suvorexant and ramelteon

Delirium is a common and serious neurobehavioral syndrome, associated with prolonged hospital stays, and increased morbidity and mortality. As it remains unclear whether suvorexant with or without ramelteon prevents delirium in elderly hospitalized patients, we conducted a systematic review and meta-analysis to evaluate, searching the PubMed, Cochrane Library, Web of Science, EMBASE, and EBSCOhost databases for all randomized controlled trials (RCTs), case-control studies, and cohort studies that investigated the effects of suvorexant with or without ramelteon on delirium in adult hospitalized patients. The primary outcome was the incidence of delirium. Two randomized controlled trials, 7 cohort studies and 2 case-control studies involving 2594 patients were included in this meta-analysis. The results showed that both suvorexant alone (odds ratio (OR) = 0.30, 95% confidence interval (CI): 0.14-0.65, P = 0.002) and suvorexant with ramelteon (OR = 0.39, 95% CI 0.23-0.65, P = 0.0003) reduced the incidence of delirium in adult hospitalized patients. Six studies involved the use of benzodiazepines; subgroup analysis performed separately in the suvorexant alone and suvorexant with ramelteon groups indicated that when benzodiazepine was administered, suvorexant with ramelteon was effective at reducing the incidence of delirium (OR = 0.53, 95% CI 0.37-0.74, P = 0.0002), but no significant difference was observed for suvorexant alone (OR = 0.40, 95% CI 0.11-1.53, P = 0.18). The current literature thus supports the effectiveness of suvorexant with or without ramelteon for delirium prevention, although suvorexant alone failed to significantly reduce the incidence of delirium when benzodiazepine was administered. The present study was limited by the significant heterogeneity among the included studies, and caution should be exercised when interpreting the results. This study was registered in the PROSPERO database (CRD4202017964).

Topics: Aged; Azepines; Delirium; Humans; Indenes; Randomized Controlled Trials as Topic; Triazoles

To assess the efficacy and safety of suvorexant for the prevention of delirium during acute hospitalization.. Pubmed (1946 to December 2019) and Embase (1947 to December 2019) were queried using the search term combination: delirium, confusion, cognitive defect, encephalopathy, critically ill patient, critical illness, or hospitalization and suvorexant or orexin receptor antagonist. Studies analyzed for relevance evaluated clinical outcomes of patients treated with suvorexant for prevention of delirium. Studies appropriate to the objective were evaluated, including two randomized controlled trials and four retrospective studies.. In acutely hospitalized patients, treatment with suvorexant 15 to 20 mg alone or in combination with ramelteon resulted in a reduction in development of delirium, time until delirium onset, and length of hospital stay. When assessed, suvorexant was well tolerated and adverse effects were no worse than placebo.. Based on the reviewed literature, suvorexant has shown positive outcomes in the prevention of delirium during an acute hospitalization. Larger trials comparing the efficacy of suvorexant to other sleep modulating options are necessary to further delineate its role for the prevention of delirium.

Topics: Aged; Aged, 80 and over; Azepines; Critical Care; Critical Illness; Delirium; Drug Therapy, Combination; Female; Humans; Indenes; Length of Stay; Male; Middle Aged; Orexin Receptor Antagonists; Randomized Controlled Trials as Topic; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Retrospective Studies; Sleep; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles

Sleep disturbances, including reduced nocturnal sleep time, sleep fragmentation, nocturnal wandering, and daytime sleepiness are common clinical problems in dementia, and are associated with significant carer distress, increased healthcare costs, and institutionalisation. Although non-drug interventions are recommended as the first-line approach to managing these problems, drug treatment is often sought and used. However, there is significant uncertainty about the efficacy and adverse effects of the various hypnotic drugs in this clinically vulnerable population.. To assess the effects, including common adverse effects, of any drug treatment versus placebo for sleep disorders in people with dementia.. We searched ALOIS (www.medicine.ox.ac.uk/alois), the Cochrane Dementia and Cognitive Improvement Group's Specialized Register, on 19 February 2020, using the terms: sleep, insomnia, circadian, hypersomnia, parasomnia, somnolence, rest-activity, and sundowning.. We included randomised controlled trials (RCTs) that compared a drug with placebo, and that had the primary aim of improving sleep in people with dementia who had an identified sleep disturbance at baseline.. Two review authors independently extracted data on study design, risk of bias, and results. We used the mean difference (MD) or risk ratio (RR) with 95% confidence intervals (CI) as the measures of treatment effect, and where possible, synthesised results using a fixed-effect model. Key outcomes to be included in our summary tables were chosen with the help of a panel of carers. We used GRADE methods to rate the certainty of the evidence.. We found nine eligible RCTs investigating: melatonin (5 studies, n = 222, five studies, but only two yielded data on our primary sleep outcomes suitable for meta-analysis), the sedative antidepressant trazodone (1 study, n = 30), the melatonin-receptor agonist ramelteon (1 study, n = 74, no peer-reviewed publication), and the orexin antagonists suvorexant and lemborexant (2 studies, n = 323). Participants in the trazodone study and most participants in the melatonin studies had moderate-to-severe dementia due to Alzheimer's disease (AD); those in the ramelteon study and the orexin antagonist studies had mild-to-moderate AD. Participants had a variety of common sleep problems at baseline. Primary sleep outcomes were measured using actigraphy or polysomnography. In one study, melatonin treatment was combined with light therapy. Only four studies systematically assessed adverse effects. Overall, we considered the studies to be at low or unclear risk of bias. We found low-certainty evidence that melatonin doses up to 10 mg may have little or no effect on any major sleep outcome over eight to 10 weeks in people with AD and sleep disturbances. We could synthesise data for two of our primary sleep outcomes: total nocturnal sleep time (TNST) (MD 10.68 minutes, 95% CI -16.22 to 37.59; 2 studies, n = 184), and the ratio of day-time to night-time sleep (MD -0.13, 95% CI -0.29 to 0.03; 2 studies; n = 184). From single studies, we found no evidence of an effect of melatonin on sleep efficiency, time awake after sleep onset, number of night-time awakenings, or mean duration of sleep bouts. There were no serious adverse effects of melatonin reported. We found low-certainty evidence that trazodone 50 mg for two weeks may improve TNST (MD 42.46 minutes, 95% CI 0.9 to 84.0; 1 study, n = 30), and sleep efficiency (MD 8.53%, 95% CI 1.9 to 15.1; 1 study, n = 30) in people with moderate-to-severe AD. The effect on time awake after sleep onset was uncertain due to very serious imprecision (MD -20.41 minutes, 95% CI -60.4 to 19.6; 1 study, n = 30). There may be little or no effect on number of night-time awakenings (MD -3.71, 95% CI -8.2 to 0.8; 1 study, n = 30) or time asleep in the day (MD 5.12 minutes, 95% CI -28.2 to 38.4). There were no serious adverse effects of trazodone reported. The small (n = 74), phase 2 trial investigating ramelteon 8 mg was reported only in summary form on the sponsor's website. We considered the certainty of the evidence to be low. There was no evi. We discovered a distinct lack of evidence to guide decisions about drug treatment of sleep problems in dementia. In particular, we found no RCTs of many widely prescribed drugs, including the benzodiazepine and non-benzodiazepine hypnotics, although there is considerable uncertainty about the balance of benefits and risks for these common treatments. We found no evidence for beneficial effects of melatonin (up to 10 mg) or a melatonin receptor agonist. There was evidence of some beneficial effects on sleep outcomes from trazodone and orexin antagonists and no evidence of harmful effects in these small trials, although larger trials in a broader range of participants are needed to allow more definitive conclusions to be reached. Systematic assessment of adverse effects in future trials is essential.

Topics: Alzheimer Disease; Azepines; Caregiver Burden; Cognition; Humans; Indenes; Melatonin; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Sleep; Sleep Wake Disorders; Time Factors; Trazodone; Triazoles

Geriatric patients often experience insomnia because of physiological and neurological changes that occur during the aging process. Use of benzodiazepines, nonbenzodiazepine hypnotics, and diphenhydramine for the treatment of insomnia pose an increased risk of cognitive impairment, falls, and fractures in this patient population. Therapeutic alternatives approved by the Food and Drug Administration include suvorexant, doxepin, ramelteon, and tasimelteon, which have shown efficacy and safety in various studies. This paper explores and outlines the available safety and efficacy data associated with these medications and reviews their potential place in therapy in treating insomnia in the geriatric population.

