Daridorexant as a novel pharmacotherapeutic approach in insomnia: a systematic review and meta-analysis

ABSTRACT Background Insomnia is a multi-factorial disorder with conventional treatment options that are not satisfactory for many patients. This metaanalysis analyzed the safety and efficacy of daridorexant. Methods An electronic database search for RCTs was conducted on Medline via PubMed, Cochrane, and Clinicaltrials.gov using the terms ‘Daridorexant,’ ‘RCT,’ ‘Insomnia’ trials evaluating the efficacy and/or safety of daridorexant for insomnia were included. The data were synthesized using Cochrane review manager version 5.4.1. Cochrane risk of bias 2.0 tool and GRADEpro-GDT were used to assess the methodological and evidence quality, respectively. Results Of 109 searched studies, four trials were included. The risk of treatment-emergent adverse events with 25 mg daridorexant [risk ratio (RR) = 1.12 (0.88, 1.43), p = 0.36; I2 = 0%] and 50 mg daridorexant [RR = 1.25 (0.88, 1.79), p = 0.22; I2 = 28%] and serious adverse events with 25 mg [RR = 0.86 (0.23, 3.19), p = 0.82, I2 = 56%] and 50 mg [RR = 1.32 (0.29, 6.08), p = 0.72, I2 = 52%] was comparable to placebo [Moderate quality evidence]. Risk of nasopharyngitis was also comparable to placebo. The efficacy parameters like wake after sleep onset, latency to persistent sleep, and subjective total sleep time showed significant improvement with daridorexant. The risk of bias is low for three studies and some concern for one. Conclusion Daridorexant is a safer and efficacious agent for induction and maintenance of sleep for chronic insomnia. Prospero The registration number is CRD42022335233. Clinical trial registration www.clinicaltrials.gov identifiers are NCT03575104, NCT03545191, NCT03679884, and NCT02839200).


Introduction
Sleep is a complex behavioral state that has a positive or negative impact on the physical, social, and cognitive health of an individual [1].As per the 5 th edition of DSM-5 (Diagnostic and Statistical Manual of Mental Disorders), insomnia is a sleep disorder delineated by problems in sleep onset or maintenance and early morning awakening.When these symptoms appear despite having access to enough sleep chances for at least 3 months, at least three times every week, insomnia is deemed to have occurred [2,3].The percentage of people who suffer from insomnia varies considerably around the globe, from 10-30% to 50-60% and is more common in elderly persons, women, and individuals with medical or mental illnesses [4].
In clinical settings, various non-pharmacological and pharmacological treatments have been used to manage insomnia.Based on the evidence, cognitive behavior therapy (CBT) has emerged as the first-line therapy for treating chronic insomnia.The approach of CBT is multidirectional focusing on the various aspect of insomnia and has more benefits and fewer adverse effects than drug therapies [5,6].However, CBT is not ideal for all patients as fewer patients are motivated to undergo CBT, and if they are, the limited number of trained therapists restricts CBT as the option of treatment for insomnia [5,7].In the absence of appropriate non-pharmacological treatment, the patient frequently seeks pharmacological therapy for insomnia.Over-the-counter drugs are not recommended by the authorities because of a lack of efficacy and safety data [8].Prescription medications include Z drugs, benzodiazepines, orexin receptor antagonists, low-dose doxepin and melatonin receptor agonists.Benzodiazepines have well-documented efficacy in patients who have trouble falling or staying asleep.However, they are used with caution in elderly patients because of an increased risk of falls and fractures, cognitive impairment, ataxia, alteration in sleep architecture, dependency, and sedation.In addition, polypharmacy is widespread among elderly patients.Benzodiazepines show multiple drug interactions and are associated with an increased incidence of respiratory depression, coma, and death when used along with other CNS depressant drugs [8][9][10].When compared to benzodiazepines, Z drugs including zolpidem, zaleplon, zopiclone, and eszopiclone have a more specific action on GABA A receptors and have less effect on sleep architecture.However, both of the drug classes have shared similar adverse effect profiles.The use of Z drugs in the elderly has also been linked to a higher rate of hospitalization and emergency room visits [8].To treat insomnia associated with difficulty falling asleep and staying asleep, ramelteon, a melatonin agonist, has received approval.The drug has a minor effect on sleep architecture and can be safely given to the elderly who have balance and mobility problems [9].Recently orexin receptor antagonists have emerged as a therapeutic measure for elderly patients who are suffering from insomnia disorder [11].Endogenous ligands known as orexins increase wakefulness by binding to OXR 1 and 2. Dual orexin receptor antagonist (DORA) acts by blocking both the orexin receptors and is deemed useful in insomnia treatment.DORA has a low abuse potential and has rare chances of causing rebound insomnia on sudden stoppage of the drug [12,13].Suvorexant was the first molecule in this category that was authorized by the FDA ('Food and Drug Administration') in 2014, followed by another agent lemborexant in 2019.Daridorexant has just received FDA approval (January 2022) to treat adult patients with insomnia who have issues getting to sleep or staying asleep [14].For the treatment of adults with insomnia characterized by symptoms present for 3 months and a significant impact on daytime functioning, the first DORA to receive approval in the European Union is daridorexant [15].Daridorexant is to be taken between 25 and 50 mg 30 minutes before night and at least 7 hours before waking up.The effective duration of daridorexant is (8 hours) favorable in terms of minimizing the effect of the drug on daytime activities.The main excretion pathways for daridorexant are urine and feces and it is metabolized by CYP3A4.Nasopharyngitis, nausea, headache, fatigue, and dizziness are the most common side effect as compared to placebo while rare episodes of sleep paralysis and hypnagogic and hypnopompic hallucinations were also observed [14].There are no major safety warnings reported by the regulatory bodies yet they warn and advise caution against daytime sleepiness, depression, compromised respiratory function, etc [16].In the available literature, most of the studies have reported daridorexant to be safe and superior to the counterpart medications.We planned to systematically analyze the data and conclude on the safety and efficacy of the drug based on the randomized controlled trials available.

