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.

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Publication Details

Journal
Nature Communications
Published
2026-07-17
DOI
https://doi.org/10.1038/s41467-026-74743-0
Primary Topic
Pain Management and Placebo Effect
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Davide Duzzi, Ulrike Bingel, Tor Dessart Wager, Katja Wiech et al.
Nature Communications
Pain Management and Placebo Effect
article

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

Davide Duzzi, Ulrike Bingel, Tor Dessart Wager, Katja Wiech, Lieven A. Schenk, Jae Chan Choi, Luana Colloca, Nathalie Wrobel, Matthias Zunhammer, Helena Hartmann, Stephan Geuter, Christian Büchel, Alexa Huber, Dan‐Mikael Ellingsen, Tamás Spisák, Falk Eippert, Sigrid Elsenbruch, Fausta Lui, Bálint Kincses, Fadel Zeidan, Irene Tracey, Carlo A. Porro, Irving Kirsch, Ted J. Kaptchuk, Fabrizio Benedetti, Siri Leknes, Jian Kong, Lauren Atlas
article en

Abstract

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.

Nature CommunicationsVol. 17(1)
Dartmouth College (US), University of Modena and Reggio Emilia (IT), University of Maryland, Baltimore (US), Oslo University Hospital (NO), University of Vienna (AT), National Institutes of Health (US), Beth Israel Deaconess Medical Center (US), National Institute on Drug Abuse (US), Harvard University (US), Johns Hopkins University (US), Universität Hamburg (DE), University of Oslo (NO), Yonsei University (KR), Høyskolen Kristiania (NO), Karolinska Institutet (SE), Plateau State University (NG), University of Oxford (GB), National Center for Complementary and Integrative Health (US), Massachusetts General Hospital (US), Wellcome Centre for Integrative Neuroimaging (GB), Korea Institute of Brain Science (KR), Korea Soongsil Cyber ​​University (KR), University Medical Center Hamburg-Eppendorf (DE), Essen University Hospital (DE), Max Planck Institute for Human Cognitive and Brain Sciences (DE), Cyber University of Korea (KR), Wake Forest University (US), University of Turin (IT), Ruhr University Bochum (DE), University of Bologna (IT)
Deutsche Forschungsgemeinschaft, National Institutes of Health
Openalex Percentile: Top 7%
Pain Management and Placebo Effect
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