Drug Treatments. Abstract. History. Uses of Respiratory Medicine

Transcription

1 SLEEP APNEA / Drug Treatments 59 airway pressure increases nasal airway resistance. American Journal of Respiratory and Critical Care Medicine 154: Sin DD, Mayers I, Man GC, and Pawluk L (2002) Long-term compliance rates to continuous positive airway pressure in obstructive sleep apnea: a population-based study. Chest 121: Wiest GH, Harsch IA, Fuchs FS, et al. (2002) Initiation of CPAP therapy for OSA: does prophylactic humidification during CPAP pressure titration improve initial patient acceptance and comfort. Respiration 69: Young T, Palta M, Dempsey J, et al. (1993) The occurrence of sleep-disordered breathing among middle-aged adults. New England Journal of Medicine 328: Pathophysiology of SDB Airway collapse Symptoms of SDB Treatment options Nasal steroids Modafenil Drug Treatments D Auckley, Case Western Reserve University, Cleveland, OH, USA & 2006 Elsevier Ltd. All rights reserved. Abstract The conventional first-line treatments available for sleep apnea (continuous positive airway pressure therapy, oral appliances, and surgical intervention) are appropriate for people with symptomatic disease. The benefit of a drug treatment approach is one of convenience and ability to intervene at an earlier stage of the disease, or an alternative for those who cannot or will not accept or tolerate surgical or mechanical treatments. However, drug therapy at present is an uncertain option for the management of sleep apnea. Medications for sleep apnea can broadly be divided into the following functional categories: those that alter the upper airway neuromechanical properties, those that affect the control of respiration, and those that work as adjunctive therapy to minimize symptoms. Some drugs are known to act through more than one discrete pathway. While most attempts at drug therapy for sleep apnea have generally been unsuccessful, certain medications may have some use in specific clinical settings. In summary, convincing data for drug treatment as primary therapy is lacking, and additional therapy with one of the conventional sleep apnea treatments is often still the better option. Recent interest has focused on serotonin active agents as a treatment for obstructive sleep apnea. However, this class of medications is not yet approved for this indication. History Sleep apnea has been recognized as a significant clinical disorder for only the last three decades. As data accumulates linking multiple adverse outcomes to obstructive sleep apnea (OSA), the importance of treating this condition has become widely accepted. Likewise, central sleep apnea (CSA) is associated with worse outcomes in those with impaired cardiac function. Conventional therapies for sleep apnea include the use of pneumatic airway splints (continuous positive airway pressure (CPAP) devices), oral appliances to enlarge the upper airway, and surgery Abnormal control of breathing to either modify the airway, help facilitate ventilatory support, and/or to bypass the site of obstruction altogether (tracheotomy). While these therapies can be very successful for controlling or eliminating sleep apnea, each is hampered by limitations that impact their effectiveness in clinical practice. CPAP is problematic from a patient compliance standpoint. Oral appliances are effective in only a subset of patients with OSA and are also limited by suboptimal patient compliance. Surgical interventions can be highly effective in the right setting, but are generally restricted to OSA patients with surgically amenable anatomy who are willing to accept the risk of complications and the possibility of unacceptable long-term consequences. Thus, the use of a pill to treat sleep apnea seems highly desirable and remains a field of intense study. This article will review the current state of medical therapy for sleep apnea (Figure 1). Uses of Respiratory Medicine Thyroid hormone MPA Theophylline Acetazolamide Figure 1 Pathophysiology of and treatment options for sleep disordered breathing (SDB). If any agent is used as monotherapy for sleep apnea, then repeat objective testing is recommended (with the exception of modafinil). * Treatment options for OSA; w treatment options for CSA; MPA, medroxyprogesterone. Medications Affecting Airway Neuromechanical Properties Serotonin active agents Upper airway dilator muscle activity decreases during sleep, narrowing the airway. In the presence of abnormal pharyngeal anatomy, this results in repetitive airway collapse during sleep, or OSA. The neurotransmitter serotonin (also known as 5-HT) plays an integral role in maintaining patency of the upper airway by

