Acetazolamide for Opioid-Related Sleep Apnea
(MORPHO Trial)
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
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
Prior Safety Data
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.12345
Is acetazolamide safe for human use?
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.1231112
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.
See 1 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.
See 18 more
Trial 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 (Other)
- Placebo (Other)
Trial OverviewThe 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
2Treatment groups
Experimental Treatment
Group I: Placebo followed by acetazolamideExperimental Treatment2 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 placeboExperimental Treatment2 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of California San DiegoSan Diego, CA
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Who Is Running the Clinical Trial?
University of California, San DiegoLead Sponsor
National Heart, Lung, and Blood Institute (NHLBI)Collaborator
References
Acute and long-term effects of acetazolamide in presumed high loop gain sleep apnea. [2023]The acute effect during positive pressure titration and long term efficacy of acetazolamide (AZT) in high loop gain sleep apnea (HLGSA) is inadequately assessed. We predicted that AZT may improve HLGSA in both conditions.
Acetazolamide as an adjunct to CPAP treatment: a case of complex sleep apnea in a patient on long-acting opioid therapy. [2021]A 41-year-old white woman on long-acting opioid therapy was diagnosed with moderate obstructive sleep apnea. On initiation of continuous positive airway pressure (CPAP), she manifested severe central apnea that was unresponsive to supplemental oxygen and interfered with CPAP titration. Acetazolamide, 250 mg, nightly at bedtime was initiated, and CPAP titration was repeated. On acetazolamide, optimal CPAP pressure was obtained with no manifestation of clinically significant central respiratory disturbance. This case suggests that acetazolamide may be an effective adjunct to positive airway pressure therapy in patients on long-acting opioids. A need exists for examination of acetazolamide in this capacity.
Effects of acetazolamide on the sleep apnea syndrome and its therapeutic mechanism. [2019]Twenty male patients with sleep apnea syndrome were treated with acetazolamide (AZM), a carbonic anhydrase inhibitor. In 14 of the patient a significant decrease was found in the number of apnea, apnea index and % apnea time (percentage of time spent with apnea to the total sleep time) with improvement in sleep structure, clinical symptoms, such as insomnia, daytime excessive sleepiness and snoring. A significant decrease was also observed in arterial blood pH and HCO-3 in the 14 improved patients. On the other hand, no improvement occurred in the parameters of sleep apnea and sleep with AZM in the remaining six patients. Moreover, metabolic acidosis and an improvement in arterial blood gases did not occur with AZM in the six patients.
The effect of acetazolamide on sleep apnea at high altitude: a systematic review and meta-analysis. [2018]Acetazolamide has been investigated for treating sleep apnea in newcomers ascending to high altitude. This study aimed to assess the effect of acetazolamide on sleep apnea at high altitude, determine the optimal therapeutic dose, and compare its effectiveness in healthy trekkers and obstructive sleep apnea (OSA) patients.
Central sleep apnea. Improvement with acetazolamide therapy. [2013]Respiratory rhythm during sleep may be dependent on blood pH with apneas being associated with alkalosis. Acidification may therefore have therapeutic value in some forms of sleep apnea. We administered acetazolamide to six patients with symptomatic central sleep apnea, a disorder of respiratory rhythm with little or no upper airway obstruction. Sleep studies were carried out before and after one week of drug therapy, during which time the mean arterial pH decreased from 7.42 to 7.34. All six patients had significant improvement, demonstrating a 69% reduction in total apneas. Five of the six patients reported better-quality sleep and decreased daytime hypersomnolence. Subsequent studies in normal subjects showed that acetazolamide, like other agents known to produce a metabolic acidosis, shifted the hypercapnic ventilatory response to the left 5 +/- 0.54 mm Hg. This may be important in mediating the observed decrease in apneas.
In vivo pharmacokinetics of selective mu-opioid peptide agonists. [2007]Recent evidence suggests that highly selective mu-opioid agonists may provide good analgesia with less development of tolerance and dependence. H-Tyr-D-Arg-Phe-Lys-NH2 (DALDA) and H-Dmt-D-Arg-Phe-Lys-NH2 ([Dmt1]DALDA) were found to display high binding affinity and much greater selectivity for the mu-opioid receptor (K(i)delta/K(i)mu) > 10,000) compared with H-Tyr-D-Ala-Gly-MePhe-Gly-ol (DAMGO). In addition, [Dmt1]DALDA was 3000-fold more potent than morphine when administered intrathecally. A potential problem with peptide analogs as therapeutic agents is their susceptibility to enzymatic degradation in vivo and short elimination half-lives. In this study, we compared the stability of DAMGO, DALDA, and [Dmt1]DALDA after systemic administration in sheep. Peptide concentrations were measured using high performance liquid chromatography-mass spectrometry. When incubated in sheep blood at 37 degrees C, DAMGO, DALDA, and [Dmt1]DALDA were stable over 2 h. When given intravenously to sheep, the apparent volume of distribution was 50 to 80 ml/kg for all three peptides, suggesting that distribution was limited to blood volume. Plasma clearance of DAMGO (223 ml/kg/h) was 10-fold faster than DALDA and [Dmt1]DALDA (24 ml/kg/h), and their elimination half-lives were 0.24, 1.5, and 1.8 h, respectively. The half-lives of DALDA and [Dmt1]DALDA are even longer than morphine or meperidine in sheep. These favorable pharmacokinetic properties of DALDA and [Dmt1]DALDA, together with their mu-selectivity, potency, and long duration of action, make them ideal candidates as opioid analgesics.
