Pharmacological management of sleep-disordered breathing.pdf

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Chapter 19

Pharmacological

management of sleep-disordered breathingJ. Hedner and D. Zou

Summary

Several attempts have been made to identify a uniformlyeffective pharmacological remedy in obstructive sleep apnoea(OSA). However, no currently described drug has consistentlyreduced the severity of the condition by more than 50% incontrolled trials. Most of the data is based on testing ofcompounds used in other therapeutic areas and there are fewexamples of rational strategic drug development. OSA isfrequently associated with considerable comorbidities, includ-ing: hypertension, obesity, metabolic derangement and hormo-

nal dysfunction, beside the more or less consistent symptoms ofdaytime sleepiness and cognitive dysfunction. Hence, specificconsiderations, such as classification of phenotype, existingcomorbidityetc., should be taken into account when explorativeclinical trials are designed in patients with OSA. The clinicianshould be made aware that there is no systematicallydocumented drug yet available for the treatment of sleepapnoea. Future drug development is likely to incorporate amore global approach to comorbid conditions and risk

modification in OSA.

Keywords: Clinical trial, drug, hypertension, obesity, sleepapnoea, treatment

Dept of Pulmonary Medicine andAllergology, Sahlgrenska UniversityHospital, Gothenburg, Sweden.

Correspondence: J. Hedner, SleepDisorders Centre, Dept of PulmonaryMedicine and Allergology,Sahlgrenska University Hospital,41345 Gothenburg, Sweden, Email

[email protected]

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

The complicated pathogenesis of obstructive sleep apnoea (OSA) involves an anatomicalpredisposition for airway collapse, a decreased compensatory neuromuscular control of upperairway and unstable central neurochemical ventilatory control during sleep [1]. Continuouspositive 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 theunderlying pathophysiological mechanisms. However, the clinical utility of CPAP is somewhatlimited by incomplete tolerability and poor compliance [2]. Many patients only use CPAP for apart of their night sleep, thereby leaving a window of vulnerability to apnoeas for a considerableperiod of time. To the best of our knowledge, other treatment alternatives, such as oral appliancesand surgical methods, provide highly variable results for this disorder. Hence, multiple attempts

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have been made to identify aneffective pharmacological treat-ment in patients with OSA andseveral potential targets have beenproposed (fig. 1). However, it isimportant to recognise that appro-priate and detailed targets for

rational drug development for thiscondition have still not been fullydefined. Most studies in this areaare based upon clinical experimen-tal protocols that apply drugs,already used in other medicalconditions and with establishedtoxicity and tolerability.

It is important to note that sleepapnoea comprises a spectrum of

phenotypes that may require spe-cific approaches. We cannot expectthat a single form of pharmaco-logical treatment will fit all OSApatients. A series of special con-

siderations are, therefore, needed when pharmacological studies are conducted and treatmenteffects are evaluated. This chapter will first address some of the major methodological problemsfaced in clinical drug trials in sleep apnoea. The chapter will then discuss the major principlesexplored in existing studies. This will address the three following areas: 1) drugs explored forspecific 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 replacementtherapy, 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 havepredominantly central or obstructive apnoeas. The expression of the disorder is highly influencedby phenotypic characteristics, such as sex, age of onset, body composition, craniofacial structureand comorbid conditions, e.g. obesity and heart failure. The operational physiologicalcompensatory mechanisms in an obese patient, with compromised upper airway patency duringsleep, may differ completely from that in a lean person whose airway collapse only occurs duringepisodes of rapid eye movement (REM) sleep. If these two patients are treated with a mechanicalmodality 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 ofaction, be completely ineffective in another. Although the critical descriptors for this phenotypicclassification are incomplete, components such as ventilatory control, fat deposition, craniofacialabnormalities, circadian rhythm and sleep regulation, may be considered.