Protocol and registration
The PRISMA ('Preferred Reporting Items for Systematic Reviews and Meta-Analyses') statement was followed while conducting the current systematic review and meta-analysis.The protocol's registration number is CRD42022335233 in the PROSPERO ('International Prospective Register of Systematic Reviews') database.

Study inclusion criteria
Only RCTs (randomized clinical trials) examining daridorexant efficacy and/or safety in patients with insomnia were considered.All other study categories, such as epidemiological studies, observational studies, and review articles were excluded.

Search strategy and study selection
Up to 28 June 2022, an electronic literature search was carried out using databases including the Cochrane Central Register of Controlled Trials, Medline via PubMed, and Clinicaltrials.gov.We also conducted a bibliographic search of papers that were already published; neither the language (English) nor the publication status was constrained.For database searches, the following medical topic headings (MeSH) were used: 'Daridorexant,' 'RCT,' and 'Insomnia.'The papers were screened by two independent researchers [SD, SS], and the duplicates were removed and assessed for possible suitability.The entire texts of the papers were evaluated after the first review, and any discrepancies were addressed with the cooperation of the other authors [RS, JC, MH].

Data extraction
Data specific to each trial were documented for the design of the study, daridorexant dosages, the number of individuals in each category, data on sleep endpoints, and safety results is filled out in a predefined form.

Study objectives and parameters selected for pooled results
This study aims to assess the safety of daridorexant in patients with insomnia which included SAE (Serious Adverse Events), TEAE (Treatment-Emergent Adverse Events), and other specific nonserious side effects.The secondary objectives were assessing the efficacy of daridorexant in improving sleep duration and quality through WASO (Wake After Sleep Onset), LPS (Latency to Persistent Sleep), and sTST (Subjective Total Sleep Time).

Quality assessment of studies
Two authors (SD and RS) independently rated the RCTs' methodological quality according to the Cochrane Collaboration risk of bias 2 tool (ROB-2), classifying each as high, low, or with some complications [17,18].Using the Robvis (visualization tool) software, the figure plots for the bias risk were created [19].
The assessment of publication bias was not done as the number of studies was less than 10.
For assessment of the overall quality of evidence, GRADE proGDT (guideline development tool) software was used.They were graded as high, moderate, and low.The GRADEpro-GDT software was accessed online from the site: https://gradepro.org/[20,21].

