Eszopiclone (Lunesta): Independent Evidence on Insomnia, Side Effects & Risks

Table of contents

• Evidence summary
• What eszopiclone is
• How it works
• What it is prescribed for
• What works and what does not
• Benefits by claim
• Risks and all side effects
• All interactions
• Who should avoid eszopiclone
• Dosage and how to take it
• Follow the money: who makes it and who funded the evidence
• Related research
• Frequently asked questions
• Sources and funding notes

Evidence summary

The table ranks the main claims about eszopiclone by the strength of the human evidence. The cleanest sources are listed first where they exist.

Independent evidence and credibility scorecard

Independence tier: 1 means no money from the product's sellers; 4 means paid for by the seller. Credibility runs from A (highest) to D.

What eszopiclone is

Eszopiclone is a sedative-hypnotic (sleeping pill) in the group usually called "Z-drugs", alongside zolpidem, zopiclone and zaleplon (FDA). Chemically it is one of the two mirror-image forms of the older drug zopiclone, which has been used for insomnia in the EU since the mid-1980s (EMA). Its structure is unrelated to the benzodiazepines, but the US label says it "shares some of the pharmacologic properties of the benzodiazepines" (Lunesta label).

• Brand names: Lunesta (US) and Lunivia (UK). Many US generics exist: openFDA lists 10 approved generic (ANDA) applications (openFDA).
• US approval: 15 December 2004 under NDA 021476 (openFDA Drugs@FDA). It went on sale in the US in April 2005 (Sepracor 10-K 2008).
• Originator: Sepracor Inc., Marlborough, Massachusetts, USA. Sepracor licensed eszopiclone in 1999 from Rhône-Poulenc Rorer, the predecessor of Aventis, now Sanofi (Sepracor 10-K).
• Current US label holder: Waylis Therapeutics LLC. The label reads "Manufactured for: Waylis Therapeutics LLC Wixom, MI" (DailyMed).
• US status: prescription only, Schedule IV controlled substance.
• UK status: eszopiclone is licensed in the UK. Lunivia 1, 2 and 3 mg tablets are prescription-only medicines (POM), held by axunio Pharma GmbH (Hamburg, Germany) under licence PL 47848/0043, first authorised on 1 June 2023 (UK SmPC). This is recent. Most older UK sources describe eszopiclone as unavailable, and NICE's 2004 hypnotics appraisal does not cover it (NICE TA77).
• EU status: Sepracor applied for EU approval as "Lunivia", then withdrew the application on 13 May 2009. The EU's medicines committee (CHMP) had given a positive opinion but decided eszopiclone "could not be considered to be a new active substance", which would have denied it 10 years of market exclusivity (EMA). See Follow the money.

How it works

The FDA label is candid: "The mechanism of action of eszopiclone as a hypnotic is unclear." Its effect probably comes from acting on GABA-A receptor complexes "at binding domains located close to or allosterically coupled to benzodiazepine receptors" (Lunesta label). GABA is the brain's main calming chemical messenger, and drugs that boost it at these receptors cause sedation. The EMA summarises the mechanism the same way: eszopiclone "activates receptors in the brain called gamma-aminobutyric acid A (GABA-A) receptors, which are involved in bringing about sleep" (EMA).

How long the drug stays in the body explains much of the next-day risk (all figures from the US label):

• Speed of absorption. Eszopiclone reaches peak blood levels in about 1 hour.
• Half-life. Its elimination half-life (the time for blood levels to halve) is about 6 hours, rising to about 9 hours in people aged 65 and over, whose total exposure is 41% higher.
• Metabolism. The liver breaks it down mainly through the enzymes CYP3A4 and CYP2E1. That is why strong CYP3A4 blockers such as ketoconazole raise exposure about 2.2-fold.
• Food. A heavy, high-fat meal cuts peak levels by 21% and delays them by about an hour, which can blunt the effect on falling asleep.

With a 6–9 hour half-life, a meaningful amount of drug can remain in the blood at breakfast. This is what the FDA's 2014 driving data showed (FDA 2014).

What it is prescribed for

Licensed uses.

• US: "treatment of insomnia". The supporting trials lasted up to 6 months and showed shorter time to sleep and better sleep maintenance (US label).
• UK: "treatment of insomnia, in adults, usually for short-term duration". The UK licence adds that benzodiazepine-like drugs "are only indicated when the disorder is severe, disabling or subjecting the individual to extreme distress" (UK SmPC).
• Not approved for children. A 12-week trial in 483 children and teenagers with ADHD-related insomnia found no significant improvement in how long it took to fall asleep. Suicidal ideation was reported in 0.3% on eszopiclone compared with 0% on placebo (US label).

