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Background: Modafinil is a novel wakepromoting agent that has U.S. Food and Drug
Administration approval for narcolepsy and
shift work sleep disorder and as adjunctive
treatment of obstructive sleep apnea/hypopnea
syndrome. Modafinil has a novel mechanism
and is theorized to work in a localized manner,
utilizing hypocretin, histamine, epinephrine,
-aminobutyric acid, and glutamate. It is a welltolerated medication with low propensity for
abuse and is frequently used for off-label indications. The objective of this study was to systematically review the available evidence supporting
the clinical use of modafinil.
Data Sources: The search term modafinil OR
Provigil was searched on PubMed. Selected articles were mined for further potential sources
of data. Abstracts from major scientific conferences were reviewed. Lastly, the manufacturer
of modafinil in the United States was asked to
provide all publications, abstracts, and unpublished data regarding studies of modafinil.
Data Synthesis: There have been 33 doubleblind, placebo-controlled trials of modafinil. Additionally, numerous smaller studies have been
performed, and case reports of modafinils use
abound in the literature.
Conclusions: Modafinil is a promising drug
with a large potential for many uses in psychiatry
and general medicine. Treating daytime sleepiness is complex, and determining the precise nature of the sleep disorder is vital. Modafinil may
be an effective agent in many sleep conditions. To
date, the strongest evidence among off-label uses
exists for the use of modafinil in attention-deficit
disorder, postanesthetic sedation, and cocaine
dependence and withdrawal and as an adjunct
to antidepressants for depression.
(J Clin Psychiatry 2006;67:554566)
Received Feb. 13, 2005; accepted Jan. 30, 2006. From the
Department of Psychiatry, University of California, San Diego, San
Diego (Drs. Ballon and Feifel); and the Department of Psychiatry and
Behavioral Science, Stanford University, Stanford, Calif. (Dr. Ballon).
Drs. Ballon and Feifel report no financial affiliations or other
relationships relevant to the subject of this article.
Corresponding author and reprints: David Feifel, M.D., Ph.D., 200
West Arbor Dr., San Diego, CA 92103-8218 (e-mail: dfeifel@ucsd.edu).
554
odafinil is a novel wake-promoting agent approved by the U.S. Food and Drug Administration (FDA) for use in treating narcolepsy18 and shift
work sleep disorder (SWSD)9,10 and as adjunctive treatment for obstructive sleep apnea/hypopnea syndrome
(OSAHS).1015 Modafinils mechanism remains unknown,
although evidence strongly supports a mechanism distinct
from that of typical amphetamine-derived stimulants.16
Modafinil is associated with increased adrenergic, histaminergic, glutaminergic, and hypocretin activity and decreased -aminobutyric acid (GABA) activity in specific
parts of the brain. A generally well-tolerated medication,
modafinil is increasingly being used for many off-label
indications.17 The objective of this study was to systematically review the available evidence supporting the clinical
use of modafinil.
DATA SOURCES
To conduct this literature review, the search term
modafinil OR Provigil was searched on PubMed. This
resulted in 397 articles. Selected articles were mined for
further potential sources of data. Abstracts from major
scientific conferences were reviewed to identify articles
relevant to the topic of this review. Lastly, the U.S. manufacturer of Provigil, Cephalon, Inc. (Frazer, Pa.), was
asked to provide all publications, abstracts, and unpublished data regarding studies of modafinil.
DATA SYNTHESIS
Possible Mechanisms of Action
Modafinils precise mechanism of action is not known.