Data synthesis and summary measures
The data for the adverse events (AEs) such as treatment-emergent adverse events, serious adverse events, and others were summarized as Risk Ratios (RR), along with 95% CI (confidence intervals) and Mantel-Haenszel statistic was used for comparing the dichotomous data.TEAE was taken as the aggregate of SAE and non-SAEs.The efficacy data on sleep was assessed with changes in WASO, LPS, and sTST and were represented as pooled mean change and the effect estimate was analyzed by inverse variance method.Review Manager Version 5.4.1.(Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2020) was used for the estimation of a pooled effect by a random effect model [22].Heterogeneity was assessed using I 2 and I 2 greater than 50% was taken as substantial heterogeneity [23].The findings of the random effect model were used to interpret the meta-analysis [24].

Study selection
A total of 109 studies were extracted based on the predefined search strategy mentioned above.After removing the duplicates and other studies, 13 studies were found, of which the full text or results were not posted for nine studies.Based on the inclusion criteria, finally, four studies were selected for this metaanalysis [Supplementary figure S1].

Study characteristics
The current study included four RCTs with three studies (NCT03575104, NCT 03545191, and NCT 03679884) registered on Clinicaltrials.govand one published article (Dauvilliers et al., 2020) of a registered trial (NCT02839200) [25][26][27][28][29]. Table 1 provides a summary of RCT characteristics.The total number of patients from all four included trials was 1962 in daridorexant (10 mg, 25 mg, and 50 mg) and 806 in the placebo group.The participants in the placebo group were common for comparison for various dosages of daridorexant.

Risk of bias (ROB) within the studies
Since three of the included studies had low ROB and one had some concerns, the total ROB was rated as 'Low.'One trial had some concerns about missing outcome data, and there were no problems with randomization, variation from intervention, or presentation of findings.Additionally, it was determined that the total ROB evaluated for GRADE analysis was low.Clinicaltrials.govwas used to evaluate unpublished RCT protocols for the evaluation of ROB [Figure 1].

Safety outcomes
For analyzing the safety of daridorexant, we analyzed various adverse events with 10 mg, 25 mg, and 50 mg doses of daridorexant as compared to placebo.A total of 3752 participants from four trials were included for analysis with 1958 participants in the daridorexant group and 1794 participants in the placebo group.For analyzing safety parameters, in the 10 mg dose, three studies with 506 vs. 494 participants; for 25 mg, four studies with 946 vs. 803 participants, and for 50 mg, three studies with 506 vs. 497 participants, were included in daridorexant vs. placebo group, respectively.

Efficacy outcomes
For assessment of efficacy, we analyzed various parameters at 25 and 50 mg doses of daridorexant as compared to placebo.The patients were initially given a 25 mg dose of daridorexant for 1 month and the same patients were continued on treatment for 3 months for follow-up.The efficacy parameters were analyzed at 1 month and 3 months.The data for 1 month's efficacy parameters were available from three RCTs (Dauvilliers et al., 2020; NCT03545191 and NCT03575104) and 3 months' efficacy parameters were available for two RCTs (NCT03545191 and NCT03575104).Similarly, the data of efficacy parameters for 50 mg were available from two RCTs (Dauvilliers et al., 2020 and NCT03545191) for 1 month however data for 3 months was available from only one RCT (NCT03545191), hence it could not be included for pooled analysis.

Wake After Sleep Onset (WASO)
Firstly, we analyzed three RCTs with 679 participants in the daridorexant group and 678 in the placebo and a significant reduction in WASO with 25 4].

Latency to Persistent Sleep (LPS)
Analysis of three RCTs with 679 participants in the daridorexant group and 678 in the placebo showed a significant reduction in LPS with 25

Subjective Total Sleep Time (sTST)
Analysis with 25

GRADE analysis of the efficacy outcomes
The GRADE Pro GDT analysis for safety parameters like TEAE and SAE was observed to be moderate, and efficacy parameters like WASO and LPS were 'Moderate to High' quality of evidence.The GRADE evidence quality and summary of finding characteristics for the safety and efficacy parameters are summarized in Table 2.

