This randomized, double-blind, sham-controlled clinical trial will evaluate the safety and efficacy of a 30-day home-based transcutaneous auricular vagus nerve stimulation (taVNS) intervention in adults with cerebral palsy (CP) and chronic musculoskeletal pain. Participants will be randomized to receive either active taVNS targeting the auricular branch of the vagus nerve or sham stimulation delivered to the earlobe. The primary outcomes are changes in musculoskeletal pain severity and pain interference, as well as safety assessed through treatment-emergent adverse events. Exploratory outcomes include health-related quality of life, depression, fatigue, spasticity, systemic inflammatory biomarkers, and blinding success.
Diagnosis of cerebral palsy
Age ≥18 years
Chronic musculoskeletal pain present for ≥1 year
Moderate or greater pain severity (≥4/10 on Numeric Pain Rating Scale)
Cardiovascular disease
Pacemaker or implanted electrical device
Cerebral shunt
Pregnancy or intent to become pregnant
Parallel
Active Transcutaneous Auricular Vagus Nerve Stimulation
DeviceStimulation will target the auricular branch of the vagus nerve by applying stimulation to the cymba conchae region of the ear using the tVNS R device (taVNS Technologies, Erlangen, Germany). To achieve adequate stimulation while avoiding unpleasant or painful sensations, the stimulation intensity will be gradually increased in increments of 0.1mA (milliamps) until the subjective pain threshold is reached, and then reduced to a stimulus intensity just below the individuals pain threshold (expected range based on prior studies 1 - 3.2mA). Pulse width will be set at 100μs (microseconds) and frequency will be set at 25Hz (Hertz). Parameters will be set for the duration of the intervention consisting of 4 hours of daily stimulation for a period of 30 days.
Sham Transcutaneous Auricular Vagus Nerve Stimulation
DeviceStimulation will target the ear lobe using the tVNS R device (taVNS Technologies, Erlangen, Germany). To achieve adequate stimulation while avoiding unpleasant or painful sensations, the stimulation intensity will be gradually increased in increments of 0.1mA until the subjective pain threshold is reached, and then reduced to a stimulus intensity just below the individuals pain threshold (expected range based on prior studies 1 - 3.2mA). Pulse width will be set at 100μs and frequency will be set at 25Hz. Participants will perform 4 hours of stimulation per day for a period of 30 days. Stimulation will be applied to the ear lobe in order to ensure participant feel the stimulation while avoiding activation of the vagus nerve.
Change in Musculoskeletal Pain Assessed by the Brief Pain Inventory
Musculoskeletal pain severity and pain interference will be assessed using the Brief Pain Inventory (BPI). The BPI pain severity subscale evaluates pain intensity using four 0-10 numeric rating scale items assessing worst, least, average, and current pain. A composite pain severity score will be calculated as the mean of these four items, in accordance with IMMPACT recommendations. Pain interference will be assessed using the BPI interference subscale, which evaluates the extent to which pain interferes with general activity, mood, walking ability, normal work, relationships, sleep, and enjoyment of life using 0-10 numeric rating scales. Higher scores indicate greater pain severity or interference. Assessments will be conducted by trained outcome assessors blinded to group allocation.
Change in Musculoskeletal Pain Assessed by the Numeric Pain Rating Scale
Musculoskeletal pain severity will also be assessed using the Numeric Pain Rating Scale (NPRS), a simple and widely used self-report measure of pain intensity. Participants will rate their average pain intensity on an 11-point numeric rating scale ranging from 0 (no pain) to 10 (worst imaginable pain). The NPRS will serve as a complementary, standardized measure of pain intensity to enhance the robustness and interpretability of pain assessment.
Incidence of Treatment-Emergent Adverse Events During Intervention
All treatment-emergent adverse events occurring during the intervention period will be recorded through weekly phone calls and/or study visits. Adverse events will be summarized by type, frequency, severity, and relationship to the study intervention. The number and proportion of participants experiencing at least one adverse event will be compared between the active taVNS and sham taVNS groups.
Change in Health-Related Quality of Life (EQ-5D-5L)
Health-related quality of life will be assessed using the EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L), a validated self-report measure of health status. The EQ-5D-5L assesses five domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, each rated across five levels of severity. Change in health-related quality of life from baseline to the end of the 30-day intervention period will be compared between the active taVNS and sham taVNS groups. Higher index values and visual analogue scale scores indicate better health status.
Change in Depressive Symptoms assessed by the Patient Health Questionnaire-9
Depressive symptoms will be assessed using the Patient Health Questionnaire-9 (PHQ-9), a validated self-report questionnaire that measures the severity of depressive symptoms experienced over the past two weeks. Total scores range from 0 to 27, with higher scores indicating greater depressive symptom severity. Change in PHQ-9 scores from baseline to the end of the 30-day intervention period will be compared between the active taVNS and sham taVNS groups.
Change in Depressive Symptoms assessed by the Hamilton Depression Rating Scale
Depressive symptoms will be assessed using the Hamilton Depression Rating Scale (HAM-D), a clinician-administered measure of depression severity. The HAM-D will be completed by a trained assessor blinded to group allocation. Higher scores indicate greater depressive symptom severity. Change in HAM-D scores from baseline to the end of the 30-day intervention period will be compared between the active taVNS and sham taVNS groups.
Change in Fatigue Severity and Impact assessed by the Fatigue Impact and Severity Self-Assessment
Fatigue will be assessed using the Fatigue Impact and Severity Self-Assessment (FISSA), a self-report questionnaire developed for individuals with cerebral palsy. The FISSA includes 31 items assessing fatigue severity, the impact of fatigue on daily activities, and fatigue management behaviors. Items are rated on a five-point Likert scale, with higher scores indicating greater fatigue severity and impact. Change in fatigue from baseline to the end of the 30-day intervention period will be evaluated using the FISSA total score and compared between the active taVNS and sham taVNS groups.
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