Eszopiclone
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Treatment of insomnia — demonstrated to decrease sleep latency and improve sleep maintenance | Adults and elderly | Monotherapy; the registration program included controlled trials of up to 6 months’ duration in adults | FDA Approved |
| Insomnia associated with comorbid conditions (depression, generalized anxiety disorder, perimenopause, post-traumatic stress disorder) | Adults | Adjunctive to disease-specific therapy | Off-Label |
| Restless legs syndrome — refractory cases | Adults | Adjunctive when first-line agents fail | Off-Label |
Eszopiclone is the active S-enantiomer of racemic zopiclone, approved by the FDA in December 2004 for the treatment of insomnia. Among the FDA-approved Z-drugs (zolpidem, zaleplon, eszopiclone), eszopiclone is unique in that its prescribing information does not restrict use to short-term treatment, and its registration program included a pivotal 6-month controlled trial in adults that demonstrated maintained efficacy without development of objective tolerance. Despite this regulatory distinction, current clinical practice guidelines (American Academy of Sleep Medicine 2017 and American College of Physicians 2016) position cognitive behavioural therapy for insomnia (CBT-I) as the first-line treatment for chronic insomnia disorder, with pharmacotherapy reserved for patients in whom CBT-I is unavailable, declined, or insufficient. The AASM 2017 guideline gives eszopiclone a weak recommendation for both sleep-onset and sleep-maintenance insomnia, the latter reflecting its longer half-life (~6 hours) compared with immediate-release zolpidem (~2.5 hours).
Insomnia comorbid with depression — co-administration with fluoxetine has been studied in a randomized trial (n=545); improved sleep without worsening of mood symptoms was observed. Evidence quality: low–moderate.
Insomnia associated with generalized anxiety disorder — co-administration with escitalopram in a randomized trial (n=595) showed improved sleep and earlier anxiolytic response. Evidence quality: low–moderate.
Refractory restless legs syndrome — sometimes used at bedtime for patients who fail dopamine agonists, alpha-2-delta ligands, or iron repletion. Evidence quality: low.
Perimenopausal insomnia, post-traumatic stress disorder sleep disturbance — commonly prescribed but evidence is limited to small studies. Evidence quality: low.
Eszopiclone is not indicated for, and should not be used to treat: alcohol or sedative withdrawal, paediatric insomnia, or chronic non-restorative sleep without an evaluation for comorbid sleep-disordered breathing. The 12-week paediatric ADHD-insomnia trial failed to demonstrate efficacy and showed elevated rates of psychiatric adverse events.
Dosing
Eszopiclone is dosed once nightly, immediately before bedtime, with at least 7–8 hours of intended sleep available. Use the lowest effective dose. Unlike zolpidem, eszopiclone dosing is not formally sex-stratified in the FDA label, but the principle of starting low and titrating to response applies universally. Dose reduction is required in elderly or debilitated patients, severe hepatic impairment, and concomitant strong CYP3A4 inhibitors.
