Modafinil Effects during Acute Continuous Positive
Airway Pressure Withdrawal
A Randomized Crossover Double-Blind Placebo-controlled Trial
Shaun C. Williams1, Nathaniel S. Marshall1, Marina Kennerson2,3,4, Naomi L. Rogers5, Peter Y. Liu1,6,
and Ronald R. Grunstein1
1Sleep and Circadian Research Group/NHMRC Centre for Sleep Medicine, Woolcock Institute, University of Sydney and Royal Prince Alfred Hospital,
Sydney, Australia;2Northcott Neuroscience Laboratory, ANZAC Research Institute, and4Molecular Medicine Laboratory,6Concord Hospital,
Concord, NSW, Australia.3Faculty of Medicine, and5Chronobiology & Sleep Group, Brain & Mind Research Institute, University of Sydney,
Rationale: Continuous positive airway pressure (CPAP) use is associ-
ated with reduced motor vehicle accidents in patients with obstruc-
tive sleep apnea (OSA). However, interruption of CPAP therapy is
common and is associated with a decline in daytime function.
Objectives: We hypothesized that the wakefulness promoter, mod-
afinil, would ameliorate this decline.
Methods: Patients were admitted to the laboratory for three consec-
day, and was then withdrawn for the two subsequent nights (nasal
airflow monitored). On each of the mornings after the two CPAP
withdrawal nights, patients received 200 mg modafinil or placebo
periods were separated by a 5-week washout. Driving simulator
were measured by the AusEd driving simulator, psychomotor vigi-
lance task, and Karolinska Sleepiness Scale, respectively.
Measurements and Main Results: During CPAP withdrawal, severe
afinil improved simulated driving performance (steering variability,
P , 0.0001; mean reaction time, P < 0.0002; lapses, P < 0.01 on
a concurrent task), psychomotor vigilance task (mean 1/reaction
time and lapses, both P < 0.0002), and subjective sleepiness (P <
Conclusions: Modafinil prevented the decline in simulated driving
performance, neurocognitive performance, and subjective sleepi-
ness in patients with OSA with acutely interrupted CPAP therapy.
Clinical trial registered with the Australian New Zealand Clinical
Trials Registry at www.anzctr.org.au (ACTRN12606000027516).
Keywords: modafinil; obstructive sleep apnea; continuous positive
airway pressure; withdrawal
Obstructive sleep apnea (OSA) is associated with increased risk
of motor vehicle accidents (MVAs) (1), which is reversed after
compliant treatment with continuous positive airway pressure
(CPAP) (2, 3). In general, CPAP adherence is poor and even
regular CPAP users will temporarily interrupt therapy during
travel, with upper respiratory tract infections, or because of
mask-related problems (4). CPAP interruption is therefore
potentially costly to society, and this cost may be amplified
among transport industry workers in whom OSA prevalence is
high (5). Methods to ameliorate the effects of CPAP interrup-
tions are clearly required.
Interrupting CPAP therapy results in immediate recurrence
of OSA and impaired neurobehavioral performance (6, 7).
Methods to manage daytime symptoms associated with acute
CPAP withdrawal are needed. The wakefulness promoter,
modafinil, is a short-term candidate treatment approach in this
situation. Modafinil induces wakefulness primarily by inhibit-
ing dopamine and noradrenaline reuptake transporters (8). In
addition, modafinil inhibits the development of sleepiness and
neurobehavioral deficit normally caused by sleep deprivation (9).
Modafinil is licensed in the United States, Australia, and
elsewhere to improve wakefulness in patients with narcolepsy,
shift-work sleep disorder, and in patients with OSA who ex-
perience residual daytime sleepiness despite CPAP use. Ex-
tending the indications for its use has been widely discussed (10,
11). One possibility is that modafinil could be used to enhance
alertness during activities such as driving a motor vehicle dur-
ing the interruption of CPAP treatment in normally adherent
patients with OSA. Although a preliminary study conducted in
our laboratory showed that modafinil administration after one
night of CPAP withdrawal did not significantly alter morning
driving simulator performance (12), the medium-to-large effect
sizes observed encouraged us to perform a larger study.
We therefore conducted a randomized placebo-controlled
crossover study to examine the hypothesis that modafinil
ameliorates the decline in simulated driving performance,
neurocognitive performance, and subjective sleepiness associ-
AT A GLANCE COMMENTARY
Scientific Knowledge on the Subject
Continuous positive airway pressure (CPAP) is associated
with a reduction in the noted risk of motor vehicle
accidents in patients with obstructive sleep apnea (OSA).
However, interruption of CPAP therapy is common be-
cause of travel or upper respiratory tract infection and is
associated with a decline in daytime function.
What This Study Adds to the Field
Modafinil administration during acute interruption of
CPAP in patients with OSA significantly improved simu-
lated driving performance, neurobehavioral performance,
and subjective sleepiness.
