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| Name | Class |
|---|---|
| Azienda Policlinico Umberto I | OTHER |
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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:
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:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
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| Measure | Description | Time Frame |
|---|---|---|
| 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. | From baseline to end of treatment at Week 4 |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Pietro Falco, MD, PhD | Contact | +393462159105 | pietro.falco@uniroma1.it |
| Name | Affiliation | Role |
|---|---|---|
| Andrea Truini, MD, PhD | University of Roma La Sapienza | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Human Neuroscience | Recruiting | Rome | Lazio | 00185 | Italy |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29034226 | Background | 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. | |
| 21812908 | 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. |
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De-identified individual participant data underlying the results reported in this study will be made available upon reasonable request to the corresponding investigator, following publication, for purposes of scientific research and after approval of a methodologically sound proposal.
Beginning 6 months and ending 5 years following article publication.
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.
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| ID | Term |
|---|---|
| D005356 | Fibromyalgia |
| ID | Term |
|---|---|
| D009135 | Muscular Diseases |
| D009140 | Musculoskeletal Diseases |
| D012216 | Rheumatic Diseases |
| D009468 | Neuromuscular Diseases |
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| 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. |
|
| 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. | From baseline to end of treatment at Week 4 |
| 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. | From baseline to the end of Week 4 |
| 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. | From baseline to Week 2 |
| Change in Widespread Pain Index (WPI) Score at Week 4 | Change from baseline to Week 4 in pain distribution measured using the Widespread Pain Index (WPI). Higher scores indicate a greater number of painful body regions. Questionnaire data will be collected electronically using a REDCap-based application. | From baseline to end of treatment at Week 4 |
| Change in Symptom Severity Score (SSS) at Week 4 | Change from baseline to Week 4 in symptom severity measured using the Symptom Severity Score (SSS). Higher scores indicate greater severity of fibromyalgia-related symptoms. Questionnaire data will be collected electronically using a REDCap-based application. | From baseline to end of treatment at Week 4 |
| Change in Pittsburgh Sleep Quality Index (PSQI) Score at Week 4 | Change from baseline to Week 4 in sleep quality measured using the Pittsburgh Sleep Quality Index (PSQI). Higher scores indicate poorer sleep quality. Questionnaire data will be collected electronically using a REDCap-based application. | From baseline to end of treatment at Week 4 |
| Change in Fatigue Severity Scale (FSS) Score at Week 4 | Change from baseline to Week 4 in fatigue severity measured using the Fatigue Severity Scale (FSS). Higher scores indicate greater fatigue severity. Questionnaire data will be collected electronically using a REDCap-based application. | From baseline to end of treatment at Week 4 |
| Change in COMPASS-31 Score at Week 2 | Change from baseline to Week 2 in autonomic symptom burden measured using the Composite Autonomic Symptom Score (COMPASS-31). Higher scores indicate greater autonomic symptom severity. Questionnaire data will be collected electronically using a REDCap-based application. | From baseline to Week 2 |
| Change in Widespread Pain Index (WPI) Score at Week 2 | Change from baseline to Week 2 in pain distribution measured using the Widespread Pain Index (WPI). Higher scores indicate a greater number of painful body regions. Questionnaire data will be collected electronically using a REDCap-based application. | From baseline to Week 2 |
| Change in Symptom Severity Score (SSS) at Week 2 | Change from baseline to Week 2 in the Symptom Severity Score (SSS), a measure of the severity of core fibromyalgia symptoms, including fatigue, unrefreshing sleep, cognitive symptoms, and other somatic symptoms. Higher scores indicate greater symptom severity. Questionnaire data will be collected electronically using a REDCap-based application. | From baseline to Week 2 |
| Change in Pittsburgh Sleep Quality Index (PSQI) Score at Week 2 | Change from baseline to Week 2 in sleep quality measured using the Pittsburgh Sleep Quality Index (PSQI). Higher scores indicate poorer sleep quality. Questionnaire data will be collected electronically using a REDCap-based application. | From baseline to Week 2 |
| Change in Fatigue Severity Scale (FSS) Score at Week 2 | Change from baseline to Week 2 in fatigue severity measured using the Fatigue Severity Scale (FSS). Higher scores indicate greater fatigue severity. Questionnaire data will be collected electronically using a REDCap-based application. | From baseline to Week 2 |
