Dual orexin receptor antagonists for insomnia: Clinical experience

Prof. Phyllis Zee
Division of Sleep Medicine
Northwestern University Feinberg School of Medicine
Chicago, Illinois, US
11 Oct 2021
Understanding of the role of the orexin signalling pathway in regulating sleep and wakefulness has led to the development of novel pharmacotherapies for insomnia, such as the dual orexin receptor antagonist (DORA), lemborexant. At an Eisai-sponsored symposium, Professor Phyllis Zee of the Division of Sleep Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, US, discussed guidelines and considerations for insomnia management and shared her clinical experience in using lemborexant in different subgroups of patients with insomnia.

Insomnia management: Guidelines and considerations

“Personalized management of insomnia is based on the patient’s clinical insomnia subtype [eg, sleep onset and/or maintenance], with cognitive behavioural therapy for insomnia [CBT-I] recommended as first-line treatment and pharmacotherapy offered either as an adjunct to CBT-I or if CBT-I is unavailable,” said Zee. [J Sleep Res 2017;26:675-700]

According to the American Academy of Sleep Medicine’s guidelines, considerations for personalized pharmacotherapy in adults with chronic insomnia include the patient’s primary symptom(s), age, comorbidities, as well as safety concerns including next-day effects (ie, sedation, impairment, impact on driving), post-dose effects (eg, confused behaviour at night, balance), and polypharmacy (ie, excessive sedation). [J Clin Sleep Med 2017;13:307-349]

“In older adults, age-related anatomical and physiological changes affecting different organ systems and their impact on pharmacokinetics and pharmacodynamics of drugs also need to be considered,” added Zee. [Br J Clin Pharmacol 2004;57:6-14]

“Newer pharmacotherapies for insomnia are more selective and specific than benzodiazepine receptor agonists [BZRAs] and over-the-counter antihistamines, providing efficacy with improved safety profiles,” she noted. (Figure) [Annu Rev Physiol 2010;72:517-549; Drugs Context 2013;2013:212257]


DORAs: Novel pharmacotherapy for insomnia

“Hyperarousal from cognitive and physiological processes is recognized as an overarching pathophysiological factor contributing to insomnia,” said Zee. [Nat Sci Sleep 2018;10:193-201; Lancet Neurol 2015;14:547-558; Sleep Med Rev 2010;14:9-15]

Understanding of the role of orexins in sleep-wake regulation has led to the development of DORAs, a novel class of pharmacotherapy for insomnia with high specificity. (Figure) [Annu Rev Physiol 2010;72:517-549; Drugs Context 2013; Annu Rev Pharmacol Toxicol 2013:212257; 2011;51:243-266]

Orexin pathway and sleepwake regulation

Orexin (hypocretin) neurons in the posterior lateral hypothalamus are crucial for maintaining normal wakefulness, while γ-aminobutyric acid (GABA)-ergic and galanigeric neurons in the ventrolateral preoptic nucleus are necessary for normal sleep. Interactions between these neurons play a role in hypothalamic regulation of wakefulness and sleep. [Trends Neurosci 2001;24:726-731] In human cerebrospinal fluid samples, a low-amplitude diurnal rhythm of orexin levels (rise during wake time and decline during sleep) is observed. [Sleep 2006;29:295-297; Biol Psychiatry 2003;54:96-104]

Lemborexant: Efficacy and safety

Lemborexant is effective in both sleep-onset and sleep-maintenance insomnia. [JAMA Netw Open 2019;2:e1918243; Sleep 2020;43:1-11]

In an open-label pilot study of adults with insomnia (n=53) who were taking immediate-release or extended- release zolpidem, either intermittently (3–4 times per week) or frequently (≥5 times per week), 81.1 percent transitioned to lemborexant (5 mg or 10 mg) after 2 weeks of lemborexant treatment. [Rosenberg R, etal, AAN 2021, abstract P26.007]

“All study participants who transitioned to lemborexant chose to continue lemborexant maintenance treatment in the study’s 12-week extension phase,” said Zee. “Treatment-emergent adverse events associated with lemborexant were mild to moderate. The safety profile of lemborexant during the switch-over and extension phases was consistent with the known safety profile of the drug.”


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