Narcolepsy
Narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness occurring alone or together with features of rapid-eye movement (REM) sleep dissociation and disrupted nighttime sleep. There are two main subtypes of narcolepsy: Narcolepsy Type I (NT1) is accompanied by cataplexy (i.e., a sudden loss of muscle control often triggered by strong emotion) whilst Narcolepsy Type II (NT2) does not include cataplexy. Cataplexy occurs when the body enters a state of paralysis that normally only occurs during REM sleep to prevent you from acting out your dreams. Reducing the frequency of these cataplexy episodes is a crucial aspect of managing the treatment of NT1 since they can be quite dangerous if they happen at the wrong time (e.g., while handling heavy or hazardous items).
Orexins
Narcolepsy is thought to be caused by abnormally low levels of a type of chemical in the brain called orexins. Orexins are a class of neurotransmitters produced in the hypothalamus whose primary function is to regulate wakefulness. These neurotransmitters can bind to two types of receptors: OXR1 and OXR2. When they bind to OXR2 receptors, this activates several wake-promoting systems involving other neurotransmitters including, but not limited to, norepinephrine, serotonin, and dopamine. They also help regulate and maintain those downstream wake-promoting systems, essentially keeping them organized and working properly. OX1R receptors, on the other hand, are more involved in functions related to motivation and reward, such as appetite. In the case of narcolepsy, insufficient binding of orexin to OXR2 receptors during wakefulness means that the body’s sleep-promoting systems will start to take over prematurely.
Orexin antagonists vs. Orexin agonists
Orexin antagonists (i.e., medications that block OXR2 receptors to prevent orexin from being absorbed by them) have been used as a pharmacological treatment for insomnia since 2014. Unlike conventional sleep medications that induce sedation, orexin antagonists induce more natural sleep by inhibiting the brain’s wakefulness signals, thus allowing the brain’s sleep signals to take over. As well as providing more natural sleep, this also reduces the risk of dependence, tolerance buildup, or other long-term complications.
However, it is much harder to reproduce the effect of a neurotransmitter many times the drug’s own size than it is to simply block the receptor it binds to. Because of this, the first orexin agonists (i.e., medications that bind to and activate OXR2 receptors to mimic the effects of natural orexin) were only approved for use by the FDA last year. In a recent clinical trial, 112 patients with NT1 were given either an orexin agonist (n = 90) or a placebo (n = 22) prior to undertaking a Maintenance of Wakefulness Test, where the patient sits in a darkened room and is told to stay awake as long as possible. The group that received the orexin agonist were able to stay awake for an additional 12.5 to 25 minutes (depending on the dosage given) compared to the placebo group. In many cases this was enough to bring the participants back within the normal range for those without narcolepsy. Furthermore, cataplexy episodes were also reduced by approximately two-thirds compared to the placebo group.
By targeting the key regulator of wakefulness, orexin agonists provide more natural and stable wakefulness with fewer side-effects and less potential for abuse than traditional wake-promoting medications (e.g. stimulants), which instead target the downstream neurotransmitters that are regulated by orexin. However, this is not to say they are free of side effects, with the most commonly reported side effects being insomnia and an increased need to urinate – similar to other wake-promoting medications. Regardless, this new class of medications presents a promising option for those suffering from narcolepsy.
References:
Ruoff, C., & Rye, D. (2016). The ICSD-3 and DSM-5 guidelines for diagnosing narcolepsy: clinical relevance and practicality. Current medical research and opinion, 32(10), 1611–1622. https://doi.org/10.1080/03007995.2016.1208643
Muehlan, C., Roch, C., Vaillant, C., & Dingemanse, J. (2023). The orexin story and orexin receptor antagonists for the treatment of insomnia. Journal of sleep research, 32(6), e13902. https://doi.org/10.1111/jsr.13902
Dauvilliers, Y., et al. (2025). Oveporexton, an Oral Orexin Receptor 2-Selective Agonist, in Narcolepsy Type 1. The New England journal of medicine, 392(19), 1905–1916. https://doi.org/10.1056/NEJMoa2405847
