Morphine failed to improve chronic breathlessness

Long-acting morphine did not relieve chronic breathlessness. Phase 3 multi-site, parallel-group, double-blind randomized controlled trial; Level 1b (2011 OCEBM).

Background

Opioids reduce exertional breathlessness in lab studies, but clinical effectiveness in daily life remains uncertain.

Patients

Ambulant adults with chronic breathlessness (mMRC ≥3) mainly due to chronic lung disease; UK, 11 centers. mITT: 140 (morphine 73; placebo 67); mean age 70.5; 66% men.

Intervention

Oral modified-release morphine 5 mg twice daily, optional uptitration to 10 mg twice daily at day 15; blinded laxative; 56 days.

Control

Matching placebo morphine and placebo laxative.

Outcome

Primary: Worst breathlessness (0–10 NRS) at day 28. Secondary: Physical activity (actigraphy), cough NRS, quality of life, sedation, cognition, adverse events.

Follow up period

Primary at 28 days; treatment to 56 days; safety to 84 days.

Results

Outcome Morphine Placebo Effect (95% CI) NNT/NNH
Primary worst breathlessness (NRS) day 28 6.19 6.10 Adj. mean diff 0.09 (–0.57 to 0.75) —
Secondary cough (NRS) day 56 2.53 3.94 Adj. mean diff –1.41 (–2.18 to –0.64) —
Moderate–vigorous activity day 28 (min/day) 63.0 53.4 Adj. mean diff 9.51 (0.54 to 18.48) Signal
Adherence ≥90% (day 28) 88% 99% –11% absolute —
Withdrew study drug (≤56 days) 17.8% 3.0% +14.8% absolute NNH 7
≥1 adverse event (≤56 days) 86% 76% +10% absolute NNH 10
≥1 serious adverse event (≤56 days) 17.8% 4.5% +13.3% absolute NNH 8
Deaths (≤56 days) 2/73 1/67 No treatment-related deaths —

Limitations

  • No standardized isotime/isoload exercise test.
  • Cough measure lacks established MCID; multiple comparisons.
  • Population mostly respiratory disease; women and minorities under-represented.
  • Suboptimal laxative; some missing withdrawal data.

Funding

NIHR Health Technology Assessment programme; public funder, low bias risk.

Citation

Johnson MJ, Williams B, Keerie C, et al. Lancet Respir Med. 2025;13:967–77. doi:10.1016/S2213-2600(25)00205-X.