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Insomnia — non-elderly adults | 1 mg PO at bedtime | 1–3 mg at bedtime | 3 mg/night | Increase to 2 or 3 mg only if clinically indicated; 2–3 mg increases next-day impairment risk Take with ≥7–8 h sleep available; avoid heavy/high-fat meals before dose |
| Insomnia — elderly or debilitated patients | 1 mg PO at bedtime | 1–2 mg at bedtime | 2 mg/night | Both 1 mg (sleep onset) and 2 mg (sleep maintenance) demonstrated efficacy in elderly trials Elderly have ~41% higher AUC and longer half-life (~9 h) |
| Severe hepatic impairment | 1 mg PO at bedtime | 1–2 mg at bedtime | 2 mg/night | Systemic exposure is approximately doubled in severe hepatic impairment No adjustment needed for mild-to-moderate impairment |
| Co-administration with strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir, nelfinavir, nefazodone) | 1 mg PO at bedtime | 1–2 mg at bedtime | 2 mg/night | Ketoconazole 400 mg daily for 5 days produced a 2.2-fold increase in eszopiclone AUC Consider an alternative sleep agent or alternative anti-infective if combination is short-term and avoidable |
| Co-administration with CNS depressants (opioids, benzodiazepines, alcohol) | Consider lower dose or avoid | Individualized | 2 mg/night | Additive CNS and respiratory depression; downward dose adjustment recommended Co-prescription with two sedative-hypnotics is not recommended |
Dose Adjustments in Special Populations
| Population | Recommendation | Rationale |
|---|---|---|
| Renal impairment (any severity) | No dose adjustment | <10% of eszopiclone is excreted unchanged in urine; AUC and Cmax were unchanged in patients with mild, moderate, or severe renal impairment |
| Mild-to-moderate hepatic impairment | No dose adjustment | Pharmacokinetics not significantly altered |
| Pediatric (<18 years) | Not recommended | The 12-week ADHD-insomnia trial (n=323 eszopiclone, n=160 placebo, ages 6–17) failed to decrease sleep latency vs placebo and showed elevated rates of dysgeusia (9% vs 1%), dizziness (6% vs 2%), hallucinations (2% vs 0%), and suicidal ideation (0.3% vs 0%) |
| Pregnancy | Use only if benefit outweighs risk | Animal reproduction studies showed offspring toxicity at exposures ~200× the maximum recommended human dose |
Discontinuation
Eszopiclone should be discontinued promptly if a patient experiences any episode of complex sleep behaviour (boxed warning), if therapeutic benefit is lost, if depression worsens, or after the shortest clinically appropriate course. The Lunesta label notes that the clinical trial program revealed no evidence of a serious withdrawal syndrome, but adverse events compatible with sedative-hypnotic withdrawal (anxiety, abnormal dreams, nausea, upset stomach) were reported following placebo substitution at incidences of 2% or less. For patients on chronic therapy, taper gradually rather than stop abruptly. Although the 6-month registration trial demonstrated no objective tolerance, dose escalation requests should prompt re-evaluation of the underlying insomnia.
Eszopiclone’s ~6-hour half-life (more than twice that of immediate-release zolpidem at ~2.5 hours) is the source of both its clinical advantage and its principal limitation. The advantage: better sleep maintenance, supporting approval for long-term use. The limitation: greater next-morning impairment at higher doses (2–3 mg), which underlies the explicit FDA caution against driving the day after a 3 mg dose. For a patient whose primary complaint is sleep onset (not maintenance), zolpidem’s shorter half-life may be preferable. For sleep maintenance with morning impairment as the dose-limiting concern, eszopiclone 1 mg is often the most defensible starting position.
Pharmacology
Mechanism of Action
Eszopiclone is the active S-enantiomer of racemic zopiclone, structurally a pyrrolopyrazine derivative of the cyclopyrrolone class. The Lunesta label states explicitly that the precise mechanism of action as a hypnotic is unclear; the drug’s hypnotic effect is thought to derive from interaction with GABAA-receptor complexes at binding domains located close to or allosterically coupled to benzodiazepine receptors. Compared with zolpidem, which is highly α1-selective, eszopiclone shows less subunit selectivity, binding to multiple GABAA subtypes; this broader binding profile may underlie its more sustained sleep-maintaining effect and its higher rates of metallic-bitter taste and morning psychomotor impairment at therapeutic doses. Eszopiclone’s primary plasma metabolites are (S)-zopiclone-N-oxide (no significant GABAA binding) and (S)-N-desmethyl zopiclone (substantially lower potency at GABAA than the parent drug). Drug effects are reversible by flumazenil.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Rapidly absorbed orally; Tmax ~1 hour. Pharmacokinetics are dose-proportional from 1–6 mg. Heavy/high-fat meal: no change in AUC, ~21% reduction in Cmax, Tmax delayed ~1 hour | Take on an empty stomach immediately before bed; high-fat meals delay sleep-onset effect |
