Rescue Pharmacotherapy for OSA

Persistent obstructive sleep apnea (OSA) is common in people treated with mandibular advancement device (MAD) or hypoglossal nerve stimulation (HGNS). For most patients, these treatments are the last line of defense. If MAD or HGNS do not work, then patients are left to suffer the consequences of undertreated OSA. In this study, the investigators want to test the addition of a drug treatment to their regimen. Endotypes will be targeted pharmacologically with one of the following drugs: acetazolamide for a high loop gain, atomoxetine-plus-eszopiclone for poor pharyngeal muscle compensation, or trazodone for a low arousal threshold.

This aim is expected to provide treatment strategies for rescuing non-responders to MAD or HGNS therapy.


Eligibility Criteria:
Inclusion Criteria:

* Individuals who have failed MAD or HGNS therapy, defined as a residual AHI ≥ 15 events/hr on MAD or HGNS therapy.

Exclusion Criteria:

* Sleep disordered breathing or respiratory disorders other than obstructive sleep apnea:

central sleep apnea (\>50% of respiratory events scored as central), chronic hypoventilation/hypoxemia (awake SaO2 \< 92% by oximetry) due to chronic obstructive pulmonary disease or other respiratory conditions.

* Other sleep disorders: periodic limb movements (periodic limb movement index \> 20/hr), narcolepsy, or parasomnias.
* Any unstable major medical condition.
* Medications expected to stimulate or depress respiration (including opioids, barbiturates, benzodiazepines, doxapram, almitrine, theophylline, 4-hydroxybutanoic acid).
* Use of SSRIs/SNRIs.
* Contraindications for atomoxetine, including:
* pheochromocytoma
* use of monoamine oxidase inhibitors
* benign prostatic hypertrophy, urinary retention
* untreated narrow angle glaucoma
* bipolar disorder, mania, psychosis
* clinically significant constipation, gastric retention
* pre-existing seizure disorders
* clinically-significant kidney disorders
* clinically-significant liver disorders
* clinically-significant cardiovascular conditions
* severe hypertension (SBP\>180 mmHg or DBP\>110 mmHg measured at baseline)
* cardiomyopathy (LVEF\<50%) or heart failure
* advanced atherosclerosi
* history of cerebrovascular events
* history of cardiac arrhythmias e.g., atrial fibrillation, QT prolongation
* other serious cardiac conditions that would raise the consequences of an increase in blood pressure or heart rate
* myasthenia gravis
* pregnancy/breast-feeding
* Contraindications for eszopiclone, including:
* Hypersensitivity to eszopiclone
* Chronic Obstructive Pulmonary Disease (COPD)
* Pregnancy
* Breast feeding
* Liver disease
* Contraindications for acetazolamide, including:
* Hyperchloremic acidosis
* Hypokalemia
* Hyponatremia
* Adrenal insufficiency
* Impaired kidney function
* Hypersensitivity to acetazolamide or other sulfonamides.
* Marked liver disease or impairment of liver function, including cirrhosis.
* Contraindications for trazodone, including:
* suicidal ideation
* bipolar disorder, mania
* use of monoamine oxidase inhibitors
* coronary artery disease
* cardiac arrhythmias
* QT prolongation
* hepatic disease
* renal failure or impairment
* closed angle glaucoma
* priapism
* pregnancy/breast-feeding