Optimal Treatment of Obstructive Sleep Apnea and Excessive Sleepiness
Russell Rosenberg · Paul Doghramji
Russell Rosenberg ( )Atlanta School of Sleep Medicine and Technology, 1100 Johnson Ferry Road, Suite 580, Atlanta, GA 30342, USA. Email: [email protected]
Paul DoghramjiCollegeville Family Practice, Collegeville, PA, USA
Introduction: Collapsibility of the upper air-way in obstructive sleep apnea (OSA) causes repeated arousals from sleep, decreased oxy-gen saturation of the blood, and excessive sleepiness (ES). Patients with OSA are at increased risk of cardiovascular and cerebro-vascular disease, and experience occupational and vehicular accidents more frequently than the general population. Furthermore, the life expectancy of patients with untreated OSA is significantly reduced. Methods: A MEDLINE search of articles published between 2003 and 2008 was conducted using the search terms: obstructive sleep apnea [ti/ab] AND treatment; obstructive sleep apnoea [ti/ab] AND treatment; and excessive sleepiness [ti/ab] AND treatment. Searches were limited to
articles in English; clinical trials; meta-analy-ses; practice guidelines; randomized, control-led trials; and reviews. Results: Continuous positive airway pressure (CPAP) is the refer-ence-standard treatment for patients with OSA. CPAP addresses the symptoms of OSA and reduces the risk of heart disease and depression associated with this sleep disorder. However, the efficacy of CPAP is contingent on patient adherence, and ≥4 hours of ther-apy per night are required for patients with OSA to experience significant clinical ben-efits. However, reports of nonadherence to CPAP therapy range from 29% to 83%. Other therapies are available for patients who refuse or cannot adhere to CPAP treatment, includ-ing dental devices and surgery, but these treatments are generally considered to be less efficacious. A significant number of patients continue to experience residual ES despite CPAP treatment. Pharmacologic therapies, eg, modafinil and armodafinil, may be of use in patients with OSA to improve tolerance with CPAP or to address residual ES. Conclusion: There are a variety of treatments available for patients with OSA. Successful treatment involves encouraging patient compliance with CPAP or oral appliances. Primary-care
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physicians play a crucial role in recognizing this disorder and ensuring the best possible outcome through support and education.
Patients with obstructive sleep apnea (OSA) experience repeated complete and par-tial blockages of the upper airway during sleep, referred to as apneas and hypopneas, respectively. The severity of OSA is meas-ured using the apnea-hypopnea index (AHI), which assesses the total number of apneas and hypopneas per hour of sleep.1 Guidelines produced by the Institute for Clinical Systems Improvement (ICSI) state that diagnosis of mild OSA requires an AHI score of 5-15, whereas AHI scores of 16-30 and >30 indicate moderate and severe OSA, respectively.1 OSA severity is also determined by the patient’s degree of oxygen desaturation, which can be measured by oximetry, and reflects the degree of hypoxemia (reduction in blood oxy-gen levels) caused by interrupted breathing.1 Excessive sleepiness (ES) is a primary symp-tom of OSA,2 and the ICSI recommends that ES should also be evaluated during the diag-nosis of OSA in order to fully quantify the severity of this sleep disorder.1
Comorbidities are frequently present in patients with OSA, including hyperten-sion, diabetes mellitus, coronary artery dis-ease, stroke, gastroesophageal reflux disorder, depression, obesity, metabolic syndrome, gout, and glaucoma.3,4 Consequences of OSA, such as ES and impaired cognition, contribute to higher rates of motor vehicle crashes and work-related accidents in this population.5,6
Moreover, respiratory instability and hypox-emia resulting from OSA can cause increased perioperative morbidity and mortality in patients with this sleep disorder, leading the American Society of Anesthesiologists to rec-ommend careful airway management in surgi-cal patients with OSA.7 Furthermore, patients’ relationships may be affected because of OSA, as a patient’s bed partner can also experience ES and reduced quality of life due to disturbed sleep; OSA is also associated with erectile dysfunction.8-10
This paper reviews the efficacy and appli-cability of the current therapeutic options for OSA and ES, and also highlights the essential role of the primary care physician in support-ing and ensuring treatment compliance.