This expected heterogeneity suggests that we should expect various subgroups of OSA patients to beselectively responsive for a specific pharmacological intervention. In a scientific sense, this notionmay also provide the possibility of better understanding of the fundamental principles of thisdisorder. If patients present with a variable responsiveness to a drug, this may provide us with thepossibility of diagnostically recognising various subtypes of patients with sleep-disordered breathing.

Sleep/wakeinfluences on

breathing

Brainstemrespiratorycontroller

Hypoglossalnerve activity

Tongue motorfunction and

salivary glands

Pulmonarygas exchange

Acidbasemetabolic control

Chemosensoryfunction

Haemodynamiccontrol

Figure 1. The principal mechanisms that have been targeted forthe pharmacological treatment of sleep-disordered breathing. Theproposed mechanisms may involve either single or multiple levels of

action, as well as modulation of a feedback respiratory loop systemfor stabilisation.

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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 ofspecific problems. The condition is quantified by continuous physiological recordings and factorssuch 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 toapply 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 positionalchanges, 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 eventsand the diagnosis of sleep apnoea, the standards applied throughout clinical trials still need to bebetter established. For instance, several trials use apnoea/hypopnoea index (AHI) as a primaryefficacy variable, although thermistor or pressure cannula may be used in protocols. It is unclearwhether or not data should be presented after adjustment for body position. Minimum total sleeptime 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 clinicaldrug trials. Although most trials have used various definitions of AHI as a primary efficacymeasure, it should be pointed out that this measure shows only a moderate association withsleepiness, cognitive dysfunction, or cardiovascular complications, e.g. blood pressure elevationand coronary artery disease. Other measurements, e.g.hypoxaemia or sleep fragmentation, may beassociated more closely with the vascular or metabolic sequels of the condition. Moreover, a drugused for treatment of sleep apnoea could have specific and synergistic effects on comorbidconditions, such as cardiovascular or metabolic disease, daytime cognitive function or daytimesleepiness, which could represent a useful end-point in clinical trials. This possibility has not beenexplored 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 globalevaluation of breathing events during sleep, daytime symptoms, vascular sequels and disease-specific outcome measurements of quality of life.

With some of these factors taken into account, there is a reasonable body of literature on drugstudies in different forms of sleep-related disordered breathing [35]. Although most of the trialsare limited in size, there are some that meet the stringent quality criteria that are applied in drugdevelopment. Most studies have addressed the direct interventional effects on sleep-disorderedbreathing, while others focused the effects on OSA following treatment of conditions associatedwith 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 adrenergicreceptors throughout the brain and spinal cord. Importantly, however, the activity in this system ishighly state dependent and influenced by sleep and arousal mechanisms. Periodic activation ofautonomic 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 trialssuggested a weak beneficial effect of the tricyclic protriptyline in patients with OSA [68]. Thesestudies were small but pointed towards a reduction of oxygen saturation during sleep, along withchanges in sleep architecture. However, a more recent randomised placebo-controlled trial couldnot 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 nocturnalhypoxaemia after protriptyline [10]. The lowest overnight oxygen saturation value increased by 7.1and 5.0% after 2 and 10 weeks, respectively, of protriptyline treatment but pulmonary functiontests 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 mayinclude protriptyline-induced suppression of REM sleep, a sleep stage frequently associated withmore 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 isless evident. There have been only a few studies dealing with dopamine-related mechanisms insleep apnoea. However, dopamine is also an inhibitory neurotransmitter in the mammaliancarotid body [12] and may, therefore, provide a target for interaction with the ventilatory responsein this group of patients. Indeed, the peripherally acting dopamine antagonist domperidone hasbeen shown to increase the hypercapnic ventilatory response in patients with sleep apnoea [13]. Arecent 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 inthe gastrointestinal tract, platelets and central nervous system. The brainstem raphe nucleiconstitute 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 acidL-tryptophan, mediates both excitatory and inhibitory neurotransmission via seven differentserotonin receptor families, which contain various subtypes of G protein-coupled receptors andligand-gated ion channels, located in the central and peripheral nervous systems. Serotoninmodulates 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 inthe context of sleep-disordered breathing.

