Pharmacotherapy of residual excessive sleepiness among continuous positive airway pressure (CPAP) treated patients with sleep apnea

ABSTRACT

Introduction

Patients with persistent sleepiness after adequate treatment of obstructive sleep apnea (OSA) with nasal continuous positive airway pressure (nCPAP) experience impaired cognition, reduced productivity, and worse quality of life. Although the mechanisms responsible for this phenomenon are not completely understood, neuroimaging studies have identified reduced gray matter in the frontal cortex and alterations in white matter integrity suggestive of axonal and myelin damage. The intermittent hypoxia with resulting oxidative injury is considered a prime culprit behind the loss of wake-promoting catecholaminergic neurons.

Areas covered

This narrative review gives an overview of the pathophysiology and approaches to managing patients with residual sleepiness. The authors explore different targeted strategies aimed at improving selection of appropriate pharmacotherapy.

Expert opinion

Wake-stimulant medications (modafinil and armodafinil) have demonstrated efficacy in reducing sleepiness in adequately treated OSA. The recent FDA approval of pitolisant and solriamfetol complements the use of modafinil by substituting for direct sympathomimetic agents. The distinctive pharmacologic profile and mode of action of each of these agents offer the opportunity of a personalized approach to the management of this disorder. Further studies should be conducted on the long-term effect of these agents alone or in combination on brain structural and functional changes.

KEYWORDS:

• Excessive daytime sleepiness
• sleep apnea
• continuous positive airway pressure
• modafinil
• solriamfetol
• pitolisant

Articles highlights

• Excessive daytime sleepiness persists in up to 55% of OSA patients adherent to CPAP.

• The pathophysiology of EDS implicates loss of wake-promoting neurons due to oxidative injury attributed to chronic intermittent hypoxia.

• The diagnosis can be considered after optimizing CPAP use and excluding other neurologic disorders associated with hypersomnolence.

• Modafinil, armodafinil and solriamfetol, schedule IV-controlled agents, share a common mechanism of action in eliciting wakefulness via blocking dopamine reuptake through dopamine transporters.

• Pitolisant is a first-in-class of H3R antagonist/inverse agonist to be approved for the use of EDS that is not scheduled as a controlled substance.

• The choice of treatment should be tailored according to the pharmacokinetic profile, patient comorbid conditions, and past treatment history.

Declaration of Interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed

Reviewer disclosures

One reviewer is a consultant for Jazz Pharmaceuticals and CHEST/GlaxoSmithKline. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

The manuscript was supported in part by a grant from the US Department of Veterans Affairs (IO1CX001656).