Chronic Musculoskeletal PainRESTORE-MSKNCT07409363
Non-invasive Vagus Nerve Stimulation for Chronic Musculoskeletal Pain
A study testing Active Vagus Nerve Stimulation in people with Chronic Musculoskeletal Pain and Autonomic Dysfunction, run by University of Leeds at 1 site in United Kingdom.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Chronic Musculoskeletal Pain, Autonomic Dysfunction, Dysautonomia
- What is being tested?
- Active Vagus Nerve Stimulation
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 12 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 14 May 2026to 31 Jul 2026
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United Kingdom1 site
Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Chapeltown Road, Leeds, LS7 4SA, United Kingdom
Leeds, West Yorkshire, LS7 4SA
Norah Almutairi, +44 (0)113 392 4396, ml22n2aa@leeds.ac.uk
About this study
Official title: A Randomised, Single-blind, Sham-controlled, Crossover Pilot Study Assessing the Effect of Non-invasive Vagus Nerve Stimulation (nVNS) on Autonomic Symptoms and Pain Management in Patients With Chronic Musculoskeletal Pain and Autonomic Dysfunction
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).
Read more
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.
Read the detailed description
BACKGROUND: Musculoskeletal pain affects approximately 1.75 billion individuals worldwide. In the United Kingdom alone, chronic pain is reported in at least 28 million individuals. Chronic musculoskeletal pain (CMP) may arise from physical injury, muscular overuse, inflammatory processes, or degenerative changes, and is frequently associated with comorbid conditions such as fibromyalgia, osteoarthritis, and rheumatoid arthritis.
Emerging evidence suggests that autonomic dysfunction (AD), described as altered sympathetic nervous system reactivity, has been implicated in the pathogenesis of chronic pain. Despite this, conventional therapies often fail to address the autonomic component. Non-invasive vagus nerve stimulation (nVNS) offers a non-pharmacological means to influence autonomic tone and central pain processing, with studies demonstrating analgesic effects across conditions including fibromyalgia, chronic pelvic pain, and migraine.
The GammaCore device is a CE-marked, non-invasive vagus nerve stimulator approved for primary headaches and supported by NICE for migraine and cluster headache treatment. However, its therapeutic potential in chronic MSK pain with autonomic dysfunction remains underexplored.
STUDY DESIGN: This is a randomised, single-blind, sham-controlled, crossover pilot study conducted at a single site (Chapel Allerton Hospital, Leeds). The crossover design allows each participant to serve as their own control, enhancing statistical efficiency in this small feasibility study.
INTERVENTION: Participants will self-administer the GammaCore device bilaterally under the angle of the mandible, guided by the carotid pulse. Each stimulation consists of a two-minute application per side. Participants will complete two stimulations per day (morning and evening) for two 14-day treatment periods, separated by a 2-week washout period. The same device is used with intensity set at subtherapeutic level.
RANDOMISATION: Participants will be randomly assigned to one of two treatment sequences: (A) Active stimulation followed by sham, or (B) Sham followed by active stimulation. Randomisation will be stratified by baseline COMPASS-31 score (<40 vs 40+) and implemented via REDCap.
BLINDING: This is a single-blind study where participants are blinded to treatment allocation. A blinding assessment will be conducted at study completion.
- Being tested
- Active Vagus Nerve Stimulation, Subtherapeutic Stimulation (Sham Control)
- Keywords
- Vagus Nerve Stimulation, Non-invasive Neuromodulation, Chronic Pain, Autonomic Nervous System, GammaCore, COMPASS-31
- Medical subject headings
- Primary Dysautonomias, Autonomic Nervous System Diseases, Chronic Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Active Vagus Nerve StimulationDevice
Also called gammaCore Sapphire
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.
Subtherapeutic Stimulation (Sham Control)Device
Also called gammaCore Sapphire
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.
| Study group | Role | What they receive |
|---|---|---|
| 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). Receives: 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). Receives: Device: Active Vagus Nerve Stimulation; Device: Subtherapeutic Stimulation (Sham Control) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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: 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
The NASA Lean Test procedure is a clinical assessment of autonomic function measuring cardiovascular response to postural change. It provides a single binary outcome of positive or negative response to the challenge.