| Distribution | Plasma protein binding 52–59% (low; weakly bound); blood-to-plasma ratio <1; presence in human breast milk not characterized | Low protein binding makes displacement-type drug interactions clinically unimportant; counsel breastfeeding mothers despite limited human data |
| Metabolism | Extensively hepatic via oxidation and demethylation. CYP3A4 (major) and CYP2E1 (minor) are responsible. Major metabolites — (S)-zopiclone-N-oxide and (S)-N-desmethyl zopiclone — have minimal or no GABAA activity. Eszopiclone does not inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, or 3A4 in human hepatocytes | Significant interactions with CYP3A4 inhibitors and inducers; eszopiclone itself is not a clinically important CYP perpetrator |
| Elimination | Primarily as inactive metabolites in urine (up to 75% of dose by extrapolation from racemic zopiclone); <10% excreted unchanged. Mean t½ ~6 h in adults; ~9 h in elderly; prolonged in severe hepatic impairment | Longer half-life than other Z-drugs supports sleep maintenance but increases morning impairment risk; renal impairment requires no dose change |
Side Effects
The frequency data below come from the Lunesta FDA prescribing information. Adult data derive from a 6-week placebo-controlled trial in non-elderly adults (n=104 at 2 mg, n=105 at 3 mg, n=99 placebo). Elderly data derive from pooled 2-week placebo-controlled trials (n=72 at 1 mg, n=215 at 2 mg, n=208 placebo, ages 65–86). The hallmark dose-related effect of eszopiclone is unpleasant (metallic/bitter) taste, which reaches 34% at the 3 mg dose — the highest single-event rate in the entire registration program.
| Adverse Effect | Incidence (eszopiclone vs placebo) | Clinical Note |
|---|---|---|
| Unpleasant taste (metallic/bitter dysgeusia) — non-elderly adults, 3 mg | 34% vs 3% | Defining adverse effect of eszopiclone; clearly dose-related (17% at 2 mg). Often reported on awakening; counsel before initiation |
| Headache — non-elderly adults, 2 mg | 21% vs 13% | Most frequent body-system effect. Rate at 3 mg: 17% |
| Headache — elderly, 1 mg / 2 mg | 15% / 13% vs 14% | Rate close to placebo in elderly population |
| Somnolence — non-elderly adults, 2 mg | 10% vs 3% | Rate at 3 mg: 8%; counsel about morning carry-over |
| Respiratory infection — non-elderly adults, 3 mg | 10% vs 3% | Dose-related; rate at 2 mg: 5% |
| Unpleasant taste — elderly, 2 mg | 12% vs 0% | Rate at 1 mg: 8% |
| Adverse Effect | Incidence (eszopiclone vs placebo) | Clinical Note |
|---|---|---|
| Dry mouth — non-elderly adults, 3 mg | 7% vs 3% | Dose-related; rate at 2 mg: 5% |
| Dry mouth — elderly, 2 mg | 7% vs 2% | Dose-related in elderly |
| Dizziness — non-elderly adults, 3 mg | 7% vs 4% | Dose-related; rate at 2 mg: 5% |
| Dizziness — elderly, 2 mg | 6% vs 2% | Counsel about night-time mobility and fall risk |
| Dyspepsia — non-elderly adults | 4–5% vs 4% | Generally mild |
| Dyspepsia — elderly, 1 mg | 6% vs 2% | Notably higher at 1 mg than 2 mg in elderly trials |
| Nausea — non-elderly adults, 2 mg | 5% vs 4% | Generally mild; rate at 3 mg: 4% |
| Nervousness — non-elderly adults, 2 mg | 5% vs 3% | Not dose-related; rate at 3 mg was 0% |
| Rash — non-elderly adults, 3 mg | 4% vs 1% | Dose-related; rate at 2 mg: 3% |
| Anxiety — non-elderly adults, 2 mg | 3% vs 0% | Rate at 3 mg: 1% |
| Depression — non-elderly adults, 2 mg | 4% vs 0% | Rate at 3 mg: 1%; caution in patients with pre-existing depression |
| Confusion — non-elderly adults, 3 mg | 3% vs 0% | Dose-related; absent at 2 mg |
| Hallucinations — non-elderly adults, 3 mg | 3% vs 0% | Dose-related; rate at 2 mg: 1% |
| Decreased libido — non-elderly adults, 3 mg | 3% vs 0% | Dose-related; absent at 2 mg |
| Vomiting — non-elderly adults, 2 mg | 3% vs 1% | Absent at 3 mg in trial |
| Viral infection — non-elderly adults | 3% vs 1% | Reported during 6-week trials |
| Pain — elderly, 2 mg | 5% vs 2% | Dose-related in elderly trials |
| Pruritus — elderly, 1 mg | 4% vs 1% | Counsel about new rash or itching |
| Diarrhoea — elderly, 1 mg | 4% vs 2% | Generally mild and self-limiting |
| Abnormal dreams — elderly, 1 mg | 3% vs 0% | Reported in elderly population |
