Orexin receptor antagonists (daridorexant, suvorexant, lemborexant)

What orexin receptor antagonists are

The class comprises three approved substances: suvorexant (Belsomra, US since 2014), lemborexant (Dayvigo, US since 2019) and daridorexant (Quviviq, EU since 2022). All three are prescription-only sleep medicines for adults with insomnia, that is, with problems falling asleep or staying asleep. In Germany, only daridorexant is available.

What is rated is the state of knowledge. For a sleep medicine it is good: several large double-blind trials with sleep laboratory measurement, an extension over one year, dedicated driving and abuse studies. Anyone interested in the orexin system itself will find more about the wakefulness peptide at whose receptors these substances act on the page on orexin B. General information on sleep is under Sleep & sleep hygiene.

How they work

Orexin is a messenger substance from the brain that promotes wakefulness. The substances occupy both orexin receptors and thereby block this wake signal; according to the European Medicines Agency, this helps people fall asleep faster, stay asleep longer and function better during the day. The approach differs fundamentally from benzodiazepines and Z-drugs, which enhance the inhibitory GABA effect throughout the brain.

The limits also follow from the principle of action: in narcolepsy, a sleep disorder with sudden, involuntary falling asleep, the medicines must not be used. According to the EMA, daridorexant must also not be used together with strong CYP3A4 inhibitors, a group of medicines.

What the studies show

Mignot 2022: daridorexant in two pivotal trials

Two phase 3 trials at 156 centers in 17 countries randomized 930 and 924 adults with insomnia to daridorexant 10, 25 or 50 mg or placebo, every evening for three months. With 50 mg, wake time after sleep onset fell by 22.8 minutes more than on placebo after one month and by 18.3 minutes after three months, and the time to persistent sleep by 11.4 and 11.7 minutes respectively; self-reported sleep time rose by 22.1 and 19.8 minutes respectively. 25 mg had a weaker effect, 10 mg missed the sleep laboratory endpoints. Side effects occurred in 38 to 39 percent on daridorexant and 33 to 34 percent on placebo, most commonly nasopharyngitis and headache.

Kunz 2023: one year of daridorexant

Those who had completed the pivotal trials could take part for a further 40 weeks in a double-blind design; 804 patients did so, and 68.4 percent completed the extension. Side effects occurred at a similar rate in all groups (35 to 40 percent), and morning sleepiness did not increase. In a one-week placebo phase at the end, neither withdrawal symptoms nor rebound appeared. With 50 mg, self-reported sleep time in week 12 of the extension was 20.4 minutes above placebo; the efficacy analyses were explicitly exploratory.

Rosenberg 2019: lemborexant versus zolpidem

SUNRISE 1 randomized 1,006 people aged 55 and over with problems staying asleep to placebo, extended-release zolpidem or lemborexant 5 or 10 mg, for one month. Lemborexant shortened the time to fall asleep in the sleep laboratory (ratio to placebo 0.77 and 0.72 respectively), increased sleep efficiency by 7.1 to 8.0 percentage points and shortened wake time by 24.0 to 25.4 minutes. In the second half of the night, participants on lemborexant lay awake 6.7 to 8.0 minutes less than on zolpidem. 86 percent of participants were women.

Herring 2016: suvorexant over three months

The pooled analysis of two identical phase 3 trials looked at the 20 mg dose level (15 mg in older people), which corresponds to the maximum approved dose, with 493 treated compared with 767 on placebo. Falling asleep and staying asleep improved subjectively and in the sleep laboratory, with the exception of the laboratory-measured time to fall asleep after three months. 3 percent stopped because of side effects, compared with 5.2 percent on placebo; sleepiness occurred in 6.7 versus 3.3 percent.

De Crescenzo 2022: the big comparison

The network meta-analysis in the Lancet compared 30 sleep medicines from 154 double-blind trials with 44,089 participants. In acute treatment, lemborexant, together with benzodiazepines, eszopiclone, zolpidem and zopiclone, was more effective than placebo. Zopiclone led to study dropouts because of side effects more often than daridorexant (OR 3.45) and suvorexant (OR 3.13). Overall, eszopiclone and lemborexant had the most favorable profile, but the safety data on lemborexant were not conclusive. Melatonin showed no substantial overall benefit in insomnia.