A positive response (indicating autonomic dysfunction) is defined as an increase in heart rate of more than 30 beats per minute (or more than 40 bpm in participants under 20 years) from supine to standing without a substantial drop in blood pressure, over the course of 10 minutes' observation.
A negative response (indicating no evidence of autonomic dysfunction) is when the above criteria have not been met.
Measured: 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
As part of the NASA Lean Test to identify a positive/negative response to the Lean Test challenge, heart rate is monitored continuously over a 10 minute period. We shall report the maximum increase in heart rate (beats per minute) from supine to standing, over the course of 10 minutes' observation, as an additional outcome measure that may offer insight on symptomatic individuals who do not meet the threshold for a positive Lean Test.
Measured: 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
Description: The BPI-SF is a validated self-report questionnaire assessing pain intensity and interference. The Pain Severity Score is calculated as the mean of four items: worst pain in last 24 hours, least pain in last 24 hours, average pain, and pain right now. Each item is rated on a 0-10 numeric rating scale where 0 = no pain and 10 = pain as bad as you can imagine. The Pain Severity Score therefore ranges from 0 to 10, with higher scores indicating greater pain severity.
Measurement: Self-reported questionnaire completed on paper or electronically via REDCap.
Measured: 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
Description: The Pain Interference Score is calculated as the mean of seven items assessing how much pain has interfered with: general activity, mood, walking ability, normal work (including housework), relations with other people, sleep, and enjoyment of life. Each item is rated on a 0-10 numeric rating scale where 0 = does not interfere and 10 = completely interferes. The Pain Interference Score therefore ranges from 0 to 10, with higher scores indicating greater interference with daily functioning.
Measurement: Self-reported questionnaire completed on paper or electronically via REDCap.
Measured: 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
Description: The HADS is a validated 14-item self-report questionnaire designed to assess anxiety and depression in medical populations. The Anxiety subscale comprises 7 items, each scored 0-3, producing a total anxiety score ranging from 0 to 21. Scores of 0-7 indicate non-cases, 8-10 indicate possible cases, and 11-21 indicate probable cases of anxiety disorder. Higher scores indicate greater anxiety symptom severity.
Measurement: Self-reported questionnaire completed on paper or electronically via REDCap.
Measured: 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): Depression subscale score
Description: The Depression subscale of the HADS comprises 7 items, each scored 0-3, producing a total depression score ranging from 0 to 21. Scores of 0-7 indicate non-cases, 8-10 indicate possible cases, and 11-21 indicate probable cases of depression. Higher scores indicate greater depression symptom severity.
Measurement: Self-reported questionnaire completed on paper or electronically via REDCap.
Measured: 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).
EuroQol EQ-5D-5L: Index value
Description: The EQ-5D-5L is a validated generic health-related quality of life instrument comprising five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels of severity (no problems, slight problems, moderate problems, severe problems, unable to/extreme problems). Responses are converted to a single index value using UK value set tariffs, ranging from negative values (states worse than dead) through 0 (dead) to 1 (full health). Higher values indicate better health-related quality of life.
Measurement: Self-reported questionnaire completed on paper or electronically via REDCap.
Measured: 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).
EuroQol EQ-5D-5L: Visual Analogue Scale (EQ-VAS)
Description: The EQ-VAS records the participant's self-rated health on a vertical visual analogue scale with endpoints labelled 'The best health you can imagine' (100) and 'The worst health you can imagine' (0). Participants mark their health state on the scale and record the corresponding number.
Measurement: Self-reported on paper or electronically via REDCap.
Measured: 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).
Intervention acceptability: Theoretical Framework of Acceptability (TFA) questionnaire
Description: The TFA is a validated, theory-informed questionnaire assessing intervention acceptability across seven constructs: affective attitude (how the participant feels about the intervention), burden (perceived effort required), ethicality (fit with personal values), intervention coherence (understanding of how the intervention works), opportunity costs (extent to which benefits were given up), perceived effectiveness (perception that the intervention works), and self-efficacy (confidence in performing required behaviours). Each construct is assessed using a single item on a 5-point Likert scale (1 = strongly disagree to 5 = strongly agree), plus one overall acceptability item. Higher scores indicate greater acceptability.
