Pulsed Radiofrequency and Epigenetic Modulation of Pain Pathways: A Systematic Review Based on Preclinical Evidence

Felice Occhigrossi,1 Jacopo Mosca,2 Fabrizio Micheli,3 Roberto Gazzeri,1 Christopher L Robinson,4 Giuliano Lo Bianco5 1Pain Therapy Unit, San Giovanni-Addolorata Hospital, Rome, Italy; 2Pain Therapy Unit, Policlinico Umberto I Hospital, Rome, Italy; 3Unit of Interventional and Surgical Pain Management, Guglielmo da Saliceto Hospital, Piacenza, Italy; 4Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; 5Anesthesiology and Pain Department, Foundation G. Giglio Cefalù, Palermo, ItalyCorrespondence: Felice Occhigrossi, Pain Therapy Unit, San Giovanni-Addolorata Hospital, Rome, Italy, Email [email protected]: Pulsed radiofrequency (PRF) is used for refractory neuropathic pain, yet its mechanisms remain incompletely defined. The dorsal root ganglion (DRG) and peripheral nerves (eg, sciatic nerve) are common targets and key nodes in nociceptive transmission and neuro-immune crosstalk. Compared with implantable electrical neuromodulation (SCS/PNS), PRF provides non-invasive, percutaneous neuromodulation. Epigenetic regulation after PRF is plausible because chronic pain causes transcriptional modifications and electrical neuromodulation may influence chromatin-based gene control.Objective: To summarize preclinical evidence on epigenetic and molecular changes after PRF applied to the DRG or peripheral nerves.Methods: PubMed, Embase, and Scopus were searched (PRISMA-S); synthesis followed SWiM. Studies assessed direct epigenetic modifications and/or gene/protein expression changes after PRF at DRG or peripheral nerve targets. Risk of bias was evaluated using the JBI checklist for animal studies.Results: Seventeen rodent studies were included. One study reported a direct epigenetic modification, showing that PRF reversed complete Freund’s adjuvant (CFA)-induced histone H3/H4 hypoacetylation at the Kcc2 locus, restoring KCC2 expression. Other studies linked PRF to attenuation of microglial/MAPK signaling, modulation of neurotrophic mediators, downregulation of pro-inflammatory cytokines, and normalization of sensory neuron excitability markers across DRG, sciatic nerve, and spinal dorsal horn tissue. Target-specific trends emerged: DRG PRF more consistently attenuated spinal microglial/MAPK signaling, whereas sciatic PRF emphasized normalization of DRG channels/neuropeptides. No human studies and no circulating epigenetic biomarkers were identified.Conclusion: Preclinical data support a non-destructive PRF mechanism involving dampening of neuro-immune signaling and restoration of inhibitory tone. Direct epigenetic evidence remains limited (single study) and absent in humans. Priorities include standardized PRF parameter reporting, time-course and multi-omic profiling beyond Kcc2, and prospective clinical studies incorporating molecular endpoints and circulating epigenetic readouts.Keywords: pulsed radiofrequency, dorsal root ganglion, neuropathic pain, epigenetics, histone acetylation, microglia, MAPK, KCC2, TRPV1, GDNF