Introduction
Zopiclone is a non-benzodiazepine hypnotic agent belonging to the cyclopyrrolone class. It is commonly prescribed for the short-term treatment of insomnia. First introduced in the 1980s, zopiclone acts as a sedative-hypnotic with similar effects to benzodiazepines but with a distinct chemical structure.
Mechanism of Action
Zopiclone exerts its therapeutic effects through positive allosteric modulation of the gamma-aminobutyric acid (GABA-A) receptor complex. It binds to a site distinct from but functionally coupled to the benzodiazepine binding site, enhancing GABAergic neurotransmission by increasing the frequency of chloride channel opening. This results in central nervous system depression, producing sedative, hypnotic, anxiolytic, and muscle relaxant effects.
Indications
- Short-term treatment of insomnia (typically 2-4 weeks)
- Difficulty falling asleep
- Frequent nocturnal awakenings
- Early morning awakenings
Dosage and Administration
Adults: 7.5 mg orally once daily before bedtime Elderly/debilitated patients: 3.75 mg orally once daily (initiate with lower dose) Hepatic impairment: 3.75 mg initially; caution advised Renal impairment: No specific dosage adjustment required Duration: Treatment should not exceed 4 weeks, including tapering period Administration: Take immediately before bedtime, ensure 7-8 hours available for sleepPharmacokinetics
Absorption: Rapidly absorbed with peak plasma concentrations reached within 1-2 hours Bioavailability: Approximately 80% Distribution: Volume of distribution: 91.8-104.6 L; protein binding: 45-80% Metabolism: Extensive hepatic metabolism via cytochrome P450 system (primarily CYP3A4) to inactive and active metabolites (N-oxide zopiclone and N-desmethyl zopiclone) Elimination: Half-life: approximately 5 hours; excreted primarily in urine (75%) and feces (15%) Special populations: Elimination half-life prolonged in elderly patients and those with hepatic impairmentContraindications
- Hypersensitivity to zopiclone or any component of the formulation
- Severe hepatic impairment
- Myasthenia gravis
- Severe respiratory depression
- Sleep apnea syndrome
- Concurrent use with potent CYP3A4 inhibitors in patients with hepatic impairment
Warnings and Precautions
- Risk of dependence: Physical and psychological dependence may occur, especially with prolonged use
- Withdrawal symptoms: Abrupt discontinuation may cause rebound insomnia, anxiety, agitation, and confusion
- Amnesia: Anterograde amnesia may occur, particularly when sleep is interrupted
- Complex sleep behaviors: Reports of sleep-walking, sleep-driving, and other complex behaviors
- CNS depression: Additive effects with other CNS depressants; caution with alcohol consumption
- Elderly patients: Increased sensitivity to effects; higher risk of falls and cognitive impairment
- Depression: May worsen depression; monitor for suicidal ideation
- Pregnancy: Category C - use only if potential benefit justifies potential risk to fetus
- Lactation: Excreted in breast milk; not recommended during breastfeeding
Drug Interactions
- CNS depressants: Enhanced sedative effects with alcohol, opioids, barbiturates, other sedatives
- CYP3A4 inhibitors: Ketoconazole, clarithromycin, ritonavir - may increase zopiclone levels
- CYP3A4 inducers: Rifampin, carbamazepine, St. John's wort - may decrease efficacy
- Erythromycin: May increase zopiclone concentrations
- Theophylline: May reduce hypnotic effects
Adverse Effects
Common (≥1%):- Bitter or metallic taste (dysgeusia)
- Dry mouth
- Somnolence
- Dizziness
- Headache
- Nausea
- Complex sleep behaviors
- Anterograde amnesia
- Depression
- Suicidal ideation
- Severe allergic reactions
- Respiratory depression
- Dependence and withdrawal symptoms
Monitoring Parameters
- Sleep patterns and quality
- Cognitive function and coordination
- Signs of dependence or misuse
- Mood changes and depressive symptoms
- Renal and hepatic function (periodically)
- Adverse effects, particularly CNS effects
- Withdrawal symptoms upon discontinuation
Patient Education
- Take immediately before going to bed
- Ensure 7-8 hours of uninterrupted sleep time
- Avoid alcohol and other CNS depressants
- Do not drive or operate machinery until effects are known
- Report any unusual behaviors during sleep
- Do not abruptly stop medication without medical supervision
- Be aware of possible bitter/metallic taste
- Use non-pharmacological sleep hygiene measures concurrently
- Limit treatment duration as prescribed
- Store securely to prevent misuse by others
References
1. Canadian Pharmacists Association. Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 2023. 2. FDA Prescribing Information: Zopiclone Tablets. 3. Dundar Y, Dodd S, Strobl J, et al. Comparative efficacy of newer hypnotic drugs for the short-term management of insomnia: a systematic review and meta-analysis. Hum Psychopharmacol. 2004;19(5):305-322. 4. National Institute for Health and Care Excellence. Guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia. Technology Appraisal 2004. 5. Holm KJ, Goa KL. Zopiclone: an update of its pharmacology, clinical efficacy and tolerability in the treatment of insomnia. Drugs. 2000;59(4):865-889. 6. American Academy of Sleep Medicine. Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults. J Clin Sleep Med. 2017;13(2):307-349.