Effects of oral casokefamide on plasma levels, tolerance, and intestinal transit in man. [2019]Food-derived opioid peptides such as beta-casomorphins are of interest for treatment of chronic diarrhea. The beta-casomorphin analog casokefamide was administered orally at doses of 5.5, 8.0, and 16.0 mg to 10 healthy male volunteers, respectively. Dose-dependent increases of plasma levels with a maximum of 350 fmol/l were determined. No side-effects due to casokefamide has been observed. In comparison to placebo, casokefamide showed a trend toward prolongation of oro-caecal transit time. Orally applied casokefamide is well tolerated and may represent a useful tool for treatment of diarrhea in the future.
Characterization of the antinociceptive effects of intrathecal DALDA peptides following bolus intrathecal delivery. [2019]Background and aims We systematically characterized the potency and side effect profile of a series of small opioid peptides with high affinity for the mu opioid receptor. Methods Male Sprague Dawley rats were prepared with intrathecal (IT) catheters, assessed with hind paw thermal escape and evaluated for side effects including Straub tail, truncal rigidity, and pinnae and corneal reflexes. In these studies, DMT-DALDA (dDAL) (H-Dmt-D-Arg-Phe-Lys-NH2 MW=981), dDALc (H-Dmt-Cit-Phe-Lys-NH2 MW=868), dDALcn (H-Dmt-D-Cit-Phe-Nle-NH2 MW=739), TAPP (H-Tyr-D-Ala-Phe-Phe-NH2 MW=659), dDAL-TICP ([Dmt1]DALDA-(CH2)2-NH-TICP[psi]; MW=1519), and dDAL-TIPP (H-Dmt-D-Arg-Phe-Lys(Nε-TIPP)-NH2 were examined. In separate studies, the effects of approximately equiactive doses of IT DMT DALDA (10 pmol), morphine (30 nmol) and fentanyl (1 nmol) were examined on formalin-induced flinching at different pretreatment intervals (15 min - 24 h). Results (1) All agents resulted in a dose-dependent reversible effect upon motor function (Straub Tail>Truncal rigidity). (2) The ordering of analgesic activity (%MPE) at the highest dose lacking reliable motor signs after bolus delivery was: DMT-DALDA (80%±6/3 pmol); dDALc (75%±8/1 pmol); dDALcn (84%±10/300 pmol); TAPP (56%±12/10 nmol); dDAL-TICP (52%±27/300 pmol). (3) All analgesic effects were reversed by systemic (IP) naloxone (1 mg/kg). Naltrindole (3 mg/kg, IP) had no significant effect upon the maximum usable peptide dose. (4) Tolerance and cross-tolerance development after 5 daily boluses of DMT-DALDA (3 pmol) and morphine (30 nmol) revealed that both agents displayed a progressive decline over 5 days. (5) Cross-tolerance assessed at day 5 revealed a reduction in response to morphine in DMT-DALDA treated animal but not DMT-DALDA in the morphine treated animal, indicating an asymmetric cross-tolerance. (6) IT DMT-DALDA, morphine and fentanyl resulted in significant reductions in phase 1 and phase 2 flinching. With a 15 min pretreatment all drugs resulted in comparable reductions in flinching. However, at 6 h, the reduction in flinching after DMT-DALDA and morphine were comparably reduced while fentanyl was not different from vehicle. All effects on flinching were lost by 24 h. Conclusions These results emphasize the potent mu agonist properties of the DALDA peptidic structure series, their persistence similar to morphine and their propensity to produce tolerance. The asymmetric cross-tolerance between equiactive doses may reflect the relative intrinsic activity of morphine and DMT-DALDA. Implications These results suggest that the DALDA peptides with their potency and duration of action after intrathecal delivery suggest their potential utility for their further development as a spinal therapeutic to manage pain.
