Context: Randomized controlled trials can answer questions of efficacy, but long-term pharmacovigilance studies generate complementary safety data. Objectives: Level I evidence supports short-term efficacy of opioids in reducing chronic refractory dyspnea. This study aimed to determine the minimum effective once-daily dose of sustained-release morphine, and whether net clinical benefits are sustained safely. Methods: In a Phase II dose increment study, 10 mg daily of sustained-release morphine was administered, and increased in nonresponders by 10 mg daily each week to a maximum of 30 mg daily. The participant was withdrawn if there were unacceptable side effects or no response to maximum dose. If participants had a 10% improvement in dyspnea over their own baseline, they joined a long-term Phase IV effectiveness/safety study at that dose. Complying with Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines, response and side effects are described, with demographic and clinical characteristics of responders. Results: Eighty-three participants (53 males, mean age 75 years, 54% with chronic obstructive pulmonary disease) provided more than 30 patient-years of data. Fifty-two participants derived ≥10% benefit (on average 35% improvement over baseline), giving a response rate of 62% (number needed to treat of 1.6: number needed to harm 4.6); for 70%, this dose was 10 mg/24 h. Benefit was maintained at three months for 28 (33%) people. Ranking of breathlessness was reduced significantly (P < 0.001), but constipation increased (P < 0.001) despite laxatives. There were no episodes of respiratory depression or hospitalizations as a result of the sustained-release morphine. Overall, one in three people continued to derive benefit at three months. Conclusion: Ten milligrams of sustained-release oral morphine once daily is safe and effective for most people who respond.