Chapter 19

Pharmacological management of sleepdisordered breathing

J. Hedner and D. Zou

Summary
Several attempts have been made to identify a uniformly effective pharmacological remedy in obstructive sleep apnoea (OSA). However, no currently described drug has consistently reduced the severity of the condition by more than 50% in controlled trials. Most of the data is based on testing of compounds used in other therapeutic areas and there are few examples of rational strategic drug development. OSA is frequently associated with considerable comorbidities, including: hypertension, obesity, metabolic derangement and hormonal dysfunction, beside the more or less consistent symptoms of daytime sleepiness and cognitive dysfunction. Hence, specific considerations, such as classification of phenotype, existing comorbidity etc., should be taken into account when explorative clinical trials are designed in patients with OSA. The clinician should be made aware that there is no systematically documented drug yet available for the treatment of sleep apnoea. Future drug development is likely to incorporate a more global approach to comorbid conditions and risk modification in OSA. Keywords: Clinical trial, drug, hypertension, obesity, sleep apnoea, treatment
Dept of Pulmonary Medicine and Allergology, Sahlgrenska University Hospital, Gothenburg, Sweden. Correspondence: J. Hedner, Sleep Disorders Centre, Dept of Pulmonary Medicine and Allergology, Sahlgrenska University Hospital, 41345 Gothenburg, Sweden, Email jan.hedner@lungall.gu.se

Eur Respir Mon 2010. 50, 321339. Printed in UK all rights reserved. Copyright ERS 2010. European Respiratory Monograph; ISSN: 1025-448x. DOI: 10.1183/1025448x.00020010

he complicated pathogenesis of obstructive sleep apnoea (OSA) involves an anatomical predisposition for airway collapse, a decreased compensatory neuromuscular control of upper airway and unstable central neurochemical ventilatory control during sleep [1]. Continuous positive airway pressure (CPAP) is the most effective treatment for OSA, as it produces a pneumatic splint in the upper airway, thus preventing the collapse of the airway irrespective of the underlying pathophysiological mechanisms. However, the clinical utility of CPAP is somewhat limited by incomplete tolerability and poor compliance [2]. Many patients only use CPAP for a part of their night sleep, thereby leaving a window of vulnerability to apnoeas for a considerable period of time. To the best of our knowledge, other treatment alternatives, such as oral appliances and surgical methods, provide highly variable results for this disorder. Hence, multiple attempts

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Sleep/wake influences on breathing Brainstem respiratory controller Haemodynamic control Hypoglossal nerve activity Tongue motor function and salivary glands Pulmonary gas exchange Chemosensory function

Acidbase metabolic control

have been made to identify an effective pharmacological treatment in patients with OSA and several potential targets have been proposed (fig. 1). However, it is important to recognise that appropriate and detailed targets for rational drug development for this condition have still not been fully defined. Most studies in this area are based upon clinical experimental protocols that apply drugs, already used in other medical conditions and with established toxicity and tolerability.

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It is important to note that sleep apnoea comprises a spectrum of Figure 1. The principal mechanisms that have been targeted for phenotypes that may require spethe pharmacological treatment of sleep-disordered breathing. The proposed mechanisms may involve either single or multiple levels of cific approaches. We cannot expect action, as well as modulation of a feedback respiratory loop system that a single form of pharmacofor stabilisation. logical treatment will fit all OSA patients. A series of special considerations are, therefore, needed when pharmacological studies are conducted and treatment effects are evaluated. This chapter will first address some of the major methodological problems faced in clinical drug trials in sleep apnoea. The chapter will then discuss the major principles explored in existing studies. This will address the three following areas: 1) drugs explored for specific treatment of sleep apnoea; 2) treatment of associated conditions, such as excessive daytime sleepiness, obesity, hypertension, reflux disease and conditions of the oronasal airway; and 3) hormone-related mechanisms, including treatments used in menopausal hormone replacement therapy, hypothyroidism and acromegaly.

Challenges in developing pharmaceutical agents for OSA

Which patients should be included in clinical trials?
Sleep-disordered breathing exists in fundamentally different forms. Patients may have predominantly central or obstructive apnoeas. The expression of the disorder is highly influenced by phenotypic characteristics, such as sex, age of onset, body composition, craniofacial structure and comorbid conditions, e.g. obesity and heart failure. The operational physiological compensatory mechanisms in an obese patient, with compromised upper airway patency during sleep, may differ completely from that in a lean person whose airway collapse only occurs during episodes of rapid eye movement (REM) sleep. If these two patients are treated with a mechanical modality like CPAP, both may experience a similar benefit from the positive airway pressure. However, a drug proven to be effective in one phenotype may, depending on its mechanism of action, be completely ineffective in another. Although the critical descriptors for this phenotypic classification are incomplete, components such as ventilatory control, fat deposition, craniofacial abnormalities, circadian rhythm and sleep regulation, may be considered. This expected heterogeneity suggests that we should expect various subgroups of OSA patients to be selectively responsive for a specific pharmacological intervention. In a scientific sense, this notion may also provide the possibility of better understanding of the fundamental principles of this disorder. If patients present with a variable responsiveness to a drug, this may provide us with the possibility of diagnostically recognising various subtypes of patients with sleep-disordered breathing.

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How should sleep study data be handled in clinical trials?

