title: Zopiclone Increases the Arousal Threshold without Impairing Genioglossus Activity in Obstructive Sleep Apnea.
abstract: OBJECTIVE
  To determine the effects of the nonbenzodiazepine sedative zopiclone on the threshold to arousal with increasing respiratory effort and genioglossus muscle activity and to examine potential physiological factors mediating disparate effects of zopiclone on obstructive sleep apnea (OSA) severity between patients.
  
  
  METHODS
  Twelve patients with OSA (apnea-hypopnea index = 41 ± 8 events/h) were studied during 2 single night sleep studies conducted approximately 1 w apart after receiving 7.5 mg of zopiclone or placebo according to a double-blind, placebo-controlled, randomized, crossover design. The respiratory arousal threshold (epiglottic pressure immediately prior to arousal during naturally occurring respiratory events), genioglossus activity and its responsiveness to pharyngeal pressure during respiratory events, and markers of OSA severity were compared between conditions. Genioglossus movement patterns and upper airway anatomy were also assessed via magnetic resonance imaging in a subset of participants (n = 7) during wakefulness.
  
  
  RESULTS
  Zopiclone increased the respiratory arousal threshold versus placebo (-31.8 ± 5.6 versus -26.4 ± 4.6 cmH2O, P = 0.02) without impairing genioglossus muscle activity or its responsiveness to negative pharyngeal pressure during respiratory events (-0.56 ± 0.2 versus -0.44 ± 0.1 %max/-cmH2O, P = 0.48). There was substantial interindividual variability in the changes in OSA severity with zopiclone explained, at least in part, by differences in pathophysiological characteristics including body mass index, arousal threshold, and genioglossus movement patterns.
  
  
  CONCLUSIONS
  In a group of patients with predominantly severe OSA, zopiclone increased the arousal threshold without reducing genioglossus muscle activity or its responsiveness to negative pharyngeal pressure. These properties may be beneficial in some patients with OSA with certain pathophysiological characteristics but may worsen hypoxemia in others.
  
  
  BACKGROUND
  Australian New Zealand Clinical Trials Registry, http://www.anzctr.org.au, trial ID: ACTRN12614000364673.
authors.affiliation: Neuroscience Research Australia (NeuRA) and the University of New South Wales, Randwick, Sydney, New South Wales, Australia.
authors.forename: Sophie G
authors.initials: SG
authors.lastname: Carter
authors.affiliation: Neuroscience Research Australia (NeuRA) and the University of New South Wales, Randwick, Sydney, New South Wales, Australia.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Berger
authors.affiliation: Neuroscience Research Australia (NeuRA) and the University of New South Wales, Randwick, Sydney, New South Wales, Australia.
authors.forename: Jayne C
authors.initials: JC
authors.lastname: Carberry
authors.affiliation: Neuroscience Research Australia (NeuRA) and the University of New South Wales, Randwick, Sydney, New South Wales, Australia.
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Bilston
authors.affiliation: Neuroscience Research Australia (NeuRA) and the University of New South Wales, Randwick, Sydney, New South Wales, Australia.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Butler
authors.affiliation: Neuroscience Research Australia (NeuRA) and the University of New South Wales, Randwick, Sydney, New South Wales, Australia.
authors.forename: Benjamin K Y
authors.initials: BK
authors.lastname: Tong
authors.affiliation: Neuroscience Research Australia (NeuRA) and the University of New South Wales, Randwick, Sydney, New South Wales, Australia.
authors.forename: Rodrigo T
authors.initials: RT
authors.lastname: Martins
authors.affiliation: Neuroscience Research Australia (NeuRA) and the University of New South Wales, Randwick, Sydney, New South Wales, Australia.
authors.forename: Lauren P
authors.initials: LP
authors.lastname: Fisher
authors.affiliation: Prince of Wales Hospital, Randwick, Sydney, New South Wales, Australia.
authors.forename: David K
authors.initials: DK
authors.lastname: McKenzie
authors.affiliation: Woolcock Institute of Medical Research and the University of Sydney, Glebe, New South Wales, Australia.
authors.forename: Ronald R
authors.initials: RR
authors.lastname: Grunstein
authors.affiliation: Neuroscience Research Australia (NeuRA) and the University of New South Wales, Randwick, Sydney, New South Wales, Australia.
authors.forename: Danny J
authors.initials: DJ
authors.lastname: Eckert
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001143:Arousal / Q000187:drug effects*; D001315:Australia; D053961:Azabicyclo Compounds / Q000494:pharmacology* / Q000627:therapeutic use*; D015992:Body Mass Index; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009068:Movement / Q000187:drug effects; D009520:New Zealand; D010614:Pharynx / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use*; D017286:Polysomnography; D011312:Pressure; D012119:Respiration / Q000187:drug effects; D020181:Sleep Apnea, Obstructive / Q000503:physiopathology*; D014059:Tongue / Q000187:drug effects* / Q000502:physiology; D014851:Wakefulness / Q000187:drug effects; D055815:Young Adult
chemical_list: D053961:Azabicyclo Compounds; D006993:Hypnotics and Sedatives; D010879:Piperazines; C515050:zopiclone
keywords: hypnotic; respiratory physiology; sedative; sleep disordered breathing; upper airway physiology