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

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.

Inclusion Criteria: * 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. Exclusion Criteria: * 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; * Carotid artery atherosclerosis; * Chronic kidney disease stage II or higher; * Concomitant immune-mediated rheumatic disease; * Pregnancy; * Active malignancy or previous malignancy not in remission; * Ongoing infection; * Changes in pharmacological treatment within 1 month before enrollment; * Concomitant central or peripheral nervous system disorders, except isolated small-fiber pathology on skin biopsy; * Cognitive impairment detected during neurological examination; * Severe psychiatric comorbidities requiring specific treatment; * Pain caused by other medical conditions that cannot be distinguished from fibromyalgia-related pain; * Current or previous alcohol or substance abuse; * Inadequate understanding of the Italian language.