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

Fibromyalgia syndrome (FMS) is a chronic pain condition characterized by widespread painassociated with fatigue, sleep disturbances, cognitive symptoms, mood alterations, andautonomic dysfunction, leading to substantial impairment in quality of life and dailyfunctioning. Current evidence supports the concept of FMS as a nociplastic pain disorder,in which altered central pain processing and impaired descending pain modulation play akey pathophysiological role. However, increasing evidence suggests that peripheralnervous system involvement and autonomic nervous system dysfunction may also contributesignificantly to symptom generation and clinical heterogeneity in this condition.Several studies have demonstrated that patients with FMS frequently exhibitcardiovascular autonomic dysfunction, characterized by sympathetic nervous systemhyperactivity at rest and impaired autonomic adaptive responses during orthostaticchallenge. These abnormalities have been documented through heart rate variability (HRV)analysis and other autonomic function tests and have been associated with orthostaticintolerance symptoms, fatigue, and pain severity. In addition, approximately 50% ofpatients with fibromyalgia show evidence of reduced intraepidermal nerve fiber density onskin biopsy, a condition referred to as small fiber pathology (SFP). Recent findingssuggest 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 FMSè ancora sconosciuto, tuttavia un recente studio ha dimostrato come la SFP contribuiscaalla disfunzione autonomica nella FMS.Despite the availability of pharmacological and non‐pharmacological therapeuticapproaches, including antidepressants, gabapentinoids, physical therapy, andpsychological interventions, treatment efficacy in FMS remains limited. Consequently,there is growing interest in mechanism‐based neuromodulation strategies targetingautonomic dysfunction and central pain modulation pathways.Transcutaneous vagus nerve stimulation (tVNS) is a non‐invasive neuromodulation techniquedesigned to stimulate the auricular branch of the vagus nerve through cutaneouselectrical stimulation applied to specific regions of the external ear. By enhancingparasympathetic activity and modulating central autonomic and pain‐processing networks,tVNS has emerged as a promising therapeutic strategy for chronic pain disorders andconditions associated with autonomic imbalance. Preliminary studies in FMS suggest thattVNS may improve pain, autonomic symptoms, mood, and quality of life; however, currentlyavailable studies are limited by relatively small sample sizes and heterogeneousmethodologies.The RESET‐FMS study is a randomized, sham‐controlled, double‐blind clinical trialdesigned to evaluate the efficacy of transcutaneous vagus nerve stimulation in femalepatients with fibromyalgia syndrome and to investigate clinical and biological predictorsof treatment response.Female participants meeting the diagnostic criteria for fibromyalgia according to the2016 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR)classification criteria will be enrolled and randomized to receive either active tVNS orsham stimulation. Randomization will be computer‐generated with variable block sizes inorder to ensure allocation concealment and balance between groups throughout theenrollment period. Both participants and outcome assessors will remain blinded totreatment allocation.The intervention will consist of daily 30‐minute stimulation sessions administered forfour consecutive weeks using the Nurosym™ device applied at the tragus of the externalear. Participants allocated to the active treatment group will receive standardtranscutaneous vagus nerve stimulation, whereas the sham group will undergo identicalprocedures using a stimulation modality that does not deliver a therapeutic vagalstimulation pattern.The primary objective of the study is to assess the efficacy of active tVNS compared withsham stimulation on fibromyalgia severity, measured by the revised Fibromyalgia ImpactQuestionnaire (rFIQ) at the end of treatment (T4), adjusted for baseline values.Exploratory objectives include: ‐ evaluation of autonomic symptoms, fatigue, pain distribution, symptom severity, andsleep quality using validated clinical scales, including the Composite AutonomicSymptom 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 treatmentdiscontinuation (T8); ‐ evaluation of treatment effects during intermediate assessment (T2); ‐ comparison of treatment response between patients with and without evidence of smallfiber pathology on skin biopsy; ‐ evaluation of the effects of tVNS on non‐invasive indices of autonomic nervoussystem function, including heart rate variability (HRV) and sudomotor functionassessed by dynamic sweat test (DST); ‐ evaluation of changes in serum biomarkers potentially associated with autonomicdysfunction 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. Clinicalassessments will be performed at baseline, during treatment, at the end oftreatment, and during follow‐up evaluations. Participants will complete validatedquestionnaires assessing fibromyalgia severity, autonomic symptoms, fatigue, sleepquality, and symptom burden. Cardiovascular autonomic function will be assessedthrough ECG‐derived HRV analysis, including spectral analysis of R‐R intervalvariability. Skin biopsy will be performed at baseline to evaluate intraepidermalnerve fiber density and morphological evidence of small fiber pathology. Bloodsamples collected at baseline and at the end of treatment will be used for serumbiomarker analysis.Statistical analyses will be conducted according to the intention‐to‐treat principle. Theprimary endpoint will be analyzed using mixed‐effects models for repeated measures withadjustment for baseline values. Exploratory analyses will evaluate treatment effects onautonomic function parameters and biomarker levels, as well as predictors of clinicalresponse. Additional subgroup analyses will compare treatment response in patients withand without evidence of small fiber pathology.The study is expected to provide clinically relevant evidence regarding the efficacy andsafety of transcutaneous vagus nerve stimulation in fibromyalgia syndrome and to improveunderstanding of the relationship between autonomic dysfunction, peripheral nervoussystem involvement, and nociplastic pain mechanisms in this condition. Furthermore, theidentification of predictors of response to vagal neuromodulation may contribute to thedevelopment of more personalized therapeutic strategies for patients with fibromyalgia.