| Change in Revised Fibromyalgia Impact Questionnaire (FIQR) Score at Week 8 | Change from baseline to Week 8 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. | From baseline to Week 8 |
| Change in COMPASS-31 Score at Week 8 | Change from baseline to Week 8 in autonomic symptom burden measured using the Composite Autonomic Symptom Score (COMPASS-31). Higher scores indicate greater autonomic symptom severity. Questionnaire data will be collected electronically using a REDCap-based application. | From baseline to Week 8 |
| Change in Widespread Pain Index (WPI) Score at Week 8 | Change from baseline to Week 8 in pain distribution measured using the Widespread Pain Index (WPI). Higher scores indicate a greater number of painful body regions. Questionnaire data will be collected electronically using a REDCap-based application. | From baseline to Week 8 |
| Change in Symptom Severity Score (SSS) at Week 8 | Change from baseline to Week 8 in the Symptom Severity Score (SSS), a measure of the severity of core fibromyalgia symptoms, including fatigue, unrefreshing sleep, cognitive symptoms, and other somatic symptoms. Higher scores indicate greater symptom severity. Questionnaire data will be collected electronically using a REDCap-based application. | From baseline to Week 8 |
| Change in Pittsburgh Sleep Quality Index (PSQI) Score at Week 8 | Change from baseline to Week 8 in sleep quality measured using the Pittsburgh Sleep Quality Index (PSQI). Higher scores indicate poorer sleep quality. Questionnaire data will be collected electronically using a REDCap-based application. | From baseline to Week 8 |
| Change in Fatigue Severity Scale (FSS) Score at Week 8 | Change from baseline to Week 8 in fatigue severity measured using the Fatigue Severity Scale (FSS). Higher scores indicate greater fatigue severity. Questionnaire data will be collected electronically using a REDCap-based application. | From baseline to Week 8 |
| Change in Total Heart Rate Variability Power at Week 4 | Change from baseline to Week 4 in total heart rate variability power derived from electrocardiogram R-R interval recordings. Total power reflects overall heart rate variability across the analyzed frequency spectrum and is expressed in milliseconds squared (ms²). | From baseline to Week 4 |
| Change in Low-Frequency Heart Rate Variability Power at Week 4 | Change from baseline to Week 4 in low-frequency heart rate variability power derived from electrocardiogram R-R interval recordings. Low-frequency power is expressed in milliseconds squared (ms²). | From Baseline to Week 4 |
| Change in Low-Frequency Heart Rate Variability in Normalized Units at Week 4 | Change from baseline to Week 4 in low-frequency heart rate variability expressed in normalized units (LFnu), derived from electrocardiogram R-R interval recordings. Higher values indicate a greater relative contribution of low-frequency oscillations to heart rate variability. | From baseline to week 4 |
| Change in LF/HF Ratio at Week 4 | Change from baseline to Week 4 in the ratio between low-frequency and high-frequency heart rate variability components (LF/HF ratio), derived from electrocardiogram R-R interval recordings. The LF/HF ratio is a dimensionless measure of sympathovagal balance. | From baseline to week 4 |
| Change in Total Heart Rate Variability Power at Week 8 | Change from baseline to Week 8 in total heart rate variability power derived from electrocardiogram R-R interval recordings. Total power reflects overall heart rate variability across the analyzed frequency spectrum and is expressed in milliseconds squared (ms²). | From baseline to week 8 |
| Change in Low-Frequency Heart Rate Variability Power at Week 8 | Change from baseline to Week 8 in low-frequency heart rate variability power derived from electrocardiogram R-R interval recordings. Low-frequency power is expressed in milliseconds squared (ms²). | From baseline to week 8 |
| Change in Low-Frequency Heart Rate Variability in Normalized Units at Week 8 | Change from baseline to Week 8 in low-frequency heart rate variability expressed in normalized units (LFnu), derived from electrocardiogram R-R interval recordings. Higher values indicate a greater relative contribution of low-frequency oscillations to heart rate variability. | From baseline to week 8 |
| Change in LF/HF Ratio at Week 8 | Change from baseline to Week 8 in the ratio between low-frequency and high-frequency heart rate variability components (LF/HF ratio), derived from electrocardiogram R-R interval recordings. The LF/HF ratio is a dimensionless measure of sympathovagal balance. | from baseline to week 8 |
| 20505378 | 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. |
| 25786044 | 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. |
| 40935122 | 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. |
| 16855138 | 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. |
| 39494473 | 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. |
| 37524221 | 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. |
| 39726855 | 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. |
| 23838093 | 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. |
| 40576705 | 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. |
| 41613157 | 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. |
| D009422 |
| Nervous System Diseases |