Topics: Aged; Aged, 80 and over; Azepines; Benzofurans; Cyclopropanes; Doxepin; Humans; Hypnotics and Sedatives; Indenes; Randomized Controlled Trials as Topic; Sleep Initiation and Maintenance Disorders; Triazoles

Current hypnotic agents have next-day residual effects. The new orexin antagonist, suvorexant, has little muscle relaxation effect on the physical and cognitive function in the following morning and daytime. In this study, the effects of suvorexant, zolpidem, ramelteon and placebo in elderly subjects were evaluated.. Six men and eight women aged 63-75 years received a single tablet and lights were then turned off. Subjects were instructed to sleep from 23:00-6:00 with an interruption from 4:00-4:30 for evaluations. Suvorexant 10 mg, zolpidem 5 mg, ramelteon 4 mg or placebo was administered single time in a randomized, double-blind and crossover design with a one-week drug holiday in between each drug. Measures of objective parameters and subjective ratings were obtained every 2 h from 4:00 to 16:00.. No subjects showed serious side effects from physical observations and vital sign checks before and after hypnotics were taken. During the first sleep period, the REM sleep time with suvorexant was especially longer than that with zolpidem. During the second sleep period, suvorexant had shorter sleep latency and longer stage2 sleep time than ramelteon and zolpidem, respectively. During the whole entire sleep, the REM sleep time with suvorexant was longer than zolpidem and placebo. For the body sway test with closed eye, the main effects of the medicines and zolpidem were significantly better than suvorexant and ramelteon.. The changes of physical and cognitive functions in healthy elderly after taking hypnotics were not remarkable. Therefore, these three hypnotics maybe appropriate for the elderly people with insomnia for single-time low dose administration.

Topics: Aged; Azepines; Double-Blind Method; Female; Humans; Hypnotics and Sedatives; Indenes; Male; Orexins; Triazoles; Zolpidem

The aim of this study was to examine the effectiveness of ramelteon and suvorexant for delirium prevention in real-world practice. It explored whether ramelteon and/or suvorexant would affect delirium prevention among both patients at risk for but without delirium (patients at risk) and those with delirium the night before a consultation.. This multicenter, prospective, observational study was conducted by trained psychiatrists at consultation-liaison psychiatric services from October 1, 2017, to October 7, 2018. Patients who were aged 65 years or older and hospitalized because of acute diseases or elective surgery, had risk factors for delirium, and had insomnia or delirium on the night before the consultation were prescribed ramelteon and/or suvorexant. The decision to take medication was left to the discretion of each patient. The primary outcome was incidence of delirium based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, during the first 7 days.. Among 526 patients at risk, those taking ramelteon and/or suvorexant developed delirium significantly less frequently than those who did not, after control for the effects of risk factors on the estimate of an independent association between the effects of ramelteon and/or suvorexant and the outcome of developing delirium (15.7% vs 24.0%; odds ratio [OR] = 0.48;, 95% CI, 0.29-0.80; P = .005). Similar results were found among 422 patients with delirium (39.9% vs 66.3%; OR = 0.36; 95% CI, 0.22-0.59; P < .0001).. Ramelteon and suvorexant appear to be effective for delirium prevention in real-world practice.

Topics: Aged; Azepines; Delirium; Female; Hospitalization; Humans; Indenes; Kaplan-Meier Estimate; Male; Prospective Studies; Risk Factors; Sleep Aids, Pharmaceutical; Treatment Outcome; Triazoles

