Residual excessive daytime sleepiness (REDS) is defined as the urge to sleep during the day despite an intention to remain alert after optimal treatment of obstructive sleep apnea (OSA). This is a distressing outcome with an estimated prevalence of 9% to 22% among patients with OSA (Pépin JL, et al. Eur Respir J. 2009;33[5]:1062). The pathophysiology of the condition is complex, and experimental studies conducted on animal models have demonstrated that chronic sleep fragmentation and chronic intermittent hypoxia can result in detrimental effects on wake-promoting neurons. Additionally, there is evidence of heightened oxidative stress and alterations in melatonin secretion, with the severity and duration of the disease playing a significant role in the manifestation of these effects (Javaheri S, et al. Chest. 2020;158[2]:776). It is considered a diagnosis of exclusion, with the assessment being mostly subjective. Prior to diagnosing REDS, it is crucial to optimize positive airway pressure (PAP) therapy and nocturnal ventilation, ensure sufficient adherence to sleep hygiene practices, and exclude the presence of other sleep disorders. The Epworth Sleepiness Scale (ESS) score is widely utilized as a primary clinical tool in the assessment of sleepiness. To enhance the precision of this score, it is advantageous to take input from both family members and friends. Additional objective assessments that could be considered include the utilization of the Multiple Sleep Latency Test (MSLT) or the Maintenance of Wakefulness Test (MWT).
Dr. Ashesha Mechineni
Off-label use of traditional central nervous system stimulants, like amphetamine or methylphenidate, in these patients is almost extinct. The potential for abuse and negative consequences outweighs the potential benefits. FDA-approved medications for treatment of REDS in OSA include modafinil, armodafinil, and solriamfetol in the United States.
Dr. Ashima Sahni
Historically, modafinil and armodafinil are the first-line and most commonly used wake-promoting agents. Both agents bind to the dopamine transporter and inhibit dopamine reuptake. They have demonstrated efficacy in reducing EDS and improving wakefulness in patients with OSA treated with CPAP. A meta-analysis of 10 randomized, placebo-controlled trials of modafinil and armodafinil found that they were better than placebo by 2.2 points on the ESS score and 3 minutes on the MWT (Maintenance of Wakefulness Test) (Chapman JL, et al. Eur Respir J. 2016;47[5]:1420). Both drugs have common adverse effects of headache, nausea, nervousness, insomnia, dizziness, rhinitis, and diarrhea. Drug interaction with CYP3A4/5 substrates and oral contraceptives is a concern with these medications. In 2010, the European Medicines Agency restricted the use of modafinil only to patients with narcolepsy, considering its cardiovascular and neuropsychiatric risks (European Medicines Agency website; press release, July 22, 2010).
Solriamfetol is the newest medication being utilized for EDS in OSA and is approved in both the United States and Europe for this indication. It is a dopamine and norepinephrine reuptake inhibitor with a simultaneous effect on both transporters. It has been effective in improving wakefulness and reducing sleepiness in patients with residual OSA. In the landmark trial TONES 3, dose-dependent (37.5, 75, 150, and 300 mg/day) effects were observed, with improvements in ESS scores of –1.9 to –4.7 points and sleep latency in MWT by 4.5 to 12.8 minutes (Schweitzer PK, et al. Am J Respir Crit Care Med. 2019;199[11]:1421). The current recommended dosing for REDS in OSA is to start with the lowest dose of 37.5 mg/day and increase to the maximum dose of 150 mg/day by titrating up every 3 days if needed. A recent meta-analysis showed an indirect treatment comparison between efficacy and safety among the medications solriamfetol, modafinil, and armodafinil (Ronnebaum S, et al. J Clin Sleep Med. 2021;17[12]:2543). Six parallel-arm, placebo-controlled, randomized, controlled trials were looked at. The ESS score, MWT20 sleep latency, and CGI-C (Clinical Global Impression of Change) all got better in comparison to the placebo. Relative to the comparators and placebo at 12 weeks, solriamfetol at 150 mg and 300 mg had the highest degree of improvement in all the outcomes studied. Common adverse effects of solriamfetol include headache, nausea, decreased appetite, insomnia, dry mouth, anxiety, and minimal increase in blood pressure and heart rate. The adverse effects in terms of blood pressure and heart rate change have a dose-dependent relationship, and serial vitals monitoring is recommended for patients every 6 months to a year. This medication is contraindicated in patients receiving concomitant monoamine oxidase inhibitors (MAOIs) or within 14 days following discontinuation of an MAOI because of the risk of hypertensive reactions. Solriamfetol is renally excreted, so dose adjustment is needed in patients with moderate to severe renal impairment. It is not recommended for use in end-stage renal disease (eGFR <15 mL/min/1.73 m2) (SUNOSI. Full prescribing information. Axsome; revised 06/2023. https://www.sunosihcp.com/assets/files/sunosi.en.uspi.pdf. Accessed: Sept 24, 2023). Solriamfetol demonstrates a comparatively shorter half-life when compared with traditional pharmaceuticals like modafinil and armodafinil, implying the possibility of a decreased duration of its effects. The effect in question may exhibit interpersonal diversity in its impact on quality of life when applied in a therapeutic setting.
Pitolisant is another potential medication to treat REDS in patients with OSA. While only approved for treating EDS and cataplexy in adult US patients with narcolepsy, it is currently approved for REDS in OSA in Europe (Ozawade. European Medicines Agency. Last updated 12/05/2022. https://www.ema.europa.eu/en/medicines/human/EPAR/ozawade#product-information-section. Accessed: Oct 2, 2023). It is a selective histamine H3 receptor antagonist and an inverse agonist of the presynaptic H3 receptor. The fact that this medication is not scheduled and has a negligible or nonexistent risk of abuse is one of its advantages. It is dosed once daily, and the most frequent adverse effects include headaches and insomnia. A prolonged QT interval was observed in a few patients; caution is needed with concomitant use of other medications with known similar effects. Dosage modification is recommended in patients with moderate hepatic impairment and moderate to severe renal impairment. Drug interactions are also observed with the concomitant use of CYP2D6 inhibitors and CYP3A4 inducers. Pitolisant may reduce the efficacy of hormonal contraception, including up to 21 days after its discontinuation (WAKIX. Full prescribing information. Harmony biosciences; revised 12/2022.https://wakixhcp.com/pdf/wakix-tablets-pi.pdf. Accessed: Sept 24, 2023).
Dr. Mechineni is Sleep Attending Physician, Ascension Illinois, Alexian Brothers Medical Center, Chicago. Dr. Sahni is Assistant Professor of Clinical Medicine, Associate Program Director, Sleep Medicine Fellowship; Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois at Chicago.