Which Drug Best Reduces Sleepiness in Patients With OSA?

Kate Johnson

May 19, 2023

Solriamfetol (Sunosi), a norepinephrinedopamine reuptake inhibitor, is probably more effective than other wakefulness-promoting medications in patients with obstructive sleep apnea (OSA) who have residual daytime sleepiness after conventional treatment, according to a systematic review and meta-analysis.

In a systematic review of 14 trials that included more than 3000 patients, solriamfetol was associated with improvements of 3.85 points on the Epworth Sleepiness Scale (ESS) score, compared with placebo.

"We found that solriamfetol is almost twice as effective as modafinilarmodafinil — the cheaper, older option — in improving the ESS score and much more effective at improving the Maintenance of Wakefulness Test (MWT)," study author Tyler Pitre, MD, an internal medicine physician at McMaster University in Hamilton, Canada, told Medscape Medical News.

The findings were published online May 9 in Annals of Internal Medicine.

High-Certainty Evidence

The analysis included 3085 adults with excessive daytime sleepiness (EDS) who were receiving or were eligible for conventional OSA treatment such as positive airway pressure (PAP). Participants were randomly assigned to either placebo or any EDS pharmacotherapy (armodafinil, modafinil, solriamfetol, or pitolisant). The primary outcomes of the analysis were change in ESS and MWT. Secondary outcomes were drug-related adverse events.

The trials had a median follow-up time of 4 weeks. The meta-analysis showed that solriamfetol improves ESS to a greater extent than placebo (high certainty), armodafinil–modafinil, and pitolisant (moderate certainty). Compared with placebo, the mean difference in ESS scores for solriamfetol, armodafinil–modafinil, and pitolisant was −3.85, −2.25, and −2.78, respectively.

The analysis yielded high-certainty evidence that solriamfetol and armodafinil–modafinil improved MWT, compared with placebo. The former was "probably superior," while pitolisant "may have little to no effect on MWT, compared with placebo," write the authors. The standardized mean difference (SMD) in MWT scores, compared with placebo, was 0.90 for solriamfetol and 0.41 for armodafinil–modafinil. "Solriamfetol is probably superior to armodafinil–modafinil in improving MWT (SMD, 0.49)," say the authors.

Compared with placebo, armodafinil–modafinil probably increases the risk for discontinuation due to adverse events (relative risk [RR], 2.01), and solriamfetol may increase the risk for discontinuation (RR, 2.04), according to the authors. Pitolisant "may have little to no effect on drug discontinuations due to adverse events," write the authors.

Although solriamfetol may have led to more discontinuations than armodafinil–modafinil, "we did not find convincing evidence of serious adverse events, albeit with very short-term follow-up," they add.

The most common side effects for all interventions were headaches, insomnia, and anxiety. Headaches were most likely with armodafinil–modafinil (RR, 1.87), and insomnia was most likely with pitolisant (RR, 7.25).

"Although solriamfetol appears most effective, comorbid hypertension and costs may be barriers to its use," say the researchers. "Furthermore, there are potentially effective candidate therapies such as methylphenidate, atomoxetine, or caffeine, which have not been examined in randomized clinical trials."

Although EDS is reported in 40%–58% of patients with OSA and can persist in 6%–18% despite PAP therapy, most non-sleep specialists may not be aware of pharmacologic options, said Pitre. "I have not seen a study that looks at the prescribing habits of physicians for this condition, but I suspect that primary care physicians are not prescribing modafinil–armodafinil frequently for this, and less so for solriamfetol," he said. "I hope this paper builds awareness of this condition and also informs clinicians on the options available to patients, as well as common side effects to counsel them on before starting treatment." 

Pitre was surprised at the magnitude of solriamfetol's superiority to modafinil–armodafinil but cautioned that solriamfetol has been shown to increase blood pressure in higher doses. It therefore must be prescribed carefully, "especially to a population of patients who often have comorbid hypertension," he said.

Some limitations of the analysis were that all trials were conducted in high-income countries (most commonly the United States). Moreover, 77% of participants were White, and 71% were male.

Beneficial Adjunctive Therapy

Commenting on the findings for Medscape, Sogol Javaheri, MD, MPH, who was not involved in the research, said that they confirm those of prior studies and are "consistent with what my colleagues and I experience in our clinical practices."

Javaheri is associate program director of the sleep medicine fellowship at Brigham and Women's Hospital and assistant professor of Medicine at Harvard Medical School in Boston.

While sleep medicine specialists are more likely than others to prescribe these medications, "any clinician may use these medications, ideally if they have ruled out other potential reversible causes of EDS," said Javaheri. "The medications do not treat the underlying cause, which is why it's important to use them as an adjunct to conventional therapy that actually treats the underlying sleep disorder and to rule out additional potential causes of sleepiness that are treatable."

These potential causes might include insufficient sleep (less than 7 hours per night), untreated anemia, and incompletely treated sleep disorders, she explained. In sleep medicine, modafinil is usually the treatment of choice because of its lower cost, but it may reduce the efficacy of hormonal contraception. Solriamfetol, however, does not. "Additionally, I look forward to validation of pitolisant for treatment of EDS in OSA patients, as it is not a controlled substance and may benefit patients with a history of substance abuse or who may be at higher risk of addiction," said Javaheri.

The study was conducted without outside funding. Pitre and Javaheri report no relevant financial relationships.

Ann Intern Med. Published online May 9, 2023. Abstract

Kate Johnson is a Montreal-based freelance medical journalist who has been writing for more than 30 years about all areas of medicine.

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