Conventional wake-promoting stimulants such as amphetamine and amphetamine analogs work as sympathomimetic drugs that increase levels of norepinephrine,
serotonin, and dopamine by blocking reuptake and stimulating release at the presynaptic terminals.18 The increased
levels of dopamine in the reticular activating system and
the prefrontal cortex are thought to be responsible for the
enhanced wakefulness and alertness produced by these
drugs.19 Additionally, increased sympathetic tone produces predictable systemic side effects.20
There is some evidence that modafinils effects are mediated by activation of noradrenergic 1 receptors, includ-
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Narcolepsy
Polio fatigue
Antipsychotic fatigue
Postanesthesia recovery
time
Billiard et al (1994)4
Czeisler et al (2005)9
Rosenberg et al (2003)55
Black and Hirshkowitz
(2005)11
Pack et al (2001)13
Kingshott et al (2001)14
Stankoff et al (2005)67
Hogl et al (2002)71
Adler et al (2003)70
Ondo et al (2005)72
Chan et al (2006)77
Sevy et al (2005)88
Larijani et al (2004)91
Randall et al (2005)76
Narcolepsy
Narcolepsy
Broughton et al (1997)3
Method
9 wk, placebo vs modafinil 200 mg/d
vs modafinil 400 mg/d
Indication
Narcolepsy
Study
US Modafinil in Narcolepsy
Multicenter Study Group
(1998)1
US Modafinil in Narcolepsy
Multicenter Study Group
(2000)2
N = 13 modafinil
N = 11 placebo
N = 17 modafinil
N = 17 placebo
N = 19 modafinil
N = 18 placebo
N = 14
N = 21
N = 15
N = 59 modafinil
N = 56 placebo
N = 14
N = 278
N = 104 placebo
N = 104 modafinil 200 mg
N = 101 modafinil 400 mg
N = 80 placebo
N = 77 modafinil
N = 32
N = 110 placebo
N = 99 modafinil
N = 50
N = 75
Sample Size
N = 92 placebo
N = 96 modafinil 200 mg
N = 95 modafinil 400 mg
N = 93 placebo
N = 89 modafinil 200 mg
N = 89 modafinil 400 mg
continued
Improvement on the ESS (p = .039) and the CGI (p = .07) with modafinil.
No difference between groups on the UPDRS.
No significant differences between groups on the ESS, the MSLT,
the UPDRS, and the HAM-D.
No significant difference between groups on the Piper Fatigue Scale,
the ESS, the Digit Span, and reaction time tests.
No significant difference between groups on the FSS or Visual Analog
Fatigue Scale, although both groups improved from baseline.
Modafinil improved subjective feelings of being worn out (p < .01),
exhaustion (p < .01), and fatigue (p < .05), in a postoperation
questionnaire.
Modafinil group showed improvement on the ESS (p < .0001) and the
CGI (= 0.035) but not on the MSLT compared with the placebo group.
No significant difference between groups on the ESS (p = .24),
the MSLT (p = .16), Trailmaking B (p = .95), and the FOSQ (p = .41).
No significant difference between groups in mood, quality of life,
and mental fatigue as measured by the Visual Analog Scale, the
Medical Outcomes Study 36-Item Short Form Health Survey, and the
11-item Fatigue Questionaire, respectively.
No significant difference between groups on the Modified Fatigue Impact
Scale (p = .27) or the ESS. Both groups improved from baseline on the
Modified Fatigue Impact Scale (p < .0001).
Improvement on the ESS (p = .011) with modafinil.
Results
Modafinil subjects had improved MSLT (p < .0001), MWT (p < .0001),
ESS (p < .0001), and CGI (p < .005) scores.
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ADHD (child)
ADHD (adult)
ADHD (child)
Bipolar depression
Cocaine dependence
Cocaine dependence
Schizophrenia cognition
Schizophrenia
Schizophrenia
Appetite suppression
Cephalon, Inc104
Biederman et al (2005)105
Fava et al (2005)109
Frye et al (2005)115
Dackis et al (2003)146
Dackis et al (2005)120
Turner et al (2004)122
Pierre et al (2005)124
Sevy et al (2005)88
Makris et al (2004)127
Method
2 wk, crossover between
dextroamphetamine and modafinil,
flexible modafinil dose
average = 209 mg/d
6 wk, flexible dose
average = 200 mg/d
N = 13 modafinil
N = 11 placebo
N = 10 modafinil
N = 10 placebo
N = 20
N=7
N = 30 modafinil
N = 32 placebo
N = 41 modafinil
N = 44 placebo
N = 164 modafinil
N = 82 placebo
N = 159 modafinil
N = 155 placebo
N = 113
N = 11 modafinil
N = 11 placebo
Sample Size
N = 22
Results
Modafinil and dextroamphetamine groups both showed improvement on
the DSM-IV ADHD Behavior Checklist for Adults (p < .0001) and the
Controlled Oral Word Association Test (p < .05) compared with placebo.
Indication
ADHD (adult)
Study
Taylor and Russo (2000)101
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placebo, for some patients a rapid and significant improvement was noted, suggesting that some Parkinsons
disease patients may benefit from modafinil.
