Methadone dose-associated risks and outcomes in opioid use disorder treatment - Summary/Abstract Significance: As the population of adults with opioid use disorder (OUD) ages, the proportion of older patients taking medications for OUD (MOUD), including methadone and buprenorphine, has increased, raising concerns that medication risks may be compounded by aging-related conditions to create potentially life- threatening conditions. For methadone specifically, known risks including respiratory depression and disordered cardiac conduction may differentially affect aging adults, whose comorbidity and polypharmacy burdens also tend to increase over time. Although Food and Drug Administration warnings exist for monitoring geriatric patients, lack of high-quality, large-scale research has precluded more specific guidance around safe MOUD management. Therefore, leveraging a national cohort of approximately 54,000 patients in care in the Department of Veterans Affairs derived from the population-level Veterans Aging Cohorts Study’s (VACS) National cohort capturing demographic, phenotypic, and healthcare utilization details from over 13 million patients’ electronic health records, the aims the proposed study are: (1) Among patients initiating methadone between 2016-2025, assess time to medically significant fall as a function of time-updated and cumulative methadone dose exposure; (2) Among patients taking methadone versus buprenorphine for OUD between 2016-2025, assess the dose-associated risk of methadone versus buprenorphine on medically significant falls; and (3) Within medication type (methadone or buprenorphine), assess the relative effect of age group on risk for medically significant falls. The study engages an investigative team of experts in addiction medicine, MOUD, epidemiology, bioinformatics, and aging. Novel algorithms developed by our investigators and validated on VA patient populations will be validated on the new cohort to identify chart-documented medically significant falls and methadone dose exposure. Using an observational cohort study design, target trial emulation techniques will be applied to balance characteristics of patients exposed to methadone versus buprenorphine, and Cox proportional hazards models will estimate dose- and age-associated risks for the primary outcome of medically significant falls and secondary outcomes of all-cause mortality and opioid-related overdose. Leveraging a well-developed study infrastructure reflecting our group’s long history of collaboration, we propose an efficient 4-year study that will engage partnerships with the VACS network of investigators and the VA Pharmacy Benefits Management office to ensure the study is advised by latest methods and medication safety priorities. As the first large-scale study to assess absolute and relative risks of MOUD dose exposure in aging patients with OUD, the study has promise to provide critical new insights to inform targeted treatment planning to support older patients’ safety and prevent avoidable, catastrophic harms. Leveraging our team’s broad professional networks and via planned publications and presentations, we will ensure results of this innovative study are widely disseminated and, as appropriate, translated into practice.
