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
Alessandra J. Booth1,2*, Yasmina Djavadkhani1 and Nathaniel S. Marshall1,3
1NHMRC
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
2Clinical Sciences Programme, University of Exeter, Heavitree Rd, Exeter, Devon EX1 2LU, England
3Sydney Nursing School, University of Sydney, 88 Mallett St, Camperdown, Sydney NSW 2050, Australia
*Corresponding author: Email: [email protected]
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 cardiovascular disease, motor vehicle accidents, poor neurocognitive performance and increased mortality. Many patients are prescribed 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 highlight 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
Obstructive sleep apnoea (OSA) is a condition of periodic
and recurrent closure of the upper airway at the end of exhalation during sleep (Guilleminault, Tilkian and Dement,
1976). This airway closure can lead to a drop in oxygen saturation levels and fluctuations in blood pressure and heart
rate. Patients can experience daytime sleepiness due to fragmented sleep and disturbances in normal sleep architecture.
Clinically, patients often present with snoring and daytime
sleepiness. The gold standard diagnostic method for OSA is
full overnight polysomnography (PSG) carried out in a sleep
laboratory. PSG combines a range of measurements such as
heart rate, blood oxygen saturation and EEG-based sleep
staging. Other simplified diagnostic techniques using fewer
overnight channels do exist, but they often provide less information for differential diagnoses such as REM Behaviour
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.
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Clinical review
Apnoea which may require a full PSG (Schlosshan and Elliott,
2004). A diagnosis of obstructive sleep apnoea syndrome
(OSAS) requires significant daytime sleepiness along with an
abnormal apnoea–hypopnoea index (AHI > 5 events per
hour of sleep), whereas a diagnosis of OSA only requires an
AHI > 5 (AASM, 2001). There may also be a contribution
from the potential sleepiness inducing effects of hypoxia and
particularly hypercapnia (Zhang et al., 2013; Wang et al.,
2014a; Wang, Yee and Rowsell, 2014b).
Daytime sleepiness is often clinically measured using the
Epworth Sleepiness Scale (ESS), a numerical questionnaire that
asks patients to choose how likely they are to doze while performing different activities. An ESS score of 10 or more (on a
scale of 0–24) is suggestive of pathologic somnolence (Johns,
1991). Although intuitive, very severe OSA is not always
accompanied by severe daytime sleepiness. Some patients seem
quite resistant to the daytime effects of poor sleep and may be
very high-functioning individuals despite severe OSA. In addition, daytime sleepiness may have many different causes. This
makes daytime sleepiness, as a symptom, neither sensitive nor
specific to sleep apnoea (Gottlieb et al., 1999).
The severity of OSA is determined by the numbers of 10
second or greater cessations of breathing per hour (apnoeas)
and reductions in airflow per hour (hypopnoeas). An apnoea
is a complete closure of the upper airway which can vary
from seconds to minutes. A hypopnoea is currently defined as
being at least a 30% reduction in airflow combined with a
3% arterial oxygen desaturation levels, or an arousal from
sleep (Berry et al., 2012). These combined to form the
apnoea–hypopnoea index of a patient. AHI is calculated by
dividing the total number of events by the hours of sleep
(AASM, 1999; Table 1).
Prognosis
Patients with untreated OSA have 2.5 times the risk of having
an accident while driving (Tregear et al., 2009). The daytime
sleepiness can cause them to have an increased reaction time
and fall asleep at the wheel, injuring both themselves and others. The poor quality of sleep associated with sleep apnoea
might also be the cause of the high rates of depression (Mccall,
Harding and O’Donovan, 2006), impaired quality of life,
anxiety and poor performance at work seen in patients with
OSA. Untreated OSA is also linked to an increase in cardiovascular disease risk (Marin et al., 2005; Chami et al., 2011)
and with hypertension (Peppard et al., 2000b), insulin resistance (Aurora and Punjabi, 2013), hyperlipidaemia (Phillips
et al., 2011) and metabolic syndrome (Bonsignore et al.,
2012). Those with OSA often have co-morbid cardiovascular
diseases and are at a six-fold higher risk of having a stroke
(Redline et al., 2010) as well as a three- to four-fold higher
mortality risk (Young et al., 2008; Punjabi et al., 2009). The
most recent longitudinal studies have indicated that some of
the excess mortality may come from cancer-related deaths
(Nieto et al., 2012; Campos-Rodriguez et al., 2013; Marshall
et al., 2014).
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Bioscience Horizons • Volume 7 2014
Table 1. ​How the clinical severity of sleep apnoea is determined from
the apnoea–hypopnoea index
Clinical severity of OSA
Apnoea–Hypopnoea index
Mild
5–15/h
Moderate
15–30/h
Severe
>30/h
Treatment strategies available for
OSA
Non-implantable medical devices
Continuous positive airway pressure
Continuous positive airway pressure (CPAP) (Sullivan et al.,
1981) is the gold standard treatment for OSA. CPAP masks
are worn throughout the night and provide a constant pressure to pneumatically splint open the collapsing upper airway
open during periods of muscle relaxation (Giles et al., 2006).
