Combination Drug-Therapy for Patients With Untreated Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is common and associated with many adverse health consequences, but many patients are unable to tolerate standard therapies such as continuous positive airway pressure (CPAP) and thus remain untreated. Single-drug therapies have shown promising results in treating sleep apnea, but on average patients have only experienced partial relief. Multi-drug therapy may offer a more effective treatment approach. The goal of this study is to test the effect of combination therapy with three FDA-approved drugs (Diamox \[acetazolamide\], Lunesta \[eszopiclone\] +/- Effexor \[venlafaxine\]) on OSA severity and physiology.

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).

Eligibility Criteria:
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).