Treatment strategies for insomnia in Japanese primary care physicians' practice: A Web-based questionnaire survey.

BACKGROUND: It is unclear how primary care physicians manage insomnia after the introduction of novel hypnotics such as orexin receptor antagonists and melatonin receptor agonists. This Web-based questionnaire survey aimed to examine treatment strategies for insomnia in Japanese primary care practice. METHODS: One-hundred-and-seventeen primary care physicians were surveyed on the familiarity of each management option for insomnia on a binary response scale (0 = "unfamiliar"; 1 = "familiar") and how they managed insomnia using a nine-point Likert scale (1 = "I never prescribe/perform it"; 9 = "I often prescribe/perform it"). Physicians who were unfamiliar with a management option were deemed to have never prescribed or performed it. RESULTS: Regarding medication, most physicians were familiar with novel hypnotics. Suvorexant was the most used hypnotic, followed by lemborexant and ramelteon. These novel hypnotics averaged 4.8-5.4 points and 4.0-4.7 points for sleep onset and sleep maintenance insomnia, respectively. By contrast, most benzodiazepines were seldom used below two points. Regarding psychotherapy, only approximately 40% of the physicians were familiar with cognitive behavioral therapy for insomnia (CBT-I) and they rarely implemented it, at an average of 1.5-1.6 points. More physicians were familiar with single-component psychotherapies (i.e., relaxation, sleep restriction therapy, and stimulus control) compared to CBT-I, and 48-74% of them implemented it slightly more often, with scores ranging from 2.6 to 3.4 points. CONCLUSION: This study suggests that Japanese primary care physicians seldom use CBT-I to treat insomnia. In addition, they use novel sleep medications more frequently than benzodiazepines in terms of pharmacotherapy. The use and availability of CBT-I in Japanese primary care might be facilitated by: educating primary care physicians, implementing brief or digital CBT-I, and/or developing collaborations between primary care physicians and CBT-I specialists.

Orexin Facilitates the Peripheral Chemoreflex via Corticotropin-Releasing Hormone Neurons Projecting to the Nucleus of the Solitary Tract.

We previously showed that orexin neurons are activated by hypoxia and facilitate the peripheral chemoreflex (PCR)-mediated hypoxic ventilatory response (HVR), mostly by promoting the respiratory frequency response. Orexin neurons project to the nucleus of the solitary tract (nTS) and the paraventricular nucleus of the hypothalamus (PVN). The PVN contributes significantly to the PCR and contains nTS-projecting corticotropin-releasing hormone (CRH) neurons. We hypothesized that in male rats, orexin neurons contribute to the PCR by activating nTS-projecting CRH neurons. We used neuronal tract tracing and immunohistochemistry (IHC) to quantify the degree that hypoxia activates PVN-projecting orexin neurons. We coupled this with orexin receptor (OxR) blockade with suvorexant (Suvo, 20 mg/kg, i.p.) to assess the degree that orexin facilitates the hypoxia-induced activation of CRH neurons in the PVN, including those projecting to the nTS. In separate groups of rats, we measured the PCR following systemic orexin 1 receptor (Ox1R) blockade (SB-334867; 1 mg/kg) and specific Ox1R knockdown in PVN. OxR blockade with Suvo reduced the number of nTS and PVN neurons activated by hypoxia, including those CRH neurons projecting to nTS. Hypoxia increased the number of activated PVN-projecting orexin neurons but had no effect on the number of activated nTS-projecting orexin neurons. Global Ox1R blockade and partial Ox1R knockdown in the PVN significantly reduced the PCR. Ox1R knockdown also reduced the number of activated PVN neurons and the number of activated tyrosine hydroxylase neurons in the nTS. Our findings suggest orexin facilitates the PCR via nTS-projecting CRH neurons expressing Ox1R.

The differential effects of blocking retinal orexin receptors on the expression of retinal c-fos and hypothalamic Vip, PACAP, Bmal1, and c-fos in Male Wistar Rats.

