Non-Invasive Brain Stimulation for Core Symptoms of Chronic Primary Pain: A Systematic Review and Meta-Analysis of randomized controlled trials

Chronic Primary Pain (CPP) is a new diagnostic category including chronic pain conditions lacking clinical signs or a clear etiopathogenetic origin. These disorders may share a common neural mechanism known as central sensitization, where nociceptive neurons become hyper-responsive to standard or subthreshold pain stimuli, resulting in pain hypersensitivity. In this context, non-invasive brain stimulation (NIBS) seems a promising tool to improve CPP symptoms by targeting maladaptive brain activity and connectivity. To date, NIBS effects on CPP symptoms remain unexplored. To fill this gap, we conducted a meta-analysis, investigating the effect of NIBS in improving the three core symptoms of CPP, namely pain intensity, emotional distress, and functional disability. Following PRISMA guidelines, we screened four databases up to the end of January 2023. Thirty-five English-written randomized clinical trials were included, comprising 874 participants assigned to the real stimulation condition and 713 to the sham. Findings highlighted the effect of the real over the sham stimulation in improving CPP core symptoms immediately after the treatment. For pain intensity and functional disability, the improvement persisted also at the one-month follow-up. Meta-regression analyses highlighted that a longer CPP duration reduced the effects of NIBS, while an increased number of sessions was associated with greater pain relief at follow-up. Taken together, our results suggest that NIBS can effectively alleviate CPP symptoms in the short and medium term. Further research is needed to define standardized NIBS protocols for CPP management and explore whether combining NIBS with other therapeutic interventions can enhance effects duration and efficacy.