The efficacy of Non-invasive Brain Stimulation techniques on Chronic Primary Pain disorders: a systematic review and meta-analysis

Background: Chronic Primary Pain (CPP) is characterized by an intense pain, not explained by lesions/damage to the nervous system, lasting for more than three months. Not all CPP patients benefit from standard pharmacological therapies nor are suitable for invasive neurosurgery treatments. Non-invasive brain stimulation (NIBS) uses cortical stimulation to reduce pain by directly altering brain activity, and its effects in treating CPP is still unclear. Objectives: We aimed at evaluating NIBS effects on CPP patients. Methods: A PRISMA systematic review was performed in PubMed, Embase, Scopus and Web of Science in May 2021. English-written, original studies measuring the effects of NIBS on pain perception were considered. The quality of studies was assessed with the Cochrane Risk of Bias and the Robins-I. The meta-analysis was conducted only on sham-controlled double-blinded studies. The pain intensity, measured through visual or numerical rating scales, was used as outcome of interest. Results:134 studies were included, comprising 2444 patients and 5 different Primary Pain conditions. The meta-analysis was run on a preliminary cohort of 42 studies. When compared to sham effects, real NIBS induced a significant decrease of pain intensity (SMD −0.59 [CI: −0.85, −0.34]; p < 0.001). Meta-regression analysis did not show any effect of type of NIBS (i.e., rTMS vs tDCS), target region (i.e., DLPFC, M1, S1, dACC, PFC, VC) and protocol type (i.e., excitatory vs inhibitory). Discussions: Our findings show a reduction of perceived pain after real vs sham stimulation. This result was confirmed also separately for tDCS and TMS. The target region, as well as the protocol intensity didn’t influence the results. This suggests that NIBS can be used as an alternative or as a combined approach in CPP treatment, but more randomized clinical trials are needed to further explore the mechanisms underlying its effects.