafinil may interact with
include phenytoin (CYP2C9 and CYP2C19 sub-
strate) and diazepam and propranolol (CYP2C19
substrates).[4,62] Lower dosages of TCAs and SSRIs
may be needed in patients deficient in CYP2D6 who
are receiving concomitant modafinil, given that the
ancillary route of drug elimination via CYP2C19 is
more important in these patients.[4]
The potential for interaction between modafinil
and other drugs with CNS activity has been ex-
amined. Low-dose dexamfetamine (20 mg/day)[69]
or methylphenidate (20 mg/day)[70] did not alter the
steady-state pharmacokinetics of modafinil (200mg
once daily for 1 week then 400mg once daily for 3
weeks). In these studies, dexamfetamine was admin-
istered 7 hours[69] and methylphenidate was admin-
istered 8 hours[70] after modafinil. However, the tmax
of modafinil was significantly prolonged when a
single dose of dexamfetamine 10mg[71] or
methylphenidate 40mg[72] was administered simul-
taneously with a single dose of modafinil 200mg (p
< 0.05 vs modafinil alone); the median tmax was 3.0
hours with modafinil plus dexamfetamine versus 1.5
hours with modafinil alone,[71] and the tmax range
was 1.0–6.0 hours with modafinil plus methylpheni-
date versus 0.5–3.0 hours with modafinil alone.[72]
 2005 Adis Data Information BV. All rights reserved.
Keating & Raffin
No other significant alterations in the pharmacoki-
netics of modafinil occurred.[71,72]
4. Clinical Efficacy
4.1 In Patients with Obstructive Sleep
Apnoea/Hypopnoea Syndrome (OSA/HS)
Using Nasal Continuous Positive Airway
Pressure Therapy
The efficacy of oral modafinil in patients with
residual excessive sleepiness associated with OSA/
HS has been examined in three randomised, double-
blind, placebo-controlled studies; two studies were
of parallel-group multicentre design (n = 309[73] and
157[53]) and one was of crossover single-centre de-
sign (n = 30).[52] In these studies, the modafinil
dosage was titrated to a final dosage of 200[73] or
400mg[52,53,73] once daily in the morning, with a
treatment duration of 2,[52] 4[53] or 12[73] weeks.
Patients were receiving treatment with
nCPAP.[52,53,73]
Patients had excessive sleepiness (Epworth
Sleepiness Scale [ESS] score of ≥10[53,73] or ≥11[52]
[total ESS scores range from 0–24 points with
higher scores indicating greater sleepiness]).
Wakefulness was assessed in these studies using
subjective (ESS[52,53,73]) and objective (the Multiple
Sleep Latency Test [MSLT],[52,53] the Maintenance
of Wakefulness Test [MWT][52,73]) measures. Mild,
moderate and severe sleepiness are usually defined
as MSLT sleep-onset latencies of 10–15, 5–10 and
<5 minutes.[1] Psychomotor Vigilance Task (PVT)
testing[74] was used to measure the reaction time of
patients to stimuli to assess deficits in attention and
performance. Other outcome measures included the
Clinical Global Impression of Change (CGI-C),[53,73]
a global evaluation of the patient’s condition,[52]
functional status (assessed using the Functional Out-
comes of Sleep Questionnaire [FOSQ])[52,73,74] and
health-related quality of life (HR-QOL; assessed
using the 36-item Short Form Health Survey
[SF-36]).[52] Nocturnal polysomnography was also
performed.[52,53,73] Primary endpoints included the
change from baseline in ESS[52,53] and MWT[73]
scores and the CGI-C.[73]
CNS Drugs 2005; 19 (9)
Modafinil: A Review 793

Table II. Effect of modafinil (MOD) on residual excessive sleepiness in patients with obstructive sleep apnoea/hypopnoea syndrome who
were receiving nasal continuous positive airway pressure therapy. Results of three randomised, double-blind, placebo (PL)-controlled
studies of parallel-group[53,73] or crossover[52] design
Study Treatment regimena No. of Mean ESS score Mean MSLT SOL (min) Mean MWT SOL (min)
(mg) [duration of randomised baseline study end baseline study end baseline study end
treatment; weeks] patients
Black and MOD 200 od [12] 104 –4.5***b +1.6***b,c
Hirshkowitz[73] MOD 400 od [12] 101 –4.5***b +1.5***b,c
PL [12] 104 –1.8b –1.1b,c
Kingshott et al.[52] MOD 400 od [2] 30d 15 11c 6.9 10.3 16.5 18.3*
PL [2] 30d 15 13c 6.9 9.0 16.5 16.6
Pack et al.[53] MOD 400 od [4] 77 14.2 9.6**c 7.4 8.6*
PL [4] 80 14.4 12.4c 7.5 7.2
a MOD was titrated to the stated dosage.
b Mean change from baseline.
c Primary endpoint.
d Total no. of patients who completed the study.
