INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Keywords: sleep apnea; obstructive; positive pressure respiration; wakefulness; modafinil

Obstructive sleep apnea/hypopnea syndrome (OSA/HS) is a serious and chronic disorder characterized by repeated episodes of complete or partial collapse of the upper airway during sleep. The resulting disruption (or fragmentation) of sleep leads to excessive daytime sleepiness (EDS). A relatively common condition, OSA/HS is estimated to affect 2 to 4% of middle-aged adults (1). Because the disorder has been associated with impairments in neurophysiologic, respiratory, cardiovascular, and cerebrovascular function, patients with OSA/ HS may experience significant morbidity and there is suggestive evidence of increased mortality (2). Results from the Sleep Heart Health Study indicate that sleep-disordered breathing is associated with an increased risk for systemic hypertension (9), and prospective data from the Wisconsin Sleep Cohort Study demonstrate a dose-response association between sleep-disordered breathing at baseline and the presence of hypertension 4 yr later (10). Other studies have suggested that the incidence rates of occupational accidents (11) and automobile accidents (12) are increased in patients with untreated OSA/HS.

Nasal continuous positive airway pressure (nCPAP) therapy is the treatment of choice in the management of patients with clinically significant OSA/HS (16) (i.e., respiratory disturbance index [RDI]  30 events/h or RDI of 5 to 30 events/h with symptoms of EDS, impaired cognition, mood disorder, insomnia, or cardiovascular disease). When used properly, nCPAP effectively manages apneas and hypopneas, eliminates arterial oxygen desaturation, and improves quality of life (6, 17). Furthermore, in studies with various designs, nCPAP therapy has been reported to significantly improve self-reported (18, 19, 21) and objectively assessed (18, 21, 23) daytime sleepiness in patients with OSA/HS. However, the results of some of these studies indicate that the mean level of sleepiness does not return to normal levels (24, 28) or the level of sleepiness in individual patients does not always normalize (23, 29) with nCPAP therapy. Although it has been suggested that a reduction in the use of nCPAP adversely affects daytime wakefulness in patients with OSA/HS (22, 25), it is unclear why some degree of EDS persists in some regular nCPAP users.

Because nCPAP therapy does not always fully resolve EDS, additional treatment modalities may be of benefit in regular users of nCPAP therapy. CNS stimulants such as low-dose dextroamphetamine have been used to treat EDS in patients with OSA (30), although their use warrants a thorough risk-benefit assessment because of associated abuse potential, interference with sleep, and possible adverse cardiovascular consequences (31).

The novel wake-promoting agent modafinil is an effective and well-tolerated treatment for EDS associated with narcolepsy (32), and there are promising results with modafinil in subjects with idiopathic hypersomnia and sleep deprivation (37). Modafinil is chemically dissimilar to and has a pharmacologic profile that differs from CNS stimulants. It has negligible sympathomimetic activity, is associated with a low potential for abuse (41), has no apparent adverse effects on nighttime sleep (32), and is associated with a low frequency of adverse cardiovascular effects (34). However, there has been a single report that modafinil may lead to overconfidence (42), an effect that is yet to be replicated in similar trials.

The use of modafinil for other conditions in which there is hypersomnolence has raised interest in its use for the treatment of residual EDS in patients who are receiving effective treatments for OSA/HS. To date, modafinil has been studied in two small pilot trials in patients with OSA/HS (43, 44), albeit with different doses and designs from those of the present study. Both studies showed that modafinil improved daytime wakefulness but had no significant effect on sleep-disordered breathing or resting blood pressure monitored during the day. Neither study, however, assessed the efficacy and safety of modafinil in patients receiving nCPAP treatment. The present study was undertaken to evaluate the efficacy and safety of modafinil in the treatment of residual EDS in a large population of patients with OSA/HS who were effectively treated with, and regular users of, nCPAP therapy.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

This double-blind, randomized, placebo-controlled parallel group trial was conducted at 22 centers in the United States, with the approval of the institutional review board at each center. The study included a 1-d screening period, a 2-d period to confirm nCPAP effectiveness, a 3-wk period to monitor nCPAP use, a 2-d period for baseline assessments, and a 4-wk, double-blind treatment period (Figure 1).