Delirium in acute stroke is associated with poor clinical outcome. The purpose of this study was to examine the effect of sleep medications on sleep quality and delirium in acute stroke.. In this retrospective cohort study, sleep disturbances, and delirium were investigated in acute stroke patients treated in April 2013-March 2017 who were prescribed ramelteon plus either an alpha-aminobutyric acid receptor (GABAR) agonist or a selective dual orexin receptor antagonist (suvorexant).. Of the patients included, 104 received a GABAR agonist and 128 received suvorexant in addition to ramelteon. Patient characteristics did not differ significantly between the groups, except for a higher proportion of cerebral infarction in suvorexant group (P = .033). Subjective sleep quality was significantly improved in suvorexant group compared to GABAR agonist group (difficulty staying asleep: 6.3% versus 34%, P < .001; daytime sleepiness: 33% versus 63%, P < .001). Delirium was significantly less frequent in suvorexant group than GABAR agonist group (7.0% versus 31%, P < .001). The length of hospital stay was significantly shorter in suvorexant group than in GABAR agonist group (in days, 21 [15-29] versus 25 [18-33]; P = .019). Multivariable logistic regression analysis revealed that the addition of suvorexant was significantly associated with a reduced occurrence of delirium (odds ratios .19, 95% confidence interval .085-.43, P < .001).. Addition of suvorexant to ramelteon therapy, rather than a GABA receptor agonist, can improve subjective sleep quality without inducing delirium in acute stroke patients.

Topics: Aged; Aged, 80 and over; Azepines; Delirium; Drug Therapy, Combination; Female; GABA Agonists; Humans; Indenes; Male; Orexin Receptor Antagonists; Receptors, Melatonin; Retrospective Studies; Risk Factors; Sleep; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Stroke; Treatment Outcome; Triazoles

There is no clear evidence on the prevention of postoperative delirium with pharmacotherapy in elderly patients with esophageal cancer. This retrospective study aimed to evaluate the efficacy of ramelteon and suvorexant in preventing postoperative delirium in this patient group.. Data on 251 patients who received radical esophagectomy for thoracic esophageal cancer were collected from January 2010 to September 2021. In total, 74 patients did not receive preventive intervention, and 177 received ramelteon and suvorexant. After propensity score matching, the rate of postoperative delirium was compared between the two groups.. Seventy-two well-balanced patients in each group demonstrated similar clinical and pathological characteristics. The mean ages of the intervention and control groups were 70.8 and 70.3 years, respectively. All the patients underwent McKeown esophagectomy, and in the volume of intraoperative blood loss or operative time did not significantly differ between the two groups. The incidence rates of postoperative hyperactive delirium were 7% (5/72) in the intervention group and 32% (23/72) in the control group (p < 0.001). No severe adverse event potentially attributable to the intervention drug was observed. The multivariate analysis showed that the use of ramelteon and suvorexant was the only independent protective factor against postoperative delirium (hazard ratio 0.157, 95% CI 0.055-0.448, p < 0.001).. Ramelteon and suvorexant may play an important role in reducing postoperative delirium in elderly patients with esophageal cancer.

Topics: Aged; Delirium; Emergence Delirium; Esophageal Neoplasms; Humans; Retrospective Studies

Patients with delayed sleep-wake phase disorder (DSWPD) suffer from difficulties in sleep initiation at night, difficulties in waking up at the socially required time, and daytime somnolence. About half of the patients resist conventional light therapy and melatonin therapy. Therapy using hypnotics is not recommended due to its adverse effects. Recently, suvorexant, an orexin receptor antagonist, has become available for clinical use. The drug is relatively safer than traditional hypnotics such as benzodiazepines. We report three DSWPD patients who were successfully treated by the combination therapy of suvorexant and ramelteon. The first case was a 19-year-old woman who was experiencing difficulties in sleep initiation, difficulty in waking up in the morning, and daytime somnolence. She showed a prompt response to the combination therapy of suvorexant and ramelteon. Her sleep phase advanced, and her daytime somnolence reduced. The second and third cases were 21-year-old and 17-year-old men, respectively, who also showed significant sleep phase advances. Although case 2 was resistant to ramelteon treatment, his sleep phase advanced after suvorexant started. His difficulty in falling asleep and his habit of daytime napping disappeared after the combination therapy of suvorexant and ramelteon was started. Case 3 also showed a prompt response. His difficulties in falling asleep and waking up in the morning were ameliorated immediately after suvorexant with ramelteon was started. No obvious side effects were observed. Therapy using the combination therapy of suvorexant and ramelteon might be a reasonable option for DSWPD patients.

