nVNS sham significantly affects the trigeminal-autonomic reflex

Abstract

ObjectiveTo determine whether high placebo effects observed in recently published clinical noninvasive vagal nerve stimulation (nVNS) trials can be attributed to an active modulation of the trigeminal-autonomic reflex by the sham device.MethodsTwenty-eight healthy participants were investigated in a randomized, controlled, single-blind, within-participant design. The 4 different conditions of no stimulation, regular nVNS of the left cervical vagal nerve, stimulation of the posterior neck with the same device (sham I), and stimulation of the left cervical vagal nerve with a sham device (sham II) were applied in randomized order. Parasympathetic output (lacrimation) was provoked with kinetic oscillation stimulation (KOS) of the nasal mucosa. Lacrimation was quantified with the Schirmer II test, an objective measure of lacrimal secretion after local anesthesia, and the difference between baseline and KOS-induced lacrimation served as a measure of autonomic output.ResultsnVNS treatment resulted in a significant reduction of ipsilateral KOS-induced lacrimation compared to no stimulation (p = 0.003) and sham I (p = 0.02). A similar effect was observed for sham II (p = 0.003, p = 0.001). There was no significant difference between nVNS and sham II.ConclusionThese results suggest that both the regular nVNS and the sham device used in some of the clinical nVNS trials modulate the trigeminal-autonomic reflex. This could explain the high sham effect in these trials and suggests that stimulation of the posterior neck may be considered as a real sham condition.

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

“…The International Headache Society–recommended primary outcome for the reduction in migraine days from run-in to 3 months was −2.26 days with nVNS and −2.06 days with supraorbital transcutaneous stimulation (6,33). The clinical benefit of nVNS in this study, which may have been understated because of the partially active effects of the sham device (28), complements the good tolerability and safety profile of nVNS.…”

“…This study had three notable limitations: a) the vagal activity of the sham device, b) the use of bilateral stimulations, and c) suboptimal subject adherence to the TID treatment regimen. Subsequent to the PREMIUM trial, another study revealed parasympathetic activity caused by the sham device used in this study, indicating vagal activation and representing a key limitation of the current study (28). The vagal activity of the sham device likely decreased the therapeutic gain seen in this study.…”

“…Preventive effects of nVNS in episodic migraine were not superior to sham stimulation (ITT). The “sham” device used in this study, however, produced a level of active vagus nerve stimulation (28) that likely affected the therapeutic gain observed in the study. A post hoc analysis demonstrated some significant effects of nVNS for patients with ≥67% adherence to treatment.…”

“…2 weeks of data) for the 4-week run-in period or the last 4 weeks of the 12-week double-blind period were adjusted to reflect an estimated number of days with the outcome of interest per 28-day interval. The adjustment was made using the formula 28 x à y, where x is the number of days with observed data per 28 days and y is the number of observed days with the outcome of interest. If fewer than 21 days of data were observed in the run-in period, the run-in value was not calculated and was considered missing.…”

Non-invasive vagus nerve stimulation for primary headache: A clinical update

“…To increase adherence, the PREMIUM II study includes subjects with a higher overall headache burden than those in the original PREMIUM study, who may be more highly motivated to adhere to the three-times-per-day treatment regimen (43). The sham device used in PREMIUM produced some level of vagal activation (55). A modified inactive sham device has been adopted in the PREMIUM II study to address this issue (43).…”