Once-Daily Opioids for Chronic Dyspnea: A Dose Increment and Pharmacovigilance Study

ContextRandomized controlled trials can answer questions of efficacy, but long-term pharmacovigilance studies generate complementary safety data.ObjectivesLevel 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.MethodsIn 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 The participant was withdrawn if there were unacceptable side effects or no response to maximum dose.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.ResultsEighty-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.ConclusionTen milligrams of sustained-release oral morphine once daily is safe and effective for most people who respond.