Background Chronic neuropathic pain is a complex experience, posing a major challenge in personalizing its treatment. Present treatments consist of non-specific, standardized drugs that are often addictive, leaving many patients non-respondent and with significant side effects. Designing individualized therapies requires targeting the multidimensionality of pain and developing objective endpoints to demonstrate their effectiveness. Currently, non-pharmacological alternatives are emerging, such as neurostimulation and Virtual Reality (VR), activating pain relief via peripheral neuromodulation and attention modulation. Similarly to drugs, many neurostimulation approaches are unspecific, targeting areas near the pain site and disregarding the neural pathway of pain. Above all, neurostimulation and VR are yet to be evaluated as a combined synergistic intervention, particularly in a randomized controlled trial (RCT).

Methods and Findings To this aim, we developed a targeted neurostimulation congruent with immersive VR platform providing a multisensory pain intervention through the synergistic application of somatotopic electro-tactile and visual stimuli. The endpoints included measuring sensory, neurophysiological (EEG), and self-reported indicators of pain. We tested the efficacy of the multisensory intervention against the control consisting of VR-only intervention on four consecutive intervention days in an RCT (N=18 neuropathic patients). The multisensory intervention resulted in a clinically significant reduction of pain (>50%), lasting up to one-week follow-up. The provided analgesic effect was statistically stronger compared to the VR-only control across treatment days and at follow-up. The clinically relevant pain decrease was accompanied with objective improvements in tactile acuity, proprioceptive measures, and changes in EEG pain biomarkers for the multisensory intervention group only.

Conclusions The developed multisensory treatment showed a clinically significant reductions in self-reported pain, supported by improvements in objective sensory and neurophysiological measures. These results represent a significant advancement in the treatment and assessment of pain, offering a non-invasive, accessible, and cost-effective solution for neuropathic pain, a major societal burden and one of the most prevalent neurological conditions worldwide.

The authors have declared no competing interest.

NCT05483816

European Research Council (ERC) under the European Unio's Horizon 2020 research and innovation program (FeelAgain grant agreement No. 759998) Swiss National Science Foundation (SNSF) (MOVEIT No. 197271) IDEJE by Science Fund of the Republic of Serbia (DiabeticReTrust no. 7753949)

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The experiments were designed and conducted in accordance with the Declaration of Helsinki and received approval by the Kantonale Ethikkommission Zurich (Nr. 2021-02258).

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