View larger version (16K): [in this window] [in a new window]   Figure 1.   Study Design.

Patients, 18 to 65 yr of age, with OSA/HS and a respiratory disturbance index (RDI; number of apneas plus hypopneas per hour of sleep) of  15 before or in the absence of nCPAP therapy were eligible. Participants were required to have used nCPAP for  2 mo before screening, with evidence of residual EDS while using nCPAP (i.e., Epworth Sleepiness Scale [ESS] score  10 at baseline) (45). Effective use of nCPAP (apnea-hypopnea index [AHI] of < 10 and with a > 50% reduction versus historical AHI obtained prior to nCPAP therapy) was required. nCPAP effectiveness was monitored at home on two consecutive nights using an AutoSet T device (ResMed Corp., San Diego, CA) in the manual (i.e., constant pressure) mode that operated at each patient's prescribed therapeutic level. Autoset T data recorded for each patient included median pressure, median leak, maximum leak, mask on time, time in apnea, apnea index, and hypopnea index. At baseline, patients meeting inclusion criteria for nCPAP effectiveness were required to be regular users of nCPAP (i.e.,  4 h/night on  5 of 7 nights) (46) during 3 wk of monitoring at home with a ResMed Elite 5 device, with continued EDS. During monitoring with the ResMed Elite device, nightly use was determined based on the time on mask. Nocturnal polysomnography (NPSG), performed at baseline, was used to verify the effectiveness of nCPAP. RDI determinations from NPSG data were analyzed and scored at each individual center. Patients were excluded if they had a sleep disorder other than OSA/HS or active, clinically significant disease, prior experience with modafinil, a history of drug abuse, or a positive urine drug screen. Other exclusion criteria included pregnancy/lactation, excessive caffeine consumption ( 500 mg/d), and the use of various prescription drugs (e.g., methylphenidate, amphetamines, pemoline). Of the 232 patients who were recruited and screened, 157 patients were randomized to double-blind treatment; 75 patients were not randomized for various reasons (RDI > 10 on nCPAP, n = 18; nCPAP noncompliance, n = 13; excluded disease or concomitant medication, n = 10; voluntary withdrawal, n = 9; abnormal laboratory test value or vital sign measurement, n = 8; ineffective nCPAP therapy, n = 5 (e.g., mask leaks because of loose dentures, inadequate nCPAP pressure at baseline); ESS score < 10 at baseline, n = 3; and other, n = 9). There was no difference in the mean historical RDI prior to nCPAP therapy between those randomized (50.1 ± 32.8 SD events/h) and those not randomized (51.1 ± 32.8 events/h) (p = 0.84). All participants provided written informed consent before screening. Patients were told that nCPAP was necessary for treating their condition, that they were enrolled because they were regular users of nCPAP, and to always use nCPAP when sleeping.

Modafinil (PROVIGIL) and identical-looking placebo were supplied by Cephalon, Inc. (West Chester, PA). Patients were instructed to take a once-daily oral dose (200 mg/d, Week 1; 400 mg/d, Weeks 2 to 4) after the morning meal. Subjective sleepiness was evaluated using the ESS (45). Physiologic sleepiness was objectively measured using the Multiple Sleep Latency Test (MSLT) (47). Illness severity was established at baseline for 115 of the patients using the Clinical Global Impression of Severity (CGI-S) (48). The change in illness severity was determined using the CGI-C scale. NPSG was performed at baseline and at Week 4 during the night before MSLT sessions and scored according to standardized criteria (49). nCPAP use was objectively monitored during double-blind treatment using the ResMed Elite 5 device based on the total time "on mask" recorded for each night of the study. Adverse events were monitored and recorded, with severity and relationship to study medication rated by the investigator. Blood and urine samples were collected for laboratory evaluation of standard clinical parameters at the screening, baseline, and at Weeks 1 and 4 visits. A medical examination was performed at the screening and the Week 4 visits. Vital signs were evaluated and a 12-lead ECG was conducted at the screening, baseline, and Weeks 1 and 4 visits.

