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

NCT07682090 | Recruiting

• 1 other identifier: RESET-FMS-2026
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Fibromyalgia Syndrome

Outcome Measures

Primary Outcomes (1)

• 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.

  From baseline to end of treatment at Week 4

Other Outcomes (27)

• Change in COMPASS-31 questionnaire at Week 4

  From baseline to end of treatment at Week 4

• Change in Sudomotor Function at Week 4

  From baseline to end of treatment at Week 4

• Change in Serum Biomarker Levels at Week 4

  From baseline to the end of Week 4

Study Arms (2)

Active Transcutaneous Vagus Nerve Stimulation

EXPERIMENTAL

Participants assigned to this arm will receive active transcutaneous vagus nerve stimulation (tVNS) using the Nurosym™ device applied at the tragus of the external ear. Stimulation sessions will last 30 minutes and will be administered once daily for four consecutive weeks. Stimulation intensity will be individually adjusted by participants until a mild tingling sensation is perceived at the stimulation site. The device delivers an active therapeutic vagal stimulation pattern intended to modulate autonomic nervous system activity and pain processing pathways.

Device: Transcutaneous Vagus Nerve Stimulation

Sham Transcutaneous Vagus Nerve Stimulation

SHAM COMPARATOR

Participants assigned to this arm will receive sham transcutaneous vagus nerve stimulation using the Nurosym™ device applied at the tragus of the external ear. Sham stimulation sessions will last 30 minutes and will be administered once daily for four consecutive weeks. Participants will follow the same procedures used for active stimulation, including adjustment of stimulation intensity until a mild tingling sensation is perceived. However, after the session is initiated, the device will automatically reduce stimulation output to zero within a few seconds, without delivering an active therapeutic vagal stimulation pattern.

Device: Sham Transcutaneous Vagus Nerve Stimulation

Interventions

Transcutaneous Vagus Nerve Stimulation DEVICE

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.

Active Transcutaneous Vagus Nerve Stimulation

Sham Transcutaneous Vagus Nerve Stimulation DEVICE

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.

Sham Transcutaneous Vagus Nerve Stimulation

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

• University of Roma La Sapienza: lead
• Azienda Policlinico Umberto I: collaborator

Study Sites (1)

Department of Human Neuroscience

Rome, Lazio, 00185, Italy

RECRUITING

Related Publications (12)

• Shaffer F, Ginsberg JP. An Overview of Heart Rate Variability Metrics and Norms. Front Public Health. 2017 Sep 28;5:258. doi: 10.3389/fpubh.2017.00258. eCollection 2017.

  PMID: 29034226 BACKGROUND

• Lange G, Janal MN, Maniker A, Fitzgibbons J, Fobler M, Cook D, Natelson BH. Safety and efficacy of vagus nerve stimulation in fibromyalgia: a phase I/II proof of concept trial. Pain Med. 2011 Sep;12(9):1406-13. doi: 10.1111/j.1526-4637.2011.01203.x. Epub 2011 Aug 3.

  PMID: 21812908 BACKGROUND

• Beekwilder JP, Beems T. Overview of the clinical applications of vagus nerve stimulation. J Clin Neurophysiol. 2010 Apr;27(2):130-8. doi: 10.1097/WNP.0b013e3181d64d8a.

  PMID: 20505378 BACKGROUND

• Zamuner AR, Barbic F, Dipaola F, Bulgheroni M, Diana A, Atzeni F, Marchi A, Sarzi-Puttini P, Porta A, Furlan R. Relationship between sympathetic activity and pain intensity in fibromyalgia. Clin Exp Rheumatol. 2015 Jan-Feb;33(1 Suppl 88):S53-7. Epub 2015 Mar 18.

  PMID: 25786044 BACKGROUND

• Lommano MG, Farah S, Bianchi B, Risa AM, Sarzi-Puttini P, Salaffi F, Di Carlo M. Non-invasive auricular vagus nerve stimulation in fibromyalgia: Impacts on autonomic function, central sensitization and pain catastrophizing. Joint Bone Spine. 2026 Jan;93(1):105966. doi: 10.1016/j.jbspin.2025.105966. Epub 2025 Sep 9.

