Combination Drug-Therapy for Patients With Untreated Obstructive Sleep Apnea

Study participants will undergo three 3-day drug regimens. On days 1 and 2 of each drug regimen, subjects will take the study drugs at home; on day 3 of each drug regimen subjects will take the study drugs as part of an overnight inlab sleep study (including assessments of sleepiness/alertness, sleep quality and blood pressure). Initially subjects will take dual-therapy (acetazolamide+eszopiclone) vs placebo in random order; if sleep apnea resolved with dual-therapy, then subjects will undergo an open-label single-drug regimen (acetazolamide), else an open-label triple-drug regimen (acetazolamide + eszopiclone + venlafaxine).

Inclusion criteria

• BMI 18-40 kg/m2
• Untreated Moderate or Severe OSA (AHI during supine NREM sleep >15/h) with a fraction of hypopneas >25% of all events

Exclusion criteria

• Pregnancy
• Breastfeeding
• Prisoners
• Adherent with effective therapy for OSA
• Other known untreated sleep fragmenting disorder, such as periodic limb movement disorder, or narcolepsy
• Inability to sleep supine for overnight sleep studies
• Circadian rhythm disorder
• Unrevascularized coronary artery disease, angina, prior heart attack or stroke, congestive heart failure
• Uncontrolled hypertension (systolic blood pressure >160mmHg, diastolic blood pressure >95mmHg)
• Presence of tracheostomy
• Hospitalization within the past 90 days
• Prior peptic ulcer disease, esophageal varices, or gastrointestinal bleeding (< 5 years)
• Prior gastric bypass surgery
• Chronic liver disease or end-stage kidney disease
• Active illicit substance use or >2 oz daily alcohol use (i.e. >2 12 oz bottles of beers, >2 5 oz glasses of wine, >2 1.5 oz glasses of hard liquor such as spirits, gin, whiskey, etc.)
• Psychiatric disease, other than well controlled depression/anxiety
• Cognitive impairment, inability to provide consent, or inability to complete research procedures (e.g. questionnaires that are only available/validated in English)
• Chronically using study drugs or drugs with similar pharmacodynamic effects (acetazolamide - carbonic anhydrase inhibitors, eszopiclone - benzodiazepine receptor agonists, venlafaxine - serotonin/norepinephrine reuptake inhibitors and other antidepressants)
• Regular use of medications known to affect control of breathing (opioids, benzodiazepines, theophylline)
• Contraindications to taking study drugs, including allergies to any of the drugs or sulfa allergy; concomitant use of antidepressants, opioids, sedatives/hypnotics, thiazide diuretics or angiotensin-receptor blockers; or severe nocturnal hypoxia (SpO2 nadir <70% on diagnostic sleep study).