The possible involvement of serotonin mechanisms in sleep generation and upper airway dilatormotor neuron activity has received the most intense interest. Tonic serotonergic input to thehypoglossal motor neurons from the medullary raphe decreases from wakefulness to non-REMsleep and reaches a minimum during REM sleep. Transgenic mice, lacking mono-amino oxidaseA, exhibit increased rates of central apnoea, which is sharply reduced after administration ofodansetron and fluoxetine [15].

Increased upper airway muscular tone during sleep has been proposed as a target forpharmacotherapeutic development in OSA. For instance, the local injection of tetanus neurotoxinto increase upper airway muscle tone reduced respiratory events during sleep in British bulldogs[16]. Hypoglossal nerve firing and genioglossus muscle activity are facilitated by serotoninergicturnover [17], which is reduced during REM sleep. The physiological relevance of this influencemay be reflected by the more pronounced severity of OSA seen in many patients during REMsleep. Importantly, this would leave less of a therapeutic window during REM sleep forcompounds that inhibit serotonin reuptake. A recent association study in the Chinese Hanpopulation demonstrated a lower AHI paralleled with lower plasma concentrations of 5-HT andthe metabolite 5-hydroxyindolacetic acid in male patients carrying an S-12 haplotype constructedby polymorphisms of the serotonin transporter gene [18].

The serotonin receptor pharmacology of airway and central nervous system respiratory control iscomplex. Functional characterisation based on animal experiments suggests that the dilator motorneuron post-synaptic serotonin receptor is predominantly of the 5-HT2Aand, to a lesser degree, ofthe 5-HT2Csubtype and, in adults, it is the inhibitory presynaptic 5-HT1Breceptor. 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 ofrespiration, most likelyviaan action at the level of the nodose ganglion [19]. The exact functionalcharacterisation of the respiratory effects of these receptors is most likely to be influenced by speciesdifferences and animal preparations used. For instance, the role of serotonin mechanisms may beoverestimated in studies using vagotomised animals [20]. The use of clinically irrelevant dose levelsor concurrent administration of agents that produce feedback influences on the mechanisms

studied, will affect the net respiratory responses. For instance, the 5-HT3 receptor antagonistondansetron has been shown to reduce the respiratory disturbance index (RDI) in REM sleep by54% 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 andinterestingly these seem to reduce AHI mainly during non-REM sleep. In an open trial, fluoxetinereduced AHI by approximately 40% [23], and paroxetine, evaluated under double-blindcontrolled 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 importantduring sleep when serotonergic medullary raphe activity is particularly low [26]. Theantidepressant drug mirtazapine has a complex pharmacology with 5-HT1 agonistic, and5-HT2and 5-HT3antagonistic properties. In healthy participants, mirtazapine increased the slow-wave sleep without REM sleep suppression [27]. Animal studies have demonstrated increasedgenioglossus activity [28] and a suppression of apnoea during sleep [29] after the use ofmirtazapine. 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 recentrandomised controlled trials did not confirm these early findings [31]. Side-effects, such assedation and weight gain, were recorded and clearly limit the usefulness of mirtazapine in sleepapnoea.

In spite of the prospects provided by animal experiments for a serotonergic mechanism in OSAthere is limited evidence for a clinically useful effect in the hitherto completed human trials. It ispossible that future strategies, addressing subreceptor-specific compounds and strategies, mayprovide better results.

Acetylcholine mechanisms

An alternative approach potentially related to sleep-stage modulation is exemplified by agents thatmodulate acetylcholinergic activity. As a neurotransmitter of both the peripheral and centralnervous systems, acetylcholine plays a major role for autonomic nervous function. Collectively,

there is data to suggest that cholinergic mechanisms may modulate several different mechanismsassociated with sleep-disordered breathing. For instance, as one of the main neurotransmittersystems active during REM sleep, acetylcholine is involved in the modulation of the respiratorydrive. Animal studies have demonstrated reduced genioglossal muscle tone after hypoglossalmotor nucleus application of compounds that facilitate acetylcholinergic tone [32]. Theimplications of these findings for human OSA are unclear, but the trials of tricyclic antidepressantsdo not suggest beneficial effects attributable to the variable anticholinergic properties of thecompounds.

