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.

The authors have declared no competing interest.

AV was supported in part by a 2019 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation, and in part by the National Recovery and Resilience Plan (PNRR), funded by the European Union NextGenerationEU (project code PNRR-MCNT2-2023-12378259). GL was supported by the same PNRR funding.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors