Non-CPAP Therapies for Obstructive Sleep Apnea in Adults

Abstract

Obstructive sleep apnea (OSA) is a widespread sleep disorder characterized by repeated collapse of the upper airway during sleep, resulting in disruption of sleep. This condition is linked to a host of symptoms, including excessive daytime sleepiness, cardiovascular disorders, and a variety of other comorbidities. Continuous positive airway pressure (CPAP) is, by far, the most common treatment for OSA, and has long served as the standard treatment for most patients. However, CPAP therapy has a variety of limitations, including low adherence, and the heterogenous presentation of OSA. Thus, there exists an increasing need for alternative therapies for OSA. Some of these include lifestyle modifications, positional therapy, mandibular advancement devices, upper airway surgery, pharmacological therapies, and hypoglossal nerve stimulation. Because OSA presents heterogeneously, effective treatment for most patients would likely include a combination of these treatments.

Introduction

Obstructive sleep apnea (OSA) is a common disease defined by repeated episodes of partial or complete upper airway collapse during sleep, leading to cyclic intermittent hypoxia, intrathoracic pressure swings, and sleep fragmentation.¹ This can result in excessive daytime sleepiness, increased risk of hypertension, coronary artery disease, metabolic disease, cognitive impairment, reduced quality of life, and increased risk for motor vehicle accidents.² Studies suggest that sleep-disordered breathing can be detected in 9–38% of the general adult population.³ Moreover, as rates of obesity have increased, occurrence of sleep apnea in patients has increased by 14–55% over the last 20 years depending on severity, gender, and age group.⁴ While obesity is the most common risk factor associated with OSA, other common risk factors include family history, male gender, use of alcohol and opiates, and craniofacial abnormalities.

However, recent research has recognized that OSA is a highly heterogenous disorder presenting with a variety of clinical and physiological phenotypes.⁵ Each patient may present with different risk factors, clinical presentation, and potential prognoses. Thus, traditional “one size fits all” continuous positive airway pressure (CPAP) therapy must be reevaluated. While its effectiveness is typically high, low long-term compliance and a lack of patient-specific care ensure its net effects remain insufficient.⁶ This review aims to provide an overview of common alternatives to CPAP therapy that can help physicians best tailor the treatment to their patients’ unique clinical phenotypes (Table 1) These treatments include lifestyle modification, positional therapy, maxillofacial surgery, hypoglossal nerve stimulation, and pharmacological solutions. While personalized treatments for patients will likely involve some combination of these therapies, this review will discuss each of them individually.

Table 1.

Non-CPAP therapies for the treatment of Obstructive Sleep Apnea

	Advantages	Disadvantages
Positional therapy	Affordable for a substantial proportion of patients	Less efficacious versus PAP Potential to cause back discomfort
Mandibular advancement devices	Good acceptance and adherence	Residual apnea-hypopnea events are frequent. Long-term dental alterations
Negative pressure therapies	More effective for mild to moderate OSA	Dental or oral discomfort
Pharmacotherapy	Desire from many patients for a nondevice treatment	Not currently approved
Hypoglossal nerve stimulator	Minimal input required after placement Encouraging results from recent studies	High upfront cost

Lifestyle Modification

Obesity is the most prevalent risk factor for developing OSA and yields the greatest reversal of symptoms if reduced. Fat deposition associated with obesity typically obstructs upper airway anatomy, and other neurological factors like depressed neuromuscular control of the upper airway can also cause OSA.⁷ Numerous epidemiological studies have shown that weight gain is the strongest predictor of OSA as up to 60% of obese patients suffer from the disease.⁸ Moreover, a longitudinal study in the Wisconsin Sleep Cohort indicated that a 10% increase in weight was observed to be associated with a 32% increase in patients’ apnea-hypopnea index (AHI).⁹ Thus, weight loss should be considered as a first-line treatment for overweight and obese patients afflicted with OSA. Weight loss has been shown to decrease the apnea-hypopnea index, improve sleep architecture, and decrease daytime somnolence.¹⁰ Exercise may also reasonably improve OSA even in the absence of significant weight. ¹¹ Although limited data indicates that CPAP therapy may be associated with weight gain, studies suggest that the initial improvement in AHI achieved through weight loss can persist for a number of years in spite of regaining weight.^12,13

