Combination Upper-Airway Electrical and Pharmacological Stimulation for Obstructive Sleep Apnea

Inclusion Criteria for Enrolment:

* Ages 18 - 79 years
* Diagnosed OSA
* Implantation of a hypoglossal nerve stimulation device (HGNS, Inspire Medical) or scheduled for implantation (implantation required for randomization)
* Willingness to withhold HGNS while testing therapies (up to 6 weeks with HGNS off \[with/without pharmacotherapy\] to assess benefits of HGNS therapy).

Exclusion Criteria:

* Any uncontrolled medical condition
* Current use of the medications under investigation.
* Issues relating to short-term withdrawal of HGNS therapy

  * Excluded: Occupational driving (truck drivers, fork-lift operation, taxi/uber drivers)
  * Excluded: History of traffic accidents attributable to sleepiness or fatigue (\<2 years).
* Use of SNRIs/SSRIs or anticholinergic medications during the study.
* Conditions likely to affect obstructive sleep apnea physiology: neuromuscular disease or other major neurological disorder, heart failure (also below), or any other unstable major medical condition.
* Respiratory disorders other than sleep disordered breathing:

chronic hypoventilation/hypoxemia (awake SaO2 \< 92% by oximetry) due to chronic obstructive pulmonary disease or other respiratory conditions.

* Other sleep disorders: narcolepsy, parasomnias. Insomnia
* Contraindications for atomoxetine and oxybutynin, including:

  * hypersensitivity to atomoxetine or oxybutynin (angioedema or urticaria)
  * pheochromocytoma
  * use of monoamine oxidase inhibitors
  * diagnosed benign prostatic hypertrophy, urinary retention
  * suspected benign prostatic hypertrophy / urinary retention based on a positive answer to either of the following questions:

    1. "During the last month, when urinating, have you had the sensation of not emptying your bladder completely more often than 1 out of 5 times?"
    2. "During the last month, have you had a weak urinary stream more often than 1 out of 5 times?
  * known untreated narrow angle glaucoma
  * known bipolar disorder, mania, psychosis
  * known history of major depressive disorder (age\<24).
  * known history of attempted suicide or suicidal ideation within one year prior to screening
  * known clinically significant constipation, gastric retention
  * known pre-existing seizure disorders
  * known clinically-significant kidney disorders (eGFR\<60 ml/min/1.73m2)
  * known clinically-significant liver disorders
  * known clinically-significant cardiovascular conditions
  * moderate-to-severe hypertension (SBP\>160 mmHg or DBP\>100 mmHg measured at baseline; average of evening and morning measures)
  * known cardiomyopathy (LVEF\<50%) or heart failure
  * known advanced atherosclerosis
  * recent cerebrovascular events (within 2 years)
  * recent history of cardiac arrhythmias e.g., atrial fibrillation, QT prolongation (within 2 years)
  * other serious cardiac conditions that would raise the consequences of an increase in blood pressure or heart rate
  * myasthenia gravis
  * pregnancy/breast-feeding