Editorial: Non-invasive Therapy for Pain Relief

Michael D Staudt^1*Nader Pouratian²Jan Kubanek³Julie G Pilitsis⁴

• ¹University Hospitals Cleveland Medical Center, Cleveland, United States
• ²The University of Texas Southwestern Medical Center, Dallas, United States
• ³The University Of Utah Department of Biomedical Engineering, Salt Lake City, United States
• ⁴The University of Arizona College of Medicine Tucson, Tucson, United States

Editorial Chronic pain is prevalent and imposes significant suffering on patients and burdens on the healthcare system (Dahlhamer et al., 2018). Furthermore, pain-related conditions are the primary reason that patients seek medical care or visit an emergency department in the United States (Chang et al., 2014). As such, the management of chronic pain can be exceedingly complex, and requires a multimodal and multidisciplinary approach (Staudt, 2022). Although there is no singular approach for the management of chronic pain syndromes, conservative therapies are initially preferred, with interventional procedures, neuromodulation, and surgery reserved for refractory pain; however, there is an unmet treatment need for a "middle ground" approach with non-invasive therapies. Non-invasive non-pharmacological therapies can broadly be categorized into physical modalities, psychological interventions such as cognitive-behavioral therapy, and complementary and alternative therapies including acupuncture and yoga (Shi and Wu, 2023). Non-invasive neuromodulation therapies, such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and focused ultrasound (FUS), have emerged as promising alternatives to conventional treatments, although questions remain regarding their efficacy and durability. This special collection of articles aims to explore the advancements, clinical applications, and mechanistic insights of non-invasive therapies in pain management. Non-invasive brain stimulation, including TMS and tDCS, has received much interest as a potential modality for modulating pain perception. Compared to TMS, which utilizes a magnetic field to stimulate specific brain regions, tDCS uses low-level electrical currents which are applied directly to the scalp. In a single-blinded, randomized, sham-controlled study, Tsai et al. evaluated pain detection thresholds in 53 healthy patients following active or sham tDCS. The anode and cathode were placed over the left primary sensorimotor cortex and the right dorsolateral prefrontal cortex, respectively, and were oriented either superior-medially or ventral-laterally. These authors found that the location and orientation of the anodal tDCS electrode influenced the modulation of pain sensitivity, as pain thresholds were increased when the connector was aligned superior-medially along the central sulcus. A novel target for pain relief is the epidermis, which can serve as an interface for pain modulation via neuroimmune and endocrine signaling. Selva-Sarzo et al. evaluated the efficacy of transcutaneous neuromodulation applied to the lumbar spine to reduce pain in patients with chronic nonspecific low back pain. Their study followed a single-group crossover design, in which 39 patients underwent two interventions in a randomized sequence: transcutaneous neuromodulation tape with magnetic particles and placebo with kinesiology tape. Transcutaneous neuromodulation applied to the lumbar spine significantly reduced perceived pain and increased ankle dorsiflexion range of motion compared to placebo, suggesting a potential role in the modulation of pain perception and motor function through via interaction with epidermal afferents. This study demonstrated immediate improvements in pain relief and mobility, but the long-term efficacy is unclear and requires further investigation. Furthermore, comparisons with other non-invasive techniques are warranted, as are the potential influences of transcutaneous neuromodulation on pain processing at a cortical level. FUS is a novel, non-invasive therapeutic technology, which has the potential to treat a wide range of neurological conditions. The currently approved clinical applications for intracranial use rely on high intensity focused ultrasound for the purposes of ablation in the treatment of movement disorders. In contrast, low intensity focused ultrasound (LIFU) is a non-destructive technique which has the potential to modulate neuronal activity without necessitating hardware implantation. Seol et al. present a scoping review on the potential for LIFU of the spine in the treatment of chronic pain and movement disorders. Chronic neuropathic pain is perhaps the most studied indication for LIFU, with most preclinical studies focus on targeting of the lumbar dorsal root ganglia – many studies demonstrate increased pain thresholds without histological evidence of tissue damage. Preclinical studies of the effects of LIFU on movement disorders and spinal cord injury are less common, although there is early evidence to support some suppression of tremors and spasticity. Due to the limited literature base, a particular knowledge gap is that the optimal ultrasound parameters are unknown, and thus it is not possible to determine a relationship between treatment parameters and their effect on pain or spasticity/tremor modulation – this calls for standardization in reporting parameters and in the use of a common nomenclature. The final article by Aboumerhi et al. reviews the treatment of chemotherapy-induced peripheral neuropathy, which is a dose-limiting side effect of several cancer chemotherapeutic agents that can profoundly affect pain and function. The current standard of care primarily relies on neuropathic pain medications, with emerging evidence for the use of implantable neuromodulation devices such as spinal cord stimulators; however, there remains a significant unmet treatment need for non-invasive or minimally invasive therapeutic modalities. Scrambler therapy is a non-invasive electro-analgesia treatment for chronic neuropathic and cancer-related pain. This technology requires the placement of cutaneous electrodes at the site of pain, followed by the algorithmic delivery of a low-intensity electrical current which is intended to mimic a neuronal action potential with continuously changing waveform patterns. This therapy is purported to work by disrupting the transmission of pain by replacing them with artificial pain-free signals. This review evaluated multiple observational and randomized studies, and identified mixed results in terms of pain relief and duration of efficacy. As for many other non-invasive neuromodulation techniques for pain control, there is a lack of standardization for how the therapy is delivered, and studies are limited by low enrollment and short follow-up. This research topic showcases some of the most recent advancements in treatment for chronic pain using novel non-invasive neuromodulation therapies. As highlighted in this topic, such therapies can be used to target different substrates, such as the brain, spine and skin, each with different purported mechanisms of disrupting pain transmission at the central or peripheral level. There continues to be great interest in elucidating the mechanisms of pain transmission (Apkarian et al., 2005), as well as potentially targeting maladaptive circuitry (Wang et al., 2025). A critical question to ask when evaluating the efficacy of these therapies is, to what extent are they effective beyond placebo? Outcomes in the treatment of chronic pain are notoriously prone to the placebo effect, with one meta-analysis reporting that non-specific effects accounted for approximately 78% of the improvement from invasive procedures in the treatment of chronic pain conditions (Jonas et al., 2015). This finding aligns with a common theme which consistently emerges when evaluating non-invasive neuromodulation therapies – there is tremendous heterogeneity in treatment protocols and patient responses. Many studies have short-term follow-up, lack randomization or appropriate blinding, and are limited by small sample sizes. As such, the study of non-invasive neuromodulation therapies requires more rigor and standardization before appropriate guidelines for their use can be developed. Ultimately, their implementation in the treatment of chronic pain will likely best be served in a personalized, multi-modal approach.