Z-Drugs: Non-Benzodiazepine Hypnotics
Z-drugs are a class of non-benzodiazepine hypnotic medications that include zopiclone, zaleplon, and zolpidem, which were developed in the 1990s primarily for the treatment of insomnia. 1
Key Z-Drugs and Their Properties
- Zopiclone, zaleplon, and zolpidem are the three main Z-drugs, named for the first letter of their chemical names and their classification as hypnotics 1
- These medications were developed with the aim of preventing the over-sedation and daytime sleepiness associated with benzodiazepines 1
- Z-drugs are Schedule IV controlled substances, the same classification as benzodiazepines 2
Mechanism of Action
- Z-drugs work by enhancing γ-aminobutyric acid (GABA) transmission at GABA-type A receptors, similar to benzodiazepines 3
- Unlike benzodiazepines, Z-drugs interact preferentially with omega-1 receptors (responsible for sedative effects) rather than omega-2 receptors (associated with adverse cognitive and memory effects) 4
- This selective binding profile was intended to provide hypnotic effects with fewer side effects than benzodiazepines 4, 5
Pharmacokinetic Properties
- Z-drugs have rapid onset of action (within 30 minutes) and short half-lives (1-7 hours), approaching the profile of an ideal hypnotic 3, 4
- Zaleplon has an ultra-short half-life of approximately 1 hour 3, 4
- Zolpidem has a half-life of approximately 2.4 hours 4
- Zopiclone has the longest half-life among Z-drugs at approximately 5 hours 4
- These short half-lives were designed to reduce residual daytime effects 4
Clinical Use
- Z-drugs are primarily indicated for the short-term treatment of insomnia 1, 4
- They reduce sleep latency (time to fall asleep) and improve sleep quality, though they may not significantly increase total sleep duration 3
- In England, dispensed prescriptions of Z-drugs increased from 5.4 million to 6.5 million between 2008 and 2014, before falling to 6.0 million by 2018 1
Safety Concerns and Adverse Effects
- Initially believed to have a low risk of dependence, Z-drugs are now recognized to carry significant risks similar to benzodiazepines 1, 6
- Neuropsychiatric adverse events have been reported with Z-drugs, including:
- Cognitive and memory impairment typically coincides with peak plasma concentration (first few hours after administration) 4
- FDA labels warn about cognitive and behavioral changes that may be serious or life-threatening 1
Dependence, Tolerance, and Withdrawal
- Z-drugs carry risks of abuse, dependence, and withdrawal similar to benzodiazepines 2, 6
- Approximately half of patients prescribed Z-drugs in England had been treated continuously for at least 12 months, despite recommendations against long-term use 1
- Sudden cessation can lead to physical and psychological withdrawal symptoms 1
- Patients treated long-term should be offered careful tapering and support if discontinuation is planned 1
Special Considerations
- Dose reduction is advised in women, elderly, and debilitated adults 1
- Taking Z-drugs with food may delay onset of action and reduce effectiveness 2
- Z-drugs should be used for limited periods, even in chronic relapsing conditions 4
- The risk of abuse and dependence increases with higher doses, longer duration of treatment, and concomitant use of other psychoactive drugs 2
Comparative Safety Profile
- While Z-drugs were developed to have improved safety profiles over benzodiazepines, evidence suggests their adverse effects, neuropsychiatric sequelae, and risk of dependence may be similar to older hypnotics 3
- The relative incidence of reported dependence appears to be lower than that of benzodiazepines used for sleep disorders, but the risk remains significant 7
- Patients with a history of substance abuse or psychiatric conditions appear to be at increased risk for Z-drug abuse 2, 7
Z-drugs represent an important class of sleep medications with specific pharmacokinetic advantages, but their use should be carefully monitored due to significant risks of adverse effects and dependence.