Belsomra (suvorexant) / Merck (MSD) - LARVOL DELTA

Efficacy of Suvorexant in the Treatment of Insomnia in Midlife Women With Pre-Diabetes (clinicaltrials.gov) - P4 | N=61 | Recruiting | Sponsor: Brigham and Women's Hospital | Trial completion date: Sep 2024 ➔ Dec 2025 | Trial primary completion date: Sep 2024 ➔ Dec 2025

Trial completion date • Trial primary completion date • CNS Disorders • Diabetes • Insomnia • Metabolic Disorders • Sleep Disorder

Adverse events of pharmacological interventions for insomnia disorder in adults: a systematic review and network meta-analysis. (PubMed, Front Psychiatry) - "Compared with placebo, zolpidem (somnolence: relative risk [RR] 1.85; dizziness: RR 2.33; headache: RR 1.26), zopiclone (somnolence: RR 2.02; dizziness: RR 2.33; dysgeusia: RR 7.84), indiplon (somnolence: RR 3.46; dizziness: RR 2.30; headache: RR 1.63), gaboxadol (dizziness: RR 3.44), eszopiclone (somnolence: RR 2.00; dizziness: RR 3.18; dysgeusia: RR 10.54), estazolam (somnolence: RR 2.08), flunitrazepam (somnolence: RR 3.04), flurazepam (somnolence: RR 2.52), lemborexant (somnolence: RR 6.57), nitrazepam (somnolence: RR 3.80), Ramelteon (somnolence: RR 2.19), suvorexant (somnolence: RR 3.32), Temazepam (somnolence: RR 3.77), trazodone (somnolence: RR 2.86), triazolam (somnolence: RR 2.35), and esmirtazapine (somnolence: RR 4.63; dizziness: RR 2.87) had the most harmful profile in nervous system disorders...Data on some drugs like flurazepam, nitrazepam, triazolam, and zaleplon in some outcomes were mainly based on limited study with rare event and thus was highly..."

Adverse events • Journal • Retrospective data • Review • CNS Disorders • Gastroenterology • Gastrointestinal Disorder • Infectious Disease • Insomnia • Otorhinolaryngology • Pain • Psychiatry • Respiratory Diseases • Sinusitis • Sleep Disorder • Xerostomia

Suvorexant: A Dual Orexin Receptor Antagonist for Treating Sleep Disturbance in Posttraumatic Stress (clinicaltrials.gov) - P4 | N=190 | Recruiting | Sponsor: VA Office of Research and Development | N=144 ➔ 190

Enrollment change • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder • Sleep Disorder

Molecular Insights into the Interaction of Orexin 1 Receptor Antagonists: A Comprehensive Study Using Classical and Quantum Computational Methods. (PubMed, Molecules) - "In this study, we investigate the molecular interactions of three OXR1 antagonists-daridorexant, lemborexant, and suvorexant-using an integrated computational approach combining molecular dynamics (MD) simulations, density functional theory (DFT) calculations, and the molecular fractionation with conjugate caps (MFCC) methodology. By elucidating drug-receptor interactions at the atomic level, this research underscores the impact of integrated computational approaches in drug discovery. It supports the development of precise targeted therapies for sleep disorders."

Journal • Alzheimer's Disease • Cardiovascular • CNS Disorders • Cognitive Disorders • Insomnia • Narcolepsy • Sleep Disorder

Discovery, asymmetric synthesis and biological evaluation of new bisbenzylisoquinoline-orexin receptor antagonists for insomnia treatment. (PubMed, Eur J Med Chem) - "Biological assay results indicated that (R,S)-neferine demonstrated superior OXR antagonistic activity than suvorexant, with good binding affinities of KD (OX1R) 0.68 and (OX2R) 0.81 nM. In vivo pharmacodynamic studies showed that (R,S)-neferine reduced spontaneous activities in mice more effectively than daridorexant and significantly improved sleep in insomnia mice...(R,S)-neferine carried outstanding pharmacokinetic (F = 63.7 %) and safety profiles (LD50 > 500 mg/kg), no mortality or histopathological changes were observed during the acute toxicity test. Overall, this work highlights the therapeutic potential of the OXR antagonist (R,S)-neferine, providing candidates and viable drug development strategies for the treatment of insomnia."

