Sleep & wakefulness
Explore the pathways used to treat insomnia or promote wakefulness, with the evidence and safety behind each approach.
Difficulty falling or staying asleep despite an opportunity to sleep. Treatments address learned sleep patterns or act through orexin, histamine, GABA or melatonin pathways; their indications, benefits and risks differ.
Reduce wake signaling
Reduced wake drive can help with sleep onset or maintenance.
Simplified pathway; the treatment can have other effects.
Blocks orexin A/B signaling at both receptors, reducing wake drive.
The label describes this explanation of clinical benefit as presumed.
Daridorexant · Quviviq
Adult insomnia involving sleep onset or maintenance; contraindicated in narcolepsy.
Indication & guideline context
The adult U.S. indication includes difficulty falling asleep and/or staying asleep.
Coverage source ↗Improved measured nighttime sleep maintenance in a three-month trial.
Polysomnography measures minutes awake after initially falling asleep. This selected plot measures sleep maintenance; it does not measure time to fall asleep.
95% CI -24 to -13 minutes · Less wake time favors treatment
18 fewer minutes awake after initially falling asleep versus placebo; 95% confidence interval. This is not extra total sleep time.
The plotted adult label endpoint remains sleep maintenance. DARI-DREAM NCT07843329 is a separate planned study with sleep time primary and daytime impairment secondary; it has no results. No comparison with another treatment or individual prediction.
Trial context, safety & sources
Polysomnography measures minutes awake after initially falling asleep. This selected plot measures sleep maintenance; it does not measure time to fall asleep.
- Study
- Study 1 · NCT03545191
- Population
- Adults with insomnia
- Randomized
- 930 total
- Follow-up
- 3 months
- Dose / arms
- 50 mg nightly (310 randomized); placebo (310); third arm: 25 mg (310)
- Endpoint
- Wake after sleep onset, assessed by polysomnography
- Measure
- Least-squares mean change from baseline; label-rounded values
- Treatment change
- -29 minutes
- Control change
- -11 minutes
18 fewer minutes awake after initially falling asleep versus placebo; 95% confidence interval. This is not extra total sleep time.
Read the trial source ↗Safety in context
Headache, sleepiness or fatigue, and dizziness.
Study 1, 50 mg versus placebo: headache 7%/5%; sleepiness or fatigue 5%/4% (308/309 treated participants; three months).
Warnings include impaired driving, complex sleep behaviors, depression/suicidality and respiratory considerations; hypersensitivity is a contraindication.
- Quviviq U.S. prescribing information, revised September 2024
- DARI-DREAM primary registry, first posted September 28, 2026
Source date: 2024-09 · Checked 2026-10-06
Less nighttime wakefulness in insomnia and longer daytime wakefulness in narcolepsy are different endpoints. Read each result within its own trial.
Evidence records
All selected treatments, with primary sources and study limits.
Cognitive behavioral therapy for insomniaGuideline recommended
A structured combination of cognitive and behavioral techniques, including stimulus control and an individualized sleep schedule. It changes factors that perpetuate insomnia rather than binding an orexin receptor.
Established clinical treatment; several components contribute, so this is not a single molecular mechanism.
The U.S. AASM strongly recommends multicomponent CBT-I for chronic insomnia in adults. This recommendation is distinct from approval or clearance of an individual digital product.
AASM recommends multicomponent CBT-I for chronic insomnia, including difficulty falling asleep or staying asleep. This recommendation concerns the treatment approach; individual digital products require their own evidence.
Coverage source ↗An established option with benefits that can persist after the treatment course. Basic sleep-hygiene advice alone is not equivalent to CBT-I.
Requires participation and access to an appropriate program. A recommendation for CBT-I does not validate every consumer sleep app.
Safety in context
Requires adapting routines and attending sessions over several weeks; daytime sleepiness should be discussed when choosing the approach.
No single placebo comparison is represented here; guideline evidence spans different programs and control conditions.
The schedule and components should be individualized to other medical conditions and daytime safety needs. No pooled serious-event rate is supplied.
