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A critical review of the treatment options available for obstructive sleep apnoea: an overview of the current literature available on treatment methods for obstructive sleep apnoea and future research directions

A critical review of the treatment options available for obstructive sleep apnoea: an overview of... BioscienceHorizons Volume 7 2014 10.1093/biohorizons/hzu011 Clinical review A critical review of the treatment options available for obstructive sleep apnoea: an overview of the current literature available on treatment methods for obstructive sleep apnoea and future research directions 1,2 1 1,3 Alessandra J. Booth *, Yasmina Djavadkhani and Nathaniel S. Marshall NHMRC Centre for Research Excellence NeuroSleep, the Centre for Translational Sleep and Circadian Neurobiology, the Woolcock Institute for Medical Research, University of Sydney, 431 Glebe Point Rd, Glebe, Sydney NSW 2037, Australia Clinical Sciences Programme, University of Exeter, Heavitree Rd, Exeter, Devon EX1 2LU, England Sydney Nursing School, University of Sydney, 88 Mallett St, Camperdown, Sydney NSW 2050, Australia *Corresponding author: Email: ajb263@icloud.com Obstructive sleep apnoea (OSA) is a leading yet often undiagnosed cause of daytime sleepiness. It affects between 3 and 7% of the adult population, and the prevalence is expected to increase due to the obesity epidemic and ageing population. OSA is a sleep-related breathing disorder in which the airway completely (apnoea) or partly closes (hypopnea) during sleep at the end of expiration. This can lead to decreases in blood oxygen saturation and sleep fragmentation. Those who suffer with OSA are often unaware of their symptoms. Severe, untreated OSA can have serious implications such as an increased risk of cardio- vascular disease, motor vehicle accidents, poor neurocognitive performance and increased mortality. Many patients are pre- scribed continuous positive airway pressure (CPAP) as a treatment, but compliance with CPAP is often low. We briefly review the diagnosis and prognosis for obstructive sleep apnoea. But the main focus of our review is the critical evaluation of the numerous treatment strategies available for sleep apnoea as a multi-comorbid and multi-factorial condition. We also high- light areas that need further research. Key words: pharmacotherapy, sleep-disordered breathing, cardiovascular diseases, critical, surgery, mandibular advancement splints Submitted on 11 May 2014; accepted on 6 November 2014 Introduction Clinically, patients often present with snoring and daytime sleepiness. The gold standard diagnostic method for OSA is Obstructive sleep apnoea (OSA) is a condition of periodic full overnight polysomnography (PSG) carried out in a sleep and recurrent closure of the upper airway at the end of exha- laboratory. PSG combines a range of measurements such as lation during sleep (Guilleminault, Tilkian and Dement, heart rate, blood oxygen saturation and EEG-based sleep 1976). This airway closure can lead to a drop in oxygen satu- staging. Other simplified diagnostic techniques using fewer ration levels and fluctuations in blood pressure and heart overnight channels do exist, but they often provide less infor- rate. Patients can experience daytime sleepiness due to frag- mation for differential diagnoses such as REM Behaviour mented sleep and disturbances in normal sleep architecture. Disorder, Periodic Limb Movement Disorder or Central Sleep © The Author 2014. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Clinical review Bioscience Horizons • Volume 7 2014 Table 1. How the clinical severity of sleep apnoea is determined from Apnoea which may require a full PSG (Schlosshan and Elliott, the apnoea–hypopnoea index 2004). A diagnosis of obstructive sleep apnoea syndrome (OSAS) requires significant daytime sleepiness along with an Clinical severity of OSA Apnoea–Hypopnoea index abnormal apnoea–hypopnoea index (AHI > 5 events per hour of sleep), whereas a diagnosis of OSA only requires an Mild 5–15/h AHI > 5 (AASM, 2001). There may also be a contribution from the potential sleepiness inducing effects of hypoxia and Moderate 15–30/h particularly hypercapnia (Zhang et al., 2013; Wang et al., Severe >30/h 2014a; Wang, Yee and Rowsell, 2014b). Daytime sleepiness is often clinically measured using the Epworth Sleepiness Scale (ESS), a numerical questionnaire that Treatment strategies available for asks patients to choose how likely they are to doze while per- OSA forming different activities. An ESS score of 10 or more (on a scale of 0–24) is suggestive of pathologic somnolence (Johns, Non-implantable medical devices 1991). Although intuitive, very severe OSA is not always Continuous positive airway pressure accompanied by severe daytime sleepiness. Some patients seem quite resistant to the daytime effects of poor sleep and may be Continuous positive airway pressure (CPAP) (Sullivan et al., very high-functioning individuals despite severe OSA. In addi- 1981) is the gold standard treatment for OSA. CPAP masks tion, daytime sleepiness may have many different causes. This are worn throughout the night and provide a constant pres- makes daytime sleepiness, as a symptom, neither sensitive nor sure to pneumatically splint open the collapsing upper airway specific to sleep apnoea ( Gottlieb et al., 1999). open during periods of muscle relaxation (Giles et al., 2006). The pressure required to prevent apnoea varies between indi- The severity of OSA is determined by the numbers of 10 viduals and is determined by a personalized overnight titra- second or greater cessations of breathing per hour (apnoeas) tion procedure. This involves increasing CPAP pressure until and reductions in airflow per hour (hypopnoeas). An apnoea breathing is normalized in all stages of sleep. Patients with is a complete closure of the upper airway which can vary OSA who comply with CPAP treatment have reduced blood from seconds to minutes. A hypopnoea is currently defined as pressure (Martinez-Garcia et al., 2013), arterial stiffness being at least a 30% reduction in airflow combined with a (Kartali et al., 2014) and have a lower risk of having a car- 3% arterial oxygen desaturation levels, or