The pressure required to prevent apnoea varies between individuals and is determined by a personalized overnight titration procedure. This involves increasing CPAP pressure until
breathing is normalized in all stages of sleep. Patients with
OSA who ­comply with CPAP treatment have reduced blood
pressure (Martinez-Garcia et al., 2013), arterial stiffness
(Kartali et al., 2014) and have a lower risk of having a cardiovascular event compared with those with untreated moderate–severe OSA (Marin et al., 2005). While CPAP is a
highly efficacious treatment when used correctly, many
patients struggle to adapt to it and non-adherence rates are
probably at least 50% (Weaver and Grunstein, 2008). Some
patients report finding the mask uncomfortable, too invasive
or experience claustrophobia (Chasens et al., 2005). Newer
CPAP machines that vary the pressure overnight in an effort
to increase patient comfort do not increase compliance (Ayas
et al., 2004; Bakker and Marshall, 2011). In addition, even in
quite sleepy patients with mild OSA, CPAP is not very effective in treating daytime sleepiness (Marshall et al., 2006) and
does not improve neurocognitive outcomes in a large proportion of patients, even those with moderate–severe OSA and
high compliance (Antic et al., 2011). Despite this, it remains
the gold standard treatment for sleepy patients with moderate–severe OSA (Giles et al., 2006).
Mandibular advancement splints
The mandibular advancement splint (MAS) is another treatment modality for OSA. It is similar to a mouthguard that
when fitted to the teeth pulls the lower jaw forward. This
increases the area and support in the upper airway (Lim et al.,
2006). MAS is currently regarded as a second-line therapy for
OSA, because it only completely alleviates OSA in 40% of
patients (Sutherland and Cistulli, 2011). Current guidelines
suggest a repeat sleep study with MAS in situ to determine its
effectiveness. However, MAS is often recommended to patients
Bioscience Horizons • Volume 7 2014
with mild-to-moderate OSA or for patients with severe OSA
who cannot tolerate CPAP (Kushida et al., 2006). MAS has
been shown to be effective in reducing AHI by 14 and ESS by
just <2 points in a randomized controlled trial (RCT) lasting 4
weeks (Petri et al., 2008). Short-term, RCTs have shown that
patients comply with MAS therapy better than CPAP and that
patients generally report preferring MAS (Gagnadoux et al.,
2009; Phillips et al., 2013). Observational long-term compliance focused studies have suggested that ~64% of patients continue to use MAS regularly (Almeida et al., 2005). Unfortunately,
some patients experience MAS-associated side effects such
as migration of the lower dentition (Marklund et al., 2001;
Hammond et al., 2007) and dry mouth (Fritsch et al., 2001).
Patients who comply with MAS have experienced improvements in vascular function (Itzhaki et al., 2007; Trzepizur et al.,
2009), blood pressure (Gotsopoulos et al., 2004; Phillips et al.,
2013), daytime sleepiness (Gindre et al., 2008) and an increased
quality of life (Phillips et al., 2013). Clinical prediction of which
patients will benefit from MAS is currently an open line of
research (Sutherland et al., 2014), but it is currently used for
patients with mild-to-moderate OSA and those who cannot tolerate CPAP (Marklund, Verbraecken and Randerath, 2012).
Surgery
There are a large and increasing number of surgical procedures aimed at directly reducing sleep apnoea severity.
Maxillomandibular Advancement (MMA) is probably the
most efficacious but least suitable for general use, and uvulopalatopharyngoplasty (UPPP) is one of the oldest, most
widely studied and used procedures.
Maxillomandibular advancement
MMA involves surgically repositioning both the upper and
lower jaws forward to correct an abnormally small upper airway space caused by a small bony enclosure. By bringing
both the upper and lower jaws forward the upper airways are
enlarged, thus reducing the likelihood of upper airway collapse (Varghese et al., 2012). MMA is thought to be the most
effective surgical treatment for OSA but is often used after
other options have been exhausted due to the long recovery
time and potential risks of the surgery. MMA is only effective
in carefully selected patients with a particular facial phenotype (Aurora et al., 2010) and those without significant comorbidities that may impact surgical risk.
Uvulopalatopharyngoplasty
This procedure is the most common surgery aimed at alleviating OSA and involves removing excess tissue at the back of the
throat such as the uvula to create a wider airway (Sundaram,
Lim and Lasserson Toby, 2005). This approach has been heavily criticized in recent years as it has marginal efficacy in many
cases (Elshaug et al., 2008). The procedure may suffer from
large variations both in the hands of different surgeons but
also in its efficacy in different patients. For this reason, much
like MMA, it should be used sparingly in carefully selected
patients (Mackay, Jefferson and Marshall, 2013).
