The use of long-term opioid therapy for chronic pain remains common, yet data on long-term outcomes, especially after dose escalation, are sparse. This study examined potential benefits and harms associated with prescription opioid dose escalation. Participants from 2 institutions were enrolled in a 2-year prospective cohort study. All participants (n = 517) had a musculoskeletal pain diagnosis and were receiving a stable dose of long-term opioid therapy at baseline. Participants completed self-report measures of pain, disability, depression, and potential adverse effects at baseline and every 6 months for 2 years. We reviewed electronic health record data weekly to identify episodes of prescription opioid dose escalation; participants who had increases in their dose were seen for additional research visits within 1 month of dose escalation. Over 2 years, 19.5% of participants had prescription opioid dose increases. After controlling for covariates, there were no significant changes on any variable after dose escalation. Of those with a dose increase, 3% experienced a clinically meaningful improvement in pain after dose escalation. Participants in the entire sample had small improvements in pain intensity, depressive symptoms, medication-related side effects, and lower risk for prescription opioid misuse during the study period. Sexual functioning worsened over time. There were no significant changes in the full sample on pain disability, sleep functioning, or experiencing a fall. In summary, patients prescribed stable doses of long-term opioid therapy may demonstrate small changes in key pain-related outcomes over time, but prescription opioid dose escalation status is unrelated to clinical outcomes.