Transcutaneous Vagus Nerve Stimulation for Pain and Autonomic Dysfunction in Fibromyalgia (RESET-FMS)

Condition(s) studied

Investigational drug(s) / intervention(s)

Transcutaneous Vagus Nerve Stimulation: Transcutaneous vagus nerve stimulation (tVNS) will be delivered using the Nurosym™ device applied at the tragus of the external ear. Participants will undergo one 30-minute stimulation session daily for four consecutive weeks. Stimulation intensity will be individually adjusted until a mild tingling sensation is perceived at the stimulation site. The intervention is designed to activate the auricular branch of the vagus nerve and modulate autonomic nervous system activity and pain-processing pathways.

Sham Transcutaneous Vagus Nerve Stimulation: Sham transcutaneous vagus nerve stimulation will be delivered using the Nurosym™ device applied at the tragus of the external ear. Participants will undergo one 30-minute session daily for four consecutive weeks and will follow the same procedures used for active stimulation, including adjustment of stimulation intensity until a mild tingling sensation is perceived. However, after initiation of the session, the device will automatically reduce stimulation output to zero within a few seconds and will not deliver an active therapeutic vagal stimulation pattern.

Study summary

Fibromyalgia syndrome (FMS) is a chronic pain condition characterized by widespread pain, fatigue, sleep disturbances, cognitive symptoms, and autonomic dysfunction, significantly impairing quality of life. Increasing evidence suggests that, beyond central pain dysregulation, patients with FMS frequently exhibit autonomic nervous system dysfunction, characterized by sympathetic nervous system (SNS) hyperactivity at rest, with reduced SNS recruitment during orthostatic challenge. Moreover, approximately 50% of patients with FMS show reduced intraepidermal small fiber density on skin biopsy, a condition referred to as small fiber pathology (SFP), which has recently been suggested to contribute to autonomic dysfunction in these patients. Despite currently available pharmacological and non-pharmacological treatments, therapeutic efficacy remains limited, highlighting the need for novel mechanism-based interventions.

Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive neuromodulation technique that enhances parasympathetic activity through stimulation of the auricular branch of the vagus nerve. Preliminary studies suggest that tVNS may improve pain, autonomic symptoms, mood, and quality of life in patients with FMS, although available evidence is limited by small sample sizes and heterogeneous methodologies.

The RESET-FMS study is a randomized, sham-controlled, double-blind clinical trial designed to evaluate the efficacy of tVNS in patients with FMS. Participants will be randomized in a 1:1 ratio to receive either active tVNS or sham stimulation for four consecutive weeks. Stimulation will be administered daily for 30 minutes using the Nurosym™ device applied at the tragus of the external ear.

The primary objective is to assess the effect of active tVNS compared with sham stimulation on fibromyalgia severity, measured by the revised Fibromyalgia Impact Questionnaire (rFIQ) at the end of treatment (T4), adjusted for baseline values.

Exploratory objectives include:

* evaluation of autonomic symptoms, fatigue, pain distribution, symptom severity, and sleep quality using validated clinical scales, including the Composite Autonomic Symptom Score (COMPASS-31), Fatigue Severity Scale (FSS), Widespread Pain Index (WPI), Symptom Severity Score (SSS), and Pittsburgh Sleep Quality Index (PSQI) at T4;
* assessment of the persistence of treatment effects four weeks after treatment discontinuation (T8);
* evaluation of treatment effects during intermediate assessments (T2);
* evaluation of the effects of tVNS on non-invasive indices of autonomic nervous system function, including heart rate variability (HRV) and sudomotor function assessed by dynamic sweat test (DST);
* analysis of serum biomarkers potentially associated with autonomic dysfunction, neuroinflammation, and cognitive symptoms, including neuropeptide Y (NPY), interleukin-6 (IL-6), and neurofilament light chain (NFL);
* comparison of treatment response between patients with and without evidence of small-fiber pathology on skin biopsy;
* identification of clinical and biological predictors of response to tVNS. The study is expected to provide clinically relevant evidence regarding the efficacy and safety of tVNS in FMS and to improve the understanding of the relationship between pain modulation, autonomic dysfunction, and peripheral nervous system involvement in this condition. The identification of predictors of treatment response may contribute to the development of more personalized therapeutic strategies for patients with FMS.

Eligibility

Primary outcome measure(s)

• Change in Revised Fibromyalgia Impact Questionnaire (rFIQ) Score at Week 4 — From baseline to end of treatment at Week 4
  The primary outcome measure will be the difference between active transcutaneous vagus nerve stimulation and sham stimulation in the change from baseline to Week 4 in the revised Fibromyalgia Impact Questionnaire (rFIQ) score. The rFIQ is a validated questionnaire assessing the overall impact of fibromyalgia on daily functioning and symptom severity, with higher scores indicating greater disease burden. Questionnaire data will be collected electronically using a REDCap-based application.

Trial sites (1)

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