Measurement: Self-reported questionnaire completed on paper or electronically via REDCap.
Measured: Measured once at final visit (Day 43 ±2 days).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Feb 2026
- Study start14 May 2026 (estimated)
- Primary completion9 Jul 2026 (estimated)
- Study completion31 Jul 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Chronic Musculoskeletal PainStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Randomised crossover with 2-week washout period between treatment periods. Each participant receives both active nVNS and subtherapeutic (sham) stimulation in randomly allocated
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 12 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Leeds
- Sponsor type
- University, hospital or other
- Collaborators
- The Leeds Teaching Hospitals NHS Trust
- Responsible party
- Principal investigator, Darren Greenwood, University of Leeds
- Investigators
- Manoj Sivan, Prof, Principal investigator, University of LeedsDarren C Greenwood, PhD, Principal investigator, University of Leeds
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07409363
- Sponsor's protocol ID
- 2025-NCT57
- Acronym
- RESTORE-MSK
- Status last verified
- May 2026
- First submitted
- 30 Jan 2026
- Last updated
- 11 May 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Identifiable individual participant data will not be shared, but anonymised data, with identifiable information removed, may be made available to researchers upon reasonable request consistent with consent received and ethical approval given, to the Chief Investigator after publication of study results.
Publications
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.
PubMed 35232455Zigmond 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.
PubMed 6880820Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singap. 1994 Mar;23(2):129-38.
PubMed 8080219Sletten 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.
PubMed 23218087
Study at a glance
From the registry record, last updated by the sponsor on 11 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomised, Single-blind, Sham-controlled, Crossover Pilot Study Assessing the Effect of Non-invasive Vagus Nerve Stimulation (nVNS) on Autonomic Symptoms and Pain Management in Patients With Chronic Musculoskeletal Pain and Autonomic Dysfunction
- ClinicalTrials.gov ID
- NCT07409363
- Acronym / sponsor ID
- RESTORE-MSK / 2025-NCT57
- Keywords
- Vagus Nerve Stimulation, Non-invasive Neuromodulation, Chronic Pain, Autonomic Nervous System, GammaCore, COMPASS-31
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 12 participants (estimated)
- Lead sponsor
- University of LeedsUniversity, hospital or other
- Collaborators
- The Leeds Teaching Hospitals NHS Trust
- Study start
- 14 May 2026 (estimated)
- Primary completion
- 9 Jul 2026 (estimated)
- Study completion
- 31 Jul 2026 (estimated)
- First posted
- 13 Feb 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
BACKGROUND: Musculoskeletal pain affects approximately 1.75 billion individuals worldwide. In the United Kingdom alone, chronic pain is reported in at least 28 million individuals. Chronic musculoskeletal pain (CMP) may arise from physical injury, muscular overuse, inflammatory processes, or degenerative changes, and is frequently associated with comorbid conditions such as fibromyalgia, osteoarthritis, and rheumatoid arthritis.
Emerging evidence suggests that autonomic dysfunction (AD), described as altered sympathetic nervous system reactivity, has been implicated in the pathogenesis of chronic pain. Despite this, conventional therapies often fail to address the autonomic component. Non-invasive vagus nerve stimulation (nVNS) offers a non-pharmacological means to influence autonomic tone and central pain processing, with studies demonstrating analgesic effects across conditions including fibromyalgia, chronic pelvic pain, and migraine.
The GammaCore device is a CE-marked, non-invasive vagus nerve stimulator approved for primary headaches and supported by NICE for migraine and cluster headache treatment. However, its therapeutic potential in chronic MSK pain with autonomic dysfunction remains underexplored.
STUDY DESIGN: This is a randomised, single-blind, sham-controlled, crossover pilot study conducted at a single site (Chapel Allerton Hospital, Leeds). The crossover design allows each participant to serve as their own control, enhancing statistical efficiency in this small feasibility study.
