Use of taVNS for Painful Diabetic Neuropathy: 12-Week Randomized, Sham-Controlled Trial

Transcutaneous Auricular Vagus Nerve Stimulation for Painful Diabetic Peripheral Neuropathy: A 12-Week Randomized, Double-Blind, Sham-Controlled, Parallel-Group Trial With Biomarker Endpoints

This 12-week, randomized, double-blind, sham-controlled, parallel-group trial will evaluate the analgesic and mechanistic effects of home-based transcutaneous auricular vagus nerve stimulation (taVNS) in adults with painful diabetic peripheral neuropathy (DPN). To increase the likelihood of detecting a biological signal, enrollment is biomarker-enriched for low-grade systemic inflammation and autonomic imbalance (e.g., elevated high-sensitivity C-reactive protein/interleukin-6 or reduced heart-rate variability \[HRV]). Participants are randomized 1:1 to active taVNS (ear-clip stimulation, twice daily) or an indistinguishable sham device for 12 weeks; background diabetes and pain therapies are kept stable where possible. Adherence and daily pain ratings are captured via a smartphone application.

The primary outcome is change in average daily pain intensity (11-point Numeric Rating Scale) from baseline to Weeks 10-12. Secondary outcomes assess proposed mechanisms of action and include HRV indices, inflammatory biomarkers (interleukin-6, tumor necrosis factor-α, high-sensitivity C-reactive protein), serum neurofilament light (sNfL) measured from finger-prick dried-spot samples, and corneal confocal microscopy (CCM) metrics of small-fiber integrity (corneal nerve fiber length/density). Additional outcomes include sleep interference, DN4 score, Patient Global Impression of Change, responder rate (≥2-point pain reduction), and safety.

The study is multicenter in Pakistan and is designed to test whether taVNS reduces painful symptoms and favorably shifts objective autonomic, inflammatory, and nerve-injury biomarkers, providing scalable evidence relevant to low- and middle-income settings.

This 12-week randomized, double-blind, sham-controlled, parallel-group trial will evaluate the analgesic and mechanistic effects of home-based transcutaneous auricular vagus nerve stimulation (taVNS) in adults with painful diabetic peripheral neuropathy (DPN). To enhance biological signal detection, enrollment is biomarker-enriched for low-grade systemic inflammation and autonomic imbalance. Participants will be assigned (1:1) to active taVNS or an indistinguishable sham device. The primary outcome is the change in average daily pain intensity on an 11-point Numeric Rating Scale (NRS), averaged over Weeks 10-12 versus baseline. Secondary outcomes include autonomic function (heart-rate variability), inflammatory biomarkers (IL-6, TNF-α, hs-CRP), serum neurofilament light (sNfL; finger-prick dried-spot sampling), small-fiber structure by AI-assisted corneal confocal microscopy (CCM), sleep interference, quality of life, and safety.

Inclusion Criteria:

Age 30-70 years. Type 2 diabetes mellitus diagnosed ≥ 1 year.

Painful distal symmetric polyneuropathy ≥ 3 months, meeting all:

DN4 score ≥4; Average daily pain NRS ≥4 during a 7-day run-in; Clinical examination consistent with DPN (e.g., reduced vibration or abnormal monofilament, or neuropathy disability score >0).

Stable antidiabetic regimen and neuropathic-pain medications for ≥4 weeks before randomization, with no planned changes during the 12-week treatment unless medically necessary.

Biomarker enrichment: at least one of the following at screening:

hs-CRP ≥2.0 mg/L or IL-6 above laboratory median; or Reduced heart-rate variability (e.g., RMSSD at or below the age/sex-adjusted 25th percentile) on standardized 5-minute ECG.

Able to use the ear-clip device and the study smartphone app (or willing to use a study phone), and to attend baseline, Week 6 and Week 12 visits (including corneal confocal microscopy and finger-prick sampling).

Provides written informed consent

Exclusion Criteria:

Peripheral neuropathy not due to diabetes (e.g., vitamin B12 deficiency, hypothyroidism, uremia/CKD-related, chemotherapy-induced, HIV, hereditary neuropathies), or predominant radiculopathy/entrapment neuropathy.

Implanted electronic medical devices (e.g., pacemaker, ICD, deep brain stimulator, cochlear implant) or other contraindication to transcutaneous electrical stimulation.

History of epilepsy/seizure disorder, clinically significant arrhythmia, or unexplained syncope within 6 months.

Unstable cardiovascular disease within 3 months (e.g., acute coronary syndrome, decompensated heart failure).

Severe renal impairment (eGFR <30 mL/min/1.73 m²) or on dialysis. Active diabetic foot ulcer Grade ≥2, active systemic infection, or dermatologic disease at the ear-clip site.

Corneal disease precluding CCM (e.g., active keratitis) or inability to undergo CCM imaging.

Current systemic immunosuppressive therapy (e.g., ≥10 mg/day prednisone equivalent or biologic agents) or expected to start during the trial.

Uncontrolled psychiatric illness (including active suicidal ideation) or cognitive impairment limiting consent/compliance.

Initiation/change of neuromodulation treatments for pain within 3 months or prior taVNS use within 3 months.

Pregnant or breastfeeding, or planning pregnancy during the study. Any condition or circumstance that, in the investigator's judgment, would interfere with safe participation or with study assessments.