| Accidental injury — elderly, 2 mg | 3% vs 1% | Counsel on night-time mobility; falls risk |
| Dysosmia (post-marketing) | Frequency not estimable | Distortion of the sense of smell; reported spontaneously after marketing — not in clinical trials |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Complex sleep behaviours (sleep-driving, sleep-eating, sleep-walking, sleep-phone calls, with amnesia for the event) — boxed warning | Rare; basis for FDA boxed warning across all Z-drugs in April 2019 | Can occur after a single dose, even at the lowest recommended dose | Permanent discontinuation; FDA contraindication to rechallenge with any Z-drug after one episode |
| Anaphylaxis / angioedema (tongue, glottis, larynx) | Rare | After first or any subsequent dose | Discontinue; do not rechallenge; emergency airway management if needed |
| Worsening depression / suicidal ideation / completed suicide | Postmarketing reports; in paediatric ADHD trial, suicidal ideation 0.3% vs 0% placebo | Variable | Prescribe smallest tablet quantity feasible; screen for depression; refer for psychiatric evaluation if symptoms emerge |
| Respiratory depression | Healthy-volunteer studies at 7 mg (2.5× max recommended dose) showed no respiratory depression; risk increases with respiratory disease, sleep apnea, opioid co-use | Within hours of dosing | Caution in compromised respiratory function; emergency support for severe cases; flumazenil reverses GABAA effect |
| Hallucinations and other behavioural changes (decreased inhibition, agitation, depersonalization, bizarre behaviour) | 3% in adults at 3 mg vs 0% placebo; 2% in paediatric ADHD trial vs 0% placebo | Hours after dose | Discontinue; immediate clinical evaluation |
| Falls and fractures (particularly in elderly) | Class effect; AGS Beers Criteria designate Z-drugs as potentially inappropriate in older adults | During night-time awakenings or next morning | Reduce dose; counsel on night-time mobility; consider deprescribing in frail elderly |
| Tolerance, abuse, and dependence | Schedule IV; no objective tolerance over 6 months at 3 mg in pivotal trial; abuse-liability study showed euphoria similar to diazepam at 6–12 mg | Weeks to months | Limit duration; avoid in active substance-use disorder; taper rather than stop abruptly |
| Withdrawal symptoms (anxiety, abnormal dreams, nausea, upset stomach; rarely seizures) | Reported within 48 h of placebo substitution at incidences ≤2%; serious withdrawal syndrome was not observed in registration trials | Within 48 h of cessation | Taper gradually after prolonged use; consider cross-taper to longer-acting agent in heavy or long-term users |
| CNS depression in overdose (somnolence to coma; rarely fatal alone but often combined with alcohol/opioids in fatalities) | Spontaneous overdoses up to 270 mg (90× max recommended dose) with full recovery reported; methemoglobinemia reported with racemic zopiclone overdose | Within 1–2 h of ingestion | Supportive care; flumazenil may be useful; gastric lavage if recent; airway support if severe; consider monitoring methemoglobin in high-dose overdose |
| Reason for Discontinuation | Approx. Incidence | Context |
|---|---|---|
| Unpleasant taste (clinical practice) | Common reason in real-world use | Although no single AE drove >2% discontinuation in trials, persistent dysgeusia is a frequent cause of patient-initiated discontinuation in practice |
| Daytime drowsiness / next-day impairment | Dose-related | The principal driver of dose reduction from 3 mg to 2 mg or 1 mg |
| Mood disturbance / depression / anxiety | ~1–4% in trials | Should prompt evaluation for underlying mood disorder |
| Complex sleep behaviour | Mandatory permanent discontinuation regardless of frequency | Per FDA boxed warning & contraindication added April 2019 |
Unpleasant taste is the highest-incidence adverse event of any kind in the eszopiclone registration program (34% at 3 mg, 17% at 2 mg), is the most clearly dose-related effect, and is a frequent driver of real-world non-adherence. It is typically reported on awakening and may persist for several hours. Strategies that improve tolerability without abandoning therapy: (1) use the lowest effective dose; (2) warn patients explicitly before initiation that the taste is expected, time-limited, and not a sign of toxicity; (3) recommend rinsing with water or chewing gum on awakening; (4) for persistent intolerance, switch to zolpidem rather than escalate the eszopiclone dose; (5) reassess the taste effect at 2–4 weeks — some patients accommodate.