Professional-society clinical practice guideline and patient guide · Source date: 2021-02-01 · Checked 2026-09-19
Daridorexant · QuviviqU.S. approved
Blocks orexin A/B signaling at both receptors, reducing wake drive.
The label describes this explanation of clinical benefit as presumed.
Adult insomnia involving sleep onset or maintenance; contraindicated in narcolepsy.
The adult U.S. indication includes difficulty falling asleep and/or staying asleep.
Coverage source ↗Improved measured nighttime sleep maintenance in a three-month trial.
The plotted adult label endpoint remains sleep maintenance. DARI-DREAM NCT07843329 is a separate planned study with sleep time primary and daytime impairment secondary; it has no results. No comparison with another treatment or individual prediction.
Polysomnography measures minutes awake after initially falling asleep. This selected plot measures sleep maintenance; it does not measure time to fall asleep.
- Study
- Study 1 · NCT03545191
- Population
- Adults with insomnia
- Randomized
- 930 total
- Follow-up
- 3 months
- Dose / arms
- 50 mg nightly (310 randomized); placebo (310); third arm: 25 mg (310)
- Endpoint
- Wake after sleep onset, assessed by polysomnography
- Measure
- Least-squares mean change from baseline; label-rounded values
- Treatment change
- -29 minutes
- Control change
- -11 minutes
18 fewer minutes awake after initially falling asleep versus placebo; 95% confidence interval. This is not extra total sleep time.
Read the trial source ↗Safety in context
Headache, sleepiness or fatigue, and dizziness.
Study 1, 50 mg versus placebo: headache 7%/5%; sleepiness or fatigue 5%/4% (308/309 treated participants; three months).
Warnings include impaired driving, complex sleep behaviors, depression/suicidality and respiratory considerations; hypersensitivity is a contraindication.
Current DailyMed prescribing information; randomized placebo-controlled trial · Source date: 2024-09 · Checked 2026-10-06
Lemborexant · DayvigoU.S. approved
Prevents orexin from activating its wake-promoting receptors.
Receptor antagonism is established; the label calls the clinical mechanism presumed.
Adult sleep-onset or sleep-maintenance insomnia; contraindicated in narcolepsy.
The adult U.S. indication includes difficulty falling asleep and/or staying asleep.
Coverage source ↗Placebo-controlled trials support sleep-onset and maintenance benefit, including six-month patient-reported outcomes.
Sharing a mechanism with daridorexant does not establish equal efficacy or safety. No between-drug ranking is shown.
Safety in context
Sleepiness or fatigue, headache, and abnormal dreams.
Pooled first-30-day data: sleepiness/fatigue 6.9% with 5 mg, 9.6% with 10 mg, 1.3% with placebo (n=580/582/528).
Warnings include next-day impairment, falls, complex sleep behaviors, depression/suicidality and respiratory considerations.
Current DailyMed prescribing information; randomized placebo-controlled trials · Source date: 2025-02 · Checked 2026-09-19
Suvorexant · BelsomraU.S. approved
Blocks orexin signaling at OX1R and OX2R, reducing wake drive through the same broad pathway as daridorexant and lemborexant.
Receptor antagonism is established; the label describes the clinical mechanism as presumed.
Approved for insomnia involving difficulty falling or staying asleep. Contraindicated in narcolepsy; Schedule IV. The evidence shown concerns adults.
The U.S. indication includes difficulty falling asleep and/or staying asleep. The AASM 2017 recommendation specifically addresses sleep maintenance.
Coverage source ↗AASM 2017 weakly suggests suvorexant for sleep maintenance. VA/DoD 2025 includes it among suggested drugs when a medication course is offered; CBT-I remains first-line.
Two three-month trials randomized 1,021 and 1,019 participants. At 15 mg in older adults or 20 mg in younger adults, sleep onset and maintenance improved; results vary by measure and trial.
Pivotal trial doses are not necessarily the starting dose. The label reports differing laboratory and patient-reported effects. Sharing an orexin mechanism does not establish equal efficacy or safety.
Safety in context
Sleepiness, headache, dizziness and abnormal dreams.