an arousal from diovascular event compared with those with untreated mod- sleep (Berry et al., 2012). These combined to form the erate–severe OSA (Marin et al., 2005). While CPAP is a apnoea–hypopnoea index of a patient. AHI is calculated by highly efficacious treatment when used correctly, many dividing the total number of events by the hours of sleep patients struggle to adapt to it and non-adherence rates are (AASM, 1999; Table 1). probably at least 50% (Weaver and Grunstein, 2008). Some patients report finding the mask uncomfortable, too invasive Prognosis or experience claustrophobia (Chasens et al., 2005). Newer CPAP machines that vary the pressure overnight in an effort Patients with untreated OSA have 2.5 times the risk of having to increase patient comfort do not increase compliance (Ayas an accident while driving (Tregear et al., 2009). The daytime et al., 2004; Bakker and Marshall, 2011). In addition, even in sleepiness can cause them to have an increased reaction time quite sleepy patients with mild OSA, CPAP is not very effec- and fall asleep at the wheel, injuring both themselves and oth- tive in treating daytime sleepiness (Marshall et al., 2006) and ers. The poor quality of sleep associated with sleep apnoea does not improve neurocognitive outcomes in a large propor- might also be the cause of the high rates of depression (Mccall, tion of patients, even those with moderate–severe OSA and Harding and O’Donovan, 2006), impaired quality of life, high compliance (Antic et al., 2011). Despite this, it remains anxiety and poor performance at work seen in patients with the gold standard treatment for sleepy patients with moder- OSA. Untreated OSA is also linked to an increase in cardio- ate–severe OSA (Giles et al., 2006). vascular disease risk (Marin et al., 2005; Chami et al., 2011) and with hypertension (Peppard et al., 2000b), insulin resis- Mandibular advancement splints tance (Aurora and Punjabi, 2013), hyperlipidaemia (Phillips et al., 2011) and metabolic syndrome (Bonsignore et al., The mandibular advancement splint (MAS) is another treat- 2012). Those with OSA often have co-morbid cardiovascular ment modality for OSA. It is similar to a mouthguard that diseases and are at a six-fold higher risk of having a stroke when fitted to the teeth pulls the lower jaw forward. This (Redline et al., 2010) as well as a three- to four-fold higher increases the area and support in the upper airway (Lim et al., mortality risk (Young et al., 2008; Punjabi et al., 2009). The 2006). MAS is currently regarded as a second-line therapy for most recent longitudinal studies have indicated that some of OSA, because it only completely alleviates OSA in 40% of the excess mortality may come from cancer-related deaths patients (Sutherland and Cistulli, 2011). Current guidelines (Nieto et al., 2012; Campos-Rodriguez et al., 2013; Marshall suggest a repeat sleep study with MAS in situ to determine its et al., 2014). effectiveness. However, MAS is often recommended to patients 2 Bioscience Horizons • Volume 7 2014 Clinical review with mild-to-moderate OSA or for patients with severe OSA Weight loss who cannot tolerate CPAP (Kushida et al., 2006). MAS has Weight loss is an effective treatment for overweight and obese been shown to be effective in reducing AHI by 14 and ESS by patients with OSA. This is both because of a reduction in the just <2 points in a randomized controlled trial (RCT) lasting 4 apnoea–hypnoea index and also because of beneficial effects on weeks (Petri et al., 2008). Short-term, RCTs have shown that other associated cardiometabolic risk factors. In the commu- patients comply with MAS therapy better than CPAP and that nity-based Wisconsin Sleep Cohort, a 10% decrease in weight patients generally report preferring MAS (Gagnadoux et al., has been shown to be associated with a 26% reduction in AHI 2009; Phillips et al., 2013). Observational long-term compli- (Peppard et al., 2000a). Although weight loss reduces OSA ance focused studies have suggested that ~64% of patients con- severity, it may take a relatively long time to achieve and may tinue to use MAS regularly (Almeida et al., 2005). Unfortunately, not cure OSA. Therefore, weight loss is considered an adjunc- some patients experience MAS-associated side effects such tive therapy. Weight loss therapy via diet, pharmacotherapy as migration of the lower dentition (Marklund et al., 2001; and surgery is increasingly being researched for OSA and may Hammond et al., 2007) and dry mouth (Fritsch et al., 2001). eventually come to replace or join CPAP as the first-line therapy Patients who comply with MAS have experienced improve- in overweight–obese patients. Indeed in a recent RCT, weight ments in vascular function (Itzhaki et al., 2007; Trzepizur et al., loss alone caused greater improvements in cardiometabolic risk 2009), blood pressure (Gotsopoulos et al., 2004; Phillips et al., factors than CPAP did (Chirinos et al., 2014). 2013), daytime sleepiness (Gindre et al., 2008) and an increased quality of life (Phillips et al., 2013). Clinical prediction of which Weight loss in OSA patients has also been rigorously tested patients will benefit from MAS is currently an open line of via dietary interventions (Foster et al., 2009; Tuomilehto research (Sutherland et al., 2014), but it is currently used for et al., 2009). It is recommended that patients with OSA who patients with mild-to-moderate OSA and those who cannot tol- are overweight begin a weight reduction program. Weight erate CPAP (Marklund, Verbraecken and Randerath, 2012). gain around the neck is thought to narrow the upper airways due to a build-up of fat around the upper airways. But weight Surgery gain inside the abdomen may also play an important physical and indirect cause of OSA. Weight loss may help to reduce a There are a large and increasing number of surgical proce- patient’s AHI (Johansson et al., 2009) and also reduce the dures aimed at directly reducing sleep apnoea severity. significant cardiovascular risk that accompanies sleep apnoea. Maxillomandibular Advancement (MMA) is probably the However, as with weight loss programs in all people who are most efficacious but least suitable for general use, and uvulo - overweight, weight loss in patients