Mechanism of action
Zopiclone is a positive allosteric modulator of the GABA-A receptor chloride channel complex. Unlike benzodiazepines that bind nonselectively to multiple GABA-A receptor subtypes, zopiclone shows preferential binding to receptors containing the α1 subunit. This selective action produces sedative and hypnotic effects with relatively less anxiolytic, muscle relaxant, and anticonvulsant activity compared to benzodiazepines.
Binding to the GABA-A receptor enhances the inhibitory effects of GABA, the primary inhibitory neurotransmitter in the central nervous system. This increases chloride ion influx into neurons, causing hyperpolarization and decreased neuronal excitability. The result is rapid sleep onset and maintenance with less disruption of normal sleep architecture, particularly preservation of slow-wave sleep and REM sleep compared to traditional benzodiazepines.
The pharmacologic profile of zopiclone leads to its classification as a "Z-drug" alongside zolpidem and zaleplon. Despite structural differences from benzodiazepines, zopiclone produces similar clinical effects and shares the risk of tolerance, dependence, and withdrawal.
- Zopiclone is a nonbenzodiazepine Z-drug that acts as a GABA-A receptor positive allosteric modulator with preferential α1 subunit binding
- Characteristic metallic or bitter taste (dysgeusia) occurs in 20-40% of patients and is pathognomonic for zopiclone
- Indicated only for short-term insomnia treatment (2-4 weeks maximum) due to risk of tolerance and dependence
- Complex sleep behaviors (sleep-driving, sleepwalking) can occur and may result in serious injury or death
- Not available in the United States; eszopiclone (S-enantiomer) is the marketed alternative
- Half-life is 3.5-6.5 hours but prolonged in elderly and hepatic impairment, requiring dose reduction
- Contraindicated in severe hepatic impairment, severe respiratory insufficiency, myasthenia gravis, and sleep apnea
- Flumazenil can reverse zopiclone toxicity as it acts on benzodiazepine binding site of GABA-A receptor
Indications
Zopiclone is indicated for the short-term treatment of insomnia, including difficulty falling asleep, nocturnal awakening, and early morning awakening. Treatment duration should generally not exceed 2 to 4 weeks, as prolonged use increases the risk of tolerance and dependence.
Primary indication:
- Insomnia (short-term management)
Off-label uses:
Zopiclone is occasionally used off-label for other sleep disturbances, but evidence supporting these uses is limited. The drug is not approved for chronic insomnia management, anxiety disorders, or other psychiatric conditions. Non-pharmacologic interventions and cognitive-behavioral therapy for insomnia (CBT-I) should be considered first-line treatment before initiating hypnotic medications.
Zopiclone is not available in the United States, where the S-enantiomer eszopiclone is marketed instead. Both agents have similar pharmacologic properties and clinical applications.
Pharmacokinetics
Zopiclone exhibits predictable pharmacokinetics that contribute to its clinical utility as a sleep aid.
Absorption: Rapidly absorbed after oral administration with peak plasma concentrations occurring within 1.5 to 2 hours. Bioavailability is approximately 75-80%. Food may delay absorption but does not significantly affect overall bioavailability.
Distribution: Moderate volume of distribution (approximately 90-100 L). Protein binding is relatively low at 45-80%, which is less than most benzodiazepines.
Metabolism: Extensively metabolized in the liver primarily via oxidation and dealkylation. CYP3A4 and CYP2C8 are the main enzymes involved. The N-oxide and N-desmethyl metabolites are pharmacologically active but less potent than the parent compound.
Elimination: Eliminated primarily in urine (approximately 80%) with a smaller fraction in feces. The elimination half-life is 3.5 to 6.5 hours in healthy adults, allowing for overnight sedation without significant daytime residual effects. Half-life is prolonged in elderly patients (up to 7 hours) and those with hepatic impairment, necessitating dose adjustment. Renal impairment has minimal effect on elimination.
The relatively short half-life makes zopiclone suitable for sleep initiation without causing significant next-day sedation in most patients when taken at appropriate doses.
Adverse effects
Zopiclone is generally well-tolerated for short-term use, but several adverse effects are clinically significant.
Common adverse effects:
- Metallic or bitter taste (dysgeusia): The most characteristic side effect, occurring in 20-40% of patients. This taste disturbance is a frequent reason for discontinuation
- Drowsiness and residual daytime sedation
- Dry mouth
- Dizziness and lightheadedness
- Headache
- Gastrointestinal disturbances (nausea, vomiting)
Serious adverse effects:
- Complex sleep behaviors: Sleepwalking, sleep-driving, and other activities performed while not fully awake. These behaviors can result in serious injury or death
- Cognitive impairment: Anterograde amnesia, confusion, and impaired concentration, particularly at higher doses
- Paradoxical reactions: Agitation, aggression, and behavioral disinhibition, more common in elderly patients and those with psychiatric disorders
- Respiratory depression: Risk increased when combined with other CNS depressants or in patients with respiratory compromise
- Falls and fractures: Particularly in elderly patients due to sedation, dizziness, and impaired coordination
Tolerance and dependence:
Tolerance to hypnotic effects may develop with regular use beyond 2-4 weeks. Physical and psychological dependence can occur, especially with prolonged use or higher doses. Abrupt discontinuation after chronic use may precipitate withdrawal symptoms including rebound insomnia, anxiety, tremor, sweating, and in severe cases, seizures. Zopiclone has abuse potential and is classified as a controlled substance in many countries.