Muehlan 2022: driving in the morning

60 healthy people aged 50 to 79 took daridorexant 50 or 100 mg, zopiclone 7.5 mg or placebo in the evening and drove in a driving simulator 9 hours later. After the first dose, lane position on 50 mg daridorexant varied by 2.19 cm more than on placebo, and markedly on zopiclone as well. After four nights, daridorexant was below the impairment threshold and no longer above placebo. The authors advise not driving until you know how the medicine affects you.

Where the data stop

• The size of the effect. Ten to 25 minutes more sleep or less time lying awake is statistically clear, but for the individual often less than the level of distress would lead one to expect. A large network meta-analysis counts daridorexant and suvorexant among the medicines that can work in acute treatment but for which long-term information is missing or tolerability is limited.
• More than one year. The longest controlled data cover twelve months. Studies on continuous treatment over years are missing.
• The comparison among themselves. Direct trials between daridorexant, suvorexant and lemborexant were not found in the research. Differences can only be estimated indirectly.
• Healthy people with occasional poor sleep. What has been studied and approved is chronic insomnia with consequences for the day. For sleep optimization in healthy people there are no data.

Status, approval and legal

Daridorexant (Quviviq) has been centrally approved in the EU since April 29, 2022, for adults with insomnia whose symptoms have lasted at least three months and considerably impair daytime functioning. It is prescription-only and is not covered by the German Narcotics Act (BtMG). According to the EMA, the approved dose is one 50 mg tablet in the evening, no more than 30 minutes before going to bed, or 25 mg based on medical assessment; treatment should be as short as possible and reviewed by a doctor within three months. The medicine is subject to additional monitoring.

Suvorexant (Belsomra) has been approved in the US since August 13, 2014, lemborexant (Dayvigo) since December 20, 2019. Neither is approved in the EU. In the US, both are classified as Schedule IV, that is, as controlled substances with a low potential for abuse.

Safety

According to the EMA, the most common side effects of daridorexant are headache and sleepiness, in up to 1 in 10 people treated, mostly mild or moderate. In the pivotal trials, the overall rate of side effects was only a few percentage points above placebo.

The US prescribing information lists as warnings impaired alertness and coordination the next morning, sleep paralysis, hallucinations when falling asleep or waking up, cataplexy-like symptoms, complex sleep behaviors such as sleepwalking or driving while half asleep, and a worsening of depression up to suicidal thoughts. For suvorexant 20 mg and lemborexant 10 mg, it advises against driving the next day; in the driving simulator, daridorexant was measurably impairing after the first dose, but no longer after four nights.

Abuse is possible: in a study with 29 recreational users of sedatives, they rated lemborexant similarly positively to zolpidem 30 mg and suvorexant 40 mg and more positively than placebo (US prescribing information Dayvigo). Alcohol and other sedating substances enhance the effect.

Sources

• Mignot E et al., Lancet Neurol 2022 – daridorexant, two phase 3 trials with 1,854 patients
• Kunz D et al., CNS Drugs 2023 – daridorexant, 40-week extension study with 804 patients
• Herring WJ et al., J Clin Sleep Med 2016 – suvorexant, pooled 3-month data from the phase 3 trials
• Rosenberg R et al., JAMA Netw Open 2019 – lemborexant versus placebo and zolpidem, SUNRISE 1 with 1,006 participants
• Muehlan C et al., Clin Pharmacol Ther 2022 – driving performance after daridorexant in a driving simulator, 60 healthy people
• De Crescenzo F et al., Lancet 2022 – network meta-analysis of drugs for insomnia, 154 trials
• Riemann D et al., J Sleep Res 2023 – European insomnia guideline 2023
• EMA – Quviviq (daridorexant), European public assessment report and authorization of April 29, 2022
• FDA, Drugs@FDA – Belsomra (suvorexant, NDA 204569), approval August 13, 2014, prescribing information
• FDA, Drugs@FDA – Dayvigo (lemborexant, NDA 212028), approval December 20, 2019, prescribing information