ABSTRACT This R01 application follows a successfully completed R34 project and addresses our overarching goal of optimizing methadone dosing as a method for managing comorbid chronic pain and opioid use disorder (OUD) among persons receiving methadone for the treatment of OUD. Up to 62% of persons maintained on methadone for OUD experience clinically significant pain, versus 31% in the general population. Pain in MMP is associated with poor OUD treatment outcomes and severe distress. No effective treatment for comorbid pain and OUD currently exists; though preclinical and human data suggest divided methadone dosing may be a more optimal strategy for managing pain than once daily dosing, this has never been empirically examined. This study will evaluate an intervention for comorbid chronic pain among MMP using a double-blind, randomized, placebo-controlled comparison of ONCE versus TWICE daily methadone dosing. This project is strongly supported by our recent successful completion of an R34, which demonstrated strong feasibility and acceptability of an electronic, autonomous, cellular-enabled commercially available pillbox (MedMinder) to manage methadone take-home dosing. Participants in that study indicated they would use the pillbox again (86%) and recommend it to others (95%), local clinics adopted the MedMinder box into their routine take-home management operations, and preliminary within-person data showed clear and orderly pain reductions during the TWICE vs. ONCE dosing periods. Patients from two methadone clinics will be enrolled into a Phase II between-group study and randomized to ONCE versus TWICE-daily methadone dosing for 12-weeks. Methadone will be dispensed via the same electronic pillbox used in the R34. Primary outcomes are weekly assessments of pain and OUD outcomes, ecological momentary assessment of pain before and after dosing, and point-prevalence measures of laboratory-induced pain to explore mechanism of effects. We will assess the following aims: (Primary 1) Determine impact of methadone dose interval (ONCE vs. TWICE) on pain severity, (Primary 2) Determine impact of methadone dose interval (ONCE vs. TWICE) on pain-related function, (Primary 3) Determine impact of methadone dose interval (ONCE vs. TWICE) on OUD-related metrics, and (Secondary 1) Determine impact of methadone dosing interval on response to laboratory-induced pain using quantitative sensory testing. We expect participants assigned to TWICE daily dosing will show decreases in pain severity, improved pain-related function, and no change or improvements in OUD-related outcomes relative to persons receiving standard-of-care ONCE daily dosing. If effective, this approach could transform the care of MMP with pain because it would be feasible to implement within the operational structure of a methadone clinic and would impose low provider burden. Results could provide a high magnitude treatment for the substantial number of MMP who experience daily pain with no rel...