MAtErIALs AND MEtHODs
In order to capture the most recent devel-opments in the treatment of OSA and ES, a MEDLINE search of articles published between 2003 and 2008 was conducted on July 12, 2008 using the search terms: obstructive sleep apnea [ti/ab] AND treatment; obstructive sleep apnoea [ti/ab] AND treatment; and excessive sleepiness [ti/ab] AND treatment. Searches were limited to articles in English; clinical tri-als; meta-analyses; practice guidelines; rand-omized, controlled trials; and reviews. Search limits also excluded patients aged ≤19 years. In total, 220 articles were identified; articles concerning other sleep disorders, other forms of apnea, or case studies were excluded. In addition, a number of reviews were not cited in order to avoid repetition of information. The reference lists of articles thus identified were searched manually to find additional articles of interest. Publications cited included studies and reviews concerned with the prev-alence of OSA, its recognition and manage-
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ment within primary care, and the treatment of OSA in general. In total, 119 articles were cited with particular emphasis placed on the treatment of OSA and ES over the last 5 years.
rEsULts
Prevalence of OSA
OSA of at least mild severity (AHI score ≥5) affects 24% of men and 9% of women.11
However, the prevalence of OSA in the pri-mary-care population is higher (32%),12 as patients with OSA may experience comorbid-ities and symptoms that instigate patients to seek medical attention. In the USA, 22.6% of women with OSA also have ES (2% of women in the general population), while 15.5% of men with OSA report experiencing ES (4% of men in the general population).11
Although OSA is more common in men than in women, the rates of OSA in men and postmenopausal women are similar: 3.9% and 2.7% of men and postmenopausal women, respectively, have an AHI score ≥10 accom-panied by daytime symptoms versus 0.6% of premenopausal women.13 Intriguingly, women with OSA have a 3.4-times greater risk of mor-tality than their male peers (P=0.003), an observation that has been attributed to higher rates of comorbidity in female patients.14
There is a disparity between the estimated prevalence of OSA and ES and the number of patients who have their conditions rec-ognized and treated. Young and colleagues15 reported that at least 80% of cases of moder-ate and severe OSA in adults aged 30-60 years in the general population go undiagnosed, whereas a more recent study showed that the true prevalence of OSA and associated ES may be three-times higher than the number of
patients diagnosed with this sleep disorder.16
As the majority of patients with OSA are not recognized or treated, their risk of morbidity and mortality is greatly increased.
Women with OSA are particularly under- recognized, which may be due to masking of OSA symptoms by comorbidities, resulting in a misdiagnosis.17 For example, women with OSA are significantly more likely than men to be severely obese (P<0.001), or to have fibromyalgia (P<0.001), migraine (P<0.001), depression (P=0.010), and irritable bowel syndrome (P=0.010). A number of these con-ditions have symptoms similar to those of OSA17 and added vigilance for OSA may be appropriate in women presenting with any or a combination of these conditions.
Recognition of OSA and ES in the Primary-Care Setting
Patients rarely present in the primary-care setting with an overt complaint of OSA; rather the physician may be alerted to a patient’s OSA by the existence of a condition that is frequently comorbid with OSA (eg, hyperten-sion, diabetes, or obesity) or the presence of risk factors for OSA.3 These risk factors include male gender, increasing age, craniofacial vari-ation/pharyngeal crowding/nasal obstruction, large neck size, alcohol and sedative use, and smoking.18 If comorbidities or risk factors are present, it is recommended that the patient is asked whether they feel sleepy or drowsy during normal waking hours, have involun-tary sleep episodes, have received complaints from their bed partner regarding episodes of snoring, or have a sore throat or nasal dryness as a result of snoring.18 An algorithm for the recognition and management of OSA and ES in primary care is presented in Figure 1.
