Clinical trial NCT02714400: The Impact of Venlafaxine on Apnea Hypopnea Index in Obstructive Sleep Apnea
Official title: The Impact of Venlafaxine on Apnea Hypopnea Index in Patients With Obstructive Sleep Apnea
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Obstructive Sleep Apnea
Keywords: Obstructive Sleep Apnea
Arousal threshold
Venlafaxine
Lead sponsor: University of California, San Diego
Sponsor class: OTHER
First posted: 2016-03-21
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The investigators hypothesis is that obstructive sleep apnea (OSA) patients with a low arousal threshold may wake up too early during a respiratory event, before upper airway muscles can be activated to achieve stable ventilation. Thus, strategies to manipulate the respiratory arousal threshold could potentially improve the quality of sleep and sleep disordered breathing. Agents that raise arousal threshold are therefore likely to benefit some patients with OSA. The overall goal of this project is to determine the importance of the arousal threshold in OSA, determine which patients might benefit from a raised arousal threshold, and test this hypothesis by using pharmacological manipulation of the arousal threshold to achieve this goal.

Detailed description: This study is a randomized double-blinded crossover pilot study. The investigators will test whether Venlafaxine has important effects on the apnea hypopnea index. Venlafaxine is a serotonin-norepinephrine reuptake inhibitor (SNRI) for the treatment of depression and anxiety. Venlafaxine increases serum serotonin level, which may affect arousal threshold. Furthermore, higher serotonin level theoretically may improve muscle tone, including upper airway muscle. Therefore, the investigators hypothesize that venlafaxine may decrease arousal threshold and improve muscle tone, leading to improvement of OSA.

Eligible participants will undergo overnight polysomonography as described below and will receive either Venlafaxine(50 mg 2 hour prior to sleep) or placebo (in random order) followed roughly 7 days later with placebo or donepezil. This aim will allow us to test the impact of Venlafaxine on the apnea hypopnea index.

The change in apnea hypopnea index will be compared in the Venlafaxine groups with the placebo group.

Eligibility criteria: Inclusion Criteria:

* Ages 18-70 years
* sleep study (with apnea hypopnea index\>5)
* Diagnosis of obstructive sleep apnea

Exclusion Criteria:

* Any known cardiac (apart from treated hypertension), pulmonary (including uncontrolled asthma), renal, neurologic (including epilepsy), neuromuscular, or hepatic disease.
* Susceptible to stomach ulcers.
* co-administration of MAO inhibitors intended to treat psychiatric disorders (concurrently or within 14 days of discontinuing the MAO inhibitor); initiation of MAO inhibitor intended to treat psychiatric disorders within 7 days of discontinuing venlafaxine; initiation in patients receiving linezolid or intravenous methylene blue
* Pregnant women.
* History of hypersensitivity to Afrin, Lidocaine (all Aims) or venlafaxine
* History of bleeding diathesis and/or gastrointestinal bleeding.
* Glaucoma and Urinary Retention
* Use of any medications that may affect sleep or breathing.
* Use of any medications that have known interaction with venlafaxine and the interaction may significantly increase the risk of the subject or decrease the therapeutic effect of the medication.
* A psychiatric disorder, other than mild depression; e.g. schizophrenia, bipolar disorder, major depression, panic or anxiety disorders.
* Substantial cigarette (\>5/day), alcohol (\>3oz/day) or use of illicit drugs.
* More than 10 cups of beverages with caffeine (coffee, tea, soda/pop) per day.
* Desaturations to below 70% lasting greater than 10 seconds in duration per event

Primary outcomes:
measure: The Apnea Hypopnea Index
timeFrame: Baseline and 7-day follow up
measure: Nadir Oxygen Level During Sleep
timeFrame: Baseline and 7-day follow up
Secondary outcomes:
measure: Loop Gain
timeFrame: Baseline and 7-day follow up
measure: Arousal Threshold
timeFrame: Baseline and 7-day follow up
measure: Sleep Efficiency
timeFrame: Baseline and 7-day follow up
Other outcomes:
Locations:
city: San Diego
country: United States
facility: University of California, San Diego
state: California
Study officials:
References:
citation: Eckert DJ, White DP, Jordan AS, Malhotra A, Wellman A. Defining phenotypic causes of obstructive sleep apnea. Identification of novel therapeutic targets. Am J Respir Crit Care Med. 2013 Oct 15;188(8):996-1004. doi: 10.1164/rccm.201303-0448OC.
citation: Carter SG, Berger MS, Carberry JC, Bilston LE, Butler JE, Tong BK, Martins RT, Fisher LP, McKenzie DK, Grunstein RR, Eckert DJ. Zopiclone Increases the Arousal Threshold without Impairing Genioglossus Activity in Obstructive Sleep Apnea. Sleep. 2016 Apr 1;39(4):757-66. doi: 10.5665/sleep.5622.
citation: Deacon NL, Jen R, Li Y, Malhotra A. Treatment of Obstructive Sleep Apnea. Prospects for Personalized Combined Modality Therapy. Ann Am Thorac Soc. 2016 Jan;13(1):101-8. doi: 10.1513/AnnalsATS.201508-537FR.
citation: Edwards BA, Eckert DJ, McSharry DG, Sands SA, Desai A, Kehlmann G, Bakker JP, Genta PR, Owens RL, White DP, Wellman A, Malhotra A. Clinical predictors of the respiratory arousal threshold in patients with obstructive sleep apnea. Am J Respir Crit Care Med. 2014 Dec 1;190(11):1293-300. doi: 10.1164/rccm.201404-0718OC.
citation: Eckert DJ, Younes MK. Arousal from sleep: implications for obstructive sleep apnea pathogenesis and treatment. J Appl Physiol (1985). 2014 Feb 1;116(3):302-13. doi: 10.1152/japplphysiol.00649.2013. Epub 2013 Aug 29.
citation: Schmickl CN, Li Y, Orr JE, Jen R, Sands SA, Edwards BA, DeYoung P, Owens RL, Malhotra A. Effect of Venlafaxine on Apnea-Hypopnea Index in Patients With Sleep Apnea: A Randomized, Double-Blind Crossover Study. Chest. 2020 Aug;158(2):765-775. doi: 10.1016/j.chest.2020.02.074. Epub 2020 Apr 9.