ABSTRACT Chronic low back pain (cLBP) is the most common clinical pain condition worldwide, and the top chronic non-cancer condition for which opioids are prescribed. The current opioid crisis in the U.S. emerged in large part from overuse and misuse of opioids by patients with cLBP. Yet, there are few evidence-based interventions to reduce opioid use and misuse among patients with cLBP. Faced with a lack of effective treatment options, some cLBP patients become ensnared in a downward spiral of opioid dose escalation. Mindfulness-based interventions reduce chronic pain and opioid dosing. However, lack of mechanistic data has limited the deployment of these cost-effective and non-pharmacological treatment approaches. Multiple clinical trials indicate that Mindfulness-Oriented Recovery Enhancement (MORE), a novel mind-body therapy that integrates mindfulness with other affect regulation techniques, alleviates chronic pain symptoms as well as opioid use among people with cLBP. Yet, the active brain mechanisms of action underlying MORE’s analgesic and opioid sparing effects remain unknown. Further, no known placebo-controlled studies have disentangled the specific neural mechanisms of MORE or other mindfulness-based interventions for cLBP from nonspecific therapeutic factors like beliefs, expectancy, and social support. As such, the proposed study will employ one of the most rigorous control conditions in the mindfulness literature to date—a validated sham-mindfulness meditation technique combined with supportive psychotherapy (Sham-MORE). Integrating functional neuroimaging and psychophysics (noxious heat and behavioral pain ratings), the overarching aims of the proposed R01 study are to a) identify the neural mechanisms supporting the immediate analgesic effects of MORE (versus Sham-MORE and treatment-as- usual), and b) to determine if changes in default mode network functional connectivity predict individual differences in cLBP relief and opioid dose reduction following treatment with MORE. Ultimately, the proposed work will yield insight into the fundamental neuro-functional processes mediating the therapeutic effects of mindfulness-based interventions for cLBP, thereby facilitating the optimization of novel biobehavioral treatments for this highly prevalent and disabling chronic pain condition that helped to fuel the ongoing opioid crisis.