Where guidelines place it.

What works and what does not

Benefits by claim

Short-term sleep improvement: the independent numbers

The most useful independent summary is the Cochrane review by Rösner and colleagues (2018). It pooled 14 randomised controlled trials (RCTs) with 4,732 participants. Compared with placebo, eszopiclone gave:

• sleep onset latency (time to fall asleep): −11.94 minutes (95% CI −16.03 to −7.86; 9 studies, 2,890 participants);
• wake time after sleep onset: −17.02 minutes (95% CI −24.89 to −9.15; 8 studies, 2,295 participants);
• total sleep time: +27.70 minutes (95% CI 20.30 to 35.09; 10 studies, 2,965 participants).

Evidence was rated moderate quality for these outcomes. The authors concluded that eszopiclone "appears to be an efficient drug with moderate effects on sleep onset and maintenance". They also noted that some patient groups were underrepresented in the trials, which means the trials "might not have displayed the entire spectrum of possible adverse events".

The AASM 2017 guideline ran its own meta-analysis and set thresholds for "clinical significance". Its summary table reports:

• sleep latency 14 minutes shorter than placebo (95% CI 3 to 24);
• total sleep time 28–57 minutes longer, depending on dose;
• WASO 10–14 minutes shorter;
• a "moderate-to-large" improvement in sleep quality.

Several results fell just under the task force's own thresholds, for example subjective total sleep time of 27.53 minutes at 2 mg against a 30-minute threshold. Overall quality was rated "very low" because of inconsistency between trials, imprecision and "potential publication bias" (the risk that unfavourable trials went unpublished).

How eszopiclone compares with other sleeping pills

The publicly funded Lancet network meta-analysis (De Crescenzo et al., 2022) compared 30 treatments across 154 double-blind trials (44,089 participants). For acute treatment:

• benzodiazepines, eszopiclone, zolpidem and zopiclone "were more efficacious than melatonin, ramelteon, and zaleplon";
• eszopiclone had fewer all-cause discontinuations than ramelteon (OR 0.71);
• zopiclone caused more dropouts due to side effects than eszopiclone (OR 1.82).

For long-term treatment, eszopiclone (SMD 0.63) and lemborexant (SMD 0.41) were the only drugs that beat placebo, both at "very low" certainty. The overall verdict was that "eszopiclone and lemborexant had a favorable profile, but eszopiclone might cause substantial adverse events."

Clinical significance and the placebo problem

Two independent analyses urge caution about how big these effects really are:

• Huedo-Medina et al., BMJ 2012. This unfunded study used data submitted to the FDA, including unpublished trials, for eszopiclone, zaleplon and zolpidem. Z-drugs shortened sleep-lab sleep latency by 22 minutes more than placebo (95% CI 11 to 33). The authors judged the drug and placebo effects "rather small and of questionable clinical importance" (Huedo-Medina et al., BMJ 2012).
• Winkler & Rief, Sleep 2015. This German meta-analysis of 32 trials estimated that "63.56% of the drug responses are achieved even in the placebo groups" (Winkler & Rief, Sleep 2015).

In practice, much of the improvement someone feels after starting eszopiclone would probably have happened with a dummy tablet, through expectation, regression to the mean and the passage of time. The drug adds a real but modest increment on top.

Long-term use: the company trials

The main evidence for use over months comes from Sepracor's 6-month trial and its extension:

• The trial. 593 adults took 3 mg and 195 took placebo, nightly for 6 months. Sleep latency, WASO, total sleep time and sleep quality were significantly better at every month (P ≤ 0.003), with "no evidence of tolerance" (Krystal et al., Sleep 2003).
• The extension. A 6-month open-label extension, in which everyone knew they were taking the drug, also reported no tolerance (Roth et al., 2005).
• Who ran it. The published disclosure states that three authors "are Sepracor employees" and that the others were Sepracor consultants, investigators or advisory-board members (Sleep 2003 disclosure).
• Dropouts. In the same 6-month trial, 12.8% on eszopiclone and 7.2% on placebo stopped because of an adverse reaction (US label).

Older adults

Two 2-week trials in people aged 65–86 supported approval:

• In one, 2 mg shortened sleep latency (P = .0034) and lengthened total sleep time. The 1 mg dose helped only with falling asleep (Scharf et al., Sleep 2005).
• A Chinese meta-analysis called eszopiclone "effective and safe... especially in elderly patients" (Liang et al., Sleep Med 2019).