Journal • CNS Disorders • Insomnia • Sleep Disorder • ARNTL • BMAL1 • PER1 • PER2

Discovery of natural orexin 2 receptor antagonists from Valeriana species: A potential approach for insomnia treatment. (PubMed, Chronobiol Int) - "Principal component analysis (PCA) revealed minimal conformational variability while gibbs free energy landscape (FEL) analysis and MM-PBSA binding free energy calculations further supported the strong binding of hesperidine and valerosidate to OX2R, comparable to suvorexant. These findings support hesperidine and valerosidate as promising, naturally derived OX2R antagonists, and warrant further invitro and invivo investigations for potential therapeutic application in insomnia treatment."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Insomnia • Narcolepsy • Sleep Disorder

Reduced Accumbal Dopamine Efflux Via Orexin OX2 Receptors in Chronic Pain Models. (PubMed, Eur J Neurosci) - "Decreased paw withdrawal threshold following carrageenan treatment or sciatic nerve ligation was inhibited by morphine. However, meloxicam, a nonsteroidal anti-inflammatory drug, inhibited these changes in carrageenan-treated rats but not in those with sciatic nerve ligation...Both in carrageenan-treated and in sciatic nerve-ligated rats, the OX1- and OX2-receptor antagonist MK-4305 and OX2-receptor antagonist EMPA-induced increase in accumbal dopamine efflux was reduced, as compared to their respective controls. The OX2-receptor agonist orexin-B counteracted the EMPA-induced increase in dopamine efflux both in carrageenan-treated and in sciatic nerve-ligated rats. These results suggest that inflammatory and neuropathic pain each lead to decreased stimulation of accumbal OX2-receptors by their endogenous agonists, orexin-A and/or orexin-B, thereby inhibiting dopamine efflux."

Journal • Neuralgia • Pain

Treatment of Disturbed Sleep in Progressive Supranuclear Palsy (PSP) (clinicaltrials.gov) - P4 | N=60 | Active, not recruiting | Sponsor: University of California, San Francisco | Recruiting ➔ Active, not recruiting | Trial primary completion date: Mar 2025 ➔ Jun 2025

Enrollment closed • Trial primary completion date • CNS Disorders • Movement Disorders • Progressive Supranuclear Palsy • Sleep Disorder

Comparative efficacy and safety of daridorexant, lemborexant, and suvorexant for insomnia: a systematic review and network meta-analysis. (PubMed, Transl Psychiatry) - "Considering that there is no evidence that DORAs are associated with physiological tolerance, withdrawal symptoms, or rebound insomnia when abruptly discontinued, and that sleep architecture is not adversely affected, the DORAs appear to be a favorable choice in managing insomnia disorder in adults."

Clinical • Journal • Retrospective data • Review • CNS Disorders • Infectious Disease • Insomnia • Pain • Respiratory Diseases • Sleep Disorder

Global burden of insomnia medication-associated suicidality, 1967-2024: A disproportionality analysis of the global pharmacovigilance database. (PubMed, Psychiatry Res) - "Although this disproportionality analysis did not permit causal interpretation, our study highlights significant variations in suicidality signal risk among insomnia medications, with benzodiazepines, Z-drugs, antidepressants, and first-generation H1 antagonists posing stronger signal, and dual orexin receptor antagonists presenting a weaker signal. Given the limitations of pharmacovigilance data, further studies are needed to confirm these findings and guide safer prescribing practices, particularly for individuals at high risk of suicidality."

Adverse events • Journal • CNS Disorders • Insomnia • Sleep Disorder

The putative effects of orexin receptor antagonists on pain and sleep in humans: A systematic review. (PubMed, Sleep Med) - "Orexin receptor antagonists improve sleep, but due to the very limited number of studies and small sample sizes, evidence regarding analgesic effects in humans remains inconclusive. The lack of receptor-selective interventions, short treatment durations, and pain condition variability may contribute to these findings. Future trials should investigate mechanistic analgesic effects, receptor-specific therapies, and explore orexin's role in pain phenotypes."

Journal • Review • CNS Disorders • Fibromyalgia • Insomnia • Musculoskeletal Pain • Pain • Rheumatology • Sleep Disorder

Syntheses and preclinical evaluations of 11C-labeled radioligands for imaging brain orexin-1 and orexin-2 receptors with positron emission tomography. (PubMed, RSC Med Chem) - "Unexpectedly, both [11C]1 and [11C]2 showed slightly lower monkey brain uptakes and distribution volumes at baseline than under blocking with suvorexant (a dual OX1R/OX2R antagonist), indicating a lack of specific binding to the target receptors in healthy animals. We infer that both OXRs exist in healthy mouse and monkey brain at very low density. Animal models, where OX1R and OX2R levels might be elevated, are desirable for candidate PET radioligand development, as are candidates with higher affinity."