ESS = Epworth Sleepiness Scale; MSLT = Multiple Sleep Latency Test; MWT = Maintenance of Wakefulness Test; od = once daily; SOL =
sleep-onset latency; * p < 0.05, ** p < 0.001, *** p < 0.0001 vs PL.

4.1.1 Effects on Wakefulness
Subjective Measure
In patients with residual excessive sleepiness as-
sociated with OSA/HS, modafinil 200 or 400 mg/
day improved wakefulness, as assessed using the
ESS, to a significantly greater extent than placebo in
the parallel-group studies,[53,73] but not in the smaller
crossover study.[52]
In the parallel-group studies, reductions in ESS
scores from baseline to end of therapy were signifi-
cantly greater with modafinil 200 or 400 mg/day
than with placebo (table II).[53,73] Significant reduc-
tions with modafinil versus placebo were also seen
at week 1 (p < 0.001) in the 4-week study[53] and at
weeks 4 and 8 (p < 0.0001) in the 12-week study.[73]
In the 4-week study, ESS scores were normalised to
<10 points in a significantly greater proportion of
modafinil than placebo recipients (51% vs 27%; p <
0.01).[53]
In the crossover study, there was no significant
difference between modafinil and placebo in ESS
score after 2 weeks of treatment (table II).[52]
Patients (n = 266) from the 12-week parallel-
group study[73] continued in a 12-month noncom-
parative extension phase (available as an abstract)
during which they received modafinil 200, 300 or
400 mg/day.[75] ESS scores were significantly re-
duced from a baseline score of 14.5 points at months
3 (by 5.7 points), 6 (5.3), 9 (5.4) and 12 (4.5) with
modafinil (all p < 0.0001 vs baseline).[75]
In a 12-week noncomparative extension[76] of the
4-week parallel-group study,[53] patients (n = 125)
had an ESS score of 7.8 points at week 12 (patients
received modafinil 200, 300 or 400 mg/day).
Objective Measures
At study end, the ability to sustain wakefulness,
as assessed by MWT, improved to a significantly
greater extent with modafinil 200 or 400 mg/day
versus placebo in the 12-week parallel-group
study[73] and the crossover study[52] (table II). In the
parallel-group study, significantly greater improve-
ments in the ability to sustain wakefulness, as as-
sessed by mean MWT, were also seen with
modafinil 200 or 400 mg/day than with placebo at
weeks 4 and 8 (p ≤ 0.0001).[73]
In the 4-week parallel-group study, MSLT sleep-
onset latency had increased by a significantly
greater extent with modafinil than placebo at study
end (table II).[53] However, the improvement in
MSLT sleep-onset latency did not significantly dif-
fer between modafinil and placebo administration in
the crossover study (table II).[52]
Additional analysis[74] of the 4-week parallel-
group study[53] found that sustained attention on

 2005 Adis Data Information BV. All rights reserved. CNS Drugs 2005; 19 (9)
794
PVT testing was improved to a significantly greater
extent with modafinil than with placebo. Compared
with placebo recipients, modafinil recipients had a
significant decrease in the number of attention
lapses (p = 0.01), and significant improvements in
the median (p = 0.01) and the reciprocal of the 10%
slowest (p = 0.023) reaction times.
4.1.2 Other Outcomes
At study end, significantly greater proportions of
modafinil 200 or 400 mg/day recipients than place-
bo recipients experienced clinical improvement (as-
sessed by CGI-C ratings) in the 12-week parallel-
group study (61% and 68% vs 37%; p < 0.001).[73]
The 4-week parallel-group study yielded a similar
result with 71% of modafinil recipients versus 35%
of placebo recipients (p = 0.035) experiencing
clinical improvement at study end.[53] In a 12-week
noncomparative extension of the latter study, 71%
of modafinil recipients were rated as much or very
much improved at week 12.[76] In the crossover
study, there was no significant between-treatment
difference in the proportion of patients whose condi-
tion was rated as ‘better’.[52]
Given its benefits, a reduction in nCPAP use is
not considered desirable in patients with OSA/HS.
