Differences between Eszopiclone and Zolpidem

Eszopiclone vs. Zolpidem

Eszopiclone and zolpidem are nonbenzodiazepine sedative-hypnotics, commonly referred to as Z-drugs, prescribed for the treatment of insomnia. Both medications work by interacting with GABA-A receptors in the brain, which enhances the calming effect of the neurotransmitter GABA, leading to sedation. While they share a similar mechanism of action and are both used to help people fall asleep, there are notable differences in their chemical structure, duration of action, and approved uses. Eszopiclone is a cyclopyrrolone derivative, while zolpidem is an imidazopyridine.

These medications are classified as Schedule IV controlled substances in the United States, indicating a potential for abuse and dependence.

Comparison Table

Category	Eszopiclone	Zolpidem
Drug Class	Cyclopyrrolone	Imidazopyridine
Mechanism of Action	Positive allosteric modulator of GABA-A receptors	Positive allosteric modulator of GABA-A receptors, with selectivity for the alpha-1 subunit
Half-life	Approximately 6 hours	Approximately 2-3 hours for immediate-release
Approved Uses	Treatment of insomnia, for both sleep onset and sleep maintenance. Approved for long-term use.	Short-term treatment of insomnia, primarily for difficulty with sleep initiation. A lower-dose sublingual form is approved for middle-of-the-night awakenings.
Common Side Effects	Unpleasant or metallic taste, headache, drowsiness, dizziness, dry mouth.	Drowsiness, dizziness, memory loss, headache.
Next-Day Impairment	Risk of next-day impairment, particularly with higher doses.	Risk of next-morning impairment, which may affect activities like driving. The FDA has recommended lower doses, especially for women.
Formulations	Oral tablets	Oral tablets (immediate and extended-release), sublingual tablets, and an oral spray.

Venn diagram comparing Differences between Eszopiclone and Zolpidem

Pharmacokinetics

The primary difference in the pharmacokinetic profiles of eszopiclone and zolpidem is their elimination half-life. Eszopiclone has a longer half-life of about 6 hours. This longer duration of action can be beneficial for maintaining sleep throughout the night but also increases the risk of residual next-day effects such as drowsiness. In contrast, the immediate-release formulation of zolpidem has a shorter half-life of approximately 2 to 3 hours, which is often preferred for patients who have trouble falling asleep but not staying asleep.

Both drugs are metabolized in the liver, primarily by the cytochrome P450 enzyme system. Specifically, CYP3A4 and CYP2E1 are involved in the metabolism of eszopiclone, while CYP3A4, CYP2C9, and CYP1A2 are the main enzymes responsible for metabolizing zolpidem.

Clinical Efficacy and Use

Clinical studies have shown that both eszopiclone and zolpidem are effective in reducing the time it takes to fall asleep. Due to its longer half-life, eszopiclone may be more effective for sleep maintenance, helping individuals stay asleep longer. Zolpidem, particularly the immediate-release formulation, is often used to address sleep-onset insomnia.

A significant distinction in their approved use is the duration of treatment. Eszopiclone is approved by the FDA for long-term use in treating insomnia. In contrast, zolpidem is generally recommended for short-term use.

Side Effects and Adverse Events

The side effect profiles of eszopiclone and zolpidem have some overlap, with both medications potentially causing drowsiness, dizziness, and next-day impairment. A distinctive and common side effect of eszopiclone is an unpleasant or metallic taste in the mouth. Zolpidem has been associated with a risk of complex sleep behaviors, such as sleepwalking or sleep-driving, which has led to an FDA boxed warning for this class of drugs. Both medications can cause serious allergic reactions, including angioedema.