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.

Keywords: fear; gut-brain axis; nocebo effect; somatic pain; stress; treatment expectations; visceral hyperalgesia; visceral pain.

Figure 1

Schematic depiction of the NoVis study design. Participants are initially randomly assigned to one of four groups, combining negative instruction and negative experience (Neg-Neg), negative instruction alone (Neg-Con), negative experience alone (Con-Neg), and a control group without manipulation of negative expectations (Con-Con). On study day 1, all groups undergo an identical thresholding, calibration, and matching procedure and a baseline phase consisting of repeated application of visceral and somatic pain stimuli. Neg-Neg and Neg-Con groups subsequently receive negative treatment instructions regarding the reception of the pain-facilitating drug naloxone, whereas Con-Neg and Con-Con groups are instructed about the application of saline. During the following Experience phase, somatic pain stimuli are surreptitiously increased in Neg-Neg and Con-Neg groups and remain unaltered in Neg-Con and Con-Con. Finally, a test phase identical to baseline is accomplished in all groups. On study day 2 one week later, all groups return and undergo a second test phase consisting of repeated somatic and visceral pain stimulation identical to baseline and Test-1 phases. For thresholding and all experimental phases, gray bars depict somatic pain and black bars represent visceral pain stimuli. The figure was created using BioRender (www.biorender.com).

Figure 2

Overview of time point, content, and treatment context of negative or control instructions provided to the respective experimental groups (i.e., Neg-Neg and Neg-Con, compare to Figure 1). The figure was created using BioRender (www.biorender.com).

Figure 3

Individual sketches (top) and results from intermediate group analyses (bottom) indicating recalled localization and extent of the body area affected by visceral (left) and somatic (right) pain stimulation experienced on study day 1.

Figure 4

Symbolic depiction of anticipated group differences and interindividual variance in the magnitude of nocebo effects induced by negative instructions and experience (group Neg-Neg), negative instructions and unaltered pain experience (group Neg-Con), control instructions and negative experience (group Con-Neg) or no expectancy manipulations (group Con-Con) in the four experimental groups.