These short trials were not designed to detect falls, fractures or confusion over months. That is why the geriatric Beers panel still says "Avoid" (Beers 2023).

Risks and all side effects

Boxed warning (verbatim summary)

The US label carries a boxed warning. Complex sleep behaviours, "including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur following use of LUNESTA. Some of these events may result in serious injuries, including death. Discontinue LUNESTA immediately if a patient experiences a complex sleep behavior" (US label).

The FDA added the warning in April 2019. It said these behaviours "appear to be more common" with eszopiclone, zaleplon and zolpidem "than other prescription medicines used for sleep" (FDA 2019). Its consumer update lists reports of people "accidentally overdosing, falling, being burned, shooting themselves, and wandering outside in extremely cold weather". It adds that these behaviours can happen after the first dose and "at lower dosages, not just high doses" (FDA consumer update).

Side effects table

Serious risks

Withdrawal, rebound and stopping

The US label reports no serious withdrawal syndrome in trials. After placebo was substituted, anxiety, abnormal dreams, nausea and upset stomach occurred "at an incidence of 2% or less". The label still warns that "use of benzodiazepines and similar agents may lead to physical and psychological dependence", and that the risk rises with dose, duration and a history of substance misuse (US label).

The newer UK SmPC is more cautious:

• it describes rebound insomnia (worse sleep for one to two nights after stopping);
• it says "the dose of eszopiclone should be decreased gradually";
• it asks prescribers to agree "a strategy for ending treatment" before starting (UK SmPC).

The Cochrane review found no significant rebound in the first three nights after stopping, but that finding rests on low-quality evidence from a single study (Cochrane).

All interactions

Always give your prescriber and pharmacist a full list of medicines, including over-the-counter sleep aids, antihistamines and herbal products.

Who should avoid eszopiclone

• Anyone who has had a complex sleep behaviour after eszopiclone. The UK SmPC extends this to zopiclone or "any other hypnotic agents" (US label, UK SmPC).
• Hypersensitivity to eszopiclone, or in the UK to zopiclone.
• UK contraindications: myasthenia gravis, severe respiratory insufficiency, severe sleep apnoea, severe hepatic insufficiency (it "may precipitate encephalopathy", a brain disturbance caused by liver failure), older adults taking potent CYP3A4 inhibitors, and anyone under 18 (UK SmPC).
• Adults aged 65 and over: the Beers Criteria advise avoiding it (strong recommendation). Where it is still prescribed, the dose must not exceed 2 mg (Beers 2023, US label). Beers also lists Z-drugs among drugs to avoid in people with delirium, dementia or a history of falls or fractures.
• Pregnancy:
  • The US label says human data are "insufficient to identify a drug-associated risk".
  • The UK SmPC says it "is not recommended during pregnancy". It warns of risks to the newborn if taken late in pregnancy, including withdrawal, floppiness (hypotonia), breathing depression and low body temperature (UK SmPC).
• Breastfeeding: the UK SmPC says it "should not be used during breast feeding". Zopiclone passes into breast milk.
• History of alcohol or drug misuse, or psychiatric illness: higher risk of abuse and dependence, so careful monitoring is needed (US label).
• Liver and kidney disease:
  • Severe liver impairment doubles exposure. The US maximum is 2 mg; in the UK the drug is contraindicated.
  • Kidney impairment needs no US dose change. In the UK, the maximum in severe kidney impairment is 2 mg.
• Breathing problems: use with caution in people with impaired respiratory function.
• People who cannot allow 7–8 hours of sleep before they need to be alert.

Dosage and how to take it

Your prescriber sets the dose. The ranges below are the official licensed ranges, given for information only. They are not personal dosing advice.

Sources: US Lunesta label; UK Lunivia SmPC; FDA 2014 dose change.

How it is taken.

• Once a night, immediately before bed, with at least 7–8 hours left before waking.
• Not with or right after a heavy, high-fat meal.
• Not taken again the same night (UK SmPC).

How quickly it works. Peak levels arrive about an hour after the dose, so the effect on falling asleep is usually felt the same night (US label).

How to stop. After more than a short course, stopping should be planned with the prescriber. The UK licence advises a gradual dose reduction to limit rebound insomnia and withdrawal, and recommends agreeing an exit plan before treatment starts (UK SmPC). CBT-I can make stopping easier: the European guideline recommends it as first-line treatment for everyone with chronic insomnia.