ES (also referred to as pathologic sleepi-
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ness, inappropriate drowsiness, or sleepiness at unsuitable times) can have multiple causes other than OSA, including insufficient sleep (due to self-imposed restricted sleep time or poor sleep habits), interrupted sleep (as expe-rienced by patients with OSA), neurologic disorders (eg, narcolepsy, periodic limb move-ment disorder, stroke, or multiple sclerosis), timing issues (eg, shift-work sleep disorder or jet lag), and treatment-emergent effects from various medications.18 ES is independ-ently associated with significant morbidity and mortality.19,20 Patients describe ES using a variety of terms that may further confound diagnosis and true estimates of this trouble-some symptom.21 Patients rarely complain of “excessive sleepiness” or “drowsiness”; instead, patients are more likely to use terms such as “tired,” “fatigued,” or “no energy.” Moreover, when faced with these complaints, most clinicians will think of depression or metabolic abnormalities (eg, thyroid disease)
and will tend not to consider sleep problems. AHI score, depression, lack of exercise, and metabolic abnormalities are independent pre-dictors of ES.22 Furthermore, ES is associated with insulin resistance and may be useful as a marker for patients with OSA who are at risk of developing metabolic syndrome.23
Assessing ES in all clinic patients, in addi-tion to those undergoing therapy for OSA, may be valuable and can guide treatment or gauge treatment success. Subjective measures of ES employed primarily by sleep research-ers and specialists, and by some primary-care physicians, include the Karolinska Sleepiness Scale and the Stanford Sleepiness Scale.24,25
These measures allow assessment of sleepi-ness only at the moment of application, instead of using a recall period of a number of weeks.26 In the primary-care setting, the Epworth Sleepiness Scale (ESS) is the most frequently used questionnaire-based measure of ES (Appendix),27 consisting of a subjective,
Figure 1. Suggested algorithm for the recognition and management of patients with OSA and ES in the primary care setting. CPAP=continuous positive airway pressure; ES=excessive sleepiness; ESS=Epworth Sleepiness Scale; OSA=obstructive sleep apnea.
Patients presenting with diabetes mellitus, hypertension, coronary artery disease,
gastroesophageal re�ux disorder, depression, obesity, metabolic syndrome, gout, or glaucoma should be asking whether they are experiencing
ES or snoring, and tested with the ESS
Patients presenting with risk factors for OSA such as: male sex, postmenopausal status, large
increasing age, smoking, alcohol use, or sedative use should be asked whether they are experiencing
ES or snoring, and tested with the ESS
Patients who experience ES and/or snoring should be referred to a sleep laboratory
If OSA is con�rmed, a�er the �rst month of treatment with CPAP/dental devices the patient should return to their primary care physician for assessment with the ESS to measure possible residual ES
If residual ES is identi�ed and other possible causes are excluded (eg, poor compliance or other sleep disorders), moda�nil/armoda�nil may be suggested to the patients as an optional adjunct to treatment with CPAP/dental devices
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eight-item, self-reported questionnaire that is simple to use and takes less than 2 minutes to complete. Not only can the ESS confirm pathologic sleepiness, but it can also be used to validate post-treatment improvement in patients with OSA. An ESS score of ≥10 is con-sidered to be abnormal.27 However, the ESS does not capture variations that may occur in situations at different times of the day or over different periods of time.26 For exam-ple, one of the questions evaluates sleepi-ness when “sitting and reading.” Performing this activity for 10 minutes in the morning is less likely to result in the respondent fall-ing asleep than if they were reading for an hour in the late evening; the ESS does not assess information regarding ES in this man-ner. This limitation may account for the poor correlation between ESS scores and scores on objective sleep laboratory measures of ES such as the Multiple Sleep Latency Test (MSLT) and the Maintenance of Wakefulness Test (MWT).28-30 The MSLT consists of a series of five 20-minute nap opportunities at 2-hour intervals in a darkened room and is typically used to assess narcolepsy.31 The MWT is con-ducted in a dimly-lit room and patients are asked to stay awake in the absence of stim-ulation.31 Both tests produce a measure of a patient’s mean sleep latency and scores are compared against normative data to deter-mine the degree of pathology.31
Current Treatment Options for OSA and ES
There are a number of treatments cur-rently available for OSA and associated ES. Treatments can be used in combination, and use of these therapies can be tailored based on the severity of the sleep disorder and patient preference in order to achieve the best possi-ble outcomes.
Behavioral InterventionsMild OSA may be improved through weight
loss (in obese patients), avoidance of alco-hol and sedatives, and by sleeping in a more upright or lateral position.32-34 Patients with OSA who sleep on their back (the supine posi-tion) often have prolonged respiratory events, greater oxygen desaturation, longer arousals from sleep, and louder snoring than those who sleep laterally.35 When sleep posture was altered to a more lateral position through the use of pillows or body belts, changes occurred in the patients’ lung volume, neuromuscular activity, and airway size, so as to support their airway and reduce collapsibility.36 However, long-term, randomized trials are lacking for this intervention, and a number of small stud-ies have reported that AHI scores are only par-tially reduced by lateral sleep posture.36
Nasal dilators do not appear to alleviate the symptoms or decrease the severity of OSA.37,38 In a study of 1106 patients with OSA, physical exercise was reported to significantly improve ES in obese men with OSA and severe ES (P<0.05).22 Although it may seem attractive to use these simple interventions to address OSA, the variable results described here, par-ticularly in terms of reducing respiratory events, make it difficult to recommend these therapies as anything other than an adjunct to more widely accepted treatments.
