By Ellen Feldman, MD
Altru Health System, Grand Forks, ND
Dr. Feldman reports no financial relationships relevant to this field of study.
- This was a prospective, non-randomized, observational study initially involving 263 patients recruited from headache clinics.
- After completing a one-month headache diary, all eligible subjects were given a portable sTMS device and instructed to apply four pulses to occiput twice daily for prevention and three consecutive pulses for breakthrough headaches.
- There was no sham or placebo arm; instead, the authors used a statistically derived placebo calculation based on several previous studies to evaluate results.
- When compared with baseline, there was a mean reduction in number of headache days of 2.75 during the month-long study period, which was significantly lower than the statistically derived placebo response (P < 0.001).
This observational study adds evidence for daily use of single-pulse, transcranial stimulation (sTMS) for the prevention of migraines.
Starling AJ, Tepper SJ, Marmura MJ, et al. A multicenter, prospective, single arm, open label, observational study of sTMS for migraine prevention (ESPOUSE Study). Cephalagia 2018;38:1038-1048.
Described in 2006 as a “forgotten epidemic,” historically, migraine has been both underdiagnosed and underestimated as a major contributor to public health problems.1 With improved recognition and newer techniques for gathering and analyzing data, the 2016 Global Burden of Disease study bestowed on migraine the dubious distinction of being ranked as the number one cause of disability worldwide in persons between the ages of 15 and 49 years.2
Despite this heightened recognition, treatment and prevention lag behind. Tolerability and efficacy issues interfere with adherence to medication regimen. Current estimates are that over a period of one year, 80% of patients with chronic migraine fail to comply with preventive medication as prescribed or directed. Many patients have reported a desire for nonpharmacologic, noninvasive, and effective treatments to address this problem.3
Single-pulse transcranial magnetic stimulation (sTMS) offers patients with migraine an alternative to traditional psychopharmacological intervention. Starling et al instructed patients to apply electrical current or pulse outside the scalp on the occiput. The devices used were small, portable, and simple enough to be used safely within a home setting and without a provider’s direct supervision.
The idea is that electromagnetic induction allows current to be carried into cortical areas. Animal models have demonstrated that sTMS changes the electrical environment of neurons. Among other effects, sTMS modulates some nociceptive neurons and inhibits cortical spreading depression thought to be key in development of aura in migraines.4 The initial 2017 FDA approval for this device was for the acute treatment of migraines with aura.5 Starling et al conducted this study to provide evidence to extend and broaden the FDA approval to include migraine prevention with or without aura.
Potential participants ages 18 to 65 years were recruited from headache clinics and spent the initial month of the study completing a baseline headache diary. Of 263 subjects, 217 met eligibility criteria to participate in the study and were given sTMS devices. Notably, while a minimum number of four headache days/month was required for inclusion in this study, the presence or absence of aura was not a factor.
There was some attrition and further exclusions from this group, eventually leaving 117 subjects. The majority of the exclusions were due to participants not meeting more nuanced criteria for number of headache days.
The 117 remaining subjects completed a three-month headache diary while using the sTMS device as instructed — four pulses to occiput twice daily for prevention and three pulses consecutively when necessary, with the ability to repeat the three pulses up to three times. Acute medication was permitted to be used if a headache remained 30 minutes after the first of the three acute pulses, and preventive medications were permitted to be continued.
The primary outcome measured was a reduction in the number of headaches compared to the statistically derived placebo response or “performance goal.” The percentage of participants with a > 50% reduction in headache days also was measured. The performance goal was calculated based on three other migraine studies (two with topiramate and one with a device) conducted with a similar population to that used by Starling et al. Results are shown in Table 1 and indicate both a significant reduction in mean number of headache days and that 46% of subjects recorded at least a 50% reduction in headache days. In addition, subjects showed a mean reduction in the Headache Impact (HIT-6) questionnaire of 3.10 (P < 0.0001) and a reduction in acute medication use measured in days of -2.93 (P < 0.0001).
Table 1: Selected Results
|
| |
Subjects
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Calculated placebo or “performance goal”
|
P value
|
|
Mean number of headache days
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-2.45 (9.06 days at baseline)
|
-0.63
|
P < 0.0001
|
|
Percentage of subjects with at least 50% reduction in headache days
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46%
|
20%
|
P < 0.0001
|
Adverse effects were evaluated closely. Of the 62 side effects reported, 16 were believed to be unrelated to the device, 30 were deemed possibly related to the device, and 12 were deemed definitely related to the treatment. None of the side effects, which included lightheadedness, tingling, scalp discomfort, and difficulty tolerating noise from the device, were thought to be serious. Nine participants dropped out of the study because of side effects.
