An orexin receptor antagonist, or orexin antagonist, is a drug that inhibits the effect of

orexin Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone ("drop attacks" or cataplexy) ...

by acting as a receptor antagonist of one or both of the

orexin receptor The orexin receptor (also referred to as the hypocretin receptor) is a G-protein-coupled receptor that binds the neuropeptide orexin. There are two variants, OX1 and OX2, each encoded by a different gene (, ). Both orexin receptors exhibit ...

s, OX₁ and OX₂. Medical applications include treatment of

sleep disorder A sleep disorder, or somnipathy, is a medical disorder of an individual's sleep patterns. Some sleep disorders are severe enough to interfere with normal physical, mental, social and emotional functioning. Polysomnography and actigraphy are tests ...

s such as

insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

Examples

Marketed

* Daridorexant (nemorexant; Quviviq) – dual OX₁ and OX₂ antagonist – approved for insomnia in January 2022, formerly under development for sleep apnea – half-life 8 hours *

Lemborexant Lemborexant, sold under the brand name Dayvigo, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maint ...

(Dayvigo) – dual OX₁ and OX₂ antagonist – approved for insomnia in December 2019 and released June 1 2020, under development for circadian rhythm sleep disorders, chronic obstructive pulmonary disease, and sleep apnea – half-life 17–55 hours * Suvorexant (Belsomra) – dual OX₁ and OX₂ antagonist – approved for insomnia in August 2014, under development for delirium – half-life 12 hours

Under development

Seltorexant Seltorexant, also known by its developmental code names MIN-202 and JNJ-42847922, is an orexin antagonist medication which is under development for the treatment of depression and insomnia. It is a selective antagonist of the orexin OX2 recept ...

(MIN-202, JNJ-42847922, JNJ-922) – selective OX₂ antagonist – under development for major depressive disorder, insomnia, and sleep apnea, up to phase 3 – half-life 2–3 hours * Vornorexant (ORN-0829, TS-142) – dual OX₁ and OX₂ antagonist – under development for insomnia and sleep apnea, up to phase 2 – half-life 1.5–3 hours

Not marketed

* ACT-335827 – selective OX₁ antagonist *

Almorexant Almorexant, also known by its development code ACT-078573, is an orexin antagonist, acting as a competitive antagonist of the OX1 and OX2 orexin receptors, which was being developed by the pharmaceutical companies Actelion and GSK for the treat ...

(ACT-078573) – dual OX₁ and OX₂ antagonist – development of the drug was abandoned in January 2011 *

EMPA The Swiss Federal Laboratories for Materials Science and Technology (Empa, German acronym for ''Eidgenössische Materialprüfungs- und Forschungsanstalt'') is an interdisciplinary Swiss research institute for applied materials sciences and tech ...

– selective OX₂ antagonist * Filorexant (MK-6096) – dual OX₁ and OX₂ antagonist – development was discontinued in 2015 * GSK-649868 (SB-649868) – dual OX₁ and OX₂ antagonist – was in development for potential use in sleep disorders *

JNJ-10397049 JNJ-10397049 is a potent and highly selective OX2 receptor antagonist. In animals, JNJ-10397049 was found to have sleep-promoting effects and to attenuate the reinforcing effects of ethanol Ethanol (abbr. EtOH; also called ethyl alco ...

– selective OX₂ antagonist * RTIOX-276 – selective OX₁ antagonist * SB-334867 – first non-peptide selective OX₁ antagonist – has been shown to produce sedative and

anorectic An anorectic or anorexic is a drug which reduces appetite, resulting in lower food consumption, leading to weight loss. By contrast, an appetite stimulant is referred to as orexigenic. The term is (from the Greek ''ἀν-'' (an-) = "without" a ...

effects in animals *

SB-408124 SB-408124 is a drug which is a non-peptide antagonist selective for the orexin receptor subtype OX1, with around 70x selectivity for OX1 over OX2 receptors, and improved oral bioavailability compared to the older OX1 antagonist SB-334867. It ...