with sleep apnoea is not palatopharyngoplasty (UPPP) is one of the oldest, most always successful or sustainable. In addition, some patients widely studied and used procedures. may lose weight but not experience any improvements in Maxillomandibular advancement their sleep apnoea. MMA involves surgically repositioning both the upper and Bariatric surgery lower jaws forward to correct an abnormally small upper air- There are numerous bariatric surgery approaches that can way space caused by a small bony enclosure. By bringing be used to help reduce a patient’s AHI through weight loss. both the upper and lower jaws forward the upper airways are Laparoscopic adjustable gastric band (LAGB) surgery involves enlarged, thus reducing the likelihood of upper airway col- placing a device around the stomach that constricts the size of lapse (Varghese et al., 2012). MMA is thought to be the most the stomach pouch, therefore reducing the amount of food effective surgical treatment for OSA but is often used after consumed in one sitting. In a recent trial, OSA patients lost other options have been exhausted due to the long recovery on average 27.8 kg at 2 years with a concomitant reduction time and potential risks of the surgery. MMA is only effective in OSA severity after LAGB surgery (Dixon et al., 2012). in carefully selected patients with a particular facial pheno- Compared with conventional weight loss patients (who lost type (Aurora et al., 2010) and those without significant co- 5.1 kg), LAGB patients lost more weight but their sleep morbidities that may impact surgical risk. apnoea was not reduced by a greater amount than diet alone Uvulopalatopharyngoplasty (25.5 events and hour vs. 14.0 events, p = 0.18). This was caused by an under-powering of the trial caused by an unex- This procedure is the most common surgery aimed at alleviat- pected decline in the effectiveness of weight loss for OSA after ing OSA and involves removing excess tissue at the back of the patients lost over 10–15 kg. Once patients lost around this throat such as the uvula to create a wider airway (Sundaram, amount of weight, their sleep apnoea stopped improving. Lim and Lasserson Toby, 2005). This approach has been heav- ily criticized in recent years as it has marginal efficacy in many Pharmacotherapy for weight loss targeted at sleep apnoea cases (Elshaug et al., 2008). The procedure may suffer from Sibutramine/Meridia large variations both in the hands of different surgeons but also in its efficacy in different patients. For this reason, much Sibutramine (marketed in UK as Meridia) has been shown to like MMA, it should be used sparingly in carefully selected lower a patient’s respiratory disturbance index during the patients (Mackay, Jefferson and Marshall, 2013). night as well as ESS score via its weight loss effects (Yee et al., 3 Clinical review Bioscience Horizons • Volume 7 2014 2007). However, weight loss was only modest and in 2010 the they are a group of drugs that stimulant the central nervous FDA removed Sibutramine from the market as a high number system to promote wakefulness. of cardiovascular events were observed in patients taking the Some patients who adhere to CPAP can still experience drug (Curfman, Morrissey and Drazen, 2010; FDA, 2010). daytime sleepiness, and the FDA lists an on-label indication for modafinil for this purpose ( FDA, 2007). Modafinil, Orlistat/Xenical marketed as Provigil (UK/USA), has been shown to increase Orlistat (marketed in UK as Xenical in the higher dose pre- patient’s daily functioning as assessed by improvements in scriptive form and as Alli in the over-the-counter lower dose the Functional Outcomes of Sleep Questionnaire (FOSQ) form) works by inhibiting gastric and pancreatic lipases and (Weaver, Chasens and Arora, 2009), it has also been shown thus reducing dietary fat absorption. It blocks around 30% to improve a patient’s ability to engage in everyday activi- of fat from being absorbed and should be taken within an ties. However, as wake-promoting drugs do not prevent hour of eating (Boulghassoul-Pietrzykowska, Franceschelli apnoeas, patients who use solely wake promoters to man- and Still, 2013). Patients who had Orlistat in randomized age their OSA will probably still experience the long-term clinical trials lost 2.7 kg more than those on the placebo med- complications associated with the disease (although this has ication (Rucker et al., 2007). The only study we found that not been studied yet). Modafinil may also be of effective looked specifically at the use of Orlistat in patients with OSA symptomatic benefit in patients with mild-to-moderate was a prospective case series. The use of Orlistat was found sleep apnoea who do not use mechanical treatment, but this to benefit weight loss; however, AHI was not measured before is an off-label indication and has not been tested for a and after the Orlistat trial so it is uncertain whether the period of longer than 2 weeks (Chapman et al., 2013). The weight loss was accompanied by a reduction in AHI or what European Medicines Agency recently revoked the OSA the true placebo-adjusted weight loss effect might be for OSA indication for modafinil due to concerns about its risk/ patients (Svendsen and Tonstad, 2011). benefit ratio. The EMA also expressed concerns about the Lorcaserin/Belviq extent of off label use of Modafinil and its abuse potential (EMA, 2011). Lorcaserin marketed as Belviq is indicated to be used in conjunc- tion with a reduced calorie diet and exercise program for chronic Drugs to treat sleep apnoea airway stability weight management. The drug works by activating serotonin Drugs that specifically target the upper airway to effectively receptors in the brain which decreases hunger levels (Halford improve breathing throughout the night and reduce the severity et al., 2007). In a recent trial, overweight patients with type 2 of apnoeas could have therapeutic benefits for OSA. Patients diabetes mellitus who received a diet and exercise program may be more compliant with treatment if it involves taking a along with lorcaserin lost 5.8 kg compared with 2.2 kg in the tablet as opposed to using a CPAP machine. Drugs that aim to placebo group at 1 year (O’Neil et al., 2012). Caution should