Effect of Sustained-Release Morphine for Refractory Breathlessness in Chronic Obstructive Pulmonary Disease on Health Status A Randomized Clinical Trial

IMPORTANCE Morphine is used as palliative treatment of chronic breathlessness in patients with advanced chronic obstructive pulmonary disease (COPD). Evidence on respiratory adverse effects and health status is scarce and conflicting.

OBJECTIVE To assess the effects of regular, low-dose, oral sustained-release morphine on disease-specific health status (COPD Assessment Test; CAT), respiratory outcomes, and breathlessness in patients with COPD.

INTERVENTIONS Participants were randomly assigned to 10mg of regular, oral sustained-release morphine or placebo twice daily for 4 weeks, with the possibility to increase to 3 times daily after 1 or 2 weeks.

DESIGN, SETTING, AND PARTICIPANTS The Morphine for Treatment of Dyspnea in Patients With COPD (MORDYC) study was a randomized, double-blind, and placebo-controlled study of a 4-week intervention. Patients were enrolled between November 1, 2016, and January 24, 2019. Participants were recruited in a pulmonary rehabilitation center and 2 general hospitals after completion of a pulmonary rehabilitation program. Outpatients with COPD and moderate to very severe chronic breathlessness (modified Medical Research Council [mMRC] breathlessness grades 2-4) despite optimal pharmacological and nonpharmacological treatment were included. A total of 1380 patients were screened, 916 were ineligible, and 340 declined to participate.

MAIN OUTCOMES AND MEASURES Primary outcomeswere CAT score (higher scores represent worse health status) and arterial partial pressure of carbon dioxide (PaCO2). Secondary outcome was breathlessness in the previous 24 hours (numeric rating scale). Data were analyzed by intention to treat. Subgroup analyses in participants with mMRC grades 3 to 4 were performed.

RESULTS A total of 111 of 124 included participants were analyzed (mean [SD] age, 65.4 [8.0] years; 60 men [54%]). Difference in CAT score was 2.18 points lower in the morphine group (95% CI, -4.14 to -0.22 points; P=.03). Difference in PaCO2 was 1.19mmHg higher in the morphine group (95% CI, -2.70 to 5.07mmHg; P=.55). Breathlessness remained unchanged. Worst breathlessness improved in participants with mMRC grades 3 to 4 (1.33 points lower in the morphine group; 95% CI, -2.50 to -0.16 points; P=.03). Five participants of 54 in the morphine group (9%) and 1 participant of 57 in the placebo group (2%) withdrew because of adverse effects. No morphine-related hospital admissions or deaths occurred.

CONCLUSIONS AND RELEVANCE In this randomized clinical trial, regular, low-dose, oral sustained-release morphine for 4 weeks improved disease-specific health status in patients with COPD without affecting PaCO2 or causing serious adverse effects. The worst breathlessness improved in participants with mMRC grades 3 to 4. A larger randomized clinical trial with longer follow-up in patients with mMRC grades 3 to 4 is warranted.