2 60 SLEEP APNEA / Drug Treatments activating upper airway dilator muscles. As such, investigators have reasoned that increasing central serotonin levels may improve airway patency and eliminate OSA. Unfortunately, the physiology is not this simple as at least 14 different serotonin receptor subtypes have been identified and some of these, when stimulated, exhibit inhibitory effects on upper airway motor tone. This may in part explain why human trials of selective serotonin reuptake inhibitors (SSRIs) have failed to show a clinical benefit in OSA patients. It is likely that mixed serotonin receptor agonist antagonists are needed to produce clinically significant changes. Preliminary work with mirtazapine, a 5-HT 1 receptor agonist and 5-HT 2 and 5-HT 3 receptor antagonist, has shown promise in animal models of sleep apnea. Trials are underway to assess its effectiveness in humans with sleep apnea. It is hoped that ongoing work with serotonin and serotonin receptors will lead to better-targeted therapies. While this area holds great promise, serotonin active agents as monotherapy for OSA cannot be recommended at this time. Protriptyline Protriptyline is a nonsedating tricyclic antidepressant with REM sleep-suppressing properties. Like serotonin, protriptyline also stimulates the hypoglossal motor neurons to increase upper airway muscle activity. A number of investigators have studied protriptyline as a potential therapy for OSA. In sum, these studies have not shown clinically significant improvements in OSA (two studies found statistically significant reductions in the apnea hypopnea index (AHI), though moderate to severe OSA persisted). In addition, the high frequency of intolerable anticholinergic side effects limits protriptyline s clinical utility. Protriptyline should not be considered as a treatment option for OSA at this time. Topical nasal steroids Nasal airflow resistance may contribute significantly to the development of OSA. Available data suggests that sleep apnea is more common in individuals with chronic nasal congestion as compared to those without. Initial studies suggested that treatment of chronic nasal congestion with nasal steroids improved sleep, reduced daytime fatigue, and decreased sleepiness, though measures of sleep apnea were not specifically addressed. Only one placebo-controlled study has examined the impact of nasal steroids on parameters of OSA in adults with concomitant allergic rhinitis. This small study (23 patients total) showed an improvement in the AHI in treated patients, though the individual response to treatment was highly variable. The group on the whole decreased their AHI from 20 to 12 events per h, whereas the 13 patients entering the study meeting criteria for OSA (AHI X 5, the remainder considered to be primary snorers) only reduced their AHI from 30 to 23. Of the five individuals who decreased their AHI to o5, considered an optimal response, three had an AHI between 5 and 10 on placebo. These data suggest that in patients with mild OSA and allergic rhinitis, nasal steroid therapy may have a role, but for more severe disease, additional conventional therapy will probably be required. Medications Generally Affecting the Control of Breathing Hormonal therapy Both estrogen and progesterone have been studied as potential therapies for OSA. Medroxyprogesterone (MPA) is a recognized ventilatory stimulant, though it may exert some stimulatory effects on the upper airway motor neurons as well. By attenuating hypoventilation, MPA was hoped to reduce periodic breathing and improve sleep apnea. An early small, uncontrolled study found that MPA improved OSA in a subset of patients with baseline hypercapnia. Two subsequent placebo-controlled trials failed to show a treatment effect of MPA on OSA, though only four of the patients were known to be hypercapnic. Until larger randomized controlled trials of hypercapnic OSA patients are performed, MPA cannot routinely be recommended as a treatment option. Its role in treating patients with OSA and obesity hypoventilation syndrome is uncertain. An empiric trial could be considered in some individuals, provided objective follow-up testing is obtained. MPA has not been studied as a treatment for CSA. Estrogen has effects on upper airway musculature in addition to possible centrally mediated effects on respiration. Growing evidence suggests that the incidence of OSA in postmenopausal women increases and approaches that of age-matched men. It is of interest that in postmenopausal women on hormone replacement therapy (HRT), the incidence of OSA remains low. Despite these findings, no large randomized controlled trials of HRT in postmenopausal women with OSA have been reported to date. Two small (5 and 6 patients) nonrandomized, uncontrolled trials found significant improvements in the AHI following therapy with estrogen alone, though only one of the 11 subjects had normalization of their AHI. In contrast, another uncontrolled study of 15 postmenopausal women with moderate to severe OSA found little change in their AHI following treatment with estrogen. As might be expected from these findings, the majority of participants in all the studies did not perceive much subjective benefit in their sleep or daytime symptoms. Further study is

