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Pharmacologic therapy for sleep-related breathing disorders Expert Rev. Clin. Pharmacol. 1(3), 441–455 (2008)

Jonathan RL Schwartz†, Rod J Hughes and Tom Roth †

Author for correspondence 4200 S. Douglas, Suite 313, Oklahoma City, OK 73109, USA Tel.: +1 405 636 1111 [email protected]

Sleep-related breathing disorders (SRBDs) are characterized by disruptions in normal breathing patterns, typically caused by increased upper airway resistance or diminished ventilatory drive. SRBDs are often accompanied by impairment in sleep continuity and wakefulness. The full spectrum of features associated with SRBD syndromes can be divided into three components, each of which can be a target for pharmacological intervention: the sleep-breathing event and its immediate physiological consequences; the adverse effects of these events on sleep continuity; and impairment in daytime waking function. A number of pharmacologic agents have been studied for their ability to reduce upper airway resistance or increase ventilatory drive. Other medications have been tested for their ability to treat one or more of the symptoms of sleep or wakefulness in SRBD patients. The purpose of this article is to provide a review of the status of research related to the pharmacologic treatment of SRBDs. KEYWORDS: excessive sleepiness • insomnia • pharmacologic treatment • sleep apnea • sleep-related breathing disorder

Sleep-related breathing disorders (SRBDs) are characterized by impaired respiration during sleep and associated disturbances in sleep continuity and diminished daytime wakefulness [1]. Along with obstructive sleep apnea (OSA) syndromes (the most prevalent form), the SRBDs include central sleep apnea (CSA) syndromes and sleep-related hypoventilation/hypoxemia syndromes (BOX 1) [1]. The breathing disturbance in most SRBDs can be characterized broadly as repetitive episodes of cessation of respiration (apnea) during sleep, associated with either no ventilatory drive (CSA syndromes) or with continued or increased ventilatory drive/respiratory effort in the face of increased airway resistance or obstruction (OSA syndromes). In CSA, dysfunction in the CNS mechanisms that control respiration results in loss of ventilatory drive [2]. In OSA, ventilatory drive is intact, but adequate ventilation is prevented by upper airway resistance or obstruction. Obstruction of the airway can occur when factors that serve to keep the upper airway open during breathing (such as the dilating response of the upper airway muscles) are outweighed by factors that decrease upper airway patency (including excess tissue caused

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by obesity, reduced airway tone and the negative airway pressure caused by contraction of the diaphragm) [3]. The primary features of SRBD syndromes can be divided into three categories, each of which can be a target of pharmacologic intervention: the SRBD event and its immediate physiological consequences; the adverse effects of these events on sleep and sleep continuity; and impairment in daytime waking function, including alertness, cognition and mood. The respiratory events and their most proximal physiological consequence should ideally be the primary target for treatment. Untreated SRBDs can increase patients’ risk of a range of serious long-term health outcomes, including coronary artery disease, hypertension and stroke [4–7], as well as obesity and diabetes [8–11]. Adverse effects on sleep continuity are often the most immediate consequences of disordered respiratory events. Total sleep time and, most notably, sleep continuity can be significantly impaired in these patients. Although many patients deny sleep difficulties, even those with severe sleep disruption, as many as 50% of OSA patients report insomnia, typically sleep-maintenance insomnia and early-morning awakening [12,13]. In most cases,

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repeated arousals and awakenings within the sleep episode are accompanied by impairment in waking functions, such as alertness, vigilance, sustained attention and cognition, including executive functioning [14]. These impairments can compromise performance and productivity [15] and, on average, significantly increase the risk of motor vehicle crashes [16]. Chronic intermittent hypoxemia can also impair neurological function. Recent imaging testing in patients with OSA has demonstrated chronic neurological damage that may be responsible for residual impairment in alertness and cognitive functioning [17–21], even after successful continuous positive airway pressure (CPAP) treatment [22]. Given the range of adverse consequences of SRBDs, it is not surprising that these patients are at significantly greater risk of depression, impairment in health-related quality of life and daily functioning [23,24], and associated increased utilization of healthcare services [3]. Given these adverse affects on overall health and functioning, it is important to have therapies that can reliably treat the underlying clinical condition or reduce symptoms in these patients. The research on pharmaceutical treatments of SRBDs should be evaluated within the following context. First, the majority of studies have assessed treatments for OSA, an imbalance that likely reflects its greater prevalence. The differences in risk factors, causes and pathophysiology among different forms of SRBDs can be substantial. Therefore, it is often not possible to generalize the findings from one form of SRBD to another. Similarly, the predisposing factors, causes and pathophysiology within a given disorder, such as OSA, can be multifactorial and specific to each individual patient. Unfortunately, few studies have attempted to match a given treatment with patients who share a primary underlying cause despite the fact that the rationale for the potential use of treatments is usually based upon one specific aspect of the complex underlying pathophysiology of the disorder. Given their small sample sizes, the majority of clinical trials do not afford the ability to evaluate the treatments within a subset of patients with a similar underlying cause. These limitations should be taken into consideration when evaluating the effect size and the consistency of the trials presented in this review. Continuous positive airway pressure is the gold-standard treatment for moderate-to-severe OSA. When properly titrated and used, CPAP can effectively treat the breathing disturbance, often normalizing abnormal respiratory events and eliminating associated arousals and hypoxemia. CPAP treatment has also been shown to significantly improve sleep continuity and associated daytime alertness and performance. Although efficacious, adherence to CPAP is difficult for many patients; an estimated 30% of patients fail to remain adherent to CPAP therapy at 6 months [25]. As CPAP has been shown to be efficacious across the full spectrum of SRBD impairment, pharmacologic treatments meant to replace or supplement CPAP for SRBDs should also be tested for their ability to yield clinically meaningful improvements in sleep-breathing events, sleep and wakefulness. In the absence of an accepted pharmacologic treatment that safely achieves this goal, some medications have been evaluated for

