Non-invasive Vagus Nerve Stimulation for Chronic Musculoskeletal Pain
Trial statusNot yet recruiting
Trial phaseNot applicable
Trial typeInterventional
Biological sexAll
Age18+
SponsorUniversity of Leeds
About this trial
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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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).
Disqualifiers
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.
Trial design
Design model
Crossover
Treatments tested in this trial
Active Vagus Nerve Stimulation
DeviceStimulation 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)
DeviceStimulation 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.
Treatment groups
12 Participants
are divided into 2 treatment groupsGroup A: Arm 1: Active nVNS then ShamOther 2 interventions
Group B: Arm 2: Sham then Active nVNSOther 2 interventions
Trial outcomes
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.
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).Secondary outcomes
1
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.
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).2
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.
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).3
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.
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).4
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.
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).Other outcomes
1
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.
Time frame
Within 1 month of invitation to participate.2
Retention rate
Description: The proportion of randomised participants who complete the study. Measurement: Recorded by research team.
Time frame
Determined by completion of the primary outcome measure at last permissible date at end of second treatment period/final visit, assessed up to Day 45.3
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.
Time frame
During each 14-day treatment period (Days 1-14 and Days 29-42).4
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.
Time frame
Final visit (Day 43 ±2 days).Sponsors and contacts
Click on the lead sponsor to view all of their trials.
University of Leeds
Lead sponsor
The Leeds Teaching Hospitals NHS Trust
Collaborator
Source ClinicalTrials.gov
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