What is Lunesta (eszopiclone)?

What is Lunesta (Eszopiclone)?

Lunesta (eszopiclone) is a nonbenzodiazepine hypnotic medication FDA-approved for treating insomnia, specifically targeting both difficulty falling asleep and difficulty staying asleep, with the unique distinction of being approved for long-term use unlike most other sleep medications. 1

Drug Classification and Mechanism

• Eszopiclone is a pyrrolopyrazine derivative of the cyclopyrrolone class, representing the S-enantiomer (single isomer) of racemic zopiclone 1
• The drug acts by interacting with GABA-receptor complexes at binding domains located close to or allosterically coupled to benzodiazepine receptors, though its precise mechanism as a hypnotic remains incompletely understood 1
• Unlike benzodiazepines, eszopiclone has greater selectivity for certain GABA(A) receptor subunits, which may contribute to its safety profile 2

Pharmacokinetics and Dosing

• Eszopiclone is rapidly absorbed with peak plasma concentrations reached approximately 1 hour after oral administration 1
• The elimination half-life is approximately 6 hours in adults, extending to about 9 hours in patients 65 years or older 1
• FDA-approved dosing is 2-3 mg for adults aged 18-64 years, and should not exceed 2 mg in elderly patients (≥65 years) due to increased drug exposure 1, 3
• The 1 mg dose is specifically indicated for sleep onset difficulties in elderly patients 3

Clinical Efficacy

• The American College of Physicians guidelines confirm that eszopiclone improves global outcomes and sleep variables for carefully selected adults with insomnia disorder 4
• Eszopiclone reduces sleep onset latency by 19 minutes and increases total sleep time by 45 minutes compared to placebo 4
• The medication reduces wake after sleep onset by 11 minutes compared to placebo 4
• At 12 weeks, 50% of patients achieved remission (ISI scores <7) compared to 19% with placebo 4
• Eszopiclone is considered a first-line pharmacological option for insomnia when cognitive behavioral therapy is unsuccessful or unavailable 5, 6

Safety Profile and Adverse Effects

Common adverse effects include:

• Unpleasant or bitter taste (most frequent complaint) 4, 2
• Somnolence (occurring more frequently than placebo) 4
• Myalgias and headache 4

Serious safety concerns include:

• FDA labeling warns of daytime memory and psychomotor impairment, abnormal thinking and behavioral changes, complex behaviors (including sleep driving), and depression/suicidal thoughts 4
• Increased incidence of memory impairment, psychiatric adverse effects, depression, anxiety, and accidental injury compared to placebo 4
• Serious adverse events occurred in 3% of eszopiclone patients versus 1% with placebo 4
• Observational data suggest associations with increased infection incidence, and hypnotic drugs generally are associated with dementia (hazard ratio 2.34), fractures, motor vehicle accidents, and increased all-cause mortality 4

Important Clinical Considerations

• Taking eszopiclone with or immediately after a high-fat/heavy meal reduces Cmax by 21% and delays absorption by approximately 1 hour, potentially reducing effects on sleep onset 1
• No dose adjustment is needed for mild-to-moderate hepatic impairment, but exposure increases 2-fold in severe hepatic impairment 1
• No dose adjustment is required for renal impairment 1
• Unlike most hypnotics that are FDA-indicated only for short-term use, eszopiclone has been studied and approved for long-term treatment, with trials demonstrating sustained efficacy up to 12 months without evidence of tolerance 7, 8, 2
• The drug is weakly protein-bound (52-59%), suggesting minimal drug-drug interactions from protein binding displacement 1

Comparative Positioning

• Eszopiclone's relatively longer half-life (6 hours) makes it more effective for sleep maintenance issues compared to shorter-acting agents like zaleplon 6
• The American Academy of Sleep Medicine recommends eszopiclone as a first-line alternative to zolpidem (Ambien), with comparable efficacy for both sleep onset and maintenance 6
• The American College of Physicians found that eszopiclone, zolpidem, and suvorexant all improved outcomes, though clinical significance and long-term comparative effectiveness remain incompletely established 4

Critical Caveats

• Most patients at study end continued to have sleep measures exceeding enrollment thresholds, indicating medications typically do not result in complete remission 4
• A large placebo response is consistently noted in insomnia trials, with improvements in sleep onset latency, total sleep time, and wake after sleep onset of 19,39, and 30 minutes respectively 4
• Cognitive behavioral therapy for insomnia (CBT-I) should always be considered first-line treatment before pharmacotherapy 9