Journal • Preclinical

A Study of Suvorexant (MK-4305) for the Treatment of Insomnia in Participants With Opioid Use Disorder (MK-4305-098) (clinicaltrials.gov) - P3 | N=300 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Oct 2026 ➔ Jun 2027 | Initiation date: Jun 2025 ➔ Oct 2025 | Trial primary completion date: Oct 2026 ➔ Apr 2027

Trial completion date • Trial initiation date • Trial primary completion date • CNS Disorders • Insomnia • Sleep Disorder • Substance Abuse

Efficacy of Ramelteon, Suvorexant, and Lemborexant for Delirium Prevention in Hospitalized Patients: A Systematic Review and Meta-Analysis. (PubMed, Crit Care Med) - "Sleep-wake regulating pharmacologic agents were associated with 40%-46% relative risk reductions in delirium prevalence, based on low-certainty evidence. Although these findings are promising, the absence of credible subgroup effects limits conclusions about the comparative efficacy of individual agents. Further, high-quality, prospective trials are needed to confirm these results and to clarify the role of specific pharmacologic strategies in delirium prevention."

Journal • Retrospective data • CNS Disorders

Enhancement of in vivo dopamine efflux in the rat nucleus accumbens by orexin OX2 receptor blockade is reduced in two chronic pain models (CINP-AsCNP 2025) - "The increase in accumbal dopamine (DA) efflux induced by the OX1- and OX2-R antagonist MK-4305 (50 ng) and the OX2-R antagonist EMPA (90 ng) observed in carrageenan-treated and sciatic nerve-ligated rats was reduced compared to their respective vehicle-treated or sham-operated controls. The behavioral effects of meloxicam and morphine support our earlier findings that, in rats, carrageenan injection and sciatic nerve ligation induce inflammatory and neuropathic pain, respectively (Ishikawa et al., 2017; Yamaguchi et al., 2020). The effects of EMPA were counteracted by co-administration of orexin-B (Kawashima et al., 2022), suggesting that DA efflux in NAc is under inhibitory regulation by endogenous orexin agonists via OX2-Rs. Moreover, selective OX2-R antagonists enhanced accumbal DA efflux through disinhibition."

Preclinical • Neuralgia • Pain

Role of orexin in reward-based decision-making strategies (CINP-AsCNP 2025) - "Our data suggest that activated orexin neurons affect the processing of reward prediction error and alter strategy in reward-based decision-making."

Mental Retardation

Neurochemical, Neurocircuitry, and Psychopathological Mechanisms of PTSD: Emerging Pharmacotherapies and Clinical Perspectives. (PubMed, ACS Chem Neurosci) - "Particular emphasis is employed on the role of the hypothalamic-pituitary-adrenal (HPA) axis, monoamines, glutamate, GABAergic, and the orexinergic system, as well as emerging therapeutic agents such as 3,4-methylenedioxymethamphetamine (MDMA), ketamine, suvorexant, and cannabinoid modulators. Inclusion criteria encompassed original research, clinical trials, and reviews relevant to PTSD mechanisms and treatment. By integrating recent findings, this review advances the understanding of PTSD pathophysiology and highlights potential avenues for targeted, personalized therapies, thereby contributing to clinical and translational research in neuropsychiatry."

Journal • Review • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry

Evaluation of Suvorexant for Improving Sleep in Persons Treated for Opioid Use Disorder: A Placebo-Controlled, Randomized Clinical Trial (CPDD 2025) - "Suvorexant acutely improved several sleep parameters (accelerated time to sleep 1 and deep sleep, and minimizing awake after sleep onset), which suggest potential benefit in persons with OUD. Larger-scale controlled trials are needed to determine whether these gains are reliable and sustained."