– selective OX₁ antagonist *

TCS-OX2-29 TCS-OX2-29 is an orexin antagonist. It was the first non-peptide antagonist developed that is selective for the orexin receptor subtype OX2, with an IC50 of 40nM and selectivity of around 250x for OX2 over OX1 receptors. Orexin antagonists ar ...

– first non-peptide selective OX₂ antagonist

Medical uses

Insomnia

Orexin receptor antagonists dose-dependently improve sleep parameters including

latency to persistent sleep In sleep science, sleep onset latency (SOL) is the length of time that it takes to accomplish the transition from full wakefulness to sleep, normally to the lightest of the non-REM sleep stages. Sleep latency studies Pioneering Stanford Universi ...

(LPS),

wake after sleep onset Middle-of-the-night insomnia (MOTN) is characterized by having difficulty returning to sleep after waking up during the night or very early in the morning. This kind of insomnia (sleeplessness) is different from initial or sleep-onset insomnia, whi ...

(WASO),

sleep efficiency Sleep efficiency (SE) is the ratio between the time a person spends asleep, and the total time dedicated to sleep (i.e. both sleeping and attempting to fall asleep or fall back asleep). It is given as a percentage. SE of 80% or more is considered n ...

(SE),

total sleep time Sleep is a sedentary state of mind and body. It is characterized by altered consciousness, relatively inhibited sensory activity, reduced muscle activity and reduced interactions with surroundings. It is distinguished from wakefulness by a de ...

(TST), and

sleep quality Sleep is a sedentary state of mind and body. It is characterized by altered consciousness, relatively inhibited Perception, sensory activity, reduced muscle activity and reduced interactions with surroundings. It is distinguished from wakefuln ...

(SQ). Network meta-analyses have found that orexin receptor antagonists including suvorexant and

lemborexant Lemborexant, sold under the brand name Dayvigo, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maint ...

are more effective in the treatment of insomnia than other sleep aids including benzodiazepines (e.g.,

triazolam Triazolam, sold under the brand name Halcion among others, is a central nervous system (CNS) depressant tranquilizer of the triazolobenzodiazepine (TBZD) class, which are benzodiazepine (BZD) derivatives. It possesses pharmacological properties ...

temazepam Temazepam (sold under the brand names Restoril among others) is a medication of the benzodiazepine class which is generally used to treat severe or debilitating insomnia. It is taken by mouth. Temazepam is rapidly absorbed, and significant hyp ...

Z-drug Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive drugs that are very benzodiazepine-like in nature. They are used in the treatment of sleep proble ...

s (e.g.,

zolpidem Zolpidem, sold under the brand name Ambien, among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and behavior ...

zopiclone Zopiclone, sold under the brand name Imovane among others, is a nonbenzodiazepine used to treat difficulty sleeping. Zopiclone is molecularly distinct from benzodiazepine drugs and is classed as a cyclopyrrolone. However, zopiclone increases t ...

antihistamine Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provid ...

s (e.g.,

doxepin Doxepin is a medication falling in the tricyclic antidepressant (TCA) class used to treat major depressive disorder, anxiety disorders, chronic hives, and insomnia. For label updates seFDA index page for NDA 022036/ref> For hives it is a less ...

diphenhydramine Diphenhydramine (DPH) is an antihistamine and sedative mainly used to treat allergies, insomnia, and symptoms of the common cold. It is also less commonly used for tremor in parkinsonism, and nausea. It is taken by mouth, injected into ...

doxylamine Doxylamine, sold under the brand name Unisom among others, is an antihistamine medication which is used in the treatment of insomnia and allergies. In combination with pyridoxine ( vitamin B6), it is also used to treat morning sickness in pre ...