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 airwaycompliance and thereby collapsibility during sleep. Central cholinergic mechanisms may also actto increase chemosensitivity. A study of patients with multisystem atrophy demonstrated arelationship 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 thefinding 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 nicotinicactivity 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 areduction of AHI by 23% compared with placebo (fig. 2) [34]. Body weight and AHI reductionwere inversely related. Similar effects were seen in a subsequent placebo-controlled study of theorally available cholinesterase inhibitor donepezil given for 21 days [35]. Donepezil also induced areduction 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 promisingfindings (data not shown). The findings are somewhat incongruent and therapeutic potential ofcholinesterase inhibitors in OSA remains to be clarified. It may be that phenotypic characteristicsof patients recruited in these trials are of fundamental importance for the response. In the case ofphysostigmine, 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 effectwas inconsistent in OSA patients. Nicotine gum taken at bedtime was associated with a reduction ofAHI during the first part of the night in an early study [37]. However, two subsequent randomisedtrials 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 aconsistent increase of genioglossal muscle activity after a transmucosal nicotine patch [40]. Thebioavailability 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 adenosinein the central nervous system and stimulation on diaphragm contractility in the periphery. Oneearly placebo-controlled trial of theophylline in OSA found a 20% reduction in obstructive AHIbut 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-moderateCPAP-treated OSA described an almost identical AHI and CPAP pressure after oral sustained-release theophylline [44]. Total sleep time and sleep efficiency were significantly reduced in thetrial. 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 breathingdisorders and central sleep apnoea (CSA). A placebo-controlled trial of 15 patients with compensated

heart failure and central apnoea,found an approximate 50% reduc-tion of AHI and decreased nocturnalintermittent hypoxia after theophyl-

line when compared with placebo[45]. The right and left ventricularejection fraction were unchanged.Similar effects on central apnoeawere confirmed in a more recentuncontrolled trial of oral theophyl-line in 13 patients with compensatedheart failure and periodic breathing[46]. This study reported a reductionof over 50% in mainly central events,

along with improvement of oxyge-nation; sleep was unaffected. Thehaemodynamic and neurohormonaleffects were more closely addressedin a controlled trial of theophyllinein patients with congestive heart

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ChangeofREMAHI%

-80

-100

3

Patient n

1 5 82 4 6 7 9 10

Figure 2.The proportional reduction in the apnoea/hypopnoea index(AHI) during rapid eye movement (REM) sleep in 10 patients with

moderate-to-severe obstructive sleep apnoea, following physostig-

mine infusion. Each point represents one individual patient. Repro-

duced and modified from [34] with permission from the publisher.

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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 patientswith 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 centralapnoea treatment due to a potential pro-arrhythmogenic effect.

Carbonic anhydrase inhibition

The carbonic anhydrase inhibitor acetazolamide represents a well-established approach to reduceCSA. Metabolic acidification via carbonic anhydrase inhibition is likely to act viacentral, andperipheral, chemosensory function to increase central respiratory drive. A placebo-controlledstudy of acetazolamide in high-altitude sleep-disordered breathing, a condition characterised bycentral apnoeas or hypopnoeas, showed an almost complete restoration of ventilation andimproved oxyhaemoglobin saturation [48]. Other small studies have shown an almost 80%reduction of the frequency of apnoea after short-term acetazolamide treatment in patients withCSA [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 inpatients with predominantly CSA and effects were maintained for up to 1 month [51]. In fact, theeffect 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 long-lasting resetting of the carbon dioxide response threshold and, thereby, prevent apnoeadevelopment during sleep [53]. A short-term, randomised, placebo-controlled study, whichaddressed the effects of acetazolamide on CheyneStokes breathing associated with heart failure,found that central apnoea episodes were reduced by approximately 50%. In addition, animprovement in the nocturnal oxygenation and subjectively perceived sleep quality has also beenobserved (fig. 3) [54]. Acetazolamide was also found to completely eliminate the breathingdisorder 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 incidenceof neurological side-effects.