Clinical review
Weight loss
Weight loss is an effective treatment for overweight and obese
patients with OSA. This is both because of a reduction in the
apnoea–hypnoea index and also because of beneficial effects on
other associated cardiometabolic risk factors. In the community-based Wisconsin Sleep Cohort, a 10% decrease in weight
has been shown to be associated with a 26% reduction in AHI
(Peppard et al., 2000a). Although weight loss reduces OSA
severity, it may take a relatively long time to achieve and may
not cure OSA. Therefore, weight loss is considered an adjunctive therapy. Weight loss therapy via diet, pharmacotherapy
and surgery is increasingly being researched for OSA and may
eventually come to replace or join CPAP as the first-line therapy
in overweight–obese patients. Indeed in a recent RCT, weight
loss alone caused greater improvements in cardiometabolic risk
factors than CPAP did (Chirinos et al., 2014).
Weight loss in OSA patients has also been rigorously tested
via dietary interventions (Foster et al., 2009; Tuomilehto
et al., 2009). It is recommended that patients with OSA who
are overweight begin a weight reduction program. Weight
gain around the neck is thought to narrow the upper airways
due to a build-up of fat around the upper airways. But weight
gain inside the abdomen may also play an important physical
and indirect cause of OSA. Weight loss may help to reduce a
patient’s AHI (Johansson et al., 2009) and also reduce the
significant cardiovascular risk that accompanies sleep apnoea.
However, as with weight loss programs in all people who are
overweight, weight loss in patients with sleep apnoea is not
always successful or sustainable. In addition, some patients
may lose weight but not experience any improvements in
their sleep apnoea.
Bariatric surgery
There are numerous bariatric surgery approaches that can
be used to help reduce a patient’s AHI through weight loss.
Laparoscopic adjustable gastric band (LAGB) surgery involves
placing a device around the stomach that constricts the size of
the stomach pouch, therefore reducing the amount of food
consumed in one sitting. In a recent trial, OSA patients lost
on average 27.8 kg at 2 years with a concomitant reduction
in OSA severity after LAGB surgery (Dixon et al., 2012).
Compared with conventional weight loss patients (who lost
5.1 kg), LAGB patients lost more weight but their sleep
apnoea was not reduced by a greater amount than diet alone
(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 unexpected decline in the effectiveness of weight loss for OSA after
patients lost over 10–15 kg. Once patients lost around this
amount of weight, their sleep apnoea stopped improving.
Pharmacotherapy for weight loss targeted at sleep apnoea
Sibutramine/Meridia
Sibutramine (marketed in UK as Meridia) has been shown to
lower a patient’s respiratory disturbance index during the
night as well as ESS score via its weight loss effects (Yee et al.,
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Clinical review
2007). However, weight loss was only modest and in 2010 the
FDA removed Sibutramine from the market as a high number
of cardiovascular events were observed in patients taking the
drug (Curfman, Morrissey and Drazen, 2010; FDA, 2010).
Orlistat/Xenical
Orlistat (marketed in UK as Xenical in the higher dose prescriptive form and as Alli in the over-the-counter lower dose
form) works by inhibiting gastric and pancreatic lipases and
thus reducing dietary fat absorption. It blocks around 30%
of fat from being absorbed and should be taken within an
hour of eating (Boulghassoul-Pietrzykowska, Franceschelli
and Still, 2013). Patients who had Orlistat in randomized
clinical trials lost 2.7 kg more than those on the placebo medication (Rucker et al., 2007). The only study we found that
looked specifically at the use of Orlistat in patients with OSA
was a prospective case series. The use of Orlistat was found
to benefit weight loss; however, AHI was not measured before
and after the Orlistat trial so it is uncertain whether the
weight loss was accompanied by a reduction in AHI or what
the true placebo-adjusted weight loss effect might be for OSA
patients (Svendsen and Tonstad, 2011).
Lorcaserin/Belviq
Lorcaserin marketed as Belviq is indicated to be used in conjunction with a reduced calorie diet and exercise program for chronic
weight management. The drug works by activating serotonin
receptors in the brain which decreases hunger levels (Halford
et al., 2007). In a recent trial, overweight patients with type 2
diabetes mellitus who received a diet and exercise program
along with lorcaserin lost 5.8 kg compared with 2.2 kg in the
placebo group at 1 year (O’Neil et al., 2012). Caution should be
taken when prescribing lorcaserin to patients taking serotonergic drugs due to the risk of serotonin syndrome. There has yet to
be any sleep apnoea-specific clinical trials with lorcaserin, so it is
uncertain how effective it is at reducing sleep apnoea severity.
Bioscience Horizons • Volume 7 2014
they are a group of drugs that stimulant the central nervous
system to promote wakefulness.