(Received in original form August 31, 2009; accepted in final form January 7, 2010)
Supported by NHMRC project grant (352483), NHMRC Practitioner Fellowship
(R.R.G.), NHMRC Clinical CDA 511929 (P.Y.L.), NHMRC Howard Florey Cente-
nary Fellowship & NSW BioFirst Award (N.L.R.), CCRE Epidemiology Research
Fellowship (N.S.M.) and Australian Postgraduate Award (APA) Scholarship
(S.C.W.). This was an investigator-driven study with partial support ($50,000)
provided by Cephalon, Inc., manufacturer of modafinil.
Correspondence and requests for reprints should be addressed to Shaun C.
Williams, P.O. Box M77 Missenden Road, Camperdown NSW 2050, Sydney,
Australia. E-mail email@example.com
Am J Respir Crit Care Med
Originally Published in Press as DOI: 10.1164/rccm.200908-1307OC on January 7, 2010
Internet address: www.atsjournals.org
Vol 181. pp 825–831, 2010
ated with acute withdrawal of CPAP in patients with OSA.
Some of the results in this study have been previously reported
in the form of abstracts (13, 14).
Participants were recruited from public advertisements. They were
male patients with OSA who had been diagnosed by overnight
polysomnography with an apnea-hypopnea index (AHI) greater than
10 and were modafinil naive. Patients were excluded if they were
suffering from any uncontrolled concurrent medical or psychiatric
illness, as determined by questionnaire and physician physical exam-
ination. Patients were also excluded if they had not successfully used
CPAP (verified during the screening period as AHI ,10 and using
CPAP >4 h per night) for at least 1 year; were currently taking
(verified by urine drug screen) any medications known to affect sleep
and alertness, including anticonvulsants, amphetamines, barbiturates,
benzodiazepines, cocaine, diclofenac, fluoxetine, opiates, phenothia-
zines, spironolactone, or tricyclic antidepressants, or that may cause
a drug interaction with modafinil, or had been using or misusing any
substances of abuse; had any clinically significant serum chemistry or
hematology abnormalities (verified by fasting venous blood sample);
had received any other investigational drug within the last 60 days; had
medical conditions that would contraindicate administration of mod-
afinil (e.g., major anxiety, unstable hypertension, coronary artery
disease); had daytime blood pressure exceeding 160/100 mm Hg; or
had irregular sleep patterns, such as shift workers. Patients were
reimbursed for their time involved in the study. All patients gave
written informed consent to participate in the study, which was
approved by the Sydney South West Area Health Service Ethics Review
This study was a randomized double-blind, placebo-controlled, cross-
over trial (see Figure 1 for study design). Patients attended the
laboratory for a screening visit and those who fulfilled the inclusion
and exclusion criteria completed the Epworth Sleepiness Scale (15).
Compliance data were downloaded for all patients who had a CPAP
machine with an objective compliance monitor. After the screening
visit, patients were given a REMstar CPAP machine (Respironics,
Sydney, NSW, Australia) set at their prescribed pressure, an actigraph
(AW-64; Mini-Mitter Actiwatches, Bend, OR), and a sleep diary. For
approximately a 7-day/night at-home screening period patients used
their CPAP machine, wore an actigraph, and filled out a sleep diary
each morning. CPAP treatment efficacy and compliance were assessed
during this period and eligible patients were admitted to the laboratory
for three consecutive nights. In addition, sleep characteristics from the
actigraph during this period were also assessed to ensure patients had
regular sleep patterns. Time in bed was maintained between 22:30 and
6:30 and for all three in-laboratory nights. In addition, breakfast, lunch,
and dinner were served at approximately 7:30, 13:00, and 18:00,
respectively, during all days spent in the laboratory. During their stay
in the laboratory, patients were required to continue wearing their
Figure 1. Study protocol. Shaded rectangles 5 completion of procedure or questionnaire at visit. Solid rectangles 5 completion of procedure or
questionnaire at home. Shaded circles 5 administration of 200 mg modafinil. Hatched circles 5 administration of placebo. Moon 5 visit procedures
conducted at night. Sun 5 visit procedures conducted during the day. Screening consists of the screening visit and the screening period. Baseline
consists of the baseline night and day. Battery tests included Karolinska Sleepiness Scale, 10-minute Psychomotor Vigilance Task, and 20-minute
AusEd driving simulator scenario. CPAP 5 continuous positive airway pressure; D 5 day; Daytime S VAS 5 daytime sleepiness visual analog scale;
ESS 5 Epworth Sleepiness Score; N 5 night.
826AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 1812010
actigraph, complete the sleep diary each morning, and abstain from
alcohol and caffeine.