3 SLEEP APNEA / Drug Treatments 61 needed before HRT can be recommended in postmenopausal women for the treatment of OSA. Theophylline Theophylline is a methylxanthine that inhibits adenosine, a central-acting ventilatory depressant, as well as enhances the ventilatory response to hypoxia and hypercapnia. Thus, it might be expected that theophylline may improve CSA more than OSA. In two blinded placebo-controlled studies it was found that theophylline significantly improved central apneas with the most pronounced effect seen in the setting of left ventricular dysfunction (central apneas decreased from 26 to 6 h 1 on average in 15 subjects studied). However, sleep remained poor in these individuals due to theophyllineinduced sleep fragmentation. OSA, on the other hand, failed to improve following therapeutic range dosing of theophylline in a number of controlled trials. Two studies comparing theophylline to CPAP therapy have found CPAP to be considerably more efficacious. Before considering theophylline for patients with left ventricular dysfunction and central sleep apnea, one must consider the narrow therapeutic window and potential toxic side effects of theophylline. In addition, the sleep disruption this medication induces may lead to persistence of sleeprelated symptoms and, consequently, poor compliance with therapy. Acetazolamide Acetazolamide, a carbonic anhydrase inhibitor, produces a metabolic acidosis and thus stimulates respiration. This drug has been examined as a treatment for both central and obstructive sleep apnea. Uncontrolled data from a small number of subjects suggests acetazolamide may dramatically reduce the number of central events (mean central AHI decreased from 54 to 12 and 26 to 7 in two different studies) in sleep as well as improve associated daytime symptoms. No randomized controlled trial has been performed to confirm these findings. With regard to OSA, both uncontrolled studies and a single randomized placebo-controlled trial suggest that the AHI variably improves following treatment; however, significant OSA generally persists. Side effects, including intolerable parasthesias and severe metabolic acidosis, can occur when acetazolamide is given at higher doses and may restrict its clinical utility. At present, acetazolamide can be considered for patients with CSA, though close clinical monitoring is warranted. Thyroid replacement Hypothyroidism depresses the ventilatory drive, can impair upper airway muscle function due to myopathy, and may narrow the upper airway secondary to mucopolysaccharide deposition. Reversing these changes might be expected to improve sleep apnea in those found to be hypothyroid. Numerous small case series addressing this have yielded conflicting results as some show dramatic decreases in the AHI with thyroid replacement therapy and others show no effect. It is unclear if those failing to respond to irreversible functional or anatomic changes due to hypothyroidism or that other factors contributing to OSA risk (such as obesity or craniofacial abnormalities) may be playing a role. No randomized controlled trials addressing thyroid replacement in hypothyroid patients with OSA have been reported at this time. Based upon available data, it may be reasonable to utilize thyroid replacement as monotherapy for hypothyroid patients with mild OSA, but adjunctive conventional treatments should be considered for more severe OSA patients. All patients should undergo repeat evaluation of their sleep apnea once euthyroid status is achieved. Opioid antagonist The cerebral spinal fluid of individuals with OSA contains increased opioid levels that fall following successful treatment of the OSA. Through generalized cortical stimulation, opioid antagonists are thought to stimulate respiration. Controlled trials of continuous infusions of opioid antagonists (naloxone and doxapram) showed minor improvements in several parameters of OSA (oxygen saturation, length of apneas), though by and large these changes were of marginal clinical significance. Furthermore, these agents disturb sleep and require dosing via intravenous infusion, both undesirable qualities. Nicotine Nicotine stimulates respiratory drive by acting on central respiratory neurons. One uncontrolled trial found a decrease in the number of apneas in the first 2 h of sleep after subjects with OSA chewed nicotine gum at bedtime. However, a subsequent placebo-controlled study of transdermal nicotine found no significant improvement in the AHI or snoring intensity in a population of individuals with OSA and/or primary snoring. Nicotine was also noted to worsen sleep quality and induce intolerable gastrointestinal side effects in a number of study subjects. Benzodiazepines Benzodiazepines are not routinely recommended for patients with OSA due to concerns about depressing the arousal response, altering respiratory drive, and worsening airway collapse. It is of interest that a randomized placebo-controlled trial of the benzodiazepine receptor antagonist flumazenil found no benefit in patients with OSA, suggesting