Modafinil did not reduce nCPAP use in the large
parallel-group studies,[53,73] although nCPAP use
was slightly, but statistically significantly, lower
with modafinil than with placebo in the crossover
study (6.3 vs 6.5 hours per night; p = 0.03).[52]
Moreover, during a 12-week noncomparative exten-
sion of the 4-week parallel-group study, mean
nCPAP use was significantly reduced compared
with baseline use in the double-blind portion of the
study (5.9 vs 6.3 hours per night; p = 0.004).[76]
Modafinil did not have an adverse impact on
night-time sleep.[52,53,73] There were no significant
differences between modafinil and placebo adminis-
tration in various nocturnal polysomnography pa-
rameters (e.g. arousal frequency,[52,73] sleep efficien-
cy,[52,53,73] sleep duration,[53,73] respiratory events,[52]
respiratory disturbance index,[53] and the percentage
of time spent in stages 1–4 and REM sleep[53,73]).
However, in the 4-week parallel-group study, the
mean arousal index was significantly higher with
 2005 Adis Data Information BV. All rights reserved.
Keating & Raffin
modafinil than with placebo (14.3 vs 11.8; p =
0.018).[53]
4.1.3 Health-Related Quality-of-Life
(HR-QOL) Considerations
Modafinil improved functional status and HR-
QOL to a significantly greater extent than placebo in
the parallel-group studies.[73,74]
In the 12-week study, the improvement at study
end in the total FOSQ score was significantly
greater with modafinil 200 and 400 mg/day than
with placebo (mean change of +1.92 and +2.13 vs
+0.84; p = 0.001), as were improvements in domain
scores for vigilance, general productivity and activi-
ty level (figure 1).[73] In the extension phase, the
total FOSQ score and the mental and physical com-
ponent scores of the SF-36 were significantly im-
proved from baseline with modafinil (p < 0.01).[75]
An additional analysis[74] of the 4-week study[53]
found significant improvements in the total FOSQ
score and domain scores for vigilance and activity
level with modafinil versus placebo (p < 0.05) after
4 weeks of therapy. Changes from baseline in do-
main scores for general productivity, social outcome
MOD 200mg (n = 99)
MOD 400mg (n = 91)
p < 0.001 PL (n = 100)
0.6
Mean change from baseline in FOSQ score
p = 0.02 p = 0.05
0.5
p = 0.30
0.4 p < 0.001
0.3
0.2
0.1
0.0
Vigilance General Activity Social Intimacy
productivity outcome
Fig. 1. Effect of modafinil (MOD) on functional outcome in patients
with residual excessive sleepiness associated with obstructive
sleep apnoea/hypopnoea syndrome. Mean change from baseline to
week 12 in Functional Outcomes of Sleep Questionnaire (FOSQ)
domain scores. Patients in this randomised, double-blind, parallel-
group, multicentre study received oral MOD 200 or 400mg once
daily or placebo (PL) for 12 weeks.[73]
CNS Drugs 2005; 19 (9)
Modafinil: A Review
and intimacy did not significantly differ between
treatment groups.
In the crossover study, there were no significant
differences between modafinil and placebo with re-
gard to changes in FOSQ domain scores or SF-36
domain, or physical and mental component
scores.[52] Because of the small sample size (n = 30),
this study may not have been adequately powered to
detect a difference between treatments.