Drug Interactions
Eszopiclone’s interactions are dominated by two mechanisms: pharmacodynamic synergy with other CNS depressants (the leading driver of complex sleep behaviours and overdose deaths) and pharmacokinetic modulation through CYP3A4 (the principal metabolic enzyme). Eszopiclone itself is not a clinically important inhibitor of human CYP enzymes and does not alter the disposition of digoxin or warfarin in single-dose studies. Low protein binding (~52–59%) makes displacement-type interactions clinically unimportant.
Monitoring
Eszopiclone requires no laboratory monitoring, but it requires structured clinical follow-up. The highest-yield surveillance addresses the boxed warning (complex sleep behaviours), next-day functional impairment, depression and suicidality, dependence, and emerging contributors to insomnia that may have been missed.
-
Sleep diary & insomnia metrics
Baseline; reassess at 2–4 weeks
Routine Track sleep latency, total sleep time, wake after sleep onset, and morning function. Validated tools: Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index (PSQI). -
Complex sleep behaviour screen
Each visit, with bed partner if available
Routine Ask explicitly about sleep-walking, sleep-driving, sleep-eating, sleep-phone use, and unexplained morning evidence of activity. A single episode mandates permanent discontinuation per FDA contraindication. -
Next-day function
Each visit during titration; periodically thereafter
Routine Ask about morning sedation, attention, and driving safety. Subjective alertness is unreliable. Eszopiclone label specifically cautions against driving the day after a 3 mg dose. -
Mood & suicidality
Each visit
Routine Insomnia is frequently a symptom of depression. Screen with PHQ-9 if not already in psychiatric care; intentional overdose is more common in depressed patients. -
Taste tolerance
2–4 weeks after initiation
Routine Unpleasant taste affects 17% of adults at 2 mg and 34% at 3 mg. Specifically ask; offer dose reduction or alternative agent if persistent and bothersome. -
Need for ongoing therapy
Re-evaluate at 7–10 days; then 1–3 monthly
Routine Per FDA labelling, persistent insomnia after 7–10 days warrants evaluation for psychiatric or medical causes. Reassess goals, taper consideration, CBT-I referral. -
Substance use / aberrant behaviours
Each visit; PDMP check at refill
Routine Schedule IV drug. Check state Prescription Drug Monitoring Program. Watch for early refill requests, lost prescriptions, dose escalation requests. -
Falls (elderly)
Each visit if ≥65 years
Trigger-based Z-drugs are designated potentially inappropriate by the AGS Beers Criteria. Document risk-benefit; consider deprescribing. -
Sleep-disordered breathing screen
Before initiation; if symptoms emerge
Trigger-based Snoring, witnessed apnea, daytime sleepiness, or BMI >30 warrant evaluation for OSA before chronic eszopiclone; sedative-hypnotics can worsen apnea. -
Hepatic function
If clinical concern; not routinely required
Trigger-based Severe hepatic impairment doubles eszopiclone exposure; reduce dose to maximum 2 mg.
Contraindications & Cautions
Absolute Contraindications
- Prior episode of complex sleep behaviour (sleep-driving, sleep-walking, sleep-eating, or other behaviours while not fully awake) attributed to eszopiclone, zolpidem, or zaleplon — FDA contraindication added April 2019 alongside the boxed warning.