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Box 1. International Classification of Sleep Disorders, 2nd Edition. Central sleep apnea syndromes • Primary central sleep apnea • Central sleep apnea due to Cheyne Stokes breathing pattern • Central sleep apnea due to high-altitude periodic breathing • Central sleep apnea due to a medical condition not Cheyne Stokes • Central sleep apnea due to a drug or substance • Primary sleep apnea of infancy Obstructive sleep apnea syndromes • Obstructive sleep apnea, adult • Obstructive sleep apnea, pediatric Sleep-related hypoventilation/hypoxemic syndromes • Sleep-related nonobstructive alveolar hypoventilation, idiopathic • Congenital central alveolar hypoventilation syndrome Sleep-related hypoventilation/hypoxemia due to a medical condition • Sleep-related hypoventilation/hypoxemia due to pulmonary parenchymal or vascular pathology • Sleep-related hypoventilation/hypoxemia due to lower airways obstruction • Sleep-related hypoventilation/hypoxemia due to neuromuscular and chest wall disorders Sleep apnea/sleep-related breathing disorder, unspecified Data from [1].

their ability to relieve symptoms of sleep or wakefulness without treating the underlying breathing disorder. Pharmacologic treatments have been tested for their ability to improve sleep, either with the goal of reducing insomnia or improving CPAP adherence. Finally, medications are available to reduce excessive sleepiness (ES) and improve alertness and cognition without treating the underlying sleep-breathing events or sleep. In this paper we provide a review of these pharmacologic treatments. Pharmacologic treatments to increase airway tone

In patients with SRBDs, a variety of pharmacologic therapies have been examined for treating the underlying sleep-breathing disorder. Candidate therapies have been assessed for their ability to increase airway tone during sleep, increase ventilatory drive or reduce upper airway resistance. Among these agents are serotonergic medications, rapid eye movement (REM)-sleepstage suppressants, stimulant medications, endocrine therapies and therapies designed to reduce upper airway resistance related to nasal congestion. Serotonergic agents

Serotonin has been reported to play a role in maintaining airway patency by controlling the dilating activity of the upper airway muscles, the most prominent of which is the genioglossal

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muscle (the large, fan-shaped muscle that forms the base of the tongue). The serotonergic system is very complex, as are its potential effects on the upper airway dilating muscles and its impact on central and other peripheral systems involved in SRBDs or its consequences. Some studies in animal models of OSA have suggested that serotonergic agents may help to maintain airway patency by increasing the strength of the upper airway muscle response to inspiration [26,27]. More recent studies, however, have demonstrated a noradrenergic role in upper airway dilator muscle activity [28,29]. Studies of various serotonergic medications in humans have not shown consistent benefit in SRBDs. A randomized, openlabel trial comparing fluoxetine 20 mg and protriptyline 10 mg in 12 patients with a history of snoring, apneas and oxygen saturation events ( 15), there were no significant changes in

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obstructive apneas indices or oxygen saturation. There was a statistically significant decrease in the frequency of central and mixed apneas following active treatment, although these events were rare in this patient group. Aminophylline treatment also significantly disrupted sleep continuity [42]. In a double-blind, randomized, crossover study of theophylline in 14 patients with mild SRBDs (mean AHI: 13), 7 days of treatment produced a 4-point reduction of AHI compared with placebo [43]. A more marked reduction was seen in a 4-week, double-blind crossover study of theophylline 800 mg in which the total number of apneas was reduced from 398 on placebo to 283 [44]. Importantly, theophylline treatment significantly disrupted sleep. After adjusting for reduced total sleep time, theophylline treatment reduced the obstructive AHI from 49 on placebo treatment to 40. In a direct comparison of CPAP and theophylline in patients with moderate OSA, CPAP treatment normalized respiratory values. Theophylline improved but did not normalize the AHI, but also significantly reduced total sleep time and sleep efficiency [45]. Rieger and collegues reported a prospective, open-label, nonrandomized parallel-group study comparing theophylline (5–7 mg/kg) with CPAP in 60 patients with mild OSA and mild ES. In this study, CPAP treatment normalized AHI and yielded a 2-point improvement in Epworth Sleepiness Scale (ESS) (20% improvement). Theophylline yielded no significant effect on mean AHI and a 2-point improvement in ESS [46]. The absence of a placebo group makes it difficult to interpret the 2-point improvement in ESS seen with both medications. Finally, in a study of 16 men with mild-to-moderate OSA who received theophylline 900 mg/day as an adjunct to CPAP therapy, no additive benefit was seen with theophylline therapy [47]. Therefore, the effects of theophylline on SRBDs have been modest at best and are often accompanied by disruption in sleep continuity and associated decrease in total sleep time. There is some very preliminary evidence that theophylline may have some benefit for treating sleep-breathing disruption in patients with congestive heart failure [48,49]. Given the design and size of these studies, as well as the results of the studies in OSA, there is insufficient support for the use of the methylxanthines to treat SRBDs. Nicotine

Nicotine has been evaluated for its ability to stimulate the muscles of the upper airway, including the genioglossal muscle. Studies of this agent have produced mixed results. One small case series reporting the effects of nicotine gum 14 mg in eight obese men (>30% over ideal weight) showed improvements in a number of respiratory abnormalities in the early part of the night [50]. Two subsequent randomized, double-blind, crossover studies, one in 20 patients with a history of snoring and one in 11 OSA patients [51,52], did not yield significant improvements in breathing measures. Both studies reported impairment in sleep continuity and sleep time following nicotine treatment. Nicotine, therefore, significantly disrupts sleep continuity and does not consistently improve SRBDs.

