Prior Therapeutic Experiences, Not Expectation Ratings, Predict Placebo Effects: An Experimental Study in Chronic Pain and Healthy Participants

Abstract

Introduction: Many clinical trials fail because of placebo responses. Prior therapeutic experiences and patients' expectations may affect the capacity to respond to placebos in chronic disorders. Objective: The scope of this study in 763 chronic orofacial pain and healthy study participants was to compare the magnitude and prevalence of placebo effects and determine the putative role of prior therapeutic experiences vs. expectations. Methods: We tested placebo propensity in a laboratory setting by using 2 distinct levels of individually tailored painful stimulations (high pain and low pain) to reinforce expectations and provide a hypoalgesic experience (conditioning phase). Afterwards, both levels of pain were surreptitiously set at a moderate pain level to test for placebo effects (testing phase). Pain and expectation ratings were assessed as primary outcomes using visual analog scales. Results: In both chronic pain and healthy participants, placebo effects were similar in magnitude, with the larger prevalence of responders in the healthy participants. Although chronic pain participants reported higher pain relief expectations, expectations did not account for the occurrence of placebo effects. Rather, prior experience via conditioning strength mediated placebo effects in both pain and healthy participants. Conclusions: These findings indicate that participants with chronic pain conditions display robust placebo effects that are not mediated by expectations but are instead directly linked to prior therapeutic experiences. This confirms the importance of assessing the therapeutic history while raising questions about the utility of expectation ratings. Future research is needed to enhance prediction of responses to placebos, which will ultimately improve clinical trial designs.

Association of nocebo hyperalgesia and basic somatosensory characteristics in a large cohort

“…Nevertheless, the methodology employed here has repeatedly proven successful in inducing placebo effects in the past 9,34,44 . Moreover, other studies of comparable sample size have reported larger placebo effects 27,28 . It is therefore possible www.nature.com/scientificreports/ that the scarcity of measures associated with placebo responses was due to their small effect size, and the regression analysis for nocebo responses was more successful because of the higher effect sizes.…”

“…Fourth, the assumptions regarding the association of trait variables and outcomes are comparatively basic, and we did not consider more complex psychological process models recently applied to expectation effect research, such as the Elaboration Likelihood Model of persuasion 45 . Relatedly, expectations themselves were not assessed despite conceptual merit 6 , while empirical merit is more ambiguous 27,46 . Here, we opted against querying expectation ratings due to the risk of amplifying demand characteristics and carry-over effects inherent in a cross-over design 47 .…”

“…Regarding predictors for nocebo responses, a relationship with dispositional pessimism 22 , and neuroticism 26 has been reported. In general, placebo effects have received far more attention than nocebo effects 11 , including recent studies involving large cohorts 27,28 . However, the importance of nocebo effects for quality of life, medication adherence and ultimately treatment success are being increasingly acknowledged 14,29 .…”

Association of nocebo hyperalgesia and basic somatosensory characteristics in a large cohort

“…Regarding predictors for nocebo responses, a relationship with dispositional pessimism 14 , and neuroticism 18 has been reported. In general, placebo effects have received far more attention than nocebo effects 7 , including recent studies involving large cohorts 19,20 . However, the importance of nocebo effects for quality of life, medication adherence and ultimately treatment success are being increasingly acknowledged 21 .…”

Neural effects of placebo analgesia in fibromyalgia patients and healthy individuals

“…There was no difference in placebo analgesic responses in FM patients and HCs which is consistent with the few studies comparing placebo effects to experimental stimuli in pain patients and healthy participants. The most recent and largest behavioral study of this kind reported no differences in placebo effects between 363 chronic pain patients with temporomandibular disorder and 400 healthy controls [12]. Comparable placebo effects have also been reported between healthy participants and patients with episodic migraine [30], irritable bowel syndrome (IBS) [28], and atopic dermatitis [24].…”