First three months, pooled 15/20 mg trials: sleepiness 7%/3%, headache 7%/6%, dizziness 3%/2% with suvorexant/placebo (n=493/767).
Warnings include next-day driving impairment, complex sleep behaviors, worsening depression/suicidality, sleep paralysis and cataplexy-like symptoms. Respiratory disease and CNS-depressant interactions require consideration.
U.S. prescribing information; two randomized placebo-controlled pivotal trials · Source date: 2025-03 · Belsomra prescribing-information revision; pivotal two-trial publication in 2016. · Checked 2026-10-03
Low-dose doxepin · SilenorU.S. approved
Doxepin binds strongly to H1 receptors. At the 3–6 mg insomnia formulation, histamine blockade is the proposed explanation for improved sleep maintenance.
The U.S. label says the sleep-maintenance mechanism is unclear and may involve H1 antagonism; receptor affinity does not measure benefit.
Silenor 3 mg and 6 mg tablets are approved for difficulty staying asleep. These low-dose tablets are distinct from higher-dose antidepressant use.
Silenor 3 mg and 6 mg tablets are approved for difficulty staying asleep. This classification applies to the low-dose insomnia formulation.
Coverage source ↗AASM 2017 weakly suggests doxepin for sleep maintenance. VA/DoD 2025 includes doxepin among suggested drugs when a medication course is offered; CBT-I remains first-line.
A five-week trial found less nighttime wakefulness with 3 mg and 6 mg. The plot shows reported group means at night 29, not changes from baseline.
Selected adults aged 18–64 with primary insomnia; short follow-up. Raw group means have no reported 95% confidence interval here.
Polysomnography measures minutes awake after initially falling asleep. The plot shows group means at night 29 for this sleep-maintenance outcome.
- Study
- Krystal et al. · five-week doxepin trial
- Population
- Adults aged 18–64 with chronic primary insomnia
- Randomized
- 229 total
- Analysis population
- 221 treated participants; 73 doxepin 6 mg, 73 placebo, 75 doxepin 3 mg
- Follow-up
- 35 days; selected endpoint at night 29
- Dose / arms
- 6 mg nightly versus placebo; additional 3 mg arm. Randomized: 76/76/77; analyzed after receiving medication: 73/73/75 (221 total).
- Endpoint
- Wake after sleep onset, assessed by polysomnography
- Measure
- Reported mean wake after sleep onset at night 29; endpoint means, not baseline changes
- Treatment mean
- 40.7 minutes
- Control mean
- 60.5 minutes
The reported 6 mg mean was 19.8 minutes lower than placebo at night 29. This descriptive subtraction is not a separately reported adjusted treatment effect or total sleep gained.
Read the trial source ↗Safety in context
Sleepiness/sedation and nausea. Higher-dose antidepressant safety should not be treated as interchangeable with the 3–6 mg formulation.
Selected 35-day trial: sedation/somnolence 8% with 6 mg versus 5% with placebo; nausea 5% versus 0% (73 treated participants per arm).
Label warnings include impaired alertness, complex sleep behaviors and worsening depression/suicidality. MAOI use, untreated narrow-angle glaucoma and severe urinary retention are contraindications; ordinarily not recommended in severe sleep apnea.
U.S. prescribing information; randomized placebo-controlled primary publication · Source date: 2022-12 · Silenor prescribing-information revision; DailyMed posting April 21, 2026 is not a new efficacy result. Trial published October 1, 2011. · Checked 2026-10-03
Zolpidem · Ambien (immediate release)U.S. approved
Enhances GABA-mediated inhibition at GABA-A receptors, predominantly those containing the alpha-1 subunit.
GABA-A modulation is established pharmacology.
Ambien immediate-release tablets are approved for short-term adult insomnia involving difficulty falling asleep. Ambien CR is a distinct extended-release formulation with a different indication and evidence base.
Ambien immediate-release tablets are approved for short-term insomnia involving difficulty falling asleep. Extended-release zolpidem has separate labeling and evidence.
Coverage source ↗AASM 2017 weakly supports zolpidem for onset/maintenance symptoms; VA/DoD 2025 weakly supports it when medication is offered. Formulation-specific labeling still governs the approved indication.
