Acetazolamide for Central Sleep Apnea in Opioid Users

Recruiting in Palo Alto (17 mi)

Overseen by Sanjay R Patel, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Sanjay R Patel

Must be taking: Methadone, Buprenorphine

Disqualifiers: Sleep hypoventilation, Pregnancy, others

Prior Safety Data

Approved in 3 Jurisdictions

Trial Summary

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.

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}

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.

Trial 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 (Diuretic)

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 Canada for the following indications:

Approved in Canada as Diamox for:

• Glaucoma
• Epilepsy
• Edema
• Altitude sickness

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

University of Pittsburgh Pittsburgh, PA

Who Is Running the Clinical Trial?

Sanjay R Patel

Lead Sponsor

Trials

2

Patients Recruited

90+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2658

Patients 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]

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]

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]

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]

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]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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

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]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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

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]

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]

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]

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]

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]