Whether as a primary treatment option or as adjunctive therapy, noninvasive neuromodulation devices are hard to ignore.
*EDITOR'S NOTE: A previous version of this article published in the September 2019 print issue of NeurologyLive contained errors, which have been corrected in this online version. Please see the full correction notice at the conclusion of the article.
Huma Sheikh, MD
Migraine affliction is widespread, affecting 1 in 6 Americans and 1 in 5 women.1
Migraine-related pain and symptoms account for roughly 3% of all emergency department visits annually, solidifying migraine as a burden on both patients and the health care system as a whole.1
Thankfully, practitioners now have access to a number of ways to address migraine frequency and severity. The armamentarium has continued to expand with more effective and safe therapies, spanning abortive, preventive, and complementary options.
In addition to acute pain medications and the latest class of anti–calcitonin gene-related peptide preventives, a relatively new class of treatment has shown promise: neuromodulation techniques. The technique, which involves stimulating specific nerves to decrease hypersensitivity, is believed to function as a relay system to the central nervous system. The mechanisms of action vary between devices, from retrograde modulation of the nuclei in the brainstem to the interruption of brain hyperactivity via nerve cell modulation.2,3
Four neuromodulation devices are currently approved for the treatment of migraine, and 1 for the treatment of cluster headache. Cefaly (Cefaly Technologies) was originally approved by the FDA in 2014 as an external trigeminal nerve stimulation device indicated for the prevention of migraine4
; it received further approval in 2017 for acute use.5
The device, which patients wear across the forehead, stimulates the supraorbital nerves specifically. In 2014, eNeura received 510(k) clearance from the FDA for its SpringTMS device for the acute treatment of migraine with aura,6
as well as the prevention of migraine in 20177
and the prevention and treatment of migraine in pediatric patients in 2019.8
Also in 2017, electroCore received clearance for its gammaCore noninvasive vagus nerve stimulator device for the acute treatment of episodic cluster headache—the first FDA-approved treatment for cluster headache at the time9
—followed by additional indications for prevention of cluster headache and acute migraine pain in 2018.10,11
Most recently, the FDA granted de novo market clearance in 2019 to Theranica’s Nerivio Migra, which patients wear on the arm and control with a smartphone app.12
Transcutaneous Electrical Nerve Stimulation
Cefaly, a transcutaneous electrical nerve stimulation device, is placed on the forehead daily as a migraine preventive or at the time of a headache as an abortive therapy. Patients can customize the pulse setting on the device based on their needs. Efficacy and safety in migraine prevention was demonstrated in a randomized, double-blind, sham-controlled trial in 67 patients, in which the mean number of migraine days over 3 months decreased significantly in the treatment (6.94 vs 4.88, P
=.023) versus the sham group (6.54 vs 6.22, P
Among patients assigned to active treatment, 38.1% achieved a 50% responder rate compared with 12.1% in the sham group. Investigators observed reductions in monthly migraine attacks, monthly migraine days, and monthly use of acute migraine drugs in the treatment group.13
Investigators observed similar results in a 2018 study that evaluated the device for acute treatment.14
Patients in the treatment group saw a 59% reduction in pain intensity at 1 hour versus 30% among the sham group (P
Although the treatment effect is relatively modest, the safety profile is very good. The main adverse effect is observed at time of use, with some patients describing the feeling of the electrical stimulation as slightly uncomfortable.14
Overall, this device is an effective treatment alternative for patients who have not seen results with other preventives and acute treatments and for those who have contraindications to traditional medications.
Transcranial Magnetic Stimulation
eNeura’s SpringTMS device has shown efficacy and safety for both acute and preventive treatment of migraine. Patients place the handheld device at the back of the head, where it delivers a focused electrical current to relieve migraine pain and prevent future attacks. In a randomized, double-blind, placebo-controlled study of 201 patients, 38% of those who used the SpringTMS system were pain free at 2 hours compared with 17% of those assigned to the sham device.15
Notably, no treatment-related serious events were recorded.