Other considerations:
Hypersensitivity reactions including angioedema and anaphylaxis are rare but documented. Psychiatric symptoms including depression, suicidal ideation, and hallucinations have been reported, though causality is difficult to establish.
Contraindications and warnings
Absolute contraindications:
- Hypersensitivity to zopiclone or other cyclopyrrolone derivatives
- Severe hepatic impairment (risk of hepatic encephalopathy)
- Severe respiratory insufficiency including sleep apnea syndrome
- Myasthenia gravis (risk of respiratory depression and muscle weakness)
Relative contraindications and warnings:
- Pregnancy: Limited human data available. Animal studies suggest potential fetal harm. Should be avoided during pregnancy, particularly in the first trimester. If used near term, neonatal withdrawal and floppy infant syndrome may occur
- Breastfeeding: Zopiclone is excreted in breast milk in small amounts. Breastfeeding should be avoided or the drug should not be used
- Elderly patients: Increased sensitivity to CNS effects, prolonged half-life, and higher risk of falls, fractures, and cognitive impairment. Lower initial doses are recommended
- Hepatic impairment: Dose reduction required due to decreased metabolism and increased half-life
- Renal impairment: Mild to moderate impairment requires caution; severe impairment may necessitate dose adjustment
- Psychiatric disorders: Use with caution in patients with depression, as hypnotics may worsen depressive symptoms. Risk of paradoxical reactions in patients with personality disorders or history of substance abuse
- Respiratory disease: Caution in COPD, chronic bronchitis, and other conditions with compromised respiratory function
- History of substance abuse: Increased risk of dependence and misuse
Special populations:
Pediatric use is not established and is generally not recommended. Driving and operating machinery should be avoided until individual response is known, as zopiclone impairs psychomotor performance.
Drug interactions
Zopiclone participates in several clinically significant drug interactions, primarily through pharmacodynamic and pharmacokinetic mechanisms.
CNS depressants (major interaction):
Combination with other CNS depressants produces additive sedation and respiratory depression. This includes:
- Alcohol
- Opioid analgesics
- Benzodiazepines
- Barbiturates
- Antipsychotics
- Sedating antihistamines
- Tricyclic antidepressants
- General anesthetics
Concomitant use should be avoided or used with extreme caution at reduced doses.
CYP3A4 inhibitors:
Drugs that inhibit CYP3A4 increase zopiclone plasma concentrations and prolong half-life:
- Azole antifungals (ketoconazole, itraconazole)
- Macrolide antibiotics (erythromycin, clarithromycin)
- Protease inhibitors (ritonavir)
- Grapefruit juice
Dose reduction of zopiclone may be necessary.
CYP3A4 inducers:
Drugs that induce CYP3A4 decrease zopiclone efficacy:
- Rifampin
- Carbamazepine
- Phenytoin
- St. John's wort
Higher doses of zopiclone may be required, though alternative therapy is preferred.
Other interactions:
- Muscle relaxants: Enhanced neuromuscular blockade
- Antihypertensives: Additive hypotensive effects
- Sodium oxybate: Severe CNS and respiratory depression; combination is contraindicated
Patients should be counseled to avoid alcohol consumption while taking zopiclone due to unpredictable potentiation of sedative effects.
Clinical pearls
- Metallic taste is pathognomonic: The bitter or metallic taste is so characteristic of zopiclone that it can serve as a clinical clue to adherence or overdose. This side effect distinguishes zopiclone from other Z-drugs
- Not available in the US: Zopiclone is marketed in Europe, Canada, and other regions but not approved in the United States, where eszopiclone (the S-enantiomer, Lunesta) is used instead. Eszopiclone has similar properties but approximately twice the potency
- Short-term use only: Treatment should be limited to 2-4 weeks to minimize tolerance and dependence. If insomnia persists, underlying causes should be investigated rather than continuing hypnotic therapy
- Rebound insomnia: Abrupt discontinuation frequently causes rebound insomnia that may be worse than the original sleep disturbance. Gradual tapering is recommended for patients who have used zopiclone regularly for more than 1-2 weeks
- Complex sleep behaviors are a black box warning: Patients have engaged in sleep-driving, cooking, eating, and other complex activities while not fully awake, with no memory of the events. These behaviors have resulted in serious injuries and deaths. Patients should be counseled about this risk
- Lower doses in elderly: Start with half the standard adult dose in patients over 65 due to increased sensitivity and prolonged half-life. The elderly are particularly susceptible to falls, cognitive impairment, and paradoxical agitation
- Benzodiazepine receptor agonist: Despite being structurally distinct from benzodiazepines, zopiclone acts at the benzodiazepine binding site on GABA-A receptors. Flumazenil can reverse zopiclone toxicity, though its use in chronic users may precipitate withdrawal seizures
- Screen for sleep apnea: Before prescribing any hypnotic, screen for obstructive sleep apnea, as hypnotics can worsen respiratory depression during apneic episodes. STOP-BANG questionnaire is a useful screening tool
- CBT-I is first-line: Cognitive-behavioral therapy for insomnia has superior long-term efficacy compared to pharmacotherapy and should be recommended before or alongside zopiclone. Sleep hygiene education is an essential component of insomnia management
- Drug interactions are common: Always review the patient's medication list for CNS depressants and CYP3A4 inhibitors/inducers before prescribing. The combination of zopiclone with opioids is particularly dangerous and should be avoided
ZOPICLONE for side effects: Z-drug class, Overdose (respiratory depression), Paradoxical agitation, Insomnia rebound, Complex sleep behaviors, Late-night dosing only, Oral bitter taste, Needs short-term use, Elderly need lower doses
Practice questions
1. A 68-year-old man with chronic insomnia is started on zopiclone 7.5 mg at bedtime. Three days later, he reports that although he is sleeping better, he experiences a persistent unpleasant taste in his mouth that is particularly bothersome in the morning. He denies any oral lesions, recent dental work, or new foods. Physical examination reveals normal oral mucosa with no signs of infection. Which of the following is the most likely explanation for this patient's symptom?