be improve both airway tone and ventilatory drive have been taken when prescribing lorcaserin to patients taking serotoner- tested in randomized clinical trials (Hedner, Grote and Zou, gic drugs due to the risk of serotonin syndrome. There has yet to 2008), but none so far have reliably demonstrated a clinically be any sleep apnoea-specific clinical trials with lorcaserin, so it is relevant level of efficacy ( Mason, Welsh and Smith, 2013). uncertain how effective it is at reducing sleep apnoea severity. Lifestyle and behavioural modification Phentermine and topiramate/Qsymia A randomized clinical trial study looking at obese patients Lifestyle modification is often recommended for those diag - who were unable to comply with CPAP prescribed either nosed with OSA, but there are few studies conducted to quan- phentermine with extended release topiramate (marketed as tify the effectiveness of suggestions such as reduction alcohol Qsymia) or placebo in conjunction with a weight loss pro- and positional therapy. gram (recommended indication for overweight patients). Reducing alcohol consumption Participants allocated to taking phentermine and topiramate lost 10.2% of their body weight compared with the placebo As alcohol is a sedative, it causes relaxation of the muscles. group who lost on average 4.3% (Winslow et al., 2012). The Increased relaxation of the upper airway during sleep increases weight loss was also associated with a lowered AHI. the chances of the airway collapsing even in asymptomatic patients (Mitler et al., 1988). It is therefore recommended Pharmacotherapy for OSA that directly treats sleep apnoea that those diagnosed with sleep apnoea reduce their alcohol rather than through weight loss consumption both for its effect on upper airway stability but Apart from drug therapy for weight loss, there are also drugs also because of its high caloric content. However, the effect of that target the daytime sleepiness or that directly target air- alcohol consumption on AHI in patients with OSA has not way stability. been thoroughly investigated. Pharmacotherapy for daytime sleepiness Sleep hygiene and positional therapy Wake-promoting drugs can be prescribed to treat the daytime Medical Practitioners may offer advice on improving sleep sleepiness associated with OSA rather than the OSA itself; hygiene such as waking up and going to sleep at the same 4 Bioscience Horizons • Volume 7 2014 Clinical review time each day. It is also recommended that patients avoid 2015 with a B.Sc (Hons) in Medical Science from Exeter Medical exposure to light before bed and get adequate light stimula- School. She has an interest in clinical trials and sleep medicine. tion in the morning. In patients with OSA, apnoeas tend to occur when the patient is lying on their back (known as the Funding supine position); therefore, it is recommended that patients try to sleep on their side, this can be enforced by the patient Funded through Australian NHMRC grants 1004528 and attaching a ball into the back of their pyjama top. Current guidelines recommend positional therapy for those with mild positional OSA who cannot tolerate CPAP as it can be a cheap and effective solution for these patients (Oksenberg References and Gadoth, 2014); however, it is less effective than CPAP in Aasm. (1999) Sleep-related breathing disorders in adults: recommenda- reducing AHI (Ha, Hirai and Tsoi, 2014). Although lifestyle tions for syndrome definition and measurement techniques in clini - modification if often recommended for patients with OSA, cal research. The Report of an American Academy of Sleep Medicine there is very little evidence quantifying its effectiveness Task Force, Sleep, 22, 667–689. (Shneerson and Wright, 2001). Aasm. (2001) The International Classification of Sleep Disorders, accessed Conclusion at: http://www.esst.org/adds/ICSD.pdf (24 November 2014). Almeida, F. R., Lowe, A. A., Tsuiki, S. et al. (2005) Long-term compliance With the prevalence of OSA increasing due to an ageing pop- and side effects of oral appliances used for the treatment of snoring ulation and the obesity epidemic (Peppard et al., 2013), there and obstructive sleep apnea syndrome, Journal of Clinical Sleep is a growing need for better treatment options for OSA. Medicine, 1, 143–152. Patients with OSA are often intolerant to the gold standard Antic, N. A., Catcheside, P., Buchan, C. et  al. 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(2013) apnea-hypopnea and incident stroke: the sleep heart health study, Effect of CPAP on blood pressure in patients with obstructive sleep American Journal of Respiratory and Critical Care Medicine, 182, apnea and resistant hypertension: the HIPARCO randomized clinical 269–277. trial, The Journal of American Medical Association, 310, 2407–2415. Rucker, D., Padwal, R., Li, S. K. et al. (2007) Long term pharmacotherapy Mason, M., Welsh, E. J. and Smith, I. (2013) Drug therapy for obstructive for obesity and overweight: updated meta-analysis, British Medical sleep apnoea in adults, Cochrane Database of Systematic Reviews, 5, Journal, 335, 1194–1199. Cd003002. Schlosshan, D. and Elliott, M. W. (2004) Sleep. 3: clinical presentation and Mccall, W. V., Harding, D. and O’Donovan, C. (2006) Correlates of depres- diagnosis of the obstructive sleep apnoea hypopnoea syndrome, sive symptoms in patients with obstructive sleep apnea, Journal of Thorax, 59, 347–352. 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(2012) Randomized placebo- Reviews, 4, CD001004. controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study, Obesity (Silver Spring), 20, 1426–1436. Sutherland, K. and Cistulli, P. (2011) Mandibular advancement splints for the treatment of sleep apnea syndrome, Swiss Medical Weekly, 141, Oksenberg, A. and Gadoth, N. (2014) Are we missing a simple treatment w13276. for most adult sleep apnea patients? The avoidance of the supine sleep position, Journal of Sleep Research, 23, 204–210. Sutherland, K., Vanderveken, O. M., Tsuda, H. et al. (2014) Oral appliance treatment for obstructive sleep apnea: an update, Journal of Clinical Peppard, P. E., Young, T., Barnet, J. H. et  al. (2013) Increased prevalence Sleep Medicine, 10, 215–227. of sleep-disordered breathing in adults, American Journal of Epidemiology, 177, 1006–1014. Svendsen, M. and Tonstad, S. 