Comparisons of continuous demographic variables were performed using two-way analysis of variance (ANOVA), with main-effect terms for treatment and center. Fisher's exact tests were used to assess between-group differences in categorical demographic variables. Randomized patients with at least one efficacy measurement were included in efficacy analyses. For the ESS data at Week 4, the last-observation-carried-forward algorithm (LOCF) was used to impute missing data. The number of missing values for which LOCF was employed was five. Between treatment group comparisons of mean changes from baseline groups in ESS and MSLT scores were performed using analysis-of-covariance (ANCOVA), with treatment and center as factors and baseline score as a covariate. The addition of nCPAP use at baseline as a covariate in these analyses had no effect on the significance of any treatment effect. CGI-C data were analyzed using a Cochran-Mantel-Haenszel chi-square statistic, with adjustment for center. Data on nCPAP use were analyzed using ANCOVA, as described above. Within-treatment group comparisons of mean changes from baseline in nCPAP use were performed using a paired t test. Comparisons of mean changes from baseline in NPSG parameters were performed using two-way ANOVA, with main-effect terms for treatment and center. No significant center effect was found for any efficacy parameter. Patients receiving at least one dose of study medication were included in safety analyses. Comparisons of mean changes from baseline in heart rate, blood pressure, and body-mass index (BMI) were performed using Wilcoxon's signed-rank test.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Patient Characteristics

A total of 157 patients were randomized to treatment, with 77 patients in the modafinil group and 80 patients in the placebo group. One hundred forty-three patients (91%) completed the study (66 patients in the modafinil group and 77 patients in the placebo group). NPSG data obtained at screening (pre-nCPAP data obtained from patient medical histories) and at baseline (while using nCPAP) demonstrated that the mean RDI for patients entering the study decreased from approximately 50 events/h to approximately 2 to 3 events/h at their previously determined therapeutic level of nCPAP therapy (Table 1). AutoSet T (fixed pressure mode) data collected at screening during two nights of monitoring for nCPAP effectiveness indicated that the patients were receiving effective nCPAP therapy, with no statistical difference observed between the two treatment groups for any measurement. There were only small mask leaks. The apnea index detected by AutoSet was low, but the hypopnea index was slightly elevated (5.11 ± 2.97 SD in the placebo group and 5.19 ± 3.55 in the treatment group). This is slightly higher than in the laboratory sleep study. At baseline, there were no significant differences between the two treatment groups with respect to age, sex, BMI, heart rate, or sitting and standing blood pressures. Four percent of the modafinil group had a normal BMI, whereas 6% of the placebo group did (NS). There was also no difference between the level of thyroid-stimulating hormone (TSH) at baseline between the modafinil group, i.e., 1.8 ± 1.0 uIu/µl, and placebo group 2.1 ± 1.4 (NS). Furthermore, no significant differences between the two treatment groups were observed at baseline for any parameter determined during NPSG, baseline mean ESS scores, or mean MLST sleep latency times.

Disease severity was recorded at baseline for 115 of the 157 patients (73%) using the CGI-S scale. The majority (80%) of patients in both treatment groups were categorized as moderately (modafinil, 54%; placebo, 66%) or markedly (modafinil, 25%; placebo, 16%) ill. At baseline, 45% of patients were considered to be severely sleepy, as defined by an ESS score of  15.

Daytime Sleepiness

At Weeks 1 and 4 of double-blind treatment, mean ESS scores were reduced from baseline for both the modafinil and the placebo groups (Figure 2). This effect was significant for both treatment groups at Week 4 (p < 0.001). For patients receiving nCPAP plus placebo, the mean ESS score was 14.4 at baseline, 13.2 at Week 1, and 12.4 at Week 4 (p = 0.0001). For patients receiving nCPAP plus modafinil, the mean ESS score improved from a value of 14.2 at baseline to 10.1 at Week 1 and to 9.6 at Week 4 (p = 0.0001). The mean changes from baseline in ESS scores at Weeks 1 and 4 were significantly different between the two treatment groups (p < 0.001), with greater improvements in daytime sleepiness demonstrated in the patients receiving nCPAP plus modafinil.

View larger version (27K): [in this window] [in a new window]   Figure 2.   Mean ESS scores at baseline and after treatment with nCPAP plus modafinil (MOD) or nCPAP plus placebo (PBO). Asterisks indicate p < 0.001 for the change from baseline versus nCPCP plus placebo.