(CPAP), applied by nasal mask or full face mask, is the reference-standard treatment for OSA.39,40 CPAP therapy maintains upper airway patency during sleep by acting as a pneumatic splint and opening the airways, thus abolishing apnea, hypopnea, and snor-ing, and improving sleep quality. Bilevel positive airway pressure (BPAP) treatment is
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an alternative device that allows independ-ent adjustment of inspiratory and expiratory pressures.41 This device may be appropriate for patients who tolerate CPAP poorly, such as patients who require high pressures or those with comorbid breathing disorders, such as chronic obstructive pulmonary disease, hyperventilation syndrome, or awake hyper-capnia.1,42,43 Variable positive airway pressure and autotitrating positive airway pressure (APAP) devices are also available and are use-ful for patients whose condition may change on a nightly basis (eg, due to use of sedative medications or alcohol).44
Many of the improvements seen in the symptoms of OSA that are attributed to CPAP treatment may be due to a reversal in systemic inflammation and oxidative stress. These pathologic changes are thought to occur as a result of hypoxemia in patients with OSA, and may account for a number of its comorbidities and clinical consequences.45-47 Nitrotyrosine (a marker of oxidative stress), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS)—both markers of inflammation— were expressed at signifi-cantly higher levels in patients with OSA com-pared with control participants who did not have this sleep disorder (P<0.001, P<0.001, and P=0.040, respectively).47 Furthermore, expression of precursors of the potent vasodi-lator nitric oxide was significantly reduced (P<0.001) in patients with OSA compared with control participants.47 In the absence of appropriate nitric oxide expression, vaso-constriction due to expression of hypoxemia-induced endothelin can persist unchallenged, resulting in hypertensive effects and damage to the blood vessels.48 CPAP treatment for ≥4 hours/day significantly increased the expression of nitric oxide precursors above baseline values in patients with OSA (P<0.001),
while levels of nitrotyrosine, COX-2, and iNOS decreased significantly (all P<0.001).47
Efficacy of CPAPThe clinical benefits of CPAP are manifold
(Table 1). A retrospective case review that defined clinical success as a reduction of AHI score to ≤5 has reported that CPAP therapy resulted in nor-malization in 72% of patients with OSA.78
Compliance Issues with CPAPThe efficacy of CPAP is dictated by patient
compliance. Many patients find CPAP dif-ficult to use; embarrassment, physical dis-comfort, and psychological factors, such as claustrophobia, are commonly reported as reasons for nonadherence and discontinua-tion.79 It is important to encourage patients to be compliant with CPAP treatment, as greater use of this device has been shown to be associated with greater clinical benefits. For example, patients who used CPAP therapy for ≥4 hours/night experienced significant reduc-tions in: systolic and diastolic blood pres-sure (P=0.001 and P=0.006, respectively); global cardiovascular disease risk (P=0.001); total cholesterol (P=0.002); insulin resist-ance (P=0.031); oxidative stress (P=0.004); and inflammation (P=0.037).44,45 Patients with OSA who used CPAP therapy for <4 hours/night did not experience sig-nificant improvements in any of these parameters.46,47
Claustrophobia associated with CPAP use can be treated with behavioral therapy. A recent study has examined the efficacy of a graded in-vivo exposure therapy for enhanc-ing CPAP adherence using a retrospective case-series design.80 Objective CPAP adherence data were obtained on clinical patients who attended one or more sessions of exposure therapy with a behavioral sleep psychologist.
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After exposure therapy, CPAP use increased by a mean of 2.6 hours/night (P=0.002) and CPAP was used more often (2.4 nights more each week; P=0.007) compared with before treatment.80
Many studies assume that patients will require a minimum of 4 hours/night of CPAP therapy to experience any benefit and, there-fore, use 4 hours/night of CPAP therapy as a threshold for patient adherence.79 In studies that define adherence in this way, 29%-83% of patients have been reported to be nonadher-ent.79 It has been reported that patients with severe OSA (AHI score of 56.6±27.7; range 27-144) may have greater compliance with CPAP treatment than those with more moder-ate sleep-disordered breathing.81 Furthermore,
patients with severe OSA and associated ES are more likely to be persistent with CPAP over the long term.82 Intriguingly, a recent study has reported that women are less likely to persist with CPAP treatment than men, lead-ing the study investigators to suggest that a failure to continue with CPAP therapy may be partially responsible for the higher rate of mortality in women with OSA.14 Women tend to have less severe OSA than men,14 and per-haps, therefore, do not feel the same impera-tive to remain on treatment as male patients who have a more debilitating form of this sleep disorder.