Controlled efficacy trials lasted 4–5 weeks; sleep-onset benefit was shown through 35 days. The label discourages long-term use without reassessment.
Immediate-release evidence is not interchangeable with extended-release evidence. Short studies do not establish lasting insomnia remission.
Safety in context
Drowsiness, dizziness, diarrhea and drugged feelings.
Pooled 28–35-night trials, doses up to 10 mg: drowsiness 8%/5%, dizziness 5%/1% versus placebo (n=152/161).
FDA boxed warning: complex sleep behaviors can cause serious injury or death, even at recommended doses. Other risks include next-day impairment, falls, respiratory depression with opioids, dependence and withdrawal; morning exposure differs by sex.
U.S. prescribing information and professional guidelines · Source date: 2022-02 · Prescribing information revised February 2022; DailyMed posting updated April 15, 2025. · Checked 2026-10-03
Eszopiclone · LunestaU.S. approved
Acts at the GABA receptor complex, at sites near or allosterically coupled to benzodiazepine receptors, strengthening inhibitory signaling.
The label describes its exact hypnotic mechanism as unclear.
Approved for adult insomnia involving sleep onset or maintenance. Supporting controlled trials extended to six months; that does not establish indefinite benefit or safety.
The U.S. label reports that insomnia studies reduced time to fall asleep and improved sleep maintenance. The approved indication is insomnia; these tags describe the benefits documented in the label.
Coverage source ↗AASM 2017 weakly supports eszopiclone for onset and maintenance; VA/DoD 2025 weakly supports it when medication is offered.
A six-month randomized placebo-controlled trial supported sustained patient-reported onset and maintenance improvements during nightly 3 mg treatment.
Treatment benefit is distinct from remission after stopping. The displayed safety table uses a separate six-week trial. No efficacy confidence interval was independently retrieved.
Safety in context
Unpleasant taste, headache, sleepiness, dizziness and dry mouth.
Six-week trial, 3 mg versus placebo: unpleasant taste 34%/3%, sleepiness 8%/3% (n=105/99). In the separate six-month trial, adverse-event discontinuation was 12.8%/7.2% (n=593/195).
FDA boxed warning for complex sleep behaviors with serious injury or death. Next-day impairment, falls, respiratory cautions, dependence and withdrawal remain relevant.
U.S. prescribing information; randomized six-month trial; professional guidelines · Source date: 2023-07 · Prescribing information revised July 2023. · Checked 2026-10-03
- Lunesta U.S. prescribing information, revised July 2023
- Krystal et al., six-month randomized eszopiclone trial, Sleep (November 2003)
- FDA Z-drug complex sleep behavior boxed warning, April 30, 2019
- AASM pharmacologic insomnia guideline (2017)
- VA/DoD chronic insomnia guideline (2025), recommendations 8–10
Zaleplon · Sonata / genericsU.S. approved
Binds the benzodiazepine site of the GABA-A receptor complex, with alpha-1 selectivity, enhancing inhibition.
The label describes GABA receptor modulation as the presumed hypnotic mechanism.
Approved for short-term adult insomnia. Benefit is primarily faster sleep onset; the label does not establish increased total sleep time or fewer awakenings. Sonata identifies the familiar brand; the current source is generic labeling.
The label reports less time to fall asleep in short-term insomnia studies. Increased total sleep time and fewer awakenings were not established.
Coverage source ↗AASM 2017 weakly supports zaleplon for sleep onset; VA/DoD 2025 weakly supports it when medication is offered.
Supporting studies lasted one night to five weeks. The label reports sleep-onset benefit through 30 days; elimination half-life is about one hour.
A short half-life does not remove impairment or serious behavior risks. Consistent sleep-maintenance benefit was not established.
Safety in context
Headache, dizziness, sleepiness and memory effects.
Pooled 28/35-night studies, 5 or 10 mg versus placebo: sleepiness 5%/4%, amnesia 2%/1% (n=569/344). Doses are pooled and cannot be separated here.