Reduction of alcohol consumption and smoking must also be discussed. Cigarette smoking may increase the risk of OSA by altering sleep architecture, upper airway neuromuscular function, arousal mechanisms, and upper airway inflammation.¹⁴ Alcohol not only increases the frequency of apneas and hypopneas during sleep but also prolongs their duration by delaying arousal. Similarly, Yang et al. found a direct correlation between drinking cessation and reduced OSA risk, especially in females.¹⁵

Positional Therapy

Positional OSA (POSA) is defined by as having an AHI at least twice as high in the supine position as other positions. By this definition, nearly half of OSA patients experience some form of POSA.¹⁶ The “tennis ball” technique is a form of positional therapy that involves strapping a bulky item to the back of the patient during sleep. While this treatment has proven to be effective in reducing sleep time in the supine position, long term compliance is extremely low with less than 10% of patients continuing use 30 months after prescription.¹⁷ Similarly, this technique is not recommended for patients who struggle with any shoulder problem or other physical disability that impairs their ability to sleep in the lateral position. Novel positional therapy solutions include devices worn on the neck or chest that can correct the supine sleeping position with a subtle vibration alarm or stimulus to the body.¹⁸ In the first month of treatment, over 75% of patients used these devices for at least four hours a night for at least five days a week. However, long-term compliance of these novel treatments has yet to be studied and other long-term complications are not yet known. Positional therapy is more effective in younger and less obese patients, and not appropriate for all OSA sufferers.¹⁹

Oral Advancement Devices

Oral advancement devices (OADs) aim to reposition craniofacial or oral structures to increase pharyngeal airway space and reduce airway collapse. Some appliances work by suspending the tongue in an anterior position in the mouth. Lazard et al. showed that a tongue-retaining device could reduce mean AHI from 38 to 14.²⁰ The most common and widely researched OADs are mandibular advancement devices (MADs). The aim of MADs is to advance the mandible relative to the maxilla to enlarge and stabilize the upper airway. Moreover, the MAD resists the downward rotation of the mandible and associated mandibular retrusion during sleep, compromising upper airway flow.²¹

While MADs typically yield lesser effects to AHI than CPAP, Sutherland et al. showed that approximately two-thirds of patients experience a greater than 50% reduction in AHI with more than a third achieving complete AHI normalization.²² A custom, tailor-made devices should be preferred over non-custom devices, and patients should check in regularly with their sleep physician and a qualified dentist to ensure continued efficacy. To avoid costs and time constraints, some patients may prefer to use self-molded devices that are submerged in warm water and bitten into by the patient to create a mold of their teeth. While these thermoplastic devices may be readily available at outpatient clinics, they are often less tolerated than customized MADs and yield low tolerance.²³ Thus, custom titratable MADs are typically the most effective form of treatment. These two-piece devices cover the lower and upper teeth, allowing for titration, a gradual modification of the mandible through incremental advancements.²⁴ Due to the progressive nature of this therapy, the protrusion can be tailored to each patient. While AHI reduction associated with MADs is often incomplete, therapy adherence is higher than in CPAP. Patients often find that MADs are more comfortable, quieter, and more mobile than CPAP machines. Although severe OSA is not typically considered a good indicator for MAD treatment, Byun et al. showed a decrease in AHI of 64% after a month of treatment with especially significant results in patients with low BMIs.²⁵ Similarly, an individual patient meta-analysis found that, although titratable MADs were less effective than CPAP at reducing AHI, both devices yielded similar results for major subjective outcomes like daytime sleepiness and quality of life. Polysomnography showed that both treatments improved sleep architecture with increases in both N3 and rapid eye movement (REM) sleep.²⁶ Because MADs can yield similar relief to CPAP on average, studies tend to show that patient preference and adherence are higher in MADs.