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Acetazolamide

Correcting endocrine imbalances that contribute to SRBDs

Acetazolamide is a carbonic anhydrase inhibitor that may stabilize ventilatory control and increase ventilatory drive. In a study of six patients with idiopathic CSA treated with acetazolamide for 1 week, all six improved, achieving an overall reduction in apneas of nearly 70%. All but one patient reported improved sleep quality and daytime alertness [53]. Javaheri assessed the effects of acute acetazolamide treatment in a placebo-controlled crossover study of 12 patients with CSA secondary to heart failure. Six nights of acetazolamide taken 1 h before bedtime significantly reduced AHI from 55 to 34 compared with a slight increase in the placebo treatment [54]. In a 4-week study in nine patients with mild-to-moderate OSA, acetazolamide 250 mg reduced the mean apnea index from 25.0 to 18.1 (nearly 30%). Improvements in oxygen desaturation were also reported [55]. Most patients reported notable improvements in subjective alertness. In a second randomized, double-blind, placebo-controlled, 14-day study that used a much higher dose of acetazolamide (250 mg four times daily), the mean number of apneas/hypopneas was reduced by nearly 50% (from 50 with placebo therapy to 26) [40]. No improvements in subjective sleep and wakefulness were reported. In both studies acetazolamide treatment was accompanied by intolerable adverse effects. The positive results of acute treatment in patients with CSA suggest that acetazolamide may eventually show some clinical utility in this patient population. Additional controlled trials are both warranted and necessary. In OSA, the modest effects reported for acetazolamide are accompanied by intolerable adverse effects; therefore, acetazolamide is not recommended in this patient group.

Hormone therapies have been used in cases where SRBDs may be related to a specific endocrinologic cause, such as acromegaly, hypothyroidism and menopause. Individuals with acromegaly are at increased risk of OSA due, in part, to increased tongue volume resulting from high levels of circulating growth hormone (GH). The somatostatin analog intramuscular octreotide or long-acting release (LAR) is used in treating acromegaly by reducing GH levels, and appears to offer at least some improvement in disordered breathing. In a 14-patient study, octreotide, at a dose of 10–30 mg administered intramuscularly every 4 weeks for 6 months, reduced tongue volume and reduced the mean respiratory disturbance index by 28% [58]. A similar study in 14 patients with acromegaly and moderate OSA, using doses from 20 to 30 mg intramuscularly reported a 50% improvement in AHI and a larger reduction in snoring [59]. Despite moderate improvements, octreotide treatment alone appears insufficient to normalize SRBDs, perhaps due to skeletal abnormalities that do not resolve with normalization of GH. Therefore, treatment with octreotide alone should not be viewed as a substitute for CPAP therapy. In hypothyroidism/myxedema, SRBDs are associated with increased body mass that accompanies the loss of thyroid function. In these patients, thyroid hormone replacement with thyroxine or levothyroxine may improve SRBDs, perhaps secondary to weight loss. There is currently no adequate and wellcontrolled trial supporting pharmacologic improvement in SRBDs following hormone replacement. Two open-label reports have detailed the resolution of OSA symptoms in patients with OSA secondary to hypothyroidism. In one report, resolution of symptoms was found in a majority of patients following 3 months of thyroxine treatment [60]. In the second, an increase in respiratory drive was seen earlier in treatment, while maximum SRBD benefits were seen at 12 months [61]. In the absence of controlled clinical trials there is insufficient evidence to recommend this treatment as a monotherapy for patients with moderate-to-severe OSA and hypothyroidism, although it could be viewed as a supplement to CPAP therapy. In some patients with mild-to-moderate OSA caused by hypothyroidism, treatment may resolve OSA symptoms within 3–12 months. In these patients, CPAP therapy may be discontinued. Re-evaluation should occur after return to the euthyroid state to determine the need for continued CPAP therapy and the appropriate CPAP needed to resolve the OSA. There is evidence from population-based studies of an association between menstrual status and SRBDs [62,63], suggesting that the difference in male–female SRBD prevalence may be, at least in part, related to sex hormones. Menopause appears to be an independent risk factor for OSA. Pre- and postmenopausal women on hormone replacement have been shown to have lower prevalences of OSA than postmenopausal women not on estrogen/progesterone therapies [63]. Both estrogen and progesterone may increase ventilatory drive in

Opioid antagonists

Opioids are respiratory depressants that have been associated with decreased ventilatory drive and increased apnea activity. Therefore, opioid antagonists have been assessed for their ability to increase ventilatory drive and improve sleep-disordered breathing. Atkinson and colleagues reported a doubleblind, placebo-controlled, crossover study of the opioid antagonist naloxone in ten obese patients with sleep apnea. A single night of naloxone infusion therapy did not significantly decrease the AHI or total number of oxygen desaturations. Treatment did reduce the maximum oxygen desaturation level as well as the number of desaturations per hour; however, naloxone also significantly impaired sleep, including an 80% decrease in REM sleep [56]. A double-blind, placebo-controlled, crossover study of the oral opioid antagonist naltrexone 50 mg yielded improvements in AHI, as well as in several measures of oxygenation. However, much of the decrease in apnea activity was attributable to significant impairment in sleep, including reductions in total sleep time, REM sleep and sleep continuity [57]. In brief, opioid antagonists have shown little benefit for SRBDs.