4.2 In Patients with Shift Work Sleep
Disorder (SWSD)
The efficacy of modafinil in night-shift workers
with chronic SWSD has been examined in two
randomised, double-blind, parallel-group, placebo-
controlled, multicentre, 12-week trials (n = 204[77]
and 278[78]). One study is available as an abstract
and only reported HR-QOL outcomes.[78] The diag-
nosis of SWSD requires a primary complaint of
insomnia or excessive sleepiness that is temporally
associated with a work period occurring during the
habitual sleep phase.[1] Other diagnostic criteria in-
clude loss of a normal sleep-wake pattern (as shown
by polysomnography and the MSLT), lack of a
medical or mental disorder to account for the symp-
toms, and symptoms not meeting criteria for any
other sleep disorder associated with insomnia or
excessive sleepiness.[1]
In these studies, patients diagnosed with SWSD
received modafinil 60–30 minutes prior to the start
of each night-shift. Patients received modafinil
Table III. Effect of modafinil (MOD) on night-time wakefulness and alertness during a laboratory night shift. In this randomised, double-blind,
multicentre trial, patients with chronic shift work sleep disorder received MOD 200mg once daily (n = 96) or placebo (PL; n = 108) for 12
weeks[77]
Parameter Treatment
Mean MSLT sleep-onset latency (min) MOD
PL
Median number of attention lapsesb MOD
PL
Mean Karolinska Sleepiness Scale scoresc MOD
PL
a Primary endpoint.
b Assessed using Psychomotor Vigilance Task testing.
c Karolinska Sleepiness Scale scores range from 1 (very alert) to 9 (very sleepy).
MSLT = Multiple Sleep Latency Test; * p = 0.002, ** p < 0.001 vs PL.
 2005 Adis Data Information BV. All rights reserved.
795
200mg once daily or placebo in one study[77] and
modafinil 200 or 300mg once daily or placebo in the
other.[78]
Measures of night-time wakefulness included the
MSLT, the KSS (with scores ranging from 1 [very
alert] to 9 [very sleepy]) and CGI-C ratings.[77]
MSLT and KSS were assessed during a laboratory
night-shift.[77] PVT testing was also performed dur-
ing a laboratory night-shift, and polysomnography
was used to assess the quality of daytime sleep.[77]
Patient diary data were recorded,[77] and functional
status and HR-QOL were assessed using FOSQ and
SF-36.[78] Where specified, primary endpoints in-
cluded the change from baseline in MSLT and the
CGI-C.[77] For final visit assessments, data from the
last visit on or before month 3 were used.[77]
4.2.1 Effects on Wakefulness and Sleep
Night-time wakefulness was significantly im-
proved with modafinil 200 mg/day compared with
placebo in patients with SWSD.[77] Improvement in
the ability of patients to sustain wakefulness, as
shown by the increase in the mean MSLT from
baseline to the final visit, was significantly greater
with modafinil than with placebo (table III).[77] Sig-
nificant differences favouring modafinil were also
seen after 1 and 3 months of treatment (both p = 0.01
vs placebo). Although these between-group differ-
ences in MSLT were statistically significant, the
mean MSLT sleep-onset latency after 3 months’
therapy was still <5 minutes in modafinil recipients,
indicating marked sleepiness.
Baseline Final visit Change from baseline
to final visit
2.1 3.8 +1.7*a
2.0 2.4 +0.3a
12.5 10.3 –2.6**
16.1 23.8 +3.8
7.3 5.8 –1.5**
7.1 6.7 –0.4
CNS Drugs 2005; 19 (9)
796
At the final visit, a significantly greater propor-
tion of modafinil than placebo recipients exper-
ienced clinical improvement according to the CGI-C
(74% vs 36%; p < 0.001).[77]
Modafinil recipients performed significantly bet-
ter than placebo recipients during PVT testing.[77]
The median number of attention lapses was reduced
from baseline to a significantly greater extent with
modafinil than with placebo at the final visit (table
III). Improvements from baseline in mean KSS
scores were significantly greater with modafinil
than with placebo at the final visit (table III), and at
months 1, 2 and 3 (all p < 0.001 vs placebo).[77]
Comparison of baseline and postbaseline mean
KSS scores from patient diary data demonstrated
that maximum sleepiness during the night-shift was
reduced to a significantly (p < 0.001) greater extent
with modafinil (from 7.3 to 5.4 points) than with
placebo (from 7.4 to 6.6 points).[77] Similarly,
modafinil recipients reported a significantly (p =
0.01) greater reduction from baseline in the level of
sleepiness during the commute home (from 5.5 to
4.4 points) compared with placebo recipients (from
5.9 to 5.4 points) [assessed using KSS scores].
Moreover, the proportion of patients reporting acci-
dents or near misses during the commute home was
significantly lower in modafinil than placebo recipi-
ents (29% vs 54%; p < 0.001).