Clinical • Addiction (Opioid and Alcohol) • CNS Disorders • Insomnia • Sleep Disorder • Substance Abuse

Sex Differences in Adverse Events Reported With Concomitant Buprenorphine and Insomnia Medications Use (CPDD 2025) - "Secondary search terms included commonly prescribed medications for insomnia: “temazepam”, “triazolam”, “estazolam”, “lorazepam”, “clonazepam”, “alprazolam”, “ramelteon”, “doxepin”, “trazodone”, “mirtazapine”, “suvorexant”, “lemborexant”, “daridorexant”, “quetiapine”, “hydroxyzine”, “gabapentin”, “eszopiclone”, “zaleplon”, “zolpidem”, “zolpidem ER”. Contrary to previous research demonstrating that females are involved in more AE reports across pharmacovigilance databases (Brabete et al., 2022), and that females taking 1 buprenorphine had an increased likelihood of insomnia medications prescription receipt, compared to their male counterparts (Martin et al., 2023), we did not find sex differences in the number of AE reports. However, the data suggest that males taking concomitant buprenorphine and insomnia medications, specifically benzodiazepines and DORAs, may experience more serious AEs than females."

Adverse events • CNS Disorders • Insomnia • Sleep Disorder

Effects of Suvorexant on Nicotine Withdrawal and Sleep During Overnight Smoking Abstinence (CPDD 2025) - "Analyses found preliminary evidence for effects of suvorexant on nicotine withdrawal and sleep following overnight nicotine abstinence. Bolstering sleep quality during an 1 active quit attempt may mitigate negative effects of withdrawal and improve the odds of success."

CNS Disorders • Insomnia • Nicotine Addiction • Sleep Disorder

Sex Differences in the Effects of Suvorexant on Methamphetamine Self-Administration in Rhesus Monkeys (CPDD 2025) - No abstract available

Evaluation of Suvorexant Effects on Alcohol Seeking and Self-Administration in Baboons (CPDD 2025) - "Low dose suvorexant may acutely reduce drinking, but the magnitude of change may not be clinically meaningful. Higher doses of suvorexant may worsen heavy drinking. These data do not support suvorexant use to reduce alcohol intake during ongoing use."

Addiction (Opioid and Alcohol)

CRANK Up the Research: Novel Therapeutics for Methamphetamine Use Disorder (CPDD 2025) - "Strickland will then present data from a clinical study investigating methamphetamine and oxycodone mono- and poly-substance self-administration in the context of a medication development trial of suvorexant, emphasizing the importance of evaluating drug combinations in light of the growing prevalence of methamphetamine-opioid co-use...McPherson will describe human studies investigating mirtazapine as a treatment for methamphetamine use among patients receiving medication for opioid use disorder, supported by nonhuman primate studies with methamphetamine alone. Where applicable, sleep-related endpoints will be discussed across studies emphasizing associations between sleep dynamics and treatment efficacy. Overall, the lack of treatments for methamphetamine use disorder and associated sleep impairments represents a significant unmet public health need, and this symposium will discuss data from promising novel pharmacotherapies addressing this gap."

Addiction (Opioid and Alcohol) • CNS Disorders • Psychiatry • Substance Abuse

Dysregulations in Sleep Patterns Induced by Fentanyl Self-Administration and Acute Withdrawal are Altered by Xylazine Co-Use (CPDD 2025) - "Individuals with opioid use disorder have experienced alleviation of withdrawal severity when given the insomnia medication suvorexant, indicating that sleep dysregulation is a critical aspect of withdrawal. Akin to prior clinical reports, fentanyl use resulted in significantly increased sleep duration. Acute fentanyl withdrawal resulted in increases sleep duration, in line with reports of a “peak and valley” pattern of clinical withdrawal severity due to sequestration and release of fentanyl in storage tissues across the withdrawal syndrome. Surprisingly, co-use with xylazine attenuated these fentanyl withdrawal-induced sleep effects, raising the possibility that xylazine interrupts metabolic mechanisms of fentanyl during acute withdrawal, warranting additional studies in this area."

CNS Disorders • Insomnia • Sleep Disorder • Substance Abuse

Examining the Relationship Between Drug Demand, Craving, and Withdrawal During A Buprenorphine Taper in Opioid Use Disorder (CPDD 2025) - " The original study enrolled 38 individuals with OUD, randomized to receive 0, 20, or 40 mg of suvorexant during a 4-day buprenorphine/naloxone taper after stabilization on a buprenorphine/naloxone regimen. HPTs for a participant’s preferred nonmedical opioid (fentanyl, heroin, prescription opioids) were administered at baseline (the day before taper) and on the final taper day... These findings suggest that heroin demand decreases following a short 1 buprenorphine taper and is more closely associated with craving than withdrawal severity. This study demonstrates that HPT may be most related to anticipation of positive reinforcement and provides insight into how opioid demand functions during an opioid taper."

Addiction (Opioid and Alcohol) • Substance Abuse