Discussion
Insomnia is a multi-factorial problem having prevalence ranging from 10% to 60% in various studies conducted in India and worldwide [4].The conventional treatment with     benzodiazepines, Z-drugs, and ramelteon has been observed to have non-satisfactory results for many patients.Despite their efficacy, these drugs have several adverse effects that restrict their usage, including next-morning residual drowsiness, falls, motor incoordination, cognitive and memory loss, and the possibility of misuse, tolerance, and dependency [13].DORA is increasingly used for insomnia nowadays, daridorexant being the newest molecule of the group and most studies have supported the drug to be safe and superior to the counterpart medications available.We planned to systematically analyze the data and conclude on the safety and efficacy of the drug based on the RCTs available.
Safety analysis of daridorexant revealed that TEAE risk with daridorexant is 1.45 times higher than placebo at 10 mg but 25 and 50 mg showed no significant difference in developing TEAE as compared to placebo.SAE analysis exhibited no major difference in the placebo and daridorexant groups.Nasopharyngitis is frequently reported ADR with daridorexant in previous studies but the present analysis could not observe any statistically major difference between placebo and daridorexant.Headache was not significantly higher in individual doses of 10 mg, 25 mg and 50 mg as compared to placebo, however cumulative risk of headache was altogether significantly higher with daridorexant.The reason for high TEAE in the 10 mg group as compared to the 25 and 50 mg group has not been identified from the available literature.Even the exact mechanism for the development of headaches and nasopharyngitis needs to be explored.The findings of this study are supporting the results published from various studies on daridorexant suggesting commonly reported ADRs with daridorexant are nasopharyngitis, headache, accidental overdose, fatigue, dizziness, nausea, and somnolence [30,31].Additionally, according to prescription data provided by the manufacturer, individuals using daridorexant 50 mg and 25 mg had adverse events that resulted in treatment discontinuation in 1% and 2% of cases, respectively, compared to 3% of participants taking a placebo [16].Serious side effects (≥1) occurred in 1% of those using daridorexant 25 and 50 mg respectively, and 2% of people taking a placebo [30,31].Other side effects included sleep paralysis (0.5% with daridorexant 25 mg, 0.3% with daridorexant 50 mg, and 0% with placebo) and hypnopompic and hypnagogic hallucinations (0.6% with daridorexant 25 mg, but none with the higher daridorexant dose or placebo), which occurred in 0.6% of subjects who took the drug [16].Few studies have reported the occurrence of cardiac events like cardiac arrest as adverse events but causality association showed that they are not related to daridorexant.As evidenced by the absence of acceptable QT-prolonging at supratherapeutic and therapeutic doses, daridorexant does not affect cardiac repolarization and does not increase the risk of cardiovascular disease, according to research by Schilling U et al. in 2021 [32].Additionally, research conducted in 2021 by Mignot et al. revealed that the incidence of side effects was similar among treatment groups overall [31].The only side effects that affected more than 5% of people were nasopharyngitis and headache.Other adverse events, such as somnolence and falls, did not increase with dosage over the whole dosing range [25,26].Furthermore, there were no withdrawal symptoms after a treatment plan that was abruptly stopped.Adverse events resulting in treatment discontinuation were statistically more prevalent with placebo than the daridorexant across all treatment groups [25,26].Daridorexant's safety profile was examined in senior patients, and results showed that it is effective in helping the older population sleep better and perform better throughout the day.According to information from the ClinicalTrials.govdatabase, NCT03545191, no safety issues at either dosage were found in this vulnerable demographic population and the same was confirmed by an analysis conducted by Fietze et al. which also observed that daridorexant was safe in older populations even at the highest dose administered [26][27][28]33].Few