Non-invasive Vagus Nerve Stimulation for Chronic Musculoskeletal Pain

NCT07409363 | Not Yet Recruiting

• 1 other identifier: 2025-NCT57
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

Chronic musculoskeletal (MSK) pain affects an estimated 20-33% of the global population and is frequently associated with autonomic nervous system dysfunction, characterised by symptoms such as orthostatic intolerance, palpitations, gastrointestinal dysmotility, and fatigue. Conventional treatments often fail to address this autonomic component, limiting their effectiveness. This pilot study investigates whether non-invasive vagus nerve stimulation (nVNS) using the gammaCore Sapphire device can reduce autonomic symptom severity and improve pain in adults with chronic MSK pain and confirmed autonomic dysfunction. RESTORE-MSK is a randomised, single-blind, sham-controlled, crossover pilot study. Twelve participants with chronic MSK pain (lasting 12 weeks or longer) and autonomic dysfunction (COMPASS-31 score of 17 or more) will be recruited from musculoskeletal clinics at Chapel Allerton Hospital, Leeds. Participants will be randomly allocated to receive either active nVNS or sham stimulation first, followed by a 2-week washout period, then crossover to the alternative treatment. Each treatment period lasts 14 days, with participants self-administering the device twice daily (morning and evening). The primary outcome is change in autonomic symptom severity measured by the Composite Autonomic Symptom Score-31 (COMPASS-31). Secondary outcomes include physiological response to the NASA Lean Test, pain severity and interference (Brief Pain Inventory), anxiety and depression (Hospital Anxiety and Depression Scale), quality of life (EQ-5D-5L), intervention acceptability, and recruitment feasibility. This pilot study aims to establish feasibility and proof of concept for a larger randomised controlled trial investigating nVNS as a non-pharmacological treatment option for chronic MSK pain with autonomic dysfunction.

Conditions

Chronic Musculoskeletal Pain; Autonomic Dysfunction; Dysautonomia

Keywords

Vagus Nerve Stimulation; Non-invasive Neuromodulation; Chronic Pain; Autonomic Nervous System; GammaCore; COMPASS-31

Outcome Measures

Primary Outcomes (1)

• Composite Autonomic Symptom Score-31 (COMPASS-31) total score

  Description: The COMPASS-31 is a validated 31-item self-administered questionnaire measuring autonomic symptom severity across six domains: orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor symptoms. Each item is scored based on severity and frequency, with domain scores weighted and summed to produce a total score ranging from 0 to 100. Higher scores indicate greater autonomic dysfunction. The questionnaire will be modified to assess symptoms over the preceding 2 weeks (rather than the standard 1 year) to capture treatment effects within the study timeframe. Measurement: Self-reported questionnaire completed on paper or electronically via REDCap. Primary analysis will compare change from immediately pre-treatment to immediately post-treatment for active versus sham periods.

  Measured at baseline (Day 0), end of first treatment period (Day 15 ±2 days), end of washout/start of second treatment period (Day 28 ±2 days), and end of second treatment period/final visit (Day 43 ±2 days).

Secondary Outcomes (9)

• Positive overall response to the NASA Lean Test procedure

  Measured at baseline (Day 0), end of first treatment period (Day 15 ±2 days, in-person visits only), end of washout (Day 28 ±2 days), and final visit (Day 43 ±2 days, in-person visits only).

• Maximum increase in heart rate during NASA Lean Test procedure

  Measured at baseline (Day 0), end of first treatment period (Day 15 ±2 days, in-person visits only), end of washout (Day 28 ±2 days), and final visit (Day 43 ±2 days, in-person visits only).

• Brief Pain Inventory - Short Form (BPI-SF): Pain Severity Score

  Measured at baseline (Day 0), end of first treatment period (Day 15 ±2 days), end of washout (Day 28 ±2 days), and final visit (Day 43 ±2 days).

• Brief Pain Inventory - Short Form (BPI-SF): Pain Interference Score

  Measured at baseline (Day 0), end of first treatment period (Day 15 ±2 days), end of washout (Day 28 ±2 days), and final visit (Day 43 ±2 days).

• Hospital Anxiety and Depression Scale (HADS): Anxiety subscale score

  Measured at baseline (Day 0), end of first treatment period (Day 15 ±2 days), end of washout (Day 28 ±2 days), and final visit (Day 43 ±2 days).

Other Outcomes (4)

• Recruitment rate: Response to invitation to participate

  Within 1 month of invitation to participate.

• Retention rate

  Determined by completion of the primary outcome measure at last permissible date at end of second treatment period/final visit, assessed up to Day 45.

• Treatment adherence

  During each 14-day treatment period (Days 1-14 and Days 29-42).

Study Arms (2)

Arm 1: Active nVNS then Sham

OTHER

Participants receive active vagus nerve stimulation (intervention)(Days 1-14) followed by 2-week washout (Days 15-28), then subtherapeutic (sham) stimulation (Days 29-42).

Device: Active Vagus Nerve Stimulation; Device: Subtherapeutic Stimulation (Sham Control)

Arm 2: Sham then Active nVNS

OTHER

Participants receive subtherapeutic (sham) stimulation (Days 1-14) followed by 2-week washout (Days 15-28), then active vagus nerve stimulation (intervention)(Days 29-42).