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(2009) Lifestyle Winslow, D. H., Bowden, C. H., Didonato, K. P. et al. (2012) A randomized, intervention with weight reduction, American Journal of Respiratory double-blind, placebo-controlled study of an oral, extended- and Critical Care Medicine, 179, 320–327. release formulation of phentermine/topiramate for the treatment of obstructive sleep apnea in obese adults, Sleep, 35, 1529–1539. Varghese, R., Adams, N. G., Slocumb, N. L. et al. (2012) Maxillomandibular advancement in the management of obstructive sleep apnea, Yee, B. J., Phillips, C. L., Banerjee, D. et  al. (2007) The effect of sibutra - International Journal of Otolaryngology, 2012, 373025. mine-assisted weight loss in men with obstructive sleep apnoea, International Journal of Obesity (London), 31, 161–168. Wang, D., Piper, A. J., Yee, B. J. et al. (2014a) Hypercapnia is a key correlate of EEG activation and daytime sleepiness in hypercapnic sleep dis- Young, T., Finn, L., Peppard, P. E. et al. (2008) Sleep disordered breathing ordered breathing patients, Journal of Clinical Sleep Medicine, 10, and mortality: eighteen-year follow-up of the Wisconsin sleep 517–522. cohort, Sleep, 31, 1071–1078. Wang, D., Yee, B. J. and Rowsell, L. (2014b) Sleep-disordered breathing- Zhang, Q., Wang, D., Qin, W. et al. (2013) Altered resting-state brain activ- related neurocognitive impairment, time to think beyond hypoxia ity in obstructive sleep apnea, Sleep, 36, 651–659B. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Bioscience Horizons Oxford University Press

A critical review of the treatment options available for obstructive sleep apnoea: an overview of the current literature available on treatment methods for obstructive sleep apnoea and future research directions

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BioscienceHorizons Volume 7 2014 10.1093/biohorizons/hzu011 Clinical review A critical review of the treatment options available for obstructive sleep apnoea: an overview of the current literature available on treatment methods for obstructive sleep apnoea and future research directions 1,2 1 1,3 Alessandra J. Booth *, Yasmina Djavadkhani and Nathaniel S. Marshall NHMRC Centre for Research Excellence NeuroSleep, the Centre for Translational Sleep and Circadian Neurobiology, the Woolcock Institute for Medical Research, University of Sydney, 431 Glebe Point Rd, Glebe, Sydney NSW 2037, Australia Clinical Sciences Programme, University of Exeter, Heavitree Rd, Exeter, Devon EX1 2LU, England Sydney Nursing School, University of Sydney, 88 Mallett St, Camperdown, Sydney NSW 2050, Australia *Corresponding author: Email: ajb263@icloud.com Obstructive sleep apnoea (OSA) is a leading yet often undiagnosed cause of daytime sleepiness. It affects between 3 and 7% of the adult population, and the prevalence is expected to increase due to the obesity epidemic and ageing population. OSA is a sleep-related breathing disorder in which the airway completely (apnoea) or partly closes (hypopnea) during sleep at the end of expiration. This can lead to decreases in blood oxygen saturation and sleep fragmentation. Those who suffer with OSA are often unaware of their symptoms. Severe, untreated OSA can have serious implications such as an increased risk of cardio- vascular disease, motor vehicle accidents, poor neurocognitive performance and increased mortality. Many patients are pre- scribed continuous positive airway pressure (CPAP) as a treatment, but compliance with CPAP is often low. We briefly review the diagnosis and prognosis for obstructive sleep apnoea. But the main focus of our review is the critical evaluation of the numerous treatment strategies available for sleep apnoea as a multi-comorbid and multi-factorial condition. We also high- light areas that need further research. Key words: pharmacotherapy, sleep-disordered breathing, cardiovascular diseases, critical, surgery, mandibular advancement splints Submitted on 11 May 2014; accepted on 6 November 2014 Introduction Clinically, patients often present with snoring and daytime sleepiness. The gold standard diagnostic method for OSA is Obstructive sleep apnoea (OSA) is a condition of periodic full overnight polysomnography (PSG) carried out in a sleep and recurrent closure of the upper airway at the end of exha- laboratory. PSG combines a range of measurements such as lation during sleep (Guilleminault, Tilkian and Dement, heart rate, blood oxygen saturation and EEG-based sleep 1976). This airway closure can lead to a drop in oxygen satu- staging. Other simplified diagnostic techniques using fewer ration levels and fluctuations in blood pressure and heart overnight channels do exist, but they often provide less infor- rate. Patients can experience daytime sleepiness due to frag- mation for differential diagnoses such as REM Behaviour mented sleep and disturbances in normal sleep architecture. Disorder, Periodic Limb Movement Disorder or Central Sleep © The Author 2014. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Clinical review Bioscience Horizons • Volume 7 2014 Table 1. How the clinical severity of sleep apnoea is determined from Apnoea which may require a full PSG (Schlosshan and Elliott, the apnoea–hypopnoea index 2004). A diagnosis of obstructive sleep apnoea syndrome (OSAS) requires significant daytime sleepiness along with an Clinical severity of OSA Apnoea–Hypopnoea index abnormal apnoea–hypopnoea index (AHI > 5 events per hour of sleep), whereas a diagnosis of OSA only requires an Mild 5–15/h AHI > 5 (AASM, 2001). There may also be a contribution from the potential sleepiness inducing effects of hypoxia and Moderate 15–30/h particularly hypercapnia (Zhang et al., 2013; Wang et al., Severe >30/h 2014a; Wang, Yee and Rowsell, 2014b). Daytime sleepiness is often clinically measured using the Epworth Sleepiness Scale (ESS), a numerical questionnaire that Treatment strategies available for asks patients to choose how likely they are to doze while per- OSA forming different activities. An ESS score of 10 or more (on a scale of 0–24) is suggestive of pathologic somnolence (Johns, Non-implantable medical devices 