The primary goals of this K24 competing renewal application are to allow Sean Mackey, M.D., Ph.D. to 1) continue to devote near full time effort to his program of pain and prescription opioid research; and 2) provide high-quality and intensive mentorship of early-career investigators in patient-oriented research (P0R). A K24 renewal will continue to provide Dr. Mackey with the critical protected time for POR and mentoring that would otherwise be spent on administrative and clinical responsibilities. Dr. Mackey is the Redlich Professor and Division Chief of Pain Medicine at Stanford University. Since receiving a K24 award Dr. Mackey has accomplished the major goals of his original application and much more. Dr. Mackey's research plan for this K24 renewal application includes work as a P01 PD to investigate mechanisms of chronic low back pain (CLBP) and four therapies; characterizing the effects of opioids on brain structure in patients with CLBP; expanding his work in neuroimaging based biomarkers (Co-I on R01); continuing role in the NIDDK Multi-Disciplinary Approach to the Study of Chronic Pelvic Pain network; further development, implementation and dissemination of the Stanford-NIH based partnership for an open-source, free health registry (PI). Dr. Mackey's mentoring plan includes training his mentees in: 1) designing and implementing pain research studies; 2) preparing scientific papers and presentations; 3) writing successful grant applications; 4) responsible conduct of research; and 5) successful navigation of the academic process to achieve scientific independence. This mentoring plan will be applied to his direct mentees as well as those he oversees as the PD for his NIDA T32 Interdisciplinary Research Training in Pain and Substance Use Disorders. Dr. Mackey will accomplish this through a combination of role modeling, individual and group meetings, collaborative mentoring, and integration with Stanford's Clinical and Translational Science Award (CTSA) mentoring program. Dr. Mackey's career development plan includes further training in machine learning approaches for neuroimaging analysis as well as for his health registry; multimodal MRI collection and analysis methods; analysis of large data sets and longitudinal data. With the outstanding resources and collaborations at Stanford and novel projects, the ongoing projects are expected to be either renewed or lead to new directions in pain and substance use research and significantly contribute to our scientific understanding of these disabling conditions. Further, these projects and Dr. Mackey's mentorship will support the need to train the next generation of investigators conducting important pain and substance abuse POR.