Morphine for Refractory Dyspnea in Interstitial Lung Disease: A Phase I Study (JORTC-PAL 05)

Dyspnea is common in interstitial lung disease (ILD) patients and often refractory to conventional treatment. Little is known regarding the safety of systemic morphine in ILD patients. The objective of this study is to evaluate the safety of a single subcutaneous morphine injection and to determine the recommended dose of morphine for alleviating dyspnea in ILD patients. We conducted a dose-escalation Phase I study for investigating the recommended dose of a single subcutaneous morphine injection to alleviate dyspnea in ILD patients. Eligible subjects were ILD inpatients with dyspnea at rest who were refractory to conventional dyspnea treatment. The morphine doses used were 1 mg and 2 mg in cohort 1 and cohort 2, respectively. The primary endpoint was dose-limiting toxicity, which was defined as (1) respiratory depression, that is, 30% reduction of respiratory rate and 10 Torr increase of PaCO₂ compared with baseline; (2) hypotension, that is, 20% reduction of systemic blood pressure compared with baseline and presentation of hypotension-related symptoms; or (3) grade 3, 4, or 5 treatment-emergent adverse events graded by Common Terminology Criteria for Adverse Events (version 4). A total of six patients were enrolled, with three patients each in cohorts 1 and 2. No dose-limiting toxicities were observed; three patients experienced worsened somnolence, but no patients experienced sedation. We conclude that 2 mg of morphine has a tolerable safety profile in ILD patients with dyspnea, and can be tested in further clinical trials.