Can a Brief Relaxation Exercise Modulate Placebo or Nocebo Effects in a Visceral Pain Model?

Translational research aiming to elucidate mediators and moderators of placebo and nocebo effects is highly relevant. This experimental study tested effects of a brief progressive muscle relaxation (PMR) exercise, designed to alter psychobiological stress parameters, on the magnitude of placebo and nocebo effects in a standardized psychosocial treatment context. In 120 healthy volunteers (60 men, 60 women), pain expectation, pain intensity, and pain unpleasantness in response to individually-calibrated rectal distensions were measured with visual analog scales during a baseline. Participants were then randomized to exercise PMR (relaxation group: N = 60) or a simple task (control group: N = 60), prior to receiving positive (placebo), negative (nocebo) or neutral suggestions regarding an intravenous administration that was in reality saline in all groups. Identical distensions were repeated (test). State anxiety, salivary cortisol, heart rate, and blood pressure were assessed repeatedly. Data were analyzed using analysis of covariance, planned Bonferroni-corrected group comparisons, as well as exploratory correlational and mediation analyses. Treatment suggestions induced group-specific changes in pain expectation, with significantly reduced expectation in placebo and increased expectation in nocebo groups. PMR had no discernable effect on pain expectation, state anxiety or cortisol, but led to significantly lower heart rate and systolic blood pressure. Relaxation significantly interacted with positive treatment suggestions, which only induced placebo analgesia in relaxed participants. No effects of negative suggestions were found in planned group comparisons, irrespective of relaxation. Exploratory correlation and mediation analyses revealed that pain expectation was a mediator to explain the association between treatment suggestions and pain-related outcomes. Clearly, visceral pain modulation is complex and involves many cognitive, emotional, and possibly neurobiological factors that remain to be fully understood. Our findings suggest that a brief relaxation exercise may facilitate the induction of placebo analgesia by positive when compared to neutral treatment suggestions. They underscore the contribution of relaxation and stress as psychobiological states within the psychosocial treatment context—factors which clearly deserve more attention in translational studies aiming to maximize positive expectancy effects in clinical settings

Does Human Experimental Endotoxemia Impact Negative Cognitions Related to the Self?

A role of inflammatory processes in the pathophysiology of depression is increasingly recognized. Experimental endotoxemia offers an established model to induce transient systemic inflammation in healthy humans, and has been proposed as an experimental paradigm of depression. Indeed, different symptoms of depression can be observed during experimental endotoxemia, including negative mood or dysthymia as key symptoms of depression. Hopelessness and low self-esteem constitute common cognitive symptoms in depression, but have not been specifically assessed during endotoxemia. Thus, we pooled data from healthy volunteers who received low-dose endotoxin (i.e., 0.4 or 0.8 ng/kg lipopolysaccharide, LPS) or placebo in three randomized, controlled studies to investigate the effects of LPS on cognitive schemata related to depression. Validated questionnaires were used to assess self-esteem, hopelessness and the vulnerability factor intolerance of uncertainty after intravenous injection of LPS or placebo. Plasma tumor necrosis factor (TNF)-α and interleukin (IL)-6 were repeatedly assessed, along with self-reported mood. Because not all questionnaires were available from primary studies, data were analyzed in two separate data sets: In data set 1, self-esteem and intolerance of uncertainty were assessed in N = 87 healthy volunteers, who randomly received either 0.4 or 0.8 ng/kg LPS or placebo. In data set 2, hopelessness was measured in N = 59 volunteers who randomly received either LPS (0.8 ng/kg) or placebo. In both data sets, LPS-application led to significant increases in TNF-α and IL-6, reflecting systemic inflammation. Positive mood was significantly decreased in response to LPS, in line with inflammation-induced mood impairment. General self-esteem, intolerance of uncertainty and hopelessness did not differ between LPS- and placebo groups, suggesting that these negative cognitive schemata are not responsive to acute LPS-induced systemic inflammation. Interestingly, LPS-treated volunteers reported significantly lower body-related self-esteem, which was associated with increased TNF-α concentration. Thus, certain aspects of self-esteem related to physical attractiveness and sportiness were reduced. It is conceivable that this effect is primarily related to physical sickness symptoms and reduced physical ability during experimental endotoxemia. With respect to cognitive symptoms of depression, it is conceivable that LPS affects cognitive processes, but not negative cognitive schemata, which are rather based on learning and repeated experiences