Noninvasive VNS Promising in Chronic Migraine Prevention

Pauline Anderson

July 22, 2016

Stimulation of the vagus nerve using a noninvasive device is safe and well tolerated in patients with chronic migraine, a new pilot study shows.

And although the study wasn't powered to assess efficacy, it did show that those who completed an open-label phase following a randomization period had a greater reduction in headache days.

The results suggest that "it takes time for the device to work," said lead study author Stephen D. Silberstein, MD, professor, neurology, and director, Headache Center, Thomas Jefferson University, Philadelphia, Pennsylvania.

The EVENT study, funded by electroCore LLC, makers of the device, was published online July 13 in Neurology.

Previous studies have shown the benefits of implanted vagal nerve stimulators in patients with epilepsy and depression. Many of these patients reported that their migraine symptoms improved with the stimulation.

"The idea was to develop a noninvasive device that could be used without surgery," Dr Silberstein told Medscape Medical News.

He added that there are currently very few options for patients with chronic disabling migraine headache. "To have a new device that's safe and effective would be extremely important for these patients."

The new study was carried out at 6 US headache centers between October 2012 and April 2014. It included 59 adult patients diagnosed with chronic migraine with or without aura who had experienced 15 or more headache days a month during the previous 3 months.

The mean patient age was 39.2 years, and the mean headache frequency was 21.5 days a month.

Of the 59 patients, 30 were randomly assigned to noninvasive vagus nerve stimulation (nVNS) and 29 to the sham group.

The study involved three consecutive phases:

  • A 1-month baseline phase to collect pretreatment data and medical history;

  • A 2-month double-blind, randomized, sham-controlled phase during which participants received prophylactic treatment with nVNS or a sham device; and

  • A 6-month open-label phase during which all patients received the nVNS treatment.

The active and sham devices were identical in appearance (a horseshoe shape), weight, visual and audible feedback, and user applications and control. However, only the real VNS devices delivered electrical stimulation.

Each treatment consisted of two 2-minute self-administered stimulations 5 to 10 minutes apart to the right side of the neck. These were delivered three times a day: within 1 hour of awakening, 6 to 8 hours after the first treatment, and 6 to 8 hours after the second treatment.

Participants used a diary to record safety and tolerability information as well as efficacy and satisfaction data.

Results showed the tolerability profile of nVNS was satisfactory and generally similar to that of the sham treatment. Most adverse events (AEs) were mild or moderate and transient. The most commonly reported AEs were upper respiratory tract infections and gastrointestinal symptoms.

During the randomization phase, 6 nVNS-treated patients reported 12 AEs that were related or possibly related to the device, whereas 5 controls reported 8 such AEs. No serious AEs (SAEs) occurred during the randomization phase.

During the open-label phase, 5 patients reported 8 AEs that were related or possibly related to the device. Two reported SAEs (appendicitis and worsening headache) were both seen as unrelated to the device.

Headache Days

At the end of the randomization phase, patients in the nVNS group had a mean change in number of headache days of –1.4 (95% confidence interval [CI], –3.7 to 0.77; P = 0.44). In the control group, the mean change was –0.2 (95% CI, –1.5 to 1.1; P = .72). The mean change from baseline was not statistically different between the two groups (P = .56).

However, longer treatment with nVNS was associated with continued reductions in the number of headache days. At the end of the trial, those assigned to the active treatment had a mean change from baseline of –3.6 (95% CI, –6.3 to –8.7; P = .02) compared with –2.5 (95% CI, –5.0 to –0.04; P = .06) in the sham group after 6 months.

"The study showed that the longer a patient used the device, the better they got, suggesting a change in neuromodulatory behavior in the brain itself," said Dr Silberstein.

He noted that this has also been shown to be the case with epilepsy and depression: the longer the device is used, the better the outcome.

"I think the mistake we made in the trial — we didn't know it at the time — but if we went another month or two, we would have gotten separation," of the two groups, said Dr Silberstein.

The authors noted, however, that the 27 patients who completed the open-label phase and so received longer treatment (16 initially in the nVNS and 11 initially in the sham groups) may have been self-selected.

No True Sham

A problem with sham comparisons, said Dr Silberstein, is that it's impossible to make a perfect or true sham. "How do you control for something that you feel? I don't think anybody knows the answer to that question."

Several patients dropped out of the study. Sixteen in the nVNS group completed the study, as did 11 in the control group.

Dr Silberstein pointed out that migraine treatments — whether a device or a drug or botulinum toxin — work only about half the time.

"If it doesn't work, patients are not going to keep on using it," he said. "It's not unusual for people to drop out of a clinical trial."

Dr Silberstein is optimistic about this noninvasive approach to VNS. Some of his patients "want to run over to England," where the device is available, to get it, he said.

In an accompanying Comment published within the open-access paper, Deborah I. Friedman, MD, Department of Neurology & Neurotherapeutics and Ophthalmology, University of Texas Southwestern Medical Center, Dallas, stressed the need for further studies with a larger sample size and longer treatment phase.

"An effective non-invasive neurostimulation device is an attractive treatment alternative for patients with medically refractory migraine, and for those who are unable to take currently used oral prophylactic treatments," Dr Friedman writes.

Worth the "Hassle"?

Reached for a comment, Elizabeth Loder, MD, chief, Division of Headache and Pain, Department of Neurology, Brigham and Women's Faulkner Hospital, Boston, Massachusetts, said the pilot study is "well done" and "provides very useful information."

She pointed out, though, that it's a very small study, that according to the trial registration (on ClinicalTrials.gov) "safety" was the only prespecified outcome in the trial, and that no details were provided on how safety would be evaluated.

Despite that, the paper includes a "very nice table of adverse events" showing both the number of events and the number of participants who experienced them, said Dr Loder. "This does not raise any serious safety concerns in my mind."

Because safety was the only prespecified outcome, all reported efficacy outcomes are "best considered post-hoc and should be interpreted with great caution," said Dr Loder. "The authors seem aware of this."

Dr Loder said she didn't fully agree with the authors' conclusion that persistent prophylactic use may reduce the number of headache days in patients with chronic migraine. This conclusion, she said, seems to be based on the findings of a statistically significant reduction in headache days in the post hoc subgroup analysis of participants who completed the open-label phase of the study.

"I don't think that information provides a strong basis for inferences about efficacy."

Even making the most optimistic assumption possible — that these open-label findings will be confirmed in future studies — Dr Loder wonders whether in clinical practice the small benefit would be worth the "hassle" of having to use the device three times a day.

"The participants in this trial knew about and accepted this burden as a condition of being in the study, but acceptability in clinical practice would probably be much lower."

She commended the authors for their "careful testing" of blinding. That the blinding was not entirely successful in the sham group "is useful to know and will help in the design and interpretation of any future studies," she said.

 The study was sponsored by electroCore LLC. Dr Silberstein has received honoraria as a consultant and/or advisory panel member from Alder Biopharmaceuticals, Allergan Inc, Amgen Inc, Avanir Pharmaceuticals Inc, Depomed Inc, Dr. Reddy's Laboratories Ltd, electroCore LLC, eNeura Inc, Ipsen Biopharmaceuticals, Medscape LLC, Medtronic Inc, Mitsubishi Tanabe Pharma America Inc, National Institute of Neurologic Disorders and Stroke, St. Jude Medical, Supernus Pharmaceuticals Inc, Teva Pharmaceuticals, and Trigemina Inc. Dr Loder and Dr Friedman have disclosed no relevant financial relationships.

Neurology. Published online July 13, 2016. Full text Comment

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