FDA boxed warning for complex sleep behaviors with serious injury or death. CNS depressants, impaired driving, misuse, dependence and withdrawal are additional concerns.
Current generic U.S. prescribing information and professional guidelines · Source date: 2025-10-08 · Generic DailyMed posting updated October 8, 2025; medication guide revised June 2023. · Checked 2026-10-03
Temazepam · RestorilU.S. approved
Enhances GABA-A-mediated inhibition through the benzodiazepine binding site. Its broader sedative effects differ from selective orexin blockade.
Established benzodiazepine-class pharmacology.
Approved for short-term adult insomnia, generally 7–10 days. Supporting efficacy trials lasted two weeks. Approval does not mean preferred treatment for chronic insomnia.
AASM 2017 weakly suggests temazepam for difficulty falling asleep and staying asleep. VA/DoD 2025 weakly recommends against benzodiazepines for chronic insomnia.
Coverage source ↗AASM 2017 weakly supports temazepam for onset/maintenance. VA/DoD 2025 weakly recommends against benzodiazepines for chronic insomnia.
Two-week laboratory studies found dose-dependent sleep effects; at two weeks, total-sleep-time differences were significant at 15/30 mg and latency at 30 mg.
These are short-term findings. Tolerance, dependence and long-term cognitive/fall risks are not settled by laboratory sleep improvements.
Safety in context
Drowsiness, fatigue, dizziness, next-day hangover and confusion.
Label pooled controlled-trial table: drowsiness 9.1%/5.6%, dizziness 4.5%/3.3% versus placebo (n=1,076/783). Dose and duration are not specified for this pooled table.
Boxed warnings cover opioid-related sedation/respiratory depression, abuse/addiction, physical dependence and potentially life-threatening withdrawal. Abrupt cessation can provoke seizures. Falls, memory effects and complex behaviors also matter.
Current U.S. prescribing information and professional guidelines · Source date: 2026-06-09 · Current DailyMed posting updated June 9, 2026. · Checked 2026-10-03
Triazolam · HalcionU.S. approved
Binds the benzodiazepine site of GABA-A receptors and enhances GABA-mediated synaptic inhibition.
Mechanism described in U.S. prescribing information.
Approved for short-term insomnia in adults, generally 7–10 days. Its 1.5–5.5-hour elimination half-life differs from longer-acting benzodiazepines.
AASM 2017 weakly suggests triazolam for difficulty falling asleep. VA/DoD 2025 weakly recommends against benzodiazepines for chronic insomnia.
Coverage source ↗AASM 2017 weakly supports triazolam for sleep onset. VA/DoD 2025 weakly recommends against benzodiazepines for chronic insomnia.
Older controlled trials support short-term use. AASM assesses sleep-onset benefit; the displayed safety table pools trials lasting 1–42 days.
Short half-life does not eliminate amnesia, dependence or rebound symptoms. Efficacy confidence intervals were not independently retrieved.
Safety in context
Drowsiness, dizziness, headache, light-headedness and impaired coordination.
Pooled 1–42-day placebo-controlled trials: drowsiness 14.0%/6.4%, dizziness 7.8%/3.1%, coordination disorders 4.6%/0.8% (n=1,003/997). Dose is not specified for the pooled table.
Boxed warnings cover opioid-related respiratory depression, abuse/addiction, physical dependence and life-threatening withdrawal. Other risks include amnesia, falls and complex behaviors; strong CYP3A inhibitors are contraindicated.
Current U.S. prescribing information and professional guidelines · Source date: 2026-07 · Current prescribing information revised July 2026. · Checked 2026-10-03
Ramelteon · RozeremU.S. approved
Activates melatonin MT1 and MT2 receptors, which participate in the circadian sleep–wake system. It is a prescription receptor agonist, distinct from an over-the-counter melatonin supplement.
Receptor activity is established; the label describes its contribution to sleep promotion as believed rather than a fully proven clinical mechanism.
Approved for insomnia involving difficulty falling asleep; not specifically a sleep-maintenance indication. The labeled adult formulation is an 8 mg tablet and is not a controlled substance.
