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Lesson 23, Volume 15—Pharmacologic Treatment of Sleep-Disordered Breathing

By David W. Hudgel, MD

Effective December 31, 2004, PCCU Volume 15 is available for review purposes only. CME credit for this volume is no longer being offered.

Objectives

  1. Present an evidence-based review.
  2. Review the literature of the pharmacologic treatment of sleep-disordered breathing.
  3. Discuss the relative roles of various pharmacologic agents in the treatment of sleep-disordered breathing.
  4. Focus on the quality of the science in various studies.
  5. Present guidelines for use of medications for the treatment of sleep-disordered breathing.

Key words

obstructive sleep apnea; pharmacologic treatment; sleep apnea

Abbreviations

ACE = angiotensin-converting enzyme; CPAP = continuous positive airway pressure; CSA = central sleep apnea; OHS = obesity-hypoventilation syndrome; OSA = obstructive sleep apnea; RCT = randomized, controlled trial; SDB = sleep-disordered breathing

Some well-established types of sleep-disordered breathing (SDB), such as Cheyne-Stokes breathing, classically have been treated with pharmacologic agents, either as primary treatment or as treatment of an underlying disease entity, such as left ventricular dysfunction. Pharmacologic treatment of more recently identified entities, such as central sleep apnea (CSA) or obstructive sleep apnea (OSA), has been attempted. The primary impetus for use of drugs for these entities has been the often poorly tolerated nasal continuous positive airway pressure (CPAP) devices. Although CPAP reverses the upper airway obstruction and alleviates the majority of the symptoms related to OSA, patient compliance with CPAP is often suboptimal. If a well-tolerated pharmacologic agent could be identified for use in patients with sleep apnea, treatment success would be advanced significantly. Unfortunately, we have not identified a universally acceptable pharmacologic agent for OSA patients that can take the place of CPAP. However, as will be evidenced by the studies to be reviewed in this document, some strides have been made in this quest, but in general, work in this area is in its infancy.

In this lesson, not only will the therapeutic results of studies investigating various categories of pharmacologic agents in the treatment of SDB be reviewed, but the quality of the scientific study design used to obtain these results also will be assessed. In declining order of scientific design quality, most clinical trials fall into the following categories: (1) randomized, controlled trials (RCTs); (2) open-label, observational studies; or (3) single or multiple case reports. Consistent with the principles of evidence-based medicine, the quality of the scientific design should influence our impression of a particular study’s conclusion and affect our use of the study’s data to make therapeutic recommendations.

Theophylline

Theophylline has been used for many years as a ventilatory drive stimulant. The mechanism of action is likely through the inhibition of adenosine, a naturally occurring ventilatory drive depressant. Fortunately, there are several well-done studies addressing the use of theophylline in SDB. In one RCT, theophylline was found to be useful in adults with left ventricular dysfunction who experience periodic breathing and CSA.1 Theophylline has not been found to be useful in OSA in adults. In another RCT, Mulloy and McNicholas2 compared 800 mg/d of an oral theophylline preparation with placebo; although they found a significant decrease in apneas with theophylline, sleep was disturbed such that there was no overall improvement. Using a well-controlled study design, Espinoza et al3 showed similar results in a comparison between a one-night IV infusion of aminophylline and placebo. Although there was a decrease in the number of central and mixed apneas, obstructive events and oxygenation did not improve. Similar to the study by Mulloy and McNicholas,2 sleep was markedly disturbed.

In an observational study using a randomized design, Saletu et al4 compared CPAP with 400 mg/d of a long-acting theophylline preparation; each treatment was administered for one night 1 week apart in 13 male OSA patients. Theophylline decreased apneas minimally, increased periodic leg movements, and decreased total sleep time and sleep efficiency, while CPAP decreased apneas dramatically, increased stage 4 sleep, and decreased sleep transitions. One major problem with this study is that it is well known that theophylline is not well tolerated when a therapeutic dose is administered acutely. If the dose of theophylline had been advanced gradually prior to the study night, the authors might have found better tolerance and less disrupted sleep, although Mulloy and McNicholas2 still found sleep disruption after 4 weeks of theophylline administration in their study. Ideally, investigations comparing CPAP and pharmacologic agents should be controlled with sham CPAP and an appropriate oral placebo.

In summary, these studies demonstrate that some acceptable evidence exists that supports the appropriate use of theophylline for periodic breathing and CSA, especially when the SDB is related to heart disease. Although it may also reduce obstructive events, theophylline caused rather severe sleep disruption with the study designs used above.