studies were conducted to compare the AE profile of daridorexant with other established drugs used for insomnia.The study by Muehlan et al assessed the daytime driving performance with daridorexant, zopiclone, and placebo and reported that there was an initial poor driving performance with daridorexant which waned off on day 5 of treatment and showed better results as compared to zopiclone [34].The possibility of abuse was assessed using the drug-liking visual analogue scale (VAS), with patients being randomly assigned to doses of 50/100/150 mg of daridorexant, 150 mg of suvorexant, 30 mg of zolpidem, or placebo.The 50 mg dose of daridorexant was found to have a substantially lower VAS Emax and a lower risk of misuse compared to suvorexant and zolpidem, although the 100 mg and 150 mg doses were equivalent [35].
Efficacy analysis using WASO, LPS, and sTST showed a significant reduction in WASO, LPS, and an increase in sTST as seen in the daridorexant group as compared to placebo for 25 mg at 1 month and 3 months and 50 mg at 1 month.Similar findings were also observed in research published recently by Dos Santos JBR et al. [30].Glass and associates did a meta-analysis to assess the risks and benefits of all sedative-hypnotic medicines (barbiturates, benzodiazepines, Z-drugs, etc.) in elderly patients and reported improvement in sleep quality using WASO, TST, and objective parameters polysomnography [36].An independent examination of BZDs *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).CI: confidence interval; RR: risk ratio.GRADE Working Group grades of evidence.High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.Explanations.a Publication bias was strongly suspected and outcome was not related to the dose.b There was high heterogeneity between the studies.Out of four studies included in the analysis, one trial is published separately and the results of two trials are combined published as single study.There may be chances of publication bias in view of a smaller number of studies.
alone revealed more significant quality improvement.Both for the sedative-hypnotics combined and for the BZD group alone, there was also observed a considerable improvement in TST (total sleep time) and a decrease in the NOA (number of awakenings).Sedative-hypnotic side effects were observed to be more prevalent.As per the sleep quality measures changes by sedative-hypnotics reported by the authors in the analysis, there is an adverse risk/benefit ratio for this group since there are 13 people required to cure and only six to harm.This ratio's independent analysis for BZDs alone was not done [36].Further, the efficacy of the daridorexant is also supported by research including pre-clinical data, pharmacokinetic studies, and clinical phases of development showing promising results in humans for insomnia [37].It increases REM and non-REM sleep without disturbing the sleep architecture much and also reduces the time to fall asleep and less next-morning residual effects as per earlier research studies [11,29,37].Another meta-analysis by Winkler and Doering collected information from 31 randomized controlled trials of sedative medications such as BZDs, melatonin agonists, Z-drugs, and antidepressants that were used to treat primary insomnia.They presented the findings of a polysomnography study that only included objective data, which showed that BZDs and BZD receptor agonistic modulators (BzRAs) were both considerably more efficacious than antidepressants for the main sleep characteristics without considering treatment-emergent adverse effects [38].
The efficacy advantage of daridorexant over conventional sedative hypnotic drugs can be attributed to its novel mechanism (through orexin) [14].Orexin neuropeptides and receptors are specifically located in areas of the brain and show high activity during active wakefulness and remain dormant in sleep.These neurons connect to a variety of orexin neurons that connect to a variety of awakening-promoting regions, including the locus coeruleus' noradrenergic neurons (OX1R), the histaminic neurons of the tuberomammillary nucleus (OX2R), the ventral tegmental area's dopaminergic neurons (OX1R, OX2R), the serotoninergic neurons of the dorsal raphe (OX1R, OX2R) [39,40].These wakepromoting regions are stimulated by orexins, which stabilize wakefulness.By stimulating