Mechanism of action of non-invasive cervical vagus nerve stimulation for the treatment of primary headaches.

Stimulation of the cervical vagus nerve with implanted vagus nerve stimulation (iVNS) has been used clinically for more than 20 years to treat patients with epilepsy. More recently, a non-invasive cervical vagus nerve stimulation (nVNS), gammaCore, was developed, which has been purported to also stimulate the vagus nerve without the cost and morbidity associated with an iVNS system. gammaCore has been used to acutely treat various types of primary headaches, including migraine and cluster headaches (CH), and for the prevention of episodic, chronic, and menstrual migraines and CH. The gammaCore device was cleared by the FDA for the acute treatment of pain in episodic CH patients. In this review, we summarize the clinical work that has been published in the use of gammaCore for treating primary headache disorders, present an overview of studies demonstrating that nVNS does indeed stimulate similar vagus nerve fibers as the implantable VNS system, and then present several animal headache-related studies that address the mechanism of action of nVNS.