Orexin A and B (OXA and OXB) and their receptors are expressed in the majority of retinal neurons in humans, rats, and mice. Orexins modulate signal transmission between the different layers of the retina. The suprachiasmatic nucleus (SCN) and the retina are central and peripheral components of the body's biological clocks; respectively. The SCN receives photic information from the retina through the retinohypothalamic tract (RHT) to synchronize bodily functions with environmental changes. In present study, we aimed to investigate the impact of inhibiting retinal orexin receptors on the expression of retinal Bmal1 and c-fos, as well as hypothalamic c-fos, Bmal1, Vip, and PACAP at four different time-points (Zeitgeber time; ZT 3, 6, 11, and ZT-0). The intravitreal injection (IVI) of OX1R antagonist (SB-334867) and OX2R antagonist (JNJ-10397049) significantly up-regulated c-fos expression in the retina. Additionally, compared to the control group, the combined injection of SB-334867 and JNJ-10397049 showed a greater increase in retinal expression of this gene. Moreover, the expression of hypothalamic Vip and PACAP was significantly up-regulated in both the SB-334867 and JNJ-10397049 groups. In contrast, the expression of Bmal1 was down-regulated. Furthermore, the expression of hypothalamic c-fos was down-regulated in all groups treated with SB-334867 and JNJ-10397049. Additionally, the study demonstrated that blocking these receptors in the retina resulted in alterations in circadian rhythm parameters such as mesor, amplitude, and acrophase. Finally, it affected the phase of gene expression rhythms in both the retina and hypothalamus, as identified through cosinor analysis and the zero-amplitude test. This study represents the initial exploration of how retinal orexin receptors influence expression of rhythmic genes in the retina and hypothalamus. These findings could provide new insights into how the retina regulates the circadian rhythm in both regions and illuminate the role of the orexinergic system expression within the retina.

Selective Orexin 2 Receptor Blockade Alleviates Cognitive Impairments and the Pathological Progression of Alzheimer's Disease in 3xTg-AD Mice.

The orexin system is closely related to the pathogenesis of Alzheimer's disease (AD). Orexin-A aggravates cognitive dysfunction and increases amyloid ß (Aß) deposition in AD model mice, but studies of different dual orexin receptor (OXR) antagonists in AD have shown inconsistent results. Our previous study revealed that OX1R blockade aggravates cognitive deficits and pathological progression in 3xTg-AD mice, but the effects of OX2R and its potential mechanism in AD have not been reported. In the present study, OX2R was blocked by oral administration of the selective OX2R antagonist MK-1064, and the effects of OX2R blockade on cognitive dysfunction and neuropsychiatric symptoms in 3xTg-AD mice were evaluated via behavioral tests. Then, immunohistochemistry, western blotting, and ELISA were used to detect Aß deposition, tau phosphorylation, and neuroinflammation, and electrophysiological and wheel-running activity recording were recorded to observe hippocampal synaptic plasticity and circadian rhythm. The results showed that OX2R blockade ameliorated cognitive dysfunction, improved LTP depression, increased the expression of PSD-95, alleviated anxiety- and depression-like behaviors and circadian rhythm disturbances in 3xTg-AD mice, and reduced Aß pathology, tau phosphorylation, and neuroinflammation in the brains of 3xTg-AD mice. These results indicated that chronic OX2R blockade exerts neuroprotective effects in 3xTg-AD mice by reducing AD pathology at least partly through improving circadian rhythm disturbance and the sleep-wake cycle and that OX2R might be a potential target for the prevention and treatment of AD; however, the potential mechanism by which OX2R exerts neuroprotective effects on AD needs to be further investigated.

Effects of methamphetamine on actigraphy-based sleep parameters in female rhesus monkeys: Orexin receptor mechanisms.

BACKGROUND: The orexin system has been implicated as a mechanism underlying insomnia and methamphetamine-induced sleep disruptions, with a potential role for OX2 receptors in the sleep-modulating effects of orexin. The aim of the present study was to investigate the extent to which orexin receptors mediate the effects of acute methamphetamine administration on actigraphy-based sleep in female rhesus monkeys. METHODS: Actigraphy-based sleep measures were obtained in female rhesus monkeys (n=5) under baseline and acute test conditions. First, morning (10h) i.m. injections of methamphetamine (0.03 - 0.56mg/kg) were administered to determine the effects of methamphetamine alone. Then, saline or methamphetamine (0.3mg/kg) were administered at 10h, and evening (17h30) oral treatments with vehicle, the non-selective orexin receptor antagonist suvorexant (1 - 10mg/kg, p.o.), or the OX2-selective orexin receptor antagonist MK-1064 (1 - 10mg/kg, p.o.) were given. The ability of suvorexant and MK-1064 (10mg/kg, p.o.) to improve actigraphy-based sleep was also assessed in a group of female monkeys quantitatively identified with "short-duration sleep" (n=4). RESULTS: Methamphetamine dose-dependently disrupted actigraphy-based sleep parameters. Treatment with either suvorexant or MK-1064 dose-dependently improved actigraphy-based sleep in monkeys treated with methamphetamine. Additionally, both suvorexant and MK-1064 promoted actigraphy-based sleep in a group of monkeys with baseline short actigraphy-based sleep. CONCLUSIONS: These findings suggest that orexin-mediated mechanisms play a role in the effects of methamphetamine on actigraphy-based sleep in female monkeys. Targeting the orexin system, in particular OX2 receptors, could be an effective option for treating sleep disruptions observed in individuals with methamphetamine use disorder.

