Targeting Orexin Receptors for the Treatment of Insomnia: From Physiological Mechanisms to Current Clinical Evidence and Recommendations

Abstract

After a detailed description of orexins and their roles in sleep and other medical disorders, we discuss here the current clinical evidence on the effects of dual (DORAs) or selective (SORAs) orexin receptor antagonists on insomnia with the aim to provide recommendations for their further assessment in a context of personalized and precision medicine. In the last decade, many trials have been conducted with orexin receptor antagonists, which represent an innovative and valid therapeutic option based on the multiple mechanisms of action of orexins on different biological circuits, both centrally and peripherally, and their role in a wide range of medical conditions which are often associated with insomnia. A very interesting aspect of this new category of drugs is that they have limited abuse liability and their discontinuation does not seem associated with significant rebound effects. Further studies on the efficacy of DORAs are required, especially on children and adolescents and in particular conditions, such as menopause. Which DORA is most suitable for each patient, based on comorbidities and/or concomitant treatments, should be the focus of further careful research. On the contrary, studies on SORAs, some of which seem to be appropriate also in insomnia in patients with psychiatric diseases, are still at an early stage and, therefore, do not allow to draw definite conclusions.

Sleep disorders and cancer incidence: examining duration and severity of diagnosis among veterans

“…However, its role in cancer prevention has not been thoroughly studied. Another promising class of compounds are used for insomnia treatment by acting upon the orexin (hypocretin) receptor system that modulates sleep/wakefulness ( 89 ). These agents selectively induce apoptosis in several tumor types and thus have promising therapeutic potential ( 8 ).…”

Investigating the Role of BDNF in Insomnia: Current Insights

“…Orexins are produced by neurons in the hypothalamic region. 125 They project to various locations in the brain that contain structures important for sleep regulation, such as the ventrolateral preoptic nucleus (VLPO), locus coeruleus (LC), and the TMN. 125 Orexin neurons control the release of histamine form the TMN neurons; notably, there is no feedback loop, as histamine does not influence orexin neurons.…”

“… 125 They project to various locations in the brain that contain structures important for sleep regulation, such as the ventrolateral preoptic nucleus (VLPO), locus coeruleus (LC), and the TMN. 125 Orexin neurons control the release of histamine form the TMN neurons; notably, there is no feedback loop, as histamine does not influence orexin neurons. 125 Current medications targeting this mode of neurotransmission might be classified into two types: dual orexin receptor antagonist (DORA), antagonists of both orexin receptor type 1 (OX1R) and OX2R, which include relatively popular lemborexant and suvorexant, and selective orexin receptor antagonist (SORA), targeting only OX2R, such as seltorexant.…”

“… 125 Current medications targeting this mode of neurotransmission might be classified into two types: dual orexin receptor antagonist (DORA), antagonists of both orexin receptor type 1 (OX1R) and OX2R, which include relatively popular lemborexant and suvorexant, and selective orexin receptor antagonist (SORA), targeting only OX2R, such as seltorexant. 125 The latter group is still under development. 125 To date, studies report that they decrease sleep latency as well as wake after sleep onset, while increasing total sleep time.…”

“… 125 The latter group is still under development. 125 To date, studies report that they decrease sleep latency as well as wake after sleep onset, while increasing total sleep time. 125 Orexin might also promote BDNF production, thus exerting neuroprotective effects on neurons.…”