Nocebo effects in visceral pain: concept and design of the experimental randomized-controlled pain study ‘NoVis’

Abstract

The role of psychological factors in the pathophysiology and treatment of chronic visceral pain in disorders of gut-brain interactions (DGBI) is increasingly appreciated. Placebo research has underscored that expectations arising from the psychosocial treatment context and from prior experiences shape treatment responses. However, effects of negative expectations, i.e., nocebo effects, as they are likely crucial elements of DGBI patients’ clinical reality, have thus far only rarely been investigated in the context of visceral pain, with untapped potential for improved prevention and treatment. The experimental randomized-controlled pain study “NoVis,” carried out within the Collaborative Research Center (CRC) 289 (“Treatment Expectation”), aims to close gaps regarding the generation and persistence of nocebo effects in healthy volunteers. It is designed to elucidate effects of negative expectations in a multiple-threat paradigm with intensity-matched rectal distensions and cutaneous thermal stimuli, allowing to test nocebo effects in the visceral and somatic pain modalities. Negative expectations are experimentally induced by elements of doctor-patient communication (i.e., instruction) and/or by surreptitious amplification of symptom intensity (i.e., experience/learning) within a treatment context. Accordingly, the repeated measures between-subject design contains the between-group factors “treatment instruction” (negative vs. control) and “treatment experience” (negative vs. control), with volunteers randomized into four experimental groups undergoing several pain stimulation phases (repeated factor). This allows to compare the efficacy of instruction vs. experience, and more importantly, their combined effects on the magnitude of negative expectations and their impact on pain responses, which we expect will be greatest for the visceral modality. After a Baseline, short-term effects are assessed during a test phase accomplished on study day 1 (Test-1 Phase). To explore the persistence of effects, a second test phase is accomplished 1 week later (Test-2 Phase). Effects of negative expectations within and across pain modalities are assessed at the subjective and objective levels, with a focus on psychophysiological and neuroendocrine measures related to stress, fear, and anxiety. Since nocebo effects can play a considerable role in the generation, maintenance, or worsening of chronic visceral pain, and may even constitute risk factors for treatment failure, knowledge from experimental nocebo research has potential to improve treatment outcomes in DGBI and other clinical conditions associated with chronic visceral pain.

Preoperative Anxiolysis and Treatment Expectation (PATE Trial): open-label placebo treatment to reduce preoperative anxiety in female patients undergoing gynecological laparoscopic surgery – study protocol for a bicentric, prospective, randomized-controlled trial

“…In the video, a patient shares her positive experience of using OLP to effectively reduce anxiety before surgery. This observational learning intervention via video builds on evidence supporting the beneficial effects of digital tools in surgical settings ( 41 ). Based on our knowledge of the role of self-efficacy as a contributor to the effects of OLPs (e.g., 43 ), the content of the video will be designed to enhance expectations of self-efficacy for coping with anxiety.…”

“…Treatment expectations can also arise from previous treatment experiences, as well as information from the media or peers. Our research group has investigated the modulation of expectations by verbal instructions and conditioning in experimental human and patient studies ( 17 , 21 , 32 , 40 , 41 ), but mainly experimental studies on observational learning in placebo or nocebo treatment have been conducted ( 33 ). However, we have also begun to investigate observational learning in patient populations.…”

Working with patients’ treatment expectations – what we can learn from homeopathy

“…Context factors (e.g., the white coat of the physician, the medical equipment, the medical facility, the shape/size/color of a pill, or the act of swallowing a drug, as well as internal cues like symptoms from the patient’s disease or current mental state), could trigger expectations ( Petrie and Rief, 2019 ). Associative learning can also be involved in developing placebo effects by the association of beneficial drug effects with neutral stimuli (e.g., environmental or gustatory cues), which subsequently evoke the benefit without administration of the active drug ( Colloca and Barsky, 2020 ; Hadamitzky et al, 2020 ; Aulenkamp et al, 2023 ). The impact of learning on treatment expectation and treatment outcomes has been investigated in experimental studies showing that positive experiences with treatments in the past amplify placebo responses of subsequent treatments ( Colloca, 2019 ).…”