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 chronic obstructive pulmonary disease (COPD). Recent 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.

Research question: What are the effects of low-dose morphine on sleep efficiency and other sleep parameters in COPD?

Study design and methods: Randomized, double-blind, crossover trial of 20mg/day sustained-release morphine for three days (steady-state) versus placebo in nineteen breathless people with COPD (n=7 female). The primary outcome was sleep efficiency during in-laboratory overnight polysomnography (PSG). Secondary and exploratory outcome measures included sleep-disordered breathing frequency/hr, oxygenation, transcutaneous carbon dioxide (TcCO₂) 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 PSG.

Results: Sleep efficiency was similar between placebo and morphine (66±17 vs. 67±19%, p=0.89). Morphine did not change the frequency of sleep-disordered breathing events but reduced breathing frequency. Morphine reduced mean and nadir overnight oxygen saturation by [95%CI] 2 [-2.8 to -1.2] and 5 [-8 to -1]%, respectively. Mean TcCO₂ was 3.3 [1.6 to 5.1]mmHg higher during sleep with morphine versus placebo. Eight participants (42%) met American Academy of Sleep Medicine criteria for nocturnal hypoventilation with morphine versus four (21%) on placebo, p=0.02. 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.