4 62 SLEEP APNEA / Drug Treatments endogenous benzodiazepine receptor activation does not play a role in the pathophysiology of OSA. In contrast to concerns about decreased respiratory drive, some benzodiazepines have been shown to increase respiratory drive during sleep and therefore might improve CSA. The use of diazepam in a rat model of CSA found this to be the case. In humans, one small randomized placebo-controlled cross-over study of triazolam in idiopathic CSA demonstrated a reduction in the central apnea index and number of arousals with triazolam. Similar findings were noted in case series of subjects with periodic limb movements and CSA. Further study of benzodiazepines in CSA is warranted to clarify the specific patient populations who might stand to benefit from this therapy. Medications that Minimize Symptoms Despite optimal treatment of OSA, daytime sleepiness may not completely resolve. The reason for this is not clear, but the persistence of these symptoms can adversely impact quality of life and potentially increase the risk of accidents. Therefore, therapies to further reduce daytime symptoms of OSA in those already on conventional treatment have been studied. Modafinil Modafinil is a central-acting wake-promoting agent that has no effect on respiratory events in sleep. It has now been examined in two relatively large randomized placebo-controlled trials of OSA patients with persistence of daytime symptoms despite adequate treatment with CPAP. These studies showed consistent improvements in both subjective and objective measures of sleepiness as well as improvements in tests of vigilance and measures of quality of life. A clinically insignificant decrease in CPAP usage occurred during one of the trials, though this remains a concern when one considers the use of stimulants outside of a clinical trial setting. Based upon the available data, modafinil can be considered as an adjunct to conventional therapies for patients with residual OSA-related daytime sleepiness, though close monitoring of CPAP usage is encouraged. Other stimulants have not been tested in this setting. Etanercept Serum tumor necrosis factor alpha (TNF-a) and interleukin-6 (IL-6) are elevated in individuals with OSA, and have been proposed as mediators of the excessive daytime sleepiness that accompanies OSA. Etanercept neutralizes TNF-a and thus was tested in a small placebo-controlled pilot study of patients with OSA to assess its effects on OSA and OSA-related symptoms. While having a marginal impact on the AHI (decreased from 53 to 44, statistically significant but not clinically significant), a substantial improvement in an objective measure of sleepiness was seen. No subjective ratings of sleepiness or other quality of life measures were reported. Further study of this medication as an adjunctive therapy for persistent daytime symptoms in CPAP-treated OSA is warranted. Modification of Sleep Apnea by Other Treatments Antihypertensive agents While attempting to determine the best antihypertensive agents for patients with OSA, investigators noted that the AHI decreased modestly following treatment with betablockers or ACE inhibitors. Changing sympathetic tone or baroreceptor activity were the proposed mechanisms for these changes. These findings then led to two randomized trials of antihypertensive agents (beta-blockers, ACE inhibitors, calcium channel blockers, and diuretics) as treatments for OSA. Placebos were not included in either study. While all agents reduced blood pressure, the impact on OSA was marginal at best. One study showed a decrease in the AHI (from 40 to 27, clinically insignificant) while the other found no change in pre- and posttreatment measures. In the study reporting subjective symptoms, no improvement was noted. Clonidine, a rapid eye movement (REM)-suppressing agent, has also been evaluated as a treatment for OSA. One small placebo-controlled trial found no improvement in the AHI or symptoms following treatment with clonidine. Collectively, these data suggest that antihypertensive agents should not be utilized as therapy for the treatment of OSA. Glutamate antagonist Attenuating the respiratory response to acute hypoxia could prevent the periodic breathing pattern that may precipitate sleep apnea in some individuals. Glutamate, a neurotransmitter that may be partly responsible for hypoxia-induced respiratory stimulation, seems a reasonable target to antagonize and hopefully improve sleep apnea. One small randomized placebo-controlled trial of sabeluzole, a glutamate antagonist, documented an improved oxygen desaturation index during sleep, but did not measure the AHI specifically. On the other hand, baclofen, a glutamate antagonist and GABA agonist, did not decrease the AHI in 10 patients with mild OSA in a randomized placebo-controlled trial. Larger controlled trials of pure glutamate antagonists seem to be indicated. See also: Sleep Apnea: Overview; Adult; Continuous Positive Airway Pressure Therapy; Oral Appliances; Surgery for Sleep Apnea. Sleep Disorders: Central Apnea (Ondine s Curse); Upper Airway Resistance Syndrome.