1991). Although intuitive, very severe OSA is not always Continuous positive airway pressure accompanied by severe daytime sleepiness. Some patients seem quite resistant to the daytime effects of poor sleep and may be Continuous positive airway pressure (CPAP) (Sullivan et al., very high-functioning individuals despite severe OSA. In addi- 1981) is the gold standard treatment for OSA. CPAP masks tion, daytime sleepiness may have many different causes. This are worn throughout the night and provide a constant pres- makes daytime sleepiness, as a symptom, neither sensitive nor sure to pneumatically splint open the collapsing upper airway specific to sleep apnoea ( Gottlieb et al., 1999). open during periods of muscle relaxation (Giles et al., 2006). The pressure required to prevent apnoea varies between indi- The severity of OSA is determined by the numbers of 10 viduals and is determined by a personalized overnight titra- second or greater cessations of breathing per hour (apnoeas) tion procedure. This involves increasing CPAP pressure until and reductions in airflow per hour (hypopnoeas). An apnoea breathing is normalized in all stages of sleep. Patients with is a complete closure of the upper airway which can vary OSA who comply with CPAP treatment have reduced blood from seconds to minutes. A hypopnoea is currently defined as pressure (Martinez-Garcia et al., 2013), arterial stiffness being at least a 30% reduction in airflow combined with a (Kartali et al., 2014) and have a lower risk of having a car- 3% arterial oxygen desaturation levels, or an arousal from diovascular event compared with those with untreated mod- sleep (Berry et al., 2012). These combined to form the erate–severe OSA (Marin et al., 2005). While CPAP is a apnoea–hypopnoea index of a patient. AHI is calculated by highly efficacious treatment when used correctly, many dividing the total number of events by the hours of sleep patients struggle to adapt to it and non-adherence rates are (AASM, 1999; Table 1). probably at least 50% (Weaver and Grunstein, 2008). Some patients report finding the mask uncomfortable, too invasive Prognosis or experience claustrophobia (Chasens et al., 2005). Newer CPAP machines that vary the pressure overnight in an effort Patients with untreated OSA have 2.5 times the risk of having to increase patient comfort do not increase compliance (Ayas an accident while driving (Tregear et al., 2009). The daytime et al., 2004; Bakker and Marshall, 2011). In addition, even in sleepiness can cause them to have an increased reaction time quite sleepy patients with mild OSA, CPAP is not very effec- and fall asleep at the wheel, injuring both themselves and oth- tive in treating daytime sleepiness (Marshall et al., 2006) and ers. The poor quality of sleep associated with sleep apnoea does not improve neurocognitive outcomes in a large propor- might also be the cause of the high rates of depression (Mccall, tion of patients, even those with moderate–severe OSA and Harding and O’Donovan, 2006), impaired quality of life, high compliance (Antic et al., 2011). Despite this, it remains anxiety and poor performance at work seen in patients with the gold standard treatment for sleepy patients with moder- OSA. Untreated OSA is also linked to an increase in cardio- ate–severe OSA (Giles et al., 2006). vascular disease risk (Marin et al., 2005; Chami et al., 2011) and with hypertension (Peppard et al., 2000b), insulin resis- Mandibular advancement splints tance (Aurora and Punjabi, 2013), hyperlipidaemia (Phillips et al., 2011) and metabolic syndrome (Bonsignore et al., The mandibular advancement splint (MAS) is another treat- 2012). Those with OSA often have co-morbid cardiovascular ment modality for OSA. It is similar to a mouthguard that diseases and are at a six-fold higher risk of having a stroke when fitted to the teeth pulls the lower jaw forward. This (Redline et al., 2010) as well as a three- to four-fold higher increases the area and support in the upper airway (Lim et al., mortality risk (Young et al., 2008; Punjabi et al., 2009). The 2006). MAS is currently regarded as a second-line therapy for most recent longitudinal studies have indicated that some of OSA, because it only completely alleviates OSA in 40% of the excess mortality may come from cancer-related deaths patients (Sutherland and Cistulli, 2011). Current guidelines (Nieto et al., 2012; Campos-Rodriguez et al., 2013; Marshall suggest a repeat sleep study with MAS in situ to determine its et al., 2014). effectiveness. However, MAS is often recommended to patients 2 Bioscience Horizons • Volume 7 2014 Clinical review with mild-to-moderate OSA or for patients with severe OSA Weight loss who cannot tolerate CPAP (Kushida et al., 2006). MAS has Weight loss is an effective treatment for overweight and obese been shown to be effective in reducing AHI by 14 and ESS by patients with OSA. This is both because of a reduction in the just <2 points in a randomized controlled trial (RCT) lasting 4 apnoea–hypnoea index and also because of beneficial effects on weeks (Petri et al., 2008). Short-term, RCTs have shown that other associated cardiometabolic risk factors. In the commu- patients comply with MAS therapy better than CPAP and that nity-based Wisconsin Sleep Cohort, a 10% decrease in weight patients generally report preferring MAS (Gagnadoux et al., has been shown to be associated with a 26% reduction in AHI 2009; Phillips et al., 2013). Observational long-term compli- (Peppard et al., 2000a). Although weight loss reduces OSA ance focused studies have suggested that ~64% of patients con- severity, it may take a relatively long time to achieve and may tinue to use MAS regularly (Almeida et al., 2005). Unfortunately, not cure OSA. Therefore, weight loss is considered an adjunc- some patients experience MAS-associated side effects such tive therapy. Weight loss therapy via diet, pharmacotherapy as migration of the lower dentition (Marklund et al., 2001; and surgery is increasingly being researched for OSA and may Hammond et al., 2007) and dry mouth (Fritsch et al., 2001). eventually come to replace or join CPAP as the first-line therapy Patients who comply with MAS have experienced improve- in overweight–obese patients. Indeed in a recent RCT, weight ments in vascular function (Itzhaki et al., 2007; Trzepizur et al., loss alone caused greater improvements in cardiometabolic risk 2009), blood pressure (Gotsopoulos et al., 2004; Phillips et al., factors than CPAP did (Chirinos et al., 2014). 