Effect of Wakefulness-Promoting Agents on Sleepiness in Patients with Sleep Apnea Treated with CPAP: A Meta-Analysis

J Clin Sleep Med. 2015 Oct 15;11(10):1179-86. doi: 10.5664/jcsm.5096.


Study objectives: To perform a meta-analysis of the effect of wakefulness-promoting agents (modafinil and armodafinil) in patients with residual sleepiness after CPAP therapy for obstructive sleep apnea.

Methods: We conducted a systematic search of MEDLINE (1966 to September 2014), EMBASE (1980 to September 2014) and Cochrane Database for randomized placebo controlled trials on modafinil or armodafinil in patients who met established criteria for diagnosis of obstructive sleep apnea, adequate continuous positive airway pressure use, and who complained of residual sleepiness. Risk of bias was assessed. Primary outcomes were the Epworth Sleepiness Scale and mean sleep latencies on the maintenance of wakefulness test. Secondary outcomes were the Clinical Global Impression of Change, change in daily continuous positive airway pressure use, and the frequency of headaches.

Results: Out of 118 abstracts screened and 12 full text articles reviewed, we included 6 studies (total of 1,479 participants) in our final meta-analysis: Three evaluated modafinil, and three armodafinil. Risk of bias was unclear in one or more key domains for four studies. When compared with placebo, wakefulness promoting agents decreased Epworth Sleepiness Scale by 2.51 points (95% CI, 2.00-3.02), increased sleep latency in maintenance of wakefulness test by 2.73 minutes (95% CI, 2.12-3.34), increased the reporting of minimal improvement on the Clinical Global Impression of Change by 26% (RR 1.59; 95% CI, 1.36-1.86), and increased the risk of headaches by 8% (RR 1.98; 95% CI, 1.48-2.63). Also, there was a trend for decreased continuous positive airway pressure after treatment with these agents.

Conclusion: Wakefulness promoting agents improve objective and subjective measures of sleepiness, wakefulness, perception of disease severity in patients with residual sleepiness after CPAP therapy for OSA, and are generally well tolerated.

Keywords: CPAP; armodafinil; modafinil; residual sleepiness; sleep apnea.

Publication types

  • Meta-Analysis

MeSH terms

  • Benzhydryl Compounds / pharmacology
  • Continuous Positive Airway Pressure*
  • Disorders of Excessive Somnolence / complications*
  • Disorders of Excessive Somnolence / drug therapy*
  • Humans
  • Modafinil
  • Randomized Controlled Trials as Topic
  • Sleep Apnea, Obstructive / complications*
  • Sleep Apnea, Obstructive / therapy*
  • Treatment Outcome
  • Wakefulness / drug effects
  • Wakefulness-Promoting Agents / pharmacology*


  • Benzhydryl Compounds
  • Wakefulness-Promoting Agents
  • Modafinil