LAUSR

ABSTRACT The objective of this study is to validate a placebo pill response predictive model - a biosignature - that classifies chronic pain patients into placebo-responders (predicted-PTxResp) and non-responders (predicted-PTxNonR), and test whether it can dissociate placebo and active treatment responses. The model, based on psychological and brain functional connectivity, was derived in our previous study and blindly applied to current trial participants. 94 chronic low back pain (CLBP) patients were classified into predicted-PTxResp or predicted-PTxNonR and randomized into no-treatment, placebo treatment, or naproxen treatment. To monitor analgesia, back pain intensity was collected twice a day: 3 weeks baseline, 6 weeks of treatment, 3 weeks of washout. 89 CLBP patients were included in the intent-to-treat analyses and 77 CLBP in the per-protocol analyses. Both analyses showed similar results. At the group level, the predictive model performed remarkably well, dissociating the separate effect sizes of pure placebo response and pure active treatment response, and demonstrating that these effects interacted additively. Pain relief was about 15% stronger in the predicted-PTxResp compared to the predicted-PTxNonR receiving either placebo or naproxen, and the predicted-PTxNonR successfully isolated the active drug effect. At a single subject level, the biosignature better predicted placebo non-responders, with poor accuracy. One component of the biosignature (dorsolateral prefrontal cortex-precentral gyrus functional connectivity) could be generalized across three placebo studies and in two different cohorts - CLBP and osteoarthritis pain patients. This study shows that a biosignature can predict placebo response at a group level in the setting of a randomized controlled trial.