Modafinil did not have a deleterious effect on
daytime sleep.[77] There were no significant differ-
ences between modafinil 200 mg/day and placebo
recipients with regard to changes in daytime sleep
parameters such as sleep duration, sleep-onset laten-
cy, sleep efficiency or sleep architecture.[77]
4.2.2 HR-QOL Considerations
Modafinil improved functional status and HR-
QOL to a significantly greater extent than placebo in
patients with SWSD.[78] At week 12, FOSQ total
scores and domain scores for vigilance and general
productivity were improved from baseline to a
greater extent with modafinil 300 mg/day than with
placebo, and FOSQ activity level scores were im-
proved from baseline to a significantly greater ex-
tent with modafinil 200 or 300 mg/day versus place-
bo (all p < 0.05) [quantitative data not reported].[78]
 2005 Adis Data Information BV. All rights reserved.
Keating & Raffin
Moreover, the improvement in the mental com-
ponent of SF-36 was significantly greater with
modafinil 200 or 300 mg/day than with placebo (p <
0.05) at 12 weeks (quantitative data not reported).[78]
Twelve-month open-label extension studies (n =
166[79] and 125;[80] both available as abstracts) of the
two SWSD trials[77,78] have also been conducted. At
12 months, modafinil recipients had significant im-
provements in the total FOSQ score and domain
scores for activity, general productivity, intimacy,
social outcome and vigilance (p-values not reported)
in the extension[79] of one of the SWSD trials,[78] but
not in the extension[80] of the other trial.[77]
5. Tolerability
Tolerability data were obtained from three
randomised, double-blind, placebo-controlled stud-
ies in patients with OSA/HS[52,53,73] (section 5.1) and
in two randomised, double-blind, placebo-con-
trolled, multicentre studies in patients with
SWSD[77,78] (section 5.2) [see sections 4.1 and 4.2
for further study details]. One of the SWSD studies
is available as an abstract and did not report statisti-
cal analyses.[78]
5.1 In Patients with OSA/HS
Modafinil was generally well tolerated in patients
with OSA/HS using nCPAP.[52,53,73] Adverse events
were mostly of mild-to-moderate severity.[53,73]
With modafinil, the most commonly reported
adverse events (i.e. occurring in ≥5% of patients)
were headache, infection, nausea, anxiety, acciden-
tal injury, diarrhoea, hypertension, nervousness, diz-
ziness, insomnia, rhinitis and dry mouth (table
IV).[52,53,73] In the parallel-group studies, head-
ache,[53,73] nausea[73] and nervousness[53] occurred
significantly more frequently in modafinil than in
placebo recipients (table IV).
In the crossover study, the overall incidence of
adverse events was significantly higher with
modafinil than with placebo (74% vs 45%; p =
0.04), although there were no significant between-
treatment differences in the incidence of the most
commonly reported adverse events (table IV).[52]
CNS Drugs 2005; 19 (9)
Modafinil: A Review 797

Table IV. Incidence of adverse events in patients with obstructive sleep apnoea/hypopnoea syndrome who received modafinil (MOD).
Results of three randomised, double-blind studies of parallel-group[53,73] or crossover[52] design. Treatment duration was 2,[52] 4[53] or 12[73]
weeks
Adverse eventa Black and Hirshkowitz[73] Pack et al.[53] Kingshott et al.[52]
(% of patients) MOD 200mg MOD 400mg PL MOD 400mg PL MOD 400mg PL
od (n = 103) od (n = 99) (n = 103) od (n = 77) (n = 80) od (n = 31)b (n = 31)b
Headache 23 26 13* 23 11* 16 16
Infection 19 10 22
Nausea 10 10 2** 6 4 16 0
Anxiety 6 8 2 6 1
Accidental injury 8 5 8
Diarrhoea 8 5 8
Hypertension 4 8 2
Nervousness 6 6 2 12 3*
Dizziness 6 5 3 6 3
Insomnia 7 4 1 5 1
Rhinitis 6 5 8 8 3
Dry mouth 10 0
a Adverse events experienced by ≥5% of patients.
b Total no. of patients receiving ≥1 dose of study drug.
od = once daily; PL = placebo; * p < 0.05, ** p = 0.01 vs MOD.