A significantly greater percentage of patients in the nCPAP plus modafinil group had normalized ESS scores (i.e., < 10) at Week 4 than did patients in the nCPAP plus placebo group. At Week 4, 38 of 75 patients (51%) receiving nCPAP plus modafinil had ESS scores of < 10 compared with 21 of 79 patients (27%) receiving nCPAP plus placebo (p < 0.01).

A further post-hoc analysis of subjective daytime sleepiness was performed for patients categorized by the ESS score at baseline. For patients who were mildly to moderately sleepy at baseline (ESS score of 10 to 14), the mean improvements from baseline in ESS scores were significantly different between the modafinil and the placebo groups at Week 4 (p < 0.01), with greater improvement demonstrated in the modafinil group (Figure 3). Likewise, for patients who were severely sleepy at baseline (ESS score of  15), a significant treatment effect was observed at Week 4 (p < 0.05).

View larger version (33K): [in this window] [in a new window]   Figure 3.   Mean ESS scores at baseline and after treatment with nCPAP plus modafinil (shaded bars) or nCPAP plus placebo (open bars) according to baseline ESS score. Asterisks indicate p < 0.05 for the change from baseline versus nCPAP plus placebo.

At Week 4, the mean MSLT sleep latency time for patients receiving nCPAP plus modafinil improved to 8.6 min from the mean value at baseline of 7.4 min (Figure 4); in contrast, the mean MSLT sleep latency time at Week 4 for the nCPAP plus placebo group (7.2 min) was slightly worsened from baseline (7.5 min). The difference in the mean change in MSLT sleep latency time from baseline between the two treatment groups was statistically significant (p = 0.021). There was no difference in the percentage of subjects who normalized their MSLT, i.e., to above 10 min, between placebo (25%) and modafinil (29%) (p = 0.613).

View larger version (27K): [in this window] [in a new window]   Figure 4.   Mean MSLT times at baseline and after treatment with nCPAP plus modafinil (MOD) or nCPAP plus placebo (PBO). Asterisk indicates p = 0.021 for the change from baseline versus nCPAP plus placebo.

Change in Illness Severity

The percentage of patients rated as clinically improved was significantly greater after 4 wk of treatment with nCPAP plus 400 mg/d of modafinil than after treatment with nCPAP plus placebo. CGI-C ratings improved for 37 of 52 patients (71%) receiving nCPAP plus modafinil compared with only 20 of 57 patients (35%) receiving nCPAP plus placebo (p = 0.035; see Figure E5 in online data supplement). The percentage of patients in the modafinil treatment group rated as clinically improved after 1 wk of treatment with 200 mg/d (64%) was greater than that observed for the placebo group (42%), but the difference in the percentages was not statistically significant.

Nocturnal Polysomnography Parameters

At Week 4 of double-blind treatment, sleep duration, sleep efficiency, and the percent of time spent in sleep Stages 1, 2, 3, and 4 and in REM sleep were comparable to baseline values in both treatment groups, and there were no significant differences between the two treatment groups in the change from baseline in these parameters. The RDI at Week 4 was 3.5 events/h in patients receiving nCPAP plus modafinil and 2.6 in those receiving nCPAP plus placebo. At Week 4, no significant change from baseline was observed in the RDI within either treatment group. A small but significant difference in the mean change from baseline in the arousal index (i.e., the number of arousals per hour of sleep) between the modafinil group and the placebo group was demonstrated (p = 0.018). At Week 4, the mean arousal index was 14.3 in patients receiving nCPAP plus modafinil and 11.8 in those receiving nCPAP plus placebo.

nCPAP Use

During 2 days of nCPAP monitoring with the AutoSet T device during screening and during 3 wk of nCPAP use monitoring with the ResMed Elite device at baseline, the mean numbers of hours of nCPAP therapy per night were similar for the modafinil and the placebo groups. The mean nCPAP at baseline was 6.2 ± 1.3 h in the placebo group and 6.4 ± 1.1 h in the modafinil group. During 4 wk of treatment, the mean time of nCPAP use was 6.2 h per night in each group, with no significant change from baseline between the two groups and no significant change from baseline to Week 4 within each group.