Preclinical metabolism and the disposition of vornorexant/TS-142, a novel dual orexin 1/2 receptor antagonist for the treatment of insomnia.

We investigated the metabolism and disposition of vornorexant, a novel dual orexin receptor antagonist, in rats and dogs, and clarified in vitro metabolite profiles in humans. Furthermore, we investigated the pharmacokinetics of active metabolites in rats and dogs and their CNS distribution in rats to elucidate its contribution to drug efficacy. [14 C]vornorexant was rapidly and mostly absorbed after the oral administration in rats and dogs. The drug-derived radioactivity, including metabolites, was distributed to major organs such as the liver, kidneys in rats, and was almost eliminated within 24 h post-dose in both species. Metabolite profiling revealed that main clearance mechanism of vornorexant was metabolism via multiple pathways by oxidation. The major circulating components were the cleaved metabolites (M10, M12) in rats, and the unchanged form in dogs, followed by M1, and then M3. Incubation with human hepatocytes resulted in formation of metabolites, including M1, M3, M10, and M12. The metabolic pathways were similar in all tested species. Resulting from the PK and CNS distribution of active metabolites (M1 and M3) with weaker pharmacological activity, the concentration of the unchanged form was higher than that of active metabolites in rat CSF and dog plasma, suggesting that the unchanged form mainly contributed to the drug efficacy. These findings demonstrate that vornorexant is absorbed immediately after administration, and vornorexant and its metabolites are rapidly and completely eliminated in rats and dogs. Thus, vornorexant may have favorable pharmacokinetic profiles as a hypnotic drug to provide rapid onset of action and minimal next-day residual effects in humans.

Effect of Daridorexant on the Pharmacokinetics of Midazolam, and on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Male Subjects.

BACKGROUND AND OBJECTIVES: Daridorexant, a dual orexin receptor antagonist was recently approved for the treatment of insomnia at doses up to 50 mg once per night. This study investigated the effect of single-dose and multiple-dose daridorexant 50 mg at steady state on the pharmacokinetics (PK) of the cytochrome P450 (CYP) 3A4-sensitive substrate midazolam, and the effect of single-dose daridorexant 50 mg on the PK and pharmacodynamics (PD) of the CYP2C9-sensitive substrate warfarin. METHODS: In this prospective, single-center, open-label, fixed-sequence, phase I, drug-drug interaction study, 18 healthy male subjects sequentially received Treatment A, B, and C in three periods. Treatment A consisted of a single oral concomitant administration of midazolam 2 mg and warfarin 25 mg on day 1 of the first period. Treatment B consisted of one oral administration of daridorexant 50 mg followed 1 h later by a single oral dose of midazolam 2 mg concomitantly with a single oral dose of warfarin 25 mg on day 1 and a once-daily oral administration of daridorexant 50 mg for 6 days of the second period. Treatment C consisted of a single oral administration of daridorexant 50 mg at steady state followed 1 h later by a single oral administration of midazolam 2 mg on day 1 of the third period. Blood samples were assessed for midazolam and S-warfarin PK, and PD (international normalized ratio and factor VII). Noncompartmental  PK parameters and PD variables were evaluated with geometric mean ratios and 90% confidence intervals of Treatment B/A versus C/A for midazolam, and treatment B/A for warfarin. Safety and tolerability of each treatment were also assessed. RESULTS: Midazolam maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from 0 to 24 h (AUC0-24) were 1.13- and 1.42-fold higher, respectively, after single-dose administration of daridorexant 50 mg compared to administration of midazolam alone, while Cmax and AUC0-24 were 1.12- and 1.35-fold higher, respectively, after administration of daridorexant 50 mg once daily at steady state. Terminal half-life and time to maximum plasma concentration were comparable between treatments. Daridorexant had no influence on the PK and PD of warfarin. All treatments were safe and well tolerated. CONCLUSIONS: Daridorexant at 50 mg is classified as a weak CYP3A4 inhibitor after single- and multiple-dose administration once daily at steady state. Daridorexant 50 mg did not induce CYP3A4 activity or inhibit CYP2C9 activity. CLINICAL TRIAL REGISTRATION: This trial (NCT05480488) was registered on 29 July, 2022.

