Comprehensive Opioid Management and Breathing During Sleep

The REDUCE study will evaluate whether referral to a comprehensive opioid management program improves breathing stability during sleep in adults with chronic opioid use and sleep-disordered breathing.

This is a Phase II, single-center, randomized, controlled study. Participants will be randomly assigned to either usual care or referral to the UC San Diego Opioid Management Program. Participants referred to the program will receive individualized opioid and pain management from their treating clinician or designated opioid management provider. Treatment may include changes to opioid medications and other pain-management strategies when clinically appropriate. The research team will not prescribe opioids or direct opioid dose adjustments, and no opioid dose reductions are required by the study.

Participants will be followed for approximately 26 weeks. Study assessments will include overnight sleep studies, questionnaires, blood collection, psychomotor vigilance testing, and regular safety monitoring.

The primary objective is to determine whether comprehensive opioid management improves ventilatory stability compared with usual care.

Chronic opioid use is associated with sleep-disordered breathing, including obstructive and central sleep apnea. Opioids can alter respiratory drive and ventilatory control, contributing to breathing instability, oxygen desaturation, nocturnal hypercapnia, and sleep fragmentation.

The REDUCE study (Respiratory Effects of Dose Optimization Under Comprehensive Opioid Management) is a Phase II, single-center, randomized, controlled, parallel-group, open-label trial conducted at the University of California, San Diego. The study is designed to evaluate the effects of referral to the UC San Diego Opioid Management Program compared with usual care on ventilatory stability and sleep-disordered breathing physiology in adults with chronic opioid use.

Eligible participants will be adults aged 18 to 75 years with chronic opioid use for at least three months, a daily opioid dose of at least 20 mg oral morphine equivalents, and sleep-disordered breathing defined by an apnea-hypopnea index (AHI3A) of at least five events per hour.

Participants will be randomized in a 1:1 ratio to one of two study groups: Usual Care or Comprehensive Opioid Management.

Participants assigned to Usual Care will continue opioid and pain management under the direction of their existing treating clinician according to routine clinical practice.

Participants assigned to Comprehensive Opioid Management will be referred to the UC San Diego Opioid Management Program for individualized, guideline-concordant clinical care. Management may include opioid dose adjustments, medication optimization, non-opioid pain therapies, behavioral interventions, and other pain-management strategies when clinically appropriate. All opioid prescribing and treatment decisions will remain under the authority of the treating clinician or designated opioid management provider. The research team will not prescribe opioids, independently direct opioid dose adjustments, or require a protocol-specified opioid taper.

Participants will complete screening and baseline assessments, including medical and sleep history, physical examination, medication review, questionnaires, opioid use assessment, and blood collection. A baseline polysomnography (PSG) will be performed if a qualifying PSG has not been completed within the previous eight weeks or if a clinically significant change in medical or sleep-related status has occurred.

Following baseline assessments and randomization, participants will enter a 26-week follow-up period. During this period, participants will complete twice-weekly text-message safety check-ins and twice-monthly telephone outreach. Safety monitoring will assess opioid use, medication changes, withdrawal symptoms, pain control, mood symptoms including suicidality, respiratory symptoms, adverse events, emergency care utilization, and study adherence.

An interim assessment will occur at approximately Week 12 and will include medication and opioid use review, adverse event assessment, and study questionnaires.

At approximately Week 26, all participants will complete an end-of-study assessment, including overnight polysomnography, questionnaires, opioid use assessment, blood collection, and morning psychomotor vigilance testing. Sleep studies will assess respiratory events, ventilatory instability, oxygen saturation, and transcutaneous carbon dioxide levels.

The primary endpoint is the change in ventilatory instability as measured by loop gain from baseline to Week 26. Secondary endpoints include apnea-hypopnea index (AHI), flow-based apnea-hypopnea index (AHIflow), respiratory pattern variability, oxygen saturation metrics including time spent with SpO2 below 90%, transcutaneous carbon dioxide (TcCO2), psychomotor vigilance testing, patient-reported sleep and symptom measures, pain-related outcomes, and opioid exposure.

The study will compare changes in ventilatory stability and related physiological and clinical outcomes between participants receiving usual care and those referred for Comprehensive Opioid Management over the 26-week study period.