Abstract
Introduction
Guidelines recommend sleep hygiene and cognitive behavioral therapy as first-line treatment for insomnia. Pharmacologic treatments may be considered when symptoms are refractory and largely revolve around sedating antidepressants or antipsychotics, melatonin receptor agonists, and sedative-hypnotics such as benzodiazepines and zolpidem. These medications have been associated with limited long-term effectiveness and many are associated with loss of deep sleep involving REMs and/or other significant adverse effects such as elevated fall risk and abuse potential.1,2 Dual orexin receptor antagonists (DORAs) are a new class of medications for insomnia, and they will be reviewed in this Fast Fact. 2
Mechanism of Action
The orexin signaling system plays a crucial role in maintaining arousal and wakefulness. DORAs act as antagonists at both orexin receptors (OX1R and OX2R) within the orexin cascade in the sleep-wake cycle. This is thought to promote sleep induction and maintenance in a more localized and targeted effect than other common medications for insomnia.3,4 DORAs primarily enhance the duration of rapid eye movement (REM) sleep and leave non-REM sleep unchanged or reduced. 5
Pharmacology
DORAs are scheduled IV substances. Post-marketing surveillance data suggest low abuse and overdose potential and no evidence of physical dependence. 6 Concurrent administration with potent CYP3A4 inducers and inhibitors is discouraged.4,5 No dose adjustments are required for patients with mild hepatic impairment or mild-to-severe renal impairment, but increased somnolence is a risk in patients with severe renal impairment.5,7 Research on the optimal duration of treatment is limited. Much of the current evidence for the efficacy and safety of DORAs is based on industry-sponsored (e.g., references2,3,6) studies conducted over a maximum period of 12 months compared with placebo.2,4 Only a few studies compared DORAs with both placebo and zolpidem as an active control drug.4,8,9 The pharmacological characteristics of the primary DORAs—suvorexant, lemborexant, and daridorexant—are summarized in Table 1 below.3,5,7
Dosing, Timing, and Pharmacokinetics of Three FDA-Approved DORAs for Insomnia
DORA, dual orexin receptor antagonist.
Utility in Symptom Management
In a systematic review of 20 medications for primary insomnia in adults, DORAs had the highest values in terms of sleep latency, awake time after sleep onset (total minutes awake after initially falling asleep), total sleep time, and sleep efficiency. 10 DORAs also had the second-best safety profile behind placebo. 10 However, trials directly comparing DORAs with traditional sedatives and hypnotics are still lacking. 10 Patients with Alzheimer’s dementia (AD) have been found to have elevated levels of orexin in the cerebrospinal fluid, which has been linked to cognitive decline, reduced sleep efficiency, and reduced REM sleep. 11 Suvorexant has been approved for sleep disturbances in mild-to-moderate AD 12 since it was associated with a statistically significant improvement in total sleep time and awake time after sleep onset compared with placebo. 13 It was well-tolerated and did not impair next‐day cognitive or psychomotor performance nor worsen the underlying cognitive impairment12,13; this is somewhat unique in that most hypnotics can be cognitively harmful in patients with AD. Early research suggests that suvorexant and lemborexant may treat and/or prevent delirium by reducing sleep disruptions which could alleviate delirium.14–16
Side Effects
Dose-dependent somnolence, nasopharyngitis, and headache are most common. 17 Abnormal dreams, fatigue, and dry mouth have also been reported.4,10,17 The use of DORAs is contraindicated in patients with narcolepsy. 3 They are not recommended in patients with severe hepatic dysfunction.5,7 Additional warnings include worsening of depression and worsening of complex sleep behaviors, such as sleepwalking and sleep paralysis.18–20
Pediatrics
Suvorexant specifically has been shown to be safe and effective in adolescents with insomnia in a limited study involving 30 participants aged 10–20 years. 21 Additionally, it has shown good tolerability (other than occasional irritability) and effectiveness in managing circadian rhythm disorders in children aged 2–22, particularly among those with neurodevelopmental disorders.21,22
Cost
DORAs are generally more expensive than other insomnia treatments (e.g., usual cost of $13–20 per tablet) and are not always covered by insurance. 23 Therefore, the cost can limit their availability.
Summary
DORAs demonstrate promise to treat insomnia with fewer side effects. 10 However, further head-to-head trials by independent investigators are necessary to determine if DORAs are cost-effective.
Footnotes
Author Disclosure Statement
No competing financial interests exist.
Funding Information
No funding was received for this article.