Spinal Cord Injury, Neuropathic Pain
Conditions
Keywords
vagus nerve stimulation, inflammation, spinal cord injury, neuropathic pain, taVNS
Brief summary
This pilot randomized, double-blind, sham-controlled clinical investigation will evaluate the feasibility and safety of a 30-day home-based transcutaneous auricular vagus nerve stimulation (taVNS) intervention in adults with spinal cord injury (SCI) and neuropathic pain. Participants will be randomized to receive either active taVNS targeting the auricular branch of the vagus nerve or sham taVNS delivered to the earlobe. Primary outcomes include feasibility, safety, adherence, acceptability, and blinding success. Exploratory outcomes include changes in neuropathic pain, systemic inflammatory biomarkers, vagal tone assessed via heart rate variability, and quality of life.
Detailed description
Neuropathic pain is a common and debilitating complication following spinal cord injury (SCI) and is frequently resistant to pharmacologic treatment. Chronic neuroinflammation and reduced vagal tone are increasingly recognized contributors to persistent neuropathic pain after SCI. The vagus nerve plays a central role in immune regulation and descending pain modulation. Transcutaneous auricular vagus nerve stimulation (taVNS) is a noninvasive neuromodulation technique that stimulates vagal afferent fibers via the external ear. Prior Health Canada-authorized trials conducted by the investigative team have demonstrated the feasibility, safety, and autonomic effects of taVNS in individuals with SCI. This single-site, randomized, double-blind, sham-controlled pilot study will enroll 32 adults with SCI and neuropathic pain. Participants will be randomized 1:1 to receive either active or sham taVNS for 4 hours per day over a 30-day home-based intervention period. Outcomes will be assessed at baseline and immediately post-intervention. Feasibility and safety outcomes are primary, while exploratory clinical and mechanistic outcomes will inform the design of a future definitive randomized controlled trial.
Interventions
Stimulation 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.
Stimulation 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.
Sponsors
London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
This is a randomized, double-blind, sham-controlled, parallel-group pilot study. Thirty-two adults with spinal cord injury and neuropathic pain will be randomized in a 1:1 ratio to receive either active transcutaneous auricular vagus nerve stimulation (taVNS) or sham taVNS. Following a baseline visit for eligibility confirmation, outcome assessments, and device training, participants will complete a 30-day home-based intervention during which they will use the assigned stimulation device for 4 hours per day. Outcomes will be assessed at baseline and at the end of the 30-day intervention period. Participants, investigators, care providers, and outcome assessors will remain blinded to treatment allocation throughout the study.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* SCI of any level or severity * 18 years of age or older * current neuropathic pain * on no medications or on a stable prescribed dose (no change in prior 6-weeks) of anti-inflammatory, pain medications and/or depression medications
Exclusion criteria
* Prone to autonomic dysreflexia * presence of cardiovascular disease * pacemaker or other implanted electrical device * cerebral shunts * epilepsy * pregnant or attempting to become pregnant * current wound/infection * unstable dose of prescribed anti-inflammatory, depression, or pain medications within past 6-weeks.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recruitment Rate and Time to Recruit Target Sample Size | Up to 20 months | Recruitment feasibility will be assessed by documenting the number and proportion of eligible individuals who consent to participate and the total time required to recruit the target sample of 32 participants. Recruitment rate will be calculated as the percentage of eligible candidates who agree to participate. These data will be summarized descriptively for the overall study population. |
| Retention and Attrition During the 30-Day Intervention | 30 days | Retention will be assessed as the proportion of enrolled participants who complete the full 30-day intervention and post-intervention assessment. Attrition will be recorded as the number and proportion of participants who withdraw prior to study completion. Reasons for withdrawal or loss to follow-up will be documented where available. Retention and attrition rates will be summarized and compared descriptively between the active taVNS and sham taVNS groups. |
| Adherence to Daily taVNS Stimulation Prescription | 30 days | Adherence will be assessed using automated usage data recorded by the taVNS device and associated smartphone application. Daily adherence will be calculated as the percentage of the prescribed 4-hour daily stimulation period completed (actual stimulation time divided by prescribed stimulation time × 100). Overall adherence will be summarized as the mean daily adherence across the 30-day intervention period. Adherence will be compared descriptively between the active taVNS and sham taVNS groups. |
| Acceptability with the taVNS intervention | Day 30 | Participant acceptability will be assessed at the end of the intervention using the Acceptability of Intervention Measure (AIM). Acceptability scores will be summarized descriptively and compared between the active taVNS and sham taVNS conditions. |