  PMID: 40935122 BACKGROUND

• Sarzi-Puttini P, Atzeni F, Diana A, Doria A, Furlan R. Increased neural sympathetic activation in fibromyalgia syndrome. Ann N Y Acad Sci. 2006 Jun;1069:109-17. doi: 10.1196/annals.1351.009.

  PMID: 16855138 BACKGROUND

• Ruggieri M, Paparella G, Clemente L, Libro G, Gargano CD, de Tommaso M. Plasma neurofilament light chain in fibromyalgia: A case control study exploring correlation with clinical and cognitive features. Eur J Pain. 2025 Mar;29(3):e4752. doi: 10.1002/ejp.4752. Epub 2024 Nov 4.

  PMID: 39494473 BACKGROUND

• Falco P, Galosi E, Di Stefano G, Leone C, Di Pietro G, Tramontana L, De Stefano G, Litewczuk D, Esposito N, Truini A. Autonomic Small-Fiber Pathology in Patients With Fibromyalgia. J Pain. 2024 Jan;25(1):64-72. doi: 10.1016/j.jpain.2023.07.020. Epub 2023 Jul 29.

  PMID: 37524221 BACKGROUND

• Sommer C, Uceyler N. Small fiber pathology in fibromyalgia syndrome. Pain Rep. 2024 Dec 24;10(1):e1220. doi: 10.1097/PR9.0000000000001220. eCollection 2025 Feb.

  PMID: 39726855 BACKGROUND

• Meeus M, Goubert D, De Backer F, Struyf F, Hermans L, Coppieters I, De Wandele I, Da Silva H, Calders P. Heart rate variability in patients with fibromyalgia and patients with chronic fatigue syndrome: a systematic review. Semin Arthritis Rheum. 2013 Oct;43(2):279-87. doi: 10.1016/j.semarthrit.2013.03.004. Epub 2013 Jul 6.

  PMID: 23838093 BACKGROUND

• Dolcini G, Favretti M, Franculli D, Buoncuore G, Pellegrino G, Di Carlo M, Sarzi-Puttini P, Conti F, Iannuccelli C, Di Franco M. Vagal nerve stimulation and fibromyalgia: an additional therapeutic option. Clin Exp Rheumatol. 2025 Jun;43(6):1095-1104. doi: 10.55563/clinexprheumatol/johqvo. Epub 2025 Jun 27.

  PMID: 40576705 BACKGROUND

• Falco P, Galosi E, Litewczuk D, Evangelisti E, Di Stefano G, Arendt-Nielsen L, Truini A, Leone CM. Autonomic small fiber involvement in painful long COVID: a histological and clinical study. Front Hum Neurosci. 2026 Jan 14;19:1719705. doi: 10.3389/fnhum.2025.1719705. eCollection 2025.

  PMID: 41613157 BACKGROUND

MeSH Terms

Conditions

Fibromyalgia

Condition Hierarchy (Ancestors)

Muscular Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Neuromuscular Diseases; Nervous System Diseases

Study Officials

• Andrea Truini, MD, PhD

  University of Roma La Sapienza

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Pietro Falco, MD, PhD

CONTACT

+393462159105; pietro.falco@uniroma1.it

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Full Professor of Neurology

Study Record Dates

• First Submitted: June 12, 2026
• First Posted: July 2, 2026
• Study Start: June 8, 2026
• Primary Completion (Estimated): May 25, 2027
• Study Completion (Estimated): September 30, 2027
• Last Updated: July 2, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ANALYTIC CODE
• Time Frame: Beginning 6 months and ending 5 years following article publication.
• Access Criteria: Researchers who provide a methodologically sound proposal. Proposals should be directed to the corresponding investigator. Data will be shared after approval of the proposal and execution of a data access agreement, in accordance with institutional and ethical regulations.

Locations

IT (1)