Clinical Context

Benzodiazepines are frequently used to treat insomnia, yet they are known to cause multiple significant adverse events and also have the potential for addiction. Therefore, many prescribers prefer the "Z drugs" in treating insomnia. These drugs include zaleplon, zolpidem, zopiclone, and eszoplicone. But are the Z drugs really safe? A systematic review of 14 studies by Treves and colleagues, published in the March 2018 issue of Age and Ageing, assessed this issue.^[1]

The Z drugs were associated with an odds ratio (OR) of 1.63 (95% confidence interval [CI], 1.42-1.87) for fracture, but the OR for the risk of falling missed statistical significance. There was significant heterogeneity between studies for both of these outcomes. In contrast, there was little heterogeneity in research that demonstrated that zolpidem specifically was associated with a 2-fold increase in the risk for injury. Other analyses limited to specific drugs or to studies that included only patients with insomnia failed to change the main study findings.

The current study compares Z drugs, benzodiazepines, and all other major hypnotic agents in terms of their efficacy and safety.

Study Synopsis and Perspective

Two drugs have emerged as the optimal medications for treating insomnia based on the "best-available evidence," but there are caveats.

In a comprehensive comparative-effectiveness analysis, lemborexant and eszopiclone showed the best efficacy, acceptability, and tolerability for acute and long-term insomnia treatment.

However, eszopiclone may cause adverse effects, and safety data on lemborexant were inconclusive, the researchers note.

Not surprisingly, short-acting, intermediate-acting, and long-acting benzodiazepines were effective in the acute treatment of insomnia, but they have unfavorable tolerability and safety profiles, and there are no long-term data on these issues.

For many insomnia medications, there is a "striking" and "appalling" lack of long-term data, study investigator Andrea Cipriani, MD, PhD, professor of psychiatry, University of Oxford, Oxford, United Kingdom, noted during a press briefing.

"This is a call for regulators to raise the bar and ask for long-term data when companies submit an application for licensing insomnia drugs," Dr Cipriani said.

The findings were published online July 16 in the Lancet.^[2]

Insomnia is highly prevalent, affecting up to 1 in 5 adults, and can have a profound effect on health, well-being, and productivity.

Sleep hygiene and cognitive-behavioral therapy for insomnia (CBT-I) are recommended first-line treatments, but they are often unavailable, which often leads patients and clinicians to turn to medications.

However, "insomnia drugs are not all created equal. Even within the same drug class there are differences," Dr Cipriani said.

In a large-scale systematic review and network meta-analysis, the researchers analyzed data from 154 double-blind, randomized controlled trials of medications (licensed or not) used for acute and long-term treatment of insomnia in 44,089 adults (mean age, 51.7 years; 63% women).

Results showed that for the acute treatment of insomnia, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more effective than placebo (standardized mean difference [SMD] range, 0.36-0.83; high to moderate certainty of evidence).

In addition, benzodiazepines, eszopiclone, zolpidem, and zopiclone were more effective than melatonin, ramelteon, and zaleplon (SMD, 0.27-0.71; moderate to very low certainty of evidence).

"Our results show that the melatonergic drugs melatonin and ramelteon are not really effective. The data do not support the regular use of these drugs," coinvestigator Phil Cowen, PhD, professor of psychopharmacology, University of Oxford, said at the briefing.

What little long-term data are available suggest that eszopiclone and lemborexant are more effective than placebo. Plus, eszopiclone is more effective than ramelteon and zolpidem, but with "very low" certainty of evidence, the researchers report.

"There was insufficient evidence to support the prescription of benzodiazepines and zolpidem in long-term treatment," they write.

Another problem was lack of data on other important outcomes, they add.

"We wanted to look at hangover effects, daytime sleepiness, rebound effect, but often there was no data reported in trials. We need to collect data about these outcomes because they matter to clinicians and patients," Dr Cipriani said.

Summing up, the researchers note the current findings represent the "best available evidence base to guide the choice about pharmacological treatment for insomnia disorder in adults and will assist in shared decision making between patients, carers, and their clinicians, as well as policy makers."

They caution, however, that all statements comparing the merits of one drug with another "should be tempered by the potential limitations of the current analysis, the quality of the available evidence, the characteristics of the patient populations, and the uncertainties that might result from choice of dose or treatment setting."

In addition, it is important to also consider nonpharmacologic treatments for insomnia disorder, as they are supported by "high-quality evidence and recommended as first-line treatment by guidelines," the investigator write.

In an accompanying editorial, Myrto Samara, MD, University of Thessaly, Larissa, Greece, agrees with the researchers that discussion with patients is key.^[3]

"For insomnia treatment, patient–physician shared decision-making is crucial to decide when a pharmacological intervention is deemed necessary and which drug [is] to be given by considering the trade-offs for efficacy and side effects," Dr Samara writes.

The study was funded by the UK National Institute for Health Research Oxford Health Biomedical Research Center. Dr Cipriani has received research and consultancy fees from the Italian Network for Pediatric Trials, CARIPLO Foundation, and Angelini Pharma, and is the chief and principal investigator of 2 trials of seltorexant in depression that are sponsored by Janssen. Dr Samara has reported no relevant financial relationships.

Lancet. Published online July 16, 2022.

Clinical Implications

• A previous review found that Z drugs were associated with a higher risk for fracture, but the OR for falls associated with Z drugs missed statistical significance. These conclusions were also noted for individual drugs and in analyses limited to patients with insomnia.
• On the basis of limited data in the current network meta-analysis, lemborexant and eszopiclone were judged to have the best combination of efficacy and tolerability in the treatment of insomnia.
• Implications for the healthcare team: Members of the healthcare team should emphasize nonpharmacologic strategies as first-line treatment for insomnia. When medications are warranted for insomnia, team members should employ a shared decision-making and educate patients about the safety and efficacy of available treatments.

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