Safety Outcomes

For both treatment groups, the most common treatment-emergent adverse events of all causes were headache (modafinil, 23%; placebo, 11%) and nervousness (modafinil, 12%; placebo, 3%) (Table 2). These differences between modafinil and placebo were significant for headache (p = 0.044) and nervousness (p = 0.024). The most common adverse events that were considered by the investigator to be treatment- related were headache (modafinil, 17%; placebo, 9%) and rhinitis (modafinil, 8%; placebo, 3%). In general, adverse events were predominantly mild or moderate in nature. One patient receiving nCPAP plus modafinil experienced a serious adverse event (chest pain) that was considered to be unrelated to treatment. The overall rate of discontinuation of treatment was 14% (11 of 77 patients) for patients receiving nCPAP plus modafinil and 4% (three of 80 patients) for those receiving nCPAP plus placebo (p = 0.015). Eight patients (10%) receiving nCPAP plus modafinil withdrew from the study because of adverse events compared with one patient (1%) receiving nCPAP plus placebo (p = 0.016). Other reasons for treatment discontinuation were noncompliance with the drug or alcohol restriction (nCPAP plus modafinil, n = 2; nCPAP plus placebo, n = 1), lost to follow-up (nCPAP plus modafinil, n = 1), and protocol violation (nCPAP plus placebo, n = 1). Of the eight patients receiving modafinil who discontinued because of adverse events, six had adverse events considered to be treatment-related (headache, dizziness/paresthesia, nervousness, anxiety, twitch, and insomnia; one patient each). No clinically meaningful differences were observed between treatment groups with respect to laboratory parameters, ECG recordings, physical examinations, or vital sign measurements (see Table E3 in online data supplement). Small but statistically significant differences between treatment groups were observed at Week 4 in mean changes from baseline in BMI (modafinil, 0.32; placebo, 0; p = 0.019) and sitting systolic blood pressure (modafinil, 1.0 mm Hg; placebo, 2.6 mm Hg; p = 0.035).

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

In the present study, the efficacy and safety of 400 mg of modafinil taken once daily in the morning were evaluated in 157 patients with OSA/HS who experienced residual EDS despite effective and regular use of nCPAP therapy. Although nCPAP was used for at least 4 h/d for at least 5 d each week (mean use was greater than 6 h/night) and the mean RDI was 2.3 at baseline while receiving nCPAP, all patients in this study presented with abnormal levels of daytime sleepiness (i.e., ESS scores  10) and 45% could be categorized as severely sleepy (i.e., ESS scores  15). Treatment with nCPAP plus modafinil significantly improved both subjective and objective measures of daytime sleepiness compared with that observed with treatment with nCPAP plus placebo. Improvements in self-reported EDS were observed within 1 wk of modafinil administration, and were maintained throughout the 4-wk treatment period. ESS scores were normalized (i.e., < 10) in a significantly greater proportion of patients receiving nCPAP plus modafinil (51%) than the proportion of patients receiving nCPAP plus placebo (27%). Significant improvements in mean ESS scores were observed with nCPAP plus modafinil treatment for patients with mild-to-moderate EDS (baseline ESS score of 10 to 14). Even those patients with more severe EDS (baseline ESS score of  15) demonstrated significant improvements in mean ESS scores with nCPAP plus modafinil. Modafinil was well tolerated, with mild-to-moderate headache and nervousness being the most common adverse events. Treatment with modafinil had no clinically significant effect on heart rate, blood pressure, ECGs, BMI, RDI, or nocturnal sleep parameters. At Week 4, a small but statistically significant increase in the mean arousal index was found in patients receiving nCPAP plus modafinil. This is unlikely to be clinically meaningful because the mean arousal index for the modafinil group at baseline (11.3) and at Week 4 (14.3) were comparable to those reported for normal subjects (50). Moreover, at this time, subjects receiving modafinil were less sleepy during the daytime both by self-report and on an objective measure. Finally, changes from baseline in nightly nCPAP use were not significantly different between the modafinil and the placebo treatment groups or within the modafinil or the placebo group.

