Traits that Affect Response to a Placebo Pill in Chronic Pain

Post by Amanda McFarlan

What's the science?

The placebo response is a phenomenon whereby an individual perceives or experiences an improvement in symptoms after receiving an inactive treatment. The relief of pain after exposure to placebo is of particular interest in the study of chronic pain, since many treatments for pain can have long-term adverse effects or addictive properties. So, the question remains – why do some people experience analgesia (pain relief) in response to an inert treatment? Efforts to study the underlying mechanisms of the placebo effect have been achieved using randomized placebo-controlled trials in chronic pain patients. These studies have provided evidence that individuals with chronic pain may exhibit different brain connectivity that predispose them to respond to a placebo treatment. This week in Nature Communications, Vachon-Presseau and colleagues examined the psychological and neural traits among individuals with chronic back pain to determine what traits predispose an individual to respond to a placebo.

How did they do it?

The authors analyzed a total of 63 participants in their randomized placebo-controlled clinical trial on placebo response. Participants were separated into three groups: placebo pill responding, placebo pill non-responding  and no treatment. The authors asked participants to visit the lab 6 times over an 8-week period for pain assessments, including verbal recall of pain ratings and questionnaires, and brain imaging using resting state fMRI. Participants received the placebo treatment during the second and fourth visits, both followed by a washout period in which no treatment was administered. In addition to assessments in the lab, participants used a smartphone app to rate their back-pain intensity twice a day in their natural environment. The participants’ pain ratings, questionnaire scores (for pain rating as well as psychological measures) and MRI scans were used to determine whether psychological, structural and functional differences were present in placebo responding individuals.

What did they find?

The authors determined that the placebo pill responding group had psychological, structural and functional differences in the brain compared to the placebo pill non-responding and no treatment groups. First, the participants’ daily pain rating using the smartphone app revealed that participants taking the placebo pill reported significantly lower levels of pain compared to those in the no treatment group, indicating the placebo pill was sufficient to induce analgesia. Second, the magnitude of analgesic response was found to be correlated with four sub-scales from the Multidimensional Assessment of Interoceptive Awareness questionnaire, including Emotional Awareness and Not Distracting, and the quality of ‘openness’ from the Neo-5 Personality Dimensions, suggesting these traits may be psychological factors predisposing an individual to a placebo pill response. Third, brain scans (structural MRI) obtained prior to the first placebo pill treatment revealed that the volume in limbic (subcortical) regions of the brain was asymmetric in patients who responded to placebo compared to non-responding individuals and that this asymmetry remained consistent in all four brain scans throughout the trial. Additionally, measurements of cortical thickness revealed that non-responding participants had thicker cortex in the prefrontal cortex (right superior frontal gyrus) compared to responding participants. Finally, an analysis of functional connectivity in the brain prior to the first treatment revealed that the patients who responded to placebo, compared to the non-responding group, had stronger connections between the ventrolateral prefrontal cortex and the precentral gyrus and weaker connections between the ventrolateral prefrontal cortex and the rostral anterior cingulate gyrus (these regions of the brain are generally involved in cognition, emotion, and movement). These differences in connections remained consistent throughout the trial, suggesting they may be predisposing factors to a placebo response. Anatomical and functional brain measurements in the no treatment group remained consistent throughout the trial.  


What's the impact?

This is the first study in chronic pain to compare a placebo-receiving group with a non-treatment group in a brain imaging randomized placebo-controlled clinical trial. The authors in this study found that there are psychological traits as well as structural and functional brain differences between individuals who respond to the placebo pill and individuals who do not. These findings suggest these factors are predisposing to the placebo pill response and may be used in computational models to predict the likelihood that an individual will respond to a placebo.


Vachon-Presseau et al. Brain and psychological determinants of placebo pill response in chronic pain patients. Nature Communications (2018). Access the original scientific publication here.