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Brain and Psychological Determinants of Placebo Pill Response in Chronic Pain Patients


Brain and Psychological Determinants of Placebo Pill Response in Chronic Pain Patients

Etienne Vachon-Presseau et al. Nat Commun.


The placebo response is universally observed in clinical trials of pain treatments, yet the individual characteristics rendering a patient a 'placebo responder' remain unclear. Here, in chronic back pain patients, we demonstrate using MRI and fMRI that the response to placebo 'analgesic' pills depends on brain structure and function. Subcortical limbic volume asymmetry, sensorimotor cortical thickness, and functional coupling of prefrontal regions, anterior cingulate, and periaqueductal gray were predictive of response. These neural traits were present before exposure to the pill and most remained stable across treatment and washout periods. Further, psychological traits, including interoceptive awareness and openness, were also predictive of the magnitude of response. These results shed light on psychological, neuroanatomical, and neurophysiological principles determining placebo response in RCTs in chronic pain patients, and they suggest that the long-term beneficial effects of placebo, as observed in clinical settings, are partially predictable.

Conflict of interest statement

The authors declare no competing interests.


Fig. 1
Fig. 1
Placebo pill ingestion diminishes back pain intensity while trial participation non-specifically decreases qualitative pain outcomes. a Experimental design and time line: CBP patients entered a six-visit (V1-6) 8-week randomized controlled trial, including baseline (BL), treatment (T1, T2), and washout (W1, W2) periods. Participants entering and completing the study are indicated. b Example time series of smartphone app pain ratings in 2 patients (values in parentheses are numbers of ratings). c The patients receiving placebo treatment (PTx) showed lower pain levels during the last week of each treatment period, compared to the patients in the no treatment arm (NoTx). d Within-subject permutation tests between pain ratings entered during BL and T1 or T2 identified responders in PTx and NoTx groups. The group-averaged %change in phone app ratings of back pain intensity (2 bins/week) is displayed in d. e The magnitude of response represents the stronger response between the two treatment periods and is displayed in original score (left) and after conversion in %analgesia (right). f Placebo analgesia was present the first day after placebo pill ingestion. g, h Pain intensity decreased by about 20–30% for numerical rating scale (NRS) and memory during both treatment periods. i Qualitative outcome measures (McGill pain questionnaire, MPQ-sensory) decreased in time similarly in all groups, including the NoTx and PTxNonR. j Principal component analyses clustered pain outcomes into 2 factors, segregating intensity and quality. Group by time by Pain (intensity vs quality) interaction indicated that only the pain intensity was diminished by placebo pill ingestion. In ci number of subjects are in parentheses, &p < 0.12; *p < 0.05; **p < 0.01; ***p < 0.001, n.s. not significant. Error bars indicate SEM. For each figure, a description of the analyses and p-values are reported in Supplementary Table 7
Fig. 2
Fig. 2
Personality traits and psychological factors were strongly linked to the magnitude of response. a The covariance matrix shows the relationship between each subscale in the questionnaire data described in detail in Supplementary Table 4. b Univariate statistics showed no group differences surviving Bonferroni correction for 37 comparisons. c However, openness (from the big 5 personality dimensions) and 4 out of 8 subscales from the Multidimensional Assessment of Interoceptive Awareness (MAIA)- Not Distracting (maia/nd), Attention Regulation (maia/a), Emotional Awareness (maia/e), and Self-Regulation (maia/sr)- correlated with the magnitude of response after correcting for multiple comparisons (p < 0.0013; shown in black). Patients with increased emotional awareness experience greater placebo analgesia (Maia/e displayed in d), whereas patients who tend not to ignore or distract themselves from discomfort experience less placebo analgesia (Mais/nd displayed in e). The red circle marks an outlier on the magnitude of response that was excluded. Other abbreviations used: Pain Anxiety Symptoms Scale (PASS) and its 4 subscales—Avoidance (pass/a), Cognitive (pass/c), Fear (pass/f), and Physiological (pass/p); Pain Catastrophizing Scale (PCS) and its 3 subscales—Rumination (pcs/r), Magnification (pcs/m), and Helplessness (pcs/h); Chronic Pain Acceptance Questionnaire (CPAQ) and its 2 subscores—Activity Engagement (cpaq/a) and Pain Willingness (cpaq/pw); the remaining 4 MAIA subscales—Noticing (maia/n); Not Worrying (maia/nw); Body Listening (maia/bl); and Trusting (maia/t); Pain Sensitivity Questionnaire (PSQ) and its 2 subscales—Painful (psq/p) and Non-Painful (psq/np); Positive and Negative Affect Scale (PANAS) with Positive (panas/p) and Negative (panas/n) subscales; Five Facets of Mindfulness (FFM) with its 5 subscales—Observe (ffm/o), Describe (ffm/d), Act with Awareness (ffm/a), Non-Judge (ffm/nj), and Non-React (ffm/nr); Emotional Regulation Questionnaire with its Reappraisal (erq/r) and Suppression (erq/s) subscales; Attentional Control Scale (acs); Emotional Attentional Control Scale (eacs); Life Orientation Test—Revised version (lotr); Loss Aversion Questionnaire (laq); and Beck Depression Index (bdi)