INTERVENTION: Participants will self-administer the GammaCore device bilaterally under the angle of the mandible, guided by the carotid pulse. Each stimulation consists of a two-minute application per side. Participants will complete two stimulations per day (morning and evening) for two 14-day treatment periods, separated by a 2-week washout period. The same device is used with intensity set at subtherapeutic level.
RANDOMISATION: Participants will be randomly assigned to one of two treatment sequences: (A) Active stimulation followed by sham, or (B) Sham followed by active stimulation. Randomisation will be stratified by baseline COMPASS-31 score (<40 vs 40+) and implemented via REDCap.
BLINDING: This is a single-blind study where participants are blinded to treatment allocation. A blinding assessment will be conducted at study completion.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind (participant)
- Number of arms
- 2
- Model description
- Randomised crossover with 2-week washout period between treatment periods. Each participant receives both active nVNS and subtherapeutic (sham) stimulation in randomly allocated
| Arm | Type | Receives |
|---|---|---|
| Arm 1: Active nVNS then Sham | Other | Device: Active Vagus Nerve Stimulation, Device: Subtherapeutic Stimulation (Sham Control)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). |
| Arm 2: Sham then Active nVNS | Other | Device: Active Vagus Nerve Stimulation, Device: Subtherapeutic Stimulation (Sham Control)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). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (5 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Active Vagus Nerve StimulationAlso: gammaCore SapphireStimulation 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. | Device | Arm 1: Active nVNS then Sham, Arm 2: Sham then Active nVNS |
| Subtherapeutic Stimulation (Sham Control)Also: gammaCore SapphireStimulation 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. | Device | Arm 1: Active nVNS then Sham, Arm 2: Sham then Active nVNS |
Primary outcome
Composite Autonomic Symptom Score-31 (COMPASS-31) total score
Time frame: 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).
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.
9 secondary outcomes
Positive overall response to the NASA Lean Test procedure
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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): Depression subscale score
Time frame: 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).
EuroQol EQ-5D-5L: Index value
Time frame: 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).
EuroQol EQ-5D-5L: Visual Analogue Scale (EQ-VAS)
Time frame: 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).
Intervention acceptability: Theoretical Framework of Acceptability (TFA) questionnaire
Time frame: Measured once at final visit (Day 43 ±2 days).
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 May 2026.
- Background: PubMed 35232455Sekhon 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.
- Background: PubMed 6880820Zigmond 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.
- Background: PubMed 8080219Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singap. 1994 Mar;23(2):129-38.
- Background: PubMed 23218087Sletten 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.
- Individual participant dataSharing planned: Yes. Identifiable individual participant data will not be shared, but anonymised data, with identifiable information removed, may be made available to researchers upon reasonable request consistent with consent received and ethical approval given, to the Chief Investigator after publication of study results.
Related trials for Chronic Musculoskeletal Pain
Recruiting
BioPoly® Partial Resurfacing Knee Implant IDE
Knee Pain Chronic, Knee Osteoarthritis
RecruitingPhase 4
PENG vs L-ESPB With S-ESPB for Analgesia in Total Hip Arthroplasty
Hip Osteoarthritis, Hip Arthropathy
RecruitingPhase 2
A Master Protocol Study (LY900028) of Multiple Intervention-Specific-Appendices (ISAs) in Participants With Chronic Pain
Osteoarthritis, Knee, Diabetic Neuropathic Pain
Recruiting
Marine Lipids Ease Painful TMD
Temporomandibular Disorder (TMD)
RecruitingPhase 2
A Chronic Pain Master Protocol (CPMP): A Study of LY4065967 in Participants With Osteoarthritis Pain
Osteoarthritis, Knee, Chronic Pain
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Manoj Sivan, Prof principal investigator
University of Leeds
Darren C Greenwood, PhD principal investigator
University of Leeds
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Active Vagus Nerve Stimulation in people with Chronic Musculoskeletal Pain and Autonomic Dysfunction, run by University of Leeds at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 11 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Norah Almutairi (+44 (0)113 392 4396, ml22n2aa@leeds.ac.uk), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Composite Autonomic Symptom Score-31 (COMPASS-31) total score (time frame: 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).). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07409363, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 May 2026.