The improvements in EDS observed after treatment with modafinil in the present study are consistent with the results reported in two large U.S. trials of modafinil in narcolepsy (32, 33). In these two studies, mean baseline ESS scores in the different fixed-dose treatment arms actually ranged from 17.1 to 18.3 and decreased significantly by 3.5 to 5.7 points after 9 wk of treatment with modafinil compared with a 1.2- to 1.8-point decrease after treatment with placebo. In the present study, mean ESS scores at baseline (approximately 14.3) were somewhat lower than those observed in patients with narcolepsy. However, during 4 wk of treatment with nCPAP plus modafinil, mean ESS scores improved by 4.6 points versus a 2.0-point decrease for those who received nCPAP plus placebo. Mean MSLT sleep latency times at baseline in the narcolepsy trials ranged from 2.2 to 3.3 min and improved by 1.8 to 2.4 min after treatment with modafinil and by 0.5 to 1.3 min after treatment with placebo. Mean MSLT sleep latency times at baseline in the present study were longer (approximately 7.4 min) and improved by 1.2 min after treatment with nCPAP plus modafinil but worsened by 0.3 min with nCPAP plus placebo.

The changes we observed in ESS scores in the placebo group are comparable with previous studies with randomized placebo-controlled designs for the assessment of the efficacy of nCPAP for the treatment of apnea. When either subtherapeutic nCPAP (18) or a placebo pill that subjects are told is an effective treatment for apnea (19) are used, significant improvements in ESS scores of similar magnitude to those reported here are found. In the present study, the effect size of ESS improvements in the modafinil group was 1.15. This degree of improvement in ESS score is likely to be reflected in an improvement in quality of life, as changes in ESS scores are correlated with improvements in quality of life instruments (53). In contrast, the degree of improvement of our objective measure of sleepinessthe MSLTwas small with an effect size of only 0.26. As with other studies in OSA/HS (18, 19), no significant placebo effect for an objective measure of sleepiness was found. That there is a dissociation between the effect size for subjective and objective sleepiness is not surprising as these measures are likely to be assessing different domains of functioning. It is currently unclear whether subjective or objective sleepiness is the best predictor of outcomes. It has been argued that the ESS is the most discriminating test for sleepiness (54), and at least one study has found the ESS to be a better predictor of quality of life outcomes than the MSLT (53).

This study was conducted in a subset of patients receiving nCPAP therapy, namely, those who are residually sleepy despite effective therapy. The prevalence of residual EDS in patients with OSA/HS who are receiving effective nCPAP therapy is unknown. Although previous studies have reported that nCPAP improves mean values for subjective and objective measures of EDS in patients with OSA/HS (18, 19, 21), the values for individual patients before and after nCPAP therapy are rarely stated. The present study, which enrolled only those patients who had residual EDS despite effective and regular use of nCPAP, was not designed to evaluate the prevalence of this condition. This needs to be the subject of a future study. The basis for this residual sleepiness in such patients is unknown. Two possible reasons that might explain why the enrolled patients continued to experience residual EDS during regular use of nCPAP therapy include inadequate treatment of OSA/HS or inadequate sleep duration. However, our results do not lend support to either of these possibilities. The mean RDI of the patients receiving regular nCPAP therapy in the laboratory was in the normal range (2.3 events/h at baseline and 3.1 at Week 4). The residual respiratory events measured at home by the AutoSet were slightly higher (approximately 5 events/h) than our laboratory measurements. This might reflect differences in sleep stage distribution at home or larger mask leaks than in the laboratory. Even though the residual AHI at home was higher, it is still not in the range that sleepiness should ensue as a result. Furthermore, an objective assessment of the duration of nCPAP use indicated a mean value of 6.2 h/night, which is higher than or comparable to the mean values (3.1 to 6.3 h/night) reported in several previous studies of adherence to CPAP (19, 21, 22, 24, 25, 55, 56). Thus, inadequate OSA/HS treatment with nCPAP or inadequate duration of CPAP use do not appear to explain the residual EDS in the patients in the present study. Also, the relatively high nightly use of CPAP makes inadequate sleep duration not a particularly likely explanation, although actual sleep duration at home was not measured in our study.