Patients with OSA who have high expec-tations of the outcomes of CPAP therapy are more adherent to their treatment regimen
Table 1. Bene�ts of various therapies for obstructive sleep apnea.Treatment Bene�tsContinuous positive Reduces: AHI scores; heart rate; blood pressure; excessive sleepiness; night-time sympathetic airway pressure (CPAP) nervous system tone; arterial sti�ness; in�ammation and oxidative stress of the vascular endothelium; depression and suicidal ideation; global cardiovascular disease risk45-47,49-55
Improves: vitality; physical, mental, and social functioning domains of quality-of-life instruments in patients with OSA and their bed partners; vasodilation; insulin sensitivity; barore�ex sensitivity; le� ventricular ejection fraction10,46,56-60
SurgeryUPPP and septoplasty Reduces: levels of the in�ammatory cytokines tumor necrosis factor-α and interleukin-667
UPPP and tongue base Reduces: AHI scores; excessive sleepiness; snoring68
reductionNasal surgery Reduces: excessive sleepiness; snoring;69,70 AHI scores70
Improves: general quality of life; oxygen saturation69,70
Maxillomandibular Improves: oxygen saturation; general productivity; social outcome; activity level; vigilance; advancement intimacy and sex; total score on the Functional Outcomes of Sleep Questionnaire71
than those who are skeptical about its effi-cacy.83 Therefore, educating patients about the numerous benefits of CPAP therapy and also about exactly what to expect when they begin using the device may improve patient compliance. Furthermore, compliance may be improved by switching to a different type of positive airway pressure device. Patients with severe OSA used APAP therapy for a signif-icantly greater number of hours than CPAP when presented with both devices in a rand-omized cross-over study (P<0.04).84 However, although both positive airway pressure devices improved OSA symptoms equally, paradoxically, patients preferred CPAP over APAP when asked to consciously choose between the two devices.84 In a double-blind, randomized study of BPAP and CPAP use in patients persistently noncompliant with OSA therapy, 49% and 28% of patients, respec-tively, achieved compliance (≥4 hours/night of therapy).85
A number of interventions can be sug-gested to patients that may increase their compliance with positive airway pressure devices. For example, adjustments to the fit of the positive airway pressure mask, heated humidification, topical nasal spray, additional education concerning OSA, and support from the prescribing physician have all been found to improve compliance with CPAP therapy in some patients with OSA.85 A 2-week study of 10 male patients with OSA and their wives, reported that adherence to CPAP therapy was improved when patients shared a bed with their partner compared with nights when they slept alone.86 Furthermore, significant improvements in quality of life and ES have been reported by the bed partners of patients with OSA after the initiation of treatment with CPAP (P<0.05 and P<0.02, respectively).8,10
Recounting these findings may provide the
motivation for couples to work together to maintain compliance with CPAP and, as a consequence, improve clinical outcomes.
Follow-up contact between primary-care physicians and patients receiving treatment for OSA is essential and allows assessment of adherence to CPAP therapy, evaluation of its correct use, and any requirement for patient education regarding their device. Addressing patient problems with CPAP therapy, such as discomfort or issues with the supplier of the machine, is also important. Persistence and resolution of symptoms, particularly ES, can also be carefully monitored at follow-up visits.
Tolerability and Adverse Effects of CPAPTo date, few negative effects have been
reported for CPAP therapy. Nasal dryness is common in patients with OSA treated with CPAP, and can be addressed by use of heated humidification in the bedroom or titration of the device to avoid leakage of air from the mouth.79
CPAP therapy has been shown to signifi-cantly increase overnight intraocular pres-sure above pretreatment levels in patients with OSA (P<0.05).87 Intraocular pressure and cardiovascular disease are major risk fac-tors for the development of glaucoma.88 The prevalence of glaucoma is high in patients with OSA (7.2% vs. 2% in the general pop-ulation) and OSA occurs in 50% of patients with glaucoma.4,89 The observation that glau-coma is common in patients with OSA is per-haps unsurprising considering the high rates of cardiovascular comorbidity in this patient population.90 Furthermore, abnormally high 24-hour fluctuations in intraocular pressure have been reported in patients with OSA even before the initiation of CPAP.87 Therefore, it may be judicious to assess the intraocular
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pressure of patients with OSA, particularly if they are being treated with CPAP.87 If any such issues are detected, topical therapy should be initiated to lower intraocular pressure; CPAP use should be maintained so that patients can continue to experience the clinical benefits associated with this treatment modality.87
Dental DevicesOral appliances are currently recom-
mended by the American Academy of Sleep Medicine (AASM) for the treatment of mild to moderate OSA in patients who prefer them to CPAP therapy or who do not respond to CPAP therapy.91 Dental devices may also be useful as a back-up treatment option for patients on vacation or in case of CPAP machine breakdown. Dentists with training in sleep medicine and oral appliance ther-apy can work alongside primary-care physi-cians to fit and monitor dental devices. The American Academy of Dental Sleep Medicine web site has a useful “find a dentist” applica-tion to assist in locating dental sleep special-ists (www.aadsm.org).