Follow the money: who makes it and who funded the evidence

Who developed and sold it

• Origin. Sepracor Inc. (Marlborough, Massachusetts) licensed eszopiclone in October 1999 from Rhône-Poulenc Rorer, the predecessor of Aventis, now Sanofi. Under that agreement Sepracor was "obligated to pay a 5% royalty on sales of LUNESTA in the United States" (Sepracor 10-K for 2008).
• Revenue. Lunesta sales were $565.4 million in 2006, $600.9 million in 2007 and $600.3 million in 2008, about 46–49% of the company's total revenue. Sepracor blamed the 2008 dip partly on generic zolpidem (Ambien) arriving in April 2007. Sepracor's selling, marketing and distribution costs across all its products were $699.3 million in 2007 and $654.1 million in 2008, which included advertising for Lunesta (Sepracor 10-K).
• Takeover. In 2009, Dainippon Sumitomo Pharma (Japan) bought Sepracor through a cash tender offer at $23.00 per share, completed in October 2009 (SEC Schedule 14D-9/A). Sumitomo Pharma (Osaka, Japan) now describes Lunesta as "developed by Sunovion", its US subsidiary, "and launched in the U.S. in 2005".
• Sale to Woodward. On 15 December 2022, Sunovion sold its Lunesta rights in all countries except Canada to Woodward Pharma Services LLC, a specialty company based in Wixom, Michigan that acquires and sells branded and generic drugs (Sumitomo Pharma release).
• Current label holder. The US label now names Waylis Therapeutics LLC, Wixom, Michigan (DailyMed). Waylis's website gives a Rahway, New Jersey headquarters (Waylis). We could not verify the corporate relationship between Woodward and Waylis from primary documents.
• Other markets.
  • In 2007, Sepracor licensed Japanese rights to Eisai.
  • Also in 2007, it signed a deal with a GlaxoSmithKline affiliate covering "all markets worldwide excluding the United States, Canada, Mexico and Japan". That deal was worth up to $155 million in licence and milestone payments plus royalties, with the product to be sold "primarily as LUNIVIA" (Sepracor 10-K).
  • The UK licence is now held by axunio Pharma GmbH, Hamburg, Germany (UK SmPC).
• Generics. Ten US generic applications are listed, from Sun, Teva, Mylan, Lupin, Dr Reddy's, Aurobindo and others (openFDA). The FDA estimated about 3 million US retail prescriptions for eszopiclone in 2013, covering 923,000 patients (FDA 2014).

The European episode

This is a documented regulatory event, not an allegation:

• The EU's medicines committee (CHMP) gave Lunivia a positive opinion, which meant "the application could have been approved".
• It also concluded that eszopiclone, as a purified half of the long-available zopiclone, "could not be considered to be a new active substance". So Lunivia would not get 10 years of market exclusivity, the period during which generics are blocked.
• Sepracor asked for a re-examination. The committee confirmed its view.
• Sepracor withdrew the application on 13 May 2009, before a final decision was issued (EMA).

The company's stated reasons are in a letter on the EMA site, which we did not review. The facts show that commercial exclusivity, not safety or efficacy, was the sticking point.

Who funded the evidence

• Pivotal and long-term trials: Sepracor. In the 6-month trial, three authors were Sepracor employees and the other four were Sepracor consultants or advisers (Krystal et al., 2003 disclosure). The AASM task force wrote that "all of these studies were industry sponsored" and downgraded the evidence for potential publication bias (AASM 2017).
• Fluoxetine add-on trial: its author list includes Wessel, Caron and Amato. Those three were named as Sepracor research staff in the 2003 trial. We did not retrieve this paper's own funding statement (Fava et al., 2006).
• AASM guideline: funded by the AASM. Co-author Andrew Krystal, first author of Sepracor's 6-month trial, declared research support from Sunovion and consultancy for Pernix, which later marketed low-dose doxepin, among others. The disclosure notes he stepped aside only from the suvorexant recommendation (AASM 2017). This is a disclosed allegiance, not proof of bias.
• Independent syntheses:
  • The Lancet NMA was publicly funded, with disclosed author ties to other companies.
  • The BMJ FDA-data analysis had no funding.
  • The Cochrane review includes one author (Hajak) who declared advisory-board and research-funding links with Sepracor and many other companies.
  These sources agree on the direction of benefit and give similar effect sizes.

Our reading. The sources converge on a small but real short-term benefit. The strongest safety warnings come from regulators and geriatric experts, not from the manufacturer's trials, which were too short and too selective to detect sleep-driving or hip fractures.

