Dataset Information

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

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 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 outcomes were 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 1.19 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 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.

Trial registration

ClinicalTrials.gov Identifier: NCT02429050.

SUBMITTER: Verberkt CA

PROVIDER: S-EPMC7432282 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceChronic breathlessness is common in people with chronic obstructive pulmonary disease (COPD). Regular, low-dose, extended-release morphine may relieve breathlessness, but evidence about its efficacy and dosing is needed.ObjectiveTo determine the effect of different doses of extended-release morphine on worst breathlessness in people with COPD after 1 week of treatment.Design, setting, and participantsMulticenter, double-blind, placebo-controlled randomized clinical trial including people with COPD and chronic breathlessness (defined as a modified Medical Research Council score of 3 to 4) conducted at 20 centers in Australia. People were enrolled between September 1, 2016, and November 20, 2019, and followed up through December 26, 2019.InterventionsPeople were randomized 1:1:1 to 8 mg/d or 16 mg/d of oral extended-release morphine or placebo during week 1. At the start of weeks 2 and 3, people were randomized 1:1 to 8 mg/d of extended-release morphine, which was added to the prior week's dose, or placebo.Main outcomes and measuresThe primary outcome was change in the intensity of worst breathlessness on a numerical rating scale (score range, 0 [none] to 10 [being worst or most intense]) using the mean score at baseline (from days -3 to -1) to the mean score after week 1 of treatment (from days 5 to 7) in the 8 mg/d and 16 mg/d of extended-release morphine groups vs the placebo group. Secondary outcomes included change in daily step count measured using an actigraphy device from baseline (day -1) to the mean step count from week 3 (from days 19 to 21).ResultsAmong the 160 people randomized, 156 were included in the primary analyses (median age, 72 years [IQR, 67 to 78 years]; 48% were women) and 138 (88%) completed treatment at week 1 (48 in the 8 mg/d of morphine group, 43 in the 16 mg/d of morphine group, and 47 in the placebo group). The change in the intensity of worst breathlessness at week 1 was not significantly different between the 8 mg/d of morphine group and the placebo group (mean difference, -0.3 [95% CI, -0.9 to 0.4]) or between the 16 mg/d of morphine group and the placebo group (mean difference, -0.3 [95%, CI, -1.0 to 0.4]). At week 3, the secondary outcome of change in mean daily step count was not significantly different between the 8 mg/d of morphine group and the placebo group (mean difference, -1453 [95% CI, -3310 to 405]), between the 16 mg/d of morphine group and the placebo group (mean difference, -1312 [95% CI, -3220 to 596]), between the 24 mg/d of morphine group and the placebo group (mean difference, -692 [95% CI, -2553 to 1170]), or between the 32 mg/d of morphine group and the placebo group (mean difference, -1924 [95% CI, -47 699 to 921]).Conclusions and relevanceAmong people with COPD and severe chronic breathlessness, daily low-dose, extended-release morphine did not significantly reduce the intensity of worst breathlessness after 1 week of treatment. These findings do not support the use of these doses of extended-release morphine to relieve breathlessness.Trial registrationClinicalTrials.gov Identifier: NCT02720822.

Project description:AimsMorphine is shown to relieve chronic breathlessness in chronic obstructive pulmonary disease. There are no definitive data in people with heart failure. We aimed to determine the effectiveness and cost-effectiveness of 12 weeks morphine therapy for the relief of chronic breathlessness in people with chronic heart failure compared with placebo.Methods and resultsParallel group, double-blind, randomized, placebo-controlled, phase III trial of 20 mg daily oral modified release morphine was conducted in 13 sites in England and Scotland: hospital/community cardiology or palliative care outpatients. The primary analysis compared between-group numerical rating scale average breathlessness/24 hours at week 4 using a covariance pattern linear mixed model. Secondary outcomes included treatment-emergent harms (worse or new). The trial closed early due to slow recruitment, randomizing 45 participants [average age 72 (range 39-89) years; 84% men; 98% New York Heart Association class III]. For the primary analysis, the adjusted mean difference was 0.26 (95% confidence interval, -0.86 to 1.37) in favour of placebo. All other breathlessness measures improved in both groups (week 4 change-from-baseline) but by more in those assigned to morphine. Neither group was excessively drowsy at baseline or week 4. There were no between-group differences in quality of life (Kansas) or cognition (Montreal) at any time point. There was no exercise-related desaturation and no change between baseline and week 4 in either group. There was no change in vital signs at week 4. The natriuretic peptide measures fell in both groups but by more in the morphine group [morphine 2169 (1092, 3851) pg/mL vs. placebo 2851 (1694, 5437)] pg/mL. There was no excess serious adverse events in the morphine group. Treatment-emergent harms during the first week were more common in the morphine group; all apart from 1 were ? grade 2.ConclusionsWe could not answer our primary objectives due to inadequate power. However, we provide novel placebo-controlled medium-term benefit and safety data useful for clinical practice and future trial design. Morphine should only be prescribed in this population when other measures are unhelpful and with early management of side effects.