Neuromodulation and Stimulation Devices Offer Additional Options to Patients With Headache Disorders

Headaches are a frequent complaint in the outpatient setting as well as in the emergency department, with migraine being the most common cause along with cluster headaches. Migraine is a signifi­cantly disabling neurological disease, and its main symptoms include severe headache and a number of other neurological indicators such as nausea, vomiting, and sensitivity to light, sound, and smells.

Migraine can also cause other transient neurological phenomena including numbness, weakness, and tingling on 1 side of the body, as well as difficulty with speech and cognition. Cluster headaches also present with severe pain, usually behind 1 eye, along with autonomic symptoms, which can include eye tearing and rhinorrhea.

Several pharmacotherapies are available for the treatment of migraine and other headache disorders, although recent years have seen a number of stimulation and neuromodulation devices come to market to address this debilitating condition. As many patients with migraine and other disorders are resistant to currently available options, this increase in device development has brought forward additional path­ways to treatment for patients.

Treatment Options

There are 2 main categories of treatment for migraine and cluster headaches: abortive therapy and preventive therapy. Abortive therapy involves medications used during an episode of a migraine or a cluster attack and is usually aimed at treating the symptoms, mainly the head­ache in either case. Triptans and nonsteroidal anti-inflammatory drugs are the 2 largest classes of abortive treatments used in migraine, with triptans also commonly used in cluster headaches.

Preventive therapy, on the other hand, is aimed at the underlying pathophysiology, thought to be central nervous system oversensitiza­tion, which can sometimes extend into the peripheral nervous system as well. The majority of traditional medications in these 2 categories comprise pills and injectable medications.

Even with both of these types of treatments, many patients do not experience full and effective relief from migraine attacks and chronic headaches. The newest line of preventive medications developed for migraine is a class of drugs known as calcitonin gene-related peptide inhibitors, medications specific to migraine that target a molecule believed to be involved in the underlying pathophysiology of migraines. In trials, these medications provided good results, with effective reduc­tion in migraine attacks over a month and few adverse effects (AEs). The results of these trials showed a roughly 50% reduction in the number of migraine days compared with placebo.^1-3

In addition to this new class of medications and the preventive treatment options already available, a couple of new medications as abortive treatments are in trial phases. Yet even with these new medi­cations in the pipeline, a need exists for more effective abortive and preventive medications for better relief of migraine and other primary headaches, including cluster, hemicranias continua, and new daily persistent headache.

To address this need, a number of medical devices that work via nerve stimulation or neuromodulation have been developed (see TABLE). Investigators have explored several targets for modulation and stimu­lation, including the peripheral nervous system, the trigeminal nerve, and the vagus nerve, among others.

Neuromodulation

Neuromodulation has become an increasing trend in the treatment of headaches, especially migraines. It involves the stimulation of the peripheral nervous system and is a noninvasive and reversible form of treatment that has been previously used in the management of other neurological illnesses, including seizures, with some success.⁴

A few neuromodulation devices are available to patients, and most of these devices stimulate peripheral pericranial nerves, including the occipital and supraorbital.⁵ These are the prominent areas that investi­gators believe are hypersensitive in patients with migraine. Another of the neuromodulation techniques targets the vagus nerve.⁶ Most of the available neuromodulation devices are aimed at treating patients with migraine, though 1 device was recently approved by the FDA for use with cluster headaches.^6-8

The available treatments include the Cefaly external trigeminal nerve stimulation (e-TNS) device, ElectroCore’s gammaCore nonin­vasive vagus nerve stimulator (VNS), and the sTMS mini, a transcra­nial magnetic stimulation (TMS) unit by eNeura. The eNeura device was approved by the FDA in December 2013, the Cefaly e-TNS was approved for preventive use in March 2014 and for abortive use in September 2017, and gammaCore was approved for use in migraine in April 2017.

Although investigators are not entirely certain, they believe the treatments work by retrograde modulation of the brainstem nuclei involved in the pathophysi­ology of headaches, specifically migraines.⁹ With the aforementioned devices now available, patients can use most of these treatments at home, with few AEs. The devices can be used as both abortive and preventive therapy as well.

Shirin Issa, MD, a headache specialist at the Center for Healing Neurology in Seattle, Washington, told NeurologyLive that she likes to use “nonmedication devices for acute migraine and cluster [head­aches]” when patients have exhausted other oral medications.

Regarding the devices’ efficacy, Susan Hutchinson, MD, a head­ache specialist and a board-certified family practice physician and the founder of the Orange County Migraine & Headache Center, said she has seen “positive results with all 3 devices” among her patients.

Hutchinson explained that most of her patients who continue with neuromodulation are highly motivated since initiating treatment, adding that about 30% to 50% of patients have had success.

Neuromodulation is also very helpful for particular subsets of patients, Hutchinson further noted, including pregnant women, for whom many of the other treatment options are not safe. Although patients may face difficulty with insurance coverage and prior autho­rization, they can overcome some of these hurdles through free trials offered by the manufacturers.

Occipital Nerve Stimulation

Occipital nerve stimulation has also been found to be effective for the treatment of migraine. Investigators have also found some evidence for its usefulness in other primary headache disorders, such as cluster headaches, hemicrania, and occipital neuralgia.^9,10 However, it is one of the oldest and most invasive of the neuromodulation techniques currently available.¹¹

Investigators believe occipital nerve stimulation works by stimulating the occipital afferent systems at the C2 vertebra of the spinal cord, which then affect the trigeminocervical system. This is the central pain pathway thought to play a prominent role in many of the primary headache syndromes—most pertinently in migraine. As such, occipital nerve stimulators are commonly used for migraines and other chronic headache disorders, which have a large occipital pain component.¹⁰

Occipital nerve stimulation has most often involved implantation of percutaneous occipital leads into the subcutaneous tissue in the region of the greater and lesser occipital nerves. It has been evolving as a treat­ment since 1993, with a number of trials supporting its use since then.