Some patients who adhere to CPAP can still experience
daytime sleepiness, and the FDA lists an on-label indication
for modafinil for this purpose (FDA, 2007). Modafinil,
­marketed as Provigil (UK/USA), has been shown to increase
patient’s daily functioning as assessed by improvements in
the Functional Outcomes of Sleep Questionnaire (FOSQ)
(Weaver, Chasens and Arora, 2009), it has also been shown
to improve a patient’s ability to engage in everyday activities. However, as wake-promoting drugs do not prevent
apnoeas, patients who use solely wake promoters to manage their OSA will probably still experience the long-term
complications associated with the disease (although this has
not been studied yet). Modafinil may also be of effective
symptomatic benefit in patients with mild-to-moderate
sleep apnoea who do not use mechanical treatment, but this
is an off-label indication and has not been tested for a
period of longer than 2 weeks (Chapman et al., 2013). The
European Medicines Agency recently revoked the OSA
indication for modafinil due to concerns about its risk/­
­
benefit ratio. The EMA also expressed concerns about the
extent of off label use of Modafinil and its abuse potential
(EMA, 2011).
Drugs to treat sleep apnoea airway stability
Drugs that specifically target the upper airway to effectively
improve breathing throughout the night and reduce the severity
of apnoeas could have therapeutic benefits for OSA. Patients
may be more compliant with treatment if it involves taking a
tablet as opposed to using a CPAP machine. Drugs that aim to
improve both airway tone and ventilatory drive have been
tested in randomized clinical trials (Hedner, Grote and Zou,
2008), but none so far have reliably demonstrated a clinically
relevant level of efficacy (Mason, Welsh and Smith, 2013).
Phentermine and topiramate/Qsymia
Lifestyle and behavioural modification
A randomized clinical trial study looking at obese patients
who were unable to comply with CPAP prescribed either
phentermine with extended release topiramate (marketed as
Qsymia) or placebo in conjunction with a weight loss program (recommended indication for overweight patients).
Participants allocated to taking phentermine and topiramate
lost 10.2% of their body weight compared with the placebo
group who lost on average 4.3% (Winslow et al., 2012). The
weight loss was also associated with a lowered AHI.
Lifestyle modification is often recommended for those diagnosed with OSA, but there are few studies conducted to quantify the effectiveness of suggestions such as reduction alcohol
and positional therapy.
Reducing alcohol consumption
Apart from drug therapy for weight loss, there are also drugs
that target the daytime sleepiness or that directly target airway stability.
As alcohol is a sedative, it causes relaxation of the muscles.
Increased relaxation of the upper airway during sleep increases
the chances of the airway collapsing even in asymptomatic
patients (Mitler et al., 1988). It is therefore recommended
that those diagnosed with sleep apnoea reduce their alcohol
consumption both for its effect on upper airway stability but
also because of its high caloric content. However, the effect of
alcohol consumption on AHI in patients with OSA has not
been thoroughly investigated.
Pharmacotherapy for daytime sleepiness
Sleep hygiene and positional therapy
Wake-promoting drugs can be prescribed to treat the daytime
sleepiness associated with OSA rather than the OSA itself;
Medical Practitioners may offer advice on improving sleep
hygiene such as waking up and going to sleep at the same
Pharmacotherapy for OSA that directly treats sleep apnoea
rather than through weight loss
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Bioscience Horizons • Volume 7 2014
time each day. It is also recommended that patients avoid
exposure to light before bed and get adequate light stimulation in the morning. In patients with OSA, apnoeas tend to
occur when the patient is lying on their back (known as the
supine position); therefore, it is recommended that patients
try to sleep on their side, this can be enforced by the patient
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
and Gadoth, 2014); however, it is less effective than CPAP in
reducing AHI (Ha, Hirai and Tsoi, 2014). Although lifestyle
modification if often recommended for patients with OSA,
there is very little evidence quantifying its effectiveness
(Shneerson and Wright, 2001).
Conclusion
With the prevalence of OSA increasing due to an ageing population and the obesity epidemic (Peppard et al., 2013), there
is a growing need for better treatment options for OSA.
Patients with OSA are often intolerant to the gold standard
treatment of CPAP and also the second-line therapy, MAS.
Apart from upper airway surgery and weight loss measures,
there are few alternative options. Patients with untreated
severe OSA are at risk of lowered quality of life as well as the
significant co-morbid health issues associated with OSA. In
addition to this, the daytime sleepiness associated with sleep
apnoea can also lead to work and traffic-related accidents.
Clinical review
2015 with a B.Sc (Hons) in Medical Science from Exeter Medical
School. She has an interest in clinical trials and sleep medicine.
Funding
Funded through Australian NHMRC grants 1004528 and
1060992.
References
Aasm. (1999) Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine
Task Force, Sleep, 22, 667–689.
