Modafinil for excessive daytime sleepiness: A systematic review and meta-analysis of randomized controlled trials

Excessive daytime sleepiness (EDS) is a common and disabling symptom of obstructive sleep apnea (OSA) and shift work sleep disorder (SWSD). Modafinil is widely used as a wakefulness-promoting agent; however, its efficacy and safety remain debatable.

To evaluate the efficacy and safety of modafinil for EDS in adults with OSA or SWSD.

We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). MEDLINE/PubMed, EMBASE, LILACS, and CENTRAL were searched from inception to May 2026, along with clinical trial registries. Eligible studies compared modafinil with placebo in adults with EDS related to OSA or SWSD. The primary outcomes were daytime sleepiness, assessed using the Epworth Sleepiness Scale (ESS), and objective wakefulness, assessed using the Maintenance of Wakefulness Test (MWT). The secondary outcomes included clinical global improvement (CGI-C), vigilance performance, and adverse events (AEs). The risk of bias was assessed using RoB2, and the certainty of the evidence was assessed using GRADE.

Nine RCTs (1265 participants) were included in this review. In patients with OSA, continuous ESS analyses, both change-from-baseline and endpoint, did not demonstrate statistically significant differences between the modafinil and placebo groups. Clinical response analyses based on the predefined ESS responder criteria generally favored the use of modafinil. For objective wakefulness, pooled MWT endpoint analyses demonstrated a statistically significant improvement favoring modafinil (MD 2.95 min, 95% CI 0.66-5.23, p = 0.01; I² = 36%). Modafinil also improved the CGI-C and vigilance performance outcomes. The certainty of evidence was rated as low for ESS outcomes and moderate for MWT outcomes. In patients with SWSD, two trials (487 participants) reported improvements in objective wakefulness, subjective sleepiness, and selected functional outcomes with modafinil; however, findings were not consistent across all outcome measures, and meta-analysis was not feasible because of insufficient reporting. Modafinil was associated with a higher risk of treatment discontinuation due to adverse events (RR 2.50; 95% CI 1.24-5.07). Headache, insomnia, nausea, and anxiety/nervousness occurred significantly more frequently with modafinil than with placebo, with pooled RRs of 1.38 (95% CI 1.10-1.72), 4.64 (95% CI 2.21-9.75), 2.57 (95% CI 1.33-4.97), and 3.08 (95% CI 1.49-6.39), respectively. No significant heterogeneity was observed between the studies reporting the tolerability outcomes.

Modafinil improved objective wakefulness and neurobehavioral outcomes in patients with OSA-related EDS. ESS responder analyses favored modafinil, but continuous ESS outcomes did not show statistically significant benefits. In SWSD, available studies reported improvements in wakefulness, sleepiness, and some functional outcomes, although findings were not consistent across all measures. These results suggest that modafinil may improve wakefulness and daytime functioning in selected patients with EDS, but treatment is associated with an increased risk of adverse events.

PROSPERO CRD420251149258.