- Known hypersensitivity to eszopiclone, including prior anaphylaxis or angioedema involving the tongue, glottis, or larynx.
Relative Contraindications — Specialist Input Recommended
- Active alcohol or substance-use disorder — high risk of misuse, overdose, and complex sleep behaviours.
- Severe hepatic impairment — clearance is reduced; dose limited to 2 mg per FDA label.
- Significant respiratory disease — severe COPD, untreated obstructive sleep apnea, neuromuscular disease (myasthenia gravis), or hypoventilation syndromes; risk of respiratory depression.
- Suicidal ideation or active major depressive disorder — intentional overdose risk; prescribe smallest quantity feasible and screen carefully.
- Concurrent opioid therapy — if combination is unavoidable, use lowest doses, provide naloxone, monitor closely.
- Pregnancy — available human data are insufficient to establish risk; animal reproduction studies show offspring toxicity at exposures ~200× the maximum recommended human dose. Use only if benefit outweighs risk.
- Older adults ≥65 years — AGS Beers Criteria designate eszopiclone as potentially inappropriate; falls and cognitive impairment are amplified. Limit dose to 2 mg.
Use with Caution
- Operating motor vehicles or heavy machinery the morning after a dose, particularly with the 3 mg dose, after less than 7–8 hours of sleep, or when combined with other CNS depressants. The Lunesta label specifically cautions against driving the day after a 3 mg dose.
- Lactation — presence in human breast milk and effects on the infant are not characterized; weigh maternal need against potential infant exposure.
- Patients with a personal or family history of parasomnias or sleep-walking — baseline risk for complex sleep behaviour may be increased.
- Children and adolescents under 18 years — not recommended; the 12-week ADHD-insomnia trial failed to demonstrate efficacy and showed elevated rates of psychiatric and nervous system events.
- Concomitant strong CYP3A4 inhibitors — limit dose to 2 mg.
Complex sleep behaviours including sleep-walking, sleep-driving, and engaging in other activities while not fully awake have occurred with eszopiclone and other Z-drugs (zolpidem, zaleplon). These behaviours have resulted in serious injuries and deaths, including burns, drowning, fatal motor-vehicle collisions, gunshot wounds, hypothermia, and suicide attempts. They can occur in patients with no prior history of such events, after the first dose, and at the lowest recommended dose. Risk is increased by alcohol and other CNS depressants but events have occurred without these.
Discontinue eszopiclone immediately and permanently if a patient experiences any complex sleep behaviour. Eszopiclone is contraindicated in patients with a history of complex sleep behaviour after taking any Z-drug; do not rechallenge with eszopiclone, zolpidem, or zaleplon. Counsel every patient before starting therapy and at each refill.
Patient Counselling
Purpose of Therapy
Eszopiclone (Lunesta) is a sleep medication used to help with both falling asleep and staying asleep. It works at the GABA receptor system in the brain, similar to benzodiazepines but with a different chemical structure. Eszopiclone has the longest duration of action among the FDA-approved Z-drugs and was studied for up to six months. Cognitive behavioural therapy for insomnia (CBT-I) addresses the root causes of insomnia and is the recommended first-line treatment, with medications added when behavioural therapy is unavailable, declined, or insufficient.
How to Take
Take eszopiclone only when you are ready to go to bed and have at least 7–8 hours available before you need to wake up. Take it on an empty stomach — a heavy or high-fat meal can delay how quickly the medication works. Do not take a second dose during the same night. Swallow the tablet whole. Never combine eszopiclone with alcohol, opioid pain medication, or other sleep aids. If you take the 3 mg dose, do not drive the next day until you know how the medication affects you.
Sources
- Lunesta (eszopiclone) tablets — full prescribing information. U.S. Food and Drug Administration; revised November 2018. Available at accessdata.fda.gov Primary source for adult and elderly dosing, hepatic and CYP3A4 dose adjustments, adverse-event tables (Table 1 adults; Table 2 elderly), drug interactions, pharmacokinetics, and pediatric ADHD-insomnia trial data.