Aasm. (2001) The International Classification of Sleep Disorders, accessed
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
and side effects of oral appliances used for the treatment of snoring
and obstructive sleep apnea syndrome, Journal of Clinical Sleep
Medicine, 1, 143–152.
Antic, N. A., Catcheside, P., Buchan, C. et al. (2011) The effect of CPAP in
normalizing daytime sleepiness, quality of life, and neurocognitive
function in patients with moderate to severe OSA, Sleep, 34, 111–119.
Aurora, R. N., Casey, K. R., Kristo, D. et al. (2010) American Academy of
Sleep Medicine. Practice parameters for the surgical modifications
of the upper airway for obstructive sleep apnea in adults, Sleep, 33,
1408–1413.
With so many patients unable to use CPAP, there has recently
been a change in treatment options available. Newer studies
focusing on phenotyping patients will allow clinicians to recommend the best suitable treatment for that specific patient.
For example, encouraging patients with mild sleep apnoea to
engage with a weight loss program to reduce their likelihood of
progressing to severe OSA (Tuomilehto et al., 2013).
Aurora, R. N. and Punjabi, N. M. (2013) Obstructive sleep apnoea and
type 2 diabetes mellitus: a bidirectional association, Lancet Respir
Med, 1, 329–338.
Future research will investigate a multimodality care strategy for those with OSA to treat night-time and daytime symptoms separately and addressing the multi-morbities that are
often seen with OSA. Pharmaceutical products have thus far
been ineffective treatments to directly reduce OSA but because
of their potential to be more easily adhered to by patients and
their ease of translation into routine practice pharmaceuticals
remain an open avenue for research (e.g. clinical trial registration number ACTRN12614000364673).
Bakker, J. P. and Marshall, N. S. (2011) Flexible pressure delivery modification of continuous positive airway pressure for obstructive sleep
apnea does not improve compliance with therapy: systematic
review and meta-analysis. Chest, 139, 1322–1330.
Further investigation should be done into finding strategies to help overweight patients with OSA to lose weight and
in determining the effectiveness of combining different treatment options for OSA in one patient.
Bonsignore, M. R., Esquinas, C., Barceló, A. et al. (2012) Metabolic syndrome, insulin resistance and sleepiness in real-life obstructive
sleep apnoea, European Respiratory Journal, 39, 1136–1143.
Author biography
A.J.B. undertook a research placement at The Woolcock
Institute of Medical Research in Sydney, Australia investigating
obstructive sleep apnoea in 2013-14. She is graduating in June
Ayas, N. T., Patel, S. R., Malhotra, A. et al. (2004) Auto-titrating versus standard continuous positive airway pressure for the treatment of
obstructive sleep apnea: results of a meta-analysis, Sleep, 27, 249–253.
Berry, R. B., Budhiraja, R., Gottlieb, D. J. et al. (2012) Rules for scoring
respiratory events in sleep: update of the 2007 AASM Manual for the
Scoring of Sleep and Associated Events. Deliberations of the Sleep
Apnea Definitions Task Force of the American Academy of Sleep
Medicine, Journal of Clinical Sleep Medicine, 8, 597–619.
Boulghassoul-Pietrzykowska, N., Franceschelli, J. and Still, C. (2013) New
medications for obesity management: changing the landscape of
obesity treatment, Current Opinion in Endocrinology, Diabetes, and
Obesity, 20, 407–411.
Campos-Rodriguez, F., Martinez-Garcia, M. A., Martinez, M. et al. (2013)
Association between obstructive sleep apnea and cancer incidence
5
Clinical review
in a large multicenter Spanish cohort, American Journal of Respiratory
and Critical Care Medicine, 187, 99–105.
Chami, H. A., Resnick, H. E., Quan, S. F. et al. (2011) Association of incident
cardiovascular disease with progression of sleep-disordered breathing, Circulation, 123, 1280–1286.
Chapman, J. L., Kempler, L., Chang, C. L. et al. (2013) Modafinil improves
daytime sleepiness in patients with mild to moderate obstructive
sleep apnoea not using standard treatments: a randomised placebo-controlled crossover trial, Thorax, 3, 274–279.
Chasens, E. R., Pack, A. I., Maislin, G. et al. (2005) Claustrophobia and
adherence to CPAP treatment, Western Journal of Nursing Research,
27, 307–321.
Chirinos, J. A., Gurubhagavatula, I., Teff, K. et al. (2014) CPAP, weight loss,
or both for obstructive sleep apnea, The New England Journal of
Medicine, 370, 2265–2275.
Curfman, G. D., Morrissey, S. and Drazen, J. M. (2010) Sibutramine–
another flawed diet pill, The New England Journal of Medicine, 363,
972–974.
Dixon, J. B., Schachter, L. M., O’brien, P. E. et al. (2012) Surgical vs conventional therapy for weight loss treatment of obstructive sleep apnea:
a randomized controlled trial, The Journal of American Medical
Association, 308, 1142–1149.
