Oxygen + Acetazolamide for Sleep Apnea

(SDB Trial)

Recruiting at 1 trial location

Overseen By Ruchi Rastogi, MS

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: VA Office of Research and Development

Must be taking: Opioids

Must not be taking: Tramadol, Suboxone

Disqualifiers: Morbid obesity, Cardiac disease, Stroke, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

150 Participants Needed

Trial Summary

What is the purpose of this trial?

There is an increased risk for sleep disordered breathing (SDB), sleep-related hypoventilation and irregular breathing in individuals on chronic prescription opioid medications. Almost 30% of a veteran sleep clinic population had opioid-associated central sleep apnea (CSA). The proposal aims to identity whether oxygen and acetazolamide can be effective in reducing unstable breathing and eliminating sleep apnea in chronic opioid use via different mechanisms. We will study additional clinical parameters like quality of life, sleep and pain in patients with and without opioid use. This proposal will enhance the investigators' understanding of the pathways that contribute to the development of sleep apnea with opioid use. The investigators expect that the results obtained from this study will positively impact the health of Veterans by identifying new treatment modalities for sleep apnea.

Do I have to stop taking my current medications for the trial?

The trial does not specify if you need to stop taking your current medications, but it does exclude patients on tramadol and suboxone/buprenorphine. It seems you can continue other prescription opioids.

What evidence supports the effectiveness of the drug acetazolamide for treating sleep apnea?

Research shows that acetazolamide can reduce the number of apnea episodes and improve sleep quality in some patients with sleep apnea. It has been particularly effective in reducing apnea at high altitudes and in cases of central sleep apnea, where it helps stabilize breathing patterns. ^{1 2 3 4 5}

Is acetazolamide safe for humans?

Acetazolamide can cause serious allergic reactions in people with sulfonamide allergies, leading to life-threatening conditions like anaphylactic shock. It is important to check for such allergies before using the medication. ^{1 6 7 8 9}

How does the drug acetazolamide work for sleep apnea?

Acetazolamide is unique for sleep apnea treatment because it acts as a carbonic anhydrase inhibitor, which helps reduce the number of apnea episodes by increasing the body's drive to breathe through changes in blood chemistry, such as lowering blood pH and bicarbonate levels. This drug is particularly beneficial for mild cases of obstructive sleep apnea and can also help improve sleep apnea symptoms at high altitudes. ^{1 3 4 10 11}

Research Team

Susmita Chowdhuri, MD

Principal Investigator

John D. Dingell VA Medical Center, Detroit, MI

Eligibility Criteria

This trial is for veterans aged 18-89 who are on prescription opioids and may have sleep issues like apnea due to their medication. It's not open to those with severe untreated mental or physical health conditions, recent strokes or heart problems, pregnant women, very high BMI (>40), or anyone unable to consent.

Inclusion Criteria

I am a veteran prescribed opioids.

I am a veteran aged between 18 and 89.

Exclusion Criteria

I do not have severe lung, brain, liver, or kidney diseases.

I have ongoing chest pain or discomfort.

I have ongoing seizures that aren't controlled.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment - Hyperoxia

Participants undergo sustained hyperoxia overnight to assess its effect on ventilatory control during sleep

2-30 days

Overnight study

Treatment - Acetazolamide

Participants receive oral acetazolamide therapy for 6 days to study its effect on cerebrovascular responsiveness to CO2

6 days

Experimental night study, experimental day study, polysomnography night study

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Acetazolamide
• Hyperoxia

Trial Overview The study tests if oxygen (hyperoxia) and a drug called acetazolamide can help reduce irregular breathing and eliminate sleep apnea in people taking chronic opioid medications. It also looks at how these treatments affect life quality, sleep, and pain levels.

Participant Groups

Group I: Hyperoxia Experimental Treatment 1 Intervention

Determine the effect of sustained hyperoxia overnight vs room air overnight on ventilatory control during sleep, including the apneic threshold, carbon-dioxide reserve and chemosensitivity measured via pressure support ventilation (PSV) during non-rapid eye movement sleep (NREM) sleep.