cholinergic/monoaminergic neuronal pathways in the ascending arousal system, orexin neuropeptides operate as regulators of the transition between sleep and wakefulness and provide an initial transitory influence toward awakeness.Daridorexant specifically inhibits the wake-promoting areas of the brain caused by orexin, but it does not prevent the activation of the same regions by other neurotransmitters that may be generated when one needs to wake up [41].Contrarily, positive GABA-A receptor modulators cause sleep by widely inhibiting the CNS, raising the threshold for alertness, and perhaps contributing to the effects of hangovers the day after.This might be a factor in DORA's superior effectiveness and lower incidence of adverse effects when compared to other sleep disorder medicines.Additionally, it is claimed that improvements in daily performance and sleep characteristics were made without causing excessive drowsiness the following morning [39,40,42].Also, DORA does not affect motor or sensory function much as well as preserves memory which is contributing to its safety profile in terms of daytime sleepiness, motor disturbances, falls, balance, etc. are less with them.Similar to other DORAs, daridorexant is anticipated to retain cognitive function, have a very low potential for addiction, and not cause tolerance or rebound after prolonged usage, thereby eliminating many of the drawbacks of more conventional hypnotic drugs [13,43].
The prescribing information of daridorexant also shows special caution needs to be taken in patients with compromised respiratory function, complex sleep behavior, and other co-morbid conditions that need further evaluation [16].On further exploring the https://clinicaltrials.gov/ database, the drug is also under trials for several specific conditions like obstructive sleep apnea, chronic obstructive pulmonary disease, renal and hepatic impairment, abuse potential, pharmacokinetic studies among 10 to < 18 years of age, insomnia and comorbid nocturia, insomnia in patients with mild cognitive impairment and mild to moderate Alzheimer disease, post-traumatic stress disorder, nighttime body posture, the noise level required to wake up, and the ability to remember words previously presented and drug-drug interactions for generating additional evidence for long-term use of this molecule [14].
A metaanalysis conducted by Albadrani et al. also reported daridorexant to be superior in efficacy but had a higher incidence of adverse events as compared to placebo [44].The previous review was based on the data available till February 2022, however in our analysis, safety profile being our primary objective, we analyzed a larger number of patients as compared to the previous analysis as we included the long-term safety [44 weeks] analysis study [ClinicalTrials.govIdentifier: NCT03679884] which was crucial for assessing the safety of the novel drug in patients with insomnia.
This metaanalysis has systematically compiled and analyzed the results of all available data meeting the inclusion-exclusion criteria.In this systematic review and metaanalysis, the quality of the evidence for safety parameters was moderate and efficacy parameters were found to be moderate to high as per GradePro GDT analysis.For the trials in the majority of domains, a low risk of bias was determined.In view of a small number of missing outcome data in one of the studies [NCT03679884], the possibility of bias remained uncertain [27].Randomization bias, variation from the planned intervention, measurement results, or selective reporting of outcomes were not present.The limitation of this systematic analysis is that subjective total sleep duration was considered as one of the efficacy parameters which might vary with many factors.There are several techniques available to evaluate the quality and quantity of sleep, but there is no agreement on the best approach.Publication bias analysis was not conducted as the number of studies included was only four in this meta-analysis.To date, very few studies were published for evaluating the efficacy and safety of daridorexant in a clinical setting.Further larger studies involving more patients with different genetic and ethnic backgrounds, and different comorbidities are required to shed more light on the effective and safe use of daridorexant in a larger population.