During the in-laboratory phase CPAP was used for the first night
(baseline night), followed by a baseline day, and then was withdrawn
for the two subsequent nights (Nights 1 and 2). Before sleep on the
baseline night patients were trained on the AusEd driving simulator
(Woolcock Institute of Medical Research, Sydney, Australia) (16) and
psychomotor vigilance task (PVT) (Ambulatory Monitoring, Inc.,
Ardsley, NY) (17). On the nights that CPAP was withdrawn a nasal
airflow device was used to quantify sleep apnea severity (Flow Wizard;
Diagnose IT Pty Ltd., Sydney, Australia) (18).
On each of the mornings after the two CPAP withdrawal nights,
patients received treatment A (200 mg modafinil or placebo) with
breakfast. Participants repeated the protocol but received the alter-
nate treatment (treatment B) after approximately 5 weeks’ washout
during which they used CPAP. After breakfast on baseline and Day 1
patients completed a Karolinska Sleepiness Scale (KSS), a 10-minute
PVT, and a 20-minute driving simulation (AusEd) bi-hourly from
08:00 to 20:00. After breakfast on Day 2 patients were only tested
bi-hourly from 08:00 to 14:00. Patients were free to leave at ap-
proximately 15:30 on Day 2 with taxis provided to their preferred
Allocation Concealment, Randomization, and Blinding
Randomization occurred on Day 1 after the first night of CPAP
withdrawal. The sequence was generated using simple randomization
and was held by the pharmacy that dispensed the drug. No person who
had any knowledge of the randomization sequence was involved in
recruiting patients or measuring outcomes. All data collection was
undertaken such that at no point was any person who was aware of
drug allocation in the presence of any participant. Modafinil (200 mg)
and placebo tablets were provided by Cephalon, Inc. (Frazer, PA) and
double-blinding was ensured by identical encapsulation of these
tablets. The analysis of the primary and secondary outcomes of the
trial was undertaken by an investigator (S.C.W.) who was blinded to
Baseline questionnaires. The Epworth Sleepiness Scale was used to
provide a measurement of chronic daytime sleepiness (19). The sleep
diary was used as an adjunct to actigraphy and was based on the
Karolinska Sleep Diary (20).
In-laboratory assessments. DRIVING
The AusEd driving simulator was used to assess driving performance
(16, 21). The simulator was installed on a Windows workstation in
a sound-insulated room, with a 19-inch LCD screen and a Logitech
Momo Racing Force Feedback steering wheel with pedals (Logitech
Asia Pacific LTD, Quarry Bay, Hong Kong). All room lighting was
turned off during testing.
One 5-minute practice and one 20-minute driving simulator sce-
nario were devised. The scenarios simulated a monotonous nighttime
drive and took place on a two-lane rural road, with the usual lane
divisions and the road edges marked by reflective posts. A speedometer
was displayed in the top left corner of the computer screen. The
scenario consisted of 5/7 of the road being straight, whereas 2/7 of the
road consisted of chicanes. Patients were instructed to maintain
a central position in the left-hand lane and to maintain speed within
60 to 80 km/h. In addition, 10 divided attention (DA) subtasks were
used throughout the driving simulation to measure visual search and
recognition and to provide an additional workload for the driver. The
DA tasks consisted of trucks randomly appearing in the distance in the
driver’s lane; when this happened patients were required to firmly press
the brake pedal as quickly as possible. The driving simulator was
programmed to randomly present 10 trucks during the 20-minute task.
The outcome measures chosen were (1) steering variability (calculated
as the mean deviation from the driver’s median lane position) (cm), (2)
mean reaction time (RT) to DA tasks (s), and (3) mean number of
lapses to DA tasks (i.e., RT >3 s) (22).
NEUROCOGNITIVE PERFORMANCE. The PVT was used to assess
behavioral alertness (17). The PVT is a hand-held box with a red light-
emitting diode display of a three-digit millisecond counter. Patients
were instructed to respond as fast as possible when they first saw
a visual stimulus appear. The time that it took patients to respond to
the stimulus was displayed in milliseconds after a reaction. During each
10-minute PVT session, visual stimuli appeared at variable intervals of
2 to 10 seconds. Reaction times (RTs) were collected from each
10-minute session and outcome measures chosen were (1) mean of
the reciprocal reaction times (1/RT), and (2) mean number of lapses
(i.e., RT >500 ms) (17).
SUBJECTIVE SLEEPINESS. The KSS (23) was used to measure sub-
jective sleepiness. The Daytime Sleepiness visual analog scale (VAS)
was used to measure treatment effect on patients’ global sleepiness
levels. It used the question ‘‘Please rate your level of sleepiness within
the LAST TWO DAYS’’ with the word descriptor anchors ‘‘Extremely
sleepy’’ and ‘‘Extremely alert’’ at either end.
On CPAP. Actigraphic and CPAP treatment efficacy and com-
pliance data were collected at home during the screening period
for 7 to 15 days before patients were admitted to the laboratory.