5 SLEEP APNEA / Genetics of Sleep Apnea 63 Further Reading Hudgel DW and Thanakitcharu S (1998) Pharmacologic treatment of sleep-disordered breathing. American Journal of Respiratory and Critical Care Medicine 158: Javaheri ST, Parker J, Wexler L, et al. (1996) Effect of theophylline on sleep-disordered breathing in heart failure. New England Journal of Medicine 335: Kiely JL, Nolan P, and McNicholas WT (2004) Intranasal corticosteroid therapy for obstructive sleep apnoea in patients with co-existing rhinitis. Thorax 59(1): Kingshott RN, Vennelle M, Coleman EL, et al. (2001) Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of residual excessive daytime sleepiness in the sleep apnea/hypopnea syndrome. American Journal of Respiratory and Critical Care Medicine 163: Magalang UJ and Mador MJ (2003) Behavioral and pharmacologic therapy of obstructive sleep apnea. Clinics in Chest Medicine 24: Pack AI, Black JE, Schwartz JRL, and Matheson JK (2001) Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea. American Journal of Respiratory and Critical Care Medicine 164: Smith I, Lasserson T, and Wright J (2003) Drug treatments for obstructive sleep apnoea. Cochrane Database of Systematic Reviews 2001(4), article CD Smith IE and Quinnell TG (2004) Pharmacotherapies for obstructive sleep apnoea: where are we now? Drugs 64(13): Veasey SC (2003) Serotonin agonists and antagonists in obstructive sleep apnea: therapeutic potential. American Journal of Respiratory Medicine 2(1): Vgontzas AN, Zoumakis E, Lin HM, et al. (2004) Marked decrease in sleepiness in patients with sleep apnea by Etanercept, a tumor necrosis factor-alpha antagonist. Journal of Clinical Endocrinology and Metabolism 89(9): Yap WS and Fleetham JA (2001) Central sleep apnea and hypoventilation syndrome. Current Treatment Options in Neurology 3: Genetics of Sleep Apnea S R Patel, Brigham and Women s Hospital at Harvard Medical School, Boston, MA, USA S Redline, Case Western Reserve University, Cleveland, OH, USA & 2006 Elsevier Ltd. All rights reserved. Abstract Obstructive sleep apnea is a disorder that has a clear genetic component. A familial basis for the disorder is evidenced by the substantially increased risk for snoring or sleep apnea among relatives of affected individuals. Approximately one-third of the population variance in apnea severity, as measured by the apnea/hypopnea index, is explained by familial clustering. The pathways by which genetic predisposition may influence the development of sleep apnea are multiple. Obesity, craniofacial anatomy, and ventilatory control are all traits that are highly heritable, and each influences the risk of apnea development. The genetics of obesity has been most well studied, with dozens of candidate genes proposed to influence a person s weight. Data suggest that these obesity-defining loci explain only half of the genetic variance in sleep apnea. Thus, other mechanisms are also important. Work is under way to identify risk genes for sleep apnea, and several candidates such as APOE have emerged. Research has also begun to identify genetic loci that may modulate the physiologic effect of sleep apnea on the development of secondary disorders, such as sleepiness, hypertension, and cardiac disease. Since a report in 1978 of three brothers with obstructive sleep apnea (OSA), it has become increasingly clear that this disease clusters within families. This suggests that genetic susceptibility plays an important role in apnea pathogenesis. Knowledge of sleep apnea genetics provides not only an opportunity to better understand an individual s predisposition to develop OSA and its neuropsychiatric and cardiovascular consequences but also insight into the molecular pathways that, when dysregulated, produce OSA. The ability to predict individual risk will allow for more efficient prevention and screening programs while knowledge of pathophysiology may allow for novel treatment strategies that specifically target the molecular defects. Sleep Apnea Phenotypes An important consideration in understanding the role of genetics in sleep-disordered breathing is to identify the most relevant phenotype. A feature of OSA shared by many other complex disorders is the lack of a standardized phenotypic definition of disease. OSA is typically defined as the presence of an apnea/hypopnea index (AHI) above a certain threshold (often 45 or 10 events per hour of sleep). Obstructive sleep apnea hypopnea syndrome (OSAHS) represents the combination of OSA with symptoms of sleepiness referable to the OSA. One study found familial aggregation of a phenotype that included symptoms of sleepiness to be greater than phenotypes defined purely on polysomnographic criteria. An important issue is whether heritability is greater for a phenotype based strictly on AHI level or one that uses associated symptoms, such as sleepiness or daytime dysfunction. In addition, the choice of a dichotomous phenotype, such as OSA or OSAHS, versus a continuous phenotype, such as AHI, need also be considered. Although continuous phenotypes typically provide more power for identifying genetic susceptibility loci and do not require arbitrary threshold cutoffs that may vary across subgroups (e.g., children vs. adults), they also make more assumptions regarding scaling (a doubling of AHI from 2 to 4 is of equivalent importance as one from 10 to 20) that may or may not be appropriate.