An orexin receptor antagonist is a type of medication for insomnia that works by targeting the brain’s system for regulating sleep and wakefulness. Unlike other sleep aids that cause broad sedation, this medication reduces the signals in the brain that promote wakefulness. This allows for a more natural transition to sleep. The primary use for these medications is to help individuals who have difficulty falling asleep or staying asleep.
The Role of Orexin in the Sleep-Wake Cycle
The orexin system is a main player in maintaining wakefulness and regulating the body’s sleep-wake cycle. Orexin, also known as hypocretin, is a neuropeptide produced by a small cluster of neurons in the hypothalamus. These neurons send signals throughout the brain that influence arousal, alertness, and appetite.
The activity of orexin-producing neurons follows a daily rhythm. During the day, these neurons are highly active, releasing orexin to promote a state of wakefulness. This release helps consolidate wakefulness into a single, sustained period. As night approaches, the activity of these neurons decreases, acting as a switch that allows the brain to transition into sleep. The discovery of orexin’s role was linked to studying narcolepsy, a condition caused by an orexin deficiency that results in excessive daytime sleepiness.
Mechanism of Action
The brain has two types of receptors that orexin binds to: orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R). When orexin molecules attach to these receptors, they activate pathways that keep a person awake and alert. Orexin receptor antagonists are designed to block these specific receptors.
By occupying the orexin receptors, the antagonist drug prevents the brain’s natural orexin from binding to them. This action is similar to placing a blocker in a keyhole so the “wakefulness key” cannot fit. This targeted inhibition of the orexin system quiets the wake-promoting signals, which permits sleep to occur rather than forcing the brain into a state of sedation.
Approved Medications and Clinical Use
Several orexin receptor antagonists have been approved for the treatment of insomnia in adults. The first such drug approved by the U.S. Food and Drug Administration (FDA) was suvorexant (Belsomra) in 2014. Following suvorexant, lemborexant (Dayvigo) was approved in 2019, and daridorexant (Quviviq) received approval in 2022.
All three of these medications are dual orexin receptor antagonists (DORAs), meaning they block both orexin receptor types. Their clinical use is for adults with insomnia, and studies have shown they improve measures such as the time it takes to fall asleep and the amount of time spent awake after initially falling asleep.
Comparison to Traditional Sleep Aids
The approach of orexin receptor antagonists differs from older sleep medications, such as benzodiazepines and non-benzodiazepine “Z-drugs.” Traditional hypnotics work by enhancing the effects of gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain. This action causes a widespread depression of the central nervous system, which can disrupt the natural stages of sleep and lead to next-day grogginess, cognitive impairment, and a risk of dependence.
Orexin receptor antagonists, in contrast, offer a more targeted mechanism. Instead of inducing broad sedation, they selectively block the orexin system involved in promoting wakefulness. This allows the brain’s natural sleep-promoting pathways to take over. As a result, these newer medications are thought to better preserve natural sleep architecture and may lead to fewer side effects like motor incoordination compared to GABA-acting drugs.
Side Effects and Safety Considerations
Like all medications, orexin receptor antagonists are associated with potential side effects. The most commonly reported adverse effects are often dose-related and include:
- Somnolence, or next-day drowsiness
- Headaches
- Dizziness
- Fatigue
Some individuals may also experience abnormal dreams or nightmares.
There are also less common but more serious safety considerations. This class of drugs has been associated with complex sleep behaviors, such as sleepwalking or sleep-driving. Other potential effects include sleep paralysis, which is a temporary inability to move or speak upon waking, and hallucinations that can occur when falling asleep or waking up. A contraindication for these medications is narcolepsy, as blocking the few remaining orexin signals can worsen the condition’s symptoms.