Multiple agents effective for excessive daytime sleepiness but may be discontinued due to side effects, review finds

Solriamfetol, armodafinil-modafinil, and pitolisant reduced excessive daytime sleepiness in those with obstructive sleep apnea (OSA), but patients may stop using them due to adverse events such as headache, anxiety, and insomnia, a review found.

Solriamfetol and armodafinil-modafinil are approved for OSA treatment in the U.S., but pitolisant, an H3-autoreceptor antagonist, is not. Researchers conducted a systematic review and meta-analysis of 14 trials that enrolled 3,085 patients and evaluated armodafinil, modafinil, solriamfetol, and pitolisant. They extracted data for the Epworth Sleepiness Scale (ESS) and Maintenance of Wakefulness Test (MWT), as well as for adverse events. Results were published May 9 by Annals of Internal Medicine.

Solriamfetol, armodafinil-modafinil, and pitolisant reduced daytime sleepiness for patients with OSA who were already on conventional therapy, and solriamfetol was likely superior in effectiveness. At four weeks, compared with placebo, solriamfetol improved ESS scores (mean difference [MD], −3.85; 95% CI, −5.24 to −2.50; high certainty) and armodafinil- modafinil (MD, −2.25; 95% CI, −2.85 to −1.64; moderate certainty) and pitolisant (MD, −2.78; 95% CI, −4.03 to −1.51; moderate certainty) probably did. For the MWT, at four weeks, compared with placebo, solriamfetol (standardized mean difference [SMD], 0.9; 95% CI, 0.64 to 1.17) and armodafinil-modafinil (SMD, 0.41; 95% CI, 0.27 to 0.55) improved scores (both high certainty), while pitolisant probably did not (moderate certainty).

However, adverse events, including headache, insomnia, and anxiety, were associated with an increased risk for medication discontinuation in several trials. At four weeks, armodafinil-modafinil probably increases the risk for discontinuation due to adverse events (relative risk [RR], 2.01; 95% CI, 1.14 to 3.51; moderate certainty), and solriamfetol may do so (RR, 2.07; 95% CI, 0.67 to 6.25; low certainty), the researchers found. Low-certainty evidence suggested that these drugs may not increase the risk for serious adverse events.

According to the authors, future research should address potential long-term and rare harms that may be associated with these drugs and their potential differential effects in patients who are not adherent to conventional OSA treatment.

“Solriamfetol appears to be the most effective for improving ESS and MWT, though it is considerably more costly than alternatives,” they concluded. “Patients may be more likely to discontinue armodafinil-modafinil or solriamfetol due to adverse events. Potential for long-term harm of all available pharmacotherapy remains unclear.”