Means for this at-home period and also for the first in-laboratory
night (baseline night) were calculated. Paired sample t tests were
then used to test for potential differences in sleep characteristics
between the periods before modafinil and placebo administra-
tion for both the screening period and baseline night.
CPAP withdrawal. Paired sample t tests were used to test for
potential differences in actigraphically defined sleep character-
istics between the baseline night and each of the two nights after
CPAP withdrawal (Nights 1 and 2). They were also used to test
that the changes in sleep characteristics of CPAP withdrawal
were consistent between the periods before modafinil and
placebo administration. Data from the first arm were used in
these calculations because paired sample t tests determined that
there were no significant differences between the first and
second arm of the crossover for any actigraphy variable.
Flow Wizard data that were collected during CPAP with-
drawal provided an AHI value for the four nights. Paired sample
t tests were used to detect differences in AHI between the nights
before modafinil administration and placebo administration for
each of two nights (Nights 1 and 2) of CPAP cessation.
Neurocognitive performance outcomes. Data from the prac-
tice sessions of PVT and AusEd were not analyzed. The
reciprocals of the RTs (1/RT) (1/ms), the reciprocals of the
slowest 10% of RTs (1/ms), and the number of lapses were
measured during each PVT trial, and the mean of these data
was calculated. PVT mean reciprocal 10% slowest RTs data are
not shown as the outcome reflected PVT mean reciprocal RT.
Initiation effects on the AusEd driving simulator were
minimized by excluding the first 4 minutes and also the first
DA task. This was done to minimize acclimatization, which may
have occurred as patients were settling into the driving simula-
tion task (22, 24). The primary outcome, position on the road
(cm) from the center roadway dividing line, was measured
during each patient’s driving simulator scenario. The mean
deviation from the driver’s median lane position was then
calculated to give a measure of the steering variability or the
tendency to drift during the driving simulator scenario. RT (s)
and the number of lapses to DA tasks were measured during
each patient’s driving simulator scenario. The mean of these
data were used to give a measure of secondary reaction time
and lapses of attention, respectively, throughout the driving
Values at each of the 11 time points after modafinil or
placebo treatment were subtracted from the same time on the
baseline day. Mixed model analyses of variance in SAS were
used to investigate drug treatment effects overall and at each
time point for the PVT, driving simulator measurements, and
KSS (SAS Institute, v. 9.1, Cary, NC). Treatment was the fixed
Williams, Marshall, Kennerson, et al.: Modafinil for OSA 827
effect and individual patients were treated as random effects.
Main effects and any interactions were regarded as statistically
significant when P was less than 0.05. Order and learning effects
were examined by standard methods (25). Our analyses and
trial design allowed for learning effects because outcome values
in each arm were subtracted from the corresponding baseline
values before analysis and are balanced by randomization.
Effect sizes were used to identify potentially clinically relevant
treatment effects. These were calculated by dividing the mean
benefit of modafinil compared with placebo by the standard
deviation of that measurement at baseline. Effect sizes were
defined as small (,0.50), medium (0.50–0.79), and large (>0.80)
(26). Negative effect sizes indicate modafinil resulted in better
outcomes than placebo, apart from PVT mean reciprocal RT
and Daytime Sleepiness VAS for which beneficial effects of
modafinil are indicated by positive effect sizes.
Twenty-three patients were recruited. One patient withdrew
from the study prerandomization because of a CPAP technical
problem that rendered the patient ineligible, and another
withdrew postrandomization because of scheduling difficulties.
The baseline characteristics, while using CPAP, of the 21
patients who completed the study are summarized in Table 1.
Sleep Characteristics on CPAP
There were no significant differences in any actigraphically
measured sleep characteristics or CPAP efficacy and compliance
variables between the periods preceding modafinil and placebo
administration or between the first and second arms of the study.
Sleep Characteristics during CPAP Withdrawal
On the first night of CPAP withdrawal there was no difference
in actigraphically determined sleep quality compared with the
on-CPAP baseline night. However, the second night of CPAP
withdrawal was associated with significant worsening in mean
(95% confidence interval) wake after sleep onset, 44.1 minutes
(34.1–54.0) to 57.1 minutes (43.5–70.7), and the mean move-
ment and fragmentation index, 22.3 (14.5–30.1) to 30.1 (22.8–
37.4), compared with the on-CPAP baseline night (both P <
0.05). There were no significant differences in any actigraphic
parameters between the periods preceding modafinil and pla-
cebo administration or between modafinil and placebo during
Significant sleep apnea reemergence was also evident during
CPAP withdrawal, with a mean AHI of 40.2 (31.1–49.3)
observed during the first night and 38.8 (27.9–49.6) during the
second night. Mean AHIs were not different in the periods
preceding or during modafinil and placebo administration.
