Non-Invasive Brain Stimulation for Core Symptoms of Chronic Primary Pain: A Meta-Analysis of RCTs

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 hyper-sensitivity. In this context, non-invasive brain stimulation (NIBS) appears to be a promising tool for improving CPP symptoms by targeting maladaptive brain activity and connectivity. To date, the effects of NIBS 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 February 2025 for English-language, peer-reviewed randomized clinical trials that included CPP patients treated with NIBS and reported pre/post or follow-up scores on validated measures of at least one core symptom. Quality of life was examined as an additional outcome.

Fifty-four studies were included, with 1371 participants receiving real stimulation and 1103 sham. Findings highlighted that real stimulation improved CPP symptoms immediately after treatment and at one-month follow-up. Meta-regressions showed that longer CPP duration reduced short-term effects on emotional distress and diminished all outcomes at one-month follow-up.

Further research is needed to establish standardized NIBS protocols for CPP management, to investigate the effectiveness at longer follow-up periods, and to test whether combining NIBS with other interventions enhances treatment effectiveness and durability.