Related research

• Sleep: prevention and management guide: CBT-I, sleep scheduling and other non-drug first steps
• Sleep supplements: independent evidence
• Melatonin · Magnesium · L-theanine
• Stress, anxiety and depression prevention guide
• Sibling medicine reviews: Low-dose doxepin · Zolpidem · Zopiclone · Trazodone · Daridorexant

Frequently asked questions

Sources and funding notes

• Lunesta (eszopiclone) US prescribing information, DailyMed / openFDA. Manufacturer-written label, approved and regulated by the FDA (USA). Label holder: Waylis Therapeutics LLC.
• openFDA Drugs@FDA record, NDA 021476 and eszopiclone ANDA listing. US government data.
• Lunivia 2 mg SmPC, electronic medicines compendium. Licence-holder text approved by the MHRA (UK). Holder: axunio Pharma GmbH, Germany.
• FDA, New boxed warning for certain insomnia medicines (30 April 2019). US regulator. Drug review is partly funded by industry user fees.
• FDA consumer update, Taking Z-drugs for insomnia? Know the risks. US regulator.
• FDA Drug Safety Communication on Lunesta next-day impairment (15 May 2014), archived copy. US regulator.
• European Medicines Agency, Lunivia: withdrawn application. EU regulator, largely fee-funded.
• Rösner S et al. Eszopiclone for insomnia. Cochrane Database Syst Rev 2018. Academic (Switzerland/Germany). Hajak declared advisory and research-funding ties to Sepracor and many others; Soyka declared various industry honoraria; other authors none. We could not access the review's sources of support.
• Sateia MJ et al. AASM clinical practice guideline for the pharmacologic treatment of chronic insomnia. J Clin Sleep Med 2017 (PubMed). Funded by the AASM (USA). Krystal declared Sunovion research support and consultancy for Pernix, Merck, Jazz and others; Neubauer consulted for Purdue.
• De Crescenzo F et al. Pharmacological interventions for insomnia: network meta-analysis. Lancet 2022. Funded by the NIHR Oxford Health BRC (UK public). The first author was employed by Boehringer Ingelheim; the senior author leads Janssen-sponsored seltorexant trials; some authors had Angelini fees.
• Riemann D et al. The European Insomnia Guideline 2023. J Sleep Res. European Sleep Research Society (pan-European). We could not verify author conflicts from the abstract.
• Huedo-Medina TB et al. Z-drugs: meta-analysis of FDA data. BMJ 2012. USA/UK academics. No funding and no conflicts declared.
• Winkler A, Rief W. Placebo response in primary insomnia. Sleep 2015. Academic (University of Marburg, Germany). Funding not stated in the abstract.
• American Geriatrics Society 2023 Beers Criteria. "There was no sponsor for this paper" (USA). Individual panel disclosures are listed in the paper.
• Treves N et al. Z-drugs and falls/fractures in older adults. Age Ageing 2018. Academic (Hebrew University, Israel). Observational meta-analysis.
• Joya FL et al. Meta-analyses of hypnotics and infections. J Clin Sleep Med 2009. Academic (USA), based on FDA files. Funding not stated in the abstract.
• Krystal AD et al. Sustained efficacy of eszopiclone over 6 months. Sleep 2003 (disclosure). Manufacturer-linked: three Sepracor employees; the other authors were Sepracor consultants or advisers.
• Roth T et al. Eszopiclone over 12 months (open-label extension). Sleep Med 2005. Extension of the Sepracor trial; the author list overlaps with it.
• Scharf M et al. Eszopiclone in elderly patients, 2-week study. Sleep 2005. Pivotal registration trial; funding statement not retrieved.
• Fava M et al. Eszopiclone with fluoxetine in depression with insomnia. Biol Psychiatry 2006. The author list includes staff named as Sepracor employees in the 2003 trial; funding statement not retrieved.
• Liang L et al. Eszopiclone for primary insomnia: meta-analysis. Sleep Med 2019. Academic (Wuhan, China). Conflicts not stated in the abstract.
• NHS, Insomnia (reviewed 19 March 2024). UK public health service.
• NICE TA77, Zaleplon, zolpidem and zopiclone for insomnia (2004). UK public body.
• Sepracor Inc. Annual report (Form 10-K) for 2008. Company filing to the SEC (USA). Legally regulated financial figures.
• Sepracor Schedule 14D-9/A (October 2009), Dainippon Sumitomo tender offer. SEC filing.
• Sumitomo Pharma, Divestiture of Lunesta to Woodward Pharma Services (15 December 2022). Company press release (Japan).
• Waylis Therapeutics website. Company site (USA), used only for the headquarters address.

Last reviewed: 26 September 2026. Educational information from Pure City Research, not medical advice. Medicine decisions belong with a qualified prescriber.