Neurocognitive Performance Outcomes
The overall effects of drug administration on simulated driving
performance, PVT performance, and subjective sleepiness are
presented in Table 2. The effects of drug administration, at each
time point, on simulated driving performance, PVT perfor-
mance, and subjective sleepiness are presented in Figures 2A–
2F). Modafinil treatment reduced steering variability and the
mean RT to DA probes on the AusEd driving simulator. In
addition, modafinil prevented the overall worsening of the mean
number of lapses to DA probes on the AusEd relative to
placebo. Furthermore, modafinil reduced the overall mean
1/RT and the mean number of lapses on the PVT, relative to
placebo. Subjective sleepiness, evaluated by the KSS and Day-
time Sleepiness VAS, was lower on modafinil than placebo.
A learning effect was found with the steering variability on
the AusEd. That is, steering variability was significantly better
on the second (60.9 cm [59.2–62.5]) compared with the first arm
(65.2 cm [63.2–67.3]) (P 5 0.007). No treatment order effects of
modafinil from the first to the second arm were found.
In this randomized placebo-controlled crossover trial, we show
for the first time that modafinil administration during acute
TABLE 1. BASELINE CHARACTERISTICS OF COMPLETED
PATIENTS WHILE ON CPAP
No. of patients21
Neck circumference, cm
Systolic blood pressure, mm Hg
Diastolic blood pressure, mm Hg
Heart rate, beats/min
AHI at diagnosis*
On CPAP residual AHI†
Number of yr CPAP used‡
CPAP use, h/night†
Actigraphy sleep duration, h
55 6 8
32.7 6 4.1
8.7 6 4.0
43.4 6 2.6
133 6 10
84 6 8
66 6 10
48.7 6 23.9
2.6 6 1.2
4.7 6 5.3
7.1 6 0.8
6.3 6 0.9
Definition of abbreviations: AHI 5 apnea-hypopnea index; BMI 5 body mass
index; ESS 5 Epworth Sleepiness Score.
Values are given as no. or mean 6 SD.
* n 5 17 patients.
†Data from the week before the first arm of study.
‡n 5 20 patients.
TABLE 2. THE EFFECTS OF MODAFINIL ON SIMULATED DRIVING PERFORMANCE, PSYCHOMOTOR
VIGILANCE TASK PERFORMANCE, AND SUBJECTIVE SLEEPINESS
Mean Change from Baseline (95% CI)*
P Value for
Difference Modafinil Placebo
PVT mean reciprocal RT, 1/ms
PVT mean number of lapses
Steering variability, cm
AusEd mean RT to DA tasks, s
AusEd mean number of lapses to DA tasks
Daytime sleepiness VAS
0.1 (0 to 0.2)
20.5 (21.3 to 0.4)
26 (29 to 24)
20.011 (20.051 to 0.030)
0 (20.1 to 0.1)
20.3 (20.6 to 0.1)
4.0 (27.1 to 15.0)
20.1 (20.2 to 20.1)
0.7 (20.1 to 1.5)
0 (23 to 2)
0.055 (0.014 to 0.096)
0.1 (0 to 0.2)
0.0 (20.3 to 0.4)
212.45 (219.8 to 25.1)
Definition of abbreviations: AusEd 5 AusEd driving simulator; CI 5 confidence interval; DA 5 divided attention; RT 5 reaction
time; SS 5 Sleepiness Scale; VAS 5 visual analog scale.
Effect size is the mean change of modafinil over placebo divided by the standard deviation of this change.
* Negative figures in these columns indicate modafinil was associated with better outcomes than placebo. The opposite is true
for the PVT mean reciprocal RT and Daytime Sleepiness VAS.
828AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 181 2010
CPAP withdrawal in patients with OSA improved simulated
driving performance, neurobehavioral performance, and sub-
jective sleepiness. If these improvements translate into the
prevention of real-world MVAs then short-term modafinil
therapy, possibly targeting at-risk populations such as transport
workers, could prevent unnecessary morbidity and mortality in
these patients and other road users. Such benefits would be
significant to the community because even compliant long-term
CPAP users commonly report interruption of CPAP therapy in
conjunction with travel or other long road trips that disrupt
their normal lifestyle.
Modafinil therapy improved all measured parameters of
driving simulator performance in normally CPAP-adherent
men who interrupted CPAP therapy. Modafinil caused less
drift in median lane position and faster braking (DA events).
Our previous study also noted a large effect size in driving
performance but was underpowered because of a smaller
sample size and fewer repeated measurements, and also because
it only included one night of CPAP withdrawal (12). Our
current study indicates that one morning of modafinil therapy
after even a single night of CPAP withdrawal improves driving
performance (see Figures 2C–2E). Whether such improvements
are maintained with prolonged modafinil therapy in conjunction
with longer CPAP withdrawal requires further investigation.
