Acetazolamide for Opioid-Related Sleep Apnea

(MORPHO Trial)

Overseen By Jeremy Orr, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, San Diego

Must be taking: Opioids

Must not be taking: Diuretics, Potassium supplements

Disqualifiers: Chronic lung, Cardiac, Kidney, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

Duration: 6 weeks

34 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test whether acetazolamide, a diuretic medication, can improve breathing issues during sleep for people who use opioids. These breathing problems, known as sleep disordered breathing (SDB), often require a CPAP machine, but not everyone can use it. Participants will take acetazolamide for one week and a placebo (sugar pill) for another week to determine if the medication alleviates their symptoms. Suitable candidates include those with chronic pain who use opioids daily and experience breathing difficulties while sleeping. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to potentially improve their symptoms.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you use diuretics, potassium supplements, or medications that affect potassium.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that acetazolamide might safely address sleep breathing problems in people using opioids. Studies have found that acetazolamide can improve nighttime breathing by increasing oxygen levels during sleep and reducing time spent with low oxygen in the blood. This suggests it could help with breathing issues caused by opioid use.

The FDA has already approved acetazolamide for other uses, indicating it is generally safe. However, like any medication, it can cause side effects. Common side effects include tingling in the fingers or toes and increased urination. These side effects are usually mild and manageable.

In summary, while acetazolamide appears promising for improving sleep breathing issues related to opioids, participants should be aware of possible side effects. Discuss any concerns with the trial team or a healthcare provider before joining a study. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for sleep apnea?

Researchers are excited about acetazolamide for treating opioid-related sleep apnea because it offers a unique mechanism of action. Unlike traditional treatments that focus on airway management or using devices like CPAP machines, acetazolamide works by stimulating breathing through metabolic pathways. This medication, commonly used as a diuretic, enhances respiratory drive by inducing a mild metabolic acidosis, which naturally encourages the body to breathe more deeply and frequently. This approach could potentially provide a much-needed alternative for patients who struggle with standard treatments.

What evidence suggests that acetazolamide might be an effective treatment for opioid-related sleep apnea?

Research has shown that acetazolamide might help people who struggle with breathing during sleep while using opioids. Some studies suggest that acetazolamide could manage sleep apnea, a condition where breathing stops and starts during sleep. In this trial, participants will receive acetazolamide in one arm and a placebo in another, using a crossover design. For those taking long-acting opioids, acetazolamide supported the use of positive airway pressure therapy, a common treatment for sleep apnea. Another study found that acetazolamide might improve sleep apnea by addressing central sleep apnea, where the brain struggles to send the right signals to control breathing. These findings suggest that acetazolamide could be a promising option for those who find it difficult to use CPAP machines for sleep-related breathing issues. ^{1 4 6 7 8}

Who Is on the Research Team?

Jeremy Orr, MD

Principal Investigator

UC San Diego

Are You a Good Fit for This Trial?

This trial is for adults over 18 with chronic pain who regularly use opioids and have a sleep disorder where they stop breathing often during the night. They must not be pregnant, nursing, or planning pregnancy soon, and should not have major kidney disease, uncontrolled psychiatric disorders, recent hospitalization, heavy alcohol use, or other serious health issues.

Inclusion Criteria

You have a condition where you stop breathing or have shallow breathing many times per hour while sleeping.

I experience chronic pain.

I have been using opioids daily for more than 3 months at a dose of 20mg or more.

Exclusion Criteria

You are allergic to the study drug or similar drugs like sulfa drugs.

You drink more than 2 standard drinks every day.

I have a condition that affects my breathing due to neurological or developmental issues.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline Assessment

Comprehensive history and physical exam, questionnaires on sleep quality, daytime function, pain, and quality of life, and cold pressor test

1 day

1 visit (in-person)

Treatment

Participants receive acetazolamide or placebo for 1 week, followed by a 2-week washout, then crossover to the alternate treatment for another week

6 weeks

2 visits (in-person), weekly phone follow-ups

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Acetazolamide
• Placebo

Trial Overview

The study tests if acetazolamide can help people with opioid-related sleep breathing problems as an alternative to the usual mask treatment (CPAP). Participants will take either acetazolamide or a placebo for one week each to see which helps more.

