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.

Study Overview

• Status: Recruiting
• Conditions: Sleep Apnea; Sleep Disordered Breathing; Opioid Use
• Intervention / Treatment: Other: Hyperoxia; Drug: Acetazolamide

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Ruchi Rastogi, MSc; Phone Number: (313) 576-1000; Email: ruchi.rastogi@va.gov

Study Locations

• United States
  • Michigan
    • Detroit, Michigan, United States, 48201-1916
      • Recruiting
      • John D. Dingell VA Medical Center, Detroit, MI
      • Principal Investigator: Susmita Chowdhuri, MD
      • Contact: Ruchi Rastogi, MSc; Phone Number: 313-576-1000; Email: ruchi.rastogi@va.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 89 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Hyperoxia; 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.	Other: Hyperoxia; 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.; Other Names: oxygen
Experimental: Acetazolamide (ACZ); 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).	Drug: Acetazolamide; 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.; Other Names: ACZ

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Apneic threshold- a measure of breathing instability	Measures of breathing instability including: Apneic threshold: this is the end-tidal Co2 at which a central apnea closes to a hypopnea is produced.	2 days to 30 days
Cerebrovascular responsiveness to carbon-dioxide	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	7 days
Ventilatory responsiveness	Hypocapnic ventilatory response; this is calculated as the change in minute ventilation for corresponding changes in PETCO2.	2 days to 30 days
Carbon -dioxide reserve	This is a derived measure. This is calculated as the difference between the apneic threshold PETCO2 (given above) and the control PETCO2.	2 days to 30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Apnea hypopnea index	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.	2 days to 30 days

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Collaborators: John D. Dingell VA Medical Center
• Investigators: Principal Investigator: Susmita Chowdhuri, MD, John D. Dingell VA Medical Center, Detroit, MI

Study record dates

Study Major Dates

• Study Start (Actual): May 2, 2019
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: October 18, 2022
• First Submitted That Met QC Criteria: October 18, 2022
• First Posted (Actual): October 21, 2022

Study Record Updates

• Last Update Posted (Actual): September 21, 2023
• Last Update Submitted That Met QC Criteria: September 18, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Respiratory Tract Diseases; Apnea; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Sleep Apnea Syndromes; Respiratory Aspiration; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Carbonic Anhydrase Inhibitors; Natriuretic Agents; Diuretics; Anticonvulsants; Acetazolamide
• Other Study ID Numbers: PULM-003-18F; 1904002203 (Other Grant/Funding Number: John D. Dingell VA Medical Center)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No