nVNS sham significantly affects the trigeminal-autonomic reflex: A randomized controlled study.

OBJECTIVE

To 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.

METHODS

Twenty-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.

RESULTS

nVNS 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.

CONCLUSION

These 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.