Out of the Pipeline
Eszopiclone: Targeting chronic insomnia
Nonbenzodiazepine hypnotics have become mainstays in insomnia treatment. These agents do not interfere with cognitive function upon awakening, compared with benzodiazepines and other agents used off-label as hypnotics.1
Eszopiclone has shown efficacy in clinical trials for treating short-term and long-term (lasting ≥3 weeks) insomnia. By contrast, zaleplon and zolpidem are indicated for short-term insomnia treatment.
HOW IT WORKS
Eszopiclone, a cyclopyrrolone, is the racemic form of zopiclone, an agent used worldwide to treat insomnia but not available in the United States. The racemic zopiclone has a high affinity for benzodiazepine binding sites in the cerebral cortex, hippocampus, and cerebellum.
As with the selective benzodiazepine receptor agonists zaleplon and zolpidem, information on eszopiclone’s receptor binding profile is limited. It is unclear if the agent binds directly to the benzodiazepine receptor or to a related site on the GABA receptor complex.
Eszopiclone: Fast facts
Novel cyclopyrrolone, nonbenzodiazepine hypnotic
Dec. 15, 2004
1-, 2-, and 3-mg tablets
2 to 3 mg HS (at bedtime) for adults age ≤65
1 to 2 mg HS for adults age >65
Preliminary studies suggest eszopiclone is rapidly absorbed from the GI tract, mostly within 1 hour of taking it.2,3 The agent reaches peak concentration within 30 minutes to 4 hours in healthy persons. A high-fat or heavy meal may delay hypnotic onset by approximately 1 hour.
Eszopiclone is metabolized mostly through the 3A4 isoenzyme of the cytochrome P(CYP)-450 system, although the CYP 2E1 isoenzyme also plays a minor role. About 75% of the dose is excreted in urine.4 Because its elimination half-life is approximately 6 hours, eszopiclone leaves no residual effects when patients awaken after about 6 hours of sleep.1
Because they take weeks to eliminate, some older sleep-promoting medications can cause increasing daytime sedation when used daily. By contrast, eszopiclone can be taken once daily with no risk of drug accumulation.
Although relatively few clinical studies of eszopiclone have been published, the new-drug application submitted to the FDA summarized 24 clinical trials totaling more than 2,700 subjects.
Zammit et al5 gave 308 patients eszopiclone, 2 or 3 mg HS (at bedtime), or placebo for 6 weeks. Eszopiclone decreased time to falling asleep, increased total sleep time, improved continuity of sleep, and increased overall sleep quality throughout the night. After 6 weeks, patients in the treatment group showed:
- no residual morning sedation based on repeated polysomnography and morning questionnaire measures
- no residual daytime sedation based on results of the Digit Symbol Substitution Test, which gauges psychomotor impairment.
Patients taking 3 mg showed reduced wakefulness at night on objective and subjective measures compared with the placebo group.
A randomized, double-blind, multicenter, placebo-controlled study (N=788)6,7 assessed eszopiclone’s safety and efficacy across 6 months in patients with chronic insomnia. Before enrollment, patients slept <6.5 hours/night with initial sleep latency ≥30 minutes. Within 1 week and thereafter, eszopiclone reduced initial sleep latency, increased total sleep time, increased sleep continuity, and improved sleep quality compared with placebo.
SAFETY AND TOLERABILITY
Eszopiclone was well tolerated in preclinical and clinical trials. The most common adverse event was a bitter taste reported by 34% of participants; this prompted 1.7% of patients in one study4 to discontinue eszopiclone, compared with 0.5% of patients taking placebo. Other common adverse effects included:
- daytime somnolence, (8% prevalence, 2.2% dropout rate
- depression (1% dropout rate).4
Few significant interactions between eszopiclone and other drugs have been reported. However:
- Increased sedation and decreased psychomotor functioning were observed with eszopiclone, 3 mg, and olanzapine, 10 mg.
- Drugs that inhibit (eg, ketoconazole) or induce (eg, rifampicin) the CYP 3A4 isoenzyme may alter eszopiclone levels.8
- A possible drug-drug interaction between eszopiclone and alcohol, 0.7 g/kg, decreased psychomotor performance for up to 4 hours after alcohol use.8
No significant drug-drug interactions were reported between eszopiclone and paroxetine or lorazepam.4
In another case, the parent compound zopiclone given concomitantly with trimipramine decreased both drugs’ bioavailability but did not noticeably change either drug’s clinical effect.9 As eszopiclone and zopiclone are chemically similar, be careful when giving eszopiclone to patients taking trimipramine or similar medications, such as tricyclic antidepressants.
Start eszopiclone at 2 mg HS for adults and titrate to 3 mg as needed. For many patients, 3 mg may suffice as maintenance therapy. The risks and benefits of dosing eszopiclone at >3 mg are not known.
Lower doses are recommended for patients age >65 because of the risk of decreased motor and/or cognitive performance. Give 2 mg for maintenance and 1 mg for difficulty falling asleep. There are no other known contraindications to eszopiclone use.
As with other hypnotics, supplement eszopiclone with sleep hygiene education and relaxation techniques.
Eszopiclone has shown efficacy for >2 weeks in primary insomnia, suggesting the agent may help treat chronic insomnia.
As with other nonbenzodiazepine hypnotics, off-label use of eszopiclone with antidepressants may help treat insomnia secondary to depressive or anxiety disorders. Research is needed to gauge the drug’s effectiveness for this use.
Drug brand names
- Eszopiclone • Lunesta
- Ketoconazole • Nizoral
- Lorazepam • Ativan
- Olanzapine • Zyprexa
- Paroxetine • Paxil
- Trimipramine • Surmontil
- Zaleplon • Sonata
- Zolpidem • Ambien
Dr. Krahn reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
1. Terzano MG, Rossi M, Palomba V, et al. New drugs for insomnia: comparative tolerability of zopiclone, zolpidem, and zaleplon. Drug Safety 2003;26:261-82.
2. Fernandez C, Martin C, Giminez F, Farinotti R. Clinical pharmacokinetics of zopiclone. Clin Pharmacokinet 1995;29:431-41.
3. Leese P, Maier G. Eszopiclone: Pharmacokinetic (PK) and pharmacodynamic effects of a novel sedative anti-insomnia agent after daytime administration in healthy subjects. Sleep 2002;25 (suppl):A45.-
4. Lunesta (eszopiclone) prescribing information. Available at: http://www.lunesta.com. Accessed Jan. 6, 2005.
5. Zammit GK, Gillin JC, McNabb L, et al. Eszopiclone, a novel non-benzodiazepine anti-insomnia agent: a six-week efficacy and safety study in adult patients with chronic insomnia. Sleep 2003;26(suppl):A297.-
6. Krystal A, Walsh J, Roth T, et al. The sustained efficacy and safety of eszopiclone over six months of nightly treatment: a placebo controlled study in patients with chronic insomnia. Sleep 2003;26(suppl):0779.-
7. Krystal A, Walsh J, Laska E, et al. Sustained efficacy of eszopiclone over six months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep 2003;26:793-9.
8. Hesse LM, von Moltke LL, Greenblatt DJ. Clinically important drug interactions with zopiclone, zolpidem, and zaleplon. CNS Drugs 2003;17:513-32.
9. Caille G, du Souich P, Spenard J, et al. Pharmacokinetic and clinical parameters of zopiclone and trimipramine when administered simultaneously to volunteers. Biopharm Drug Dispos 1984;5:117-25.