Original articleEffects of modafinil on sustained attention performance and quality of life in OSA patients with residual sleepiness while being treated with nCPAP
Introduction
Daytime sleepiness is a serious and debilitating symptom of many sleep disorders, including narcolepsy and obstructive sleep apnea/hypopnea syndrome (OSA/HS). Deficits in intellectual function, attention or vigilance, memory, executive and motor function, and motivation also have been demonstrated in patients with OSA/HS [1], [2], [3], [4], [5], [6], [7], [8], [9], [10]. Moreover, untreated OSA/HS is associated with an increased risk for cardiovascular disease [11], [12], increased rates of accidents [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], and increased mortality [23], [24], [25], [26].
The impairments in neuropsychological function experienced by individuals with OSA/HS contribute to decreased quality of life. The results of various studies [27], [28], [29], [30], [31], [32], [33] have demonstrated that patients with OSA/HS have significantly poorer health status compared with that of healthy control subjects, as measured with both generic (i.e. the Medical Outcomes Study short-form health survey (SF-36) [34] and the Nottingham Health Profile) [35] and disease-specific instruments (i.e. the FOSQ) [33]. Moreover, SF-36 scores were significantly related in a dose–response manner to the apnea–hypopnea index (AHI) after adjusting for age, sex, body-mass index, smoking status, alcohol use, and cardiovascular history [36]. These AHI-related decreases in SF-36 scores were comparable to those reported in arthritis, angina, hypertension, and diabetes [37].
Nasal continuous positive airway pressure (nCPAP) therapy is the standard non-surgical treatment for the management of clinically significant OSA/HS [38], [39]. Proper use of nCPAP manages apneas and hypopneas, eliminates hypoxia, restores normal sleep architecture, and significantly improves subjective and objective measures of wakefulness [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50]. Improvements in reaction times (RTs), driving skills, cognitive performance, and quality of life also have been reported with nCPAP therapy [23], [31], [36], [40], [41], [42], [43], [45], [46], [51], [52], [53]. Despite the proven efficacy of nCPAP in clinical trials, some patients who are regular users of nCPAP may experience inadequate or compromised sleep and residual daytime sleepiness [45], [46], [47], [48], [49]. The prevalence of and reasons for residual daytime sleepiness in some regular users of nCPAP therapy remain unknown. To manage persistent sleepiness in patients with OSA/HS who are regular users of nCPAP therapy, pharmacological treatment with central nervous system (CNS) stimulants has been described [54]. However, the benefit-to-risk ratio of CNS stimulants for the treatment of daytime sleepiness is not well documented in the medical literature. Cardiovascular side effects (i.e. tachycardia and hypertension) [55] of CNS stimulant treatment that have been reported in patients with daytime sleepiness associated with narcolepsy may be relevant because of the increased risk for cardiovascular disease in patients with OSA/HS [11], [12].
Modafinil, a novel wake-promoting agent that appears to be chemically and pharmacologically distinct from CNS stimulants, is effective for improving wakefulness in a variety of clinical models. Modafinil significantly improves wakefulness in patients with narcolepsy [56], [57], [58], and has been recommended by the American Academy of Sleep Medicine as a ‘standard’ treatment for this patient population [55]. In patients with excessive daytime sleepiness associated with narcolepsy, treatment with modafinil improves health-related quality of life, with significant improvements in the SF-36 domains of vitality, physical functioning, role limitations due to physical problems, role limitations due to emotional problems, and social functioning, and in the mental health summary scale [59]. Modafinil is well tolerated and its efficacy is maintained during long-term treatment [60], [61]. Modafinil has negligible sympathomimetic activity, does not adversely affect nighttime sleep, and is associated with a low frequency of adverse cardiovascular events [56], [57], [58]. The abuse potential for modafinil is low, and there is no clinical evidence for the development of dependence or tolerance [60], [62], [63].
Its efficacy and safety profiles and preliminary clinical trial results suggest that modafinil may be a promising adjunct treatment for residual daytime sleepiness in patients with OSA/HS. Four preliminary double-blind studies of modafinil in OSA/HS patients have been reported [64], [65], [66], [67]. The results of these studies suggest that modafinil (either with or without nCPAP therapy) may improve wakefulness, cognitive performance, and memory without affecting nighttime sleep parameters, blood pressure, or heart rate. The present randomized, placebo-controlled, parallel-group, multicenter study was conducted to evaluate the efficacy and safety of modafinil as an adjunct treatment for residual daytime sleepiness in a large cohort of OSA/HS patients who were effectively treated with and regular users of nCPAP therapy. The results of this study on the effects of adjunct modafinil treatment on objective and subjective measures of daytime sleepiness and on overall clinical condition have been reported previously [68]. Briefly, both subjective and objective measures of daytime wakefulness and physician-determined disease severity were significantly improved with nCPAP plus modafinil treatment. Importantly, modafinil did not have a clinically significant effect on nCPAP use or cardiovascular parameters. Presented here are additional results from this trial [68], involving assessment of the effects of nCPAP plus modafinil on sustained attention performance and sleep-related functional status and quality of life.
Section snippets
Study design and patients
A double-blind, randomized, placebo-controlled, parallel-group study was conducted at 22 centers in the United States, with the approval of the local institutional review boards. The study design and patient selection criteria have been described previously [68]. The study included a 1-day screening period; a 2-day period to confirm nCPAP effectiveness; a 3-week period to monitor nCPAP use; a 2-day period for baseline assessments; and a 4-week, double-blind treatment period (Fig. 1).
Inclusion
Patient characteristics
Of 232 patients screened, 157 qualified patients with residual daytime sleepiness were randomized to double-blind treatment at baseline. Seventy-five patients were excluded for reasons described elsewhere [68]. Of 157 patients randomized, 143 patients (91%) completed the study. In the nCPAP plus placebo group, 77 of 80 patients (96%) completed the study compared with 66 of 77 patients (86%) in the nCPAP plus modafinil group (P=0.015). Baseline characteristics, including age, sex, weight, and
Discussion
When used as an adjunctive therapy for patients who have sleepiness refractory to nCPAP treatment, modafinil had beneficial effects on daytime functioning as assessed by the FOSQ, and on performance requiring sustained attention as measured by the PVT. These functional improvements were consistent with the previously reported reductions in objective sleepiness as measured by MSLT, and subjective sleepiness as assessed by ESS in these same patients with OSA/HS (e.g. mean [SD] ESS scores improved
Acknowledgements
The study was supported by Cephalon, Inc., West Chester, PA. Study results were presented in part at the 6th World Congress on Sleep Apnea, March 2000, Sydney, Australia, and at the CHEST 2000 meeting, October 2000, San Francisco, California. Members of the US Modafinil in Sleep Apnea Multicenter Study Group are as follows: Jed E. Black, Stanford, CA; Richard K. Bogan, Columbia, SC; Bruce Corser, Cincinnati, OH; William Devor, San Diego, CA; Russell Dodge, Tuscon, AZ; Helene Emsellem,
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