There has been a focus on selective carbonic anhydrase isoenzyme V inhibitors in obesity research andthis 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 andsleep-disordered breathing. At leasttopiramate, according to a case re-port, may reduce OSA severity duringshort-term treatment independent of

weight change [56].

GABA and glutamatemechanisms

GABA is the main inhibitoryneurotransmitter in the centralnervous system. This amino acidregulates neuronal excitability bybinding to specific transmembrane

receptors both pre- and post-synaptically. GABA is synthetisedin vivoby conversion of glutamate,the principal excitatory neuro-transmitter. Episodic hypoxia hasbeen speculated to accelerate the

Baseline AcetazolamidePlacebo

LowestSa,O2%

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progression of OSA by GABAergic mechanisms [57]. This occurs as a result of impairment ofneural control of upper airway patency and respiratory contractile function. The possibility ofinterfering 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 bya slight reduction of overnight oxygen saturation but no change in AHI under the GABA agonistbaclofen [58]. A small double-blind, controlled study of the putative glutamate antagonist sabeluzolein 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 releaseinhibitor riluzole, a reduction of post-sigh apnoeas but not spontaneous apnoeas in rats was observed[60]. The influence of post-synapticN-methyl-D-aspartate glutamate receptor sensitivity in OSA wastested in a double-blind, randomised, placebo-controlled, single-dose crossover study of the N-methyl-D-aspartate receptor antagonist AR-R15896AR in 15 males with moderate-to-severe sleepapnoea [61]. Overall AHI, as well as oxygen saturation variables, remained unchanged at all dosagelevels 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. Nasallyadministrated oxygen lead to an improvement of oxyhaemoglobin saturation and a reduction ofthe 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 onapnoea frequency when the period of administration was extended [64]. A split-night studycomparing supplemental oxygen 4 L?min-1 by nasal cannula and room air did not alter thefrequency of apnoeic events, although there was some improvement in daytime symptoms after anextended treatment period with oxygen (30 nights) [65]. Transtracheal oxygen therapy has alsobeen shown to reduce nocturnal hypoxaemia and to reduce AHI in OSA patients [66, 67]. Thevariable 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, butonly among OSA patients with high loop gain of their ventilatory control system as a cause forventilatory instability [68]. Indirectly this suggests that ventilator instability is an importantmechanism causing sleep-disordered breathing in some, but not all, patients. Interestingly, in anexperimental human model of intermittent hypoxia, reactive oxygen species overproduction wasfound to increase the acute hypoxic ventilatory response [69]. Whether antioxidants have apotential 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 centralapnoea and periodic breathing. Improvement of periodic breathing, along with a virtualelimination of arterial oxyhaemoglobin desaturation episodes following nasal oxygen adminis-tration, has been documented in several studies of patients with stable heart failure [7072].However, oxygen supplementation was relatively ineffective in modifying the increased autonomicnervous activity associated with the breathing disorder in these patients [71].

