Non-invasive Vagus Nerve Stimulation for Chronic Musculoskeletal Pain

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).

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.

Inclusion Criteria:

1. 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.
2. Identified as having autonomic dysfunction (AD) defined as a score of 17 or more on the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire.
3. Ability to understand and willingness to sign a written informed consent document.
4. Stated willingness to comply with all study procedures and be available for the duration of the study (approximately 6 weeks).
5. Ability to read and understand English sufficiently to complete study questionnaires.

Exclusion Criteria:

1. Pregnancy (self-reported; safety of nVNS in pregnancy not established).
2. Advanced heart disease, including: severe heart failure (NYHA Class III-IV), myocardial infarction within the preceding 6 months, or ongoing investigations for cardiac arrhythmias.
3. 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.
4. Concurrent use of another electrical stimulation device, including: transcutaneous electrical nerve stimulation (TENS) unit, muscle stimulator, or any other portable electronic stimulation device.
5. Inability to provide informed consent.