The Effects of Low-Dose Morphine on Sleep and Breathlessness in COPD: A Randomized Trial

Background: Low-dose morphine may be prescribed to reduce chronic breathlessness in COPD. Subjective findings suggest morphine may influence breathlessness through sleep-related mechanisms. However, concerns exist regarding opioid safety in COPD. The effects of morphine during sleep in COPD have not been objectively investigated. This study aimed to objectively determine the effects of low-dose morphine on sleep in COPD. Research Question: What are the effects of low-dose morphine on sleep efficiency and other sleep parameters in COPD? Study Design and Methods: This was a randomized, double-anonymized, crossover trial of sustained-release morphine (20 mg/d for 3 days) (steady-state) vs placebo in 19 breathless people with COPD (n = 7 female participants). The primary outcome was sleep efficiency during in-laboratory overnight polysomnography. Secondary and exploratory outcome measures included sleep-disordered breathing (events/h), oxygenation, transcutaneous CO₂ levels, blood and physiology biomarkers, the relationship between sleep and breathlessness, external resistive load responses, and driving simulator performance. Physiology outcomes and pharmacokinetics were measured before and after each polysomnogram. Results: Sleep efficiency was similar between placebo and morphine (66 ± 17% vs 67 ± 19%; P = .89). Morphine did not change the frequency of sleep-disordered breathing events but reduced breathing frequency. Morphine reduced mean and nadir overnight oxygen saturation by 2% (95% CI, –2.8% to –1.2%) and 5% (95% CI, –8% to –1%), respectively. Mean transcutaneous CO₂ was 3.3 mm Hg (95% CI, 1.6-5.1 mm Hg) higher during sleep with morphine vs placebo. Eight participants (42%) met American Academy of Sleep Medicine criteria for nocturnal hypoventilation with morphine vs four (21%) receiving placebo (P = .02). Morphine did not systematically reduce breathlessness or impair next-day driving simulator performance. Adverse events (most frequently nausea) were increased with morphine. Interpretation: Steady-state, low-dose morphine does not change sleep efficiency, sleep-disordered breathing frequency, or next-day alertness but may cause hypoventilation during sleep, a potentially harmful effect. Clinical Trial Registration: Australian New Zealand Clinical Trials Registry; No.: ACTRN12621000752864; URL: https://www.anzctr.org.au