Managing Opioid Related Sleep Apnea With Acetazolamide (MORPHO)

Patients with chronic pain who use opioids appear to be at increased risk for breathing issues during sleep, termed sleep disordered breathing (SDB). Treatment of SDB often consists of use of a device during sleep that provides continuous positive airway pressure (CPAP) via a mask interface. However, this device is not effective or tolerated in all individuals. The goal of this study is to examine whether a medication called acetazolamide can improve SDB, as an alternative to CPAP treatment.

The investigators will measure the improvement in SDB, as well as any change in symptoms, during a 1 week treatment with acetazolamide compared with 1 week of placebo (sugar pill). This study will help to provide data for longer term studies of treatment for SDB in patients who use opioids.

Study Overview

• Status: Recruiting
• Conditions: Chronic Pain; Obstructive Sleep Apnea; Opioid Use; Sleep-Disordered Breathing; Central Sleep Apnea
• Intervention / Treatment: Drug: Acetazolamide; Other: Placebo

Detailed Description

Patients who use chronic opioids for chronic pain daily for >3 months will be recruited. The investigators will study patients with established sleep disordered breathing (SDB; defined as an apnea-hypopnea index (AHI) >/= 10 events/hr). Patients with a prior diagnosis of SDB can enroll provided they can hold their CPAP treatment for the duration of the study. Persons with chronic lung or kidney disease will be excluded, along with those with heart failure, liver failure, kidney disease, medications affecting potassium levels, recreational opioid use, cancer pain, limited life expectancy, prisoners, pregnant women, psychiatric disease other than controlled mood disorders, and those unable to provide consent or cooperate with research procedures. Potential subjects will discuss the planned research protocol, risks, benefits, and alternatives with the study staff.

Once the individual has given written informed consent, they will be scheduled for a baseline study visit, which will begin in the early evening. Subjects will undergo a comprehensive history and physical exam, questionnaires examining sleep quality, daytime function, pain, and quality of life. The cold pressor test will be administered, which includes submerging the non-dominant hand in a 4 degree Celsius water bath, and reporting the onset of pain and maximal tolerable submersion time.

The subjects will be randomized into two groups: Group A will take acetazolamide 500 mg by mouth nightly for 1 week, followed by placebo (sugar pill) by mouth nightly for 1 week. Group B will take placebo (sugar pill) by mouth nightly for 1 week, followed by acetazolamide 500 mg by mouth nightly for 1 week. There will be a 2 week washout (i.e. no placebo or acetazolamide) between the treatments. The subjects and study staff will be blinded to the treatment that each subject is taking, in order to avoid introducing bias into the results. Study staff will be follow up with a phone call mid-week and will be available by phone if any issues arise.

At the end of each week (acetazolamide and placebo conditions), the subject will return for a follow up visit, during which they will undergo the same assessment tools as the baseline visit. They will then be instrumented for an overnight sleep study, which will include the application of electrodes to the scalp (electroencephalogram), beside the eyes (electro-oculogram), chin and legs (electromyogram). Elastic bands will be applied around the chest and abdomen, a pulse oximeter will be affixed to the finger, and airflow monitors placed just inside the nose and outside the mouth. The subject will then be allowed to sleep until the morning. Upon awakening, they will undergo a computer test of alertness.

• Study Type: Interventional
• Enrollment (Estimated): 34
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jeremy Orr, MD; Phone Number: 858-246-2183; Email: sleepresearch@health.ucsd.edu

Study Locations

• United States
  • California
    • San Diego, California, United States, 92037
      • Recruiting
      • University of California San Diego
      • Contact: Pamela N DeYoung, RPSGT; Phone Number: 858-246-2183; Email: pdeyoung@health.ucsd.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18+
• Chronic pain
• Chronic opioid use (daily use for >3 months duration) with >/= 20 oral Morphine Equivalent Dose (MEqD) per day
• Apnea-hypopnea index >/= 10 events/hr (hypopnea definition: ≥ 3% desaturation or arousal criteria per American Academy of Sleep Medicine 2012 scoring rules)

Exclusion Criteria:

