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

Abstract

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: ClinicalTrials.gov (NCT03716505).

Neuromodulation for Prevention and Treatment of Headache Disorders

“…73,74 Recently, the results of the PREMIUM II trial were published, which aimed to evaluate the efficacy and safety of nVNS for migraine prevention. 75 Even though the results for the primary endpoint of mean reduction in monthly migraine days did not reach statistical significance, secondary endpoints favoured nVNS. The percentage rate of patients with greater than 50% reduction in migraine days was greater in the treatment group.…”

Migraine: from pathophysiology to treatment

“…Regarding non-invasive vagus nerve stimulation (nVNS), it has shown evidence of efficacy in a RCT for the acute treatment of migraine [211], but not for prevention [212][213][214]. From a mechanistic perspective, this approach at the bench can suppress cortical spreading depression [215] and inhibit trigeminocervical neurons responding to durovascular nociceptive activation [216].…”

Effects on neuromodulation, acupuncture, and aerobic exercises on migraine and tension-type headache outcomes: A systematic review and meta-analysis

“…Another source of high risk of bias was the concealment of allocation protocol. [13,17,18,[29][30][31][35][36][37][38][39][40][41][42] Some trials were open to random allocation and some were alternate enrollment. [18,31,32,34] The Kappa coefficient was 0.63 (P < .001), indicating moderate agreement on the bias analysis between the 2 analysts (PCH and LYL).…”

“…Of the twenty-seven included studies, nineteen investigated the effect of interventions for migraine [13][14][15][16][17][18][19]21,[29][30][31][32][33][34][35][36][37] and 7 for TTH. [23,[38][39][40][41][42] One study [22] investigated both TTH and migraine using separate data analyses.…”

“…[23,[38][39][40][41][42] One study [22] investigated both TTH and migraine using separate data analyses. Fourteen studies focused on acupuncture, [17][18][19]32,33,[37][38][39][40][41][42] 9 on neuromodulation therapy, [13][14][15][16]30,31,35,36,42] and 4 on aerobic exercise. [21][22][23]34] The specific characteristics of the selected studies are described in Table 2.…”