Assessing Condition‐Specific Adverse Event Profiles of Modafinil for Labelled and Off‐Label Uses: A Systematic Review and Meta‐Analysis

Modafinil is approved for excessive daytime sleepiness in narcolepsy, obstructive sleep apnoea (OSA), and shift work sleep disorder (SWSD), but its widespread off-label use raises safety concerns. We evaluated the risk of adverse events (AEs) associated with both labelled and off-label use of modafinil. A systematic search of PubMed, Embase, and Cochrane identified 54 studies that met the inclusion criteria. In labelled uses, narcolepsy patients had significantly elevated risks of diarrhoea (risk ratio [RR]: 2.16, 95% confidence interval [CI]: 1.06-4.41) and nausea compared to those with placebo (RR: 2.44, 95% CI: 1.05-5.72). OSA/hypopnea syndrome patients had higher risks of insomnia (RR: 5.82), anxiety/nervousness (RR: 3.26), and headache (RR: 1.92). SWSD patients had elevated risks of insomnia (RR: 4.09), anxiety/nervousness (RR: 3.85), and nausea (RR: 2.93). Among off-label users, patients with attention deficit hyperactivity disorder had higher risks of insomnia (RR: 4.97) and decreased appetite (RR: 4.21). Patients with major depressive disorder showed higher risks of anxiety/nervousness (RR: 1.95). While modafinil users share common AEs, specific risks vary across patient groups. Our findings on condition-specific AE profiles would support cautious prescribing of modafinil and careful consideration of alternative treatments.