Efficacy and Safety of Pitolisant for Excessive Daytime Sleepiness in Narcolepsy and Obstructive Sleep Apnea: An Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE

To assess the efficacy and safety of pitolisant, a selective histamine H₃ receptor antagonist/inverse agonist, for excessive daytime sleepiness (EDS) in narcolepsy or obstructive sleep apnea (OSA).

DATA SOURCES: PubMed, Cochrane, Embase, Scopus, and Web of Science were searched through August 2025 for randomized placebo-controlled trials (RCTs).

STUDY SELECTION AND DATA EXTRACTION: Eligible RCTs reported Epworth Sleepiness Scale (ESS) or Pediatric Daytime Sleepiness Scale (PDSS), mean sleep latency, EQ-5D, or global impression outcomes. Two reviewers independently screened studies, extracted data, and assessed bias using Cochrane RoB 2.0. Publication bias was evaluated using funnel plots and Egger's test; certainty of evidence was rated with GRADE.

DATA SYNTHESIS: Six RCTs (n = 1149) met the inclusion criteria. Compared with placebo, pitolisant significantly reduced Sleepiness Scale scores (SSS) (mean difference [MD] = -2.97; 95% confidence interval [CI] -3.62 to -2.33), increased mean sleep latency (MD = 3.06; 95% CI 2.12-3.99), and improved EQ-5D scores (MD = 2.68; P = 0.009). Patient global opinion (risk ratio [RR] = 1.40) and clinical global impression of change (CGI-C) (RR = 1.41) also favored pitolisant. Rates of treatment-emergent adverse events, serious adverse events, and withdrawals were comparable with placebo, and common adverse effects, such as headache, insomnia, nausea, and anxiety, were infrequent and not significantly increased.

RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Pitolisant provides an effective, nonstimulant option for EDS in narcolepsy and OSA, including residual symptoms despite continuous positive airway pressure (CPAP). Its distinct mechanism and tolerability profile make it a valuable alternative or adjunct to existing therapies, supporting personalized care and enhanced daily functioning.

CONCLUSION AND RELEVANCE: Pitolisant significantly improves subjective and objective wakefulness and quality of life in EDS due to narcolepsy or OSA, with robust evidence for ESS benefit and a favorable safety profile.