Pharmacologic Interventions for Insomnia Effective but Flawed

While pharmacologic interventions are common for insomnia disorder, many are poorly tolerated and can lead to significant adverse events, according to a systematic review and network meta-analysis.

Among 154 double-blind, randomized controlled trials with over 44,000 participants included in the meta-analysis, benzodiazepines, doxylamine, eszopiclone, lemborexant (Dayvigo), seltorexant, zolpidem, and zopiclone were shown to be more efficacious than placebo (standardized mean difference [SMD] range 0.36-0.83; confidence in network meta-analysis estimates of certainty high to moderate), reported Andrea Cipriani, MD, PhD, of the University of Oxford in England, and colleagues.

Furthermore, the long-term use of eszopiclone was more effective than placebo (SMD 0.63, 95% CI 0.36-0.90; very low) and the same was true for lemborexant (SMD 0.41, 95% CI 0.04-0.78; very low), they noted in The Lancet.

However, the use of many of these drugs led to poor tolerability and substantial adverse events, such as dizziness, headache, fatigue, sedation, and nausea, Cipriani and team said.

The meta-analysis showed that intermediate- and long-acting benzodiazepines, as well as eszopiclone, were associated with significantly fewer discontinuations due to any cause versus ramelteon (ORs 0.72, 0.70, and 0.71, respectively), while zopiclone and zolpidem led to more dropouts due to adverse events compared with placebo (ORs 2.00 and 1.79). Zopiclone also led to more dropouts versus eszopiclone (OR 1.82), daridorexant (Quviviq; OR 3.45), and suvorexant (Belsomra; OR 3.13).

For the participants with side effects at the end of the study, benzodiazepines, eszopiclone, zolpidem, and zopiclone were worse than placebo, doxepin, seltorexant, and zaleplon (OR range 1.27-2.78). Moreover, compared with ramelteon, eszopiclone and zolpidem had a lower rate of all-cause discontinuations (OR 0.43 for both), though zolpidem was associated with a higher number of dropouts due to side effects versus placebo (OR 2.00).

Therefore, nonpharmacologic treatments, such as cognitive behavioral therapy, should still be prioritized when possible, they stressed, while acknowledging that lack of training or resources could limit these options for certain patients.

“Our study is not a recommendation that drugs should always be used as the first line of support to treat insomnia, not least because some of them can have serious side effects,” Cipriani told MedPage Today in an email. “However, our research shows that some of these drugs can also be effective, and should be used in clinical practice, when appropriate.”

“The findings from this network meta-analysis represent the best evidence base that is currently available to guide the choice of pharmacological treatment for insomnia in adults,” he continued. “From a clinical point of view, it is important to also consider non-pharmacological treatments for insomnia disorder, as they are supported by high-quality evidence and recommended as first-line treatment by guidelines.”

In head­-to­-head comparisons, short­-acting benzodiazepines were more effective than daridorexant, lemborexant, and zaleplon (SMDs 0.47-0.64; high to moderate), while eszopiclone and zolpidem were more effective than zaleplon (SMD 0.33, 95% CI 0.08-0.58; moderate; and SMD 0.27, 95% CI 0.08-0.45; moderate) after 4 weeks of treatment.

In an accompanying commentary, Myrto Samara, MD, PhD, of the Technical University of Munich in Germany, noted that the finding that benzodiazepines were the most effective short-term treatment was not surprising, adding that the lack of long-term data was unfortunate, considering the potential for misuse and dependence.

Along with Cipriani and colleagues, she argued that more research is crucial to understanding the long-term efficacy and safety of these treatment options.

“Trials with a duration longer than 3 months that directly compare active drug treatments and non-pharmacological interventions are warranted to provide clear answers to clinicians and patients,” Samara wrote. “For insomnia treatment, patient-physician shared decision making is crucial to decide when a pharmacological intervention is deemed necessary and which drug to be given by considering the trade-offs for efficacy and side effects.”

The study authors noted that only eight studies included in the meta-analysis looked at the long-term efficacy and safety of these drugs. “Clinicians and patients should be aware that most of the pharmacological agents used long term for insomnia have only indications for acute treatment from regulatory agencies,” they wrote.

For this systematic review and network meta-analysis, Cipriani and team used the Cochrane Central Register of Controlled Trials, Medline, PubMed, Embase, PsycINFO, the WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and regulatory agency websites from inception to Nov. 25, 2021 to find published and unpublished randomized controlled trials comparing pharmacologic treatments or placebo for the treatment of adults with insomnia disorder.

Of 170 trials included in the review, 154 with 44,089 participants were used for the meta-analysis. Primary outcomes were efficacy, treatment discontinuation for any reason and due to side effects specifically, and safety for both acute and long-term treatment.