Topics: Adult; Azepines; Disorders of Excessive Somnolence; Female; Humans; Indenes; Male; Sleep; Sleep Initiation and Maintenance Disorders; Triazoles; Young Adult

We investigated the effects of sleep-inducing agents with different mechanisms of action on the loss of the righting reflex induced by isoflurane or a mixture of medetomidine, midazolam, and butorphanol (MMB), followed by atipamezole reversal. Chlorpromazine and brotizolam delayed recovery from both types of anesthesia, whereas the melatonin receptor agonist ramelteon had no effect. The orexin receptor antagonist suvorexant delayed recovery from anesthesia only in the case of MMB, while the sleep-promoting supplement glycine only delayed recovery in the case of isoflurane. These results suggest that the simple comparison method is applicable for testing substances expected to exert sleep-inducing effects.

Topics: Anesthesia; Anesthetics; Animals; Azepines; Butorphanol; Chlorpromazine; Drug Combinations; Imidazoles; Indenes; Isoflurane; Male; Medetomidine; Mice; Mice, Inbred ICR; Midazolam; Orexin Receptor Antagonists; Sleep Aids, Pharmaceutical; Triazoles

We investigated whether use of hypnotic drugs, including benzodiazepine receptor agonists, as well as ramelteon and suvorexant are associated with fall incidents in elderly inpatients aged no less than 75 years, who were hospitalized at an acute care general hospital in Japan, between November 1st, 2016 and October 31st, 2017. Multivariate analysis results were reported as odds ratio (OR) with 95% confidence interval (CI). Following to a case-crossover study protocol, the time windows of the case and the control days were assigned to the day or the days, which are one day or 2-8 d before the fall incidents, respectively. In the enrolled 111 patients, the accumulated total available numbers of the cases and the control days were 111 and 554 patient days, respectively. Hypnotic drug use was significantly associated with fall incidents (OR: 2.85, 95% CI: 1.03-7.90, p = 0.04). Especially benzodiazepine receptor agonists (OR: 5.79, 95% CI: 1.52-22.1, p = 0.01) showed statistically significant association with fall incidents. In contrast, neither ramelteon (OR: 7.95, 95% CI: 0.72-87.9, p = 0.09) nor suvorexant (OR: 0.25, 95% CI: 0.06-1.06, p = 0.06) were significantly associated with fall incidents. Thus, benzodiazepine receptor agonists, but not ramelteon or suvorexant, showed significant association with fall incidents. Therefore, special care should be taken especially when benzodiazepine receptor agonists are administrated to elderly subjects. In contrast, fall risk may be much less in patients treated with ramelteon or suvorexant. These results could help us to conduct safer drug treatment for insomnia patients aged no less than 75 years.

Topics: Accidental Falls; Aged; Aged, 80 and over; Azepines; Cross-Over Studies; Female; GABA-A Receptor Agonists; Hospitalization; Humans; Hypnotics and Sedatives; Indenes; Japan; Male; Receptors, GABA-A; Risk Factors; Triazoles

Sedative hypnotics are among the classes of drugs reported to influence falls. However, the effects of the sedative hypnotic drugs, suvorexant and ramelteon, on falls are not well known. Therefore, we conducted this retrospective case-control study to examine the association of the use of these two sedative hypnotics with the risk of falls. Conducted at the Sapporo Medical University Hospital in Japan, our study included 360 patients with fall incidents and 819 randomly selected control patients. Patients in the fall group were significantly older with a lower body mass index, and had a history of falls, disabilities in activities of daily living, cognitive impairment, and delirium. Monovariate analysis revealed that patients in the fall group frequently used ramelteon [odds ratio (OR) 2.38, 95% confidence interval (CI): 1.49-3.81, p<0.001], but rarely used suvorexant (OR 0.66, 95% CI: 0.29-1.39, p=0.317), compared with control patients. Furthermore, multivariate analysis revealed that ramelteon use did not increase the risk of falls (adjusted OR 1.43, 95% CI: 0.82-2.48, p=0.207), whereas suvorexant use significantly decreased the risk of falls (adjusted OR 0.32, 95% CI: 0.13-0.76, p=0.009). Although ramelteon tends to be used in patients at a high risk of falls, it may not increase the risk of falls. In contrast, the use of suvorexant may reduce the risk of falls.