Modafinil also improved overall reaction time and reduced
the frequency of lapses on the PVT. The apparent early
Figure 2. The effects of modafinil (200 mg) and placebo on simulated driving performance, psychomotor vigilance task (PVT) performance, and
subjective sleepiness, as a function of clock time, from treatment administration. (A) PVT mean reciprocal reaction time (RT) (1/RT); *P < 0.05; **P <
0.0004. (B) PVT mean number of lapses; *P < 0.02; **P < 0.006. (C ) Steering variability (mean deviation from the driver’s median lane position) on
the AusEd driving simulator; *P < 0.02; **P < 0.006. (D) Mean reaction time to divided attention tasks on the AusEd; *P < 0.05. (E) Mean number of
lapses to divided attention tasks on the AusEd; *P < 0.05. (F) Mean Karolinska Sleepiness Scale (KSS). For simplicity the unadjusted P values are
presented. However, P < 0.005 for each comparison yields an experimentwise a of 0.05. Error bars denote the 95% confidence intervals (CIs). Solid
lines 5 modafinil; Dashed lines 5 placebo. CPAP 5 continuous positive airway pressure.
Williams, Marshall, Kennerson, et al.: Modafinil for OSA829
afternoon circadian trough in performance was also ameliorated
by modafinil (see Figures 2A and 2B). Modafinil treatment in
patients with OSA who experience residual daytime sleepiness,
despite effective CPAP treatment, has previously been found to
improve PVT performance (27–29). Furthermore, modafinil
administration in healthy adults undergoing sleep loss is found
to suppress the early morning circadian trough in cognitive
performance (30). Suppression of the afternoon trough in
performance in this study may have important real-world
implications because at this time of the day there is a correspond-
ing increase in MVAs in middle-aged and older people (31).
Patients on modafinil also felt more alert (KSS) during the trial
and when retrospectively assessing their subjective sleepiness
(VAS). Similar effects have been observed previously (9, 12).
More than 10 million CPAP devices have been prescribed
worldwide for treatment of OSA (32). CPAP improves simu-
lated driving ability (24) and its use in the real world is
associated with reduced MVAs in people with OSA (2, 3).
However, adherence to CPAP is poor and even regular users
may temporarily withdraw from therapy for reasons that might
include travel, mask-related problems, or upper respiratory
tract infections. The benefits of modafinil use may be increased
during travel because the risk of MVAs in patients with OSA
may be amplified via combinations of disrupted circadian sleep–
wake cycles, sleep loss, and increased time-on-road driving in
Although the current study supports the use of modafinil
during an interruption of CPAP for up to two nights we did not
investigate its role during longer-term CPAP withdrawal nor
did we investigate its use in patients with OSA who are not
normally CPAP adherent. This latter caution is pertinent
because most patients with OSA use CPAP for only a few
hours per night or intermittently throughout the week (4, 33).
The dose of modafinil used in this study should also be noted as
doses greater than 200 mg may not offer any additional benefits
for neurobehavioral performance, with 300 mg previously being
shown to impair an individual’s ability to accurately assess their
own performance on neurocognitive (34) and simulated driving
tasks (9, 35). This study examined only males because OSA and
MVAs are both male-preponderant, so these data may not be
generalizable to women. Caution needs to be exercised in an
attempt to extrapolate the simulated driving performance findings
to on-road driving performance, because there is little evidence
correlating these two.
Nevertheless, these data provide a strong rationale for the
short-term use of modafinil in the context of acute CPAP
interruption, in the hope that such a strategy could prevent
direct and opportunity costs to the community arising from
MVAs. Further public health studies are required. Unintended
consequences should also be considered. For example, the
significant off-label use of modafinil as a wakefulness promoter
raises the possibility of modafinil negatively affecting CPAP
compliance in patients with OSA. However, only one out of
three (28, 29, 36) randomized controlled trials of modafinil
treatment in patients with OSA showed a significant reduction
in nightly CPAP hourly use in those receiving modafinil
compared with placebo, which was probably clinically irrelevant
(mean 5 12 min/night). Furthermore, this study had the smallest
sample size (n 5 30) compared with the other two studies (n 5
157 and 305), which reported after 4 (29) and 12 (28) weeks of
modafinil there was a reduction of only 12 and 6 min/night
CPAP hourly use, respectively. Nonetheless, unintended conse-
quences are important because the likely beneficial impact of
CPAP on cardiovascular disease morbidity and mortality is
unlikely to be replicated with modafinil therapy alone (37–41).
Modafinil administration during short-term cessation of CPAP
in patients with OSA significantly improves simulated driving
sleepiness. This supports modafinil being used as a short-term
treatment option in preventing the decline of daytime function
in patients with OSA who require an acute interruption of their
Conflict of Interest Statement: S.C.W. does not have a financial relationship with
a commercial entity that has an interest in the subject of this manuscript. N.S.M.
received $10,001–$50,000 grant in aid of research-investigator initiated clinical
trial from Fisher & Paykel Healthcare and $10,001–$50,000 from Cephalon for an
agreement to supply in-kind support (drug and placebo) for a future investigator-
initiated trial. M.K. does not have a financial relationship with a commercial entity
that has an interest in the subject of this manuscript. N.L.R. does not have
a financial relationship with a commercial entity that has an interest in the subject
of this manuscript. P.Y.L. does not have a financial relationship with a commercial
Figure 2. (continued).
830AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 1812010
entity that has an interest in the subject of this manuscript. R.R.G. does not have Download full-text
a financial relationship with a commercial entity that has an interest in the subject
of this manuscript.
Acknowledgment: The authors thank the staff at the Woolcock of Medical
Research for their technical support. Although partial support was provided by
Cephalon, Inc., this study was performed and the results analyzed in a completely
1. Tera ´n-Santos J, Jime ´nez-Go ´mez A, Cordero-Guevara J. The association
between sleep apnea and the risk of traffic accidents. Cooperative
Group Burgos-Santander. N Engl J Med 1999;340:847–851.
2. George C. Reduction in motor vehicle collisions following treatment of
sleep apnoea with nasal CPAP. Thorax 2001;56:508–512.
3. Ellen R, Marshall S, Palayew M, Molnar F, Wilson K, Man-Son-Hing M.
Systematic review of motor vehicle crash risk in persons with sleep
apnea. J Clin Sleep Med 2006;2:193–200.
4. Weaver T, Grunstein R. Adherence to continuous positive airway
pressure therapy: the challenge to effective treatment. Proc Am
Thorac Soc 2008;5:173–178.
5. Howard M, Desai A, Grunstein R, Hukins C, Armstrong J, Joffe D,
Swann P, Campbell D, Pierce R. Sleepiness, sleep-disordered breath-
ing, and accident risk factors in commercial vehicle drivers. Am
J Respir Crit Care Med 2004;170:1014–1021.
6. Yang Q, Phillips CL, Melehan KL, Rogers NL, Seale JP, Grunstein RR.
Effects of short-term CPAP withdrawal on neurobehavioral perfor-
mance in patients with obstructive sleep apnea. Sleep 2006;29:545–
7. Kribbs NB, Pack AI, Kline LR, Getsy JE, Schuett JS, Henry JN, Maislin
G, Dinges DF. Effects of one night without nasal cpap treatment on
sleep and sleepiness in patients with obstructive sleep apnea. Am Rev
Respir Dis 1993;147:1162–1168.
8. Minzenberg M, Carter C. Modafinil: a review of neurochemical actions and
effects on cognition. Neuropsychopharmacology 2008;33:1477–1502.
9. Bonnet MH, Balkin TJ, Dinges DF, Roehrs T, Rogers NL, Wesensten
NJ. The use of stimulants to modify performance during sleep loss:
a review by the sleep deprivation and stimulant task force of the
American Academy of Sleep Medicine. Sleep 2005;28:1163–1187.
10. Sahakian B, Morein-Zamir S. Professor’s little helper. Nature 2007;450:
11. Pack AI. Should a pharmaceutical be approved for the broad indication
of excessive sleepiness? Am J Respir Crit Care Med 2003;167:109–111.
12. Williams SC, Rogers NL, Marshall NS, Leung S, Starmer GA, Grunstein
RR. The effect of modafinil following acute CPAP withdrawal:
a preliminary study. Sleep Breath 2008;12:359–364.
13. Williams SC, Marshall NS, Kennerson M, Liu PY, Rogers NL, Grunstein
RR. Modafinil effects during acute cpap withdrawal: a randomised
crossover double-blind placebo-controlled trial [abstract]. Sleep Biol
14. Williams SC, Marshall NS, Liu PY, Rogers NL, Grunstein RR. Modafinil
effects during acute cpap withdrawal: a randomised crossover double-
blind placebo-controlled trial [abstract]. Sleep 2009;32:A209.
15. Johns MW. A new method for measuring daytime sleepiness: the
Epworth Sleepiness Scale. Sleep 1991;14:540–545.
16. Banks S, Catcheside P, Lack L, Grunstein RR, McEvoy RD. Low levels
of alcohol impair driving simulator performance and reduce percep-
tion of crash risk in partially sleep deprived subjects. Sleep 2004;27:
17. Dinges D, Powell J. Microcomputer analyses of performance on
a portable, simple visual rt task during sustained operations. Behav
Res Methods Instrum Comput 1985;17:652–655.
18. Rofail-Makarie L, Wong KK, Unger G, Grunstein R. The in-laboratory
validation of a portable flow monitor for OSA diagnosis. Sleep Biol
19. Johns MW. Daytime sleepiness, snoring, and obstructive sleep apnea:
the Epworth Sleepiness Scale. Chest 1993;103:30–36.