Conclusion
Daridorexant is a dual orexin type 1 and 2 (OX1 and OX2) receptor antagonist (DORA) that may be used orally to treat people with chronic insomnia.It may be used for people with insomnia that have a significant negative effect on daytime activities and issues with sleep onset or maintenance.The findings of this meta-analysis suggest that daridorexant is an efficacious agent for induction and maintenance of sleep without disturbing the sleep architecture, reduction in time to go for sleep latency to persistent sleep, decrease in WASO, and increase in overall sleep duration.Also, daridorexant is found to be a safer option at an approved dosages of 25 and 50 mg with fewer daytime disturbances and daytime somnolence and hangover and comparable TEAE, SAE, and other minor side effects.

Expert opinion
With insomnia, being a lingering disorder, there is a need for an efficacious and safe therapeutic option that is superior to the existent and conventional therapies.The limitations of the existing prescription drugs like benzodiazepines and Z drugs encompass sedation, increased risk of falls and fractures, cognitive impairment, ataxia, alteration in sleep architecture, dependence, etc. which are more frequent in the elderly population [9].Daridorexant is a novel dual orexin type 1 and type 2 receptor antagonist approved for the treatment of insomnia.This article meta-analyzed the existing evidence of the randomized clinical trials to assess the efficacy and safety of the newly approved molecule.Daridorexant was found to have comparable safety as the placebo for the approved dosage i.e. treatment-emergent adverse events (TEAE) with 25 mg [RR = 1.12 (0.88, 1.43), p = 0.36; I 2 = 0%] and 50 mg [RR = 1.25 (0.88, 1.79), p = 0.22; I 2 = 28%] daridorexant and serious adverse events (SAE) with 25 mg [RR = 0.86 (0.23, 3.19), p = 0.82, I 2 = 56%] and 50 mg [RR = 1.32 (0.29, 6.08),p = 0.72, I 2 = 52%].Evidence reveals headache is one of the most common adverse effects with daridorexant and the current analysis observed an overall significantly elevated risk of headache with daridorexant as compared to placebo but failed to observe any significantly elevated risk as compared to placebo at individual approved doses of 25 mg [RR = 1.53 (0.93, 2.54), p = 0.10; I 2 = 0%] and 50 mg [RR = 1.86 (0.96, 3.61), p = 0.07; I 2 = 0%].The risk of nasopharyngitis with 25 mg [RR = 0.91 (0.56, 1.48), p = 0.69, I 2 = 29%] and 50 mg dose [RR = 1.10 (0.67, 1.83), p = 0.70, I 2 = 9%] also did not show any significantly enhanced risk as compared to placebo.The sleep efficacy parameters like wake after sleep onset, latency to persistent sleep, and subjective total sleep time showed significant improvement in sleep quality and duration with daridorexant.
Existing clinical trials have proven its safety and efficacy for chronic insomnia in adults and few studies have analyzed its effectiveness in elderly patients also.As elderly people are the vulnerable group for developing chronic insomnia, further studies directed toward them would be beneficial for establishing a management guideline for all patients.Physiological changes with age affect the pharmacokinetics and pharmacodynamics of the drug in the elderly, which require special attention.They also suffer from multiple comorbid disorders, simultaneously leading to the use of polypharmacy and risk of adverse events and drug interactions [45].This meta-analysis has opened the path for developing research about the use of daridorexant in the elderly, as it is observed to be comparatively safe and efficacious as compared to existing options.Scientists have studied and evaluated different indices of obstructive sleep apnea (OSA) severity and sleep and found that for patients with mild-to-moderate OSA, the 50 mg dose of daridorexant was proven to be safe [46].Evidence also shows that daridorexant does not have any relevant correlation with cardiac repolarization [32].Furthermore, daridorexant's effect on driving in simulation models revealed that it was a little bit safer than other hypnotic medicines, yet the prescribing information does mention that patients might experience impaired daytime wakefulness and driving on the following day and other tasks demanding full mental alertness should be avoided [34].Therefore, it appears that daridorexant can be used as a hypnotic substitute to enhance the lives of patients who suffer from insomnia [47].
For the past few years, the research is directed toward finding an efficacious and safe drug for the management of chronic insomnia in adults and the elderly.This meta-analysis is one step further in that direction.
The drug is currently under trial for a few vulnerable population-like patients with obstructive sleep apnea, chronic obstructive pulmonary disease, hepatic and renal impairment, and so on.Based on the comparable safety profile and efficacious nature of the molecule as evident from the existent evidence, daridorexant can be recommended as an effective option for sleep induction and maintenance in the therapy of insomnia.However, we need long-term follow-up and larger trials in the future for further exploration of long-term safety.

Figure 1 .
Figure 1.Risk of bias assessment in RCTs evaluating daridorexant in therapy of insomnia.

Figure 2 .
Figure 2. Treatment emergent adverse events with daridorexant compared to placebo.

Figure 3 .
Figure 3. Serious adverse events with daridorexant compared to placebo.

Figure 4 .
Figure 4. Efficacy of daridorexant in reducing wake after sleep onset as compared to placebo.

Figure 5 .
Figure 5. Efficacy of daridorexant in reducing latency to persistent sleep as compared to placebo.

Table 1 .
Study characteristics summary of the included studies.

Table 2 .
Summary of findings table and Grade analysis of safety and efficacy parameters for use of daridorexant in patients with insomnia.Safety and Efficacy compared to placebo for Insomnia Intervention: Daridorexant Patient or population: Insomnia Comparison: placebo Wake After Sleep Onset; LPS: Latency to Persistent Sleep; sTST: Subjective Total Sleep Time; MD: mean difference; RCTs: randomized clinical trial.