What are the long-term effects of zopiclone (non-benzodiazepine hypnotic agent)?

Long-Term Effects of Zopiclone

Zopiclone should not be used long-term due to significant risks of dependence, tolerance, withdrawal symptoms, and potential for serious adverse effects including complex sleep behaviors, cognitive impairment, and increased risk of falls and injuries. 1, 2

Pharmacology and Classification

Zopiclone is a non-benzodiazepine hypnotic agent (cyclopyrrolone derivative) that acts on GABA-receptor complexes at binding domains located close to benzodiazepine receptors 2. Despite having a chemical structure different from benzodiazepines, it shares many of their pharmacologic properties and risks 2.

Adverse Effects with Long-Term Use

Dependence and Tolerance

• Physical and psychological dependence can develop with prolonged use 2
• Risk of dependence increases with:
  • Higher doses
  • Longer duration of treatment
  • Concomitant use of other psychoactive drugs
  • History of alcohol or drug abuse
  • History of psychiatric disorders 2
• Case reports document severe dependence (doses up to 112.5 mg/day) with significant withdrawal symptoms upon discontinuation 3

Withdrawal Symptoms

• Can include anxiety, abnormal dreams, nausea, and upset stomach 2
• More severe cases may present with palpitations, sweating, irritability, hallucinations, and impulsive behavior 3
• Rebound insomnia can occur after withdrawal, though earlier studies suggested this was not common with short-term use 4, 5

Cognitive and Behavioral Effects

• FDA warnings include:
  • Daytime memory and psychomotor impairment
  • Abnormal thinking and behavioral changes
  • Complex sleep behaviors (sleep driving, sleep eating)
  • Depression and suicidal thoughts 1
• Observational data has linked hypnotic drugs (including non-benzodiazepines like zopiclone) to increased risk of dementia (hazard ratio 2.34) 1

Physical Risks

• Increased risk of falls and injuries, particularly in elderly patients 1
• Risk for serious injuries caused by sleep behaviors (sleepwalking, sleep driving) 1

Recommendations for Use

Duration Limitations

• FDA has approved pharmacologic therapy for short-term use only (4 to 5 weeks) 1
• Patients should not continue using zopiclone for extended periods 1
• Prescriptions should ideally be limited to occasional or intermittent use, or courses not exceeding 2 weeks 6

Dosing Considerations

• If prescribed, zopiclone should be administered at the lowest effective dose and for the shortest possible duration 1
• Caution and downward dosage adjustment is advised in elderly patients 1

Monitoring

• Patients with insomnia that does not remit within 7-10 days of treatment should be further evaluated 1
• All patients should be counseled on the potential risks 1

Alternative Approaches

First-Line Treatment

• Cognitive behavioral therapy for insomnia (CBT-I) is recommended as first-line treatment for chronic insomnia disorder 1
• Non-pharmacologic behavioral interventions are more effective than pharmacologic therapies for treatment of chronic insomnia disorder 1

Alternative Pharmacotherapy

• If medication is necessary, low-dose doxepin (3 or 6 mg) may be considered as it has a better safety profile for long-term use 1
• For short-term use, eszopiclone may be preferable to zopiclone in some cases, though it carries similar risks 1

Clinical Pitfalls to Avoid

1. Prolonged prescribing: Never prescribe zopiclone for longer than 4-5 weeks without careful reassessment 1
2. Dose escalation: Avoid increasing doses to overcome tolerance, as this increases dependence risk 2
3. Abrupt discontinuation: Taper gradually to minimize withdrawal symptoms 7
4. Overlooking alternatives: Don't neglect non-pharmacological approaches like CBT-I 1
5. Ignoring high-risk patients: Exercise extra caution in patients with history of substance abuse or psychiatric disorders 2

While zopiclone was initially thought to have lower dependence potential than benzodiazepines 4, 5, more recent evidence and guidelines indicate that its long-term risks are substantial and similar to those of benzodiazepines 1, 2. The safest approach is to limit use to short periods and prioritize non-pharmacological interventions for chronic insomnia.