Progestational Agents

Since progesterone has been shown to be a ventilatory stimulant in humans, progestational agents and even estrogen have been used in patients with SDB, including OSA patients. Although studied in small groups of patients, often in an uncontrolled fashion, progesterone has been shown to be beneficial to patients with obesity-hypoventilation syndrome (OHS).5 In both female and male OSA patients, a high dose of oral progesterone has not been found to be very helpful.6,7 Block et al6 used a parallel-group, blinded design in 21 postmenopausal women with OSA, comparing medroxyprogesterone 30 mg/d given for 30 days, with placebo. No significant improvement occurred in the progesterone-treated group overall, except for a decrease in apnea length. In an unblinded study in 10 male OSA patients, Rajagopal et al7 examined the effect of a higher dose, 60 mg/d of medroxyprogesterone, given for the same length of time. Essentially, there was no response in these patients. In a recent unblinded study, five postmenopausal women with OSA were treated with a menopausal replacement dose of estradiol for 3 to 4 weeks.8 There was a significant decrease in the average number of nocturnal abnormal respiratory events and an improvement in sleep-related oxygenation. However, these effects were incomplete in that the patients still had 25 events/h with treatment. The addition of progesterone 10 mg/d led to a further reduction in apneas to 18 events/h. With menopausal replacement doses of estrogen and progesterone, Cistulli et al9 did not see a response in an observational study.

From this group of studies, some of them RCTs, we conclude that progestational agents with or without the addition of estrogen may be helpful in CSA and OHS, but they are not likely to be extremely helpful in OSA. These agents may be of some help in postmenopausal women. More RCTs are needed.

Opioid Antagonists and Nicotine

Opioid antagonists stimulate ventilation centrally. These agents have been shown to improve oxygenation in OSA patients, but they have not been useful clinically because of two disadvantages: they disrupt sleep and they are very short-acting.10-13 In an uncontrolled study, Hein et al14 used transdermal nicotine in eight smokers with OSA. The OSA was not changed although the oxygenation was improved significantly.14 In an RCT in 20 nonsmoking OSA patients divided equally by sex, Davila et al13 found no improvement in apnea and snoring, but patients developed significant sleep disruption and gastric upset with the 11-mg long-acting nicotine patch. Therefore, these agents have not been shown to be useful in SDB.

Thyroxine

Three studies have now shown that hypothyroidism has only a 3% or lower prevalence in OSA patient populations,15-17 although up to 25% of hypothyroid patients will have OSA. Varying results have been found with thyroid hormone replacement in hypothyroid OSA patients. Skjodt et al17 and Rajagopal et al18 found that thyroid replacement resolved the OSA in these patients in long-term observational studies. These studies suffer from having a small number of hypothyroid OSA patients (three and 11 patients, respectively). In contrast to these findings, Grunstein and Sullivan19 did not find improvement in OSA with thyroid replacement therapy in six of eight hypothyroid OSA patients observed longitudinally. Surely, hypothyroidism in OSA patients needs treatment, but whether this treatment will resolve the OSA needs to be examined with a polysomnogram after the patient has been taking thyroid replacement medication for some time. Weight loss will likely help these patients resolve their OSA.

Acetazolamide

By producing metabolic acidosis, acetazolamide stimulates ventilatory control centrally. In high-altitude residents with periodic breathing and CSA, acetazolamide was shown to be useful in a placebo-controlled study.20 White et al21 found that acetazolamide 250 mg qid for 1 week improved CSA in a group of eight patients in an observational study. DeBacker et al22 observed 14 CSA patients before and after acetazolamide therapy of 250 mg/d given for 1 month. This dose was used to avoid the bothersome paresthesias associated with higher doses of acetazolamide. The number of arousals decreased although the total sleep time, sleep efficiency, and the number of central apneas did not change. Symptoms improved, but the subjective reporting is suspicious as this was not a blinded study. In contrast, Verbraecken et al23 found that 250 mg/d produced improvement in a group of eight CSA patients studied for 1 month; the apnea/hypopnea count went from 25 to 4 events/h, associated with a dramatic decrease in arousals. Difficult to explain, although not studied in a controlled fashion, was the finding that the number of central apneas remained low 6 months after therapy was stopped, but more obstructive apneas were seen in the patients at that time. The increase in obstructive apneas with acetazolamide therapy has been noted by others24 but was not confirmed by Tojima et al.25 Using an average dose of 350 mg/d for 40 days in an open-label observational study, Inoue et al26 showed a significant decrease in central, obstructive, and mixed apneas in 75 patients. Those who responded to therapy were less obese than the nonresponders. However, in an RCT using 250 mg qid for 2 weeks, Whyte et al27 found a 50% improvement in OSA, but at that dose the paresthesias were bothersome.

In summary, acetazolamide appears to be very useful in patients with periodic breathing and/or CSA, as observed in several uncontrolled studies. It may be helpful in some OSA patients but the therapeutic effect would need to be verified by polysomnography during therapy. Because of the possibility of worsening OSA after acetazolamide therapy is stopped, one must consider conducting a polysomnogram a few weeks after cessation of therapy.

