Sleep Disordered Breathing With Opioid Use (SDB)

Targeting Chemoreceptor Control of Breathing During Sleep to Mitigate Opioid-Associated Sleep Disordered Breathing

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.

Determine the effect of sustained hyperoxia overnight vs room air overnight on ventilatory control during sleep, including the apneic threshold, carbon-dioxide reserve and chemosensitivity measured via pressure support ventilation (PSV) during non-rapid eye movement sleep (NREM) sleep.

Determine the effect of acetazolamide on cerebrovascular responsiveness to CO2 during wake and sleep. Participants will receive oral ACZ therapy for 6 days, While on the medication following studies will be performed - experimental night study, experimental day study, polysomnography night study (PSG).

The ventilatory effects of brief hyperoxia will be assessed by analyzing control breaths on room air immediately preceding the hyperoxic exposure, and comparing with the primary end-point, nadir minute ventilation breath, immediately following the brief hyperoxic exposure.

Participants with sleep apnea will ingest capsules containing either placebo or acetazolamide 500 mg twice a day for 6 days. On the final 4 consecutive nights while still on ACZ, the investigators will perform i) physiology tests and ii) in-lab follow-up PSG.

Measures of breathing instability including: Apneic threshold: this is the end-tidal Co2 at which a central apnea closes to a hypopnea is produced.

Cerebrovascular response to different levels of CO2: this is a measure of the response of the cerebral blood flow to changes in carbon dioxide levels and is used as a measure of ventilatory control of breathing

Hypocapnic ventilatory response; this is calculated as the change in minute ventilation for corresponding changes in PETCO2.

This is a derived measure. This is calculated as the difference between the apneic threshold PETCO2 (given above) and the control PETCO2.

Apnea hypopnea index- is a measure of severity of sleep apnea - this is calculated as the total number of apneas and hypopneas recorded during a sleep study divided by the total sleep time during the sleep study.

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