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Many commonly used insomnia drugs poorly tolerated and have adverse results – Oxford meta-analysis

Insomnia is a highly prevalent disorder, with a chronic course and heavy burden for patients and the healthcare system.

Although both non-pharmacological and pharmacological interventions are available, medications are often prescribed due to greater accessibility, despite being associated with substantial adverse events (i.e., falls, especially in older adults), reports MedPage Today.

Pharmacological treatments have been mostly investigated in placebo-controlled trials so little information is available about their comparative effectiveness.

In the scientific literature, Dr Andrea Cipriani of the University of Oxford in England, and colleagues, found five network meta-analyses, but these focused only on very specific populations (e.g., older adults or people with diagnosed autoimmune disease) or had important methodological limitations (e.g., including only placebo-controlled studies or a small subset of pharmacological treatments).

To fill this gap, they did a systematic review and network meta-analysis including licensed and non-licensed medications for the acute and long-term treatment of insomnia disorder.

They found that while pharmacologic interventions are common for insomnia disorder, many are poorly tolerated and can lead to significant adverse events.

Among 154 double-blind, randomised controlled trials with more than 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 (standardised mean difference [SMD] range 0.36-0.83; confidence in network meta-analysis estimates of certainty high to moderate).

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, they 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, non-pharmacologic treatments, such as cognitive behavioural therapy, should still be prioritised 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. “However, it shows that some of these drugs can also be effective, and should be used in clinical practice, when appropriate.

“The findings represent the best evidence base currently available to guide the choice of pharmacological treatment for insomnia in adults,” she added. “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.

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

They 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.

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.

Study details

Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis

Franco De Crescenzo, Gian Loreto D'Alò, Edoardo G Ostinelli, Marco Ciabattini, Valeria Di Franco, Norio Watanabe, et al

Published in The Lancet on 16 July 2022

Summary

Background
Behavioural, cognitive, and pharmacological interventions can all be effective for insomnia. However, because of inadequate resources, medications are more frequently used worldwide. We aimed to estimate the comparative effectiveness of pharmacological treatments for the acute and long-term treatment of adults with insomnia disorder.

Methods
In this systematic review and network meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, PsycINFO, WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and websites of regulatory agencies from database inception to Nov 25, 2021, to identify published and unpublished randomised controlled trials. We included studies comparing pharmacological treatments or placebo as monotherapy for the treatment of adults (≥18 year) with insomnia disorder. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. Primary outcomes were efficacy (ie, quality of sleep measured by any self-rated scale), treatment discontinuation for any reason and due to side-effects specifically, and safety (ie, number of patients with at least one adverse event) both for acute and long-term treatment. We estimated summary standardised mean differences (SMDs) and odds ratios (ORs) using pairwise and network meta-analysis with random effects.

Findings
We included 170 trials (36 interventions and 47 950 participants) in the systematic review and 154 double-blind, randomised controlled trials (30 interventions and 44 089 participants) were eligible for the network meta-analysis. In terms of acute treatment, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more efficacious than placebo (SMD range: 0·36–0·83 [CINeMA estimates of certainty: high to moderate]). Benzodiazepines, eszopiclone, zolpidem, and zopiclone were more efficacious than melatonin, ramelteon, and zaleplon (SMD 0·27–0·71 [moderate to very low]). Intermediate-acting benzodiazepines, long-acting benzodiazepines, and eszopiclone had fewer discontinuations due to any cause than ramelteon (OR 0·72 [95% CI 0·52–0·99; moderate], 0·70 [0·51–0·95; moderate] and 0·71 [0·52–0·98; moderate], respectively). Zopiclone and zolpidem caused more dropouts due to adverse events than did placebo (zopiclone: OR 2·00 [95% CI 1·28–3·13; very low]; zolpidem: 1·79 [1·25–2·50; moderate]); and zopiclone caused more dropouts than did eszopiclone (OR 1·82 [95% CI 1·01–3·33; low]), daridorexant (3·45 [1·41–8·33; low), and suvorexant (3·13 [1·47–6·67; low]). For the number of individuals with side-effects at study endpoint, benzodiazepines, eszopiclone, zolpidem, and zopiclone were worse than placebo, doxepin, seltorexant, and zaleplon (OR range 1·27–2·78 [high to very low]). For long-term treatment, eszopiclone and lemborexant were more effective than placebo (eszopiclone: SMD 0·63 [95% CI 0·36–0·90; very low]; lemborexant: 0·41 [0·04–0·78; very low]) and eszopiclone was more effective than ramelteon (0.63 [0·16–1·10; very low]) and zolpidem (0·60 [0·00–1·20; very low]). Compared with ramelteon, eszopiclone and zolpidem had a lower rate of all-cause discontinuations (eszopiclone: OR 0·43 [95% CI 0·20–0·93; very low]; zolpidem: 0·43 [0·19–0·95; very low]); however, zolpidem was associated with a higher number of dropouts due to side-effects than placebo (OR 2·00 [95% CI 1·11–3·70; very low]).

Interpretation
Overall, eszopiclone and lemborexant had a favourable profile, but eszopiclone might cause substantial adverse events and safety data on lemborexant were inconclusive. Doxepin, seltorexant, and zaleplon were well tolerated, but data on efficacy and other important outcomes were scarce and do not allow firm conclusions. Many licensed drugs (including benzodiazepines, daridorexant, suvorexant, and trazodone) can be effective in the acute treatment of insomnia but are associated with poor tolerability, or information about long-term effects is not available. Melatonin, ramelteon, and non-licensed drugs did not show overall material benefits. These results should serve evidence-based clinical practice.

 

MedPage Today article – Pharmacologic interventions for insomnia effective but flawed (Open access)

 

The Lancet article – Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis (Open access)

 

See more from MedicalBrief archives:

 

Sleep meds make no difference to insomnia over the long term

 

New US clinical practice guidelines on treatment of chronic insomnia disorder

 

SA psychiatrist’s insomnia therapy hailed in the UK

 

Less sleep may harm bone health in women

 

 

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