Placebo hypoalgesia and nocebo hyperalgesia induced by observational learning may be difficult to disentangle in a laboratory setting

Observational learning (OBL) (seeing pain/pain treatment in others) can evoke placebo hypoalgesia and nocebo hyperalgesia. Data that compare these effects and illuminates the role of expectations and empathy are scarce. Healthy participants (n = 105) were randomized to: 1) placebo OBL, 2) nocebo OBL, or 3) no -observation control group. OBL consisted of a model simulating pain relief or increase after a sham ointment was applied to one arm. Pain was evoked with thermal stimuli on both arms (ointment, contralateral) at baseline and postobservation. Expectations, pain ratings, and physiological data (eg, skin conductance level) were collected. A 3 x 2 x 2 (Group x Arm x Phase) mixed analyses of variance revealed a 3 -way interaction that confirmed that OBL modulates pain: F(2, 93) = 6.08, P = .003, eta(2)(p) = .12. Significant baseline -to -post -observation pain increases were shown in the nocebo OBL group, with a bigger increase for the arm with ointment (both P <= .007). In the placebo OBL group, pain was higher for the contralateral relative to the ointment arm (P < .001). Baseline -to -post -observation pain increase was significant for the contralateral arm (P < .001). Expectation mediated these effects. Skin conductance level decreased over time during ointment trials in the nocebo OBL group, suggesting reduced physiological arousal. The findings illustrate that OBL modulates pain through expectations. In the placebo OBL group, the pain did not decrease for the ointment but increased for the contralateral stimuli, which may reflect nocebo learning. Experimental OBL paradigms typically examine relative differences between ointment and contralateral cues. This can complicate disentangling placebo hypoalgesia and nocebo hyperalgesia in laboratory settings. Implications for existing theories are discussed. Perspective: Data that systematically compare placebo hypoalgesia and nocebo hyperalgesia induced by OBL are scarce. The current work illustrates that these effects may be more difficult to disentangle than previously assumed, which could have implications for existing theories on OBL and placebo effects and their translation to clinical practice. (c) 2023 The Author(s). Published by Elsevier Inc. on behalf of United States Association for the Study of Pain, Inc