Acetazolamide for Central Sleep Apnea in Opioid Users

Overseen By Julia Sherman

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Sanjay R Patel

Must be taking: Methadone, Buprenorphine

Disqualifiers: Sleep hypoventilation, Pregnancy, others

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

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

Compensation: Varies

Number of Visits: 2

Duration: 1 week

40 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, since it involves patients already on medication for opioid use disorder, it seems likely that you can continue those medications during the trial.

What evidence supports the effectiveness of the drug acetazolamide for treating central sleep apnea in opioid users?

Research shows that acetazolamide can significantly reduce the number of apneas in patients with central sleep apnea, improving sleep quality and reducing daytime sleepiness. It works by altering blood pH, which helps stabilize breathing during sleep. ^{1 2 3 4 5}

Is acetazolamide generally safe for humans?

Acetazolamide can cause side effects, and there is a risk of severe allergic reactions, especially in people with sulfonamide allergies. It's important to discuss any allergies with your doctor before using this medication. ^{6 7 8 9 10}

What makes the drug Acetazolamide unique for treating central sleep apnea in opioid users?

Acetazolamide is unique for treating central sleep apnea in opioid users because it works by altering the acid-base balance in the blood, which can help stimulate breathing. This mechanism is different from other treatments that primarily focus on the opioid receptors or respiratory stimulants. ^{11 12 13 14 15}

What is the purpose of this trial?

Patients with opioid use disorder treated with either methadone or buprenorphine are at risk of developing central sleep apnea (CSA) from these medications. Investigators will conduct a mechanistic trial using acetazolamide, a medicine known to improve CSA in other settings, to determine if acetazolamide can improve CSA due to medication for opioid use disorder and whether this leads to physiologic changes that might lead to reduced drug craving. Patients treated with medication for opioid use disorder and who have central sleep apnea will be randomized to treatment with acetazolamide or matching placebo for 7 days. At the end of the 7 days, they will undergo an overnight sleep study to assess the impact on breathing during sleep as well as sleep quality. In addition, measures of sympathetic tone, anxiety, arousal, cognition, and drug craving will be measured to determine if treatment of CSA with acetazolamide can produce physiologic changes that might contribute to improved health.

Research Team

Sanjay R Patel, MD

Principal Investigator

University of Pittsburgh

Eligibility Criteria

This trial is for people with opioid use disorder who are being treated with methadone or buprenorphine and have developed central sleep apnea. Participants must be currently receiving medication for opioid use disorder to qualify.

Inclusion Criteria

I am taking medication for opioid addiction and have central sleep apnea.

Exclusion Criteria

My central sleep apnea is not caused by opioid use.

Pregnancy

I have trouble breathing while asleep.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Treatment

Participants are randomized to receive either acetazolamide or placebo for 7 days

1 week

Daily medication administration

Outcome Assessment

Participants undergo an overnight sleep study to assess the impact on breathing during sleep and other physiological measures

1 day

1 overnight visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2-4 weeks

Treatment Details

Interventions

• Acetazolamide

Trial Overview The study tests if acetazolamide can improve sleep apnea in patients using opioids. Half will receive acetazolamide, the other half a placebo, over 7 days. Their sleep quality and various health measures like anxiety and drug craving will be evaluated.

Participant Groups

Group I: Acetazolamide Experimental Treatment 1 Intervention

All participants in this group will receive one acetazolamide 250 mg pill in the evening for 7 days.

Group II: Placebo Placebo Group 1 Intervention

All participants in this group will receive one matching placebo pill in the evening for 7 days.

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?

Sanjay R Patel

Lead Sponsor

Trials

2

Recruited

90+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

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]

Acetazolamide (ACET) significantly reduces the number of central apneas in patients with central sleep apnea, with improvements observed during treatment and persisting for at least 6 months after stopping therapy.

