A Comprehensive Monograph on Eszopiclone (Lunesta)

1.0 Executive Summary

Eszopiclone, marketed principally as Lunesta, is a nonbenzodiazepine hypnotic agent of the cyclopyrrolone chemical class. It is the pharmacologically active (S)-stereoisomer of the racemic compound zopiclone. Approved by the U.S. Food and Drug Administration (FDA) for the treatment of insomnia, Eszopiclone is distinguished by its indication for both sleep-onset and sleep-maintenance difficulties without a restriction on the duration of use, setting it apart from many other hypnotics limited to short-term therapy. Evidence supports its efficacy for periods of up to 12 months.

The drug's therapeutic effect is mediated through its action as a positive allosteric modulator of the gamma-aminobutyric acid type A (GABA-A) receptor complex. By enhancing the inhibitory effects of GABA, Eszopiclone reduces neuronal excitability, thereby promoting sleep. Its pharmacokinetic profile is characterized by rapid oral absorption, a peak plasma concentration reached in approximately one hour, and an elimination half-life of approximately 6 hours in non-elderly adults. Metabolism is extensive and occurs primarily in the liver via the cytochrome P450 enzymes CYP3A4 and CYP2E1.

While generally well-tolerated, the most common adverse effect associated with Eszopiclone is a dose-related unpleasant or metallic taste (dysgeusia). More significant safety concerns exist, including a dose-dependent risk of next-day psychomotor impairment, which prompted an FDA recommendation to lower the starting dose. The most severe risk is highlighted by an FDA Black Box Warning for complex sleep behaviors, such as sleep-driving, which can result in serious injury or death. As a U.S. Schedule IV controlled substance, Eszopiclone carries a risk of dependence, abuse, and withdrawal symptoms upon abrupt discontinuation.