Personality trait predictors of placebo analgesia and neurobiological correlates

Abstract

Personality traits have been shown to interact with environmental cues to modulate biological responses including treatment responses, and potentially having a role in the formation of placebo effects. Here, we assessed psychological traits in 50 healthy controls as to their capacity to predict placebo analgesic effects, placebo-induced activation of μ-opioid neurotransmission and changes in cortisol plasma levels during a sustained experimental pain challenge (hypertonic saline infused in the masseter muscle) with and without placebo administration. Statistical analyses showed that an aggregate of scores from Ego-Resiliency, NEO Altruism, NEO Straightforwardness (positive predictors) and NEO Angry Hostility (negative predictor) scales accounted for 25% of the variance in placebo analgesic responses. Molecular imaging showed that subjects scoring above the median in a composite of those trait measures also presented greater placebo-induced activation of μ-opioid neurotransmission in the subgenual and dorsal anterior cingulate cortex (ACC), orbitofrontal cortex, insula, nucleus accumbens, amygdala and periaqueductal gray (PAG). Endogenous opioid release in the dorsal ACC and PAG was positively correlated with placebo-induced reductions in pain ratings. Significant reductions in cortisol levels were observed during placebo administration and were positively correlated with decreases in pain ratings, μ-opioid system activation in the dorsal ACC and PAG, and as a trend, negatively with NEO Angry Hostility scores. Our results show that personality traits explain a substantial proportion of the variance in placebo analgesic responses and are further associated with activations in endogenous opioid neurotransmission, and as a trend cortisol plasma levels. This initial data, if replicated in larger sample, suggest that simple trait measures easily deployable in the field could be utilized to reduce variability in clinical trials, but may also point to measures of individual resiliency in the face of aversive stimuli such as persistent pain and potentially other stressors.

Figure 1

Simple linear regression representing percent change in Placebo Response associated with 1 SD increase in Trait Measure (with 95% confidence intervals). (** indicates P<0.01; * indicates P<0.05).

Figure 2

Scatterplot and least squares regression line: Percent placebo response (change in pain intensity ratings) and standardized x-score from the optimal PLS model: scatterplot and least squares regression line.

Figure 3

Upper left: experimental design. Two [¹¹C] carfentanil scans were obtained in each subject, with and without administration of a placebo. Lower left: regions of greater μ-opioid release during placebo administration in subjects with High x-scores vs Low x-score. Upper right: x-scores correlations with μ-opioid system activation (change in μ-opioid BP_ND) in the NAc after placebo administration. Lower right: correlations between μ-opioid system activation in the NAc during placebo and the change in pain ratings as measured with the MPQ. BP_ND, binding potential nondisplaceable; MPQ, McGill Pain Questionnaire; NAc, Nucleus accumbens; PAG, Periaqueductal gray; sgACC/dACC, subgenual/dorsal Anterior Cingulate Cortex; VAS, Visual analog scale.

Figure 4

Left: reductions in cortisol plasma levels (μg/dl) after placebo administration. The sustained pain challenge was administered during 20 min, starting at 45 min scan time. Right: Pearson correlations between total MPQ scores and decreases in cortisol plasma levels (μgr/dl) during (pain+placebo)−pain condition 5 min after pain starts. Decreases in cortisol plasma levels within the first 10 min of the pain challenge during placebo administration predicted 33% of the variance of the MPQ scores.