Treatment discontinuation because of adverse 5.2 In Patients with SWSD

events occurred significantly more frequently with
modafinil than with placebo in the parallel-group
studies (10% [200mg] and 11% [400mg] vs 3%; p <
0.05[73] and 10% vs 1%; p = 0.016[53]) but not in the
crossover study (3% vs 0%).[52]
Serious adverse events, none of which were con-
sidered related to the study drug, occurred in four
modafinil recipients (cellulitis, hernia, accidental
overdose of methanol de-icer, vomiting) in the
12-week parallel-group study[73] and in one
modafinil recipient (chest pain) in the 4-week
parallel-group study;[53] no serious adverse events
were reported in the crossover study.[52]
No clinically meaningful differences between
modafinil and placebo administration were observed
with regards to laboratory parameters, physical ex-
amination findings, ECG recordings or vital signs
(see also section 2.4).[52,53,73]
In a 12-month extension study, the most com-
monly reported treatment-emergent adverse events
in modafinil 200–400 mg/day recipients included
infection, nervousness, headache, accidental injury,
sinusitis, rhinitis, depression, anxiety, insomnia and
dizziness (5–11% of patients).[75]
Modafinil was generally well tolerated in patients
with SWSD.[77,78] Adverse events were generally of
mild-to-moderate severity.[77,78]
The most commonly reported treatment-emer-
gent adverse events (i.e. occurring in ≥5% of pa-
tients in either treatment arm) in modafinil and
placebo recipients included headache (26% vs
19%), nausea (9% vs 3%), infection (6% vs 10%),
accidental injury (6% vs 8%), abdominal pain (6%
vs 2%), nervousness (6% vs <1%), insomnia (6% vs
0%), dry mouth (5% vs 4%), tooth disorder (5% vs
<1%) and rhinitis (3% vs 6%).[77] Only insomnia
occurred in significantly more modafinil than place-
bo recipients (p = 0.01). No serious adverse events
occurred in modafinil recipients.
In the study available as an abstract, modafinil
200 and 300 mg/day and placebo recipients reported
headache (17%, 26% and 16%), nausea (6%, 19%
and 5%) and nervousness (3%, 10% and 2%).[78]
No clinically meaningful differences between
modafinil and placebo recipients were seen with
regards to laboratory parameters, physical examina-
tion findings, ECG recordings or vital signs.[77,78]

 2005 Adis Data Information BV. All rights reserved. CNS Drugs 2005; 19 (9)
798
Modafinil was generally well tolerated in
12-month extension studies in patient with SWSD;
the most commonly reported adverse events includ-
ed headache, infection and pain (11–19% of pa-
tients).[79,80]
6. Dosage and Administration
In the US and certain European countries,
modafinil is indicated to improve wakefulness in
patients who have excessive sleepiness associated
with OSA/HS or SWSD, in addition to its original
indication in patients with excessive sleepiness as-
sociated with narcolepsy.[4,62] Modafinil should be
used as an adjunct to standard treatment (e.g.
nCPAP) in patients with OSA/HS.[4,62] In the US and
the EU, the recommended modafinil dosage is
200mg once daily in OSA/HS (although in the EU it
may be titrated to 400 mg/day if necessary).[4,62] The
recommended modafinil dosage is 200mg once dai-
ly in SWSD (taken ≈1 hour prior to the work shift)
in both the US and the EU.[4,62]
Local prescribing information should be con-
sulted for contraindications, warnings and precau-
tions related to modafinil use, for specific dosage
recommendations in special patient populations and
for information about drug interactions.
7. Place of Modafinil in the
Management of Excessive Sleepiness
Associated With OSA/HS and SWSD
Excessive sleepiness is a symptom associated
with various disorders.[81,82] In patients reporting
excessive sleepiness, the underlying cause should be
established and sleep hygiene evaluated. For some
conditions (e.g. OSA/HS) there are specific mea-
sures that can be taken to ameliorate excessive
sleepiness.[81,82]