There exists little evidence regarding the effects of MADs on cardiovascular and metabolic health. Short-term randomized controlled trials report no effect on rates of hypertension or endothelial functions.²⁷ Long-term interventional randomized trials are necessary to determine the impact of MADs on respiratory events, cardiovascular events, and other forms of mortality. A variety of factors contribute to limiting the application of MADs in clinical practice. For over a third of patients, dental issues like insufficient maximum protrusive distance, a lack of teeth, and temporomandibular joint pain rule out MADs as a potential treatment.²⁸ Even for patients who are viable candidates for titratable MADs, follow-ups are typically required every six months to ensure prevention of dental side effects like tooth movements or bite changes. Similarly, a reduction in efficacy can occur if the mandible is advanced too far forward, shifting the airway from a wide to more narrow lateral diameter. Moreover, the exact clinical characteristics that suggest MADs as an effective therapy have not yet been determined. Currently, some accepted characteristics associated with favorable outcomes for MAD therapy include non-severe OSA, lower BMI, and younger age.²⁹ Thus, there exists a need for studies validating potential clinical indicators for MADs and determining the exact location of airway obstruction during sleep. Vroegop et al. used drug-induced sleep endoscopies (DISE) to find that tongue base collapse is a likely indicator of MAD effectiveness and complete lateral oropharyngeal collapse and complete collapse of the airway at the palatal level do not elicit responses from MADs.^30,31 Moreover, patients with lower airway collapsibility overall tend to respond more strongly to MADs.

Upper Airway Surgery

Upper airway surgery aims to improve anatomy to prevent pharyngeal collapse. The widely used form of upper airway surgery for OSA is uvulopalatopharyngoplasty (UPPP). UPPP reduces pharyngeal collapse and increases the retropalatal lumen volume through removal of the uvula and soft palate. This procedure is often accompanied by a tonsillectomy. A meta-analysis by Stuck et al. showed that UPPP in adult OSA patients yielded a significant decrease in AHI with an average AHI difference of 18.59 following surgery.³² UPPP also yielded a significant decrease in daytime sleepiness based on the Epworth Sleepiness Scale. However, UPPP typically leads to rhinolalia, dysphagia, nasopharyngeal regurgitation, soft palatal edema, velopharyngeal insufficiency, and abnormal scarring with velopharyngeal stenosis. Given the variety of complications associated with UPPP, palatal surgery has been expanded to methods that do not require total ablation. Instead, lateral pharyngoplasty has become an increasingly common treatment for OSA.³³ One such method of palatal surgery is barbed reposition pharyngoplasty (BRP). Vicini et al. showed that BRP presents a safer and potentially more effective form of treating pharyngeal obstruction.³⁴ Pang et al introduced another form of palatal surgery with expansion sphincter pharyngoplasty (ESP).³⁵ Retrospective comparison studies analyzing UPPP, BRP, and ESP have established that BRP and ESP are typically as effective in terms of AHI with fewer postoperative complications than UPPP.³⁶ Radiofrequency thermotherapy (RFTT) can be used in combination with UPPP if a patient has a hypertrophic tongue. A retrospective study done by Plzak et al. showed that RFTT combined with UPPP successfully reduced severe OSA in 51.7% of patients as opposed to a success rate of 41.9% for patients treated with UPPP alone.³⁷ Maxillo-mandibular advancement (MMA) surgery has also been shown to be an effective treatment, with an initial improvement in 80% of patients, and is more successful in patients with lower BMI, younger age and with a higher AHI. ^38,39

Hypoglossal Nerve Stimulation

Hypoglossal nerve stimulation (HNS) is a novel approach to treating upper airway collapse. During sleep, it is common for muscle tone in the upper airway to decrease slightly. However, for individuals afflicted with OSA, this can often lead to narrowing or total collapse of the upper airway. Thus, studies have turned to HNS as a potential method of mitigating this patency. The hypoglossal nerve is comprised of exclusively motor fibers, innervating the genioglossus muscle bilaterally, and the genioglossus is the primary pharyngeal dilator muscle. Electrical stimulation of the hypoglossal nerve thus causes the tongue to protrude and stiffens the anterior pharyngeal wall, significantly increasing the diameter of the upper airway.

