Investigating the Feasibility of Combining Mindfulness Intervention and Open-Label Placebo Treatment for Chronic Pain - PROJECT SUMMARY: Chronic pain affects over one third of the U.S. population and is a leading cause of disability. Hence, there is pressing need for developing innovative, safe, and accessible non-opioid treatments that effectively alleviate chronic pain. Mindfulness-based therapies (MBTs) have emerged as widely used mind-body interventions for chronic pain, focusing on enhancing present-moment attention, non-judgmental awareness, and acceptance. Despite their popularity, the overall effects of MBTs on pain-related outcomes remain modest. Recent mechanistic studies have shed light on the fact that mindfulness meditation does not modulate the endogenous opioid system, a crucial player in pain relief. This revelation underscores the potential for improving the efficacy of an MBT by integrating it with a safe, non-opioid intervention capable of directly modulating endogenous opioid system. Open-label placebo (OLP), a non-deceptive placebo, presents a promising, safe, and ethical intervention for chronic pain that can be combined with an MBT. Research has indicated that placebo-induced analgesia is mediated by the release of endogenous opioids. Consequently, there is a strong rationale to hypothesize that the combined application of an MBT and OLP treatment may yield more potent and enduring effects in alleviating chronic pain than either treatment used in isolation. This R34 study proposes a single-site three-arm randomized-controlled trial to evaluate the feasibility and acceptability of combining Mindfulness-Based Stress Reduction (MBSR), one of the most established and extensively studied MBTs for chronic pain, with OLP treatment for individuals living with chronic pain. A total of 45 participants will be randomly assigned to one of the following three conditions for an 8-week trial with a 3- month follow-up period: (1) MBSR-only; (2) OLP-only; and (3) a combination of MBSR and OLP treatment. The feasibility of conducting the proposed trial will be determined by several metrics, including: (1) the rate of participant enrollment, (2) participant retention from baseline to 3-month post-treatment follow-up, (3) adherence to the MBSR program, (3) adherence to OLP treatment monitored using a smart pillbox and the detection of urinary riboflavin tracer in mid- and post-treatment sessions; and (5) compliance with daily diary assessments. The acceptability of combining MBSR and OLP treatment will be determined by self-report ratings regrading (1) treatment satisfaction, (2) intervention effectiveness, (3) intervention convenience, (4) side effects, (5) appropriateness of intervention and daily diary assessment length and frequency; and (6) appropriateness of other study measures. The ultimate goal of this study is to advance chronic pain management strategies for millions of individuals with chronic pain. The proposed study will serve as a pivotal initial step in establishing procedures and strategies necessary for a comprehensive evaluation of combined MBSR and OLP treatment in a future fully-powered multi-site clinical trial.