Why can orexin receptor antagonists improve insomnia? In-depth analysis of the mechanism of action of suvorexant, lebrexant, and dalirexant!

18 Tháng 3, 2025

1. Why do traditional sleeping pills have limitations?

Insomnia is not just about not being able to fall asleep , but is also the result of an overactive brain wakefulness system. Many people rely on traditional sleeping pills (such as diazepam, alprazolam, and zopiclone ) to help them fall asleep, but the way these drugs work may cause dependence, tolerance, and disruption of sleep structure .

📌 Problems with traditional sleeping pills :

❌ Forced sedation affects natural sleep - they reduce overall brain activity by enhancing the inhibitory effect of GABA ( gamma -aminobutyric acid) receptors , but do not actually regulate sleep mechanisms ( Lader, 2011 ).

❌ Impact on deep sleep - Studies have found that benzodiazepines may reduce REM (rapid eye movement) sleep , affecting memory consolidation and brain repair ( Kuriyama & Endo, 2018 ).

❌ It is easy to become addicted, and insomnia worsens after stopping the drug - after long-term use, the brain will develop tolerance to the enhancing effects of GABA , requiring larger doses to achieve the same effect, and rebound insomnia may occur after stopping the drug ( Lader, 2011 ). ❌ Feeling sleepy when waking up in the morning affects daytime performance - Due to the long half-life of traditional sleeping pills, you may still feel sleepy and slow to react the next morning, which may even affect work and driving safety ( Billioti de Gage et al., 2014 ).

In order to find a safer and more natural way to help people sleep, scientists began to study how to help improve insomnia by adjusting the brain's own sleep-wake system . Orexin receptor antagonists (ORAs ) came into being as a new sleep-aid solution that is non-addictive and does not cause morning drowsiness .

2. What is orexin? How does it affect sleep?

Orexin is a neurotransmitter secreted by the hypothalamus of the brain. Its main function is to maintain wakefulness and prevent sleep. When the orexin system is abnormally active, the brain will remain awake, leading to difficulty falling asleep or waking up easily at night ( Sakurai, 2007 ).

📌 How Orexin works :

✅ High levels of orexin → maintain wakefulness (i.e. active time during the day).

✅ Low levels of orexin → promote sleep (normally, orexin levels decrease before going to bed at night). ❌ Problems faced by insomniacs : The orexin system is overactive , and even when one wants to fall asleep, the brain continues to receive “ wakefulness ” signals, leading to difficulty falling asleep or unstable sleep ( Mahlios et al., 2013 ).

Orexin receptor antagonists ( ORAs ) work by inhibiting the effects of orexin , reducing the brain's wakefulness signals, and thus helping the body enter a natural sleep, rather than directly sedating the nervous system like traditional sleeping pills.

3. How do Suvorexant, Lebrexant, and Darilexant improve insomnia?

The core mechanism of orexin receptor antagonists is to block the brain's orexin receptors ( Orexin Receptors OX1R and OX2R ), reduce wakefulness signals, and allow the body to naturally fall asleep ( Sun et al., 2021 ). Currently, the three new generation sleep aids approved on the market - Suvorexant , Lemborexant , and Daridorexant - are optimized for different types of insomnia.

drug	Main Function	Target Group	Mechanism of action
Suvorexant	Helps to sleep soundly throughout the night and reduce nighttime awakenings	People who wake up easily at night and have sleep maintenance disorders	It mainly acts on OX1R & OX2R , reducing nighttime awakenings and helping maintain deep sleep.
Lemborexant	Shorten the time to fall asleep and enter sleep quickly	Difficulty falling asleep	It acts on OX2R to reduce wakefulness signals more quickly, and is suitable for people who have difficulty initiating sleep.
Daridorexant	Improve the proportion of deep sleep and reduce morning fatigue	Those who have light sleep and feel sleepy in the morning	It acts on OX1R & OX2R , optimizes sleep structure, increases the proportion of deep sleep, and makes you more energetic when you wake up in the morning.

📌 Research data supports :

• Clinical studies on suvorexant have found that it can reduce the number of nighttime awakenings by 43% and improve sleep continuity throughout the night ( Herring et al., 2016 ).

• Lebroxan can shorten the time it takes to fall asleep by 52% and help people enter sleep mode quickly ( Ueno et al., 2022 ).

• Dauvilliers et al.'s research shows that it can increase the proportion of deep sleep without affecting daytime wakefulness ( Dauvilliers et al., 2022 ).

4. Orexin receptor antagonists vs. traditional sleeping pills, which one is safer?

Features	Traditional sleeping pills (eg, diazepam, zopiclone)	Orexin receptor antagonists (suvorexant, lebrexant, darilexant)
Mechanism of action	Directly enhances GABA inhibition, forcing sedation	Block wake-up signals and let the body fall asleep naturally
Does it affect deep sleep?	May reduce REM sleep and affect memory consolidation	Does not affect deep sleep and improves sleep quality
Is it addictive?	Long-term use can lead to addiction and increased tolerance	No dependency, can be used for a long time
Morning state	Feeling sleepy in the morning and having decreased concentration	Wake up the next day, no effect

📌 Why do doctors recommend orexin receptor antagonists?

✅ No dependence, can be used for a long time .

✅ It will not affect deep sleep and improve the overall sleep quality .

✅ You won’t feel dizzy or have a decreased concentration the next day .

✅ Suitable for patients with long-term insomnia and safer .

5. Conclusion: Orexin receptor antagonists are a safer long-term sleep aid

📌 Core summary :

• Traditional sleeping pills help people fall asleep by calming the nervous system, but they are addictive and may affect deep sleep ( Lader, 2011 ).

• Orexin receptor antagonists (such as suvorexant, leborexant, and darilexant) reduce wakefulness signals rather than forced sedation, allowing the brain to fall asleep naturally and without dependence ( Sun et al., 2021 ).

• Studies have shown that these new sleeping aids can be used for a long time and sleep will not rebound after discontinuation , making them a safer choice for sleeping aids ( Ueno et al., 2022 ).

📌 Recommended for symptoms :

✅ Difficulty falling asleep ➝ Lebron (helps you fall asleep quickly) .

✅ Waking up easily at night ➝ Suvorexant (reduces nighttime awakenings) .

✅ Light sleep, tiredness in the morning ➝ Daryl Leydig (Improve Deep Sleep) .

If you are looking for a more scientific and safer sleep aid, orexin receptor antagonists may be the best choice!

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