The placebo effect: From concepts to genes

Abstract

Despite its initial treatment as a nuisance variable, the placebo effect is now recognized as a powerful determinant of health across many different diseases and encounters. This is in light of some remarkable findings ranging from demonstrations that the placebo effect significantly modulates the response to active treatments in conditions such as pain, anxiety, Parkinson's disease, and some surgical procedures. Here, we review pioneering studies and recent advances in behavioral, neurobiological, and genetic influences on the placebo effect. Consistent with recent conceptualizations, the placebo effect is presented as the product of a general expectancy learning mechanism in which verbal, conditioned, and social cues are centrally integrated to change behaviors and outcomes. Examples of the integration of verbal and conditioned cues, such as instructed reversal of placebo effects are also incorporated into this model. We discuss neuroimaging studies that have identified key brain regions and modulatory mechanisms underlying placebo effects using well-established behavioral paradigms. Finally, we present a synthesis of recent genetics studies on the placebo effect, highlighting a promising link between genetic variants in the dopamine, opioid, serotonin, and endocannabinoid pathways and placebo responsiveness. Greater understanding of the behavioral, neurobiological, and genetic influences on the placebo effect is critical for evaluating medical interventions and may allow health professionals to tailor and personalize interventions in order to maximize treatment outcomes in clinical settings.

Keywords: conditioning; expectancy; learning; modeling; pain.

Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Figures

Fig. 1

A learning framework. The integrated conceptual framework posits that the placebo effect is a learned response, whereby various types of cues - verbal, conditioned, observational, and social - trigger expectancies that generate behavioral and clinical outcome changes via central nervous system mechanisms. Adapted from Colloca and Miller, 2011.

Fig. 2

Placebo analgesia elicited by continuous (CRF) and partial (PRF) reinforcement paradigms. The cumulative placebo analgesia (+SE) over the entire test/extinction phase was comparable in magnitude for CRF and PRF groups with no significant differences between the two conditions (A). However, the trial-by-trial graphs show that placebo analgesic responses induced by CRF extinguished while those evoked by the PRF did not extinguish over the entire test phase. The Control group received neither conditioning nor verbal suggestion and showed no difference between placebo and control trials (B). Data are presented as mean pain reports ± S.D. The black dots indicate the Control trials and the white dots represent the placebo trials. The pain intensity was set at the same level to test for placebo-induced pain modulation. Data from Au Yeung et al., 2014.

Fig. 3

Placebo analgesia elicited by social learning, conditioning and verbal suggestions. Placebo analgesia was comparable in magnitude in the social learning and classical conditioning groups without a significant difference between the two conditions. Both the learning paradigms produced significantly larger effects than verbal suggestions (A). The graphs show the placebo responses following prior observation, first-person experience via classical conditioning (acquisition and testing phase), and verbal suggestions of benefit (B). Social observational learning and classical conditioning induced significant effects that did not extinguish over the entire experimental session. Conversely, verbal suggestions alone produced smaller and more variable placebo responses. Data are presented as mean pain reports ± S.D. with the black dots indicating the Control trials and the white dots representing the placebo test trials. Data are from Colloca and Benedetti 2009

Fig. 4

Expectancy-drug interactions in a balanced placebo design. Behaviorally, participants who received treatment experienced significantly less pain. Open treatment led to significantly less experienced pain compared to hidden treatment. Most importantly, there was a significant interaction between expectancy and drug treatment: The effect of expectancy was significantly larger in the treatment conditions compared to the no treatment conditions (A). At the level of neural responses, the treatment effect was associated with BOLD signal decreases in the anterior insular cortex (B). The interaction between expectancy and drug treatment was associated with BOLD signal changes in the insular cortex, the rACC and the ventral striatum (C). (Data from Schenk et al., 2014).

Fig. 5

Arginine vasopressin increased placebo analgesia significantly as compared to no treatment, oxytocin, and saline in women but not in men. Participants were instructed to self-administer intranasal oxytocin, vasopressin or placebo. A no treatment group (nor drugs neither saline) was included to control for effects related to the mere administration of drugs. Forty minutes after the acute administration of one of the three agents or watchful waiting, the placebo manipulation took place and participants were tested for placebo analgesic effects while receiving red- and green-paired stimuli set at a painful level. Data are presented as differences between red- and green-pain reports. (Data from Colloca et al. 2015).

Fig. 6

Genetic variant findings. The bar-plot summarizes current results in genetics of placebo effects. Number of publications (y axis) for each published gene (x axis) are presented. Color represent distinct gene pathways (e.g. opioidergic pathway) associated with placebo effects.