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sleep. Studies of medroxyprogesterone (MPG)-only regimens have tended to support its partial benefit [64–67]. However, direct comparisons of estrogen with and without progesterone have not tended to support a distinct or additive effect for the progesterone component [68–70], while some findings suggest that progesterone may in fact mitigate any positive benefits from estrogen. Thus, additional clarification of the degree of benefit from hormone-replacement therapies is necessary. There is increasing understanding of the long-term adverse consequences of hormone-replacement therapy. Given these risks, as well as the modest and inconsistent improvements, hormone-replacement therapy is not a recommended treatment for SRBDs and should not be viewed as a substitute for CPAP. A few studies have looked at the effects of hormone therapies in men. None of the strategies, including testosterone injections or androgen blockade with flutamide, have been of benefit [71–73].

approximately half of whom had OSA. The intranasal corticosteroid fluticasone significantly reduced AHI (by nearly 50%) and increased subjective alertness [84]. Testing a different mechanism for reducing upper airway inflamation, Goldbart and colleagues assessed the leukotriene modifier montelukast in a 16-week, open-label study in 24 children with mild SRBDs. In this study montelukast reduced adenoid size and AHI [85]. The nasal corticosteroids have been shown to improve AHI in patients with OSA and concurrent rhinitis [84]. There is considerable evidence that nasal corticosteroids may be useful adjuncts to primary therapies, such as CPAP, in patients with OSA and concurrent rhinitis. In addition to improvements in SRBD outcomes, these medications may also improve CPAP tolerance and adherence. Use of montelukast has also been shown to improve mild SRBD, suggesting that montelukast may have a small effect in children. Additional research is necessary to characterize the risk–benefit in children.

Options for improving nasal patency & reducing upper airway resistance

Pharmacologic treatments to improve sleep

Nasal breathing has been shown to increase ventilatory drive and decrease airway patency [74]. Inflammatory processes in the nasal passages and nasopharynx from rhinitis may increase the risk of airway obstruction, disrupted sleep and daytime sleepiness [74–79]. A number of studies have shown that, in children and adults, rhinitis and nasal congestion are associated with an increased risk of SRBDs [74,77–79]. Topical therapies, including nasal decongestants and corticosteroids, have the potential to improve disordered breathing by reducing inflammation and/or congestion in the nasal passages and nasopharynx. A study of 20 asymptomatic male snorers that compared single nights of positional therapy, nasal decongestants (oxymetazoline) and their combination against a night of placebo found that the combination approach significantly reduced both their AHI and snoring frequency. The nasal decongestant alone offered no improvement, however [80]. A study of ten men that examined the use of phosphocholinamin, a soft-tissue lubricant, to reduce airway surface tension found significant reductions in both AHI and arousal index [81]. There is increasing evidence that topical/intranasal corticosteroids can improve sleep respiratory function in children and adults with OSA. In a randomized, parallel-group, placebocontrolled trial of 25 children with OSA and adenotonsillar hypertrophy who received 6 weeks of intranasal fluticasone, the mean AHI was reduced from 10.7 to 5.8, compared with an increase from 10.9 to 13.1 in a placebo group. Measures of oxygen saturation also improved [82]. In an open-label study of 14 children using intranasal budesonide, the mean AHI was reduced from 8.4 to 1.2, and was accompanied by an improvement in subjective assessments of rhinitis-related quality of life [83]. Similar results were seen in a randomized, doubleblind, placebo-controlled study of 24 consecutive adult snorers,

Approximately half of all patients with SRBDs complain of insomnia, particularly sleep-maintenance insomnia and earlymorning awakening [12,13]. In one retrospective review of 231 patients with SRBDs, 50% of patients reported symptoms of insomnia and in nearly 20% of these, insomnia was the presenting or chief complaint [86]. A recent study reported that 30% of patients with undiagnosed OSA had received a prescription for a sedating medication and that a third of these prescriptions were for benzodiazepines. This same report found that nonspecialists were five-times more likely to prescribe sedating medications to patients with undiagnosed sleep apnea [87]. Therefore, a considerable number of patients with undiagnosed OSA are currently taking sedating medications for insomnia. There are potential risks associated with use of sedative–hypnotics in these patients, including reduction in airway tone and blunting of the arousal response. Benzodiazepines have been shown to reduce genioglossal muscle tone and blunt the arousal response to hypoxia and hypercapnia. Furthermore, use of sedating medications (including benzodiazepines) in undiagnosed OSA patients has been associated with an increased risk of motor vehicle accidents [87]. The nonbenzodiazepine, benzodiazepine-receptor agonists, including zolpidem, zopiclone and eszopiclone, have been shown to treat insomnia, including sleep-maintenance insomnia, and sleep efficiency in patients with SRBDs without adversely affecting measures of disordered breathing [88,89]. Zaleplon and the new melatonin analog, ramelteon, have been reported to treat sleep-onset insomnia with no adverse effects on SRBDs and improvements in sleep-onset insomnia [90,91]. Some physicians prescribe sedative–hypnotics in order to improve adherence to CPAP therapy. Zaleplon has been reported to reduce sleep-onset latency without adversely affecting AHI and CPAP use in OSA patients [90]. Zolpidem has

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been shown to improve sleep-maintenance insomnia in severe OSA patients on CPAP therapy, without adversely affecting AHI and CPAP use [92]. Zolpidem did not improve CPAP compliance in this study. In patients with SRBD, the newer hypnotics have been shown to improve symptoms of sleep-onset insomnia (zaleplon, zolpidem, eszopiclone and ramelteon) and some have been shown to reduce sleep-maintenance insomnia (zolpidem and eszopiclone) without adversely affecting measures of sleep and breathing. However, hypnotics should not be considered a substitute for the appropriate diagnosis and management of SRBDs. Symptomatic treatment of insomnia will not mitigate the long-term adverse health consequences of untreated SRBDs and recent evidence suggests that there may be additional risks associated with the use of sedating medications in undiagnosed OSA patients. Zolpidem and zaleplon have been evaluated in OSA patients treated with CPAP. Although both showed no adverse effects on sleep respiratory measures or CPAP use, these medications did not improve CPAP use or measures of daytime alertness. Therefore, as an adjunct to CPAP, zolpidem has been shown to improve sleep-maintenance insomnia without adversely affecting measures of SRBD or CPAP effectiveness. Pharmacologic treatments to improve wakefulness

