Background: Over the past decade, VA has implemented opioid policies, most notably the 2013 Opioid Safety Initiative, designed to address the burgeoning opioid crisis. As the pendulum has swung away from opioid prescribing, it is possible that some patients with serious illness may have experienced unintended consequences, including uncontrolled pain, even while others may have avoided potential complications of opioid use. This project examines the potential impact of these policies on Veterans with end-stage renal disease (ESRD), a population of approximately 35,000 Veterans for whom balancing the benefits and harms of opioids may be particularly challenging. These Veterans have very limited life expectancy and a substantial pain burden, comparable to Veterans with metastatic cancer, but often under-appreciated. They are at increased risk of opioid-related serious adverse events (SAE; e.g. opioid overdose). Yet compared with other seriously-ill populations, they have fewer non-opioid analgesic alternatives to fall back on and may face barriers to non-pharmacologic pain management strategies. Moreover, most Veterans with ESRD receive dialysis in the community either under VA Community Care or Medicare, exposing them to the potential adverse impact of care fragmentation on opioid safety and pain control. Significance/Impact: Understanding the impact of VA initiatives to improve opioid safety at the population level on Veterans with serious illness is critical to the VA’s commitment to ensure that these vulnerable Veterans are provided care that relieves distressing symptoms. The work proposed here is responsive to the VA Under Secretary for Health’s priority to improve pain management and the safety of pain medications. Innovation: The proposed study is the first to examine the impact of opioid safety initiatives and prescribing guidelines on a group of seriously-ill Veterans. It leverages VA data that include rich measures of pain control unavailable from any other national data source. The use of a sequential explanatory mixed-methods study design to triangulate quantitative and qualitative findings on pain management in the context of contemporary opioid policy is a novel contribution to the field of opioid research. Specific Aims: 1) Examine changes in pain management strategies, opioid-related SAE, and pain control among Veterans with ESRD from 2010-2018; 2) Compare changes in opioid-related SAE by setting of dialysis (VA, VA-Community Care, Medicare) from 2010-2018; 3) Elicit the perspectives and experiences of Veterans with ESRD and the clinicians who care for them related to pain management in the context of VA opioid safety initiatives in order to inform policy and practice. Methodology: The study employs a sequential explanatory mixed-methods design. The quantitative portion of the study (Aims 1 and 2) includes Veterans on dialysis across all VAs between 2010 and 2018. We will conduct an interrupted time series analysis of linked VA, Me...