Non-invasive vagus nerve stimulation for prevention of migraine: The multicenter, randomized, double-blind, sham-controlled PREMIUM II trial

Cephalalgia. 2022 Jun;42(7):560-569. doi: 10.1177/03331024211068813. Epub 2022 Jan 9.


Aim: Evaluate the efficacy and safety of non-invasive vagus nerve stimulation for migraine prevention.

Methods: After completing a 4-week diary run-in period, adults who had migraine with or without aura were randomly assigned to receive active non-invasive vagus nerve stimulation or sham therapy during a 12-week double-blind period.

Results: Of 336 enrolled participants, 113 (active, n = 56; sham, n = 57) completed ≥70 days of the double-blind period and were ≥66% adherent with treatment, comprising the prespecified modified intention-to-treat population. The COVID-19 pandemic led to early trial termination, and the population was ∼60% smaller than the statistical target for full power. Mean reduction in monthly migraine days (primary endpoint) was 3.12 for the active group and 2.29 days for the sham group (difference, -0.83; p = 0.2329). Responder rate (i.e. the percentage of participants with a ≥50% reduction in migraine days) was greater in the active group (44.87%) than the sham group (26.81%; p = 0.0481). Prespecified subgroup analysis suggested that participants with aura responded preferentially. No serious device-related adverse events were reported.

Conclusions: These results suggest clinical utility of non-invasive vagus nerve stimulation for migraine prevention, particularly for patients who have migraine with aura, and reinforce the well-established safety and tolerability profile of this therapy.Trial Registration: (NCT03716505).

Keywords: Neuromodulation; clinical trial; migraine prophylaxis; nonpharmacologic treatment; preventive therapy.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • COVID-19*
  • Double-Blind Method
  • Epilepsy*
  • Humans
  • Migraine Disorders* / drug therapy
  • Migraine Disorders* / prevention & control
  • Pandemics
  • Treatment Outcome
  • Vagus Nerve Stimulation* / adverse effects
  • Vagus Nerve Stimulation* / methods

Associated data