Topics: Accidental Falls; Age Factors; Aged; Aged, 80 and over; Azepines; Body Mass Index; Case-Control Studies; Female; Humans; Hypnotics and Sedatives; Indenes; Male; Middle Aged; Retrospective Studies; Triazoles

The aim of this study was to examine the risk of falls associated with the use of non-gamma amino butyric acid (GABA) sleep medications, suvorexant and ramelteon. This case-control and case-crossover study was performed at the Kudanzaka Hospital, Chiyoda Ward, Tokyo. A total of 325 patients who had falls and 1295 controls matched by sex and age were included. The inclusion criteria for the case group were hospitalized patients who had their first fall and that for the control were patients who were hospitalized and did not have a fall, between January 2016 and November 2018. The internal sleep medications administered were classified as suvorexant, ramelteon, non-benzodiazepines, benzodiazepines, or kampo. In the case-control study, age, sex, clinical department, the fall down risk score, and hospitalized duration were adjusted in the logistic regression model. In the case-control study, multivariable logistic regression showed that the use of suvorexant (odds ratio [OR]: 2.61, 95% confidence interval [CI]: 1.29-5.28), nonbenzodiazepines (OR: 2.49, 95% CI: 1.73-3.59), and benzodiazepines (OR: 1.65, 95% CI: 1.16-2.34) was significantly associated with an increased OR of falls. However, the use of ramelteon (OR: 1.40, 95% CI: 0.60-3.16) and kampo (OR: 1.55, 95% CI: 0.75-3.19) was not significantly associated with an increased OR of falls. In the case-crossover study, the use of suvorexant (OR: 1.78, 95% CI: 1.05-3.00) and nonbenzodiazepines (OR: 1.63, 95% CI: 1.17-2.27) was significantly associated with an increased OR of falls. Similar patterns were observed in several sensitivity analyses. It was suggested that suvorexant increases the OR of falls. This result is robust in various analyses. This study showed that the risk of falls also exists for non-GABA sleep medication, suvorexant, and thus it is necessary to carefully prescribe hypnotic drugs under appropriate assessment.

Topics: Accidental Falls; Aged; Aged, 80 and over; Azepines; Benzodiazepines; Cross-Over Studies; Female; Humans; Hypnotics and Sedatives; Indenes; Male; Middle Aged; Risk Factors; Sleep; Sleep Aids, Pharmaceutical; Triazoles

Non-24-hour sleep-wake disorder (N24SWD) is often observed in the visually impaired and those who isolate indoors. Melatonin receptor agonists may be used for treatment, but there is currently no evidence that they are effective in patients without visual impairment.. We report a case of a 23-year-old woman who withdrew from her social life owing to autism spectrum disorder and experienced an unusual sleep rhythm. She presented with N24SWD. The N24SWD cycle averaged 25.6 days but was extended to 42 days using ramelteon. However, this was not enough. We prescribed the addition of suvorexant and the sleep cycle returned to normal.. N24SWD is a disease that seriously impairs social life and productivity. We propose a possible treatment strategy for N24SWD using ramelteon and suvorexant.

Topics: Autism Spectrum Disorder; Azepines; Drug Therapy, Combination; Female; Humans; Indenes; Sleep Aids, Pharmaceutical; Sleep Disorders, Circadian Rhythm; Treatment Outcome; Triazoles; Young Adult

This column is the first in a two-part series exploring lessons for psychiatric drug development that can be learned from the development of six central nervous system drugs with novel mechanisms of action over the past 25 years. Part 1 presents a brief overview of the neuroscience that supported the development of each drug, including the rationale for selecting a) the target, which in each case was a receptor for a specific neurotransmitter system, and b) the indication, which was based on an understanding of the role that target played in a specific neural circuit in the brain. The neurotransmitter systems on which the development of these agents were based included serotonin for ondansetron and lorcaserin, dopamine for varenicline, substance P (or neurokinin) for aprepitant, melatonin for ramelteon, and orexin for suvorexant. The indications were chemotherapy-induced nausea and vomiting for ondansetron and aprepitant, smoking cessation for varenicline, weight loss for lorcaserin, and insomnia for suvorexant and ramelteon.

Topics: Aprepitant; Azepines; Benzazepines; Central Nervous System Agents; Drug Discovery; History, 20th Century; History, 21st Century; Humans; Indenes; Morpholines; Neurotransmitter Agents; Ondansetron; Quinoxalines; Triazoles; Varenicline