The U.S. indication is insomnia involving difficulty falling asleep.
Coverage source ↗AASM 2017 weakly suggests ramelteon for sleep onset. VA/DoD 2025 finds insufficient evidence for or against it. These assessments differ despite U.S. approval.
In a six-month trial, 451 adults received 8 mg or placebo (227/224). Laboratory sleep-onset latency improved at measured visits; patient-reported latency improvements were less consistent.
Sleep-onset minutes, perceived sleep quality and daytime function are distinct outcomes. This selected study does not establish superiority to other drugs or universal clinical benefit.
Safety in context
Dizziness, sleepiness, fatigue and nausea.
Label pooled chronic-insomnia trials: dizziness 4%/3%; sleepiness 3%/2% with 8 mg/placebo (n=1,405/1,456). Table 1 does not give one common follow-up window.
Warnings include severe allergic reactions, complex sleep behaviors, alertness impairment and reproductive-hormone effects. Fluvoxamine co-use is contraindicated; use is not recommended in severe sleep apnea or severe liver impairment.
U.S. prescribing information; randomized placebo-controlled primary publication; differing guideline recommendations · Source date: 2026-04 · Rozerem prescribing-information revision; six-month primary trial published March 1, 2009. · Checked 2026-10-03
TrazodoneOff-label for insomnia
Inhibits serotonin reuptake and blocks 5-HT2 and other monoamine receptors. α1 blockade can contribute to postural hypotension.
The antidepressant mechanism is incompletely understood; sedation and receptor pharmacology do not by themselves establish effective chronic-insomnia treatment.
Trazodone is U.S.-approved for major depressive disorder, not insomnia. Low-dose insomnia prescribing and antidepressant treatment are different uses.
The selected short crossover study found fewer nighttime awakenings. This is an off-label insomnia use; AASM 2017 and VA/DoD 2025 weakly suggest against trazodone for chronic insomnia.
Coverage source ↗AASM 2017 and VA/DoD 2025 both weakly suggest against trazodone for chronic insomnia. Common prescribing does not imply a favorable guideline recommendation.
A crossover trial in 16 adults compared 50 mg with placebo for seven nights each. Fewer awakenings accompanied small impairments in memory, balance and arm endurance the following morning.
A small, short crossover study cannot establish durable insomnia remission or long-term safety. Numerical antidepressant-trial adverse-event rates are not transferred to low-dose insomnia use.
Safety in context
Drowsiness, dizziness and orthostatic hypotension; next-day performance can be affected.
The selected 16-person, seven-night crossover trial measured cognitive and motor impairment; no reliable numerical adverse-event incidence comparison is represented here.
Label warnings include suicidality in younger patients, serotonin syndrome, arrhythmias/QT prolongation, priapism, mania/hypomania and hyponatremia. Abrupt discontinuation can cause symptoms.
U.S. antidepressant label; small randomized insomnia trial; guidelines suggesting against chronic-insomnia use · Source date: 2026-03 · Reviewed generic prescribing-information revision; selected insomnia trial published online May 30, 2011. · Checked 2026-10-03
Mirtazapine · RemeronOff-label for insomnia
Blocks H1 receptors alongside serotonin and adrenergic targets. H1 blockade may explain prominent sleepiness; this is a broader mechanism than low-dose doxepin.
The exact clinical mechanism is incompletely understood. Sedation is not equivalent to durable insomnia improvement.
U.S.-approved for major depressive disorder, not insomnia. The low-dose insomnia trials do not create an FDA insomnia indication.
DREAMING enrolled adults with difficulty staying asleep. This tag describes trial eligibility, not proof of improved sleep maintenance; the plotted result measures overall insomnia severity. Insomnia use is off-label.
Coverage source ↗VA/DoD 2025 found no qualifying mirtazapine evidence in its review. The 2025 trials add short-term evidence; they do not establish an updated positive guideline recommendation.
DREAMING found improved insomnia severity at six weeks, but no statistically significant benefit from week 12 onward. MIRAGE also found short-term benefit in older adults, with more treatment discontinuation.