The construction of clinical trials in sleep-disordered breathing is associated with a number of specific problems. The condition is quantified by continuous physiological recordings and factors such as type of recording devices used and inter-scorer variability in polysomnography studies, which may have a profound impact on the trials outcome. Multicentre trials, therefore, need to apply centralised scoring functions. Multiple evaluation points need to be considered as the data from sleep studies are subject to night-to-night variability, which are induced by body positional changes, variable sleep stage distribution and modifiable factors, e.g. drug and alcohol intake. Although there are guidelines with detailed information regarding the scoring of breathing events and the diagnosis of sleep apnoea, the standards applied throughout clinical trials still need to be better established. For instance, several trials use apnoea/hypopnoea index (AHI) as a primary efficacy variable, although thermistor or pressure cannula may be used in protocols. It is unclear whether or not data should be presented after adjustment for body position. Minimum total sleep time periods that are acceptable in studies may also still need to be better defined.

What efficacy end-points should be used in clinical trials?

There is also debate about the optimal variable(s) needed to define sleep apnoea severity in clinical drug trials. Although most trials have used various definitions of AHI as a primary efficacy measure, it should be pointed out that this measure shows only a moderate association with sleepiness, cognitive dysfunction, or cardiovascular complications, e.g. blood pressure elevation and coronary artery disease. Other measurements, e.g. hypoxaemia or sleep fragmentation, may be associated more closely with the vascular or metabolic sequels of the condition. Moreover, a drug used for treatment of sleep apnoea could have specific and synergistic effects on comorbid conditions, such as cardiovascular or metabolic disease, daytime cognitive function or daytime sleepiness, which could represent a useful end-point in clinical trials. This possibility has not been explored or systematically incorporated in the evaluation of the efficacy of intervention in the current published studies. Future interventional trials in this area may benefit from a global evaluation of breathing events during sleep, daytime symptoms, vascular sequels and diseasespecific outcome measurements of quality of life. With some of these factors taken into account, there is a reasonable body of literature on drug studies in different forms of sleep-related disordered breathing [35]. Although most of the trials are limited in size, there are some that meet the stringent quality criteria that are applied in drug development. Most studies have addressed the direct interventional effects on sleep-disordered breathing, while others focused the effects on OSA following treatment of conditions associated with the disorder, e.g. obesity, hypertension and gastro-oesophageal reflux disease.

Specific areas addressed in drug trials

Catecholamine and serotonin modulation
Adrenergic pathways have been implicated in sleep and breathing for several reasons. Noradrenergic neurons originating in the brain stem locus coeruleus act on multiple adrenergic receptors throughout the brain and spinal cord. Importantly, however, the activity in this system is highly state dependent and influenced by sleep and arousal mechanisms. Periodic activation of autonomic activity mediated via this system is a central phenomenon described in periodic breathing during sleep. Central adrenergic nerve traffic may be modulated in several ways, including neuronal reuptake inhibition by tricyclic antidepressant drugs. Several early trials suggested a weak beneficial effect of the tricyclic protriptyline in patients with OSA [68]. These studies were small but pointed towards a reduction of oxygen saturation during sleep, along with changes in sleep architecture. However, a more recent randomised placebo-controlled trial could not confirm this effect of protriptyline [9]. Other studies addressing patients with chronic

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obstructive pulmonary disease (COPD) found a specific reduction of REM sleep and nocturnal hypoxaemia after protriptyline [10]. The lowest overnight oxygen saturation value increased by 7.1 and 5.0% after 2 and 10 weeks, respectively, of protriptyline treatment but pulmonary function tests were unchanged. However, this improvement was no longer present at long-term follow-up [11]. The potential mechanism behind the short-term beneficial effects in these studies may include protriptyline-induced suppression of REM sleep, a sleep stage frequently associated with more severe apnoea. However, the disrupted sleep pattern and the poorly maintained effect clearly limit the usefulness of protriptyline in OSA. The possible involvement of central dopaminergic mechanisms in sleep and autonomic control is less evident. There have been only a few studies dealing with dopamine-related mechanisms in sleep apnoea. However, dopamine is also an inhibitory neurotransmitter in the mammalian carotid body [12] and may, therefore, provide a target for interaction with the ventilatory response in this group of patients. Indeed, the peripherally acting dopamine antagonist domperidone has been shown to increase the hypercapnic ventilatory response in patients with sleep apnoea [13]. A recent small uncontrolled study on a combination of domperidone and pseudoephedrine, suggested a strong effect on sleepiness, possibly fewer apnoeas and improved oxygenation [14]. However, part of the effects recorded may have been related to concomitant weight reduction, and further controlled randomised studies are warranted. Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter primarily found in the gastrointestinal tract, platelets and central nervous system. The brainstem raphe nuclei constitute the principal source of central 5-HT release, and axons, from the neurons in this area, reach almost every part of the central nervous system. Serotonin, synthesised from the amino acid L-tryptophan, mediates both excitatory and inhibitory neurotransmission via seven different serotonin receptor families, which contain various subtypes of G protein-coupled receptors and ligand-gated ion channels, located in the central and peripheral nervous systems. Serotonin modulates the release of many neurotransmitters, including: glutamate, c-aminobutyric acid (GABA), dopamine, adrenalin/noradrenalin, and acetylcholine. This neurotransmitter has, therefore, been implicated in a wide spectrum of physiological mechanisms. Many of them, such as sleep, cognition, respiration, appetite and cardiovascular function are of special interest in the context of sleep-disordered breathing. The possible involvement of serotonin mechanisms in sleep generation and upper airway dilator motor neuron activity has received the most intense interest. Tonic serotonergic input to the hypoglossal motor neurons from the medullary raphe decreases from wakefulness to non-REM sleep and reaches a minimum during REM sleep. Transgenic mice, lacking mono-amino oxidase A, exhibit increased rates of central apnoea, which is sharply reduced after administration of odansetron and fluoxetine [15]. Increased upper airway muscular tone during sleep has been proposed as a target for pharmacotherapeutic development in OSA. For instance, the local injection of tetanus neurotoxin to increase upper airway muscle tone reduced respiratory events during sleep in British bulldogs [16]. Hypoglossal nerve firing and genioglossus muscle activity are facilitated by serotoninergic turnover [17], which is reduced during REM sleep. The physiological relevance of this influence may be reflected by the more pronounced severity of OSA seen in many patients during REM sleep. Importantly, this would leave less of a therapeutic window during REM sleep for compounds that inhibit serotonin reuptake. A recent association study in the Chinese Han population demonstrated a lower AHI paralleled with lower plasma concentrations of 5-HT and the metabolite 5-hydroxyindolacetic acid in male patients carrying an S-12 haplotype constructed by polymorphisms of the serotonin transporter gene [18]. The serotonin receptor pharmacology of airway and central nervous system respiratory control is complex. Functional characterisation based on animal experiments suggests that the dilator motor neuron post-synaptic serotonin receptor is predominantly of the 5-HT2A and, to a lesser degree, of the 5-HT2C subtype and, in adults, it is the inhibitory presynaptic 5-HT1B receptor. The subtypes

