Abstract

Introduction: Migraine is a disabling neurological disorder with episodic, often unilateral headaches accompanied by nausea, vomiting, and sensory sensitivities. Currently, treatments are limited and frequently associated with adverse effects. Non-invasive vagus nerve stimulation (nVNS) has emerged as a promising therapy for acute and chronic primary headaches, acting via nociceptive modulation, neurotransmitter regulation, autonomic effects, and neuroimmunomodulation through the cholinergic anti-inflammatory pathway. This study aims to systematically evaluate the efficacy and safety of nVNS in migraine, focusing on clinical outcomes and adverse effects. Methods: We performed a systematic review of studies published between 2020 and 2025 in PubMed, Medline, and JAMA Network. Eligible studies included adults with episodic or chronic migraine or other primary headache disorders treated with cervical or auricular nVNS for acute or preventive therapy. Only peer-reviewed articles reporting efficacy outcomes and/or adverse effects were included. Studies on invasive VNS, pediatric populations, animal/in vitro models, or lacking safety data were excluded. Due to limited quantitative data, findings were analyzed descriptively. Results: Fourteen studies totaling 2,853 patients met inclusion criteria. nVNS consistently reduced headache frequency, severity, and duration across migraine, cluster headache, hemicrania continua, SUNCT/SUNA, and vestibular migraine. Benefits were seen in both acute and preventive use, including ≥50% reduction in attack frequency in refractory populations and decreased use of concurrent medications. Adverse effects were generally mild and transient, including local skin irritation, neck discomfort, paresthesia, erythema, and flu-like symptoms, with no serious events reported. Conclusions: nVNS is an effective and well-tolerated therapy for migraine and other primary headache disorders. Across 2,853 patients, it significantly reduced headache burden with minimal adverse effects, supporting its use as both acute and preventive therapy. Larger standardized studies are needed to confirm efficacy and guide clinical implementation