- FDA Drug Safety Communication: FDA adds Boxed Warning for risk of serious injuries caused by sleepwalking with certain prescription insomnia medicines. April 30, 2019. Available at fda.gov Source for the boxed warning and contraindication on complex sleep behaviours added across all Z-drugs (eszopiclone, zaleplon, zolpidem) based on 66 cases reviewed over 26 years.
- Krystal AD, Walsh JK, Laska E, et al. Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep. 2003;26(7):793–799. doi:10.1093/sleep/26.7.793 Pivotal 6-month chronic insomnia trial in adults aged 21–69 (eszopiclone 3 mg n=593 vs placebo n=195) supporting non-restricted-duration FDA approval for eszopiclone.
- Scharf M, Erman M, Rosenberg R, et al. A 2-week efficacy and safety study of eszopiclone in elderly patients with primary insomnia. Sleep. 2005;28(6):720–727. doi:10.1093/sleep/28.6.720 Pivotal elderly trial (n=231; ages 65–85; mean 72.3 years) supporting 1–2 mg dosing in older adults.
- Fava M, McCall WV, Krystal A, et al. Eszopiclone co-administered with fluoxetine in patients with insomnia coexisting with major depressive disorder. Biol Psychiatry. 2006;59(11):1052–1060. doi:10.1016/j.biopsych.2006.01.016 Co-administration trial (n=545) supporting use of eszopiclone alongside SSRI therapy in patients with depression and comorbid insomnia.
- Pollack M, Kinrys G, Krystal A, et al. Eszopiclone coadministered with escitalopram in patients with insomnia and comorbid generalized anxiety disorder. Arch Gen Psychiatry. 2008;65(5):551–562. doi:10.1001/archpsyc.65.5.551 Co-administration trial (n=294 eszopiclone 3 mg + escitalopram 10 mg vs n=301 placebo + escitalopram) in adults aged 18–64 with GAD and comorbid insomnia.
- Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2):307–349. doi:10.5664/jcsm.6470 AASM 2017 guideline; gives eszopiclone a weak recommendation for both sleep-onset and sleep-maintenance insomnia, with low-quality evidence.
- Qaseem A, Kansagara D, Forciea MA, Cooke M, Denberg TD; Clinical Guidelines Committee of the American College of Physicians. Management of chronic insomnia disorder in adults: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2016;165(2):125–133. doi:10.7326/M15-2175 ACP 2016 guideline; positions cognitive behavioural therapy for insomnia (CBT-I) as first-line treatment for chronic insomnia disorder in adults.
- By the 2023 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023;71(7):2052–2081. doi:10.1111/jgs.18372 Designates eszopiclone and other Z-drugs as potentially inappropriate in older adults due to delirium, falls, and fracture risk.
- Najib J. Eszopiclone, a nonbenzodiazepine sedative-hypnotic agent for the treatment of transient and chronic insomnia. Clin Ther. 2006;28(4):491–516. doi:10.1016/j.clinthera.2006.04.014 Comprehensive pharmacology and clinical-trial review of eszopiclone published shortly after FDA approval.
- Nutt DJ, Stahl SM. Searching for perfect sleep: the continuing evolution of GABAA receptor modulators as hypnotics. J Psychopharmacol. 2010;24(11):1601–1612. doi:10.1177/0269881109106927 Review comparing GABAA receptor modulators including eszopiclone, zopiclone, zolpidem, and zaleplon at the subunit level.
- Greenblatt DJ, Zammit GK. Pharmacokinetic evaluation of eszopiclone: clinical and therapeutic implications. Expert Opin Drug Metab Toxicol. 2012;8(12):1609–1618. doi:10.1517/17425255.2012.741588 Detailed pharmacokinetic review of eszopiclone documenting absorption, CYP3A4/2E1 metabolism, and dose adjustments in elderly and hepatic impairment.
- Brielmaier BD. Eszopiclone (Lunesta): a new nonbenzodiazepine hypnotic agent. Proc (Bayl Univ Med Cent). 2006;19(1):54–59. doi:10.1080/08998280.2006.11928127 Summary of registration-program adverse-event data and key drug interaction studies, including the unique long-term-use labelling distinction among Z-drugs.