Excessive sleepiness is the most common clinical symptom associated with SRBDs. Moderate-to-severe ES is often the presenting complaint and the symptom generally considered to have the greatest impact on patient functioning [1]. The prevalence of ES increases as the underlying breathing disturbance becomes more severe [93]; and approximately half of individuals in community samples with moderate-to-severe sleep-disordered breathing complain of this symptom [86,94]. Although CPAP frequently resolves most symptoms of SRBDs, including ES, residual ES can occur in 30–50% of patients adherent to CPAP [95]. Modafinil is a wake-promoting agent that is approved for the treatment of residual ES in OSA patients who are regular users of CPAP. Six double-blind, placebo-controlled studies have evaluated the effects of modafinil in OSA patients; five of these included measures of efficacy in OSA patients who were at least regular users of CPAP. In a double-blind, placebo-controlled, crossover trial in six OSA patients, Arnulf and colleagues found that modafinil significantly reduced ES and improved long-term memory following 2 weeks of treatment [96]. In a double-blind crossover study of the effects of 300 mg modafinil on blood pressure in 26 OSA patients, modafinil did not significantly increase blood pressure, although a small increase in blood pressure had been reported during increased mental and physical load [97]. In a placebo-controlled, crossover trial of modafinil in 30 OSA patients, 2 weeks of adjunct modafinil 400 mg was reported to significantly improve wakefulness on the Maintenance of Wakefulness Test (MWT) but not on other measures (ESS and Multiple Sleep Latency Test).

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A 12-min per night, but statistically significant, reduction in CPAP use was reported [98]. Modafinil (200 and 400 mg) was subsequently evaluated in two large multicenter, randomized, double-blind, placebo-controlled, parallel-group studies of efficacy and safety. In a 4-week trial in 157 patients, Pack and colleagues reported that adjunct modafinil treatment significantly improved wakefulness as measured by the ESS and Multiple Sleep Latency Test [99]. Modafinil also significantly improved the ability to sustain attention during the psychomotor vigilance task (PVT) [100]. In a 12-week trial in 327 patients, Black and Hirshkowitz reported that adjunct modafinil significantly improved wakefulness and ability to sustain attention as measured by ESS, MWT and PVT [101]. In a recent, parallel-group study employing a single-blind 1-week placebo run in, 3 weeks of modafinil treatment in 20 patients significantly improved wakefulness on the ESS and reaction time [102]. In addition to these trials, the safety of modafinil has been assessed in two open-label, follow-on studies of 3 and 12 months duration [103,104]. In the double-blind studies, modafinil did not adversely affect measures of SRBDs, such as AHI, oxygen saturation, CPAP use and sleep. Modafinil was well tolerated and had no statistically significant adverse effects on cardiovascular function, including mean heart rate and blood pressure. In the open-label, follow-on studies, modafinil was associated with a reduction in CPAP use over 12 months (34 min), although mean CPAP use remained high (5.4 h per night). Of the 266 patients who began the 12-month, open-label, follow-on study, a clinically significant increase in blood pressure was reported in six patients (five of whom had a previous history of hypertension). This increase in arterial blood pressure was sustained beyond a single visit in only one patient [104]. Armodafinil, the longer acting of the two isomers that make up racemic modafinil, has also recently been approved by the US FDA to improve wakefulness in OSA patients with residual ES despite regular use of CPAP. Armodafinil (150 and 250 mg) was evaluated in two large, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies of efficacy and safety. In a 12-week trial in 395 patients, Roth and colleagues reported that adjunct armodafinil (150 and 250 mg) significantly improved wakefulness as measured by the ESS and MWT [105]. In another 12-week trial in 259 patients, Hirshkowitz and coworkers reported that adjunct armodafinil 150 mg significantly improved wakefulness as measured by ESS, MWT, attention and longterm episodic memory [106]. The safety profile of armodafinil was similar to modafinil for measures of SRBD, CPAP use and sleep. Adjunct modafinil and armodafinil have been shown to significantly improve subjective and objective measures of wakefulness in OSA patients experiencing residual ES, despite regular use of effective CPAP. In the large, multicenter trials of modafinil and armodafinil, overall clinical condition was improved in the majority of patients; however, sleepiness was

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not normalized in most patients. Both treatments have been shown to significantly improve attention and there is greater strength of evidence that armodafinil improves long-term memory [106,107]. These effects were achieved without significant adverse effects on measures of sleep-disordered breathing, sleep continuity and duration, and CPAP compliance. However, it is always important to remember that ongoing monitoring of CPAP use is warranted with chronic use. Although modafinil and armodafinil do not significantly impact mean measures of cardiovascular function, precautions (monitoring of blood pressure) should be taken in patients with a history of hypertension. Discussion TABLE 1 summarizes changes in the AHI that have been observed in parallel-group and crossover studies of SRBDs [108]. Benefits in these studies for SRBDs have been of small-to-moderate effect size and few agents have emerged as appropriate pharmacologic options. TABLE 2 provides a brief summary of the effects of each of the most widely studied pharmacologic therapies for

the main categories of SRBD impairment: sleep-breathing events, sleep and wakefulness. This table also includes the American Academy of Sleep Medicine (AASM) recommendations based upon their evidence-based assessment of the literature and published practice parameters [109,110]. Modafinil was the only agent to be considered a ‘standard’ pharmacologic treatment for any sign or symptom associated with SRBDs (TABLE 2) [109,110]. The only other agents whose use was considered supportable by current evidence were nasal corticosteroids, which may improve AHI scores in patients with OSA and concurrent rhinitis. The AASM guidelines list nasal corticosteroids as useful adjuncts to primary therapies, such as CPAP, in patients with OSA and concurrent rhinitis [109,110]. Of the medications designed to increase airway tone, mirtazapine has so far demonstrated the largest reduction in AHI. However, this effect was only a 50% improvement in AHI and mirtazapine is associated with sedation in the majority of patients. For those agents designed to increase ventilatory drive there is no agent that reliably improves sleep breathing without adversely affecting sleep or having other intolerable adverse effects. Acetazolamide for CSA warrants