In the ESPOUSE study for migraine prevention, patients who used the device daily reported an average reduction from 9 headache days per month at baseline to 6 days per month posttreatment, with 46% of participants reporting at least a 50% reduction in headache attacks.16
Based on results of the ESPOUSE study, the device also received clearance for treatment and prevention of migraine headache in children 12 years and older in 2019.8
Vagus Nerve Stimulation
The gammaCore device first demonstrated efficacy in a 2014 study17
in which the number of cluster headache attacks per week were significantly reduced in the treatment group versus those who received standard care (–7.6 vs –2.0, P
=.002). In 2016, another randomized, sham-controlled trial found the device to be significantly effective for acute treatment of episodic cluster headache but not chronic cluster headache.18
Treatment with the device also demonstrated some positive effects on associated symptoms, including nausea and photophobia, in a study of acute treatment of migraine.19
As with the transcranial and transcutaneous stimulation devices, no serious treatment-related adverse events were reported, though some patients noted mild discomfort during stimulation with gammaCore.18
The gammaCore device is currently not indicated for treatment in women who are pregnant since it was not studied in this population.9
However, data on the use of vagus nerve stimulation in women of childbearing age or who are pregnant who have seizures or epilepsy have so far shown no signal of fetal adverse effects associated with the therapy.20,21
These data, although limited, suggest that vagus nerve stimulation may be a considerable treatment option in women with migraine who are pregnant pending the results of larger safety studies.
Remote Electrical Neuromodulation
The newest entry in the neuromodulation market is the Nerivio Migra, a wireless, battery-operated stimulation unit that patients wear on the lateral upper arm. The device stimulates peripheral nerves to induce a conditioned pain modulation that inhibits pain elsewhere in the body.12
Results from a randomized, double-blind, parallel-group, sham-controlled study showed significant pain relief achieved at 2 hours post treatment in 66.7% of patients assigned to the active device compared with 52.5% assigned to usual care (P
Notably, pain-free status at 2 hours post treatment was similar between both groups. As with other devices, some patients enrolled in the pivotal trial reported mild discomfort, namely a sensation of warmth, numbness, or some skin redness at the treatment site.22
The device is unique because it does not require patients to apply treatment to the head or the neck. Its incorporation with a smartphone app allows for real-time recording of treatment, which patients can share with their health care provider.
It is important to note that insurance coverage of neuromodulation devices is variable, and initial out-of-pocket costs can be considerable.23
Some devices require periodic maintenance or prescription renewal to keep the device active. The Cefaly forehead electrode typically lasts up to 10 to 20 uses depending on the device model, with replacement electrodes available for purchase ($25-$33, 3-pack).24
The SpringTMS device includes a pre-programmed SIM card that contains prescription information, which must be renewed and replaced to continue treatment.25
Similarly, gammaCore requires that a monthly prescription refill card be read by the device in order to continue delivering stimulations.26
Overall, neuromodulation devices are an effective alternative to traditional abortive and preventive treatments in patients with contraindications, especially those with cardiovascular risk factors who should avoid treatment with triptans and, in some cases, NSAIDs. Their use as adjunctive therapy is also beneficial for patients whose symptoms are not adequately controlled with traditional treatments and for patients who simply find therapeutic benefit from taking a more active role in their treatment at the time of an attack.
Corrections and Clarifications:
The commentary “Noninvasive Neuromodulation: Finding Its Place in Your Practice" published in the September 2019 issue contained the following errors: incorrectly stated when eNeura received 510(k) clearance from the FDA for its SpringTMS device for the acute treatment of migraine with aura. It was in 2014.6 Also, a subhead was changed to “Transcutaneous Electrical Nerve Stimulation” to properly categorize the Cefaly device.
The following paragraph was rewritten to more clearly define the potential of gammaCore in women who are pregnant based on data from women with epilepsy treated with VNS, and with supporting references:
The gammaCore device is currently not indicated for treatment in women who are pregnant since it was not studied in this population.9 However, data on the use of vagus nerve stimulation in women of childbearing age or who are pregnant who have seizures or epilepsy have so far shown no signal of fetal adverse effects associated with the therapy.20,21 These data, although limited, suggest that vagus nerve stimulation may be a considerable treatment option in women with migraine who are pregnant pending the results of larger safety studies.
A subhead and paragraph were added to provide more context about the cost and convenience-related disadvantages of neuromodulation devices, with supporting references:
It is important to note that insurance coverage of neuromodulation devices is variable, and initial out-of-pocket costs can be considerable.23 Some devices require periodic maintenance or prescription renewal to keep the device active. The Cefaly forehead electrode typically lasts up to 10 to 20 uses depending on the device model, with replacement electrodes available for purchase ($25-$33, 3-pack).24 The SpringTMS device includes a pre-programmed SIM card that contains prescription information, which must be renewed and replaced to continue treatment.25 Similarly, gammaCore requires that a monthly prescription refill card be read by the device in order to continue delivering stimulations.26
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2. Delphine M, Allena M, Bolla M, et al. Central modulation in cluster headache patients treated with occipital nerve stimulation: an FDG-PET study. BMC Neurol
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7. eNeura, Inc. receives FDA clearance for use of SpringTMS for migraine prevention [news release]. Baltimore, MD: eNeura Inc; September 7, 2017. eneura.com/press_releases/eneura-inc-receives-fda-clearance-for-use-of-springtms-for-migraine-prevention/. Accessed August 9, 2019.
