Remote Electric Stimulation May Ease Migraine Pain

Pauline Anderson

March 02, 2017

A device that provides remote electrical stimulation via a discreet armband and smartphone application safely reduces pain in patients with migraine, results of a new trial suggests.

The findings suggest that eventually, "it may not be necessary to take drugs to abort a migraine attack," lead author David Yarnitsky, MD, Rambam Healthcare Campus and Technion Faculty of Medicine, Haifa, Israel, told Medscape Medical News.

"There may be healthier and simpler ways to do it that involve fewer side effects," said Dr Yarnitsky, adding that migraine medications often leave patients low on energy.

The blinded, randomized, crossover, sham-controlled trial was published online March 1 in Neurology.

The device used in the study (Nerivio Migra, Theranica Ltd) consists of two rubber adhesive electrodes mounted on an armband with a power source controlled by a custom-made application accessible on a smartphone.

Researchers programmed five 20-minute stimulation protocols into each unit: four active programs at frequencies of 80 to 120 Hz, with pulse widths of 200, 150, 100, and 50 microseconds, and one placebo stimulation protocol (0.1-Hz frequency with 45-microsecond-long pulses).

Tingling Feeling

The stimulation is not meant to be painful. Dr Yarnitsky likened the sensation to sleeping on an arm and waking up with tingling fingers.

The theory is that the tingle, or stimulation on the skin at an intensity lower than pain threshold, activates pain inhibition centers in the brain. This is through the "conditioned pain modulation" effect, where remote noxious stimuli can exert a generalized analgesic effect, say the authors.

Patients were instructed to mount the device on their upper arm and activate it for 20 minutes as soon as possible after the onset of a migraine attack. Upon activation, a program was automatically picked in random order.

Although patients and study personnel were blinded to the order of treatments, as Dr Yarnitsky explained, a fully blinded design would be impossible because patients can feel the stimulations.

Using their smartphone, participants could adjust the stimulation intensity to a level where it was perceivable but not painful. They could use the device for up to 20 migraine attacks.

When using the device, participants were asked to refrain from using medications for 2 hours.

Study patients reported pain levels using the numeric pain scale (NPS) via the smartphone application at onset and at 10, 20, and 120 minutes after stimulation onset.

The primary outcomes were percentage of responders (those reporting a pain decrease of at least 50%) 2 hours after treatment and relative pain reduction on the NPS at 2 hours after treatment as a percentage of pretreatment pain.

The analysis included 71 patients, with 949 treatments of 356 attacks.

The researchers found that the response rate was 46% for the strongest stimulus (200 microseconds) compared with 26% for sham. For the next strongest stimulus (150 microseconds), the response rate was 48%.

While some patients had better response with 150 microseconds and others with 200 microseconds, the study "showed generally that the thinnest [pulse width] was less good and the thickest was better," said Dr Yarnitsky.

When taking all active stimulation protocols together (ie, considering best response per individual), 64% of patients had more than 50% pain reduction in more than half of their treated attacks. This is higher than the 26% response rate for placebo activation (P = .005).

Relative pain reduction for the active stimuli ranged from 16% to 26%, while for the placebo stimulation, the reduction was only 2%.

For patients with moderate or severe pain at baseline, the reduction to mild or no pain at 2 hours was 58% for the strongest stimulation and 24% for the sham.

The study found that pain reduction was highest when the device was activated within the first 20 minutes of an attack onset (mean pain relief of 46.8% compared with 24.9% when applied 20 to 180 minutes later; P = .02).

There was no complete pain relief with treatments started an hour after migraine onset. Placebo stimulation had no effect on time of pain reduction.

This makes sense in that, as the authors noted, it's common wisdom among patients with migraine that a low dose of medication taken immediately upon attack onset is more effective than a higher dose taken during a fully developed attack.

The new results, write the authors, "show a clear advantage of the stimulation protocols over the sham one."

Patients were asked to rate their perceptions of the active treatment. About 11% rated it as painful, 28% as unpleasant, 58% as pleasant, and 4% as very pleasant. For the placebo treatment, the respective rates were 1%, 13%, 61%, and 25%.

The device has several advantages over other forms of stimulation in patients with migraine, such as occipital nerve stimulation, vagal nerve stimulation, and transcranial nerve stimulation, said Dr Yarnitsky.

For one thing, it is remote and so doesn't require implantation of electrodes. It's also discreet and convenient, said Dr Yarnitsky. "If you're in the middle of your working day and feel the start of a migraine, you can just put this under your blouse or sleeve and activate it with your phone; nobody is going to know that you have it."

Dr Yarnitsky hopes that this wireless device will eventually replace drugs, at least for some patients. But before that can happen, researchers need to learn much more about how the device works in individual patients, including, for example, pregnant women.

"This is only one study and so we need more experience before we can make declarations about the end of the era of medications for migraine."

Discussions are under way with the US Food and Drug Administration (FDA) for the protocol of an upcoming pivotal trial, said Dr Yarnitsky. This study could start in about a month, with results available within a year.

Serious Issues?

Asked to comment on the findings, Elizabeth Loder, MD, chief, Division of Headache and Pain, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, said the study had some advantages, including being prospectively registered in an approved trial registry (ClinicalTrials.gov).

Other positive aspects of the trial were that the authors tried to test the treatment rigorously and included a sham protocol, said Dr Loder.

However, she pointed to several issues with this trial. The hypothesis presented to explain the potential benefit of the device — activation of descending inhibitory pathways — "does not make a lot of sense to me," said Dr Loder.

"It is also implausible that a treatment that is comparable to triptans has no side effects." 

Further, information needed to evaluate the quality of the study seems to be missing, she said. "I don't see a sample size calculation or an a priori declaration of what would be a clinically meaningful difference in pain levels. It would be helpful to see results presented as the odds ratios for achieving the primary outcome — on which a sample size calculation was based — with a 95% confidence interval."

The baseline level of pain at the time of treatment seems "rather low," making it unclear how clinically meaningful the results are, said Dr Loder.

"It appears that individual participants could contribute data for multiple headache attacks, but unless I missed it, I cannot tell if any account was made for the fact that results for individuals will be correlated and not independent."

A diagram showing the flow of patients through the study, especially dropout times, and the order in which various interventions were received, would be helpful to understand the study, said Dr Loder.

She also raised the issue of blinding. The findings "strongly suggest that participants in both groups were aware of whether they were receiving active or sham treatment," she said. "In my view, this is a serious threat to the validity of the study results."

Dr Loder said it's "surprising and disappointing" that the authors didn't test the blind by asking participants to guess whether they received active or sham treatment. "The researchers mention this in the discussion but do not interpret the results as cautiously as they should in view of this major problem."

And although the authors asserted that the treatment is safe, "I did not see a table of adverse events," said Dr Loder.

"We are only told that participants were asked to report adverse events to the investigators, so it does not appear that adverse events were rigorously sought. This is another important problem. It is not wise to assume that a device that works through electrical stimulation is necessarily safe."

She pointed to recent reports of skin burns and scars with another electrically based migraine treatment, the Zecuity (Teva) patch (for which the FDA last year issued a safety announcement).

The adverse events with the Zecuity patch were not picked up in clinical trials and did not become apparent until after the device was marketed, noted Dr Loder.

The study was sponsored by Theranica Ltd. Dr Yarnitsky serves on the Medical Advisory Board of Theranica Ltd. Dr Loder has disclosed no relevant financial relationships.

Neurology. Published online March 1, 2017. Abstract

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