Pharmacotherapy for Obstructive Sleep Apnea: From Pathophysiology to Emerging Treatments.

Background/Objectives: Obstructive sleep apnea (OSA) is a highly prevalent sleep-related breathing disorder caused by recurrent upper-airway collapse during sleep, leading to intermittent hypoxia, sleep fragmentation, and excessive daytime sleepiness. Although continuous positive airway pressure (CPAP) remains the first-line therapy, long-term adherence is often suboptimal, underscoring the need for more tolerable and flexible treatment options. This review aims to summarize the pathophysiological rationale for pharmacotherapy in OSA and to discuss recent developments in drug-based interventions. Methods: We conducted a narrative review of the literature on pharmacological interventions for OSA, with a systematic search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov up to 4 August 2026. We included randomised controlled trials, observational studies, meta-analyses, and mechanistic human or animal studies that reported relevant sleep and respiratory outcomes, and graded evidence according to the principles of GRADE framework. Results: Several drug classes have shown promise: agents that increase upper-airway dilator muscle activity, respiratory stabilizers that reduce loop gain, medications that raise the arousal threshold, topical anti-inflammatory drugs for mucosal edema, and systemic metabolic modulators such as glucagon-like peptide-1 receptor agonists and dual incretin receptor agonists. Emerging strategies, including gene therapy directed at the hypoglossal motor system, are also under investigation at the preclinical stage. Moreover, combining pharmacotherapy with CPAP or other devices can produce synergistic benefits, enabling lower device pressures and enhanced patient comfort. Conclusions: Pharmacotherapy for OSA is progressively moving from exploratory research towards targeted, phenotype-driven personalized treatment. Future studies should focus on robust patient phenotyping, multi-mechanistic combination regimens, and long-term clinical outcome evaluations to facilitate the integration of drug-based therapies into routine OSA management, particularly in specific subgroups such as those with COMISA.