Transcutaneous vagus nerve stimulation may alleviate pain in OA

Osteoarthritis (OA) is increasingly recognised as a complex condition that extends beyond local joint degeneration to involve systemic processes, including low grade inflammation and autonomic nervous system (ANS) dysregulation. The ANS comprises two antagonistic branches: the sympathetic nervous system (SNS), responsible for “fight or flight” responses, and the parasympathetic nervous system (PNS), which governs “rest and digest” functions. The vagus nerve (VN)—the 10th cranial nerve and principal efferent of the PNS—has emerged as a therapeutic target through non-invasive electrical stimulation, with growing interest in its potential to modulate pain and inflammation in OA.¹

Dr. Zsuzsa Jenei-Lanzi explained how vagal nerve stimulation (VNS) activates the cholinergic anti-inflammatory pathway, whereby afferent vagal fibres detect inflammation, relay this information to the brainstem, and trigger efferent responses that suppress pro-inflammatory cytokine release, either indirectly via modulation of systemic inflammatory mediators or directly through macrophage inhibition.  Alternative mechanisms propose that VNS may engage the SNS to increase norepinephrine release in peripheral tissues, such as joints, acting on β2-adrenergic receptors with anti-inflammatory effects.¹

OA-related pain and inflammation, Dr Zsuzsa Jenei-Lanzi states, chronically causes persistent SNS activation, leading to a suppression of the PNS, and a parallel co-activation of the hypothalamic-pituitary-adrenal (HPA) axis, creating a vicious cycle of autonomic dysfunction due to sympathetic dominance and systemic inflammation. One measurable marker of this dysregulation is heart rate variability (HRV)—notably reduced in states of sympathetic dominance.

In the Frankfurt cohort study, HRV was assessed alongside serum cortisol, dehydroepiandrosterone sulphate (DHEA-S), perceived stress, and pain across healthy individuals, early OA, and late-stage OA patients. Late-stage OA patients showed elevated cortisol, decreased HRV (specifically SDRR), and high perceived stress, all correlating with OA severity^1,2. Parallel murine studies confirmed that OA alone elevated stress hormone levels, supporting the translational relevance of autonomic involvement. Notably, combined OA and stress increased inflammation in both OA and sham-operated animals, suggesting an additive effect of stress on OA³

Dr. Zsuzsa Jenei-Lanzi presented findings supporting the hypothesis that enhancing parasympathetic tone could interrupt the cycle of pain and inflammation in OA. She described further analyses, where scientists identified three psychophysiological clusters—intermediate stress, high stress, and high resilience—suggesting that patients in the first two groups may benefit most from tailored VNS interventions.¹

In conclusion, sympathetic overactivation plays a central role in the progression of OA symptoms. Rebalancing the autonomic nervous system through VNS may represent a promising, non-pharmacological strategy to alleviate pain and reduce systemic inflammation in selected OA patient subgroups.

Bibliography

1. Jenei-Lanzi Z. Transcutaneous vagus nerve stimulation may alleviate pain in OA. In: New Potential Targets for Pain in Osteoarthritis. European Congress of Rheumatology: EULAR 2025; 2025 Jun 11-14, Barcelona, Spain.
2. Sohn R, Assar T, Kaufhold I, Brenneis M, Braun S, Junker M, Zaucke F, Pongratz G, Jenei-Lanzl Z. Osteoarthritis patients exhibit an autonomic dysfunction with indirect sympathetic dominance. J Transl Med. 2024 May 16;22(1):467
3. Yeater TD, Zubcevic J, Allen KD. Measures of cardiovascular function suggest autonomic nervous system dysregulation after surgical induction of joint injury in the male Lewis rat. Osteoarthritis Cartilage. 2022 Apr;30(4):586-595