Table 1. Summary of changes in the apnea–hypopnea index in placebo-controlled studies of sleep-related breathing disorders. Agent (study)

Active Placebo (n) (n)

Events/h, fixed (95% CI)

Paroxetine (Kraiczi, 1999)

17

17

[31]

Protriptyline (Whyte, 1988)

10

10

[40]

Ondansetron (Stradling, 2003)

10

10

[34]

Mirtazapine low dose (Carley, 2007)

9

9

[35]

Mirtazapine high dose 10 (Carley, 2007)

10

[35]

Theophylline (Hein, 2000)

14

14

[43]

Theophylline (Mulloy, 2000)

9

9

[44]

Acetazolamide (Whyte, 1988)

10

10

[40]

Naltrexone (Ferber, 1993)

12

12

[57]

Topical lubricant (Jokic, 1998)

10

10

[81]

-50

Favors treatment

0

Ref.

Favors placebo

50

CI: Confidence interval. Copyright Cochrane Collaboration, adapted with permission from [108].

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Table 2. Overall effects of pharmacologic treatment of sleep-related breathing disorders. Drug/drug class

Effect on sleep breathing events

Effect on sleep

Effect on wakefulness

AASM recommendation

CPAP

↑↑↑

↑↑↑

↑↑↑

First-line treatment

SSRI

0/↑

0

↓

Not recommended

Mirtazapine

↑

0/↑

↓

Insufficient evidence

Protriptyline

0/↑

0/↓

0/↑

Not recommended

0/↑

↓↓

0

Not recommended

0

↓

0

Insufficient evidence

↑↑

↑

↑

Not included‡

Acetazolamide OSA

↑

0

0/↑

Not included‡

Opioid antagonists

↑

↓↓

0

Not included‡

Octreotide for acromegaly

↑

0

0

Not included‡

Thyroxine for hypothyroidism

↑↑

↑

↑

Insufficient evidence

Sex hormone replacement for menopause

↑

0

0

Not indicated

Increasing airway tone

Increasing ventilatory response Methylxanthines* Nicotine Acetazolamide CSA

*

Endocrine therapy

Reducing upper airway resistance Short-acting nasal decongestants

Not recommended

Topical nasal corticosteroids in patients with OSA and concurrent rhinitis

May be a useful adjunct for OSA

Symptomatic treatment of sleep Benzodiazepine hypnotics

↓

↑↑↑

↓

Not included‡

Nonbenzodiazepine hypnotics

0

↑↑↑

↓

Not included‡

Melatonin analogs

0

↑↑

0

Not included‡

Symptomatic treatment of wake Modafinil

0

0/↓

↑↑↑

Recommended for residual ES

Armodafinil

0

0/↓

↑↑↑

Not included‡

*

Additional research may be warranted in central sleep apnea syndromes. Not included in AASM guidelines. ↑: Some improvement; ↑↑: Consistent or clinically significant improvement; ↑↑↑: Consistent and clinically significant improvement; 0: No or unknown effect; ↓: Some worsening of symptoms; ↓↓: Consistent or clinically significant worsening. AASM: American Association of Sleep Medicine; CPAP: Continuous positive airway pressure; CSA: Central sleep apnea: ES: Excessive sleepiness; OSA: Obstructive sleep apnea; SSRI: Selective serotonin reuptake inhibitor. Data from [109,110]. ‡

additional clinical research as a potential primary treatment, although it was associated with intolerable adverse effects in OSA patients. There is evidence that hormonal therapy to correct certain endocrine imbalances that contribute to SRBDs may positively impact measures of SRBDs. In patients with acromegaly, chronic octreotide therapy to reduce GH levels has been shown

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to reduce AHI by 30–50%. Although significant, octreotide should not be considered a primary therapy for patients with OSA secondary to acromegaly. In OSA secondary to hypothyroidism, thyroxine treatment has been shown to improve symptoms of SRBDs. In some patients with mild-to-moderate OSA caused by hypothyroidism, thyroxine treatment may resolve OSA symptoms within 12 months. This gives hope that it may