• Use of opioids outside medical supervision (e.g. recreational use)
• Unable or unwilling to withhold any ongoing SDB treatment (e.g. CPAP) for the duration of the study
• Urgent need to initiate effective SDB therapy
• Chronic lung disease (other than well-controlled asthma)
• Active cardiac disease including heart failure, chest pain, or heart rhythm problems
• Neurological or developmental problems affecting breathing
• Major sleep disorders other than sleep apnea
• Chronic kidney disease
• Cirrhosis of the liver
• Active cancer treatment or limited life expectancy
• Psychiatric disease other than controlled mood disorders
• Use of diuretics, potassium supplementation, or medications that may affect potassium
• Allergy to study drug or related compounds including sulfa drugs
• Know electrolyte disturbances
• Hospitalized in the last 90 days or anticipated hospitalization within 3 months
• Alcohol use >2 standard drinks per day
• Presence of tracheostomy or artificial airway
• Prisoners
• Pregnancy or anticipating pregnancy in next 2 months, or nursing
• Unable or unwilling to provide informed consent
• Unable to follow study protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Placebo followed by acetazolamide; Subjects will start with a 1-week PLACEBO regimen Day 1-7: Placebo (matching Acetazolamide) nightly After a 2 week wash-out period, subjects will then cross-over to a 1-week ACETAZOLAMIDE regimen: Day 1-7: Acetazolamide 500 mg nightly	Drug: Acetazolamide; Acetazolamide 250 mg 2 capsules by mouth nightly; Other: Placebo; Sugar capsule manufactured to match encapsulated Acetazolamide 2 capsules by mouth nightly
Experimental: Acetazolamide followed by placebo; Subjects will start with a 1-week ACETAZOLAMIDE regimen Day 1-7: Acetazolamide 500 mg nightly After a 2 week wash-out period, subjects will then cross-over to a 1-week PLACEBO regimen: Day 1-7: Placebo (matching Acetazolamide) nightly	Drug: Acetazolamide; Acetazolamide 250 mg 2 capsules by mouth nightly; Other: Placebo; Sugar capsule manufactured to match encapsulated Acetazolamide 2 capsules by mouth nightly

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Apnea-hypopnea index, NREM Supine	The AHI is a measure of sleep apnea severity and is defined as the number of apneas (no breathing for 10+ seconds) and hypopneas (reduced breathing for 10+ seconds associated with a >=3% desaturation or cortical arousal) per hour of sleep. For the primary outcome, the study will evaluate the AHI during non-rapid eye movement sleep in the supine position.	1 week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Apnea-hypopnea index, Total	The AHI is a measure of sleep apnea severity and is defined as the number of apneas (no breathing for 10+ seconds) and hypopneas (reduced breathing for 10+ seconds associated with a >=3% desaturation or cortical arousal) per hour of sleep. For the primary outcome, the study will evaluate the AHI during sleep in supine and lateral position.	1 week

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance	Higher scores indicate more symptoms	1 week
Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Related Impairment	Higher scores indicate more symptoms	1 week
Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Behavior	Higher scores indicate more symptoms	1 week
Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference	Higher scores indicate more symptoms	1 week
10 minute psychomotor vigilance test	Total lapses and mean reaction time	1 week

Collaborators and Investigators

• Sponsor: University of California, San Diego
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Jeremy Orr, MD, UC San Diego

Study record dates

Study Major Dates

• Study Start (Actual): October 18, 2023
• Primary Completion (Estimated): April 1, 2025
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: September 12, 2023
• First Submitted That Met QC Criteria: September 19, 2023
• First Posted (Actual): September 21, 2023

Study Record Updates

• Last Update Posted (Actual): October 31, 2023
• Last Update Submitted That Met QC Criteria: October 27, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Opioid; Lung; Sleep apnea
• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Pain; Neurologic Manifestations; Signs and Symptoms, Respiratory; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Chronic Pain; Apnea; Sleep Apnea, Central; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Carbonic Anhydrase Inhibitors; Natriuretic Agents; Diuretics; Anticonvulsants; Acetazolamide
• Other Study ID Numbers: 201743.2; K23HL151880 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No