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The effect of acute morphine on obstructive sleep apnoea: a randomised double-blind placebo-controlled crossover trial
  1. Luke Rowsell1,
  2. Keith K H Wong1,2,
  3. Brendon J Yee1,2,
  4. Danny J Eckert3,
  5. Andrew A Somogyi4,
  6. James Duffin5,
  7. Ronald R Grunstein1,2,
  8. David Wang1,2
  1. 1NHMRC Centre for Sleep and Chronobiology (CIRUS) and NHMRC CRE NeuroSleep, Woolcock Institute of Medical Research, Sydney Medical School, The University of Sydney, Glebe, New South Wales, Australia
  2. 2Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
  3. 3Neuroscience Research Australia (NeuRA) and the School of Medical Sciences, University of New South Wales, Randwick, New South Wales, Australia
  4. 4Discipline of Pharmacology, Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia
  5. 5Departments of Physiology and Anaesthesia, University of Toronto, Toronto, Ontario, Canada
  1. Correspondence to Dr David Wang, Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia; david.wang{at}sydney.edu.au

Abstract

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 (SpO2) <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 SpO2 nadir by 1.3%. In patients with severe OSA, a lower baseline CO2ventilatory 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 CO2 response threshold and OPRM1 genotype. Our study findings may pave the way for a precision medicine approach to avoid opioid-related risks.

Trial registration number The Australian and New Zealand Clinical Trial Registry, ACTRN12613000858796.

  • sleep apnoea
  • drug reactions
  • respiratory measurement

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Footnotes

  • Contributors Conception and design: DW, DJE and RRG. Acquisition of data: LR.

    Medical management: BJY and KKHW. Statistical analyses: LR, KKHW and DW. Plasma morphine, metabolites and genotyping: AAS. All authors contributed to the interpretation of data, drafting and revising of the article and final approval of article.

  • Funding This project was funded by Australian NHMRC Project Grant #1043633. DW was supported by NHMRC Training Fellowship (#571165) and NHMRC Project Grant (#1043633). RRG was supported by NHMRC Senior Principal Research Fellowship (#1106974). Luke Rowsell received a postgraduate scholarship from NHMRC CRE (NeuroSleep#1060992). DJE is supported by NHMRC Senior Research Fellowship (#1116942).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval NSW Sydney Local Health District SSWAHS Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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