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5-HT1A (inhibitory) and 5-HT2 are also found within central respiratory controller neurons. Stimulation of peripheral 5-HT2A, 5-HT2C and 5-HT3 receptor subtypes led to the inhibition of respiration, most likely via an action at the level of the nodose ganglion [19]. The exact functional characterisation of the respiratory effects of these receptors is most likely to be influenced by species differences and animal preparations used. For instance, the role of serotonin mechanisms may be overestimated in studies using vagotomised animals [20]. The use of clinically irrelevant dose levels or concurrent administration of agents that produce feedback influences on the mechanisms studied, will affect the net respiratory responses. For instance, the 5-HT3 receptor antagonist ondansetron has been shown to reduce the respiratory disturbance index (RDI) in REM sleep by 54% in the English bulldog [21], but was ineffective in a subsequent study of human OSA [22]. Some clinical studies in this area have applied selective serotonin reuptake inhibitor drugs and interestingly these seem to reduce AHI mainly during non-REM sleep. In an open trial, fluoxetine reduced AHI by approximately 40% [23], and paroxetine, evaluated under double-blind controlled conditions, led to a 20% reduction of the AHI during non-REM sleep [24]. Experimental studies have shown that paroxetine increases genioglossus muscle activity in awake, healthy volunteers [25]. However, the effect on upper airway stability may be less important during sleep when serotonergic medullary raphe activity is particularly low [26]. The antidepressant drug mirtazapine has a complex pharmacology with 5-HT1 agonistic, and 5-HT2 and 5-HT3 antagonistic properties. In healthy participants, mirtazapine increased the slowwave sleep without REM sleep suppression [27]. Animal studies have demonstrated increased genioglossus activity [28] and a suppression of apnoea during sleep [29] after the use of mirtazapine. A short-term placebo-controlled crossover study of mirtazapine in OSA patients, found a substantial reduction of AHI in the dose range 4.515 mg [30]. However, more recent randomised controlled trials did not confirm these early findings [31]. Side-effects, such as sedation and weight gain, were recorded and clearly limit the usefulness of mirtazapine in sleep apnoea. In spite of the prospects provided by animal experiments for a serotonergic mechanism in OSA there is limited evidence for a clinically useful effect in the hitherto completed human trials. It is possible that future strategies, addressing subreceptor-specific compounds and strategies, may provide better results.

Acetylcholine mechanisms
An alternative approach potentially related to sleep-stage modulation is exemplified by agents that modulate acetylcholinergic activity. As a neurotransmitter of both the peripheral and central nervous systems, acetylcholine plays a major role for autonomic nervous function. Collectively, there is data to suggest that cholinergic mechanisms may modulate several different mechanisms associated with sleep-disordered breathing. For instance, as one of the main neurotransmitter systems active during REM sleep, acetylcholine is involved in the modulation of the respiratory drive. Animal studies have demonstrated reduced genioglossal muscle tone after hypoglossal motor nucleus application of compounds that facilitate acetylcholinergic tone [32]. The implications of these findings for human OSA are unclear, but the trials of tricyclic antidepressants do not suggest beneficial effects attributable to the variable anticholinergic properties of the compounds. Other studies suggest that increased cholinergic activity may be beneficial in OSA. Acetylcholine is a modulator of upper airway mucosal secretory activity and may, by this action, reduce airway compliance and thereby collapsibility during sleep. Central cholinergic mechanisms may also act to increase chemosensitivity. A study of patients with multisystem atrophy demonstrated a relationship between reduced thalamic cholinergic nerve terminal density and the severity of OSA [33]. It was postulated that this may be due to decreased pontine cholinergic projections and the finding has revived the interest in a potential cholinergic treatment strategy in OSA.