COMMENTARY
The results of the Starling et al study, along with observational data from a U.K. study and results from a previous randomized, controlled study, led to an extension of the initial 2014 FDA approval for sTMS in the treatment of migraine with aura to prevention and acute treatment of migraine with and without aura. Currently, FDA approval for sTMS in migraines is limited to a specific device — the SpringTMS made by eNeura Therapeutics.5 Starling et al also used this device in their study.
Clearly, a simple, easy-to-administer, and effective preventive intervention for migraine is needed to combat the significant disability stemming from repetitive migraines. Migraine prevalence peaks during childbearing years; disability in this demographic is particularly worrisome because of the effect on family life and employment. A robust preventive treatment could have important “trickle-down” effects and significant public health implications.2
Conventional prophylactic migraine treatment includes medications such as anticonvulsants (topiramate and Depakote) or beta-blockers, which have varying efficacy and significant side effects. Studies show about a 50% discontinuation of preventive medication within 60 days and up to 85% noncompliance with preventive treatment by the end of 12 months.3 Although data from the Starling study regarding compliance are encouraging, it is notable that the data collection ended at week 12. It is hoped that investigataors will plan longer-term studies to determine if the pattern of noncompliance with preventive medications is reversed with the sTMS device.
Integrative methods of addressing migraine prevention include dietary modification, acupuncture, sleep hygiene, hydration, and some supplements. The efficacy of these interventions was not addressed in this study; a head-to-head comparison could be both informative and useful.6 Certainly, the lack of a true sham device or placebo arm make the results of this study somewhat less compelling. Although the reasoning for the study design is explained, Starling et al noted this as a relative weakness. Future studies should include a true randomized sample with a control group.
The cost and availability of the device will be a factor for many prospective patients. Insurance may require steps before approval, and it is not clear that any insurance plans will cover the device. The company offers an array of financial information on its website. With a $300 discount for new patients, the initial cost to rent a device is $450 for the first three months. Rentals can be arranged online with a convenient, downloadable form completed by a provider. The device comes with a SIM card that can be replaced when a prescription is renewed. There is also an online migraine diary for patients to track progress, and clinical education support specialists are available for consultation.7
The website offers a glimpse into a relatively new manner of reaching patients with medical information and offering treatment. There is a section for healthcare professionals and a link to obtain information on a certification process to prescribe the device. The bulk of the site appears devoted to marketing, education, and support for patients who desire to use the device. The commercialization of the prescribing process may be a barrier for some, but could be comfortable and convenient for others.
Notably, this device has not been studied or approved for children. Long-term effects are unknown. Contraindications to its use include the presence of any implanted device that could be affected by a magnetic field, including but not limited to metallic heart valves, stents, and plates.
The Starling et al study is interesting and provides an exploration of some of the evidence presented to FDA in approving and extending indications for use of the sTMS device to migraine prevention. Patients are very likely to ask about the device. Providers can assist in interpreting evidence, explaining limitations, and helping patients weigh risks and benefits. There is a secondary gain inherent in obtaining this information directly from the makers of the device; this may make some prospective users (and prescribers) wary or uneasy. A neutral medical provider who knows the patient and understands a holistic medical picture is a particularly valuable partner under these circumstances. Understanding that sTMS may help reduce the prevalence of migraines, that acute medication still may be needed, that there are specific contraindications, and that the long-term effect is unknown are important points for patients and providers to discuss as part of a comprehensive wellness plan.
REFERENCES
- Diener HC, Steiner TJ, Tepper SJ. Migraine – the forgotten epidemic: Development of the EHF/WHA Rome Declaration on Migraine. J Headache Pain 2006;7:433-437.
- GBD 2016. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet 2017;390:1211-1259.
- Chin JH, Vora N. The global burden of neurologic diseases. Neurology 2014;83:349-351.
- Bhola R, Kinsella E, Giffin N, et al. Single-pulse transcranial magnetic stimulation (sTMS) for the acute treatment of migraine: Evaluation of outcome data for the UK post market pilot program. J Headache Pain 2015;16:535.
- U.S. Food and Drug Administration. Treating Migraines: More Ways to Fight the Pain. Available at: https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm414707.htm. Accessed May 14, 2018.
- Millstine D, Chen CY, Bauer B. Complementary and integrative medicine in the management of headache. BMJ 2017;357:j1805.
- eNeura. Available at: http://www.eneura.com/. Accessed May 10, 2018.
