Is Zopiclone and Lorazepam Together Safe?
No, combining zopiclone and lorazepam is not safe and should be avoided. Both agents are central nervous system (CNS) depressants that potentiate respiratory depression and significantly increase the risk of fatal overdose, cognitive impairment, falls, and complex sleep behaviors.
Why This Combination Is Dangerous
Additive CNS Depression and Respiratory Risk
The CDC explicitly warns that concurrent use of benzodiazepines (lorazepam) with other CNS depressants creates dangerous polypharmacy that markedly increases the risk of respiratory depression, cognitive impairment, falls, fractures, and potentially fatal overdose 1.
When benzodiazepines are combined with opioids, the risk of overdose death quadruples compared with opioid use alone; similar additive risks occur when benzodiazepines are paired with other CNS depressants such as zopiclone 1.
The FDA drug label for zopiclone (eszopiclone/Lunesta) explicitly states that "downward dose adjustment is recommended when LUNESTA is administered with agents having known CNS-depressant effects," and warns that combining it with alcohol or other sedating medications increases the risk of complex sleep behaviors (sleep-driving, sleep-walking) 2.
Documented Pharmacodynamic Interaction
Coadministration of eszopiclone 3 mg and lorazepam 2 mg did not alter the pharmacokinetics of either drug, but the interaction is pharmacodynamic—meaning the sedative effects are additive even though drug metabolism remains unchanged 2.
An additive effect on psychomotor performance has been documented when eszopiclone is combined with other CNS depressants, creating cumulative impairment that patients often do not perceive, leading to dangerous activities such as driving while impaired 2.
Increased Risk of Complex Sleep Behaviors and Falls
All benzodiazepine-receptor agonists (including zopiclone) and benzodiazepines carry FDA warnings for complex sleep behaviors such as sleep-driving, sleep-walking, and sleep-eating; combining these agents amplifies this risk 1, 2.
Multiple sedating agents create additive psychomotor impairment and markedly increase fall risk, particularly in elderly patients who are already at heightened risk for fractures and cognitive decline 1.
What Should Be Done Instead
First-Line Non-Pharmacologic Therapy
All adults with chronic insomnia should receive Cognitive Behavioral Therapy for Insomnia (CBT-I) as the initial treatment before or alongside any medication, because it provides superior long-term efficacy and sustained benefits after drug discontinuation 3, 4.
CBT-I includes stimulus control, sleep restriction, relaxation techniques, and cognitive restructuring, and can be delivered via individual therapy, group sessions, telephone, web-based modules, or self-help books—all formats show effectiveness 3.
If Pharmacotherapy Is Necessary
- Choose a single hypnotic agent appropriate for the specific insomnia phenotype rather than combining multiple CNS depressants 3:
If the Patient Is Already Taking Lorazepam
The CDC recommends tapering benzodiazepines gradually using a 25% dose reduction every 1–2 weeks to avoid withdrawal symptoms such as rebound anxiety, hallucinations, seizures, delirium tremens, and rarely death 1.
When patients are receiving both benzodiazepines and other CNS depressants, taper the non-benzodiazepine agent first (in this case, discontinue zopiclone), because benzodiazepine withdrawal carries greater risks than hypnotic withdrawal 1.
Integrate CBT-I during the benzodiazepine taper, as behavioral therapy improves tapering success rates and provides a non-pharmacologic foundation for long-term insomnia management 1.
Critical Safety Warnings
Lorazepam is not a first-line hypnotic for insomnia; it is considered a second- or third-line option only when first-line agents have failed, the patient has comorbid anxiety, or a longer duration of action is needed for sleep maintenance 3.
Lorazepam carries significant risks including dependence, withdrawal reactions, cognitive impairment, falls, and daytime sedation, particularly in older adults 3.
Traditional benzodiazepines such as lorazepam have long half-lives leading to drug accumulation, prolonged daytime sedation, and higher fall and cognitive-impairment risk compared with short-acting non-benzodiazepine hypnotics 3.
Observational studies link benzodiazepine use to increased risk of dementia, fractures, and major injury—associations not observed with newer orexin antagonists or low-dose doxepin 3.
Common Pitfalls to Avoid
Combining multiple sedative agents without recognizing the cumulative risk of respiratory depression, cognitive impairment, falls, and complex sleep behaviors 1, 2.
Failing to initiate CBT-I before or alongside pharmacotherapy, which leads to less durable benefit and perpetuates medication dependence 3, 4.
Using adult dosing in older adults; age-adjusted dosing (e.g., eszopiclone ≤2 mg, zolpidem ≤5 mg for ≥65 years) is essential to reduce fall risk 3.
Continuing pharmacotherapy long-term without periodic reassessment; FDA labeling indicates hypnotics are intended for short-term use (≤4 weeks) 3, 4.