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Physostigmine is a cholinesterase inhibitory agent, which increases both muscarinic and nicotinic activity by a reduction of the enzymatic acetylcholine degradation. A double-blind, randomised, crossover trial of physostigmine in lean patients with OSA reported an increase of REM sleep but a reduction of AHI by 23% compared with placebo (fig. 2) [34]. Body weight and AHI reduction were inversely related. Similar effects were seen in a subsequent placebo-controlled study of the orally available cholinesterase inhibitor donepezil given for 21 days [35]. Donepezil also induced a reduction of occult sleep apnoea in patients with Alzheimers disease in a trial of 23 patients treated for 3 months [36]. However, more recent data did not fully support these initial promising findings (data not shown). The findings are somewhat incongruent and therapeutic potential of cholinesterase inhibitors in OSA remains to be clarified. It may be that phenotypic characteristics of patients recruited in these trials are of fundamental importance for the response. In the case of physostigmine, lean patients with OSA may be particularly responsive. The procholinergic respiratory stimulant nicotine has also been attempted in OSA treatment. Nicotine is a potent activator of upper airway muscle but despite promising animal data, the effect was inconsistent in OSA patients. Nicotine gum taken at bedtime was associated with a reduction of AHI during the first part of the night in an early study [37]. However, two subsequent randomised trials investigating different nicotine patches found no effect [38, 39], with the exception of a deterioration in sleep quality [38]. Another study on healthy awake participants did not find a consistent increase of genioglossal muscle activity after a transmucosal nicotine patch [40]. The bioavailability of nicotine in the pharyngeal muscle is likely to be low when this formulation is used.

Theophylline
Theophylline influences ventilation by multiple effects, including antagonistic effects on adenosine in the central nervous system and stimulation on diaphragm contractility in the periphery. One early placebo-controlled trial of theophylline in OSA found a 20% reduction in obstructive AHI but no change in total AHI and sleep quality deteriorated [41]. Small reductions of AHI have also been found in other trials [42, 43], but a more recent single-night study in mild-to-moderate CPAP-treated OSA described an almost identical AHI and CPAP pressure after oral sustainedrelease theophylline [44]. Total sleep time and sleep efficiency were significantly reduced in the trial. Theophylline, therefore, seems to have no place in the treatment of OSA. However, there may be a potential use for theophylline in patients with more complex breathing disorders and central sleep apnoea (CSA). A placebo-controlled trial of 15 patients with compensated heart failure and central apnoea, found an approximate 50% reduc20 tion of AHI and decreased nocturnal 0 intermittent hypoxia after theophyl line when compared with placebo -20 [45]. The right and left ventricular -40 ejection fraction were unchanged. Similar effects on central apnoea -60 were confirmed in a more recent -80 uncontrolled trial of oral theophyl line in 13 patients with compensated -100 heart failure and periodic breathing 1 2 3 4 5 6 7 8 9 10 [46]. This study reported a reduction of over 50% in mainly central events, Patient n along with improvement of oxygenation; sleep was unaffected. The Figure 2. The proportional reduction in the apnoea/hypopnoea index (AHI) during rapid eye movement (REM) sleep in 10 patients with haemodynamic and neurohormonal moderate-to-severe obstructive sleep apnoea, following physostigeffects were more closely addressed mine infusion. Each point represents one individual patient. Reproin a controlled trial of theophylline duced and modified from [34] with permission from the publisher. in patients with congestive heart
Change of REM AHI %

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failure and healthy controls [47]. Theophylline increased plasma renin concentration and ventilation (lowered transcutaneous carbon dioxide) but did not affect the increase sympathetic activity in patients with heart failure. Considering that the options for treating central apnoea in heart failure are limited, this data may hold some promise. However, theophylline is not routinely recommended for central apnoea treatment due to a potential pro-arrhythmogenic effect.

Carbonic anhydrase inhibition

The carbonic anhydrase inhibitor acetazolamide represents a well-established approach to reduce CSA. Metabolic acidification via carbonic anhydrase inhibition is likely to act via central, and peripheral, chemosensory function to increase central respiratory drive. A placebo-controlled study of acetazolamide in high-altitude sleep-disordered breathing, a condition characterised by central apnoeas or hypopnoeas, showed an almost complete restoration of ventilation and improved oxyhaemoglobin saturation [48]. Other small studies have shown an almost 80% reduction of the frequency of apnoea after short-term acetazolamide treatment in patients with CSA [49] and a 20% reduction in apnoea events for patients with OSA [50]. In a separate series of studies, acetazolamide was found to reduce central apnoeas and arousals in patients with predominantly CSA and effects were maintained for up to 1 month [51]. In fact, the effect on CSA was still demonstrated 6 months after treatment in a subgroup of patients [52]. These findings have led to the suggestion that carbonic anhydrase inhibitors may induce a longlasting resetting of the carbon dioxide response threshold and, thereby, prevent apnoea development during sleep [53]. A short-term, randomised, placebo-controlled study, which addressed the effects of acetazolamide on CheyneStokes breathing associated with heart failure, found that central apnoea episodes were reduced by approximately 50%. In addition, an improvement in the nocturnal oxygenation and subjectively perceived sleep quality has also been observed (fig. 3) [54]. Acetazolamide was also found to completely eliminate the breathing disorder in a patient with complex apnoea (remaining central apnoea during concomitant CPAP) [55]. A more systematic use of acetazolamide in sleep apnoea is limited by mainly a high incidence of neurological side-effects. There has been a focus on selective carbonic anhydrase isoenzyme V inhibitors in obesity research and this is based on the weight reduction documented after compounds like topiramate and zonisamide; this is discussed further later in this chapter in the section entitled Body weight reduction and sleep-disordered breathing. At least 100 50 topiramate, according to a case re45 95 port, may reduce OSA severity during 40 90 short-term treatment independent of 35 85 weight change [56].
CAI nh-1 / % of /TST at Sa,O2 <90% Lowest Sa,O2 %

GABA and glutamate mechanisms

GABA is the main inhibitory neurotransmitter in the central nervous system. This amino acid regulates neuronal excitability by binding to specific transmembrane receptors both pre- and postsynaptically. GABA is synthetised in vivo by conversion of glutamate, the principal excitatory neurotransmitter. Episodic hypoxia has been speculated to accelerate the

80 75 70 65 60 55 50 Baseline Placebo

30 25 20 15 10 5 0

Acetazolamide

Figure 3. The effects of acetazolamide on CheyneStokes breathing, associated with heart failure. Central apnoea index (CAI; $) and lowest arterial oxygen saturation (Sa,O2) during rapid eye movement sleep (& %). The percentage of total sleep time (TST) spent under 90% Sa,O2 (&) is shown at baseline, after treatment with placebo or acetazolamide in 12 patients with systolic heart failure and sleep-disordered breathing. Data taken from [54].

