Brain responses during provoked pain in patients with chronic primary pain: A systematic review and meta-analysis of fMRI studies.

Chronic pain involves complex mechanisms that remain poorly understood. To address this, the International Association for the Study of Pain introduced the Chronic Primary Pain (CPP) framework in ICD-11 to reflect advances in pain research. In this pre-registered systematic review and meta-analysis, we examined the neural substrates of CPP compared to pain-free individuals during provoked pain. A literature search identified 48 whole-brain fMRI studies (N = 2052) involving experimental pain stimulation in CPP patients (e.g., migraine, fibromyalgia, irritable bowel syndrome), with or without pain-free controls. A conjunction meta-analysis revealed robust activation in the dorsal anterior insula, mid-cingulate gyrus, and medial frontal gyrus during provoked pain across 39 within-subject experiments. Using cluster- and voxel-level corrections, we observed consistent activity in the mid-cingulate and medial frontal gyrus, with the dorsal anterior insula and mid-cingulate gyrus implicated in pain processing in CPP. PERSPECTIVE: This study indicates the need for a new generation of methodologically harmonised studies integrating within- and between-subject effects before the CPP framework can be translated into a clinical tool. Achieving this translation requires significant methodological consistency in neuroimaging research to precisely identify the CPP neural substrates and advance diagnosis.