Oral appliances are generally not consid-ered suitable in patients with full dentures or in those with <6 teeth in each mandibu-lar arch.66 Available oral appliances include: mandibular repositioning or advancement devices; tongue repositioning or retain-ing devices; soft palate lifters; tongue train-ers; and combined CPAP and oral appliance devices.92 These devices all reposition the jaw or tongue to enlarge the airway during sleep.
Efficacy of Dental DevicesTreatment of OSA with dental devices is
generally viewed as being less efficacious than treatment with CPAP.66,93-95 Current evi-dence suggests that oral devices can improve apnea, ES, snoring, oxygen saturation, and
morning headache, and may improve blood pressure (Table 1).61,64,65 However, “success-ful” treatment with oral appliances has been defined in a variety of ways: from liberal end-points (an improvement of ≥50% from base-line AHI score) to stricter criteria that indicate the complete cessation of OSA (reduction in AHI score to ≤5).66 When the efficacy of oral appliance therapy was assessed in a large sys-tematic review, 42% of patients experienced normalization of their OSA as defined by a reduction in AHI score to ≤5.66 Success rates with oral appliances were better in patients with mild OSA.66 Oral appliances have been demonstrated to reduce AHI scores to ≤5 in a greater proportion of patients compared with upper airway surgery for OSA.96
Compliance with Dental DevicesOral appliances may provide an alterna-
tive for patients with OSA who are unable or unwilling to use CPAP therapy.65,97 Patient preference for oral appliances is often greater than for CPAP devices due to ease of use and more rapid acclimatization.65,97 In turn, greater patient preference aids compliance with den-tal devices, which have been reported to be used on 77% of nights after 1 year of treat-ment in an evidence-based review performed on behalf of the AASM.66 However, compli-ance with oral appliance therapy has been shown to decline with duration of use, drop-ping from 82% at 1 year to 62% at 4 years of follow-up in a study of 32 male patients with OSA.98
Tolerability of Dental DevicesAdverse effects associated with the use of
oral appliances include excessive salivation, gagging, dryness of the tongue and throat, dental malocclusion, pain in the teeth and jaw, insomnia, and, in extreme cases, dislo-
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cation of the jaw.63 The frequency of adverse effects differs widely between studies (a sys-tematic review has reported adverse effects in 6%-86% of patients),66 probably reflect-ing variations in the types of devices avail-able and also in the fit of the appliance to each patient. Frequent follow-up visits with a dentist practiced in fitting these oral appli-ances is required at 2 weeks, 1 month, and every 6 months after first use in order to ensure that the apparatus still fits correctly and that adverse effects are not affecting compliance.92
SurgeryA variety of surgical techniques have been
used to treat patients with OSA; however, use of surgery for this condition remains somewhat controversial and is associated with limited and unpredictable efficacy that may dimin-ish in the long term.78,99,100 Therefore, surgery is not recommended for general patients with OSA, but rather is most likely to be appropriate in patients with moderate or severe OSA who are intolerant of CPAP or have severe comor-bidities or craniofacial abnormalities.100
Surgical techniques employed to treat OSA include direct enlargement of the upper air-way; modification of the soft tissue or skeletal anatomy of the throat or jaw (eg, uvulopalat-opharyngoplasty, which trims the pharyn-geal pillars and parts of the uvula and palate to reduce airway collapsibility); and trache-otomy to bypass the pharynx.100 In cases of severe OSA, the obstruction may be related to enlargement of the tongue, and a number of surgeries are available to reduce the bulk of the tongue base or increase the capacity of the oropharynx to reduce airway collapsibil-ity during sleep.101 In addition, nasal recon-struction may be used in some patients with OSA to improve breathing and optimize nasal
CPAP use.101 Table 1 presents the benefits of a number of these surgical interventions.