Discovery of Nivasorexant (ACT-539313): The First Selective Orexin-1 Receptor Antagonist (SO1RA) Investigated in Clinical Trials.

The orexin system consists of two neuropeptides (orexins A and B) and two receptors (OX1 and OX2). Selective OX1 receptor antagonists (SO1RA) are gaining interest for their potential use in the treatment of CNS disorders, including substance abuse, eating, obsessive compulsive, or anxiety disorders. While blocking OX2 reduces wakefulness, the expected advantage of selectively antagonizing OX1 is the ability to achieve clinical efficacy without the promotion of sleep. Herein we report our discovery efforts starting from a dual orexin receptor antagonist and describe a serendipitous finding that triggered a medicinal chemistry program that culminated in the identification of the potent SO1RA ACT-539313. Efficacy in a rat model of schedule-induced polydipsia supported the decision to select the compound as a preclinical candidate. Nivasorexant (20) represents the first SO1RA to enter clinical development and completed a first proof of concept phase II clinical trial in binge eating disorder in 2022.

Discovery and first-time disclosure of CVN766, an exquisitely selective orexin 1 receptor antagonist.

Modulators of orexin receptors are being developed for neurological illnesses such as sleep disorders, addictive behaviours and other psychiatric diseases. We herein describe the discovery of CVN766, a potent orexin 1 receptor antagonist that has greater than 1000-fold selectivity for the orexin 1 receptor over the orexin 2 receptor and demonstrates low off target hits in a diversity screen. In agreement with its in vitro ADME data, CVN766 demonstrated moderate in vivo clearance in rodents and displayed good brain permeability and target occupancy. This drug candidate is currently being investigated in clinical trials for schizophrenia and related psychiatric conditions.

Daridorexant treatment for chronic insomnia: a real-world retrospective single-center study.

INTRODUCTION: Chronic insomnia disorder (CID) significantly impacts well-being and daily functioning. Daridorexant, a double orexin receptor blocker, has shown efficacy in randomized clinical trials and has been recently approved for the treatment of CID in adult patients. This retrospective observational study aimed to describe real-world data on daridorexant effectiveness and safety in adult patients with CID. METHODS: Consecutive patients initiating on-label daridorexant at the Sleep Medicine Centre, University Hospital of Rome Tor Vergata were enrolled. Baseline and 30-day follow-up (FU) evaluations included patients' and CID characteristics, comorbidities, and clinicians' and patients' subjective ratings of changes with the Clinical and Patient Global Impression-Improvement scores (CGI-Is and PGI-Is), as well as Insomnia Severity Index (ISI) scores in a subgroup of patients. RESULTS: Sixty-nine patients initiated 50-mg daily dosage. At FU, 58% of both patients and clinicians rated CID as improved on CGI-Is and PGI-Is, with no differences based on comorbidities, sex, or number of previous medications. No significant predictors of CGI-Is and PGI-Is improvement were identified. At FU, ISI scores (n = 24) significantly decreased from 18.25 ± 3.21 to 12.08 ± 6.12 (Z = 8.000; p < 0.001). Of these, eight patients (33.3%) had absence of insomnia symptoms, and no patients reported a worsening in ISI score categories. CONCLUSIONS: This study suggests daridorexant to be effective and safe in real-world CID treatment whether used as a first-ever treatment, switch, or add-on, as reflected by subjective and objective measures and the absence of serious treatment-related adverse events. Future research on larger cohorts should explore daridorexant potential across diverse patient characteristics.

Treatment of Sleep, Motor and Sensory Symptoms with the Orexin Antagonist Suvorexant in Adults with Idiopathic Restless Legs Syndrome: A Randomized Double-Blind Crossover Proof-of-Concept Study.