Antinociceptive and respiratory effects of intrathecal H-Tyr-D-Arg-Phe-Lys-NH2 (DALDA) and [Dmt1] DALDA. [2013]DALDA (H-Tyr-D-Arg-Phe-Lys-NH(2)) and [Dmt(1)]DALDA (H-Dmt-D-Arg-Phe-Lys-NH(2)) (Dmt = 2',6'-dimethyltyrosine) are potent and highly selective mu-opioid agonists (K(i)(delta)/K(i)(mu) > 10,000 and K(i)(kappa)/K(i)(mu) > 100). Both peptides carry a 3+ charge at physiological pH. Their antinociceptive and respiratory effects were compared with morphine (MOR) after intrathecal administration in rats. Both DALDA and [Dmt1]DALDA produced dose-dependent and naloxone-reversible antinociceptive effects with relative potencies of 14 and 3000x that of MOR. The antinociceptive potency of [Dmt1]DALDA far exceeded its affinity and potency at the mu-opioid receptor and may be explained by its ability to inhibit norepinephrine (NE) uptake in spinal cord synaptosomes. The antinociceptive response to [Dmt1]DALDA was significantly attenuated by the alpha(2)-adrenergic antagonist yohimbine. Thus, [Dmt1]DALDA may be regarded as a drug with dual actions, and its antinociceptive potency is better described by both its affinity and potency at mu-opioid receptors, and its potency at inhibiting NE uptake. The analgesic duration of an equipotent dose of MOR, DALDA, and [Dmt1]DALDA was 3, 7, and 13 h, respectively, and the long duration may be due to the hydrophilic nature of these peptide analogs. Respiratory effects were determined using whole body plethysmography at 3 and 30x the antinociceptive ED(50). A significant depression in minute ventilation was observed with the higher dose of morphine and both doses of DALDA, but not with either dose of [Dmt1]DALDA. Because of its high antinociceptive potency, long duration of action, and low propensity to induce respiratory depression, [Dmt1]DALDA is of interest as a drug candidate for intrathecal analgesia.
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]Synthesis of N,N-dialkyl(dialkenyl)amides of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acid (5-9) and their 1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)propyl] derivatives (10-14) is described. Compounds 10-14 were tested for analgesic and sedative activities as well as for mu-opioid receptors binding affinities. All the amides, being the object of investigation, displayed an interesting analgesic action, which in case of the compounds 10-12 and 14 was superior to that of acetylsalicylic acid in two different tests. Furthermore all the amides (10-14) significantly suppressed the spontaneous locomotor activity, prolonged barbiturate sleep in mice and showed a weak affinity to mu-opioid receptors.
Effects of acetazolamide in patients with the sleep apnoea syndrome. [2019]There is as yet no convincing evidence that acetazolamide, a carbonic anhydrase inhibitor, is effective in obstructive sleep apnoea. A study was therefore designed to examine the effect of acetazolamide (250 mg/day) on sleep events and ventilatory control during wakefulness in nine patients with the sleep apnoea syndrome. In eight of the nine patients the apnoea index and the total duration of apnoea were reduced by acetazolamide, and the mean (SEM) apnoea index of all patients changed from 25.0 (6.7) to 18.1 (5.8) episodes an hour. Furthermore, the total time of arterial oxygen desaturation (SaO2)--more than 4% depression in SaO2 from the baseline sleeping level--divided by total sleep time was also significantly decreased and its mean (SEM) value improved from 24.1 (7.9) to 13.6 (4.8)% of total sleep time. Five of the seven patients with varying degrees of daytime hypersomnolence had their symptoms obviously improved. There was no patient whose predominant type of apnoea was converted from the obstructive to the central type, or vice versa. In the studies of wakefulness, metabolic acidosis, an increase of arterial oxygen tension (PaO2) and a decrease of arterial carbon dioxide tension (PaCO2) were observed. The slopes of the occlusion pressure response and the ventilatory response to carbon dioxide increased, and the carbon dioxide ventilatory response line shifted to the left. It is suggested that acetazolamide cannot remove apnoea completely but has a beneficial effect in mild cases of obstructive sleep apnoea through an augmentation of central (CO2, H+) drive and a stabilising effect on ventilatory control.
Patients with obstructive sleep apnea syndrome benefit from acetazolamide during an altitude sojourn: a randomized, placebo-controlled, double-blind trial. [2017]Many patients with obstructive sleep apnea syndrome (OSA) are unable or unwilling to use continuous positive airway pressure (CPAP) therapy when traveling to the mountains for work or recreation even though they risk pronounced hypoxemia and exacerbation of sleep apnea. Because the treatment of OSA at altitude has not been established, we tested the hypothesis that acetazolamide improves hypoxemia, sleep, and breathing disturbances in otherwise untreated patients with OSA at altitude.