Elshaug, A. G., Moss, J. R., Hiller, J. E. et al. (2008) Upper airway surgery
should not be first line treatment for obstructive sleep apnoea in
adults, British Medical Journal, 336, 44–45.
EMA. (2011) Assessment report for modafinil containing medicinal
products. European Medicines Agency, accessed at: http://www.ema.
europa.eu/docs/en_GB/document_library/Referrals_document/
Modafinil_31/WC500105597.pdf (24 November 2014).
FDA. (2007) Provigil® (modafinil) tablets (C-IV) [online]. U.S Food Drug
Administration, accessed at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020717s020s013s018lbl.pdf (24 November
2014).
FDA. (2010) FDA Drug Safety Communication: FDA recommends
against the continued use of Meridia (sibutramine). FDA U.S Food
and Drug Administration, accessed at: http://www.fda.gov/Drugs/
DrugSafety/ucm228746.htm (24 November 2014).
Foster, G. D., Borradaile, K. E., Sanders, M. H. et al. (2009) A randomized
study on the effect of weight loss on obstructive sleep apnea among
obese patients with type 2 diabetes: the Sleep AHEAD study,
Archives of Internal Medicine, 169, 1619–1626.
Fritsch, K. M., Iseli, A., Russi, E. W. et al. (2001) Side effects of mandibular
advancement devices for sleep apnea treatment, American Journal
of Respiratory and Critical Care Medicine, 164, 813–818.
Gagnadoux, F., Fleury, B., Vielle, B. et al. (2009) Titrated mandibular
advancement versus positive airway pressure for sleep apnoea, The
European Respiratory Journal, 34, 914–920.
Giles, T. L., Lasserson, T. J., Smith, B. H. et al. (2006) Continuous positive
airways pressure for obstructive sleep apnoea in adults, Cochrane
Database of Systematic Reviews, 3, Cd001106.
6
Bioscience Horizons • Volume 7 2014
Gindre, L., Gagnadoux, F., Meslier, N. et al. (2008) Mandibular advancement for obstructive sleep apnea: dose effect on apnea, long-term
use and tolerance, Respiration, 76, 386–392.
Gotsopoulos, H., Kelly, J. J. and Cistulli, P. A. (2004) Oral appliance therapy reduces blood pressure in obstructive sleep apnea: a randomized, controlled trial, Sleep, 27, 934–941.
Gottlieb, D. J., Whitney, C. W., Bonekat, W. H. et al. (1999) Relation of
sleepiness to respiratory disturbance index: the Sleep Heart Health
Study, American Journal of Respiratory and Critical Care Medicine,
159, 502–507.
Guilleminault, C., Tilkian, A. and Dement, W. C. (1976) The sleep apnea
syndromes, Annual Review of Medicine, 27, 465–484.
Ha, S. C., Hirai, H. W. and Tsoi, K. K. (2014) Comparison of positional therapy versus continuous positive airway pressure in patients with
positional obstructive sleep apnea: a meta-analysis of randomized
trials, Sleep Medicine Reviews, 18, 19–24.
Halford, J. C., Harrold, J. A., Boyland, E. J. et al. (2007) Serotonergic drugs:
effects on appetite expression and use for the treatment of obesity,
Drugs, 67, 27–55.
Hammond, R. J., Gotsopoulos, H., Shen, G. et al. (2007) A follow-up study
of dental and skeletal changes associated with mandibular advancement splint use in obstructive sleep apnea, American Journal of
Orthodontics and Dentofacial Orthopedics, 132, 806–814.
Hedner, J., Grote, L. and Zou, D. (2008) Pharmacological treatment of
sleep apnea: current situation and future strategies, Sleep Medicine
Reviews, 12, 33–47.
Itzhaki, S., Dorchin, H., Clark, G. et al. (2007) The effects of 1-year treatment with a herbst mandibular advancement splint on obstructive
sleep apnea, oxidative stress, and endothelial function, Chest, 131,
740–749.
Johansson, K., Neovius, M., Lagerros, Y. T. et al. (2009) Effect of a very low
energy diet on moderate and severe obstructive sleep apnoea in
obese men: a randomised controlled trial, British Medical Journal, 339,
4609–4730.
Johns, M. W. (1991) A new method for measuring daytime sleepiness:
the Epworth sleepiness scale, Sleep, 14, 540–545.
Kartali, N., Daskalopoulou, E., Geleris, P. et al. (2014) The effect of continuous positive airway pressure therapy on blood pressure and
arterial stiffness in hypertensive patients with obstructive sleep
apnea, Sleep and Breathing, 18, 635–640.
Kushida, C. A., Morgenthaler, T. I., Littner, M. R. et al. (2006) Practice
parameters for the treatment of snoring and Obstructive Sleep
Apnea with oral appliances: an update for 2005, Sleep, 29, 240–243.