BACKGROUND AND OBJECTIVES: Current treatment guidelines for restless legs syndrome (RLS) recommend treatment be initiated with non-dopaminergic drugs. Given the potential role of orexins in the pathophysiology of RLS, we performed a pilot, proof-of-concept study to investigate the therapeutic effects of suvorexant, a dual orexin receptor antagonist (DORA), on sleep and sensory/motor symptoms in individuals with idiopathic RLS. METHODS: This was a randomized, double-blind, crossover and placebo-controlled study. Inclusion criteria were diagnosis with idiopathic RLS, an International RLS Study Group Severity Rating Scale (IRLS) score > 15, and the absence of significant RLS symptoms before 9 pm. Following washout from any previous central nervous system (CNS)-active drugs, patients were randomized to receive either suvorexant or placebo for two consecutive 2-week treatment periods. Treatment was administered at 9 pm at a fixed dose of 10 mg/day during the first week, and 20 mg during the second week. Primary and coprimary endpoints were wake after sleep onset (WASO) and total sleep time (TST), respectively, while IRLS rating scale score, multiple suggested immobilization tests (m-SIT), and periodic limb movements (PLMs) were secondary endpoints. RLS severity was measured weekly using the IRLS and Clinical Global Improvement (CGI) scales. m-SIT were also performed between 8 pm and midnight at the end of each treatment phase and were followed by a sleep study. RESULTS: A total of 41 participants were randomized, 40 of whom completed the study. Compared with placebo, treatment with suvorexant significantly improved RLS symptoms (according to IRLS total score, CGI, and the m-SIT), PLM during sleep, and PLM with arousal. Improvement of RLS symptoms was greater in those who had not been exposed to dopaminergic agents in the past. Sleep architecture also improved with significant changes in TST, WASO, sleep onset latency, sleep efficiency, non rapid-eye movement stage 1 (N1) %, non rapid-eye movement stage 2 (N2) %, and rapid eye movement (REM) %. Suvorexant was well tolerated in RLS, with few and mild adverse events. CONCLUSIONS: Our results provide the first proof of evidence of the therapeutic efficacy of DORAs in improving sleep and sensory and motor symptoms in RLS. Given orexin's role in pain and sensory processing, potential mechanisms of action are discussed. CLASSIFICATION OF EVIDENCE: The study provides class II evidence supporting the therapeutic efficacy of suvorexant in patients with RLS with sleep disturbance. TRIAL REGISTRATION: EudraCT#: 2017-004580-12.

Is schedule IV suvorexant an appropriate reference drug of abuse to use in preclinical abuse liability testing in the rat?

The abuse potential of novel CNS-active drug candidates with low specificity for known receptors involved in abuse might be complex to test preclinically relative to an appropriate reference drug of abuse. Suvorexant, a Schedule IV dual orexin receptor antagonist was investigated for its potential use as a reference drug in Drug Discrimination Learning (DDL) studies. Firstly, toxicokinetic properties of suvorexant were determined in male and female rats after single oral doses of 160 and 325 mg/kg in MC and PEG400. Thereafter the subjective effects of suvorexant at 325 mg/kg versus vehicle were evaluated in a DDL paradigm and plasma exposures were measured. Mean maximum plasma exposures in male rats after a single dose of 325 mg/kg suvorexant were 2.5- (MC) to 10.5-fold (PEG400) the human exposure at supratherapeutic doses of 40 mg q.d. (Cmax:1.1 µM), and 4.9- (MC) to 20.8-fold (PEG400) the approved maximum human efficacious dose (20 mg q.d.; 0.557 µM). Training male rats at 325 mg/kg in the DDL study however did not result in discriminative stimulus generalisation versus respective vehicles. Suvorexant, a Schedule IV dual orexin receptor antagonist failed to serve as a robust reference drug of abuse in the DDL paradigm in rats despite appropriate exposures.

Orexin Receptor Antagonism: Normalizing Sleep Architecture in Old Age and Disease.

Sleep is essential for human well-being, yet the quality and quantity of sleep reduce as age advances. Older persons (>65 years old) are more at risk of disorders accompanied and/or exacerbated by poor sleep. Furthermore, evidence supports a bidirectional relationship between disrupted sleep and Alzheimer's disease (AD) or related dementias. Orexin/hypocretin neuropeptides stabilize wakefulness, and several orexin receptor antagonists (ORAs) are approved for the treatment of insomnia in adults. Dysregulation of the orexin system occurs in aging and AD, positioning ORAs as advantageous for these populations. Indeed, several clinical studies indicate that ORAs are efficacious hypnotics in older persons and dementia patients and, as in adults, are generally well tolerated. ORAs are likely to be more effective when administered early in sleep/wake dysregulation to reestablish good sleep/wake-related behaviors and reduce the accumulation of dementia-associated proteinopathic substrates. Improving sleep in aging and dementia represents a tremendous opportunity to benefit patients, caregivers, and health systems.

