What can be used as an adjunct to Zopiclone (eszopiclone) to help with sleep?

Adjunctive Therapies to Zopiclone for Sleep Management

Low-dose doxepin is the most appropriate adjunct to zopiclone for improving sleep maintenance, particularly if wake after sleep onset is the primary complaint. 1

First-Line Adjunctive Options

Pharmacological Options:

1. Low-dose doxepin (3-6 mg)

   • Particularly effective for sleep maintenance issues
   • Clinical guidelines suggest it as one of the preferred options when a sedating antidepressant is needed 1
   • Minimal next-day residual effects at low doses
   • Improves Insomnia Severity Index scores with moderate-quality evidence 1
   • Caution: Monitor for anticholinergic side effects, especially in elderly patients

2. Suvorexant (orexin receptor antagonist)

   • Effective for sleep maintenance insomnia
   • Recommended by clinical practice guidelines 1
   • Works through a different mechanism than zopiclone, potentially providing complementary effects
   • Less likely to cause tolerance or dependence than adding another GABA-modulating agent

3. Ramelteon (8 mg)

   • Specifically for sleep onset difficulties if zopiclone is inadequate
   • Melatonin receptor agonist with different mechanism of action than zopiclone
   • No risk of dependence (not a controlled substance)
   • Particularly useful for patients with substance use concerns 1

Algorithm for Selection Based on Specific Sleep Complaint:

For Sleep Onset Issues:

• Add ramelteon 8 mg 30 minutes before bedtime
• Alternative: Consider zaleplon for middle-of-night awakenings (short half-life)

For Sleep Maintenance Issues:

• Add low-dose doxepin 3-6 mg 30 minutes before bedtime
• Alternative: Consider suvorexant if doxepin is contraindicated or ineffective

Non-Pharmacological Adjuncts (Should Be Implemented Concurrently):

• Cognitive Behavioral Therapy for Insomnia (CBT-I)

  • Guidelines strongly recommend this as a first-line treatment 1
  • Should be implemented alongside pharmacotherapy
  • Components include stimulus control, sleep restriction, and cognitive therapy

• Stimulus Control Therapy

  • Go to bed only when sleepy
  • Use bed only for sleep
  • Leave bed if unable to sleep within 20 minutes
  • Maintain regular sleep schedule

• Sleep Restriction

  • Limit time in bed to actual sleep time
  • Gradually increase as sleep efficiency improves

Important Cautions and Considerations:

1. Avoid these combinations:

   • Adding another benzodiazepine or Z-drug to zopiclone (increased risk of respiratory depression and falls) 1
   • Antihistamines (limited efficacy data, anticholinergic effects) 1
   • Antipsychotics (significant risks outweigh benefits for insomnia) 1
   • Trazodone (guidelines specifically recommend against its use) 1
   • Melatonin, valerian, or other supplements (insufficient evidence) 1

2. Drug Interactions:

   • Eszopiclone (zopiclone) is metabolized by CYP3A4 and CYP2E1 2
   • Avoid combining with strong CYP3A4 inhibitors (e.g., ketoconazole can increase exposure 2.2-fold) 2
   • High-fat meals may reduce peak concentration and delay absorption 2

3. Monitoring:

   • Regular follow-up every few weeks during initial treatment 1
   • Assess effectiveness, side effects, and continued need for medication
   • Use lowest effective dose and taper when possible 1

Special Populations:

• Elderly patients:

  • Use lower doses of all medications
  • Doxepin may be particularly suitable at 3 mg dose
  • Higher risk of falls and cognitive impairment with multiple sedating medications

• Hepatic impairment:

  • Zopiclone exposure increases 2-fold in severe hepatic impairment 2
  • Avoid adding medications with significant hepatic metabolism

The combination of appropriate pharmacotherapy with CBT-I offers the most comprehensive approach to managing insomnia when zopiclone alone is insufficient 1. Always aim to use the lowest effective doses for the shortest duration necessary.