Unraveling nocebo effects in visceral pain: negative suggestion and adverse treatment experience uniquely shape visceral pain unpleasantness

Abstract

Visceral pain, characterized by its diffuse, poorly localized, and fear-inducing nature, may be especially prone to nocebo effects. This preregistered experimental study investigated whether (1) visceral pain is more susceptible to nocebo effects than somatic pain, and whether (2) an adverse treatment experience in the somatic modality contributes to visceral nocebo effects by cross-modal generalization. A total of 101 healthy volunteers received inert treatment and were randomized into 4 experimental groups: negative treatment suggestions, adverse somatic treatment experience, their combination, or control. Individually calibrated visceral (rectal distension) and somatic (thermal) pain stimuli were applied. Negative suggestions involved heightened pain sensitivity suggestions; adverse treatment experience was modeled by covertly amplifying thermal pain. Pain ratings, cortisol levels, and emotional states were assessed across pre-, treat-, and test-phases, and upon re-exposure to pain 1 week later. Negative suggestions increased negative expectations and cortisol levels, and the thermal pain manipulation successfully amplified somatic pain during treatment (P < 0.001). In the test-phase, both suggestions and somatic experience independently increased visceral pain unpleasantness (P = 0.004; P = 0.011), whereas no somatic nocebo effects emerged. No group differences appeared at re-exposure, but perceived treatment allocation was influenced both by suggestions and experience. Findings support the distinct vulnerability of the visceral modality to nocebo effects, which can arise or intensify through cross-modal transfer from adverse somatic treatment experiences, emphasizing the importance of provider communication and consideration of prior experiences in the treatment of chronic visceral pain conditions, especially in patients with mixed pain phenotypes.