Carbon dioxide has also been tested for OSA and CSA treatment. Administration of carbondioxide (36%) during sleep caused a marked increase in ventilation along with an increase inupper airway inspiratory muscle activity. Apnoea time was reduced by 80% in a small study ofpatients with OSA [73]. However, there are methodological problems associated with themaintenance of a stable carbon dioxide level throughout the night, and carbon dioxide seems toeither 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 ofapproximately 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 airwaypressure therapy. A small, open-label evaluation of incrementally added concentrations of carbondioxide 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 orshortness of breath (fig. 4) [75]. Arousals were reduced by 80% and no adverse effects on overallsleep architecture were reported. Hence, controlled carbon dioxide supplementation may represent away 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 isinitiated. However, daytime sleepiness remains in a subset of patients, despite appropriatecompliance with effective CPAP therapy and measures to exclude comorbid conditions. Residualdaytime sleepiness has been reported in approximately 15% of patients, adequately treated withCPAP, and acceptably compliant with therapy [76]. Several attempts have been made to institutedrugs 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 ofhypothalamic histamine levels [77]. The latter mechanism may be central to the wakefulness-promoting properties of the drug. Several randomised and placebo-controlled trials have shownthat modafinil improves subjective and objective sleepiness, vigilance and quality of life in CPAP-treated OSA patients (table 1) [7882]. Conversely, modafinil does not reduce upper airwayobstruction and the drug has no effect on the occurrence of apnoea/hypopnoeas in patients withOSA [83, 84]. In partial CPAP users, no improvement was found in overall clinical condition orsleep latency as recorded in the maintenance of wakefulness test after modafinil [82]. However, arecent randomised, placebo-controlled study showed that modafinil improved simulated drivingperformance, neurocognitive performance and subjective sleepiness in OSA patients after short-

term 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 memoryin patients with residual daytime sleepiness, in CPAP-adherent OSA patients in randomised,placebo-controlled studies [86, 87].

A recent pharmacovigilance pro-gramme, initiated by the EuropeanMedicines Agency, has pointed to astrong link between modafinil andthe risk of serious skin reactions,especially in children, as well as

psychiatric/cardiovascular adversereactions. Therefore, it was con-cluded that the benefits of medi-cines containing modafinil onlycontinue to outweigh their risksin the treatment of narcolepsy.Data regarding the effectivenessof modafinil for the treatmentof residual excessive sleepiness inOSA, shift-work sleep disorders

and idiopathic hypersomnia, werenot sufficient to outweigh the risksassociated with its use. The agency,therefore, recommended that theseindications should be removedfrom the product information [88].

0

90

80

70

60

5040

30

20

10

100

1 5432 6

Patient n

RDIeve

nts.h-1

Figure 4. Respiratory disturbance index (RDI) in six patients withrefractory mixed obstructive and central sleep-disordered breathing

at baseline, and after conventional treatment and titration with a

prototype positive airway pressure gas modulator administering0.51% 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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Table1.Moda

finiltrialsonresidualsleepinessincontinuouspositiveairwaypres

sure(CPAP)treatedobstructivesleepapnoeapatients

Firstauthor

[Ref.]

Studydesign

Studype

riod

week

s

Dosagelevel

mg?day-

1

O

utcomemeasures

Significantfindings

Side-effects

KINGSHOTT[78

]

Randomised,

placebo-

controlled,

crossover(n532)

2

400

Subjectivesleepiness(ESS),

obje

ctivesleepiness(sleep

latenc

yonMSLTandMWT),

CPAPusage,qualityoflife,

cognitiveperformance,global

evaluation,PSGvariables

ImprovementofMWT

sleeplatency,

CPAPusagedecreased

H

eadache,nausea,dry

mouth

PACK[79]

DINGES[80]

Randomised,

placebo-

controlled,parallel

group(n5157)

4

200for1week,

400for3weeks


obje


latencyonMSLT),clinical

glo

balevaluation,PSG

variables,CPAPusage[81].

P

VTtest,FOSQ[82]

Im

provementofESSscore,

im

provementofMSLTand

c

linicalglobalevaluation.

Sma

llincreaseofarousalindex

and

sittingbloodpressure[81]

Impro

vementofPVTparameters,

totalFOSQscoreandactivity

level

andvigilancesubscale[82]

Headache,dizziness,

nervousness,anxiety,

twitch,insomnia

SCHWARTZ[81

]

Open-label

(n5125)

