There is an increased risk for sleep disordered breathing (SDB), sleep-related hypoventilation and irregular breathing in individuals on chronic prescription opioid medications. Almost 30% of a veteran sleep clinic population had opioid-associated central sleep apnea (CSA). The proposal aims to identity whether oxygen and acetazolamide can be effective in reducing unstable breathing and eliminating sleep apnea in chronic opioid use via different mechanisms. We will study additional clinical parameters like quality of life, sleep and pain in patients with and without opioid use. This proposal will enhance the investigators' understanding of the pathways that contribute to the development of sleep apnea with opioid use. The investigators expect that the results obtained from this study will positively impact the health of Veterans by identifying new treatment modalities for sleep apnea.

In a national sample of Veterans, SDB was a significant risk factor for opioid-related toxicity and overdose; and the presence of CSA combined with chronic prescription opioid use compounded the mortality risk. There are only limited and partially effective therapies for this sleep disorder and the exact mechanisms by which opioids produce SDB in adults remain unclear, and varied and conflicting ventilatory control mechanisms have been suggested. This proposal will investigate whether alternative therapies can be developed by modulating specific physiologic mechanisms of ventilatory control. Specifically, the investigators will study effects of chronic oral prescription opioids on chemoresponsiveness and cerebrovascular responsiveness (CVR) (Aim 1); and whether interventions with sustained hyperoxia (Aim 2) and acetazolamide (Aim 3) will reduce the apneic threshold (AT) to alleviate breathing instability and SDB in chronic prescription opioid-associated SDB. The proposed aims will also allow us to delineate key mechanisms of breathing instability with opioid and without opioid use. The information garnered from the proposed experiments will drive development of novel personalized therapies to reduce SDB associated with chronic opioids in Veterans and, ultimately, will positively impact their long-term health and well-being.

Inclusion Criteria:

• Veterans, age 18-89 years
• Veterans with prescription opioids

Exclusion Criteria:

• Patients with BMI>40kg/m2 will be excluded to avoid the effects of morbid obesity on pulmonary mechanics and ventilatory control
• Patients with history of unresolved/untreated cardiac disease, including recent myocardial infarction, recent bypass surgery, untreated atrial and ventricular tachy-bradycardias
• Congestive heart failure with Cheyne-Stokes respiration (CSR)
• Current unstable angina
• Recent stroke
• Untreated schizophrenia
• Untreated hypothyroidism
• Unresolved seizure disorder
• Severe respiratory, neurological, liver and renal diseases
• Unstable psychiatric disorders/untreated PTSD
• Traumatic brain injury
• Pregnant women
• Significant sleep disorder such as narcolepsy, parasomnias disorder
• Failure to give informed consent
• Patients on tramadol and suboxone/buprenorphine