20. Akerstedt T, Hume K, Minors D, Waterhouse J. The subjective meaning
of good sleep, an intraindividual approach using the Karolinska Sleep
Diary. Percept Mot Skills 1994;79:287–296.
21. Desai A, Wilsmore B, Bartlett D, Unger G, Constable B, Joffe D,
Grunstein R. The utility of the AusEd driving simulator in the
clinical assessment of driver fatigue. Behav Res Methods 2007;39:
22. Vakulin A, Baulk S, Catcheside P, Antic N, van den Heuvel C, Dorrian
J, McEvoy R. Effects of alcohol and sleep restriction on simulated
driving performance in untreated patients with obstructive sleep
apnea. Ann Intern Med 2009;151:447–455.
23. Gillberg M, Kecklund G, Akerstedt T. Relations between performance
and subjective ratings of sleepiness during a night awake. Sleep 1994;
24. Hack M, Davies RJ, Mullins R, Choi SJ, Ramdassingh-Dow S, Jenkinson
C, Stradling JR. Randomised prospective parallel trial of therapeutic
versus subtherapeutic nasal continuous positive airway pressure on
simulated steering performance in patients with obstructive sleep
apnoea. Thorax 2000;55:224–231.
25. Pocock SJ. Clinical trials: a practical approach. West Sussex, NY: Wiley;
26. Kazis LE, Anderson JJ, Meenan RF. Effect sizes for interpreting
changes in health status. Med Care 1989;27:S178–S189.
27. Dinges DF, Weaver TE. Effects of modafinil on sustained attention
performance and quality of life in OSA patients with residual
sleepiness while being treated with NCPAP. Sleep Med 2003;4:393–
28. Black JE, Hirshkowitz M. Modafinil for treatment of residual excessive
sleepiness in nasal continuous positive airway pressure-treated ob-
structive sleep apnea/hypopnea syndrome. Sleep 2005;28:464–471.
29. Pack AI, Black JE, Schwartz JR, Matheson JK. Modafinil as adjunct
therapy for daytime sleepiness in obstructive sleep apnea. Am
J Respir Crit Care Med 2001;164:1675–1681.
30. Pigeau R, Naitoh P, Buguet A, McCann C, Baranski J, Taylor M,
Thompson M, Mac KII. Modafinil, d-amphetamine and placebo
during 64 hours of sustained mental work. I. Effects on mood, fatigue,
cognitive performance and body temperature. J Sleep Res 1995;4:212–
31. Pack A, Pack A, Rodgman E, Cucchiara A, Dinges D, Schwab C.
Characteristics of crashes attributed to the driver having fallen asleep.
Accid Anal Prev 1995;27:769–775.
32. MarketStrat Inc. Sleep apnea diagnostic and therapeutic devices world-
wide. Dublin, California: MarketStrat Inc; August 2008.
33. Kribbs NB, Pack AI, Kline LR, Smith PL, Schwartz AR, Schubert NM,
Redline S, Henry JN, Getsy JE, Dinges DF. Objective measurement
of patterns of nasal cpap use by patients with obstructive sleep apnea.
Am Rev Respir Dis 1993;147:887–895.
34. Baranski J, Pigeau R, Dinich P, Jacobs I. Effects of modafinil on
cognitive and meta-cognitive performance. Hum Psychopharmacol
35. Gurtman C, Broadbear J, Redman J. Effects of modafinil on simulator
driving and self-assessment of driving following sleep deprivation.
Hum Psychopharmacol 2008;23:681–692.
36. Kingshott RN, Vennelle M, Coleman EL, Engleman HM, Mackay TW,
Douglas NJ. Randomized, double-blind, placebo-controlled crossover
trial of modafinil in the treatment of residual excessive daytime
sleepiness in the sleep apnea/hypopnea syndrome. Am J Respir Crit
Care Med 2001;163:918–923.
37. Marin J, Carrizo S, Vicente E, Agusti A. Long-term cardiovascular
outcomes in men with obstructive sleep apnoea-hypopnoea with or
without treatment with continuous positive airway pressure: an
observational study. Lancet 2005;365:1046–1053.
38. Yaggi H, Concato J, Kernan W, Lichtman J, Brass L, Mohsenin V.
Obstructive sleep apnea as a risk factor for stroke and death. N Engl
J Med 2005;353:2034–2041.
39. Lavie P, Lavie L. Cardiovascular morbidity and mortality in obstructive
sleep apnea. Curr Pharm Des 2008;14:3466–3473.
40. Marshall N, Wong K, Liu P, Cullen S, Knuiman M, Grunstein R. Sleep
apnea as an independent risk factor for all-cause mortality: the
Busselton Health Study. Sleep 2008;31:1079–1085.
41. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep
apnea: a population health perspective. Am J Respir Crit Care Med
Williams, Marshall, Kennerson, et al.: Modafinil for OSA 831