Background: Dyspnea can be a severe and debilitating symptom of COPD that can greatly impact quality of life. The use of low dose opioids to treat dyspnea has been supported in the literature but there has been conflicting data with regards to long-acting opioids. This study is aimed at evaluating efficacy of long-acting opioids on breathlessness as well as its impact on daily activity.

Design and Participants: This was an Australian multicenter double blinded placebo controlled randomized control trial. Inclusion criteria required MRC breathlessness scale of 3 or 4 and at least a 3 on a numerical dyspnea scale, confirmatory spirometry and maintenance on a stable inhaler regimen. Exclusion criteria included those already on opioids and patients with hypoventilation syndrome or concomitant liver or kidney failure.  160 adult patients with COPD were enrolled and randomized to Extended Release Morphine 8mg/day, 16 mg/day or placebo. They remained on this dose for 1 week and then 50% of each group were stepped up by 8 mg/day (including the placebo group, 50% of whom then crossed over into the treatment group starting at 8 mg/day).  The remaining 50% stayed at their original dosing. They again stayed on this dose for 1 week and then there was a similar 50% step up in dosing for week 3 (groups now included placebo, 8mg/day, 16 mg/day, 24 mg/day and 32 mg/day). A wrist actigraphy was provided to the participants and worn at all times during the study and the participants had to record their breathlessness daily on a numerical 0-10 scale in a journal. Other outcomes monitored included changes in Global Impression of Change in health status, HADS, Australia modified Karnofsky PPS, QOL scores from the COPD Assessment Test, Clinical Respiratory Questionnaire Dyspnea and Mastery, overall wellbeing, ESAS, ETCP2, RR and O2 sat. Mean age of participants was 72 years old.

Results:  There was no statistical improvement in the MRC breathlessness scale or the mean daily step count between any of the study groups (Morphine 8 mg/day – 32 mg/day) compared to placebo. None of the other secondary outcomes listed above had any statistical differences between the groups either. Opioid related side effects (constipation, fatigue, dizziness, nausea, and vomiting) were as high as 78% in the Morphine 16 mg/day subgroup, though 48% in the placebo group reported similar side effects. 33% of patients in the morphine group had what was considered serious treatment-emergent adverse events compared to 12% in the placebo group. This was categorized as patients who had increased breathlessness, morphine-related adverse events and respiratory failure, hospitalization or death.

Commentary: This study unfortunately does not support the concept that long-acting Morphine is useful for treatment of chronic severe dyspnea in patients with COPD. The traditional opioid related side effects were quite high in the treatment group but the placebo group also reported these same side effects at a high prevalence of nearly 50%. Certainly, the number of severe TEAE, hospitalization and deaths were much higher in the treatment groups, though they never provide the p value or discuss the statistical significance of these results. There is no mention at all of the side effects/adverse events in their discussion which I found interesting. Additional limitations of the study include that they only dosed the long-acting Morphine once daily and that only 42% of patients completed treatment at week 3.

Bottom Line: This study does not support the use of Long-acting Morphine for treatment of severe dyspnea in patients with COPD and side effects and adverse effects should be further studied.

Source: Ekström M, Ferreira D, Chang S, et al. Effect of regular, low-dose, extended-release Morphine on chronic breathlessness in chronic obstructive pulmonary disease: The BEAMS randomized clinical trial. JAMA. 2022;328(20):2022-2032. doi:10.1001/jama.2022.20206

Download the PDF: Long acting morphine COPD