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progression of OSA by GABAergic mechanisms [57]. This occurs as a result of impairment of neural control of upper airway patency and respiratory contractile function. The possibility of interfering with these potential long-term hypoxic effects has been explored in some studies. The potential involvement of GABA and glutamate mechanisms in this context was demonstrated by a slight reduction of overnight oxygen saturation but no change in AHI under the GABA agonist baclofen [58]. A small double-blind, controlled study of the putative glutamate antagonist sabeluzole in patients with moderate-to-severe OSA suggested a reduction of hypoxaemic events in a manner related to plasma drug concentration [59]. In a subsequent animal study using the glutamate release inhibitor riluzole, a reduction of post-sigh apnoeas but not spontaneous apnoeas in rats was observed [60]. The influence of post-synaptic N-methyl-D-aspartate glutamate receptor sensitivity in OSA was tested in a double-blind, randomised, placebo-controlled, single-dose crossover study of the Nmethyl-D-aspartate receptor antagonist AR-R15896AR in 15 males with moderate-to-severe sleep apnoea [61]. Overall AHI, as well as oxygen saturation variables, remained unchanged at all dosage levels tested. Sleep efficiency was decreased and vivid dream activity was constituted as a side-effect.

Oxygen and carbon dioxide

Oxygen has been tested for both OSA and CSA with CheyneStokes respiration. Nasally administrated oxygen lead to an improvement of oxyhaemoglobin saturation and a reduction of the AHI, but some central and mixed events appeared to have beeen shifted to obstructive ones [62, 63]. A later study from the same group showed that oxygen had no additional effect on apnoea frequency when the period of administration was extended [64]. A split-night study comparing supplemental oxygen 4 L?min-1 by nasal cannula and room air did not alter the frequency of apnoeic events, although there was some improvement in daytime symptoms after an extended treatment period with oxygen (30 nights) [65]. Transtracheal oxygen therapy has also been shown to reduce nocturnal hypoxaemia and to reduce AHI in OSA patients [66, 67]. The variable results of oxygen supplementation may be explained in part by phenotypic differences within the OSA patient groups. A recent study found a greater reduction of AHI after oxygen, but only among OSA patients with high loop gain of their ventilatory control system as a cause for ventilatory instability [68]. Indirectly this suggests that ventilator instability is an important mechanism causing sleep-disordered breathing in some, but not all, patients. Interestingly, in an experimental human model of intermittent hypoxia, reactive oxygen species overproduction was found to increase the acute hypoxic ventilatory response [69]. Whether antioxidants have a potential role in the treatment of OSA is unclear and needs to be studied further. Alternatively, oxygen supplementation seems to be far more useful in conditions with central apnoea and periodic breathing. Improvement of periodic breathing, along with a virtual elimination of arterial oxyhaemoglobin desaturation episodes following nasal oxygen administration, has been documented in several studies of patients with stable heart failure [7072]. However, oxygen supplementation was relatively ineffective in modifying the increased autonomic nervous activity associated with the breathing disorder in these patients [71]. Carbon dioxide has also been tested for OSA and CSA treatment. Administration of carbon dioxide (36%) during sleep caused a marked increase in ventilation along with an increase in upper airway inspiratory muscle activity. Apnoea time was reduced by 80% in a small study of patients with OSA [73]. However, there are methodological problems associated with the maintenance of a stable carbon dioxide level throughout the night, and carbon dioxide seems to either disturb sleep quality or have a worsening effect on apnoea-related arousals. A small trial using carbon dioxide administration to raise end-tidal carbon dioxide by 24 mmHg during sleep, in patients with congestive heart failure and idiopathic CSA, reported an elimination of approximately two-thirds of the breathing events, while the arousal index remained unchanged [74]. An alternative approach is to provide carbon dioxide as adjunctive therapy to positive airway pressure therapy. A small, open-label evaluation of incrementally added concentrations of carbon dioxide in the inspired gas mix in patients with severe, poorly controlled, mixed sleep-disordered

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breathing, reported a dramatic reduction of apnoeas without subjective signs of discomfort or shortness of breath (fig. 4) [75]. Arousals were reduced by 80% and no adverse effects on overall sleep architecture were reported. Hence, controlled carbon dioxide supplementation may represent a way to control at least certain forms of mixed obstructive and central sleep-disordered breathing.