| Incidence of Treatment-Emergent Adverse Events During Intervention | 30 days | All adverse events which occur during the intervention will be recorded during the twice weekly phone calls and/or study visits and compared between the active taVNS and sham taVNS conditions. A description of the adverse event, number of events, and total number of participants affected will be recorded. |
| Success of Participant and Investigator Blinding | Day 30 | Blinding success will be assessed after completion of the intervention by asking participants and investigators to indicate which treatment group they believe the participant was assigned to (active taVNS or sham taVNS). Blinding effectiveness will be quantified using the James Blinding Index, calculated separately for participants and investigators. Blinding outcomes will be summarized descriptively. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Neuropathic Pain Assessed by the Neuropathic Pain Symptoms Inventory | Baseline and Day 30 | Neuropathic pain severity and interference will be assessed using the Neuropathic Pain Symptoms Inventory (NPSI), a self-reported questionnaire with total scores ranging from 0 to 100, where higher scores indicate greater neuropathic pain severity and pain-related interference. Change scores will be calculated as post-intervention values minus baseline values. Mean changes and variability will be summarized and compared descriptively between the active taVNS and sham taVNS groups. |
| Change in Neuropathic Pain Assessed by the International Spinal Cord Injury Pain Basic Data Set (version 3) | Baseline and Day 30 | Neuropathic pain severity and pain-related interference will be assessed using the International Spinal Cord Injury Pain Basic Data Set (ISCIPBDS), version 3, which includes numeric rating scales ranging from 0 to 10, where higher scores indicate greater pain intensity and greater pain-related interference. Change scores will be calculated as post-intervention values minus baseline values. Mean changes and variability will be summarized and compared descriptively between the active taVNS and sham taVNS groups. |
| Change in Circulating C-Reactive Protein | Baseline and Day 30 | Plasma concentrations of C-reactive protein (CRP) will be measured from fasting blood samples collected at baseline and at the end of the intervention. Concentrations will be reported in milligrams per liter (mg/L), with higher values indicating greater systemic inflammation. Change values will be calculated as post-intervention values minus baseline values and summarized descriptively between the active taVNS and sham taVNS groups. |
| Change in Circulating Interleukin-1 Beta | Baseline and Day 30 | Plasma concentrations of interleukin-1 beta (IL-1β) will be measured from fasting blood samples collected at baseline and at the end of the intervention. Concentrations will be reported in picograms per milliliter (pg/mL), with higher values indicating greater pro-inflammatory activity. Change values will be calculated as post-intervention values minus baseline values and summarized descriptively between the active taVNS and sham taVNS groups. |
| Change in Circulating Interleukin-6 | Baseline and Day 30 | Plasma concentrations of interleukin-6 (IL-6) will be measured from fasting blood samples collected at baseline and at the end of the intervention. Concentrations will be reported in picograms per milliliter (pg/mL), with higher values indicating greater pro-inflammatory activity. Change values will be calculated as post-intervention values minus baseline values and summarized descriptively between the active taVNS and sham taVNS groups. |
| Change in Circulating Interferon Gamma | Baseline and Day 30 | Plasma concentrations of interferon gamma (IFN-γ) will be measured from fasting blood samples collected at baseline and at the end of the intervention. Concentrations will be reported in picograms per milliliter (pg/mL), with higher values indicating greater pro-inflammatory activity. Change values will be calculated as post-intervention values minus baseline values and summarized descriptively between the active taVNS and sham taVNS groups. |
| Change in Circulating Tumor Necrosis Factor Alpha | Baseline and Day 30 | Plasma concentrations of tumor necrosis factor alpha (TNF-α) will be measured from fasting blood samples collected at baseline and at the end of the intervention. Concentrations will be reported in picograms per milliliter (pg/mL), with higher values indicating greater pro-inflammatory activity. Change values will be calculated as post-intervention values minus baseline values and summarized descriptively between the active taVNS and sham taVNS groups. |
| Change in Vagal Tone Assessed by Heart Rate Variability | Baseline and Day 30 | Vagal tone will be assessed using heart rate variability (HRV) derived from a 5-minute resting electrocardiogram recording. Root mean square of successive differences (RMSSD) and high-frequency power will be calculated using standard HRV analysis procedures. Change in HRV measures from baseline to post-intervention will be summarized descriptively and compared between the active taVNS and sham taVNS groups. |
| Change in Health-Related Quality of Life | Baseline and Day 30 | Quality of life will be assessed using selected short forms from the Spinal Cord Injury-Quality of Life (SCI-QOL) measurement system, including Pain Interference, Depression, and Positive Affect and Well-Being domains. Scores will be calculated as standardized T-scores. Change in quality-of-life scores from baseline to post-intervention will be summarized and compared descriptively between treatment groups. |
Countries
Canada
Contacts
CONTACTDavid J Allison, PhD.
CONTACTJoy Jiang
Outcome results
None listed