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Abstract: Pain is an unpleasant sensory and experience associated with, or resembling that associated with, actual emotional or potential tissue damage. Chronic pain is pain that persists for more than 3 months. Chronic pain is caused by a variety of conditions with high incidence. However, the use of medication to treat chronic pain has certain limitations. Non-opioid medications have limited efficacy for some types of chronic pain, such as neuropathic pain. However, opioid analgesics have limitations due to addiction and gastrointestinal side effects, so non-drug intervention therapy has gradually gained attention. Currently, common non-pharmacological interventions for chronic pain include pulsed radiofrequency (PRF), spinal cord stimulation (SCS), photobiomodulation (PBM) and repetitive transcranial magnetic stimulation (rTMS). PRF is a technique using a low temperature and pulse of electromagnetic radiation to disrupt nerve signaling without denaturing the fibers. PRF therapy involves the insertion of a radiofrequency needle around the target nerve under computer tomography (CT) guidance. The RF generator emits a pulsed current to the needle tip, forming a magnetic field near the target nerve tissue and exerting a neuromodulatory role. Compared with traditional thermocoagulation, the temperature of PRF does not exceed 42°C and finally exerts an analgesic effect without damaging the nerve. Recent studies reveal that analgesic mechanisms of PRF involve downregulations of functions of voltage-gated sodium and calcium channels and ionotropic purinergic receptors (Nav1.7, Cav2.2, and P2X3), reduction of the releases of neuropeptides (calcitonin gene-related peptide (CGRP) and substance P (SP)), neurotransmitters (glutamate) and pro-inflammatory mediators (interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α)), and suppression of intracellular signal pathways (ERK/MAPK and p38MAPK). SCS modulates the releases and functions of neurotransmitters by downregulating excitatory glutamate systems and upregulating inhibitory gamma-aminobutyric acid (GABA), endogenous opioids, and the endocannabinoid system. SCS is a therapeutic method that effectively alleviates chronic pain by electrically stimulating the spinal nerves. This procedure involves the implantation of electrodes into the epidural space under local anesthesia, with precise targeting of specific segments of the spinal cord. By delivering pulsed electrical currents, the spinal nerves can be selectively stimulated, effectively blocking the transmission of pain signals and providing much-needed relief from chronic pain. SCS suppresses neuroinflammation, including downregulating glial activation, decreasing releases of pro-inflammatory mediators (colony stimulating factor-1 (CSF-1), resolvin D1 (RVD1), TNF-α and IL-1β), and regulating p38MAPK signal pathways. SCS also increases the expression levels of lysosome-associated membrane protein 2 (Lamp2) and mature cathepsin D (matu-CTSD) to restore lysosome function and promote autophagosome degradation. Light therapies utilize specific wavelengths of light to alleviate pain and promote healing. Light therapies use different types of light sources, including visible light, infrared, and ultraviolet rays. Recent advances in light therapies on chronic pain reveal that green light irradiation enhances morphine analgesic effect, mainly by increasing beta-endorphin and enkephalin levels in rats, reducing postsynaptic glutamate receptor expression and inhibiting microglia activation. A recent study using sound to mitigate pain and reports the mechanism of sound-mediated analgesic occurs through the cortical-thalamic circuitry. The study highlights that the analgesic effect of sound is solely dependent on the intensity of the sound, regardless of its nature or characteristics. In conclusion, the analgesic mechanisms of non-pharmacological interventions suggest their potential in the clinic. This article reviews the intervention methods, advantages, disadvantages and analgesic mechanisms of the above non-pharmacological interventions. The review will help to better understand the pathogenesis of chronic pain and to optimize non-pharmacological interventions for chronic pain.
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