The prevalence of sleep apnoea syndrome was
estimated to be 2% among middle-aged women and
4% among middle-aged men in a US study.[83] Ex-
cessive sleepiness is one of the symptoms of OSA/
HS; the disorder has been linked to hypertension and
other cardiovascular morbidities, as well as im-
paired cognitive function and HR-QOL.[84] Patients
with OSA/HS also appear to have an increased risk
 2005 Adis Data Information BV. All rights reserved.
Keating & Raffin
of sudden death due to cardiac causes during the
sleeping hours.[85] OSA/HS has also been linked to
an increased risk of motor vehicle and occupational
accidents.[84]
The treatment of choice in OSA/HS is nCPAP.[86]
As well as eliminating apnoea, this therapy is associ-
ated with improvements in sleepiness and cognitive
function, as well as improvements in BP.[86] Howev-
er, some patients with OSA/HS who are receiving
nCPAP therapy experience residual excessive sleep-
iness.[53] Optimising nCPAP use is the first-line
treatment strategy in such patients and other treat-
ment options (e.g. oral appliances) may be of bene-
fit.[73,87] Modafinil is a treatment option, in addition
to nCPAP, in patients for whom residual excessive
sleepiness remains an issue, despite these measures.
In patients with residual excessive sleepiness as-
sociated with OSA/HS who were receiving nCPAP,
modafinil was associated with significantly greater
improvements in subjective and objective measures
of wakefulness in two parallel-group studies (sec-
tion 4.1.1).[53,73] Results were less consistent in a
smaller crossover study, with a significant improve-
ment in the MWT sleep-onset latency with
modafinil versus placebo, but no significant be-
tween-treatment difference in ESS scores or MSLT
sleep-onset latency (section 4.1.1).[52] Possible rea-
sons for the discrepancy in results between the par-
allel-group and crossover studies include a lack of
statistical power and a short treatment duration in
the crossover study.[52]
In patients with OSA/HS, clinical improvement
occurred in significantly more modafinil than place-
bo recipients[53,73] and modafinil did not have detri-
mental effects on night-time sleep (section
4.1.2).[52,53,73] In addition, aspects of functional sta-
tus and HR-QOL improved to a significantly greater
extent with modafinil than with placebo in the paral-
lel-group studies,[73,74] but not in the crossover
study[52] (section 4.1.3). It should be noted that only
one[73] of these three trials included a study arm
evaluating modafinil 200mg once daily, the dosage
approved in the US for use in OSA/HS (section 6).
Concerns have been raised that the improvement
in wakefulness experienced by patients with OSA/
CNS Drugs 2005; 19 (9)
Modafinil: A Review
HS who receive modafinil may lead them to reduce
their use of nCPAP.[88,89] No reduction in nCPAP
use occurred in modafinil recipients in the two par-
allel-group studies,[53,73] although a statistically sig-
nificant reduction in nCPAP use was seen in
modafinil recipients in the smaller, crossover trial[52]
(section 4.1.2). It has been suggested that the small
reduction in nCPAP use observed with modafinil
was not of clinical significance,[53] although the
lower nCPAP use seen in modafinil recipients may
have reduced the likelihood of finding improve-
ments in efficacy outcomes (i.e. ESS scores and
MSLT sleep-onset latency) with the drug.[52]
As mentioned previously, all appropriate mea-
sures should be taken to ensure that patients with
OSA/HS are making optimal use of nCPAP before
modafinil therapy is started.[73,87] In patients receiv-
ing modafinil in conjunction with nCPAP, nCPAP
use should be encouraged and compliance with
nCPAP therapy should be regularly assessed.[4] The
potential role of modafinil in patients with OSA/HS
who do not tolerate nCPAP and are refractory to
other treatment options is an area for future study.[87]
The results of a 12-month noncomparative exten-
sion study indicate that modafinil maintains its
wake-promoting effect over the longer term (section
4.1.1),[75] although there is a need for more long-
term data on the use of the drug in OSA/HS, particu-
larly concerning any possible effect on nCPAP use.
Circadian rhythm disorders affected almost 25%
of night-shift workers in a US/French study[90] and
there are almost 6 million full-time workers in the
US who work night-shifts on a regular or rotating
basis.[91] Night-shift workers have a 6- to 14-fold
greater risk of experiencing severe sleepiness than
day workers.[92] Moreover, excessive sleepiness in
shift workers is associated with numerous deleteri-
ous consequences, including an increased risk of
errors and accidents.[93,94]
Various strategies to ameliorate the adverse con-
sequences of shift work have been evaluated in
night-shift workers including bright light ther-
apy[95-97] and administration of caffeine,[98,99]
benzodiazepines,[100,101] metamfetamine[102] and me-
latonin,[103-105] as well as strategic napping during
 2005 Adis Data Information BV. All rights reserved.
799
the night-shift.[106] Whereas some of these modali-
ties (e.g. bright light therapy) have been shown to be
beneficial, others (e.g. melatonin) have yielded in-
conclusive results.