Treatments addressing associated conditions in OSA

Reduction of daytime sleepiness in sleep-disordered breathing
Most daytime somnolence associated with OSA is alleviated when the proper treatment is initiated. However, daytime sleepiness remains in a subset of patients, despite appropriate compliance with effective CPAP therapy and measures to exclude comorbid conditions. Residual daytime sleepiness has been reported in approximately 15% of patients, adequately treated with CPAP, and acceptably compliant with therapy [76]. Several attempts have been made to institute drugs with a symptomatic effect in such patients. Modafinil, an analeptic that is widely used for narcolepsy treatment, appears to have multiple pharmacological effects including facilitation of monoamine release and promotion of hypothalamic histamine levels [77]. The latter mechanism may be central to the wakefulnesspromoting properties of the drug. Several randomised and placebo-controlled trials have shown that modafinil improves subjective and objective sleepiness, vigilance and quality of life in CPAPtreated OSA patients (table 1) [7882]. Conversely, modafinil does not reduce upper airway obstruction and the drug has no effect on the occurrence of apnoea/hypopnoeas in patients with OSA [83, 84]. In partial CPAP users, no improvement was found in overall clinical condition or sleep latency as recorded in the maintenance of wakefulness test after modafinil [82]. However, a recent randomised, placebo-controlled study showed that modafinil improved simulated driving performance, neurocognitive performance and subjective sleepiness in OSA patients after shortterm CPAP cessation [85]. Armodafinil, the R- and longer-lasting isomer of racemic modafinil, has been shown to improve wakefulness, overall clinical condition, fatigue and long-term memory in patients with residual daytime sleepiness, in CPAP-adherent OSA patients in randomised, placebo-controlled studies [86, 87]. A recent pharmacovigilance programme, initiated by the European Medicines Agency, has pointed to a strong link between modafinil and the risk of serious skin reactions, especially in children, as well as psychiatric/cardiovascular adverse reactions. Therefore, it was concluded that the benefits of medicines containing modafinil only continue to outweigh their risks in the treatment of narcolepsy. Data regarding the effectiveness of modafinil for the treatment of residual excessive sleepiness in OSA, shift-work sleep disorders and idiopathic hypersomnia, were not sufficient to outweigh the risks associated with its use. The agency, therefore, recommended that these indications should be removed from the product information [88].
100 90 80 70 60 50 40 30 20 10 0

RDI events.h-1

3 Patient n

Figure 4. Respiratory disturbance index (RDI) in six patients with

refractory mixed obstructive and central sleep-disordered breathing at baseline, and after conventional treatment and titration with a prototype positive airway pressure gas modulator administering 0.51% carbon dioxide in the inhaled gas mixture across the night. Values from recordings on three separate nights are linked for each patient. Reproduced and modified from [75] with permission from the publisher.

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Table 1. Modafinil trials on residual sleepiness in continuous positive airway pressure (CPAP) treated obstructive sleep apnoea patients Outcome measures Significant findings Side-effects

First author [Ref.] 400

Study design Study period Dosage level weeks mg?day-1

K INGSHOTT [78]

Randomised, placebocontrolled, crossover (n532)

P ACK [79] D INGES [80]

Randomised, placebocontrolled, parallel group (n5157)

S CHWARTZ [81]

Open-label (n5125)

12

B LACK [82]

Randomised, placebocontrolled, parallel group (n5309)

12

Subjective sleepiness (ESS), Improvement of MWT Headache, nausea, dry objective sleepiness (sleep sleep latency, mouth latency on MSLT and MWT), CPAP usage decreased CPAP usage, quality of life, cognitive performance, global evaluation, PSG variables 200 for 1 week, Subjective sleepiness (ESS), Improvement of ESS score, Headache, dizziness, 400 for 3 weeks objective sleepiness (sleep improvement of MSLT and nervousness, anxiety, latency on MSLT), clinical clinical global evaluation. twitch, insomnia global evaluation, PSG Small increase of arousal index variables, CPAP usage [81]. and sitting blood pressure [81] PVT test, FOSQ [82] Improvement of PVT parameters, total FOSQ score and activity level and vigilance subscale [82] 200, 300 or 400 Subjective sleepiness (ESS), Improvement of ESS score, Headache, anxiety, clinical global evaluation, clinical global evaluation, total nervousness, insomnia, FOSQ, night CPAP usage FOSQ score and activity level, nausea, rhinitis, vigilance, intimacy, general infection, dizziness, productivity, social outcome pain, sinusitis subscale. CPAP usage decreased, small increase of standing diastolic blood pressure 200 or 400 Subjective sleepiness (ESS), Improvement of ESS score, Headache, nausea, objective sleepiness (sleep sleep latency of MWT, clinical anxiety, chest pain, latency on MWT), clinical global global evaluation, total FOSQ dizziness evaluation, FOSQ, PSG score and vigilance, general variables, CPAP usage productivity, activity level subscale

ESS: Epworth Sleepiness Scale; MSLT: multiple sleep latency test; MWT: maintenance of wakefulness test; PSG: polysomnography; PVT: psychomotor vigilance task; FOSQ: functional outcomes of sleep questionnaire.

Tumour necrosis factor (TNF)-a, a pro-inflammatory cytokine, was found to be elevated in OSA independent of obesity [89]. A pilot, placebo-controlled, double-blind study of the TNF-a inhibitor etanercept, in eight obese males with OSA, found a modest but significant 15% reduction in AHI [90]. Objective sleepiness, measured by multiple sleep latency test, was markedly improved suggesting that pro-inflammatory cytokines may constitute an important mediator of excessive daytime sleepiness in sleep and breathing disorders.

