According to a study published in "Sleep Medicine Reviews", orexin receptor antagonists (ORAs) are more effective than benzodiazepine-like drugs for wakefulness after sleep onset (WASO) and sleep efficiency (SE), and superior to melatonin receptor agonists (MRAs) in terms of sleep latency (SL), SE, and WASO in adults with insomnia. Researchers compared and ranked several insomnia treatments based on their tolerability and effectiveness.

Adults with primary insomnia were included in a network meta-analysis and systematic review of placebo-controlled or head-to-head randomized controlled trials that evaluated 20 medications. Seven trial registers and eight databases were explored. The discontinuation for adverse events, WASO, and SL were the major endpoints ascertained, whereas, adverse drug events (ADE), sleep quality (SQ), SE, and total sleep time (TST) were the secondary outcomes ascertained.

Pairwise and network meta-analysis with random effects were used to obtain pooled standardized mean differences or odds ratios along with 95% credible intervals. Sensitivity and subgroup analysis were used to investigate differences between trial results. GRADE was used to rate the confidence in evidence. Overall, 22,538 records were identified and 69 studies (17,319 patients) were included.

For WASO and SE, ORAs are more efficient than placebo and benzodiazepine-like medications (Z-drugs).  For SL, WASO, and SE, ORAs are superior to MRAs. In terms of SL (Surface Under the Cumulative Ranking [SUCRA] value: 0.84), SE (0.96), WASO (0.93), and TST (0.86), ORAs ranked the best. For TST, WASO, and SL, ORAs like Lemborexant and Daridorexant outperformed the placebo with better effectiveness and tolerability. Z-drugs had a higher risk to safety but were more effective than placebo in terms of SE, TST, WASO, and SL.

For TST and SQ, Zaleplon and Eszopiclone respectively were more effective than placebo. MRAs may be efficient and safe for sleep-onset insomnia. But, the long-term side effects of all drugs are not clear. Hence, drugs for insomnia vary in their tolerability and effectiveness.