Use of DORAs for Insomnia Increase Excessive Daytime Sleepiness Risk

The use of dual orexin receptor antagonists (DORAs) for insomnia is associated with an increased risk for excessive daytime sleepiness (EDS) and sleep paralysis compared to placebo, according to study findings published in the journal Sleep.

While insomnia treatment typically starts with behavioral therapy, medical interventions are available secondarily. One class of medication used for insomnia is DORAs, including suvorexant, lemborexant, and daridorexant. 

Researchers conducted a study to determine the safety of US Food and Drug Administration (FDA)-approved DORAs in treating insomnia, with a focus on narcolepsy-like symptoms.

The researchers searched through ClinicalTrials.gov, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, and World Health Organization International Clinical Trials Registry Platform (WHO-ICTRP) databases for randomized controlled trials (RCTs) on insomnia and DORAs. 

The primary outcomes were treatment-emergent adverse events (TEAEs), treatment-related TEAEs, TEAEs leading to discontinuation, and serious TEAEs (SAEs).

In the study, participants were aged 18 and older diagnosed with insomnia who received therapeutic intervention with an FDA-approved DORA. Studies were required to assess safety, tolerability, and adverse events. Patients with physical and psychiatric comorbidities were not included in this study. 

The search strategy yielded 677 studies published between 2012 and 2022. A total of 8026 participants from 11 studies were included, with 5116 patients receiving DORA treatment and 2587 patients receiving a placebo regimen. A majority of participants were women (n=5,105 [63.6%]).

The dosage for DORA treatment ranged per study: 10 to 80 mg daily for suvorexant, 1 to 25 mg daily for lemborexant, and 5 to 50 mg daily for daridorexant.

Individuals in the DORA group had a significantly higher risk for TEAEs and treatment-related TEAEs. The risk ratio (RR) for TEAEs was 1.09 (95% CI, 1.03-1.15; P =.002) with a low heterogeneity (χ2, 10.72; I², 7%; ­P =.38) among studies. 

The subgroup analysis revealed that daridorexant had the highest risk for TEAEs (RR, 1.17; 95% CI, 1.03-1.32; P =.01) and lemborexant had the lowest risk (RR, 1.04; 95% CI, 0.94-1.14; P =.50). 

There was no significant difference between the DORA group and placebo group for the incidence of TEAEs that led to discontinuation and SAEs. 

Individuals on DORAs had a higher risk for EDS (RR, 2.15; 95% CI, 1.02-4.52) and sleep paralysis (RR, 3.40; 95% CI, 1.18-9.80). Suvorexant had the highest risk of EDS (RR, 3.44; 95% CI, 1.19-9.91; P =.02) and lemborexant had the lowest risk of EDS (RR, 0.08; 95% CI, 0.00-1.95; P =.12). 

“Our meta-analysis stands out from previous studies as it specifically focused on the clinical safety of FDA-approved DORAs for insomnia treatment compared to placebo,” the researchers noted. “While there have been five previous meta-analyses on this topic, four of them only investigated specific DORAs (suvorexant and/or lemborexant) and did not cover all FDA-approved DORAs.”

They concluded, “This study contributes to understanding the safety profile of FDA-approved DORAs for treating insomnia, highlighting the need to develop alternative DORAs with a lower risk of narcolepsy-like symptoms.”

Study limitations are the variability in studies with each active treatment, the wide range in duration of each study, and the limited number of clinical trials.