What are the recommended pharmacotherapy approaches for the treatment of insomnia?

Pharmacotherapy of Insomnia

For patients with chronic insomnia requiring pharmacological treatment, short-intermediate acting benzodiazepine receptor agonists (BzRAs) or ramelteon should be used as first-line medications, followed by alternative agents in the same class if unsuccessful, then sedating antidepressants for patients with comorbid depression/anxiety. 1

First-Line Pharmacotherapy Options

Benzodiazepine Receptor Agonists (BzRAs)

• Eszopiclone is suggested for both sleep onset and sleep maintenance insomnia at doses of 2-3 mg 1
• Zaleplon is suggested for sleep onset insomnia at a dose of 10 mg 1
• Zolpidem is suggested for both sleep onset and sleep maintenance insomnia at a dose of 10 mg (5 mg in elderly) 1, 2
• These non-benzodiazepine BzRAs generally cause less disruption of normal sleep architecture than traditional benzodiazepines 3
• They have become the most commonly prescribed hypnotic agents due to proven efficacy, reduced side effects, and less concern about addiction 4

Benzodiazepines

• Temazepam is suggested for both sleep onset and sleep maintenance insomnia at a dose of 15 mg 1
• Triazolam is suggested for sleep onset insomnia at a dose of 0.25 mg, though it has been associated with rebound anxiety and is not considered first-line 1

Melatonin Receptor Agonists

• Ramelteon is suggested for sleep onset insomnia at a dose of 8 mg 1, 5
• FDA-approved specifically for treatment of insomnia characterized by difficulty with sleep onset 5
• May be particularly appropriate for patients who prefer not to use DEA-scheduled drugs or those with a history of substance use disorders 1

Second-Line Options

Sedating Antidepressants

• Doxepin (3-6 mg) is suggested for sleep maintenance insomnia 1
• Trazodone is not recommended for sleep onset or maintenance insomnia 1

Other Agents

• Suvorexant (orexin receptor antagonist) is suggested for sleep maintenance insomnia 1
• Tiagabine (anticonvulsant) is not recommended for sleep onset or maintenance insomnia 1

Not Recommended Agents

• Over-the-counter antihistamines (e.g., diphenhydramine) are not recommended due to lack of efficacy data and safety concerns 1
• Herbal supplements (e.g., valerian) and nutritional substances (e.g., melatonin) are not recommended due to insufficient evidence of efficacy 1
• Older hypnotics including barbiturates and chloral hydrate are not recommended 1

Selection Algorithm

1. Assess symptom pattern:

   • For sleep onset difficulty: Consider zaleplon, ramelteon, zolpidem, or triazolam 1
   • For sleep maintenance: Consider eszopiclone, zolpidem, temazepam, doxepin, or suvorexant 1
   • For both onset and maintenance: Consider eszopiclone, zolpidem, or temazepam 1

2. Consider patient factors:

   • History of substance abuse: Consider ramelteon (non-scheduled) 1
   • Elderly patients: Use lower doses (e.g., zolpidem 5 mg) 2
   • Comorbid depression/anxiety: Consider doxepin 1
   • Hepatic impairment: Reduce doses (e.g., zolpidem 5 mg) 2

3. Medication trial sequence:

   • Start with short/intermediate-acting BzRA or ramelteon 1
   • If unsuccessful, try alternative agent in same class 1
   • If still unsuccessful, consider sedating antidepressant (especially with comorbid depression/anxiety) 1
   • Consider combination therapy (BzRA or ramelteon plus sedating antidepressant) if monotherapy fails 1

Important Clinical Considerations

• Short-term hypnotic treatment should be supplemented with behavioral and cognitive therapies when possible 1
• Cognitive behavioral therapy for insomnia (CBT-I) is recommended as first-line treatment before pharmacotherapy 6
• Monitor patients regularly, especially during initial treatment period, to assess effectiveness and side effects 1
• While non-benzodiazepine BzRAs have lower abuse potential than traditional benzodiazepines, caution is still warranted in patients with history of substance abuse 7
• Tolerance to zolpidem appears minimal when used as recommended (≤10 mg/day for <1 month), with little evidence of rebound insomnia or withdrawal symptoms after discontinuation 8
• For optimal absorption, zolpidem should not be administered with or immediately after a meal 2

Common Pitfalls to Avoid

• Using sedating agents without considering their specific effects on sleep onset versus maintenance 1
• Prescribing medications without addressing underlying causes of insomnia 6
• Failing to consider drug interactions and contraindications 1
• Using over-the-counter sleep aids or herbal supplements with limited efficacy data 1
• Continuing pharmacotherapy long-term without periodic reassessment 1
• Overlooking the potential for dependence and abuse, particularly in patients with prior substance use disorders 7