Orexin receptors in the hippocampal dentate gyrus modulated the restraint stress-induced analgesia in the animal model of chronic pain.

Previous studies have shown that stressful stimuli induced an adaptive response of reduced nociception, known as stress-induced analgesia (SIA). Since orexin neuropeptides are involved in pain modulation, and orexin neurons, primarily located in the lateral hypothalamus (LH), project to various hippocampal regions, such as the dentate gyrus (DG), the current study aimed to examine the role of orexin receptors within the DG region in the restraint SIA in the animal model of chronic pain. One hundred-thirty adult male Wistar rats (230-250 g) were unilaterally implanted with a cannula above the DG region. Animals were given SB334867 or TCS OX2 29 (1, 3, 10, and 30 nmol, 0.5 µl/rat) into the DG region as orexin-1 receptor (OX1r) and orexin-2 receptor (OX2r) antagonists, respectively, five min before exposure to a 3-hour restraint stress (RS) period. Animals were then undergone the formalin test to assess pain-related behaviors as the animal model of chronic pain. The results showed that RS produces an analgesic response during the early and late phases of the formalin test. However, intra-DG microinjection of OX1r and OX2r antagonists attenuated the restraint SIA. OX2r antagonist was more potent than OX1r antagonist in the early phase of the formalin test, while OX1r antagonist was little more effective in the late phase. Predominantly, it could be concluded that the orexinergic system in the DG region might act as a potential endogenous pain control system and a novel target for treating stress-related disorders.

Intra-accumbal orexinergic system contributes to the stress-induced antinociceptive behaviors in the animal model of acute pain in rats.

Stress and pain are interleaved at numerous levels - influencing each other. Stress can increase the nociception threshold in animals, long-known as stress-induced analgesia (SIA). Orexin is known as a neuropeptide that modulates pain. The effect of stress on the mesolimbic system in the modulation of pain is known. The role of the intra-accumbal orexin receptors in the modulation of acute pain by forced swim stress (FSS) is unclear. In this study, 117 adult male albino Wistar rats (270-300 g) were used. The animals were unilaterally implanted with cannulae above the NAc. The antagonist of the orexin-1 receptor (OX1r), SB334867, and antagonist of the orexin-2 receptor (OX2r), TCS OX2 29, were microinjected into the NAc in different doses (1, 3, 10, and 30 nmol/0.5 µl DMSO) before exposure to FSS for a 6-min period. The tail-flick test was carried out as an assay nociception of acute pain, and the nociceptive threshold [tail-flick latency (TFL)] was measured for 60-minute. The findings demonstrated that exposure to acute stress could remarkably increase the TFLs and antinociceptive responses. Moreover, intra-accumbal microinjection of SB334867 or TCS OX2 29 blocked the antinociceptive effect of stress in the tail-flick test. The contribution of orexin receptors was almost equally modulating SIA. The present study's findings suggest that OX1r and OX2r within the NAc modulate stress-induced antinociceptive responses. The intra-accumbal microinjection of orexin receptors antagonists declares inducing antinociceptive responses by FSS in acute pain. Proposedly, intra-accumbla orexinergic receptors have a role in the development of SIA.

A retrospective clinical practice study comparing the usefulness of dual-orexin receptor antagonists and a melatonin receptor agonist in patients switching from long-term benzodiazepine receptor agonists.

