Z-Drugs Other Than Eszopiclone
The other Z-drugs (nonbenzodiazepine hypnotics) available besides eszopiclone are zolpidem and zaleplon 1, 2.
Complete List of Z-Drugs
The three FDA-approved nonbenzodiazepine hypnotics in the United States are:
- Eszopiclone (Lunesta)
- Zolpidem (Ambien) - also available as extended-release formulation
- Zaleplon (Sonata)
These medications are collectively referred to as "Z-drugs" due to their chemical names beginning with the letter "Z" 1, 3.
Key Distinguishing Features
Pharmacologic Classification
All three Z-drugs are Schedule IV controlled substances under the Controlled Substances Act, sharing this classification with benzodiazepines 3. While chemically distinct from benzodiazepines, they share similar pharmacologic properties as GABA-A receptor modulators 1, 4.
Mechanism Differences
- Zolpidem and zaleplon bind selectively to α1 subunits of GABA-A receptors
- Eszopiclone is less selective for α1 subunits compared to zolpidem, which may explain differences in clinical effects 5
- Recent evidence suggests zaleplon can modulate γ3-containing receptors with equal efficacy to γ2-containing receptors, potentially contributing to unique therapeutic effects 6
Clinical Efficacy Profiles
Eszopiclone (2-3 mg):
- Reduces sleep onset latency by 19 minutes
- Increases total sleep time by 45 minutes
- Studied for up to 6 months with sustained efficacy 1
Zolpidem (5-10 mg):
- Reduces sleep onset latency by 15 minutes
- Mixed effects on sleep maintenance
- Extended-release formulation (6.25-12.5 mg) available for elderly patients 2
Zaleplon (5-20 mg):
- 10 mg dose improves sleep onset latency by 10 minutes (though mean latency remains >30 minutes)
- Does not significantly improve total sleep time at FDA-recommended doses
- Shortest half-life of the three Z-drugs 1
Safety Considerations
Shared Adverse Effects
All Z-drugs carry FDA warnings for 1:
- Daytime memory and psychomotor impairment
- Abnormal thinking and behavioral changes
- Complex behaviors (sleep-driving)
- Depression and suicidal thoughts (primarily when combined with other sedatives)
- Association with dementia in observational data (hazard ratio 2.34)
Drug-Specific Adverse Events
- Eszopiclone: Unpleasant taste (distinctive), somnolence, myalgias
- Zolpidem: Amnesia, dizziness, somnolence (small but significant increases)
- Zaleplon: Hallucinations (slightly greater than placebo), generally well-tolerated 1, 7
Important Clinical Caveat
Zolpidem 3 mg demonstrated next-morning psychomotor and memory impairment that persisted 7.5 to 11.5 hours after dosing, with subjective perception of sedation not matching objective impairment 3. This dissociation between subjective and objective impairment is a critical safety concern.
Tapering Recommendations When Switching
When discontinuing or switching between Z-drugs 8:
- Zolpidem and eszopiclone (especially at supratherapeutic doses): Taper recommended with 1-2 day delay before starting alternative therapy
- Zaleplon: No tapering required due to ultra-short half-life
- Provide CBT-I during transitions to enhance success