2013), daytime sleepiness (Gindre et al., 2008) and an increased quality of life (Phillips et al., 2013). Clinical prediction of which Weight loss in OSA patients has also been rigorously tested patients will benefit from MAS is currently an open line of via dietary interventions (Foster et al., 2009; Tuomilehto research (Sutherland et al., 2014), but it is currently used for et al., 2009). It is recommended that patients with OSA who patients with mild-to-moderate OSA and those who cannot tol- are overweight begin a weight reduction program. Weight erate CPAP (Marklund, Verbraecken and Randerath, 2012). gain around the neck is thought to narrow the upper airways due to a build-up of fat around the upper airways. But weight Surgery gain inside the abdomen may also play an important physical and indirect cause of OSA. Weight loss may help to reduce a There are a large and increasing number of surgical proce- patient’s AHI (Johansson et al., 2009) and also reduce the dures aimed at directly reducing sleep apnoea severity. significant cardiovascular risk that accompanies sleep apnoea. Maxillomandibular Advancement (MMA) is probably the However, as with weight loss programs in all people who are most efficacious but least suitable for general use, and uvulo - overweight, weight loss in patients with sleep apnoea is not palatopharyngoplasty (UPPP) is one of the oldest, most always successful or sustainable. In addition, some patients widely studied and used procedures. may lose weight but not experience any improvements in Maxillomandibular advancement their sleep apnoea. MMA involves surgically repositioning both the upper and Bariatric surgery lower jaws forward to correct an abnormally small upper air- There are numerous bariatric surgery approaches that can way space caused by a small bony enclosure. By bringing be used to help reduce a patient’s AHI through weight loss. both the upper and lower jaws forward the upper airways are Laparoscopic adjustable gastric band (LAGB) surgery involves enlarged, thus reducing the likelihood of upper airway col- placing a device around the stomach that constricts the size of lapse (Varghese et al., 2012). MMA is thought to be the most the stomach pouch, therefore reducing the amount of food effective surgical treatment for OSA but is often used after consumed in one sitting. In a recent trial, OSA patients lost other options have been exhausted due to the long recovery on average 27.8 kg at 2 years with a concomitant reduction time and potential risks of the surgery. MMA is only effective in OSA severity after LAGB surgery (Dixon et al., 2012). in carefully selected patients with a particular facial pheno- Compared with conventional weight loss patients (who lost type (Aurora et al., 2010) and those without significant co- 5.1 kg), LAGB patients lost more weight but their sleep morbidities that may impact surgical risk. apnoea was not reduced by a greater amount than diet alone Uvulopalatopharyngoplasty (25.5 events and hour vs. 14.0 events, p = 0.18). This was caused by an under-powering of the trial caused by an unex- This procedure is the most common surgery aimed at alleviat- pected decline in the effectiveness of weight loss for OSA after ing OSA and involves removing excess tissue at the back of the patients lost over 10–15 kg. Once patients lost around this throat such as the uvula to create a wider airway (Sundaram, amount of weight, their sleep apnoea stopped improving. Lim and Lasserson Toby, 2005). This approach has been heav- ily criticized in recent years as it has marginal efficacy in many Pharmacotherapy for weight loss targeted at sleep apnoea cases (Elshaug et al., 2008). The procedure may suffer from Sibutramine/Meridia large variations both in the hands of different surgeons but also in its efficacy in different patients. For this reason, much Sibutramine (marketed in UK as Meridia) has been shown to like MMA, it should be used sparingly in carefully selected lower a patient’s respiratory disturbance index during the patients (Mackay, Jefferson and Marshall, 2013). night as well as ESS score via its weight loss effects (Yee et al., 3 Clinical review Bioscience Horizons • Volume 7 2014 2007). However, weight loss was only modest and in 2010 the they are a group of drugs that stimulant the central nervous FDA removed Sibutramine from the market as a high number system to promote wakefulness. of cardiovascular events were observed in patients taking the Some patients who adhere to CPAP can still experience drug (Curfman, Morrissey and Drazen, 2010; FDA, 2010). daytime sleepiness, and the FDA lists an on-label indication for modafinil for this purpose ( FDA, 2007). Modafinil, Orlistat/Xenical marketed as Provigil (UK/USA), has been shown to increase Orlistat (marketed in UK as Xenical in the higher dose pre- patient’s daily functioning as assessed by improvements in scriptive form and as Alli in the over-the-counter lower dose the Functional Outcomes of Sleep Questionnaire (FOSQ) form) works by inhibiting gastric and pancreatic lipases and (Weaver, Chasens and Arora, 2009), it has also been shown thus reducing dietary fat absorption. It blocks around 30% to improve a patient’s ability to engage in everyday activi- of fat from being absorbed and should be taken within an ties. However, as wake-promoting drugs do not prevent hour of eating (Boulghassoul-Pietrzykowska, Franceschelli apnoeas, patients who use solely wake promoters to man- and Still, 2013). Patients who had Orlistat in randomized age their OSA will probably still experience the long-term clinical trials lost 2.7 kg more than those on the placebo med- complications associated with the disease (although this has ication (Rucker et al., 2007). The only study we found that not been studied yet). Modafinil may also be of effective looked specifically at the use of Orlistat in patients with OSA symptomatic benefit in patients with mild-to-moderate was a prospective case series. The use of Orlistat was found