DREAMING enrolled 80 of 156 planned participants. Its adjusted estimate differs from the subtraction of raw group means. Short-term improvement does not establish sustained benefit or long-term safety.
The Insomnia Severity Index combines insomnia symptoms and their impact. Enrollment required sleep-maintenance problems, but this plot is not a separate measure of wake time after sleep onset or time to fall asleep.
- Study
- DREAMING · NL5051 / NTR7449
- Population
- Adults aged 18–85 with insomnia and sleep-maintenance problems after insufficient nonpharmacologic treatment
- Randomized
- 80 total
- Follow-up
- 16-week treatment; primary result at week 6; follow-up to 52 weeks
- Dose / arms
- Mirtazapine 7.5–15 mg/day (27 randomized); placebo (27); third arm amitriptyline 10–20 mg (26). Week-6 observed means: 25/22 respondents.
- Endpoint
- Insomnia Severity Index (ISI), range 0–28
- Measure
- Observed week-6 group means; treatment effect separately estimated by a baseline-adjusted repeated-measures model
- Treatment mean
- 10.2 points
- Control mean
- 15.8 points
The plotted six-point lower ISI score is the adjusted between-group estimate at week 6 (95% CI). Raw means are 10.2 and 15.8; their subtraction is not this estimate.
Read the trial source ↗Safety in context
Daytime drowsiness, dizziness, appetite increase and weight gain are relevant risks.
MIRAGE: daytime drowsiness 19/27 (70%) versus 15/30 (50%) during 28 days at 7.5 mg/placebo. Adverse-event discontinuations: six versus one among 30 randomized per arm; safety-table denominators differ.
Warnings include younger-patient suicidality, serotonin syndrome, mania/hypomania, rare severe neutropenia, QT concerns and severe skin reactions. Withdrawal symptoms can occur. Small insomnia trials cannot exclude uncommon harms.
Two small 2025 randomized insomnia trials; U.S. antidepressant prescribing information · Source date: 2025-06-17 · DREAMING full-text publication metadata in PMC; MIRAGE published March 26, 2025. Reviewed Remeron label remains revised November 2021. · Checked 2026-10-03
Oveporexton · OrzeyfulFDA approval announced; scheduling pending
Activates OX2R in a disorder associated with deficient orexin signaling; does not replace lost orexin neurons.
Mechanism identified in FDA labeling; clinical benefit demonstrated in randomized trials.
FDA announced adult NT1 approval August 5, 2026. The letter makes the statutory approval date and marketing contingent on DEA scheduling. The live U.S. site still forecasts availability by November 2026, pending scheduling; actual launch is unverified.
Improved laboratory-measured daytime wakefulness versus placebo.
Twelve-week controlled result; not evidence for ordinary fatigue, insomnia, or recovery of orexin neurons.
The Maintenance of Wakefulness Test measures time until sleep during daytime testing. Longer latency represents greater daytime wakefulness; this is not a nighttime insomnia endpoint.
- Study
- FirstLight / Study 1 · NCT06470828
- Population
- Narcolepsy type 1; enrolled ages 16–65; U.S. indication is adults
- Randomized
- 168 total
- Follow-up
- 12 weeks
- Dose / arms
- 2 mg twice daily (66 randomized); placebo (41); third arm: 1 mg twice daily (61)
- Endpoint
- Mean sleep latency on the 40-minute Maintenance of Wakefulness Test
- Measure
- Least-squares mean change from baseline
- Treatment change
- 15.9 minutes
- Control change
- -1.3 minutes
17.2 additional minutes before sleep versus placebo during daytime testing; 95% confidence interval. Not nighttime sleep duration.
Read the trial source ↗Safety in context
Insomnia and urinary symptoms.
Pooled 12-week trials, 2 mg twice daily versus placebo: insomnia 60%/1%; urinary frequency 58%/5% (n=136/76).
Important warnings include marked CPK elevations; two patients stopped for marked CPK/transaminase elevations. LDL increases and abuse potential also require attention.
FDA approval letter and label; current sponsor availability notice · Source date: 2026-08-05 · Checked 2026-09-19
Alixorexton · ALKS 2680Investigational · phase 3
An investigational small molecule designed to activate the orexin-2 receptor.