Investigators have conducted a number of trials whose results have shown that occipital nerve stimulation can be helpful in the treatment of chronic migraine, specifically. In 1 of the larger trials, which included 157 patients with chronic migraine, investigators observed that those who used the occipital nerve stimulators showed a significant reduc­tion in the number of headache days compared with sham treatment.¹¹

Given that occipital nerve stimulators are implantable devices, complications involved with the procedure are possible, including lead migration or fractures and surgical site infections. Neurosurgeons usually implant the device, which can then be modulated by neurol­ogists. The device itself is a magnet that can be turned off and on in response to an individual’s symptoms.

Vagus Nerve Stimulation

In 2014, Goadsby et al conducted an open-label, single-arm pilot study to test whether VNS could help with the treatment of migraine. They enrolled 30 patients with migraine who were having between 2 and 15 attacks per month and used the gammaCore device in lieu of an abortive treatment. They additionally collected pain self-assessments. The device provided two 90-second doses of stimulation to the right cervical branch of the vagus nerve, 15 minutes apart.

Results from the study showed that almost half of patients experi­enced pain relief and about 20% were pain-free after 2 hours. VNS also provided relief from some of the associated symptoms, including nausea, photophobia, and phonophobia. There were a few mild AEs.⁶

The FDA cleared gammaCore for acute migraine treatment based on the larger randomized, double-blind, sham-controlled PRESTO trial.¹² The study included 243 patients with migraine, with a sham treatment as control. The gammaCore treatment was significantly superior to sham for pain freedom at 30, 60, and 120 minutes after use. Overall, about 40% of patients found significant relief with the device when used as an abortive treatment compared with the sham device.¹²

GammaCore was then approved for the use of cluster headaches based on data from 2 trials, known as ACT1 and ACT2 clinical trials, that were conducted to determine the safety and efficacy of gammaCore for the acute treatment of episodic cluster headache. Both trials were prospective, double-blind, placebo-controlled, randomized studies, with 85 patients in ACT1 and 27 patients in ACT2.⁷

In the first trial, investigators found that 34.2% of patients with episodic cluster headache experienced a reduction in pain compared with only 10% in the placebo group. In the ACT2 trial, there was also a significant difference in pain for the patients who used the gammaCore as an abortive treatment compared with placebo. The device was also found to be safe and well tolerated in both trials, with only mild and transient AEs during the active treatment.⁸

Transcranial Magnetic Stimulation

TMS was introduced in the 1980s and involves external magnetic stim­ulation to induce electric fields and currents in the brain. Investigators believe that these currents depolarize neurons and influence the excit­ability of the cortex.

There are 2 main types of TMS, single-pulse and repetitive TMS.^12,13 Single-pulse TMS was found to be effective for the acute treatment of migraine with minimal AEs and was approved by the FDA in July 2017. Results from a study showed some benefit for the repetitive use of TMS as preventive therapy for migraine, as well, although further studies are needed to develop a common protocol for its use.¹⁴

In a study of the sTMS mini device, 132 subjects were observed for 4 months, with 1 month to establish baseline headache frequency and 3 months of treatment. The treatment protocol consisted of preven­tive treatment—4 pulses twice daily—and acute treatment—3 pulses at 15-minute intervals, repeated up to 3 times per attack. The results showed that an average reduction of 9.1 headache days per month. Additionally, no serious AEs were reported.¹⁵

Additionally, investigators showed in a second trial in the UK involving patients with medication overuse headache that 86% used less acute medication and 75% reported reduced pain severity.¹⁶

Trigeminal Nerve Stimulation

The Cefaly device is referred to as an e-TNS unit because it targets mainly the supraorbital branches. It can cost up to $300, requires regular replacement of the electrodes, and is recom­mended for daily use for about 2 minutes for effective preventive treatment.^6,13,14

Stephanie Goldberg, MD, a United Council for Neurologic Subspecialties—certified headache specialist and an assistant professor of neurology at Tufts Medical Center, told NeurologyLive™ that she has found the “Cefaly [e-TNS device] to be useful in patients with episodic migraines,” although she admitted that some patients with chronic migraine are unable to tolerate the scalp electrodes because of allodynia.

Investigators conducted 2 studies to demonstrate the Cefaly device’s effectiveness. The first, the PREMICE study, included 67 patients who had at least 2 migraine attacks per month. There was a significant decrease in the number of migraine days per month, with minimal AEs, in the patients who used the Cefaly device.¹⁷ Results from a subsequent larger survey conducted in patients who used the Cefaly device for 40 days showed that a little more than half found it helpful.¹⁸

Although there are no long-term data at this point, given the rela­tively minimal AEs associated with e-TNS, the treatment may be a good alternative for patients who have not done well on other preven­tive medications.

Offering Options

Since the approval of these stimulation and neuromodulation devices, many health providers (mainly headache specialists) have begun to offer them as treatment options for patients with headaches. Although not likely to be first-line treatments, they tend to be offered for patients who have tried other abortive treatments and expe­rienced either no relief or intolerable AEs, or as an adjunct to their existing medications.

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