The effect of acute morphine on obstructive sleep apnoea: a randomised double-blind placebo-controlled crossover trial

Objective: Anaesthesiology guidelines suggest that opioids worsen obstructive sleep apnoea (OSA) despite no randomised controlled trial evidence. We therefore conducted a randomised controlled trial to evaluate the effects of a common clinical dose of morphine on OSA, and to identify clinical phenotype and genotype vulnerability to opioid-respiratory depression. Methods: Under a double-blind, randomised, crossover design, 60 male patients with OSA attended two visits to the hospital sleep laboratory, at least 1 week apart. Either 40 mg controlled-release oral morphine or placebo was administered. Awake ventilatory chemoreflex tests were performed post dose and prior to overnight polysomnography monitoring. Blood was sampled before sleep and the next morning for toxicology and genotype analyses. Sleep time with oxygen saturation (SpO ₂ ) <90% (T90) was the primary outcome. Results: Despite a large inter-individual variability, 40 mg morphine did not worsen T90 and apnoea-hypopnoea index, and only decreased the SpO ₂ nadir by 1.3%. In patients with severe OSA, a lower baseline CO ₂ ventilatory response threshold correlated with the worsening of T90, apnoea-hypopnoea index and oxygen desaturation index with morphine use. Patients with OSA and the A118G OPRM1 polymorphism of A/A and A/G had a significantly different morphine effect on awake ventilatory chemosensitivity and T90 during sleep. Conclusions: 40 mg oral controlled-release morphine did not worsen OSA in men, challenging traditional thinking that OSA will be worsened by opioids. Individual opioid response in patients with OSA may relate to baseline CO ₂ response threshold and OPRM1 genotype. Our study findings may pave the way for a precision medicine approach to avoid opioid-related risks.