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  • Updated 04.14.2022
  • Released 04.12.2022
  • Expires For CME 04.14.2025

Vagal nerve stimulation for headaches



The vagus nerve is the largest cranial nerve of the human body. It provides an extensive network of afferent and efferent pathways that interface between the higher central nervous system and autonomic, cardiovascular, respiratory, gastrointestinal, immune, and endocrine systems (28). In a comprehensive four-part review, Yuan and Silberstein outlined the potential peripheral and central mechanisms of pain modulation induced by vagus nerve stimulation (28; 29; 30; 31). In 2020, Silberstein and colleagues put forth another comprehensive review outlining the mechanisms of action for noninvasive vagus nerve stimulation that included several clinical studies (24). According to the findings from animal and human studies combined, several possible mechanisms were proposed to explain the effect of noninvasive vagal nerve stimulation in managing headaches. These core areas include autonomic nervous system effects, cortisol spreading depression inhibition, neurotransmitter regulation, and nociceptive modulation. The interplay of these four mechanisms makes noninvasive vagal nerve stimulation an effective and safe treatment for migraine (31).

Noninvasive vagal nerve stimulation, a form of neuromodulation delivered via a portable device, has been studied as a preventive and acute treatment for migraine and cluster headache. All of these studies applied the gammaCORE device directly to the lateral neck region, stimulating the cervical branch of the vagus nerve by two stainless steel electrodes that deliver 25 Hz of burst stimulation, mostly giving 90-second doses of stimulation at a time (12; 02). Multiple clinical trials have been conducted to assess the efficacy and safety of noninvasive vagal nerve stimulation devices for acute and preventive management of headaches, such as ACT1, ACT2, and PREVA for cluster headaches, and PRESTO, EVENT, and PREMIUM for migraine. Several case series also reported meaningful benefits for use in vestibular migraine, paroxysmal hemicrania, and hemicrania continua. Here we discuss the scientific and clinical evidence of noninvasive vagal nerve stimulation devices for acute and preventive management of cluster headaches and migraines.

Key points

• The vagus nerve plays a crucial role in the nociceptive and anti-inflammatory pathways involved in headache pain.

• Vagus nerve stimulation modulates multiple neural mechanisms to elicit antinociceptive effects.

• Vagus nerve stimulation devices have significantly reduced pain intensity while being a safe and well-tolerated therapy for migraine and cluster headache.

Historical note and terminology

Being the longest cranial nerve of the body, the vagus nerve plays a significant role in multiple systems, including the autonomic, cardiopulmonary, immune, gastrointestinal, and endocrine systems. Due to its widespread interfacing of the autonomic nervous system with the body, it has been named the “great wandering protector.” The vagus nerve consists of 80% afferent pathways that sense various interoceptive stimuli, such as pain, pressure, stretch, temperature, and inflammation. The afferent pathways transmit this information to the reciprocal higher brain centers, including the nucleus tractus solitarius, nucleus ambiguus, and spinal nucleus of the trigeminal nerve. The appropriate modulatory feedback is conveyed via the remaining 20% of descending vagal efferents (28).

In the 19th century, Dr. James Corning tested the hypothesis of venous hyperemia in seizure occurrence and devised an instrument that compresses carotid arteries and stimulates the vagus nerve (15). Although his experiment did not show promising data, it gave way to many vagus nerve stimulation-related studies on seizure control in the 1980s. By the 1990s, several successful clinical trials in the treatment of refractory epilepsy led to the United States Food and Drug Administration clearance of the implantable vagal nerve stimulator. With the advancement of vagus nerve stimulation technology, many implantable vagal nerve stimulation devices have been developed for better seizure control and heart failure management.

The noninvasive devices transmitting stimulation transcutaneously to the auricular branch of the vagus nerve or carotid vagus nerve are being evaluated for epilepsy, pain, autonomic disorder, depression, and different types of headaches (19; 13). There are several noninvasive vagal nerve stimulation devices available on the market. Although some devices are essentially TENS devices with a surface electrode attaching to the auricular branch of the vagus nerve, tVNS® L (NEMOS®, Cerbomed GmbH, Erlangen, Germany) and gammaCore Sapphire™ (electroCore, Inc., Rockaway, NJ) are dedicated noninvasive vagal nerve stimulation devices.

The only United States FDA-cleared noninvasive vagal nerve stimulation device for acute and prophylactic treatment of primary headaches, including cluster headaches in adults, episodic cluster headaches in adults, and acute and preventive treatment of migraine in adolescents (ages 12 years and older) and adults is gammaCORE. It is a hand-held transcervical vagus nerve stimulation (tcVNS) device that stimulates the cervical vagus nerve by two skin electrodes applied at the neck. The device can be applied 6 to 12 times per day. gammaCORE has also received European CE marking for treatment of primary headaches, including migraine, cluster headaches, trigeminal autonomic cephalalgias, hemicrania continua, and medication overuse headaches. Another noninvasive vagal nerve stimulation device, tVNS® L is one of the first transauricular vagus nerve stimulation (taVNS) devices that has received Eurpean CE marking for treating headaches and pain. However, it is not yet cleared by the US FDA. Noninvasive vagal nerve stimulation devices exhibit a greater safety profile and prove to be more effective than their invasive counterparts.

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