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

Abstract

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 10 mg 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 PARTICIPANTSThe 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 MEASURESPrimary outcomes were CAT score (higher scores represent worse health status) and arterial partial pressure of carbon dioxide (PaCO 2 ). 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 PaCO 2 was 1.19 mm Hg higher in the morphine group (95% CI, -2.70 to 5.07 mm Hg; 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 RELEVANCEIn 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 PaCO 2 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.

Contemporary Concise Review 2020: Chronic obstructive pulmonary disease

“…A DB‐RCT of 4 weeks duration compared slow‐release morphine 10 mg bd versus placebo for relief of dyspnoea in moderate to very severe COPD 58 . Patients had received optimal pharmacological and non‐pharmacological treatment prior, including completion of pulmonary rehabilitation.…”

Professionals’, patients’ and families’ views on the use of opioids for chronic breathlessness: A systematic review using the framework method and pillar process

“…Metaanalyses of clinical trials provide evidence that, in combination with usual care including disease-modifying therapies and non-pharmacological interventions, regular low dose opioids may safely reduce moderate to severe chronic breathlessness due to advanced illness; with the majority of evidence relating to morphine. 5,6 The most recent published trials 7,8 did not show benefit for the study populations as a whole, but a significant number of participants had less severe chronic breathlessness (for whom a response is less likely 9 ). However, sub-group analyses of participants with moderate to severe chronic breathlessness in both trials showed reduction in breathlessness compared with placebo, reaching statistical significance in one.…”

Transmucosal Buprenorphine in the Treatment of Dyspnea: Case Series and Review of the Literature

“…3,4 In addition, although expert opinion considers lowdose full MORs helpful in the treatment of refractory dyspnea, their benefit has been difficult to demonstrate in randomized controlled settings. 5,6 One reason for this may be that assessment of dyspnea through questionnaires may be underestimating the impact of treatment as patients may increase their activity level to reach their previous breathlessness severity level if the treatment is helpful; it has been suggested that more objective measures, such as use of accelerometers to measure changes in activity, may be better suited to assess treatment effects. 7,8 Nevertheless, patients seen in palliative care settings often suffer from comorbid pain, also raising concerns about need for higher opioid doses (and hence side effects) than might suffice to treat isolated dyspnea.…”