Compared with placebo, modafinil significantly
improved subjective and objective measures of
wakefulness in patients with SWSD (although pa-
tients remained markedly sleepy according to the
MSLT), as well as having no adverse impact on
daytime sleep (section 4.2.1).[77] Modafinil also im-
proved aspects of functional status and HR-QOL to
a significantly greater extent than placebo (section
4.2.2).[78]
While studies to date have demonstrated the effi-
cacy of modafinil in improving wakefulness in pa-
tients with excessive sleepiness associated with
OSA/HS and SWSD, it would be of interest to
establish if the drug also reduces adverse outcomes
associated with these disorders (for example, reduc-
ing the incidence of motor vehicle accidents in pa-
tients with OSA/HS and the incidence of job errors
and/or accidents in patients with SWSD).
Modafinil is currently the only wake-promoting
drug approved for use in the US in excessive sleepi-
ness associated with OSA/HS and SWSD.[107] Al-
though amfetamines have also been shown to im-
prove daytime sleepiness in patients with OSA/
HS,[108] these agents are associated with the draw-
backs of abuse potential and cardiovascular adverse
effects.[109] Methylphenidate has a long record of
clinical efficacy in treating excessive sleepiness,
although there is a lack of data from large well
designed trials.[107] The development of tolerance is
also an issue with the use of amfetamines or
methylphenidate.[107] Pemoline was shown to im-
prove alertness during a night shift in a small tri-
al;[110] however, the use of this drug is contraindi-
cated in the US because of the risk of hepatotoxici-
ty.[107]
Although the exact mechanism by which
modafinil exerts its wake-promoting effect is un-
clear, it appears to have a different mechanism of
action from that of other CNS stimulants such as
amfetamine, dexamfetamine and methylphenidate
(section 2.1). Moreover, it seems to have a much
CNS Drugs 2005; 19 (9)
800
lower abuse potential than these other stimulants
(section 2.4).
Modafinil is generally well tolerated in the short-
term in patients with OSA/HS and SWSD (section
5). In addition, preliminary data from 12-month
extension studies indicate that the good tolerability
of modafinil is maintained over the longer term in
OSA/HS[75] and SWSD[79,80] (sections 5.1 and 5.2),
although there is a need for additional long-term
data. Modafinil has been shown to be generally well
tolerated over the longer term in patients with narco-
lepsy (mean duration of treatment 22.4 months
[range 1–114 months]).[111] Trial data indicate that
overdoses of modafinil (up to 4500mg) were not
associated with unexpected or life-threatening
events.[4] In addition, no fatal outcomes associated
with overdoses of modafinil alone (up to 12g) have
been reported during postmarketing surveillance,
although fatal outcomes have been associated with
overdoses involving multiple drugs (including
modafinil).[4]
Modafinil may also have potential in other disor-
ders which may produce excessive sleepiness (e.g.
restless legs syndrome, disrupted sleep due to medi-
cal causes such as pain);[112] however, well designed
trials evaluating the drug in these conditions are
needed.
In conclusion, oral modafinil promotes wakeful-
ness in patients with OSA/HS and SWSD. It is an
effective adjunctive therapy in patients with residual
excessive sleepiness associated with OSA/HS who
are receiving nCPAP. In SWSD, the drug improves
night-time wakefulness without disrupting daytime
sleep. Modafinil is generally well tolerated in pa-
tients with OSA/HS or SWSD and has a low abuse
potential. Thus, modafinil is a valuable new treat-
ment option for use in patients with excessive sleep-
iness associated with OSA/HS (as an adjunct to
nCPAP) or SWSD.
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Correspondence: Gillian M. Keating, Adis International
Limited, 41 Centorian Drive, Private Bag 65901, Mairangi
Bay, Auckland, 1311, New Zealand.
E-mail: demail@adis.co.nz
CNS Drugs 2005; 19 (9)