The HNS was approved by the FDA based on the findings in the Stimulation Therapy for Apnea Reduction (STAR) trial.⁴⁰ The primary outcome of this prospective trial of 126 patients included AHI and oxygen desaturation index. Secondary outcomes included quality of life measured by Functional Outcomes of Sleep Questionnaire (FOSQ) and Epworth Sleepiness Scale (ESS). Patient demographics included mean age of 54.5 years, 83% male gender, mean BMI 28, and average baseline AHI of 34/hr. These patients had tried conventional OSA therapy including CPAP but could not tolerate it. There was a 68% reduction in the AHI (29 to 9 per hour) and a 70% reduction in the ODI (25.4 to 7.4 per hour). HNS is associated with high adherence and durable benefits up to 5 years, consisting of improvements in the ESS, FOSQ and reduced AHI.⁴¹.⁴² All patients who are being evaluated for HNS are required to have drug-induced sleep endoscopy (DISE) and must show palatal collapse in an antero-posterior pattern. Concentric collapse is considered a contraindication to the HNS procedure.⁴³ The indications and contraindications are also listed in Table 2. Although HNS has been approved for adults age 22 year or older, the 2023 FDA update has included patients ages 18 to 21, and pediatric patients with Down syndrome ages 13 to 18 and an AHI 10 to 50 who are not candidates for adenotonsillectomy, and who have failed positive airway pressure therapy.⁴⁴ The main adverse effects of HNS include incision discomfort, temporary tongue weakness, headaches, risk of infection to the incision site, and discomfort from the electrical stimulation. The ongoing TESLA trial will assess transcutaneous electrical stimulation of the upper airway dilator muscles and will determine whether electrical stimulation can be a treatment modality for a wide range of patients with OSA.⁴⁵

Table 2.

Hypoglossal nerve stimulation indications and contraindications

Indications	Contraindications
Apnea-hypopnea index of 15–100 events per hour	> 25% central or mixed apneic events on sleep study
Body mass index < 40	Concentric collapse on drug-induced sleep endoscopy
Failure of or intolerant to positive pressure therapy	Pre-existing condition that comprises neurological control of the upper airway
Antero-posterior collapse on drug induced sleep endoscopy	Pregnancy or planning to become pregnant
	Require magnetic resonance imaging (in some cases)

Pharmacological Therapy

Anti-depressants like Fluoxetine are potential pharmacological solutions to increasing the patency of upper airway muscles during sleep. Because sleep-dependent serotonin delivery is responsible for stimulating upper airway dilator motor neurons, SSRIs have been studied as a method of treating OSA. Hanzel et al. found that mean AHI decreased from 57 to 34 events per hour in patients treated with Fluoxetine.⁴⁶ Recent studies have aimed to target upper airway dilator motor neurons using nonandrogenic and muscarinic agents in concert. An ongoing trial of Atomoxetine plus Oxybutynin combination has been shown to reduce OSA severity by improving upper airway collapsibility, increasing breathing stability, and augmenting the threshold for arousal in OSA. These effects lead to a reduction in the AHI and an increased genioglossal muscle responsiveness. ⁴⁷ A meta-analysis done by Lee et al. found a significant decrease in AHI of 9.03 events per hour. ⁴⁸ This combination also appeared to improve oxygen saturation and decreased hypoxic burden, likely due to a significant reduction in tongue collapsibility. However, Lee et al. also reported several side effects associated with this combination of agents, including fatigue, dryness of mouth, erectile dysfunction, and urinary hesitation. The combination therapy seems promising but is not currently available.

Negative Pressure Therapy

The iNAP device applies negative pressure through an intraoral interface held in place with a flange that fits between the teeth and the lips. It improves the retropalatal airway size by displacing the anterior-superior segment of the tongue forward and the soft palate anteriorly and superiorly.⁴⁹ In a systematic review, only 25% to 37% of patients had at least a 50% reduction in the AHI and a residual AHI of 10 or less. ⁵⁰ The baseline severity of OSA did not correlate with success. The Winx device consists of a mouthpiece that works by establishing a vacuum in the oral cavity which pulls the uvula and soft palate forward thereby increasing the pharyngeal airway lumen. Based on the limited data obtained from a cohort of 63 patients who tried the Winx device, 20 showed a clinically important response, dropping the mean AHI index by greater than 50%, and lowering Epworth Sleepiness Scores from 12.1 to 8.6.⁵¹ The long-term acceptance and adherence to the negative pressure therapy devices remains to be established.

Conclusion

Personalized medicine has become increasingly prevalent in sleep medicine, and this trend is reflected in potential treatments of OSA. The “one-size-fits-all” approach of CPAP therapy is no longer the most effective treatment plan for most patients. While CPAP is undoubtedly effective for a significant number of those afflicted with OSA, clinicians may not relieve their patients of all obstructive events during sleep with CPAP alone. Therapies like lifestyle modification, positional therapies, oral advancement devices, upper airway surgeries, hypoglossal nerve stimulation, and pharmacological therapies each provide unique advantages that, in tandem, may be more effective at treating OSA than CPAP therapy alone. However, because these therapies each provide unique advantages, further challenges for clinicians include finding the most effective combination of therapies for each unique presentation of OSA.