A systematic review and network meta-analysis offered the greatest possible evidence foundation to inform decisions about pharmaceutical treatment for people with insomnia disorder to aid patients, caregivers, clinicians, and policymakers in making decisions together. Researchers sought to determine the relative efficacy of therapies for both short-term and long-term management of adult insomnia condition.

To find published and unpublished randomised controlled trials, databases like WHO International Clinical Trials Registry Platform, Cochrane Central Register of Controlled Trials, Embase, MEDLINE, PubMed, PsycINFO, ClinicalTrials.gov, and websites of regulatory agencies were comprehensively explored. Studies evaluating the effectiveness of pharmacological therapies with placebo as monotherapy to treat adults (≥18 years) with insomnia disorders were considered. Utilizing the confidence in network meta-analysis (CINeMA) framework, the evidence's degree of certainty was determined.

The main outcomes were safety (i.e., the number of patients experiencing at least one adverse event), efficacy (i.e., sleep quality assessed using any self-rated scale), and therapy cessation for any reason and due to side effects particularly. With the help of pairwise and network meta-analysis with random effects, odds ratios (ORs) and summary standardised mean differences (SMDs) were measured.

Overall, 170 trials (36 interventions, 47950 volunteers) were encompassed. Overall, 154 double-blind, randomized controlled trials (30 interventions, 44089 volunteers) met the criteria for inclusion in the network meta-analysis. Zopiclone, Benzodiazepines, Seltorexant, Doxylamine, Lemborexant, Eszopiclone, and Zolpidem were all more effective than placebo for acute therapy (SMD range: 0.36-0.83). Melatonin, Ramelteon, and Zaleplon were less effective than Benzodiazepines, Eszopiclone, Zolpidem, and Zopiclone (SMD 0.27-0.71).

Eszopiclone, intermediate-acting Benzodiazepines, and long-acting Benzodiazepines exhibited fewer discontinuations due to any cause when compared to ramelteon. Zopiclone and Zolpidem raised the number of withdrawals due to adverse events compared to placebo (zopiclone: OR 2.00; Zolpidem: 1.79). Additionally, Zopiclone increased the number of withdrawals compared to Eszopiclone (OR 1.82), Daridorexant (OR 3.45), and Suvorexant (OR 3·13). Regarding the number of people experiencing noxious effects at study's endpoint, Zopiclone, Eszopiclone, Zolpidem, and Benzodiazepines were noted to be worse in comparison with placebo, Doxepin, Seltorexant, and Zaleplon (OR range: 1.27-2.78).

Lemborexant and Eszopiclone were more efficacious than placebo for long-term treatment (Lemborexant: SMD 0.41; Eszopiclone: SMD 0.63;). Eszopiclone was also highly efficacious than Ramelteon  (SMD 0.63) and Zolpidem (SMD 0·60). Eszopiclone and Zolpidem both exhibited lower all-cause discontinuation rates when compared to ramelteon (Eszopiclone: OR 0.43; Zolpidem: OR 0. 43), although Zolpidem was more likely to produce adverse effects when compared to placebo (OR 2.00). Eszopiclone and Lemborexant both displayed positive profiles. However, eszopiclone may have serious adverse effects.

The safety data of Lemborexant was not clear. Although Doxepin, Seltorexant, and Zaleplon were well-tolerated, there was dearth of sufficient data to draw solid judgments about their effectiveness and other significant outcomes. Numerous approved medications, such as Trazodone, Suvorexant, Benzodiazepines, and Daridorexant could be successful for the treatment of insomnia in the short term. However, they have poor tolerability or lack knowledge on their long-term effects. None of the non-licensed medications, Ramelteon, or Melatonin displayed overall meaningful advantages. These findings ought to support therapeutic care that is based on evidence.