title: Orexin receptor antagonism, a new sleep-enabling paradigm: a proof-of-concept clinical trial.
abstract: The orexin system is a key regulator of sleep and wakefulness. In a multicenter, double-blind, randomized, placebo-controlled, two-way crossover study, 161 primary insomnia patients received either the dual orexin receptor antagonist almorexant, at 400, 200, 100, or 50 mg in consecutive stages, or placebo on treatment nights at 1-week intervals. The primary end point was sleep efficiency (SE) measured by polysomnography; secondary end points were objective latency to persistent sleep (LPS), wake after sleep onset (WASO), safety, and tolerability. Dose-dependent almorexant effects were observed on SE , LPS , and WASO . SE improved significantly after almorexant 400 mg vs. placebo (mean treatment effect 14.4%; P < 0.001). LPS (–18 min (P = 0.02)) and WASO (–54 min (P < 0.001)) decreased significantly at 400 mg vs. placebo. Adverse-event incidence was dose-related. Almorexant consistently and dose-dependently improved sleep variables. The orexin system may offer a new treatment approach for primary insomnia.
authors.affiliation: Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Hoever
authors.forename: G
authors.initials: G
authors.lastname: Dorffner
authors.forename: H
authors.initials: H
authors.lastname: Beneš
authors.forename: T
authors.initials: T
authors.lastname: Penzel
authors.forename: H
authors.initials: H
authors.lastname: Danker-Hopfe
authors.forename: M J
authors.initials: MJ
authors.lastname: Barbanoj
authors.forename: G
authors.initials: G
authors.lastname: Pillar
authors.forename: B
authors.initials: B
authors.lastname: Saletu
authors.forename: O
authors.initials: O
authors.lastname: Polo
authors.forename: D
authors.initials: D
authors.lastname: Kunz
authors.forename: J
authors.initials: J
authors.lastname: Zeitlhofer
authors.forename: S
authors.initials: S
authors.lastname: Berg
authors.forename: M
authors.initials: M
authors.lastname: Partinen
authors.forename: C L
authors.initials: CL
authors.lastname: Bassetti
authors.forename: B
authors.initials: B
authors.lastname: Högl
authors.forename: I O
authors.initials: IO
authors.lastname: Ebrahim
authors.forename: E
authors.initials: E
authors.lastname: Holsboer-Trachsler
authors.forename: H
authors.initials: H
authors.lastname: Bengtsson
authors.forename: Y
authors.initials: Y
authors.lastname: Peker
authors.forename: U-M
authors.initials: UM
authors.lastname: Hemmeter
authors.forename: E
authors.initials: E
authors.lastname: Chiossi
authors.forename: G
authors.initials: G
authors.lastname: Hajak
authors.forename: J
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000081:Acetamides / Q000009:adverse effects / Q000627:therapeutic use*; D000328:Adult; D001143:Arousal / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000009:adverse effects / Q000627:therapeutic use*; D007546:Isoquinolines / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D064446:Orexin Receptors; D017286:Polysomnography; D011446:Prospective Studies; D011569:Psychiatric Status Rating Scales; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*
chemical_list: D000081:Acetamides; D006993:Hypnotics and Sedatives; D007546:Isoquinolines; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; C519150:almorexant