Serotonergic Active Agents

Possibly due to the common presence of obesity and insulin resistance, OSA patients may have a functional brain deficiency in serotonin activity.28 This central neurotransmitter deficiency may contribute to the ventilatory control instability of upper airway muscle function that exists in OSA and thereby to the periodic upper airway obstruction during sleep. Two RCTs have demonstrated that although paroxetine reduced the frequency of apneic events significantly and increased inspiratory upper airway muscle activity, this effect was not great enough to lead to an improvement in symptoms or daytime sleepiness.29,30 One open-label study showed a good therapeutic effect in some individual OSA patients.31 Prior to the use of specific serotonin reuptake inhibitors, more nonspecific agents such as protriptyline were used. Although there were some individual responders to protriptyline, the cholinergic side effects were so bothersome that most men could not tolerate this drug because of its strong tendency to produce constipation and urinary retention.31,32 Therefore, the usefulness of these agents in OSA is unsettled, although the best scientific evidence reveals little beneficial usefulness in OSA.

Other Pharmacologic Agents

Some experience exists in OSA with antihypertensive agents, glutamine antagonists, benzodiazepines, and carbon dioxide inhalation. Pharmacologic agents used to treat hypertension may affect ventilatory control by several mechanisms, including changes in autonomic nervous system input to ventilation, alterations in brain blood flow, or alterations in baroreceptor input to ventilation. An RCT with cilazapril, an angiotensin-converting enzyme (ACE) antagonist, showed no improvement in OSA, although there was an improvement in systemic BP.33 In contrast, using essentially the same design, Weichler et al34 found some improvement in the apnea index with cilazapril, but neither sleep disruption nor subjective variables were evaluated, so we do not know whether the condition improved with this treatment. In an open-label study with this drug using the same dose and time schedule, Mayer and Peter35 also showed some improvement in OSA as well as BP. Weichler et al34 found a reduction in the apnea index and improvement in BP with metoprolol, a b-adrenergic blocking agent, but because of the drawback noted above of this group’s evaluation of cilazapril, we do not know if these changes were reflected in the clinical outcome. In a single-blind, nonrandomized study, Planes et al36 showed that celiprolol, another b-adrenergic blocking agent, did not change SDB and did not affect BP during the night, except for lowering BP during REM sleep.36 Daytime BP was also lower with the drug. In OSA patients with left ventricular dysfunction, cardiomegaly, and congestive heart failure, another ACE inhibitor, captopril, was used in an uncontrolled fashion.37 This study demonstrated that SDB activity diminished; apneas, hypopnea, and arousals were lessened; and oxygenation and sleep quality were improved.37 However, it is difficult to interpret this subjective improvement because the study was not blinded. 37

It has been hypothesized that if ventilatory drive could be suppressed and sleep could be "deepened" and ventilatory control and sleep pattern fluctuations thereby regulated and stabilized, then secondarily SDB might improve. Clonidine—a potential respiratory depressant even within the therapeutic blood level range38 and therefore a potentially hazardous drug to use—was found to be effective in reducing the quantity of REM sleep and REM-related apneas and hypopneas in six of eight OSA patients in an RCT.39 However, clonidine actually led to a worsening of apneas in two of the eight patients in this study.

The glutamate antagonist sabeluzole, a potential respiratory depressant, was used in an RCT in 13 OSA patients.40 The drug did not affect sleep, and arterial oxygen desaturation episodes, which were the only variable of apneic activity monitored in this study, did not change overall. However, there was a rough correlation between the drug blood level and improvement in oxygenation in these patients. Other respiratory depressants, such as the benzodiazepine clonazepam, improved CSA in two patients in two uncontrolled case reports.41

Carbon dioxide, obviously a respiratory stimulant, was used to stabilize ventilatory control.42 In case reports, a beneficial effect of carbon dioxide has been demonstrated in OSA.43,44 The disadvantage of this therapy is that a tight-fitting mask must be worn to maintain the constant concentration of gas; otherwise, fluctuations in the inspiratory concentration of carbon dioxide will contribute to the periodicity of breathing and potentially worsen OSA.

Thus, these studies have shown the potential usefulness of ACE inhibitors and b-adrenergic blocking agents in OSA, not only to improve hypertension but also to improve SDB. The majority of trials have shown that pharmacologic ventilatory depressants are not universally useful in OSA and may be dangerous. Although effective, carbon dioxide is not convenient to use.

Summary

The search for a pharmacologic agent with which to treat SDB and OSA has been disappointing in general. Some specific subgroups of patients—especially those with OHS and those with CSA or periodic breathing, particularly in a setting of congestive heart failure—respond to medications. Menopausal hormonal and thyroid replacement therapies may also improve OSA in those patients with these hormonal deficiencies. However, the majority of OSA drug trials have been unsuccessful. There are a few patients who respond quite well to various pharmacologic compounds, but the means of identifying such individuals before therapy is started are uncertain at this time. In addition, we do not know whether combined drug therapy would work. Hopefully, future research will develop methods of determining which classes or combinations of pharmacologic agents might be useful for specific groups of patients.

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