We aimed to identify shared and distinct mechanisms of placebo analgesia induced by suggestions alone versus suggestions combined with conditioning. We conducted a systematic meta-analysis of individual participant data from 16 within-participant placebo neuroimaging studies (n = 409).

Both techniques increased activity during pain in the dorsolateral prefrontal and inferior parietal cortices and decreased activation in the insula, putamen, and primary sensory areas. Adding conditioning enhanced engagement of regions associated with context representation and pain modulation (e.g., dorsolateral/dorsomedial prefrontal cortices) and decreases in nociceptive regions (e.g., primary sensory and insular areas). Conditioning also strengthened the association between analgesia and nociceptive activity, as reflected in the Neurologic Pain Signature. Combining conditioning with instructions yielded greater analgesia, mediated by increased ventromedial prefrontal and dorsal caudate activity, alongside decreased sensory-nociceptive and cerebellar activity.

These findings suggest the two strategies rely on partially distinct mechanisms, which could be combined to optimize placebo analgesia’s clinical application. Read the full preprint on bioRxiv here.