Lim, J., Lasserson Toby, J., Fleetham, J. et al. (2006) Oral appliances for
obstructive sleep apnoea. Cochrane Database of Systematic Reviews,
1, CD004435.
Mackay, S. G., Jefferson, N. and Marshall, N. S. (2013) Beyond uvulopalatopharyngoplasty for obstructive sleep apnoea: single surgeon
case series of contemporary airway reconstruction, The Journal of
Laryngology and Otology, 127, 1184–1189.
Bioscience Horizons • Volume 7 2014
Clinical review
Marin, J. M., Carrizo, S. J., Vicente, E. et al. (2005) Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea
with or without treatment with continuous positive airway pressure:
an observational study, Lancet, 365, 1046–1053.
Petri, N., Svanholt, P., Solow, B. et al. (2008) Mandibular advancement
appliance for obstructive sleep apnoea: results of a randomised placebo controlled trial using parallel group design, Journal of Sleep
Research, 17, 221–229.
Marklund, M., Sahlin, C., Stenlund, H. et al. (2001) Mandibular advancement device in patients with obstructive sleep apnea : long-term
effects on apnea and sleep, Chest, 120, 162–169.
Phillips, C. L., Grunstein, R. R., Darendeliler, M. A. et al. (2013) Health outcomes of continuous positive airway pressure versus oral appliance
treatment for obstructive sleep apnea: a randomized controlled
trial, American Journal of Respiratory and Critical Care Medicine, 187,
879–887.
Marklund, M., Verbraecken, J. and Randerath, W. (2012) Non-CPAP therapies in obstructive sleep apnoea: mandibular advancement device
therapy, The European Respiratory Journal, 39, 1241–1247.
Marshall, N. S., Barnes, M., Travier, N. et al. (2006) Continuous positive
airway pressure reduces daytime sleepiness in mild to moderate
obstructive sleep apnoea: a meta-analysis, Thorax, 61, 430–434.
Marshall, N. S., Wong, K. K., Cullen, S. R. et al. (2014) Sleep apnea and
20-year follow-up for all-cause mortality, stroke, and cancer incidence and mortality in the busselton health study cohort, Journal of
Clinical Sleep Medicine, 10, 355–362.
Martinez-Garcia, M. A., Capote, F., Campos-Rodriguez, F. et al. (2013)
Effect of CPAP on blood pressure in patients with obstructive sleep
apnea and resistant hypertension: the HIPARCO randomized clinical
trial, The Journal of American Medical Association, 310, 2407–2415.
Mason, M., Welsh, E. J. and Smith, I. (2013) Drug therapy for obstructive
sleep apnoea in adults, Cochrane Database of Systematic Reviews, 5,
Cd003002.
Phillips, C. L., Yee, B. J., Marshall, N. S. et al. (2011) Continuous positive
airway pressure reduces postprandial lipidemia in obstructive
sleep apnea: a randomized, placebo-controlled crossover trial,
American Journal of Respiratory and Critical Care Medicine, 184,
355–361.
Punjabi, N. M., Caffo, B. S., Goodwin, J. L. et al. (2009) Sleep-disordered
breathing and mortality: a prospective cohort study, PLoS Medicine,
6, e1000132.
Redline, S., Yenokyan, G., Gottlieb, D. J. et al. (2010) Obstructive sleep
apnea-hypopnea and incident stroke: the sleep heart health study,
American Journal of Respiratory and Critical Care Medicine, 182,
269–277.
Rucker, D., Padwal, R., Li, S. K. et al. (2007) Long term pharmacotherapy
for obesity and overweight: updated meta-analysis, British Medical
Journal, 335, 1194–1199.
Mccall, W. V., Harding, D. and O’Donovan, C. (2006) Correlates of depressive symptoms in patients with obstructive sleep apnea, Journal of
Clinical Sleep Medicine, 2, 424–426.
Schlosshan, D. and Elliott, M. W. (2004) Sleep. 3: clinical presentation and
diagnosis of the obstructive sleep apnoea hypopnoea syndrome,
Thorax, 59, 347–352.
Mitler, M. M., Dawson, A., Henriksen, S. J. et al. (1988) Bedtime ethanol
increases resistance of upper airways and produces sleep apneas in
asymptomatic snorers, Alcoholism, Clinical and Experimental Research,
12, 801–805.
Shneerson, J. and Wright, J. (2001) Lifestyle modification for obstructive
sleep apnoea, Cochrane Database of Systematic Reviews, 1,
CD002875.
Nieto, F. J., Peppard, P. E., Young, T. et al. (2012) Sleep-disordered breathing and cancer mortality, American Journal of Respiratory and Critical
Care Medicine, 186, 190–194.
O’Neil, P. M., Smith, S. R., Weissman, N. J. et al. (2012) Randomized placebocontrolled clinical trial of lorcaserin for weight loss in type 2 diabetes
mellitus: the BLOOM-DM study, Obesity (Silver Spring), 20, 1426–1436.