Target pharmacology supports the rationale; benefit and safety still require indication-specific trials.
U.S. approval is not established. The August 24, 2026 sponsor update confirms the Brilliance phase 3 program underway; a designation is not approval.
Vibrance-1 randomized 92 adults with NT1 for six weeks. Wakefulness improved across the tested doses; the prespecified cataplexy comparison was significant only at 6 mg.
The publication announcement and earlier sponsor results were reviewed, but full journal text and the latest registry fields were not retrieved. Open-label follow-up is not a continuing placebo comparison.
Safety in context
Reported events included urinary frequency, insomnia, increased salivation, urgency and blurred vision.
A complete numerical placebo safety table was not independently reviewed; no safety ranking is shown.
No serious treatment-emergent events were reported in the six-week phase 2 study; this small, short trial cannot exclude uncommon or delayed harms.
Sponsor report of peer-reviewed phase 2 publication and phase 3 development · Source date: 2026-08-24 · Checked 2026-09-19
Pitolisant · WakixU.S. approved
Blocks H3 receptor activity and increases brain histamine, using a different pathway from orexin agonists.
The U.S. label says the exact clinical mechanism is unclear; H3 activity may mediate benefit.
Excessive daytime sleepiness or cataplexy in narcolepsy from age 6; the evidence discussed here concerns adults.
Placebo-controlled trials support reduced sleepiness and cataplexy. Study 3 enrolled 105 adults with narcolepsy and cataplexy for seven weeks.
Cataplexy frequency and wakefulness-test minutes are different outcomes. No comparison against an orexin agonist is established here.
Safety in context
Insomnia, nausea and anxiety.
Pooled adult narcolepsy trials: insomnia 6%/2%, nausea 6%/3%, anxiety 5%/1% for pitolisant/placebo (n=152/114).
QT prolongation creates arrhythmia risk; severe liver impairment and hypersensitivity are contraindications. Drug interactions, including reduced hormonal contraceptive efficacy, matter.
Current U.S. label; randomized placebo-controlled trials · Source date: 2026-02 · Checked 2026-09-19
Scope & how to read this explorer
October 6 selectively adds DARI-DREAM registry context; existing trial values, label indications, other treatment review dates and the synthetic architecture illustration remain unchanged.
Scope: selected treatments for adult insomnia and narcolepsy type 1; not a complete treatment inventory or prescribing guide. OSA, circadian disorders, RLS, narcolepsy type 2 and idiopathic hypersomnia are outside this version.
The four selected plots retain their own study measurements: reported differences with 95% confidence intervals for daridorexant, oveporexton and mirtazapine; raw endpoint means without a confidence interval for doxepin. Studies have different populations, durations and endpoints and do not share an efficacy scale.
Daridorexant's negative difference means less nighttime wakefulness; oveporexton's positive difference means longer daytime wakefulness. Do not convert either endpoint into total sleep gained or an individual forecast.
Trial doses identify the evidence shown and are not personalized dosing instructions. Randomized totals and safety-population counts differ and are labeled separately.
An event reported during treatment is not automatically drug-caused. Within-trial placebo comparisons support interpretation; safety percentages from separate trials must not be ranked directly.
Each treatment retains its own review date and source date. October 3, 2026 adds selected insomnia baselines; the September 19 narcolepsy records were not refreshed. Label revision, online posting, regulatory announcement and verified launch are different dates.
Alixorexton full journal text and live registry JSON were inaccessible during this check; its phase 3 status is attributed to the dated sponsor announcement. No inferred completion date or access claim is included.
Approved insomnia treatment, off-label use and guideline recommendations are separate. Low-dose doxepin and immediate-release zolpidem records identify the studied formulation. Medication options are selected examples, not an exhaustive insomnia formulary.
Sleep difficulty filters describe overlapping symptom patterns. Each record identifies the basis for its classification: approved indication, guideline assessment, studied benefit or trial population. A classification does not rank treatments, and the selected plot may measure a different or broader outcome.