), antidepressants (e.g.,

trazodone Trazodone, sold under many brand names, is an antidepressant medication. It is used to treat major depressive disorder, anxiety disorders, and difficulties with sleep. The medication is taken orally. Common side-effects include dry mouth, f ...

mirtazapine Mirtazapine, sold under the brand name Remeron amongst others, is an Atypical antidepressant, atypical antidepressant, and as such is used primarily to treat Depression (mood), depression. Its effects may take up to four weeks, but can also man ...

amitriptyline Amitriptyline, sold under the brand name Elavil among others, is a tricyclic antidepressant primarily used to treat cyclic vomiting syndrome (CVS), major depressive disorder and a variety of pain syndromes from neuropathic pain to fibromyalgi ...

), anticonvulsants (e.g.,

gabapentin Gabapentin, sold under the brand name Neurontin among others, is an anticonvulsant medication primarily used to treat partial seizures and neuropathic pain. It is a first-line medication for the treatment of neuropathic pain caused by diabeti ...

pregabalin Pregabalin, sold under the brand name Lyrica among others, is an anticonvulsant, analgesic and anxiolytic medication used to treat epilepsy, neuropathic pain, fibromyalgia, restless leg syndrome, opioid withdrawal and generalized anxiety diso ...

), and

melatonin receptor agonist Melatonin receptor agonists are analogues of melatonin that bind to and activate the melatonin receptor. Agonists of the melatonin receptor have a number of therapeutic applications including treatment of sleep disorders and depression. The disc ...

s (e.g., melatonin,

ramelteon Ramelteon, sold under the brand name Rozerem among others, is a melatonin agonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset. ...

). Orexin receptor antagonists are not currently used as

first-line treatment A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis. As a rule, each therapy has indications and contraindications. There are many different ...

s for insomnia due to cost and concerns about possible misuse liability.

Delirium

Suvorexant appears to be effective in the prevention of delirium.

Side effects

Side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s of orexin receptor antagonists include

somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...

, daytime sleepiness and sedation, headache, abnormal dreams, fatigue, and

dry mouth Xerostomia, also known as dry mouth, is dryness in the mouth, which may be associated with a change in the composition of saliva, or reduced salivary flow, or have no identifiable cause. This symptom is very common and is often seen as a side eff ...

. Rates of somnolence or fatigue with orexin receptor antagonists in clinical trials were 7% (vs. 3% with placebo) for suvorexant 15 to 20mg, 7 to 10% (vs. 1.3% for placebo) for lemborexant 5 to 10mg, and 5 to 6% (vs. 4% with placebo) for daridorexant 25 to 50mg.

Pharmacology

Pharmacokinetics

The elimination half-lives of clinically used orexin receptor antagonists are 12 hours for suvorexant, about 17 to 19 hours ("effective" half-life) or 55 hours (terminal elimination half-life) for

, and 6 to 10 hours for daridorexant. The elimination half-lives of investigational orexin receptor antagonists are 2 to 3 hours for

seltorexant Seltorexant, also known by its developmental code names MIN-202 and JNJ-42847922, is an orexin antagonist medication which is under development for the treatment of depression and insomnia. It is a selective antagonist of the orexin OX2 recept ...

and about 1.5 to 3 hours for vornorexant.

Research

Filorexant was studied for but was not found to be effective in the treatment of diabetic neuropathy, migraine, and

major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Intro ...

in phase 2

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...

is under development for treatment of major depressive disorder however and is in phase 3 trials for this indication. Also, suvorexant is in a

phase 4 Phase 4, Phase IV or Phase Four may refer to: Media * Marvel Cinematic Universe: Phase Four, a group of superhero films and television series beginning in 2021 * ''Phase IV'' (1974 film), a 1974 film * ''Phase IV'' (2002 film), a 2002 film * ...

trial for use as an adjunct to antidepressant therapy in people with major depressive disorder and residual insomnia.

References

External links

* {{Insomnia pharmacotherapies