Body weight reduction and sleep-disordered breathing

The strong association between obesity and OSA is well established. Moderate-to-severe OSA is reported in more than 50% of obese subjects [91] and conversely, depending on the population studied, approximately 50% of patients with OSA fulfil the obesity criteria (data not shown). In fact, several population studies suggest a linear relationship between body mass index (BMI) and the sleep and breathing disorder [92, 93]. Weight-reduction studies estimate that the AHI is reduced by approximately 3% for every 1% of body weight that is lost [94]. Protocols that address pharmacological weight reductions suggest not only that sleep apnoea is modifiable by weight loss but that also added metabolic benefits may be achieved in patients with a combination of the two conditions. A 6-month, open, uncontrolled cohort study of sibutramine in 87 obese males with OSA reported a 35% reduction in sleep-disordered breathing (RDI from 46 to 16.3 events?h-1) along with a body weight loss of approximately 8.5% [95]. Multiple metabolic indices, including: insulin resistance; high-density lipoprotein cholesterol; visceral and subcutaneous abdominal fat; and liver fat, were improved in parallel, while heart rate and blood pressure were unchanged [96]. However, weight reduction was less pronounced in a subsequent smaller study comparing sibutramine treatment with conventional CPAP, and the effects on sleep-disordered breathing were small and inferior to those induced by CPAP [97]. Alternative drugs applied in weight management, including the lipase inhibitor orlistat and the cannabinoid receptor antagonist rimonabant, have not been systematically studied in sleep apnoea. However, a recent abstract described a 28-week placebo-controlled study that examined the combined use of phentermine and topiramate in obese OSA patients [98]. Body weight was decreased by 10.3% in the active group compared with 4.2% after placebo treatment and the AHI was reduced by 69% and 38%, respectively. Additional beneficial effects were recorded in terms of blood pressure reduction, reduced sleep fragmentation and the improvement of sleep quality. These effects are particularly interesting in the light of carbonic anhydrase inhibitory properties ascribed to topiramate. The findings open a possibility for targeted weight-reduction therapy in obese patients with sleep apnoea. The prospect of added health benefits in this group of patients, in terms of reduction in cardiovascular risk and improved metabolic function, should spark further clinical trials in this area.
J. HEDNER AND D. ZOU

Antihypertensive therapy and OSA

More than 50% of the adult to elderly population with sleep apnoea, investigated throughout European sleep laboratories, receive treatment with antihypertensive drugs (data not shown). Consequently, the question has been raised as to whether if blood pressure reduction per se, or specific medications used for the treatment of hypertension, may influence sleep apnoea. Indeed, there is data suggesting that the level of blood pressure may influence upper airway stability [99]. Following pressure elevation, upper airway collapsibility has increased in a dog model, whereas hydralazine-induced lowering of blood pressure was accompanied by a reduction of apnoeic events in rats [100]. However, these findings in animals have not been confirmed in experimental human studies, as an induced blood pressure elevation does not alter upper airway resistance during non-REM sleep [101]. Alternatively, both the angiotensin-converting enzyme inhibitor cilazapril and the b-blocker metoprolol were found to moderately reduce apnoea frequency during sleep in an early double-blind trial [102]. But no effect on AHI was found on celiprolol compared with the placebo in a more recent study [103]. Another double-blind, randomised trial addressing

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cilazapril, reported a marginal reduction of RDI and the apnoea index during non-REM but not REM sleep [104]. This was not confirmed in a controlled trial comparing CPAP and the angiotensin II receptor antagonist valsartan [105]. Finally, a randomised study, which compared the effect of atenolol, amlodipine, enalapril, hydrochlorothiazide and losartan in 40 hypertensive OSA patients, found no effect on sleep-disordered breathing by any of the studied compounds, although the degree of blood pressure reduction achieved by treatment varied between the therapies [106]. Thus, there is little to suggest that antihypertensive treatment has any direct effect on OSA. This, however, does not preclude that certain antihypertensive regimens may be specifically suitable for treatment of elevated blood pressure and cardiovascular sequels in OSA.

Gastro-oesophageal reflux and sleep-disordered breathing

Gastro-oesophageal reflux disease is common in patients with OSA. The exact mechanistic relationship between the two conditions is unclear but may, beside common predisposing factors such as obesity and alcohol, involve the periodic reduction of intrathoracic pressure caused by OSA during sleep. Alternatively, acid reflux in gastro-oesophageal reflux disease may produce arousals and night choking as well as acid-induced long-term pharyngeal tissue swelling, which promotes upper airway obstruction during sleep. Indeed, a 50% reduction of AHI after short-term combined anti-reflux therapy of cisapride and omeprazole was described in a study in patients with the two combined conditions [107]. A small parallel group study using nizatidine reported a decrease in the arousal index, but not the AHI, after 1 month of treatment [108], while omeprazole produced reductions in the apnoea index and the AHI by 31 and 25%, respectively, in a preliminary study [109]. These findings are not supported by a more recent study, in which it was shown that pantoprazole significantly improved daytime sleepiness and the total reflux score in OSA patients with acid reflux symptoms, but the total AHI remained unchanged [110].
PHARMACOLOGICAL MANAGEMENT OF SDB

Oronasal airway and sleep apnoea

An interesting series of studies describes compounds that reduce upper airway compliance, after the use of compounds via a lowering of surface tension of the liquid in the upper airway lining. Topical application of soft-tissue lubricant in 10 patients with mild OSA caused a modest reduction of AHI, without the simultaneous detectable effects in sleep architecture in a placebo-controlled trial [111]. The administration of a surfactant led to a small, but significant, reduction of RDI in seven males with OSA [112]. Another study reported that exogenous surfactant significantly improved upper airway stability and respiratory events by 30% in nine patients with OSA [113]. Perennial allergic rhinitis was over-represented in OSA patients compared with patients with COPD in a casecontrol study [114]. Nasal airflow resistance was therefore assessed in a randomised, crossover study that compared intranasal fluticasone and placebo [115]. A total of 13 patients with mild OSA and coexisting rhinitis were investigated and the AHI was reduced, by approximately 25%, in the treatment group. However, an early randomised trial of a nasal decongestant in adults found no effect in snorers with moderate OSA [116]. Other data suggest that intranasal corticosteroids could be of potential interventional use for children with OSA; the mechanism behind this involves the reduction in size of the lymphadenoid tissue found in the upper airway [117, 118].