How Is the Trial Designed?

Group I: Placebo followed by acetazolamide Experimental Treatment 2 Interventions

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

Group II: Acetazolamide followed by placebo Experimental Treatment 2 Interventions

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

Acetazolamide is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Diamox for:

• Glaucoma
• Epilepsy
• Edema
• Altitude sickness

Approved in European Union as Diamox for:

• Glaucoma
• Epilepsy
• Edema

Approved in Canada as Diamox for:

• Glaucoma
• Epilepsy
• Edema
• Altitude sickness

Who Is Running the Clinical Trial?

University of California, San Diego

Lead Sponsor

Trials

1,215

Recruited

1,593,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

DALDA and [Dmt1]DALDA are highly selective mu-opioid agonists that show significantly greater potency and longer duration of action compared to traditional opioids like morphine, making them promising candidates for pain management.

In a study involving sheep, DALDA and [Dmt1]DALDA demonstrated favorable pharmacokinetic properties, including longer elimination half-lives than morphine, which may reduce the risk of tolerance and dependence associated with opioid use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo pharmacokinetics of selective mu-opioid peptide agonists. Szeto, HH., Lovelace, JL., Fridland, G., et al.[2007]

Casokefamide, an analog of beta-casomorphins, was administered to 10 healthy male volunteers and was found to be well tolerated with no observed side effects, indicating its safety for potential use.

The study showed a trend toward increased oro-caecal transit time with casokefamide compared to placebo, suggesting it may be effective in treating chronic diarrhea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of oral casokefamide on plasma levels, tolerance, and intestinal transit in man. Schulte-Frohlinde, E., Reindl, W., Bierling, D., et al.[2019]

In a study involving six patients with central sleep apnea, treatment with acetazolamide led to a significant 69% reduction in total apneas and improved sleep quality, indicating its potential therapeutic value.

The administration of acetazolamide decreased mean arterial pH from 7.42 to 7.34, suggesting that acidification may enhance respiratory rhythm during sleep, which could be a key mechanism in reducing apneas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Central sleep apnea. Improvement with acetazolamide therapy. White, DP., Zwillich, CW., Pickett, CK., et al.[2013]

[Dmt(1)]DALDA is a highly potent mu-opioid agonist with antinociceptive effects that are 3000 times more effective than morphine, and it also inhibits norepinephrine uptake, contributing to its pain-relieving properties.

Unlike morphine and DALDA, [Dmt(1)]DALDA does not significantly depress respiratory function, making it a promising candidate for safer intrathecal analgesia with a longer duration of action (13 hours) compared to morphine (3 hours).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antinociceptive and respiratory effects of intrathecal H-Tyr-D-Arg-Phe-Lys-NH2 (DALDA) and [Dmt1] DALDA. Shimoyama, M., Shimoyama, N., Zhao, GM., et al.[2013]

The newly synthesized compounds (10-14) demonstrated significant analgesic effects, outperforming acetylsalicylic acid in two different tests, indicating their potential as effective pain relievers.

These compounds also exhibited sedative properties by reducing spontaneous locomotor activity and prolonging barbiturate-induced sleep in mice, while showing only weak binding affinity to mu-opioid receptors, suggesting a different mechanism of action than traditional opioids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and pharmacological properties of N,N-dialkyl(dialkenyl)amides of 7-methyl-3-phenyl-1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)propyl]-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acid. Sladowska, H., Sabiniarz, A., Filipek, B., et al.[2003]

Acetazolamide (AZT) significantly improved sleep apnea symptoms in patients with high loop gain sleep apnea (HLGSA) both acutely and over a 3-month period, showing a notable reduction in the apnea hypopnea index (AHI) and breathing-related arousal index when combined with positive airway pressure (PAP) therapy.