Efficacy and Variability of Surgery for OSAElshaug and colleagues78 recently reported
the results of a particularly insightful, multi-center, retrospective study of surgery for OSA, performed in Australia. These investigators reported considerable procedural variability in the operations performed, with 41 differ-ing combinations of surgery recorded for the 94 patients studied. This finding indicates a clear lack of consensus as to the most appro-priate procedures for patients with OSA.78 Furthermore, the efficacy of these procedures was found to be poor when assessed using clinically important endpoints. The success of surgery has historically been reported in terms of ≥50% reduction in AHI score from baseline or to a score of ≤20.102 It appears question-able to declare surgery as successful if mod-erate OSA (an AHI score of 16-30)1 persists in postoperative patients. When stringent suc-cess criteria were applied to the surgical cases reviewed in the study by Elshaug and others,78 only 13% of the procedures were classified as curative (postoperative AHI of ≤5).
Adverse Effects of Surgery for OSAAdverse effects associated with surgery for
OSA vary depending on the specific surgical technique used, but can include postoperative bleeding, voice change, infection, airway edema, nerve injury, and malocclusion of the teeth.101 Furthermore, patients who undergo surgery for OSA or snoring are often dissatisfied with the outcome when surveyed postoperatively.103,104 A recent study of soft palate procedures reported that, with hindsight, 47% of patients would not have had surgery.103 In addition, 76% of patients in the same study experienced moderate or severe postoperative pain.103
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PharmacotherapyAntidepressants for the Treatment of OSAThe use of selective serotonin reuptake
inhibitors (SSRIs), such as paroxetine and fluoxetine, in an attempt to enhance sero-tonergic transmission and so improve upper airway patency and aid nocturnal breathing in patients with OSA, has been assessed in a number of studies.105-107 Significant improve-ments in OSA have not yet been demon-strated with SSRIs, and they can have adverse effects for patients.105,107 The efficacy of mir-tazapine, a noradrenergic and selective sero-tonergic antidepressant, has been assessed for the treatment of OSA. No measurement of OSA severity was improved by mirtazapine in either of two randomized, placebo-controlled trials.108 Furthermore, patients receiving the active drug reported greater weight gain than patients in the placebo group;108 this finding is particularly worrying as weight gain has been shown to exacerbate OSA in some patients.109 For these reasons, mirtazapine is not recom-mended for the treatment of OSA. In addi-tion, AASM practice guidelines and a recent Cochrane systematic review have concluded that there is currently insufficient evidence to recommend any pharmacologic agent for the treatment of OSA.110,111
Sedatives as an Adjunct to CPAP UseIn general, patients with OSA should avoid
the use of sedatives, as these drugs may relax the throat and worsen airway obstruction and snoring.112 However, some patients may benefit from initial use of a short-acting hyp-notic to improve adjustment to CPAP. A pilot study of 22 patients with OSA indicated that the sedative eszopiclone did not increase the number of apneic events in patients with AHI scores of 10-40 and may improve sleep main-tenance and efficiency.112
Wakefulness-Promoting AgentsDespite treatment for OSA, some patients
continue to experience ES. The proportion of patients with residual ES after adequate use of a CPAP device is estimated to be 22.2% or 52.2% when measured by subjective or objec-tive means, respectively.113 Residual ES is most commonly ascribed to poor patient compli-ance;114,115 however, residual ES has also been reported in patients who demonstrate good compliance, indicating that other mecha-nisms may be responsible for persistent ES in this group.113 Alternative explanations for residual ES include the presence of persistent arousals and respiratory events due to inade-quate CPAP pressure or permanent alteration by OSA of patients’ sleep-promoting mecha-nisms or wakefulness drive.113 Interestingly, a recent study has observed abnormal findings in the frontal area of the brain of patients with OSA and residual ES.116 It may be that some patients experience irreversible brain damage due to nocturnal hypoxemia, which leads to ES that cannot be addressed by CPAP.116
Despite demonstrating similar compliance (but lower persistence) with CPAP therapy to that of male patients, women with OSA have been reported to derive significantly less ben-efit in terms of reductions in ESS score during treatment with CPAP (P<0.001).14 It would be informative to perform a more detailed study regarding gender differences in the preva-lence of residual ES.