12

200,300or400


clin

icalglobalevaluation,

FOS

Q,nightCPAPusage

Im


clin

icalglobalevaluation,total

FOSQscoreandactivitylevel,

vigilance,intimacy,general

productivity,socialoutcome

subscale.CPAPusage

decreased,smallincreaseof

stand

ingdiastolicbloodpressure

Headache,anxiety,

n

ervousness,insomnia,

nausea,rhinitis,

infection,dizziness,

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

Body weight reduction and sleep-disordered breathingThe strong association between obesity and OSA is well established. Moderate-to-severe OSA isreported in more than 50% of obese subjects [91] and conversely, depending on the populationstudied, approximately 50% of patients with OSA fulfil the obesity criteria (data not shown). Infact, several population studies suggest a linear relationship between body mass index (BMI) andthe sleep and breathing disorder [92, 93]. Weight-reduction studies estimate that the AHI isreduced by approximately 3% for every 1% of body weight that is lost [94]. Protocols that addresspharmacological weight reductions suggest not only that sleep apnoea is modifiable by weight lossbut 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 withOSA 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 comparingsibutramine treatment with conventional CPAP, and the effects on sleep-disordered breathingwere small and inferior to those induced by CPAP [97].

Alternative drugs applied in weight management, including the lipase inhibitor orlistat and thecannabinoid receptor antagonist rimonabant, have not been systematically studied in sleep

apnoea. However, a recent abstract described a 28-week placebo-controlled study that examinedthe combined use of phentermine and topiramate in obese OSA patients [98]. Body weight wasdecreased by 10.3% in the active group compared with 4.2% after placebo treatment and the AHIwas reduced by 69% and 38%, respectively. Additional beneficial effects were recorded in terms ofblood pressure reduction, reduced sleep fragmentation and the improvement of sleep quality.These effects are particularly interesting in the light of carbonic anhydrase inhibitory propertiesascribed to topiramate. The findings open a possibility for targeted weight-reduction therapy inobese 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 sparkfurther clinical trials in this area.

Antihypertensive therapy and OSA

More than 50% of the adult to elderly population with sleep apnoea, investigated throughoutEuropean 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, orspecific 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, whereashydralazine-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 experimentalhuman studies, as an induced blood pressure elevation does not alter upper airway resistanceduring non-REM sleep [101]. Alternatively, both the angiotensin-converting enzyme inhibitorcilazapril and theb-blocker metoprolol were found to moderately reduce apnoea frequency duringsleep in an early double-blind trial [102]. But no effect on AHI was found on celiprolol comparedwith 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 notREM sleep [104]. This was not confirmed in a controlled trial comparing CPAP and theangiotensin II receptor antagonist valsartan [105]. Finally, a randomised study, which comparedthe effect of atenolol, amlodipine, enalapril, hydrochlorothiazide and losartan in 40 hypertensiveOSA 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 thetherapies [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 bespecifically 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 mechanisticrelationship between the two conditions is unclear but may, beside common predisposing factorssuch as obesity and alcohol, involve the periodic reduction of intrathoracic pressure caused byOSA during sleep. Alternatively, acid reflux in gastro-oesophageal reflux disease may producearousals and night choking as well as acid-induced long-term pharyngeal tissue swelling, whichpromotes upper airway obstruction during sleep. Indeed, a 50% reduction of AHI after short-termcombined anti-reflux therapy of cisapride and omeprazole was described in a study in patientswith the two combined conditions [107]. A small parallel group study using nizatidine reported adecrease in the arousal index, but not the AHI, after 1 month of treatment [108], whileomeprazole produced reductions in the apnoea index and the AHI by 31 and 25%, respectively, ina preliminary study [109]. These findings are not supported by a more recent study, in which itwas shown that pantoprazole significantly improved daytime sleepiness and the total reflux scorein OSA patients with acid reflux symptoms, but the total AHI remained unchanged [110].

Oronasal airway and sleep apnoea

An interesting series of studies describes compounds that reduce upper airway compliance, after theuse of compoundsviaa lowering of surface tension of the liquid in the upper airway lining. Topicalapplication 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 maleswith OSA [112]. Another study reported that exogenous surfactant significantly improved upperairway stability and respiratory events by 30% in nine patients with OSA [113].