The study involved 231 participants, with a strong predictor for treatment response being the non-rapid eye movement (NREM) AHI, indicating that AZT is a well-tolerated and effective option for managing HLGSA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute and long-term effects of acetazolamide in presumed high loop gain sleep apnea. Ni, YN., Holzer, RC., Thomas, RJ.[2023]

In a study of nine patients with obstructive sleep apnoea, acetazolamide (250 mg/day) significantly reduced the apnoea index from 25.0 to 18.1 episodes per hour and decreased the total time of arterial oxygen desaturation during sleep.

Acetazolamide appears to improve symptoms of daytime hypersomnolence in some patients and enhances ventilatory control by increasing the body's response to carbon dioxide, suggesting it may be beneficial for mild cases of obstructive sleep apnoea, although it does not completely eliminate apnoea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of acetazolamide in patients with the sleep apnoea syndrome. Tojima, H., Kunitomo, F., Kimura, H., et al.[2019]

Acetazolamide significantly improves sleep apnea at high altitudes by reducing the Apnea-Hypopnea Index (AHI) and increasing nocturnal oxygenation, particularly in healthy trekkers compared to those with obstructive sleep apnea (OSA).

A daily dose of 250 mg of acetazolamide may be as effective as higher doses for healthy individuals, suggesting a potential optimal therapeutic dose for treating sleep apnea in high-altitude conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of acetazolamide on sleep apnea at high altitude: a systematic review and meta-analysis. Liu, HM., Chiang, IJ., Kuo, KN., et al.[2018]

In a study involving 45 patients with obstructive sleep apnea (OSA), acetazolamide significantly improved oxygen levels and reduced breathing disturbances at high altitudes compared to a placebo, indicating its potential as an alternative treatment when CPAP is not used.

Acetazolamide not only enhanced nocturnal oxygen saturation and reduced apnea/hypopnea indices but also improved sleep quality and prevented high blood pressure during altitude exposure, suggesting it stimulates ventilation effectively in OSA patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patients with obstructive sleep apnea syndrome benefit from acetazolamide during an altitude sojourn: a randomized, placebo-controlled, double-blind trial. Nussbaumer-Ochsner, Y., Latshang, TD., Ulrich, S., et al.[2017]

The study found that small opioid peptides, particularly DMT-DALDA, exhibit strong mu opioid receptor agonist properties, providing significant pain relief comparable to morphine and fentanyl, with a notable analgesic effect lasting up to 6 hours after administration.

Despite their effectiveness, these peptides also demonstrated a tendency to produce tolerance similar to traditional opioids, indicating that while they may be promising for pain management, their long-term use could lead to reduced efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of the antinociceptive effects of intrathecal DALDA peptides following bolus intrathecal delivery. Kokubu, S., Eddinger, KA., Nguyen, TM., et al.[2019]

A 41-year-old woman with obstructive sleep apnea on long-acting opioids experienced severe central apnea when starting CPAP therapy, which complicated her treatment.

The addition of acetazolamide at 250 mg nightly allowed for successful CPAP titration without significant central respiratory disturbances, suggesting it may be a beneficial adjunct therapy for patients on opioids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acetazolamide as an adjunct to CPAP treatment: a case of complex sleep apnea in a patient on long-acting opioid therapy. Glidewell, RN., Orr, WC., Imes, N.[2021]

In a study of 20 male patients with sleep apnea, 14 showed significant improvements in apnea frequency, sleep structure, and related symptoms after treatment with acetazolamide (AZM), a carbonic anhydrase inhibitor.

The treatment led to a decrease in arterial blood pH and bicarbonate levels in the improved patients, indicating a potential mechanism of action related to metabolic changes, while the remaining 6 patients did not experience any benefits from AZM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of acetazolamide on the sleep apnea syndrome and its therapeutic mechanism. Sakamoto, T., Nakazawa, Y., Hashizume, Y., et al.[2019]

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