8. eNeura, Inc. receives FDA clearance for acute treatment and prevention of migraine in children 12 years of age and older [news release]. Baltimore, MD: eNeura Inc; February 27, 2019. prnewswire.com/news-releases/eneura-inc-receives-fda-clearance-for-acute-treatment-and-prevention-of-migraine-in-children-12-years-of-age-and-older-300803044.html. Accessed August 9, 2019.
9. FDA releases gammaCore, the first non-invasive vagus nerve stimulation therapy applied at the neck for acute treatment of pain associated with episodic cluster headache in adult patients [news release]. Basking Ridge, NJ: electroCore; April 18, 2017. electrocore.com/news/fda-releases-gammacore-the-first-non-invasive-vagus-nerve-stimulation-therapy-applied-at-the-neck-for-acute-treatment-of-pain-associated-with-episodic-cluster-headache-in-adult-patients/. Accessed August 9, 2019.
10. electroCore receives FDA clearance for gammaCore (nVNS) for adjunctive use for the preventive treatment of cluster headache in adults [news release]. Basking Ridge, NJ: electroCore; November 28, 2018. investor.electrocore.com/news-releases/news-release-details/electrocore-receives-fda-clearance-gammacoretm-nvns-adjunctive. Accessed August 9, 2019.
11. gammaCore receives FDA clearance for the acute treatment of pain associated with migraine headache in adult patients [news release]. Basking Ridge, NJ: electroCore, LLC. January 29, 2018. investor.electrocore.com/news-releases/news-release-details/gammacorer-receives-fda-clearance-acute-treatment-pain. Accessed August 9, 2019.
12. FDA grants Theranica de novo to market first smartphone-controlled acute migraine-relief wearable device [news release]. Netanya, Israel: Theranica; May 28, 2019. prnewswire.com/news-releases/fda-grants-theranica-de-novo-to-market-first-smartphone-controlled--acute-migraine-relief-wearable-device-300857281.html Accessed August 9, 2019.
13. Schoenen J, Vandersmissen B, Jeangette S, et al. Migraine prevention with a supraorbital transcutaneous stimulator: a randomized controlled trial. Neurology
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14. Chou DE, Shnayderman Yugrakh M, Winegarner D, Rowe V, Kuruvilla D, Schoenen J. Acute migraine therapy with external trigeminal neurostimulation (ACME): a randomized controlled trial. Cephalalgia
. 2019;39(1):3-14. doi: 10.1177/0333102418811573.
15. Lipton RB, Dodick DW, Silberstein SD, et al. Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a randomised, double-blind, parallel-group, sham-controlled trial. Lancet Neurol.
16. Starling AJ, Tepper SJ, Marmura MJ, et al. A multicenter, prospective, single arm, open label, observational study of sTMS for migraine prevention (ESPOUSE Study). Cephalalgia
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18. Silberstein SD, Mechtler LL, Kudrow DB, et al; ACT1 Study Group. Non-invasive vagus nerve stimulation for the acute treatment of cluster headache: findings from the randomized, double-blind, sham-controlled ACT1 study. Headache
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19. Tassorelli C, Grazzi L, de Tommaso M, et al; PRESTO Study Group. Noninvasive vagus nerve stimulation as acute therapy for migraine: the randomized PRESTO study. Neurology
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20. Rodríguez-osorio X, López-gonzález FJ, Garamendi Í, et al. VNS and pregnancy: A multicentric experience of four cases. Acta Neurol Scand.
2017;136(4):372-374. doi: 10.1111/ane.12780.
21. Suller marti A, Mirsattari SM, Steven DA, et al. Experience on the use of Vagus nerve stimulation during pregnancy. Epilepsy Res
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22. Rapoport AM, Bonner JH, Lin T, et al. Remote electrical neuromodulation (REN) in the acute treatment of migraine: a comparison with usual care and acute migraine medications. J Headache Pain
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23. Non-invasive neuromodulation devices. American Migraine Foundation website. December 14, 2017. americanmigrainefoundation.org/resource-library/non-invasive-neuromodulation-devices/. Accessed August 9, 2019.
24. Cefaly electrode. Cefaly website. cefaly.us/en/cefaly-electrodes. Accessed August 9, 2019.
25. Getting started with the sTMS mini. eNeura website. eneura.com/getting-started-with-the-stms-mini/. Accessed August 9, 2019.
26. gammaCore support. gammaCore website. gammacore.com/patient-support/. Accessed August 9, 2019.