2. A 45-year-old woman is brought to the emergency department by her husband after he found her cooking in the kitchen at 3 AM with no memory of waking up or preparing food. She was started on zopiclone 7.5 mg for insomnia one week ago. She has no history of sleepwalking and denies alcohol or illicit drug use. She appears confused and has difficulty recalling the event. Which of the following is the most appropriate next step in management?
3. A 72-year-old man with insomnia is prescribed zopiclone by his primary care physician. He has a history of moderate COPD (FEV1 55% predicted), well-controlled hypertension, and takes tiotropium, amlodipine, and occasional codeine for chronic back pain. Two days after starting zopiclone, his wife reports he is more confused than usual and his breathing seems labored. On examination, he is somnolent with respiratory rate of 8 breaths/min, oxygen saturation 88% on room air, and diminished breath sounds bilaterally. Which of the following factors most likely contributed to this patient's presentation?
Frequently asked questions
How does zopiclone work?
Zopiclone works by enhancing the activity of GABA, the brain's main inhibitory neurotransmitter, at GABA-A receptors. It acts as a positive allosteric modulator with preferential binding to receptors containing the α1 subunit, which produces sedative and hypnotic effects. This increases chloride ion flow into neurons, causing hyperpolarization and reduced neuronal excitability, resulting in sleep induction and maintenance with less disruption of normal sleep architecture compared to traditional benzodiazepines.
What are the side effects of zopiclone?
The most characteristic side effect of zopiclone is a metallic or bitter taste in the mouth, affecting 20-40% of users. Common side effects include drowsiness, dry mouth, dizziness, and headache. Serious adverse effects include complex sleep behaviors (sleep-driving, sleepwalking), anterograde amnesia, falls and fractures especially in the elderly, and respiratory depression. With prolonged use, tolerance and physical dependence can develop, and abrupt discontinuation may cause withdrawal symptoms including rebound insomnia and anxiety.
Is zopiclone a controlled substance?
Yes, zopiclone is classified as a controlled substance in many countries due to its potential for abuse, dependence, and tolerance. The specific scheduling varies by jurisdiction; for example, it is a Schedule IV controlled drug in Canada and subject to controlled drug regulations in the UK and Europe. Zopiclone shares abuse potential similar to benzodiazepines despite being structurally different. It is not available in the United States, where the related drug eszopiclone is marketed instead as a Schedule IV controlled substance.
Zopiclone vs zolpidem — what is the difference?
Both zopiclone and zolpidem are nonbenzodiazepine Z-drugs used for short-term insomnia treatment, acting on GABA-A receptors. The main differences are structural class (zopiclone is a cyclopyrrolone; zolpidem is an imidazopyridine), geographic availability (zopiclone is used in Europe and Canada but not the US, where zolpidem is widely prescribed), and side effect profile (zopiclone characteristically causes metallic taste in 20-40% of patients, which is rare with zolpidem). Both have similar efficacy, half-lives around 2-6 hours, and comparable risks of dependence and complex sleep behaviors.
Can zopiclone be taken long-term?
No, zopiclone should not be taken long-term. It is approved only for short-term treatment of insomnia, typically 2-4 weeks maximum. Prolonged use leads to tolerance (reduced effectiveness), physical and psychological dependence, and increased risk of adverse effects including cognitive impairment and complex sleep behaviors. If insomnia persists beyond 2-4 weeks, underlying causes should be investigated and non-pharmacologic interventions like cognitive-behavioral therapy for insomnia (CBT-I) should be implemented rather than continuing hypnotic medications. Abrupt discontinuation after chronic use can cause withdrawal symptoms.
Conditions it is used for
Related drugs
Sources and further reading
DailyMed (FDA labels)StatPearls (NCBI Bookshelf)MedlinePlusWHO ATC/DDD index: N05CF01
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.