STUDY OBJECTIVES: Although novel hypnotics have recently emerged, there are currently no data comparing the clinical potency of benzodiazepine receptor agonists (BZRAs) and novel hypnotics, or the effectiveness of different methods of switching between them. This study examined how novel hypnotics might help reduce BZRA use in real-world practice. METHODS: 289 patients with psychiatric disorders who took BZRAs for over 1 year before switching to either of 2 dual-orexin receptor antagonists (DORAs; suvorexant [SUV] or lemborexant [LEM]) or a melatonin receptor agonist (ramelteon [RMT]) were enrolled. We collected data on BZRAs at baseline and 3 months after commencement of SUV/LEM/RMT. RESULTS: Significant reductions in BZRAs were observed for all 3 agents: -4.10, -2.80, and -1.65 mg in diazepam-equivalent doses in the SUV, LEM, and RMT groups, respectively. Dose reduction was significantly greater in the DORA than the RMT group (F = 15.053, P < .001). Within the DORA group, dose reduction was significantly greater in patients taking SUV than those taking LEM (F = 4.337, P = .043). The switching success rate did not differ among the switching methods for any of the hypnotics. CONCLUSIONS: The reduction rate of BZRAs achieved by the switch fell into their equivalent-potency range estimated from clinical trials. The results suggest that DORAs can replace approximately 1 tablet of a BZRA. The difference in dose reduction between DORAs and RMT reflected the greater sleeping potency of the DORAs, whereas that between SUV and LEM might have reflected patient backgrounds: patients taking LEM may have been more strongly dependent on BZRAs. CITATION: Tachibana M, Kanahara N, Oda Y, Hasegawa T, Kimura A, Iyo M. A retrospective clinical practice study comparing the usefulness of dual-orexin receptor antagonists and a melatonin receptor agonist in patients switching from long-term benzodiazepine receptor agonists. J Clin Sleep Med. 2024;20(4):603-613.

Contribution of the intra-hippocampal orexin system in the regulation of restraint stress response to pain-related behaviors in the formalin test.

Stress-induced antinociception (SIA) is due to the activation of several neural pathways and neurotransmitters that often suppress pain perception. Studies have shown that the orexin neuropeptide system is essential in pain modulation. Therefore, this study aimed to investigate the role of orexinergic receptors in the hippocampal CA1 region in modulating SIA response during the formalin test as an animal model of inflammatory pain. The orexin-1 receptor (OX1r) antagonist, SB334867, at 1, 3, 10, and 30 nmol or TCS OX2 29 as an orexin-2 receptor (OX2r) antagonist at the same doses were microinjected into the CA1 region in rats. Five minutes later, rats were exposed to restraint stress (RS) for 3 h, and pain-related behaviors were monitored in 5-min blocks for the 60-min test period in the formalin test. Results showed that applying RS for 3 h reduced pain responses in the early and late phases of the formalin test. The main findings showed that intra-CA1 injection of orexin receptor antagonists reduced the antinociception caused by stress in both phases of the formalin test. In addition, the contribution of OX2r in mediating the antinociceptive effect of stress was more prominent than that of OX1r in the early phase of the formalin test. However, in the late phase, both receptors worked similarly. Accordingly, the orexin system and its two receptors in the CA1 region of the hippocampus regulate SIA response to this animal model of pain in formalin test.

Clinical safety and narcolepsy-like symptoms of dual orexin receptor antagonists in patients with insomnia: a systematic review and meta-analysis.

STUDY OBJECTIVES: Dual orexin receptor antagonists (DORAs) are emerging treatments for insomnia. This meta-analysis study aimed to assess the safety of FDA-approved DORAs (suvorexant, lemborexant, and daridorexant), focusing on narcolepsy-like symptoms associated with these drugs. METHODS: Five prominent databases were searched to identify randomized controlled trials (RCTs) on this topic. Primary safety outcomes included treatment-emergent adverse events (TEAEs), treatment-related TEAEs, TEAEs leading to discontinuation, and serious TEAEs. Excessive daytime sleepiness (EDS), sleep paralysis, and hallucinations were categorized as adverse events (AEs)-related narcolepsy-like symptoms. RESULTS: Eleven RCTs with 7703 patients were included. DORAs were associated with a higher risk of TEAEs (risk ratio [RR], 1.09; 95% confidence interval [CI], 1.03 to 1.15) and treatment-related TEAEs (RR, 1.69; 95% CI: 1.49 to 1.92) when compared to placebo. The DORA group exhibited a significantly higher risk of EDS (RR, 2.15; 95% CI: 1.02 to 4.52) and sleep paralysis (RR, 3.40; 95% CI: 1.18 to 9.80) compared to the placebo group. CONCLUSION: This meta-analysis achieved a comparative evaluation of the clinical safety and tolerability of FDA-approved DORAs for primary insomnia, specifically focusing on AEs-related narcolepsy-like symptoms. This study contributes to understanding the safety profile of FDA-approved DORAs for treating insomnia.