Supplemental Oxygen for Sleep-Disordered Breathing in Adults With Chronic Opioid Use. (OPIO2)

Inclusion Criteria:

• Age 18 to 75 years.
• Chronic opioid use for ≥3 months with a daily opioid dose equivalent to at least 20 mg of oral morphine (morphine equivalent daily dose [MEqD]). Examples include approximately 13 mg oxycodone, 20 mg hydrocodone, 100 mg tramadol, or equivalent doses of other opioids.
• Ability and willingness to comply with study procedures, including overnight laboratory polysomnography and administration of oxygen or sham air in the laboratory.
• Ability to provide written informed consent.
• For participants able to become pregnant: agreement to use an effective contraceptive method (e.g., a licensed hormonal or intrauterine method, or an effective barrier method) during study participation. The study team will review and document the method before enrollment.
• Recruitment will target approximately equal numbers of males and females to enable consideration of sex as a biological variable, consistent with NIH policy.

In addition to the enrollment criteria, participants must meet the following criterion to be eligible for randomization:

• Diagnosis of sleep-disordered breathing (SDB), defined as AASM-recommended apnea-hypopnea index (AHI3A) ≥5 events per hour on a qualifying sleep study. AHI3A includes hypopnea definition ≥30% airflow reduction lasting ≥10 seconds, accompanied by ≥3% SpO2 desaturation or arousal.

Exclusion Criteria:

• Body mass index (BMI) >35 kg/m².
• Requirement for supplemental oxygen therapy outside of the study.
• Current use of CPAP or other sleep-apnea treatment that cannot safely be withheld during OPIO2 research PSG nights.
• Known severe pulmonary disease (e.g., advanced chronic obstructive pulmonary disease) that, in the opinion of the investigator, may increase the risk of oxygen-induced hypercapnia.
• Unstable or clinically significant cardiopulmonary disease, including but not limited to decompensated heart failure, unstable angina, or clinically significant arrhythmia.
• Recent hospitalization (within the past 30 days) or anticipated need for hospitalization during the study period.
• Recreational or non-prescribed opioid use.
• Alcohol use exceeding 2 standard drinks per day or evidence of substance use disorder that may interfere with study participation.
• Presence of other sleep disorders or neurologic conditions that significantly affect breathing during sleep (e.g., neuromuscular disease), in the opinion of the investigator.
• Pregnancy or breastfeeding, or planning to become pregnant during the study period.
• Positive pregnancy test at screening (serum or urine) for participants able to become pregnant. A pregnancy test will be repeated before each awake chemoreflex session or in-laboratory PSG visit; one same-day test may cover both; a positive test triggers withdrawal from further study procedures.
• Hospitalization for respiratory failure within the prior 12 months.
• Severe untreated insomnia (Insomnia Severity Index >22) likely to preclude completion of in-laboratory PSG visits.
• Inability to communicate in English sufficient for informed consent and study procedures, where a qualified interpreter consistent with UCSD HRPP policy is not available.
• Inability to tolerate nasal cannula or study procedures.
• Inability to provide informed consent or comply with study procedures.
• Any medical, psychiatric, or social condition that, in the opinion of the investigator, would interfere with safe participation or interpretation of study results.
• Prisoners or individuals who are involuntarily incarcerated.
• Inability or unwillingness to comply with research-center oxygen-safety precautions, including restrictions on smoking, vaping, open flames, and other ignition sources near oxygen equipment.

In addition to the enrollment exclusion criteria, participants will be excluded from randomization if the following criterion is met:

• Evidence of significant hypercapnia, defined as transcutaneous carbon dioxide (TcCO2) >55 mmHg for >10 minutes during baseline polysomnography (PSG).