Group II: Acetazolamide (ACZ) Experimental Treatment 1 Intervention

Determine the effect of acetazolamide on cerebrovascular responsiveness to CO2 during wake and sleep. Participants will receive oral ACZ therapy for 6 days, While on the medication following studies will be performed - experimental night study, experimental day study, polysomnography night study (PSG).

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?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

John D. Dingell VA Medical Center

Collaborator

Trials

10

Recruited

1,100+

Findings from Research

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]

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]

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 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]

Generic acetazolamide and brand-name acetazolamide (Diamox) have equivalent effects on lowering intraocular pressure and achieve comparable blood levels after a single dose.

The cost of generic acetazolamide is 37% lower than that of the brand-name version, and food intake does not affect the absorption of acetazolamide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of generic acetazolamide. Ellis, PP., Price, PK., Kelmenson, R., et al.[2019]

There were three cases where acetohexamide was mistakenly given instead of acetazolamide due to their similar appearance and names, highlighting a significant risk for medication errors.

One patient experienced a severe hypoglycemic reaction leading to head trauma and confusion, which required emergency hospitalization, demonstrating the potential dangers of such medication mix-ups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inadvertent substitution of acetohexamide for acetozolamide. Hargett, NA., Ritch, R., Mardirossian, J., et al.[2019]

A 66-year-old woman experienced irreversible anaphylactic shock and severe pulmonary edema after being prescribed acetazolamide for glaucoma, likely due to a cross-reaction with her known sulphonamide allergy.

This case highlights the critical importance of screening for sulphonamide allergies before prescribing acetazolamide, as such allergies should be considered a contraindication due to the chemical similarities between the two drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Fatal anaphylactic reaction after oral acetazolamide (diamox) for glaucoma]. Gerhards, LJ., van Arnhem, AC., Holman, ND., et al.[2017]

In a study involving nine patients with ocular hypertension, acetazolamide effectively reduced intraocular pressure (IOP) by 30% to 35%, with the most significant response observed at a 63 mg dose, which lowered IOP by an average of 8.2 mm Hg.

Higher doses of acetazolamide (up to 500 mg) did not produce a proportionally greater reduction in IOP, indicating that a 63 mg dose is sufficient for effective treatment, as it achieves similar results to higher doses without the need for increased plasma levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-term dose response characteristics of acetazolamide in man. Friedland, BR., Mallonee, J., Anderson, DR.[2019]

In a study of 12 male patients with stable systolic heart failure, acetazolamide significantly reduced the number of central apnea episodes from an average of 49 to 23 per hour, indicating its efficacy in treating central sleep apnea.

Acetazolamide also improved overall sleep quality and reduced daytime fatigue and unintentional daytime sleepiness, suggesting it positively impacts both sleep and daily functioning in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acetazolamide improves central sleep apnea in heart failure: a double-blind, prospective study. Javaheri, S.[2022]

Acetazolamide is effective in preventing acute mountain sickness, significantly reducing symptoms like headache and nausea, and its benefits are linked to increased arterial oxygen levels and reduced fluid retention.

While Acetazolamide can help treat established acute mountain sickness by improving oxygen levels, there is limited data on its effectiveness compared to other treatments like steroids or calcium channel blockers, and faster alternatives like Methazolamide may be more suitable in emergencies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acetazolamide and high altitude diseases. Bradwell, AR., Wright, AD., Winterborn, M., et al.[2013]

References

1. Australia pubmed.ncbi.nlm.nih.gov

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

2. 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]

3. England pubmed.ncbi.nlm.nih.gov

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

Effectiveness of generic acetazolamide. [2019]

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

Inadvertent substitution of acetohexamide for acetozolamide. [2019]

8. Netherlands pubmed.ncbi.nlm.nih.gov

[Fatal anaphylactic reaction after oral acetazolamide (diamox) for glaucoma]. [2017]

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

Short-term dose response characteristics of acetazolamide in man. [2019]

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

Acetazolamide improves central sleep apnea in heart failure: a double-blind, prospective study. [2022]

11. Germany pubmed.ncbi.nlm.nih.gov

Acetazolamide and high altitude diseases. [2013]