Hormonal replacement therapy and sleep-disordered breathing

The prevalence of sleep-disordered breathing increases among females after the menopause. Hormone replacement therapy may reduce this risk. Most studies in this area suggest that sexrelated steroids may provide a protective effect against OSA. There is also experimental data that show a reduction of genioglossus electromyographic activity during wakefulness in the follicular phase, compared with the luteal phase of the menstrual cycle [119]. Genioglossus activity appears to be further reduced in postmenopausal females in a manner that may be restituted after

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hormone therapy [120]. However, the effect of sex steroids may also include other mechanisms, such as respiratory stimulation, increased chemosensitivity or a modification of the apnoea threshold during sleep.

Oestrogen and progesterone

Oestrogen and progesterone administration to postmenopausal females have produced somewhat inconsistent data. While no significant change in OSA was found after medroxyprogesterone acetate treatment in an early uncontrolled study [120], a subsequent randomised controlled study reported a reduction of apnoea duration but not the numbers of the events [121]. Another small study of combined progestin and oestrogen treatment, found a reduced number of sleepdisordered breathing episodes in healthy postmenopausal females [122]. However, the overall event number was low. A total of 15 postmenopausal females with moderate-to-severe OSA were studied after oestrogen alone, or in combination with progesterone. There was no change in terms of clinical disease severity after almost 2 months of treatment [123]. A small prospective 1 month crossover study found a 25% reduction of AHI after estradiol, and a further reduction to 50% after the addition of progestin [124]. A pilot study of six females with OSA found that oestrogen reduced AHI by 46% [125]. Another small pilot study found a 75% reduction of AHI after hormone replacement therapy [126]. The effect of progesterone may be more pronounced in females with partial upper airway obstruction. A daily dose of 60 mg of medroxyprogesterone acetate was found to improve ventilation in postmenopausal females with partial upper airway obstruction during sleep [127]. Despite the potential usefulness of hormone replacement therapy, in terms of sleep-disordered breathing, there are safety issues related to its use. These issues include an increased risk of coronary heart disease, stroke, breast cancer and thromboembolic events.
J. HEDNER AND D. ZOU

Hypothyroidism and thyroid hormone replacement in sleep apnoea

OSA is over-represented in hypothyroid patients, especially in those with a high BMI. Several mechanisms have been suggested to explain this association, including: decreased ventilatory responses; extravasation of albumin; and mucopolysaccharides in the tissues of the upper airway and hypothyroid myopathy. An early study of long-term thyroxine replacement in hypothyroid OSA patients found a massive reduction of apnoea frequency, independent of concomitant weight changes [128]. Some smaller studies [129, 130], but not all [131], have supported this finding. Hence, CPAP is recommended in patients with OSA who receive thyroxine supplementation for hypothyroidism. Once the thyroxine replacement therapy reaches steady state, a sleep study is needed to confirm that secondary apnoeas caused by hypothyroidism have been eliminated.

Acromegaly in OSA
Epidemiological studies suggest that the prevalence of sleep apnoea in patients with acromegaly is approximately 1339% [132, 133]. It has been suggested that the upper airway soft tissue hypertrophy in this condition causes airway narrowing and increased pharyngeal collapsibility during sleep. Altered respiratory control may also be a mechanism by which sleep apnoea is over-represented in acromegaly. The somatostatin analog octreotide reduced the AHI by 50% in a 6-month open-label study of acromegalic patients [134]. Two additional studies of octreotide in acromegaly with OSA found a reduction of 55 and 28%, respectively, along with an AHI reduction of tongue tissue volume [135, 136]. Hence, the suppression of the growth hormone might reduce sleep apnoea in acromegaly patients with OSA, but residual skeletal and soft tissue abnormalities of the upper airway may necessitate concomitant CPAP therapy in order to eliminate persisting apnoeic events.

Conclusion
There is a need for pharmacologically based treatment regimens in sleep-disordered breathing. This overview has listed some of the hitherto explored studies in the area. It is evident that many

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of the attempts to identify useful drugs have provided disappointing results, but there are also several promising avenues for continued development in the area. No single explored drug has been consistently shown to reduce OSA by more than 50% in controlled studies. However, compared with currently applied therapies like CPAP or oral devices, it is possible that an effect in this order of magnitude may represent an acceptable treatment goal, provided that compliance with the applied treatment is high. The process of systematic drug development typically extends over decades from early discovery to new drug application. On the one hand, serendipitous findings (i.e. a certain drug is clinically observed to reduce OSA or its sequels) do occur and in fact several explored avenues for drug treatment in OSA have been based on this rationale. On the other hand, rational drug development requires adequate biological experimental systems or animal models. Such models have been developed in the field of sleep-disordered breathing but their adequacy for the clinical condition has been questioned. Most of the current studies in the area deal with AHI/RDI as a meter to quantify effect. Clearly, we need to reach a consensus on optimal outcome variables to be used in trials in this area. Efficacy may also be rated in terms of sleep improvement, improved cognitive function, well-being, reduction of comorbid metabolic or cardiovascular disorders, as well as a modification of the risk to develop cardiovascular complications in OSA. Improved understanding of the pathophysiology of sleep apnoea is likely to open new perspectives for development of treatment strategies and specifically lead to better selection and stratification of patients in clinical drug studies.

Statement of Interest
PHARMACOLOGICAL MANAGEMENT OF SDB

J. Hedner is an owner in part of patents addressing the use of topiramate and zonisamide in sleepdisordered breathing.

Acknowledgements
teborg Medical Supported by the Swedish Heart and Lung Foundation (project 20080587), Go s senior research award. Society and Lars Werko

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