taVNS in Veterans With Knee OA (AVAHCS)

This pilot study will be the first to test home‐based taVNS against corticosteroidinjections (CSI) in knee osteoarthritis (KOA) to assess their effects on pain, function,and serum/synovial fluid pro and anti‐inflammatory biomarkers. Adult participantsdiagnosed clinically and/or radiographically with KOA (n=40) will be randomized to CSI(n=10) or 12 weeks of taVNS (high dose n=15; low dose n=15) and assessed pre‐procedureand at 1‐ and 3‐month timepoints. The following outcome measures will be assessed: PEG‐3,DVPRS, NIH‐PROMIS, KOOS, and Central Sensitization Inventory. In addition, biomarkerlevels in the serum and synovial fluid will be measured at baseline, 1‐ and 3‐monthtimepoints.This study will be the first to 1) directly compare taVNS against gold‐standard CSI, 2)examine taVNS effects on cytokines in knee OA as compared to CSI, 3) target an idealtaVNS dosing strategy for knee OA, and 4) utilize Parasym , a home‐based taVNS devicepreviously shown to reduce heart failure symptoms and decrease TNF‐ 17 that has beenclassified as non‐significant risk (NSR) by the FDA. The investigators are thereforetesting a novel veteran‐centric, nonpharmacological intervention for knee OA; taVNS withParasym offers a safe, self‐administered alternative to opioids and invasive procedures,with minimal side effects and high potential for real‐world implementation in the Veteranpopulation.Aim 1: Identify an ideal taVNS dosing regimen for analgesic effects. (30‐60 minutes perday, 3 days per week 4,17 versus 1‐2 hours per day, 7 days per week17 for 12 weeks) onclinical improvements in pain and function. Hypothesis for Aim 1: Pain (primary outcome),measured by the PEG‐3 (3‐item scale assessing pain intensity, interference with activity,and enjoyment of life)18 and DVPRS (assesses pain intensity + interference with activity,sleep, mood, stress)19 and function (secondary outcome) measured by the KOOS (Knee Injuryand Osteoarthritis Outcome Score)20 and NIH PROMIS measures21 will be more improved inthose undergoing high‐dose taVNS (n=15) than vs. low‐dose taVNS (n=15) or CSI (n=10).Central sensitization inventory will also be collected to evaluate it as a co‐variate inpredicting and monitoring treatment response.Aim 2: Evaluate taVNS dose‐dependent modulation of biomarkers associated withinflammation in Aim 1 participants. Synovial fluid and peripheral blood will be obtainedpre‐procedure and at 4‐ and 12‐weeks following initiation of therapy. Hypothesis for Aim2: taVNS results in greater reductions in pro‐inflammatory cytokines (e.g., TNF‐ , IL‐6,IL‐1 ) and increased levels of anti‐inflammatory mediators (e.g., IL‐10, TGF‐ ) insynovial fluid and peripheral blood compared to CSI. The investigators expect that thehigher dose group will demonstrate more pronounced changes in anti‐inflammatorybiomarkers as compared to low dose taVNS or CSI.This study addresses a critical need for innovative, non‐opioid OA therapies and supportsthe CReATE Motion Center's mission to advance regenerative therapies for Veterans. Basedon results of this study, the investigators will choose the taVNS dosing strategy thatbest enhances clinical and anti‐inflammatory effects. This pilot study has the potentialto advance a novel, non‐pharmacological approach to pain relief and functional recoveryin a population with high unmet needs and is a critical first step to our understandingof dose optimization in taVNS for knee OA‐related pain, function, and anti‐inflammatoryeffects.Our project is designed as a foundational step toward future combinatorial trials pairingtaVNS with other therapies for chondroprotection.