Another possible reason for the residual EDS during regular nCPAP therapy might be related to the type, rate, nightly distribution, and/or chronicity of arousals (57). In the present study, the mean arousal indices during nCPAP therapy (baseline) were comparable to values previously reported for normal subjects (50). However, because of the lack of a single universally endorsed definition of arousal and the variability of arousal scoring (58), the role of arousals in the occurrence of residual EDS during nCPAP therapy is unclear. Future studies are needed to evaluate the importance of arousals in daytime sleepiness in normal subjects and in patients with sleep disorders, including OSA/HS.

Although we cannot provide a clear explanation of the basis of residual sleepiness, two postulates are worthy of comment and will need to be the basis for further study. First, it is conceivable that the many years of sleep disruption prior to diagnosis and treatment have resulted in permanent alteration of the sleep promoting system, resulting in shorter sleep durations and/or EDS despite effective treatment. Second, it may be that there are still residual abnormalities in the upper airway during sleep despite nCPAP therapy that are not reflected in the residual apnea/hypopnea index. It is to be emphasized, however, that based on current clinical criteria, these patients were effectively treated with nCPAP.

Two methodologic issues relating to the present study deserve comment. First, the definitions of apnea and hypopnea were not standardized across the participating centers. Although one definition of apnea is widely used in clinical practice (i.e., a cessation of airflow for > 10 s), different sleep centers often do not use the same definition of hypopnea (61). However, Tsai and coworkers (62) have demonstrated that the addition of arousal-based hypopnea scoring criteria to desaturation-based criteria result in only small changes in the AHI determined from NPSG data. Second, NPSG data were analyzed and scored at each center rather than at a single central site. Because the RDI was not an outcome measure in the study and the patients initially had severe OSA/HS (mean RDI of approximately 50 in both groups) before beginning nCPAP therapy, these issues do not affect our conclusions. Moreover, effectiveness of therapy with respect to residual RDI while receiving nCPAP was also assessed by the same technology (AutoSet) for all subjects at all sites.

In clinical practice, the issue of continued compliance with nCPAP therapy after prescribing modafinil (or any other pharmacologic agent) for the treatment of residual EDS is of critical importance and should be evaluated periodically. Because treatment with modafinil reduces EDS, there might be a tendency for patients to subsequently reduce their nCPAP use. This did not occur in the present study; patients in the modafinil and placebo treatment groups maintained a high rate of nCPAP use (6.2 h/night) throughout the 4 wk of double-blind treatment. However, in a smaller, placebo-controlled, crossover study in 30 patients with OSA/HS, a small but significant reduction in nCPAP use was found after 2 wk of treatment with 400 mg/d of modafinil (6.3 ± 1.0 h/night versus 6.5 ± 1.0 h/night for placebo) (63). This finding was not replicated in the present study. It seems unlikely that this small difference is of any clinical significance. Hoy and coworkers (64) found that intensive support of nCPAP use improved nightly use of nCPAP by 1.6 h/night compared with a standard care group. However, this increase in nCPAP use was not associated with either a significant improvement in ESS score or in objective sleepiness as measured by the maintenance of the wakefulness test. Given this lack of effect, we do not believe that an average of 12 min/night of nCPAP will have any effect on the degree of sleepiness during the daytime. Because the duration of treatment with modafinil was relatively short in each of these studies, the effect of longer-term treatment with modafinil on nCPAP use should be evaluated in future studies.

The results of the present study only support the use of modafinil as an adjunct treatment for residual daytime sleepiness in patients with OSA/HS who are effectively treated with nCPAP. In this trial, considerable attention was paid to patient selection and the monitoring of nCPAP effectiveness to ensure that the primary pathology of sleep-disordered breathing was appropriately treated. In contrast to the effective use of nCPAP in the prevention of OSA/HS disease progression (65, 66) and the resulting adverse cardiovascular sequelae (3, 4, 9, 10, 67, 68), modafinil should never be used as a primary treatment of OSA/HS as it has no such anticipated beneficial effects.

In summary, the results of this trial suggest that 400 mg of modafinil taken once daily is an effective and well-tolerated adjunct treatment for residual EDS in patients with OSA/HS who are regular users of nCPAP therapy. The results further suggest that modafinil has no clinically significant effect on RDI, cardiovascular parameters, or nCPAP use.

See Acknowledgment and list of other contributors in online data supplement.