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be possible to discontinue CPAP therapy in these patients. However, these findings are based upon open-label data only. Additional controlled trials are necessary. In the absence of pharmacologic agents that safely treat SRBD across the full spectrum of impairment, research has been conducted to evaluate medications for the symptomatic treatment of sleep and wakefulness. Zolpidem and eszopiclone have been shown to treat sleep-onset and sleep-maintenance insomnia without adversely affecting sleep respiratory function. Zaleplon and ramelteon selectively improve sleep-onset insomnia without adverse effects on sleep respiratory function, although this symptom is significantly less common in patients with SRBDs. As adjunct to CPAP, zolpidem has been shown to improve sleep continuity without affecting CPAP effectiveness. In OSA patients with residual ES despite regular use of effective CPAP, modafinil consistently reduces objective and subjective ES and significantly reduces the extent to which ES interferes with daily activities. Modafinil has been shown to improve alertness and cognition, including attention and long-term memory. Modafinil has not shown adverse effects on measures of sleep, SRBDs or CPAP use. Armodafinil has shown similar effects in the same patient population. When evaluating the potential use of pharmacologic therapies, it is important to consider that patients with SRBDs are already at high risk for adverse outcomes, including cardiovascular disease [6], sleep disruption and daytime hypersomnolence. Medications that may increase these risks should be used with caution. Such medications include traditional CNS stimulants, such as amphetamines, nicotine and the methylxanthines; tricyclic antidepressants, such as protriptyline, which have substantial negative effects on sleep quality; estrogen/progestin therapies, which may increase cardiovascular risk; and the serotonergic agents that are associated with weight gain and sedation. On the other hand, some agents that have been studied may have benefits in SRBD patients that would support their use, despite being ineffective for treating the underlying sleep breathing disorder. For example, octreotide and thyroid hormone have positive effects on BMI and blood glucose levels, favorable outcomes in SRBD patients who have high levels of obesity and are at greater risk of increased insulin resistance and diabetes [8,111]. SSRIs will probably be effective in improving comorbid depression, as OSA is a significant risk factor for depression [5]. Some antihypertensives (e.g., clonidine and cilazepril) have been tested in double-blind trials for their effect on SRBDs. Although these medications do not significantly affect measures of SRBDs [108], they may mitigate some of the adverse sympathetic consequences of respiratory-related arousals. There are methodological issues that should be considered when evaluating the current state of the literature for the pharmacologic treatment of SRBD. The research to date consists of small studies designed for signal detection. The double-blind, placebo-controlled trials that have been conducted typically employ a crossover design in a small number of patients rather

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than a parallel-group design. The small sample sizes make this research capable of detecting only moderate effect sizes or larger, which could explain the inconsistent findings of some medications. Therefore, it can be concluded from these trials that these medications may yield modest effect sizes at best. Another limitation of the current set of studies is that few have attempted to match the pharmacologic treatment to the appropriate patient type. For instance, studies of REM-sleep suppressants have not been performed in patients whose SRBD has significant REM-sleep predominance. As a minority of OSA patients have predominantly REM-sleep-related OSA, it is difficult to adequately test this hypothesis without selecting the patient population. Expert commentary

As a primary treatment for SRBDs, no pharmaceutical agent has been shown to normalize sleep respiratory function. Few agents have shown consistent effects on sleep-related abnormal breathing events and none have demonstrated objective improvement in sleep and wakefulness. There is evidence that hormonal therapy to correct certain endocrine imbalances that contribute to SRBDs (i.e., acromegaly and hypothyroidism) may positively impact measures of SRBD, although these should not be considered first-line primary treatments in these patients. Nasal corticosteroids consistently reduce AHI scores and may be useful adjunct treatments to primary therapies, such as CPAP, in patients with OSA and concurrent rhinitis [109,110]. It is important to highlight that individual patients can present with many different causes, predisposing and exacerbating factors, including disease severity, facial and upper airway structure, obesity, alcohol and concomitant medication use, muscle tone, ventilatory drive, and other comorbid and contributing conditions. Furthermore, many medications have peripheral effects that may positively impact respiratory function but CNS effects that may adversely impact sleep or wakefulness. Given the complex pharmacology of respiration, sleep and wakefulness, as well as the heterogeneous causes and contributing factors across patients, it is unlikely that one pharmacologic treatment will be equally effective for all SRBD patients. The most effective tool for treating moderate-to-severe sleepdisordered breathing is still CPAP. In the many controlled trials of OSA patients using the AHI as an outcome measure, CPAP was shown to be superior to placebo, conservative management and positional therapy for reducing or eliminating respiratory disturbances. It is also effective for reducing sleep disruption and daytime hypersomnolence. Importantly, recent research demonstrated that CPAP is effective for treating SRBD-associated hypertension and other indices of cardiovascular disease risk [112]. These benefits have not yet been demonstrated with any pharamacologic treatment. Given these proven advantages, CPAP is indisputably the first-line therapy for the treatement of disordered breathing related to airway obstruction. There are

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challenges, however, to long-term use of CPAP, with some patients finding it difficult to adhere to nightly use of the mechanical device. AASM practice parameters estimate that approximately 30% of patients fail to remain adherent to CPAP for at least 6 months. Furthermore, residual ES occurs in 30–50% of those patients who continue to use CPAP. For these reasons, additional treatments are needed, as primary treatments for SRBDs, to augment CPAP therapy or to treat residual insomnia or daytime hypersomnolence. As adjunct to CPAP treatment, zolpidem has been shown to improve sleep continuity without affecting CPAP effectiveness or use. However, zolpidem and similar medications have not been shown to improve daytime alertness and their chronic use may be associated with increased risk of impaired daytime functioning (particularly in the early morning). Symptomatic treatment of insomnia is not recommended for moderate-tosevere OSA patients who are not treated with positive airway pressure. There is consistent evidence that modafinil is efficacious and well tolerated for improving wakefulness in OSA patients with residual ES, despite regular use of effective CPAP. Modafinil improves alertness and reduces the extent to which ES interferes with daily activities. Modafinil has not shown adverse effects on measures of sleep, SRBD or CPAP use. Single-isomer armodafinil has shown similar effects in the same patient population. For patients treated with adjunct modafinil and armodafinil, CPAP use and blood pressure should be monitored periodically. These medications should also be used in conjunction with some primary treatment, such as CPAP, as the symptomatic treatment of sleepiness will not mitigate the increased risk for adverse health outcomes associated with untreated SRBDs. Five-year view

Given the prevalence and consequences of SRBDs, the development of pharmacologic therapies should continue to be a focus of considerable effort. Advances in the understanding of the pharmacology of respiration in sleep as well as possible breakthroughs in genetic predisposing factors, such as obesity, may yield new candidate platforms. Candidate pharmacologic therapies with appropriate risk–benefit profiles should be tested for their ability to treat mild SRBDs. If successful, additional research should focus on the impact of early intervention on disease progression and long-term health outcomes. No medication has been shown to significantly improve SRBDs, despite the underlying cause. Therefore, additional trials should be performed to evaluate the potential for pharmaceutical agents to augment CPAP therapy. Medications should be evaluated for their ability to augment CPAP effectiveness, reduce CPAP pressure and/or improve CPAP adherence. To date, few CPAP augmentation studies have been conducted and none of these are of sufficient sample size and trial design to adequately estimate the value of these pharmacologic agents in augmenting CPAP therapy. Future research should

