Drug Trials for Obstructive Sleep Apnea

Effective drugs for primary treatment or prevention of obstructive sleep apnea in adult patients would be a paradigm shift for the field. This does not mean that the best described therapy for sleep apnea, namely continuous positive airway pressure (CPAP), will go away or that surgical therapy or oral appliance therapy are no longer needed. It means that alternatives to these mechanical and structural approaches would expand our management horizon, offer opportunities to perform controlled trials, and at least appear to provide treatment alternatives for patients that are more in the mainstream in terms of chronic disease management. While there is a general sense of futility when one reviews the current literature,^1–3 the article by Larrain et al.⁴ may give some hope, perspective and possibilities.

Currently, there are drugs used in management of obstructive sleep apnea directed at the consequences of recurrent events—the hypertension, the lipid disorders, and the sleepiness. Some of therapies for hypertension will actually reduce the number of events during sleep, but the effect is thought to be too small for primary therapy or have not been assessed for their effects on quality of life.⁵ Drugs that address the consequential symptom of sleepiness, like modafinil or armodafinil, do not alter respiratory indices, but improve the quality of life after adequate therapy of respiratory events,⁶ or in a recent off-label demonstration when CPAP is briefly discontinued.⁷

An alternative approach is to directly manipulate the respiratory control system either through its controller, its sensors, or the controlled system (Figure 1).^8,9 Drugs targeting the controlled system include those that seek to prevent apneas by reducing body weight and presumably improve the mechanical features of the upper airway and the thorax.³ Such approaches have the effect to reduce events associated with the fall in weight. Drugs that approach the controller are attractive and the amount information from basic and applied animal studies is increasing. However, the most recent reviews of pharmacologic therapy suggest that the limited number of studies and proposed approaches are either too small or too imprecise to make a statement related to potential use.^3,5 Further, the primary endpoint for these studies-the apnea-hypopnea index (AHI), respiratory disturbance index (RDI) or oxygen desaturation index (ODI)-represents the final common pathway in the pathogenesis of apneas rather than any specific element. As Hedner, Grote, and Zou suggest,⁵ there is a need to expand or at least better define the efficacy end points in clinical trials to reflect mechanisms and the intent of a therapy whether directed at cause or consequences of sleep disordered breathing.

Figure 1.

This diagram shows the elements of respiratory control that act and interact for breathing and participate in the initiation and recurrence of apnea and hypopneas during sleep.

The Sleep-Wake notation reminds one of the events that produce state and state changes. The initiation of an obstructive apnea occurs in the context of a reduction in drive that maintains upper airway patency, and the propagation of events over time results from an unstable control system, in some instances high loop gain.

The study by Larrain et al.⁴ in this issue of the Journal is a positive one, demonstrating that a combination of oral therapy with domperidone and pseudoephedrine improved self-reported snoring and sleepiness, and improved AHI and ODI values in patients with obstructive sleep apnea. The present study follows on the heels of a report from the same group on this combination being successful in reducing self-reports of snoring in a large out-patient population.¹⁰ These were open label placebo-controlled studies, with appropriate endpoints of subjective reports and conventional indices for sleep disordered breathing. Limitations aside, the body of work suggests this is a combination to consider in terms of potential use in management of sleep apnea. Furthermore, these drugs are off-patent, non-proprietary and therefore are unlikely to be supported by private pharmaceutical companies.

Domperidone has not been approved for use in the United States by the FDA, but is prescribed for its pro-kinetic properties in other countries. The authors of the present paper suggest that it has an anti-reflux function, potentially reducing apnea production and cites a trial where treatment of acid reflux reduced AHI over two weeks.¹¹ In this scenario, it is likely that a modification of the controlled system changed. However, the drug has enjoyed a prominent role in animal research as it does not cross the blood-brain barrier and selectively blocks dopaminergic receptors in the carotid and aortic bodies. The effect on ventilation is generally a reduction in hypoxic responsiveness; however, there are differences in its effect depending on species and among strains of rats,¹² suggesting that hypoxic ventilatory responses may be differently configured depending on genetic background. Indeed, in human subjects the effects of domperidone on hypoxic ventilatory responsiveness is non-uniform.¹³ This might suggest that the probable effectiveness of this agent might be through the reflex control of breathing and the controller. We do not know.

Phenylephrine, an alpha adrenergic agonist, has as its best known action that of vasoconstriction and when given systemically may increase blood pressure¹⁴; it may be a mutagen¹⁵ limiting its utility for general use. In the prior study on subjective snoring, pseudoephedrine or domperidone alone had little effect¹⁰; hence, the combination was used in this report. One could presume that pseudoephedrine could act either directly on the mucosal vessels of the upper airway and incrementally increase airway size (affecting the controlled system) or on the peripheral and/or central chemoreceptors, but it might also work indirectly on the controller by increasing baroreceptor discharge at the carotid body.

I will leave it to fellowship journal clubs and other more experienced pharmacologists to argue the pros and cons of this drug combination or alternative single or combination therapy. Instead I want to propose that given the potential success of drug therapy illustrated by this study, the field needs to develop a blue print for drug studies in sleep apnea.

First, the field needs to understand the details of clinical trial design and use approaches that rapidly proceed from open label and placebo-controlled studies to multicenter double-blind trials. The crossover or parallel design should be appropriately powered and specific for sleep apnea trials.

Second, we should address existing and novel outcome variables. Are there a core set of measures that are necessary for all trials to provide general understanding and another set that can be expanded to look at specific actions for cause or consequent events? We would do this knowing there will be new technology and computational models that potentially could bring insight into usual and customary polysomnographic data.⁵ More comprehensive measures would be needed for smaller trials while larger, multicenter trials would require easily obtainable subjective and objective measures with known reliability. For instance, oxygen saturation using known or explicit averaging and proper reporting (ODI and percent time) might be more reliable across laboratories and centers than hypopnea scoring.

Third, we need measures to address the fundamental mechanisms.⁸ In the event a therapeutic effect is equivocal on the overall event rate, measures of Pcrit, simple measures of craniofacial form, and surrogate markers of loop gain might be important in understanding variability between subjects and inform the design of future trials.¹⁶ What might make apnea length or propagation over time worse vs. better may be as important to determine as what happens to the AHI, RDI, or ODI.

One should consider whether there are some ethical issues involved in entering naïve patients into drug trials when we already have known and proven therapy. Are there patients, such as those who are excessively sleepy, who should not be entered into trials? Does the sleepiness and fatigue inherently present in many untreated patients confound outcome measures of quality of life? One might overcome these problems by utilizing the group of patients we already follow who use CPAP routinely as a pool of subjects for initial drug trials. Such patients are being treated and if selected properly will not have confounding fatigue. One could initially evaluate this approach by taking such patients off therapy for one night, and determining the reproducibility of the return of apneic events. Another potential advantage is that in the event a drug intervention increases apnea number or hypoxemia one can immediately institute a rescue therapy that the patient already knows and uses. Finally, as these patients are already on CPAP, one can determine Pcrit and loop gain more easily than in a treatment naïve patient.

DISCLOSURE STATEMENT

The author has received research support from Inspire Medical Systems.