LAS VEGAS—Although several trials of neuromodulation strategies for migraine have been conducted, and many more are under way, the accumulated evidence is still scant, and the jury is still out on these treatments, said Stewart Tepper, MD, at the 17th Annual Meeting of the North American Neuromodulation Society. “If we really look at where we stand with the level of evidence on what we’re recommending to our patients, it’s worth looking at the American Academy of Neurology (AAN) standards for what constitutes different classes of studies and also levels of evidence,” Dr. Tepper said.
Four areas of neuromodulation have been studied in migraine: vagal nerve stimulation (VNS), transcranial magnetic stimulation (TMS), sphenopalatine ganglion (SPG) stimulation, and occipital nerve stimulation (ONS). In assessing these treatment strategies, “it is really worth coming back to our levels of evidence and thinking about where we really stand,” said Dr. Tepper, who is Director of Research for the Neurological Center for Pain at the Cleveland Clinic.
Vagal Nerve Stimulation
“The reason we are interested in VNS for primary headache disorders is the relationship of the vagus to the pain matrix,” Dr. Tepper said. “The presumption is that one can stimulate one by stimulating the other.” According to the available evidence, 12 patients with migraine have been implanted, and six of them were responders. “These are case series, that’s it. And the most that you can say about a case series is that it is Level U—it is inadequate evidence so far,” Dr. Tepper said.
He also discussed an open-label study of a noninvasive VNS device for the treatment of migraine. “It was a study, not a case series. It was presented in abstract form. It has not yet been published in peer-reviewed form.” In this open-label study, 26 participants each treated up to four attacks. In total, 79 attacks were treated. The primary outcome measure was two-hour headache relief. A total of 46 of 79 attacks achieved that outcome, 22 of 79 attacks had pain-free outcome, and 20 of the 26 patients responded for at least one treated attack. Among those 20 patients, about three-quarters of the treated headaches responded. Adverse events included transient muscle and local tissue irritation and two reports of light-headedness. Most adverse events resolved as soon as the patient turned off the stimulator or within two hours of treatment.
“If this [treatment] works in a randomized controlled trial, it shifts the paradigm very dramatically for our migraine patients,” Dr. Tepper said. While there is a randomized controlled trial under way for the noninvasive VNS device for chronic migraine, “at this point, the evidence level is U—no randomized controlled trial data in the public domain, and even the open-label study is not fully published.”
Transcranial Magnetic Stimulation
“The way we think TMS works has to do with aura,” Dr. Tepper said. In migraine with aura, the cascade of events that leads to cortical spreading depression is interrupted by TMS. “There were two randomized controlled trials of TMS in migraine,” Dr. Tepper said. One was for acute treatment of migraine with aura—patients had to have at least 30% of their attacks with aura. In this study, at least one attack was treated with TMS, and one attack was treated with sham. The primary outcome measure was two-hour pain free. Close to 40% achieved that outcome with TMS, and only about 20% with sham, a finding that was statistically significant.
“Interestingly, TMS didn’t appear to terminate migraine without aura, suggesting that it may be working on cortical spreading depression and not on the central generator of pain,” Dr. Tepper noted. “However, lest you think this is clear, a preventive trial by Misra et al. published in 2013 was a study of episodic migraine prevention, all comers.” Patients had to have at least four attacks per month. The primary outcomes were diminished headache frequency by at least 50% or diminished headache severity measured by the visual analog scale (VAS) by at least 50%. Secondary outcomes included functional disability and rescue benefit. At one month, TMS decreased the frequency of the migraines by almost 79%, as opposed to 33% for the sham. In addition, VAS scores and functional disability decreased. One patient withdrew due to drowsiness, and two were lost to follow-up.
“The level of evidence for TMS is at least B,” Dr. Tepper said. “You can argue whether these were Class 1 studies, but giving them the benefit of the doubt, the study for acute treatment of migraine would be Level B based on one Class I trial, and the study for prevention of migraine would also be Level B.” He noted, however, that the study of acute treatment was for migraine with aura only, while the prevention study was for all comers. On December 13, 2013, the FDA approved the TMS device used in the acute randomized controlled trial for the indication of acute treatment of migraine with aura.