Oksenberg, A. and Gadoth, N. (2014) Are we missing a simple treatment
for most adult sleep apnea patients? The avoidance of the supine
sleep position, Journal of Sleep Research, 23, 204–210.
Peppard, P. E., Young, T., Barnet, J. H. et al. (2013) Increased prevalence
of sleep-disordered breathing in adults, American Journal of
Epidemiology, 177, 1006–1014.
Sullivan, C. E., Issa, F. G., Berthon-Jones, M. et al. (1981) Reversal of
obstructive sleep apnoea by continuous positive airway pressure
applied through the nares, Lancet, 1, 862–865.
Sundaram, S., Lim, J. and Lasserson Toby, J. (2005) Surgery for obstructive sleep apnoea in adults. Cochrane Database of Systematic
Reviews, 4, CD001004.
Sutherland, K. and Cistulli, P. (2011) Mandibular advancement splints for
the treatment of sleep apnea syndrome, Swiss Medical Weekly, 141,
w13276.
Sutherland, K., Vanderveken, O. M., Tsuda, H. et al. (2014) Oral appliance
treatment for obstructive sleep apnea: an update, Journal of Clinical
Sleep Medicine, 10, 215–227.
Peppard, P. E., Young, T., Palta, M. et al. (2000a) Longitudinal study of
moderate weight change and sleep-disordered breathing, The
Journal of American Medical Association, 284, 3015–3021.
Svendsen, M. and Tonstad, S. (2011) Orlistat after initial dietary/behavioural treatment: changes in body weight and dietary maintenance
in subjects with sleep related breathing disorders, Nutrition Journal,
10, 21.
Peppard, P. E., Young, T., Palta, M. et al. (2000b) Prospective study of the
association between sleep-disordered breathing and hypertension,
The New England Journal of Medicine, 342, 1378–1384.
Tregear, S., Reston, J., Schoelles, K. et al. (2009) Obstructive sleep apnea
and risk of motor vehicle crash: systematic review and meta-­
analysis, Journal of Clinical Sleep Medicine, 5, 573–581.
7
Clinical review
Trzepizur, W., Gagnadoux, F., Abraham, P. et al. (2009) Microvascular
endothelial function in obstructive sleep apnea: Impact of
­continuous positive airway pressure and mandibular advancement,
Sleep Medicine, 10, 746–752.
Tuomilehto, H., Seppa, J., Uusitupa, M. et al. (2013) Weight reduction and
increased physical activity to prevent the progression of obstructive
sleep apnea: a 4-year observational postintervention follow-up of
a randomized clinical trial. [corrected], The Journal of American
Medical Association Internal Medicine, 173, 929–930.
Tuomilehto, H. P. I., Seppä, J. M., Partinen, M. M. et al. (2009) Lifestyle
intervention with weight reduction, American Journal of Respiratory
and Critical Care Medicine, 179, 320–327.
Varghese, R., Adams, N. G., Slocumb, N. L. et al. (2012) Maxillomandibular
advancement in the management of obstructive sleep apnea,
International Journal of Otolaryngology, 2012, 373025.
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 disordered breathing patients, Journal of Clinical Sleep Medicine, 10,
517–522.
Wang, D., Yee, B. J. and Rowsell, L. (2014b) Sleep-disordered breathingrelated neurocognitive impairment, time to think beyond hypoxia
8
Bioscience Horizons • Volume 7 2014
and sleep fragmentation? Sleep and Breathing. doi:10.1007/s11325014-1013-x.
Weaver, T. E., Chasens, E. R. and Arora, S. (2009) Modafinil improves
functional outcomes in patients with residual excessive sleepiness
associated with CPAP treatment, Journal of Clinical Sleep Medicine,
5, 499–505.
Weaver, T. E. and Grunstein, R. R. (2008) Adherence to continuous positive airway pressure therapy, Proceedings of the American Thoracic
Society, 5, 173–178.
Winslow, D. H., Bowden, C. H., Didonato, K. P. et al. (2012) A randomized,
double-blind, placebo-controlled study of an oral, extendedrelease formulation of phentermine/topiramate for the treatment of
obstructive sleep apnea in obese adults, Sleep, 35, 1529–1539.
Yee, B. J., Phillips, C. L., Banerjee, D. et al. (2007) The effect of sibutramine-assisted weight loss in men with obstructive sleep apnoea,
International Journal of Obesity (London), 31, 161–168.
Young, T., Finn, L., Peppard, P. E. et al. (2008) Sleep disordered breathing
and mortality: eighteen-year follow-up of the Wisconsin sleep
cohort, Sleep, 31, 1071–1078.
Zhang, Q., Wang, D., Qin, W. et al. (2013) Altered resting-state brain activity in obstructive sleep apnea, Sleep, 36, 651–659B.