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

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the drug acetazolamide for treating opioid-related sleep apnea?

Research suggests that acetazolamide can help reduce sleep apnea episodes and improve sleep quality in patients with sleep apnea, including those on long-acting opioids. It has been shown to decrease the number of apneas and improve symptoms like daytime sleepiness and snoring in some patients. ^{1 2 3 4 5}

Is acetazolamide safe for human use?

The provided research articles do not contain relevant safety information about acetazolamide or its various names for human use. ^{6 7 8 9 10}

How does the drug acetazolamide differ from other treatments for opioid-related sleep apnea?

Acetazolamide is unique because it can be used alongside CPAP therapy to help manage sleep apnea in patients on long-acting opioids, potentially reducing central respiratory disturbances. It works by altering blood chemistry to improve breathing stability, which may not be addressed by standard treatments like CPAP alone. ^{1 2 3 11 12}

Research Team

Jeremy Orr, MD

Principal Investigator

UC San Diego

Eligibility Criteria

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 am 18 years old or older.

I experience chronic pain.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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]

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]

[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]

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]

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]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Acute and long-term effects of acetazolamide in presumed high loop gain sleep apnea. [2023]

2. United States 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. [2021]

3. Australia pubmed.ncbi.nlm.nih.gov

Effects of acetazolamide on the sleep apnea syndrome and its therapeutic mechanism. [2019]

4. England pubmed.ncbi.nlm.nih.gov

The effect of acetazolamide on sleep apnea at high altitude: a systematic review and meta-analysis. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Central sleep apnea. Improvement with acetazolamide therapy. [2013]

6. United States pubmed.ncbi.nlm.nih.gov

In vivo pharmacokinetics of selective mu-opioid peptide agonists. [2007]

7. United States pubmed.ncbi.nlm.nih.gov

Effects of oral casokefamide on plasma levels, tolerance, and intestinal transit in man. [2019]

8. Germany pubmed.ncbi.nlm.nih.gov

Characterization of the antinociceptive effects of intrathecal DALDA peptides following bolus intrathecal delivery. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

Antinociceptive and respiratory effects of intrathecal H-Tyr-D-Arg-Phe-Lys-NH2 (DALDA) and [Dmt1] DALDA. [2013]

10. France 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. [2003]

11. England pubmed.ncbi.nlm.nih.gov

Effects of acetazolamide in patients with the sleep apnoea syndrome. [2019]

12. United States 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. [2017]