sleep apnoea who do not use mechanical treatment, but this to benefit weight loss; however, AHI was not measured before is an off-label indication and has not been tested for a and after the Orlistat trial so it is uncertain whether the period of longer than 2 weeks (Chapman et al., 2013). The weight loss was accompanied by a reduction in AHI or what European Medicines Agency recently revoked the OSA the true placebo-adjusted weight loss effect might be for OSA indication for modafinil due to concerns about its risk/ patients (Svendsen and Tonstad, 2011). benefit ratio. The EMA also expressed concerns about the Lorcaserin/Belviq extent of off label use of Modafinil and its abuse potential (EMA, 2011). Lorcaserin marketed as Belviq is indicated to be used in conjunc- tion with a reduced calorie diet and exercise program for chronic Drugs to treat sleep apnoea airway stability weight management. The drug works by activating serotonin Drugs that specifically target the upper airway to effectively receptors in the brain which decreases hunger levels (Halford improve breathing throughout the night and reduce the severity et al., 2007). In a recent trial, overweight patients with type 2 of apnoeas could have therapeutic benefits for OSA. Patients diabetes mellitus who received a diet and exercise program may be more compliant with treatment if it involves taking a along with lorcaserin lost 5.8 kg compared with 2.2 kg in the tablet as opposed to using a CPAP machine. Drugs that aim to placebo group at 1 year (O’Neil et al., 2012). Caution should be improve both airway tone and ventilatory drive have been taken when prescribing lorcaserin to patients taking serotoner- tested in randomized clinical trials (Hedner, Grote and Zou, gic drugs due to the risk of serotonin syndrome. There has yet to 2008), but none so far have reliably demonstrated a clinically be any sleep apnoea-specific clinical trials with lorcaserin, so it is relevant level of efficacy ( Mason, Welsh and Smith, 2013). uncertain how effective it is at reducing sleep apnoea severity. Lifestyle and behavioural modification Phentermine and topiramate/Qsymia A randomized clinical trial study looking at obese patients Lifestyle modification is often recommended for those diag - who were unable to comply with CPAP prescribed either nosed with OSA, but there are few studies conducted to quan- phentermine with extended release topiramate (marketed as tify the effectiveness of suggestions such as reduction alcohol Qsymia) or placebo in conjunction with a weight loss pro- and positional therapy. gram (recommended indication for overweight patients). Reducing alcohol consumption Participants allocated to taking phentermine and topiramate lost 10.2% of their body weight compared with the placebo As alcohol is a sedative, it causes relaxation of the muscles. group who lost on average 4.3% (Winslow et al., 2012). The Increased relaxation of the upper airway during sleep increases weight loss was also associated with a lowered AHI. the chances of the airway collapsing even in asymptomatic patients (Mitler et al., 1988). It is therefore recommended Pharmacotherapy for OSA that directly treats sleep apnoea that those diagnosed with sleep apnoea reduce their alcohol rather than through weight loss consumption both for its effect on upper airway stability but Apart from drug therapy for weight loss, there are also drugs also because of its high caloric content. However, the effect of that target the daytime sleepiness or that directly target air- alcohol consumption on AHI in patients with OSA has not way stability. been thoroughly investigated. Pharmacotherapy for daytime sleepiness Sleep hygiene and positional therapy Wake-promoting drugs can be prescribed to treat the daytime Medical Practitioners may offer advice on improving sleep sleepiness associated with OSA rather than the OSA itself; hygiene such as waking up and going to sleep at the same 4 Bioscience Horizons • Volume 7 2014 Clinical review time each day. It is also recommended that patients avoid 2015 with a B.Sc (Hons) in Medical Science from Exeter Medical exposure to light before bed and get adequate light stimula- School. She has an interest in clinical trials and sleep medicine. tion in the morning. In patients with OSA, apnoeas tend to occur when the patient is lying on their back (known as the Funding supine position); therefore, it is recommended that patients try to sleep on their side, this can be enforced by the patient Funded through Australian NHMRC grants 1004528 and attaching a ball into the back of their pyjama top. Current guidelines recommend positional therapy for those with mild positional OSA who cannot tolerate CPAP as it can be a cheap and effective solution for these patients (Oksenberg References and Gadoth, 2014); however, it is less effective than CPAP in Aasm. (1999) Sleep-related breathing disorders in adults: recommenda- reducing AHI (Ha, Hirai and Tsoi, 2014). Although lifestyle tions for syndrome definition and measurement techniques in clini - modification if often recommended for patients with OSA, cal research. The Report of an American Academy of Sleep Medicine there is very little evidence quantifying its effectiveness Task Force, Sleep, 22, 667–689. (Shneerson and Wright, 2001). Aasm. (2001) The International Classification of Sleep Disorders, accessed Conclusion at: http://www.esst.org/adds/ICSD.pdf (24 November 2014). Almeida, F. R., Lowe, A. A., Tsuiki, S. et al. (2005) Long-term compliance With the prevalence of OSA increasing due to an ageing pop- and side effects of oral appliances used for the treatment of snoring ulation and the obesity epidemic (Peppard et al., 2013), there and obstructive sleep apnea syndrome, Journal of Clinical Sleep is a growing need for better treatment options for OSA. Medicine, 1, 143–152. Patients with OSA are often intolerant to the gold standard Antic, N. A., Catcheside, P., Buchan, C. et  al. 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Bioscience HorizonsOxford University Press

Published: Dec 3, 2014

Keywords: pharmacotherapy sleep-disordered breathing cardiovascular diseases critical surgery mandibular advancement splints

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