Device: Active Vagus Nerve Stimulation; Device: Subtherapeutic Stimulation (Sham Control)

Interventions

Subtherapeutic Stimulation (Sham Control) DEVICE

Stimulation parameters: The same gammaCore Sapphire device is used, with intensity set at a subtherapeutic level. This produces a perceptible sensation on the skin but does not activate the vagus nerve or cause the muscle contractions associated with therapeutic stimulation.

Also known as: gammaCore Sapphire

Arm 1: Active nVNS then Sham; Arm 2: Sham then Active nVNS

Active Vagus Nerve Stimulation DEVICE

Stimulation parameters: The device delivers a proprietary electrical signal consisting of 5,000 Hz sine wave pulses repeated at 25 Hz. Intensity is set at a therapeutic level as advised by the research clinician, sufficient to activate the vagus nerve and produce perceptible muscle contractions in the neck.

Also known as: gammaCore Sapphire

Arm 1: Active nVNS then Sham; Arm 2: Sham then Active nVNS

Eligibility Criteria

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

You may qualify if:

• Individuals diagnosed with musculoskeletal (MSK) conditions and currently experiencing MSK pain lasting for 12 weeks or longer, in line with the ICD-11 criteria for chronic pain.
• Identified as having autonomic dysfunction (AD) defined as a score of 17 or more on the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire.
• Ability to understand and willingness to sign a written informed consent document.
• Stated willingness to comply with all study procedures and be available for the duration of the study (approximately 6 weeks).
• Ability to read and understand English sufficiently to complete study questionnaires.

You may not qualify if:

• Pregnancy (self-reported; safety of nVNS in pregnancy not established).
• Advanced heart disease, including: severe heart failure (NYHA Class III-IV), myocardial infarction within the preceding 6 months, or ongoing investigations for cardiac arrhythmias.
• Use of an active implantable medical device, including: cardiac pacemaker, implantable cardioverter-defibrillator (ICD), cochlear implant, hearing aid implant, or any other implanted electronic device.
• Concurrent use of another electrical stimulation device, including: transcutaneous electrical nerve stimulation (TENS) unit, muscle stimulator, or any other portable electronic stimulation device.
• Inability to provide informed consent.

Sponsors & Collaborators

• University of Leeds: lead
• The Leeds Teaching Hospitals NHS Trust: collaborator

Study Sites (1)

Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Chapeltown Road, Leeds, LS7 4SA, United Kingdom

Leeds, West Yorkshire, LS7 4SA, United Kingdom

Location

Related Publications (4)

• Sekhon M, Cartwright M, Francis JJ. Development of a theory-informed questionnaire to assess the acceptability of healthcare interventions. BMC Health Serv Res. 2022 Mar 1;22(1):279. doi: 10.1186/s12913-022-07577-3.

  PMID: 35232455 BACKGROUND

• Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983 Jun;67(6):361-70. doi: 10.1111/j.1600-0447.1983.tb09716.x.

  PMID: 6880820 BACKGROUND

• Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singap. 1994 Mar;23(2):129-38.

  PMID: 8080219 BACKGROUND

• Sletten DM, Suarez GA, Low PA, Mandrekar J, Singer W. COMPASS 31: a refined and abbreviated Composite Autonomic Symptom Score. Mayo Clin Proc. 2012 Dec;87(12):1196-201. doi: 10.1016/j.mayocp.2012.10.013.

  PMID: 23218087 BACKGROUND

MeSH Terms

Conditions

Primary Dysautonomias; Autonomic Nervous System Diseases; Chronic Pain

Condition Hierarchy (Ancestors)

Nervous System Diseases; Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Manoj Sivan, Prof

  University of Leeds

  PRINCIPAL INVESTIGATOR

• Darren C Greenwood, PhD

  University of Leeds

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Norah Almutairi

CONTACT

+44 (0)113 392 4396; ml22n2aa@leeds.ac.uk

Manoj Sivan, Prof

CONTACT

+44 (0)113 392 2564; m.sivan@leeds.ac.uk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Participants are blinded to treatment allocation. The same gammaCore Sapphire device is used for both conditions, with intensity adjusted to therapeutic or subtherapeutic levels. A blinding assessment will be conducted at study completion.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Senior Lecturer in Biostatistics

Model Details: Randomised crossover with 2-week washout period between treatment periods. Each participant receives both active nVNS and subtherapeutic (sham) stimulation in randomly allocated

Study Record Dates

• First Submitted: January 30, 2026
• First Posted: February 13, 2026
• Study Start: May 14, 2026
• Primary Completion (Estimated): July 9, 2026
• Study Completion (Estimated): July 31, 2026
• Last Updated: May 11, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: IPD and supporting information will be available after publication of the study results, and for a minimum of 5 years following the end of the study. Approximate start date: 01/01/2027. Approximate end date: 31/06/2032.
• Access Criteria: Who will be able to access the IPD and supporting information? Bona fide clinical or academic researchers affiliated with an established research institution. What will they be able to access? Identifiable individual participant data will not be shared, but anonymised data, with identifiable information removed, may be made available, alongside protocols, questionnaires, consent forms, and other relevant supporting documentation. How will they be able to access it? On reasonable request consistent with consent received and ethical approval given, to the Chief Investigator after publication of study results (m.sivan@leeds.ac.uk).

Locations

GB (1)