Non-Invasive Transcutaneous Vagus Nerve Stimulation for the Treatment of Fibromyalgia Symptoms: A Study Protocol

Andrés Molero-Chamizo, Michael A Nitsche, Armin Bolz, Rafael Tomás Andújar Barroso, José R Alameda Bailén, Jesús Carlos García Palomeque, Guadalupe Nathzidy Rivera-Urbina, Andrés Molero-Chamizo, Michael A Nitsche, Armin Bolz, Rafael Tomás Andújar Barroso, José R Alameda Bailén, Jesús Carlos García Palomeque, Guadalupe Nathzidy Rivera-Urbina

Abstract

Stimulation of the vagus nerve, a parasympathetic nerve that controls the neuro-digestive, vascular, and immune systems, induces pain relief, particularly in clinical conditions such as headache and rheumatoid arthritis. Transmission through vagal afferents towards the nucleus of the solitary tract (NST), the central relay nucleus of the vagus nerve, has been proposed as the main physiological mechanism that reduces pain intensity after vagal stimulation. Chronic pain symptoms of fibromyalgia patients might benefit from stimulation of the vagus nerve via normalization of altered autonomic and immune systems causing their respective symptoms. However, multi-session non-invasive vagal stimulation effects on fibromyalgia have not been evaluated in randomized clinical trials. We propose a parallel group, sham-controlled, randomized study to modulate the sympathetic-vagal balance and pain intensity in fibromyalgia patients by application of non-invasive transcutaneous vagus nerve stimulation (tVNS) over the vagal auricular and cervical branches. We will recruit 136 fibromyalgia patients with chronic moderate to high pain intensity. The primary outcome measure will be pain intensity, and secondary measures will be fatigue, health-related quality of life, sleep disorders, and depression. Heart rate variability and pro-inflammatory cytokine levels will be obtained as secondary physiological measures. We hypothesize that multiple tVNS sessions (five per week, for 4 weeks) will reduce pain intensity and improve quality of life as a result of normalization of the vagal control of nociception and immune-autonomic functions. Since both vagal branches project to the NST, we do not predict significantly different results between the two stimulation protocols.

Keywords: chronic pain; fibromyalgia; transcutaneous; vagus nerve stimulation.

Conflict of interest statement

Michael A. Nitsche is member of the scientific advisory boards of Neuroelectrics and NeuroDevice. Armin Bolz is CEO and owner of tVNS Technologies GmbH, Erlangen. The other authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
tVNS®L device for transcutaneous stimulation of the vagus nerve.
Figure 2
Figure 2
Non-invasive transcutaneous auricular (A) and cervical (B) vagus nerve stimulation will be applied to evaluate the effect of this intervention on fibromyalgia symptoms. Three different electrode montages will be tested: (A) anode positioned over the cymba conchae of the left auricle (verum stimulation) or the left ear lobe (sham) and cathode (return electrode) over the antitragus, (B) anode positioned over the left cervical branch of the vagus nerve in the neck (adjacent to the carotid) (verum stimulation) or two centimeters anterior to this branch (sham) and cathode below the cheek, (C) anode over the left axillary nerve and cathode below the cheek (only verum stimulation, as an added control group). The red circles represent the anode electrode, and the blue circles represent the cathode electrode.
Figure 3
Figure 3
Study design. Measurements refer to primary and secondary outcome measures (FIQR, BPI, PGIC, PSQI, and BDI scores). Heart rate variability will be recorded before and after each tVNS session, and pro-inflammatory cytokine levels (TNF α, IL-1 β, IL-6) will be analyzed before the start of the intervention and after 10 and 20 intervention sessions, as well as 1 week, and 1 month after the end of the intervention. ANS, axillary nerve stimulation at 25 Hz frequency; atVNS, auricular vagus nerve stimulation at 25 Hz frequency; ctVNS, cervical vagus nerve stimulation at 25 Hz frequency; Sham atVNS, auricular vagus nerve stimulation at 1 Hz frequency; Sham ctVNS, cervical vagus nerve stimulation at 1 Hz frequency.

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