Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a randomised, double-blind, parallel-group, sham-controlled trial

Summary

Background

Preliminary work suggests that single-pulse transcranial magnetic stimulation (sTMS) could be effective as a treatment for migraine. We aimed to assess the efficacy and safety of a new portable sTMS device for acute treatment of migraine with aura.

Methods

We undertook a randomised, double-blind, parallel-group, two-phase, sham-controlled study at 18 centres in the USA. 267 adults aged 18–68 years were enrolled into phase one. All individuals had to meet international criteria for migraine with aura, with visual aura preceding at least 30% of migraines followed by moderate or severe headache in more than 90% of those attacks. 66 patients dropped out during phase one. In phase two, 201 individuals were randomly allocated by computer to either sham stimulation (n=99) or sTMS (n=102). We instructed participants to treat up to three attacks over 3 months while experiencing aura. The primary outcome was pain-free response 2 h after the first attack, and co-primary outcomes were non-inferiority at 2 h for nausea, photophobia, and phonophobia. Analyses were modified intention to treat and per protocol. This trial is registered with ClinicalTrials.gov, number NCT00449540.

Findings

37 patients did not treat a migraine attack and were excluded from outcome analyses. 164 patients treated at least one attack with sTMS (n=82) or sham stimulation (n=82; modified intention-to-treat analysis set). Pain-free response rates after 2 h were significantly higher with sTMS (32/82 [39%]) than with sham stimulation (18/82 [22%]), for a therapeutic gain of 17% (95% CI 3–31%; p=0·0179). Sustained pain-free response rates significantly favoured sTMS at 24 h and 48 h post-treatment. Non-inferiority was shown for nausea, photophobia, and phonophobia. No device-related serious adverse events were recorded, and incidence and severity of adverse events were similar between sTMS and sham groups.

Interpretation

Early treatment of migraine with aura by sTMS resulted in increased freedom from pain at 2 h compared with sham stimulation, and absence of pain was sustained 24 h and 48 h after treatment. sTMS could be a promising acute treatment for some patients with migraine with aura.

Funding

Neuralieve.

Introduction

Migraine is a primary headache disorder affecting about 18% of women and 6% of men in the USA and western Europe,1, 2 and it consists of two major forms—migraine without aura and migraine with aura.³ Migraine with aura is characterised by reversible focal neurological features that usually precede the onset of headache.³ Usually, symptoms of visual aura include spots of light, zigzag lines, or regions of visual loss (scotomas); non-visual symptoms include somatosensory features (tingling and numbness) and language or motor effects (weakness).⁴ Migraine with aura affects about 20–30% of patients.

The presumed substrate of migraine with aura is cortical spreading depression.5, 6 This effect consists of a wave of excitation followed by a wave of inhibition of both neurons and glia, which spreads across the cortical mantle. Work in animals suggests that cortical spreading depression depolarises meningeal nociceptors giving rise to migraine pain,⁷ and that transcranial magnetic stimulation (TMS) disrupts this depression wave.⁸

TMS is a non-invasive technique that applies a brief magnetic pulse to the scalp and underlying cortex, changing the pattern of neuronal firing. Since its discovery in 1985, it has been used for anatomic brain mapping and for diagnostic and therapeutic purposes.⁹ TMS was tested in individuals with migraine based on the hypothesis that a fluctuating magnetic field delivered by the device, when applied to the back of the head, would induce electrical current and disrupt cortical spreading depression. In view of its ability to disrupt the depression wave, TMS has promise as a non-invasive, non-pharmacological, and safe treatment for migraine.¹⁰ We aimed to assess the efficacy and safety of a novel, portable, single-pulse TMS (sTMS) device for acute treatment of migraine with aura.