Non-invasive vagus nerve stimulation (nVNS) for the preventive treatment of episodic migraine: The multicentre, double-blind, randomised, sham-controlled PREMIUM trial

Abstract

Introduction Non-invasive vagus nerve stimulation (nVNS; gammaCore®) has the potential to prevent migraine days in patients with migraine on the basis of mechanistic rationale and pilot clinical data. Methods This multicentre study included a 4-week run-in period, a 12-week double-blind period of randomised treatment with nVNS or sham, and a 24-week open-label period of nVNS. Patients were to administer two 120-second stimulations bilaterally to the neck three times daily (6–8 hours apart). Results Of 477 enrolled patients, 332 comprised the intent-to-treat (ITT) population. Mean reductions in migraine days per month (primary outcome) were 2.26 for nVNS (n = 165; baseline, 7.9 days) and 1.80 for sham (n = 167; baseline, 8.1 days) ( p = 0.15). Results were similar across other outcomes. Upon observation of suboptimal adherence rates, post hoc analysis of patients with ≥ 67% adherence per month demonstrated significant differences between nVNS (n = 138) and sham (n = 140) for outcomes including reduction in migraine days (2.27 vs. 1.53; p = 0.043); therapeutic gains were greater in patients with aura than in those without aura. Most nVNS device-related adverse events were mild and transient, with application site discomfort being the most common. Conclusions Preventive nVNS treatment in episodic migraine was not superior to sham stimulation in the ITT population. The “sham” device inadvertently provided a level of active vagus nerve stimulation. Post hoc analysis showed significant effects of nVNS in treatment-adherent patients. Study identification and registration: PREMIUM; NCT02378844; https://clinicaltrials.gov/ct2/show/NCT02378844

Alleviation of migraine symptoms by application of repetitive peripheral magnetic stimulation to myofascial trigger points of neck and shoulder muscles – A randomized trial

“…In comparison, rPMS led to a clearer decrease depending on the stimulated muscle, which probably points to a considerably higher improvement in the QoL. In this context, the side effects of rPMS tend to be less severe than those reported for VNS and SONS and, consequently, might result in higher acceptance of rPMS and better satisfaction 39,43,45 .…”

“…Despite these promising first results focusing on the peripheral part of the TCC, further insights into rPMS and its central effects for intervention in migraine are lacking. Comparing rPMS to the latest investigations of other available neuromodulative techniques for intervention in migraine, the reduction of migraine attacks and days suffering from headache are generally in a comparable range 33,36,39,43 . In the ESPOUSE study, single-pulse TMS was applied to the occiput by the study participants twice a day during three months as a prophylactic treatment and also as an acute intervention during any migraine attack occurring in this period of time 33 .…”

“…Furthermore, SONS was applied to the center of the forehead by participants once a day over three months, being capable of reducing headache frequency by 2.8 days per month 39 . Participants deploying VNS three times a day for twelve weeks experienced a decline of 2.3 days with headache per month 43 . In the present study, rPMS applied to the trapezius muscle was able to decrease headache frequency by 2.7 days per month and by 2.2 days per month when applied to the deltoid muscle, respectively.…”

“…Central modulation in migraineurs can be reached by different invasive and non-invasive techniques [26][27][28][29] . Promising examples include transcranial magnetic stimulation (TMS) [30][31][32][33] , transcranial direct current stimulation (tDCS) [34][35][36] , supra-orbital nerve stimulation (SONS) [37][38][39] , and vagus nerve stimulation (VNS) [40][41][42][43] . In addition, repetitive peripheral magnetic stimulation (rPMS) has been introduced recently as a novel method to stimulate the upper trapezius muscles in subjects with migraine, with its application being feasible, well-tolerated, and mostly free of any adverse effects among migraineurs 44 .…”

European headache federation consensus on the definition of resistant and refractory migraine

“…It is also important to note that the present definition did not consider failure to devices or nonpharmacological therapies. A number of studies have shown that vagal nerve stimulation, biofeedback, relaxation, and cognitive behavior therapy are as efficacious for migraine as placebo, but still better than no improvement [54,55]. However, behavioral treatments are less accessible, more professional-dependent and less standardized than pharmacological treatments, and in certain countries, not reimbursed by the Healthcare systems, than pharmacological treatments.…”