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 associated with fatigue, sleep disturbances, cognitive symptoms, mood alterations, and autonomic dysfunction, leading to substantial impairment in quality of life and daily functioning. Current evidence supports the concept of FMS as a nociplastic pain disorder, in which altered central pain processing and impaired descending pain modulation play a key pathophysiological role. However, increasing evidence suggests that peripheral nervous system involvement and autonomic nervous system dysfunction may also contribute significantly to symptom generation and clinical heterogeneity in this condition.

Several studies have demonstrated that patients with FMS frequently exhibit cardiovascular autonomic dysfunction, characterized by sympathetic nervous system hyperactivity at rest and impaired autonomic adaptive responses during orthostatic challenge. These abnormalities have been documented through heart rate variability (HRV) analysis and other autonomic function tests and have been associated with orthostatic intolerance symptoms, fatigue, and pain severity. In addition, approximately 50% of patients with fibromyalgia show evidence of reduced intraepidermal nerve fiber density on skin biopsy, a condition referred to as small fiber pathology (SFP). Recent findings suggest that small fiber involvement in FMS non è limitato alle piccole fibre somatiche, ma anche alle fibre autonomiche simpatiche post- gangliari. Il ruolo della SFP nella FMS è ancora sconosciuto, tuttavia un recente studio ha dimostrato come la SFP contribuisca alla disfunzione autonomica nella FMS.

Despite the availability of pharmacological and non-pharmacological therapeutic approaches, including antidepressants, gabapentinoids, physical therapy, and psychological interventions, treatment efficacy in FMS remains limited. Consequently, there is growing interest in mechanism-based neuromodulation strategies targeting autonomic dysfunction and central pain modulation pathways.

Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive neuromodulation technique designed to stimulate the auricular branch of the vagus nerve through cutaneous electrical stimulation applied to specific regions of the external ear. By enhancing parasympathetic activity and modulating central autonomic and pain-processing networks, tVNS has emerged as a promising therapeutic strategy for chronic pain disorders and conditions associated with autonomic imbalance. Preliminary studies in FMS suggest that tVNS may improve pain, autonomic symptoms, mood, and quality of life; however, currently available studies are limited by relatively 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 transcutaneous vagus nerve stimulation in female patients with fibromyalgia syndrome and to investigate clinical and biological predictors of treatment response.

Female participants meeting the diagnostic criteria for fibromyalgia according to the 2016 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria will be enrolled and randomized to receive either active tVNS or sham stimulation. Randomization will be computer-generated with variable block sizes in order to ensure allocation concealment and balance between groups throughout the enrollment period. Both participants and outcome assessors will remain blinded to treatment allocation.

The intervention will consist of daily 30-minute stimulation sessions administered for four consecutive weeks using the Nurosym™ device applied at the tragus of the external ear. Participants allocated to the active treatment group will receive standard transcutaneous vagus nerve stimulation, whereas the sham group will undergo identical procedures using a stimulation modality that does not deliver a therapeutic vagal stimulation pattern.

The primary objective of the study is to assess the efficacy 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);
• assessment of the persistence of treatment effects four weeks after treatment discontinuation (T8);
• evaluation of treatment effects during intermediate assessment (T2);
• comparison of treatment response between patients with and without evidence of small fiber pathology on skin biopsy;
• 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);
• evaluation of changes in serum biomarkers potentially associated with autonomic dysfunction and neuroinflammation following tVNS treatment, including neuropeptide Y (NPY), interleukin-6 (IL-6), and neurofilament light chain (NFL);
• identification of clinical and biological predictors of response to tVNS. Clinical assessments will be performed at baseline, during treatment, at the end of treatment, and during follow-up evaluations. Participants will complete validated questionnaires assessing fibromyalgia severity, autonomic symptoms, fatigue, sleep quality, and symptom burden. Cardiovascular autonomic function will be assessed through ECG-derived HRV analysis, including spectral analysis of R-R interval variability. Skin biopsy will be performed at baseline to evaluate intraepidermal nerve fiber density and morphological evidence of small fiber pathology. Blood samples collected at baseline and at the end of treatment will be used for serum biomarker analysis.

Statistical analyses will be conducted according to the intention-to-treat principle. The primary endpoint will be analyzed using mixed-effects models for repeated measures with adjustment for baseline values. Exploratory analyses will evaluate treatment effects on autonomic function parameters and biomarker levels, as well as predictors of clinical response. Additional subgroup analyses will compare treatment response in patients with and without evidence of small fiber pathology.

The study is expected to provide clinically relevant evidence regarding the efficacy and safety of transcutaneous vagus nerve stimulation in fibromyalgia syndrome and to improve understanding of the relationship between autonomic dysfunction, peripheral nervous system involvement, and nociplastic pain mechanisms in this condition. Furthermore, the identification of predictors of response to vagal neuromodulation may contribute to the development of more personalized therapeutic strategies for patients with fibromyalgia.

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.