Chronic fatigue syndrome is characterized by severe,
disabling fatigue in addition to musculoskeletal pain,
sleep disturbance, impaired concentration, and/or headaches.73 The mechanism for chronic fatigue syndrome is
not currently fully understood. Pharmacologic treatments
have been generally unsatisfying, although cognitivebehavioral therapy and graded exercise therapy have
shown some positive results.74 An initial case report75 suggested that modafinil was effective in treating the fatigue
of 1 patient who had suffered with chronic fatigue syndrome for over 13 years such that he was able to return to
work. However, in a small, randomized, double-blind,
placebo-controlled, crossover study (N = 14),76 modafinil
was shown to have no statistical separation from placebo
over 20 days of treatment. Outcome variables included
tests of attention and subjective ratings of fatigue, quality
of life, and mood. This was a small study, however, and
may have suffered from a low statistical power to show
differences between groups.76
Modafinil was evaluated in a double-blind, placebocontrolled, crossover trial (N = 14)77 for treatment of sedation in patients with a prior diagnosis of polio. In this
study, no difference was observed between conditions on
the ESS, the Piper Fatigue Scale (PFS), the Digit Span,
and reaction time tests over the course of the 5-week treatment arms.
Fatigue is also common in patients with the human
immunodeficiency virus (HIV). In an open-label study
(N = 30),78 80% of subjects self-reported that they had
less fatigue on modafinil treatment. Among these responders, those with a preexisting mood disorder were
noted to have improvement in depression scores on the
Hamilton Rating Scale for Depression (HAM-D) and a
general increase in cognitive functioning on neuropsychological tests. No change was noted in CD4 lymphocyte count or HIV viral load during the 4-week study. This
study was limited by the lack of a control group with
which to compare the results.
The cognitive-enhancing properties of modafinil have
been evaluated in 2 small studies of patients with dementia. In an open-label study (N = 8),79 patients with vascular dementia, subcortical dementia, or Alzheimer dementia were treated with modafinil 100 to 200 mg daily for
6 weeks. They were assessed with the ESS, caregiver reports, and wrist actigraphy. Five of the patients showed
improvements on the outcome measures, although no
cognitive benefits were noted in the study. In a retrospective review (N = 5),80 modafinil was considered moderately effective either as monotherapy or in combination
with other Alzheimer disease medication. One patient
with a history of hallucinations noted an increase in hallucinations during the time on modafinil treatment.
Fibromyalgia is a chronic musculoskeletal pain disorder characterized by pain at established soft tissue trigger
points, nonrestorative sleep, and mood disorders. Currently, there is no consensus treatment for fibromyalgia.
Modafinil in doses ranging from 150 to 300 mg/day was
reported to decrease fatigue and improve alertness in 2 of
4 patients with chronic fibromyalgia without depression.81
The Global Assessment of Functioning (GAF) score in
this small sample increased from 55 to 70 (from moderate
impairment to minimal impairment). One patient in this
sample reported increased anxiety that was mitigated by
decreasing the modafinil dose by 50 mg.81
Other case reports have shown that modafinil can be
helpful in patients with primary biliary cirrhosis,82 amyotrophic lateral sclerosis,83 and myasthenia gravis.84
Sedation as a side effect of medication. Sedation is
a common side effect of psychotropic medication and
one that frequently interferes with treatment adherence.
Modafinil has been used for treatment of sedation associated with antipsychotic, antidepressant, and moodstabilizing agents.8587
In a recent double-blind, placebo-controlled trial
(N = 24),88 modafinil was shown to be no better than placebo in improving wakefulness and cognition in people
with schizophrenia. However, both the control and active
groups showed a statistically significant improvement in
wakefulness and cognition from baseline.88 There are several case reports, however, that demonstrate benefit with
modafinil. Makela et al.89 described 3 patients taking various antipsychotics who were experiencing debilitating
levels of sedation secondary to their treatment. These patients each noted a decrease in their number of hours
needed for sleep each night, and an increase in energy
during the day when taking 200 mg/day of modafinil. The
authors did not report any significant side effects in these
patients, including changes in their presenting psychiatric
symptoms.
It is noteworthy that in these studies88,89 modafinil was
generally well tolerated; however, another report90 described a case of clozapine toxicity associated with
modafinil use that may have resulted from an interaction
between modafinil and clozapine at the cytochrome P450
2C19 liver enzyme system.
Modafinil has been reported to reduce the postanesthesia recovery time. In a double-blind, placebocontrolled study (N = 34),91 patients were given 1 dose of
200 mg of modafinil upon awakening from anesthesia and
rated over the course of 24 hours for symptoms of fatigue.
Patients who received the modafinil reported significantly
less fatigue than those who received placebo. As more
surgeries are done on an outpatient basis, leaving patients
to recover at home, decreasing recovery time boosts the
safety of such treatment.
A mainstay of pain treatment is opiate-based medications, and many patients suffer side effects of sedation.
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