Respiratory adverse effects of opioids for breathlessness: a systematic review and meta-analysis

Verberkt, Cornelia A.; Everdingen, M.H.J. van den Beuken-van; Schols, Jos M. G. A.; Datla, Sushma; Dirksen, Carmen D.; Johnson, Miriam J.; Kuijk, Sander M. J. van; Wouters, Emiel F.M.; Janssen, Daisy J.A.

doi:10.1183/13993003.01153-2017

Cited by 83 publications

(71 citation statements)

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“…17,18 The reports of (mainly mild) constipation, nausea, and vomiting in the morphine group are similar to other published reports of low dose morphine for breathlessness 14,15,38,39 but are nonetheless important. We found no respiratory depression consistent with a recent systematic review and meta-analysis.…”

Section: What This Study Addssupporting

confidence: 83%

“…17,18 The reports of (mainly mild) constipation, nausea, and vomiting in the morphine group are similar to other published reports of low dose morphine for breathlessness 14,15,38,39 but are nonetheless important. 17 In the morphine group, all breathlessness measures, apart from week 4 average breathlessness, had greater improvement from baseline than the placebo group. It is possible that patients with heart failure and renal dysfunction may be susceptible to nausea as blood brain barrier permeability is increased, at least in acute kidney injury, 40 and initial co-prescription might be useful.…”

Section: What This Study Addssupporting

confidence: 83%

“…14,15 Preliminary data suggest that people with chronic heart failure may benefit from morphine given for 3 months. Potential problems are (i) patients may be denied a helpful medication (due to unfounded fears about harms 17 and addiction); 18 (ii) they may have a poorly monitored, suboptimal regime; and (iii) there may be no net benefit in the longer term (although there is no evidence of tachyphylaxis to date). Potential problems are (i) patients may be denied a helpful medication (due to unfounded fears about harms 17 and addiction); 18 (ii) they may have a poorly monitored, suboptimal regime; and (iii) there may be no net benefit in the longer term (although there is no evidence of tachyphylaxis to date).…”

Section: Introductionmentioning

confidence: 99%

“…16 Despite the lack of definitive data, morphine is used in clinical practice although there is wide variation in willingness to prescribe, dosing, and quality of monitoring. Potential problems are (i) patients may be denied a helpful medication (due to unfounded fears about harms 17 and addiction); 18 (ii) they may have a poorly monitored, suboptimal regime; and (iii) there may be no net benefit in the longer term (although there is no evidence of tachyphylaxis to date).…”

Section: Introductionmentioning

confidence: 99%

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Oral modified release morphine for breathlessness in chronic heart failure: a randomized placebo‐controlled trial

et al. 2019

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Aims Morphine 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 results Parallel 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, À0.86 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 betweengroup 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 placebocontrolled 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.

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“…17,18 The reports of (mainly mild) constipation, nausea, and vomiting in the morphine group are similar to other published reports of low dose morphine for breathlessness 14,15,38,39 but are nonetheless important. We found no respiratory depression consistent with a recent systematic review and meta-analysis.…”

Section: What This Study Addssupporting

confidence: 83%

“…17,18 The reports of (mainly mild) constipation, nausea, and vomiting in the morphine group are similar to other published reports of low dose morphine for breathlessness 14,15,38,39 but are nonetheless important. 17 In the morphine group, all breathlessness measures, apart from week 4 average breathlessness, had greater improvement from baseline than the placebo group. It is possible that patients with heart failure and renal dysfunction may be susceptible to nausea as blood brain barrier permeability is increased, at least in acute kidney injury, 40 and initial co-prescription might be useful.…”

Section: What This Study Addssupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Oral modified release morphine for breathlessness in chronic heart failure: a randomized placebo‐controlled trial

et al. 2019

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“…Ekström and colleagues71 confirmed that short-term use of opioids are associated with statistically significant as well as clinically relevant reductions in breathlessness severity. Verberkt and colleagues72 explored respiratory adverse effects of opioids, a frequently mentioned physician-endorsed barrier towards opioid prescription. After exploring 67 studies, no evidence was found of significant or clinically relevant respiratory adverse effects of short-term use of opioids for chronic breathlessness.…”

Section: Palliative Respiratory Care In Copdmentioning

confidence: 99%

Pulmonary rehabilitation, physical activity, respiratory failure and palliative respiratory care

Spruit

Rochester

Pitta

et al. 2019

Thorax

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Effect of Regular, Low-Dose, Extended-release Morphine on Chronic Breathlessness in Chronic Obstructive Pulmonary Disease

Ekström

Chang

Louw

et al. 2022

JAMA

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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

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Respiratory adverse effects of opioids for breathlessness: a systematic review and meta-analysis

Cited by 83 publications

References 83 publications

Oral modified release morphine for breathlessness in chronic heart failure: a randomized placebo‐controlled trial

Oral modified release morphine for breathlessness in chronic heart failure: a randomized placebo‐controlled trial

Pulmonary rehabilitation, physical activity, respiratory failure and palliative respiratory care

Effect of Regular, Low-Dose, Extended-release Morphine on Chronic Breathlessness in Chronic Obstructive Pulmonary Disease

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