• Fabrizio Benedetti, Claudia Arduino, Aziz Shaibani, and Wilma Thoen.
• University of Turin Medical School, Neuroscience Department, Turin, Italy; Innovative Clinical Training, Trials & Healthcare Initiative, Zermatt, Switzerland.
• J Pain. 2024 Apr 1; 25 (4): 962973962-973.

AbstractConditioning and expectation are known to be the main mechanisms of placebo analgesia. They may operate together, so that expectations may be enhanced by a conditioning procedure. Although most of the studies have tried to potentiate expectations through conditioning in order to generate good placebo responders, a few studies have tried to mismatch conditioning and expectations in order to investigate the subsequent administration of a placebo. In this study, we want to further investigate this mismatch. We generated incongruent associations during a conditioning procedure in which the study participants did not get what they expected. In fact, although the participants received verbal instructions of pain decrease following the administration of a placebo, we surreptitiously increased the painful electric stimulation. Two pairings of these incongruent associations (mismatch between what was expected and what was experienced) disrupted expectations of analgesia as well as the placebo effect, as assessed by measuring electric pain thresholds on the hand. The effects of mismatch conditioning on the hand extended to the contralateral arm and to a different type of pain (tourniquet), which suggests that local mismatch conditioning may affect the whole body. In all cases, expectations predicted placebo analgesia. These findings indicate that placebo nonresponders can be created in the laboratory by acting on expectations and that local effects can be generalized to other parts of the body. They also stress the importance of expectations in the therapeutic outcome, with important implications for clinical trials. PERSPECTIVE: By using mismatch conditioning, in which study participants did not get what they expected, we reduced expectations of analgesia, and this reduction abolished placebo analgesia. This effect extended to other parts of the body and other types of pain, which indicates that placebo nonresponders can be created in the laboratory.Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.

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