Perennial allergic rhinitis was over-represented in OSA patients compared with patients withCOPD 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 13patients with mild OSA and coexisting rhinitis were investigated and the AHI was reduced, byapproximately 25%, in the treatment group. However, an early randomised trial of a nasaldecongestant in adults found no effect in snorers with moderate OSA [116]. Other data suggestthat intranasal corticosteroids could be of potential interventional use for children with OSA; themechanism behind this involves the reduction in size of the lymphadenoid tissue found in theupper 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 sex-related steroids may provide a protective effect against OSA. There is also experimental data thatshow a reduction of genioglossus electromyographic activity during wakefulness in the follicularphase, compared with the luteal phase of the menstrual cycle [119]. Genioglossus activity appearsto 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 apnoeathreshold during sleep.

Oestrogen and progesterone

Oestrogen and progesterone administration to postmenopausal females have produced somewhatinconsistent data. While no significant change in OSA was found after medroxyprogesteroneacetate treatment in an early uncontrolled study [120], a subsequent randomised controlled studyreported a reduction of apnoea duration but not the numbers of the events [121]. Another smallstudy of combined progestin and oestrogen treatment, found a reduced number of sleep-disordered breathing episodes in healthy postmenopausal females [122]. However, the overallevent number was low. A total of 15 postmenopausal females with moderate-to-severe OSA werestudied after oestrogen alone, or in combination with progesterone. There was no change in termsof clinical disease severity after almost 2 months of treatment [123]. A small prospective 1 monthcrossover study found a 25% reduction of AHI after estradiol, and a further reduction to 50% afterthe addition of progestin [124]. A pilot study of six females with OSA found that oestrogenreduced AHI by 46% [125]. Another small pilot study found a 75% reduction of AHI afterhormone replacement therapy [126]. The effect of progesterone may be more pronounced infemales with partial upper airway obstruction. A daily dose of 60 mg of medroxyprogesteroneacetate was found to improve ventilation in postmenopausal females with partial upper airwayobstruction 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 includean increased risk of coronary heart disease, stroke, breast cancer and thromboembolic events.

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 ventilatoryresponses; extravasation of albumin; and mucopolysaccharides in the tissues of the upper airwayand hypothyroid myopathy. An early study of long-term thyroxine replacement in hypothyroidOSA patients found a massive reduction of apnoea frequency, independent of concomitant weightchanges [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 forhypothyroidism. Once the thyroxine replacement therapy reaches steady state, a sleep study isneeded 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 isapproximately 1339% [132, 133]. It has been suggested that the upper airway soft tissue hypertrophyin this condition causes airway narrowing and increased pharyngeal collapsibility during sleep. Alteredrespiratory 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 ofacromegalic patients [134]. Two additional studies of octreotide in acromegaly with OSA found areduction 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 acromegalypatients 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 alsoseveral promising avenues for continued development in the area. No single explored drug hasbeen 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 inthis order of magnitude may represent an acceptable treatment goal, provided that compliancewith 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 clinicallyobserved to reduce OSA or its sequels) do occur and in fact several explored avenues for drugtreatment in OSA have been based on this rationale. On the other hand, rational drugdevelopment requires adequate biological experimental systems or animal models. Such modelshave been developed in the field of sleep-disordered breathing but their adequacy for the clinicalcondition has been questioned.

Most of the current studies in the area deal with AHI/RDI as a meter to quantify effect. Clearly, weneed to reach a consensus on optimal outcome variables to be used in trials in this area. Efficacymay 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 riskto develop cardiovascular complications in OSA. Improved understanding of the pathophysiologyof sleep apnoea is likely to open new perspectives for development of treatment strategies andspecifically lead to better selection and stratification of patients in clinical drug studies.

Statement of Interest

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

Acknowledgements

Supported by the Swedish Heart and Lung Foundation (project 20080587), Goteborg MedicalSociety and Lars Werkos senior research award.

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Pharmacological management of sleep-disordered breathing.pdf