1. 2021;24;525-532Pulsed Radiofrequency in Interventional Pain Management: Cellular and Molecular Mechanisms of Action – An Update and Review
   Narrative Review
   Jordan Sam, MHSc, Michael Catapano, MD, Sachin Sahni, MD, Frederick Ma, MD, Alaa Abd-Elsayed, MD, and Ognjen Visnjevac, MD.

BACKGROUND: Pulsed radiofrequency (PRF) treatment uses low energy, short pulsations to modulate tissue characteristics. PRF treatment has been effective as an interventional pain management technique to treat a variety of chronic neuropathic pain (neuralgia) disorders, but a comprehensive review of its biological mechanism has not been updated in a decade.

OBJECTIVES: In this literature review, we performed a literature search in PubMed to identify publications describing the mechanisms of action of pulsed radiofrequency for pain indications.

STUDY DESIGN: Narrative literature review.

METHODS: A systematic search was performed through PubMed from database inception to December 31, 2019, to identify all articles addressing the cellular or molecular mechanisms of action of PRF on neuropathic pain. The search terms “pulsed radiofrequency” and “pulsed radiofrequency mechanisms” were used. Cellular and molecular mechanisms of PRF interventions were subdivided into 3 broad categories: nociceptive signalling, immune activity, and synaptic function. A total of 20 publications were identified for inclusion in this updated review.

RESULTS: It was found that pulsed radiofrequency impacts many different biological pathways involved in the modulation of chronic neuropathic pain (neuralgia). With regards to nociceptive signalling, PRF treatment modulates ion channels (Na/K ATPase, HCN, P2X3), CGRP, neurotransmitters (aspartate, citrulline, M-ENK, glutamate), postsynaptic receptors (AMPA-R, GABA-B), and synaptic function (KCC2). PRF treatment also modulates immune activity, including microglial markers (CD3, CD56, Iba1), inflammatory cytokines (IL-6, IL-17, IRF8, IFN-g, TNFa), and intracellular proteins implicated in immune mediated neuropathic pain (BDNF, b-catenin, JNK, p38, ERK1/2).

LIMITATIONS: This review is primarily limited by the diverse data sets that needed to be collated and correlated, as no study was comprehensive in addressing all markers, cytokines, pathways, neurotransmitters, ion channels, proteins, genes, and gene expression changes, along with their clinical outcomes concurrently. As such, the interplay of these individual pathways and mechanisms and their isolated effects on efficacy of PRF cannot be concluded. Rather, the large majority of findings can be seen as associations instead of definitive causal relationships to clinical outcomes.

CONCLUSIONS: Herein describes a clinically relevant collated update describing the cellular and molecular mechanisms of action of PRF for pain management.

KEY WORDS: Biomarkers, chronic pain, cytokines, ganglia, hyperalgesia, immunomodulation, neuralgia, neurotransmitter, nociceptors, pulsed radiofrequency treatment, receptors, spinal