Fig. 3
Fig. 3
Placebo pill response is predetermined by subcortical limbic volume asymmetry and sensorimotor cortex thickness. a Heat maps display overlap of automated segmentation for nucleus accumbens (NAc), right hippocampus (R Hip), and amygdala (AMY) across all patients. The placebo pill responders displayed a rightward asymmetry in overall volume of these three subcortical limbic structures after controlling for peripheral gray matter volume, age, and sex at visit 2. The placebo group-dependent asymmetry was observed at all 4 visits/scans. b Whole-brain neocortical vertex-wise contrast indicated thicker sensorimotor, right superior frontal gyrus (R SFG), in PTxNonR. This effect was consistent across all 4 visits/scans. c These anatomical properties correlated with the magnitude of the response. All post hoc comparisons were Bonferroni corrected for three comparisons: *p < 0.05; **p < 0.01; ***p < 0.001. Error bars indicate SEM. The red circle marks an outlier on the magnitude of response and was excluded from the %analgesia correlation analyses
Fig. 4
Fig. 4
Placebo pills response identifies a lateral prefrontal functional network with invariant and transient components. a Previous results indicate that functional connectivity in four regions: middle frontal gyrus (MFG), rostral-anterior and posterior cingulate cortex (rACC, PCC), and sensorimotor (SM) cortices predict placebo response in OA patients. Co-activation maps derived from these seeds (green) (1000 healthy subjects from were used to restrict brain networks of interest. The connectivity matrices of our data were restricted to communities overlapping with these networks of interest: default mode network (DMN), frontoparietal (F-P), sensorimotor (SM), and subcortical limbic. b, c A permutation test was performed on the weighted 7381 resting state connections between all possible pairs of nodes within the modules of interest (FDR-corrected p < 0.05). Stronger connectivity link Ventrolateral prefrontal cortex (VLPFC)-Precentral gyrus (PreCG) and weaker connectivity links VLPFC-rACC, and VLPFC/DLPFC-periaqueductal gray (PAG) identified placebo responders prior to treatment (visit 2). df VLPFC-PreCG and VLPFC-rACC connections differentiated placebo responders and remained constant in time while VLPFC/DLPFC-PAG connectivity differentiated placebo pill response transiently (interaction time with group trending p = 0.09). g Each of these brain parameters correlated with the magnitude of the response. All post hoc comparisons were Bonferroni corrected for three comparisons: &p = 0.09; *p < 0.05; **p < 0.01; ***p < 0.001; + within comparison V2 vs. V5: p < 0.05. Error bars indicate SEM. The red circle marks an outlier on the magnitude of response and was excluded from the %analgesia correlation analyses
Fig. 5
Fig. 5
Machine learning classifies placebo response (PTxResp/PTxNonR) and predicts the magnitude of response. a A support vector machine (SVM) classifier was applied to the questionnaire data in a nested leave-one-out cross-validation (LOOCV) procedure. b The observed accuracy of this classification analysis is displayed against the null distribution generated using scrambled codes from 1000 randomized labels. cd Classification performance was assessed based on the confusion matrix. The ROC curve shows specificity and sensitivity of the model. ef LASSO regression was applied to the questionnaire data and predicted the magnitude of response in the left-out patients. g Averaged weights across the n = 43 loops of the cross-validation procedure show that six psychological factors predicted the magnitude of response. hi Features selected from rsfMRI within each training sample predicted the magnitude of response in the left-out patients. j A single set of consensus weights was generated by averaging the weight of each feature across the n = 43 loops; this consensus set is projected back onto the brain for display. Nodes of the most frequently selected features (>0.84 of loops) are labeled on the figure k. Linear regression analysis indicated that the predicted magnitude of response from rsfMRI at V2 and from personality at V1 were independent contributors that jointly explained 36% of the variance in actual response to placebo treatment. l The classifier (a) and the regression model (k) failed to predict placebo response in patients of the NoTx group. The red circle marks the predicted magnitude of response for the outlier, which was excluded for assessing the error of the model. *p < 0.05; **p < 0.01; ***p < 0.001; AMY amygdala; DLPFC dorsolateral prefrontal cortex; OFC orbitofrontal cortex; PAG periaqueductal gray; PreCG precentral gyrus; SMG supramarginal gyrus

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