The HOPE Consortium Trial to Reduce Pain and Opioid Use in Hemodialysis (HOPE Trial) is a multicenter randomized trial addressing chronic pain among patients receiving maintenance hemodialysis for end-stage kidney disease. The trial uses a sequential, multiple assignment design with a randomized component for all participants (Phase 1) and a non-randomized component for a subset of participants (Phase 2). During Phase 1, participants are randomized to Pain Coping Skills Training (PCST), an intervention designed to increase self-efficacy for managing pain, or Usual Care. PCST consists of weekly, live, coach-led cognitive behavioral therapy sessions delivered by video- or tele-conferencing for 12 weeks followed by daily interactive voice response sessions delivered by telephone for an additional 12 weeks. At 24 weeks (Phase 2), participants in both the PCST and Usual Care groups taking prescription opioid medications at an average dose of ≥20 morphine milligram equivalents per day are offered buprenorphine, a partial opioid agonist with a more favorable safety profile than full-agonist opioids. All participants are followed for 36 weeks. The primary outcome is pain interference ascertained, for the primary analysis, at 12 weeks. Secondary outcomes include additional patient-reported measures and clinical outcomes including falls, hospitalizations, and death. Exploratory outcomes include acceptability, tolerability, and efficacy of buprenorphine. The enrollment target of 640 participants was met 27 months after trial initiation. The findings of the trial will inform the management of chronic pain, a common and challenging issue for patients treated with maintenance hemodialysis. NCT04571619.