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| Name | Class |
|---|---|
| The Leeds Teaching Hospitals NHS Trust | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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). |
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| 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). |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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). |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Recruitment rate: Response to invitation to participate | Description: The proportion of individuals who consent to participate out of those approached and invited. Measurement: Recorded by research team in screening log. | Within 1 month of invitation to participate. |
| Retention rate |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| 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 |
| Name | Affiliation | Role |
|---|---|---|
| Manoj Sivan, Prof | University of Leeds | Principal Investigator |
| Darren C Greenwood, PhD | University of Leeds | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Chapeltown Road, Leeds, LS7 4SA, United Kingdom | Leeds | West Yorkshire | LS7 4SA | United Kingdom |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35232455 | Background | 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. | |
| 6880820 | 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. |
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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.
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.
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).
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jan 14, 2026 | Jan 29, 2026 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jan 14, 2026 | Jan 29, 2026 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D054969 | Primary Dysautonomias |
| D001342 | Autonomic Nervous System Diseases |
| D059350 | Chronic Pain |
| ID | Term |
|---|---|
| D009422 | Nervous System Diseases |
| D010146 | Pain |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
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Randomised crossover with 2-week washout period between treatment periods. Each participant receives both active nVNS and subtherapeutic (sham) stimulation in randomly allocated
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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.
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| 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. |
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| 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 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 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 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 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 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 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 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 once at final visit (Day 43 ±2 days). |
Description: The proportion of randomised participants who complete the study. Measurement: Recorded by research team. |
| 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 | Description: Compliance with the prescribed stimulation schedule, measured as the proportion of scheduled stimulations completed. Participants record each stimulation session (morning and evening, both sides of neck) in a paper diary. Measurement: Paper stimulation diary reviewed by research team at visits 2, 3, and final visit. | During each 14-day treatment period (Days 1-14 and Days 29-42). |
| Success of participant blinding | Description: At study completion, participants are asked to guess which treatment (active or sham) they received in each period. Measurement: Single question at final visit recorded in CRF. | Final visit (Day 43 ±2 days). |
| 8080219 | Background | Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singap. 1994 Mar;23(2):129-38. |
| 23218087 | 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. |
| D013568 |
| Pathological Conditions, Signs and Symptoms |