Meta-analytic evidence for distinct neural correlates of conditioned versus verbally induced placebo analgesia

Placebo analgesia demonstrates that belief and expectation can significantly alter pain, even without active treatment. Placebo analgesia can be induced through verbal suggestion, classical conditioning, or their combination, though the role of conditioned neural responses above and beyond effects of verbal instructions remains unclear. We conduct a systematic meta-analysis of individual participant data from 16 within-participant placebo neuroimaging studies (n = 409), employing univariate and multivariate analyses to identify shared and distinct mechanisms of placebo analgesia induced by suggestions alone versus suggestions combined with conditioning. Both techniques increase activity during pain in the dorsolateral prefrontal and inferior parietal cortices and decrease activation in the insula, putamen, and primary sensory areas. Adding conditioning enhances 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 strengthens the negative association between analgesia and nociceptive activity, as quantified by the Neurologic Pain Signature. Combining conditioning with instructions yields greater placebo 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 in the brain.