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employ larger sample sizes in order to reliably detect moderate effect sizes and accurately estimate safety, particularly when tested as adjunct or augmentation therapy to CPAP. Additional work should be done to confirm the anecdotal findings that nasal corticosteroids may allow for reduced CPAP pressure and can improve CPAP adherence in patients with CPAP and concurrent rhinitis. Similarly, research should clarify the role, if any, that CPAP may play in increasing the risk of upper airway infection as well as identifying possible prophylactic treatments to improve CPAP effectiveness and adherence. In addition to being well tolerated, the ideal pharmacologic treatment of SRBDs would normalize sleep respiratory function, sleep and daytime alertness. All clinical trials, therefore,should include standardized measures of sleep and wakefulness, such as validated insomnia scales and the ESS. The target patient population should be identified for several factors, including the severity of the SRBD that will be addressed, contributing factors for the SRBD, presence of abnormal hormone imbalances, nasal congestion and sleepstate- or sleep-stage-related SRBD. Clearly a targeted approach is more likely to lead to a more precise clinical outcome. Placebo-controlled trials large enough to accurately estimate safety are necessary to evaluate the risk–benefit of adjunct hypnotics in CPAP-treated OSA patients. Although large trials have been performed with the wake-promoting drugs modafinil and armodafinil, direct comparisons are necessary to determine whether armodafinil offers additional benefit over modafinil. Additional research is necessary to better understand the long-term cognitive consequences of the neurological impairment associated with chronic hypoxia and pharmacologic treatments should be tested for their ability to treat this impairment. Regardless of whether they are to be used as primary therapy or as adjunct or augmentation treatments to CPAP, all reasonable candidate pharmacologic treatments should be evaluated in clinical trials to demonstrate efficacy over placebo as well as effects on sleep and wakefulness, characterize long-term adherence and benefit, and accurately estimate safety and tolerability, including effects on cardiovascular function. As the recognition and treatment of SRBDs spreads to primary care, these practices should be integrated into a comprehensive strategy for screening, diagnosis, early intervention and long-term management. In this strategy, the inclusion of any pharmacologic therapy should be considered in the context of appropriate diagnosis and management of the underlying sleep breathing disorder, including positional therapy, diet, exercise and appropriate sleep–wake hygiene. Financial & competing interests disclosure

J Schwartz served as a consultant and speaker for AstraZeneca, Boehringer Ingelheim, Cephalon, Pfizer, GlaxoSmithKline, Resmed, Medpointe and Takeda. T Roth has received grants from Aventis, Cephalon, GlaxoSmithKline, Neurocrine, Pfizer, Sanofi,

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SchoeringPlough, Sepracor, Somaxon, Syrex, Takeda, TransOral, Wyeth and Xenoport; has served as a consultant for Abbott, Accadia, Acoglix, Actelion, Alchemers, Alza, Ancil, Arena, AstraZeneca, Aventis, AVER, BMS, BTG, Cephalon, Cypress, Dove, Elan, Eli Lilly, Evotec, Forest, GlaxoSmithKline, Hypnion, Impax, Intec, Intra-Cellular, Jazz, Johnson and Johnson, King, Ludbeck, McNeil, MediciNova, Merck, @Neurim, Neurocrine, Neurogen, Novartis, Orexo, Organon, Prestwick, Proctor and Gamble, Pfizer, Purdue, Resteva, Roche, Sanofi,

SchoeringPlough, Sepracor, Servier, Shire, Somaxon, Syrex, Takeda, TransOral, Vanda, Vivometrics, Wyeth, Yamanuchi and Xenoport; and has been a speaker for Cephalon, Sanofi and Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues • Sleep-related breathing disorders (SRBDs) are characterized by disruptions in normal breathing patterns during sleep. • Untreated SRBDs can increase a patient’s risk of a range of serious long-term health outcomes, such as hypertension, stroke, obesity and diabetes. • SRBDs are associated with impairment in sleep continuity and waking function, and increase a patient’s risk of long-term neurological impairment, motor vehicle accidents and depression. • As a primary treatment for SRBDs, no pharmacologic treatment has been shown to normalize sleep respiratory function during sleep and none have consistently improved symptoms of sleep continuity and daytime wakefulness. • Positive airway pressure remains the most effective treatment for moderate-to-severe SRBDs, with a demonstrated ability to normalize sleep-breathing events accompanied by improvements in sleep continuity and daytime alertness. • Nasal corticosteroids may be useful adjuncts to continuous positive airway pressure (CPAP) in patients with obstructive sleep apnea and concurrent rhinitis. • The wake-promoting agents modafinil and armodafinil have been shown to improve wakefulness in patients with residual sleepiness, despite regular use of CPAP, without adverse effects on SRBDs or sleep. • The future lies in quantifying the long-term benefit of CPAP, the prevalence and consequences of residual symptoms, and in the development of new pharmacologic therapies for mild-to-moderate SRBDs and to augment CPAP effectiveness. of the Sleep Heart Health Study. Am. J. Respir. Crit. Care Med. 163(1), 19–25 (2001).

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Affiliations •

Jonathan RL Schwartz, MD Integris Sleep Disorders Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73109, USA Tel.: +1 405 636 1111 [email protected]

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Rod J Hughes, PhD Synchrony Medical LLC, Kennett Square, PA, USA

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Tom Roth, PhD Sleep Disorders Center, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA

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