In patients compliant with therapy for OSA who experience residual ES, adjunctive phar-macologic therapy is a valuable treatment option.117 The wakefulness-promoting agents, modafinil and armodafinil, are approved in the USA for the treatment of residual ES as adjunctive therapies to CPAP or other inter-ventions for OSA, although armodafinil is not yet commercially available. Both agents have
306 Adv Ther (2009) 26(3):295-312.
been shown to significantly improve wake-fulness in this patient population in several double-blind, randomized, placebo-control-led studies (Table 1).72,73,75,76 In these studies, both agents were well tolerated, with head-ache, nausea, and dizziness being the most commonly reported adverse events. Although their mechanism of action has not been fully elucidated, it is thought that modafinil and armodafinil may promote arousal by increas-ing electrical coupling at gap junctions.118
Alternatively, these agents may act via acti-vation of hypocretin-producing neurons in the brain; hypocretins are neuropeptides that are thought to be responsible for preventing inappropriate changes in consciousness.119 It is essential that patients are encouraged to remain compliant with their OSA treatment while in receipt of adjunctive drug therapy for residual ES, because armodafinil and modafinil do not address OSA and hence do not resolve other consequences of this sleep disorder, such as cardiovascular/cerebrovascu-lar problems.73
cONcLUsION
Successful treatment of OSA and associ-ated ES involves encouraging patient com-pliance with CPAP or oral appliances via a variety of simple interventions and patient support. Lifestyle changes, such as weight loss, increased exercise, and smoking cessa-tion, may also be helpful in improving mild symptoms, but do not take the place of active treatments in the majority of patients with OSA. Surgical intervention may be warranted in some patients, but should be considered on a case-by-case basis. Patients with OSA treated with CPAP may experience residual ES, which can impact on their quality of life and daily functioning. Such patients may
require adjunctive pharmacologic treatment, but should be encouraged to remain adherent to CPAP in order to address the long-term car-diovascular effects of OSA.
Recent reviews have highlighted the com-plexity inherent in comparing the efficacy of treatment modalities for OSA because of the differing definitions of clinical success. Applying a universal definition of what con-stitutes a successful treatment for OSA would assist greatly in assessing which therapies pro-vide patients with the greatest benefits. With this in mind, it seems appropriate to apply the most stringent criteria available, namely normalization of breathing to give an AHI score of ≤5 as well as normalization of day-time alertness. Treatments that claim to be effective using other measures of clinical suc-cess should be viewed with skepticism.
There are a variety of treatments available for patients with OSA, and primary-care phy-sicians play a crucial role in recognizing this sleep disorder and ensuring the best possible outcomes for their patients through support and education. In this way, family-care physi-cians maintain an essential overview of their patients’ well-being and progress throughout the necessary interactions with other clini-cians involved in the treatment of OSA. With this in mind, we recommend the use of the algorithm shown in Figure 1 to facilitate the most appropriate and efficient treatment of patients with OSA.
AcKNOWLEDGMENts
Editorial support was provided by Jane Bryant of Anthemis Consulting Ltd. and was funded by Cephalon Inc., Frazer, PA, USA, who provided a medical accuracy review. The authors were not compensated and retained full editorial control over the content of
Adv Ther (2009) 26(3):295-312. 307
the paper. R.R. has received research fund-ing from Cephalon Inc., Pfizer Inc., Sanofi-Aventis, Respironics, Neurogen, Vanda Pharmaceuticals, Merck, and GlaxoSmithKline. P.D. has served on the speakers’ bureau of Cephalon Inc., Takeda Pharmaceuticals, Sanofi-Aventis, and Sepracor Inc.
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APPENDIX
The Epworth Sleepiness Scale (Reprinted with permission from the American Academy of Sleep Medicine.27)
How likely are you to doze off or fall asleep in the following situations, in contrast to feeling just tired? This refers to your usual way of life in recent times. Even if you have not done some of these things recently try to work out how they would have affected you.
Use the following scale to choose the most appropriate number for each situation:0 = no chance of dozing1 = slight chance of dozing2 = moderate chance of dozing3 = high chance of dozing
Situation Chance of dozing (complete using responses above)
Sitting and reading
Watching TV
Sitting inactive in a public place such as a meeting
As a passenger in a car for an hour without a break
Lying down to rest in the afternoon when circumstances permit
Sitting and talking with someone
Sitting quietly after a lunch without alcohol
In a car, while stopped for a few minutes in traffic
Total score
*System organ class and individual AE occurring in ≥5% of patients in either group.AE=adverse events; HCTZ=hydrochlorothiazide.
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