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.
Diagnosis of fibromyalgia syndrome according to the 2016 ACR/EULAR classification criteria;
Stable pharmacological treatment for at least 1 month before enrollment;
Ability to understand and complete study procedures and questionnaires;
Ability to provide written informed consent.
Presence of an active implantable medical device or any implanted metallic or electronic device near the ear or heart;
History of severe coronary artery disease or myocardial infarction;
Heart failure classified as New York Heart Association (NYHA) class II-IV;
Cardiac arrhythmias or severe bradycardia;
Parallel
Transcutaneous Vagus Nerve Stimulation
DeviceTranscutaneous 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
DeviceSham 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.
Change in Revised Fibromyalgia Impact Questionnaire (rFIQ) Score 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.
Change in COMPASS-31 questionnaire at Week 4
Change from baseline to Week 4 in autonomic symptom burden measured using the Composite Autonomic Symptom Score (COMPASS-31). The questionnaire will be administered electronically through a REDCap-based application. Higher scores indicate greater autonomic symptom severity.
Change in Sudomotor Function at Week 4
Changes in sudomotor function will be assessed using dynamic sweat testing (DST) performed at baseline and Week 4. DST will be used as a non-invasive measure of autonomic small-fiber function by evaluating sweat production and sudomotor responses.
Change in Serum Biomarker Levels at Week 4
Changes in serum biomarkers potentially associated with autonomic dysfunction and neuroinflammation will be assessed between baseline and Week 4. Serum levels of neuropeptide Y (NPY), interleukin-6 (IL-6), and neurofilament light chain (NFL) will be measured using commercially available ELISA assays.
Change in Revised Fibromyalgia Impact Questionnaire (FIQR) Score at Week 2
Change from baseline to Week 2 in fibromyalgia-related health status measured using the Revised Fibromyalgia Impact Questionnaire (FIQR). Higher scores indicate greater disease impact and functional impairment. Questionnaire data will be collected electronically using a REDCap-based application.
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University of Roma La Sapienza
Lead sponsor
Azienda Policlinico Umberto I
Collaborator
