In adults with insomnia, Lemborexant and Eszopiclone had the best profile in terms of tolerability, effectiveness, and acceptability when considering all the outcomes at distinct timepoints (acute and long-term treatment). 

This study was carried out to compare the efficacy of pharmacological therapies for acute and long-term management of insomnia disorder-affected adults (≥18 years).

To find out published and unpublished randomized controlled trials, databases like ClinicalTrials.gov,  websites of regulatory agencies, WHO International Clinical Trials Registry Platform, PsycINFO, Cochrane Central Register of Controlled Trials, Embase, MEDLINE, and PubMed were explored. In this systematic review and network meta-analysis, studies determining the effectiveness of pharmacological therapies vs placebo as monotherapy for insomnia management were considered.

With the help of confidence in network meta-analysis (CINeMA) framework, the evidence's degree of certainty was estimated. For both acute and long-term treatment, the key endpoints were safety (i.e., the number of people experiencing at least 1 adverse event), effectiveness (i.e., sleep quality estimated using any self-rated scale), and therapy cessation for any reason and owing to side effects particularly.

With the aid of pairwise and network meta-analysis with random effects, measurement of odds ratios and summary standardized mean differences (SMDs) was done.

In the systematic review, 170 trials (36 interventions, 47 950 subjects) were included. Notably, 154 double-blind, randomized controlled trials (30 interventions, 44 089 subjects) met the criteria for inclusion in the network meta-analysis. Zopiclone, zolpidem, seltorexant, lemborexant, eszopiclone,  benzodiazepines, and doxylamine were all more effective than placebo for acute therapy (SMD range: 0.36-0.83 [CINeMA estimates of certainty: high to moderate]). Melatonin, ramelteon, and zaleplon were less effective than benzodiazepines, eszopiclone, zolpidem, and zopiclone (SMD 0.27-0.71 [moderate to extremely low]).

When compared to ramelteon, Intermediate-acting benzodiazepines, long-acting benzodiazepines, and eszopiclone exhibited fewer discontinuations owing to any cause (OR 0·72, 0·70, and 0·71 respectively). Zopiclone and Zolpidem increased the number of withdrawals owing to adverse events compared to placebo (Zopiclone: OR 2.00 [very low]; zolpidem: 1.79 [moderate]). Additionally, Zopiclone increased the number of withdrawals compared to eszopiclone (OR 1.82 [low]), daridorexant

 (OR 3·45 [low]), and suvorexant (OR 3·13 [low]).

Eszopiclone, benzodiazepines, and zolpidem were worse compared to seltorexant, placebo, doxepin, and zaleplon for the number of people experiencing noxious effects at study's endpoint (OR range: 1.27-2.78 [high to extremely low]). Eszopiclone and lemborexant were both superior to placebo for long-term treatment (eszopiclone: SMD 0.63 [very low]; lemborexant: 0.41 [extremely low]). Eszopiclone performed better than zolpidem (0.60 [very low]) and ramelteon (0.63 [extremely low]).

Eszopiclone and zolpidem both showed lower rates of all-cause discontinuations than ramelteon (eszopiclone: OR 0.43 [very low]; zolpidem: 0.43 [very low]). However, Zolpidem was more frequently linked with adverse effect dropouts than placebo (OR 2.00 [very low]). For insomnia management, eszopiclone and lemborexant illustrated a good profile. Eszopiclone may cause significant side effects. For lemborexant, there were inconclusive safety data. Zaleplon, Seltorexant, and Doxepin showed good tolerability.

However, data on effectiveness and other vital outcomes were scarce and did not permit strong conclusions. Numerous approved medications, such as benzodiazepines, trazodone, suvorexant, and daridorexant can be successful to relieve insomnia in the short term but have poor tolerability. There is unavailability of data on their long-term effects. Ramelteon, Melatonin, and non-licensed drugs did not illustrate overall material advantages.

In adults with insomnia, Eszopiclone and Lemborexant have a favorable profile. Doxepin, seltorexant, and zaleplon are well-tolerated. Melatonin, ramelteon, and non-licensed drugs do not display overall material benefits.