After discontinuing ACET, while the central apnea index remained low, there was an increase in obstructive apneas and central hypopneas, suggesting that ACET may cause a lasting change in the body's CO2 sensitivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Central sleep apnea after interrupting longterm acetazolamide therapy. Verbraecken, J., Willemen, M., De Cock, W., 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]

In a study of 14 patients with central sleep apnea, low-dose acetazolamide (250 mg) significantly reduced the central apnea index (CAI) from 25.5 to 6.6 after one month of treatment, indicating its efficacy in managing central sleep apnea.

The treatment did not affect the obstructive apnea index (OAI) or total sleep time, but it did lead to a significant decrease in the number of arousals during sleep, suggesting improved sleep quality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Central apnea index decreases after prolonged treatment with acetazolamide. DeBacker, WA., Verbraecken, J., Willemen, M., et al.[2013]

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]

Acetazolamide (AZM) significantly increases the risk of common side effects such as paraesthesias, taste disturbances, polyuria, and fatigue, with a meta-analysis of 42 studies involving 1274 subjects showing a clear dose-dependent relationship for some of these effects.

Higher doses of AZM are associated with increased risks of paraesthesias and taste disturbances, suggesting that clinicians should consider using the lowest effective dose to minimize side effects while treating conditions like altitude sickness and sleep apnea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Side effects of acetazolamide: a systematic review and meta-analysis assessing overall risk and dose dependence. Schmickl, CN., Owens, RL., Orr, JE., et al.[2021]

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]

In a study involving 12 patients with chronic open-angle glaucoma, reducing the individual doses of Acetazolamide while maintaining the same application frequency did not decrease its effectiveness in lowering intraocular pressure.

The study also indicated that even a lower daily dose of 3 X 62.5 mg was effective, suggesting potential for long-term treatment with lower doses of Acetazolamide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Investigations on the effect of various doses of acetazolamide (Diamox) on intraocular pressure (author's transl)]. Merté, HJ., Heilmann, K., Hollwich, I.[2013]

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]

D-Ala2-Met-enkephalinamide (DALA) is a synthetic enkephalin analog that binds to opiate receptors nearly as effectively as methionine-enkephalin, suggesting strong potential for pain relief.

When administered in low doses (5 to 10 micrograms) directly into the rat brain, DALA produces significant and long-lasting morphine-like analgesia, demonstrating its efficacy as a pain management option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

(D-Ala2)-Met-enkephalinamide: a potent, long-lasting synthetic pentapeptide analgesic. Pert, CB., Pert, A., Chang, JK., 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 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]

In a study involving 10 cancer patients with chronic pain, intrathecal D-Ala-D-Leu-enkephalin (DADL) provided effective pain relief for all participants, with 6 experiencing greater relief compared to intrathecal morphine sulfate (MS).

While both DADL and MS had similar side effects, primarily drowsiness, the study suggests that DADL could be a viable alternative for patients tolerant to systemic opiates, although further research is needed to determine its relative analgesic potency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The analgesic efficacy of intrathecal D-Ala2-D-Leu5-enkephalin in cancer patients with chronic pain. Moulin, DE., Max, MB., Kaiko, RF., et al.[2021]

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]

References

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

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

2. Netherlands pubmed.ncbi.nlm.nih.gov

Central sleep apnea after interrupting longterm acetazolamide therapy. [2019]

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

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

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

Central apnea index decreases after prolonged treatment with acetazolamide. [2013]

5. 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]

6. England pubmed.ncbi.nlm.nih.gov

Side effects of acetazolamide: a systematic review and meta-analysis assessing overall risk and dose dependence. [2021]

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

Effectiveness of generic acetazolamide. [2019]

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

[Investigations on the effect of various doses of acetazolamide (Diamox) on intraocular pressure (author's transl)]. [2013]

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

Inadvertent substitution of acetohexamide for acetozolamide. [2019]

10. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

(D-Ala2)-Met-enkephalinamide: a potent, long-lasting synthetic pentapeptide analgesic. [2019]

12. 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]

13. Germany pubmed.ncbi.nlm.nih.gov

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

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

The analgesic efficacy of intrathecal D-Ala2-D-Leu5-enkephalin in cancer patients with chronic pain. [2021]

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

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