What is the best medication for insomnia?

Best Medication for Insomnia

Cognitive Behavioral Therapy for Insomnia (CBT-I) should be the initial treatment for all adults with chronic insomnia, but when pharmacotherapy is necessary, short-to-intermediate acting benzodiazepine receptor agonists (BzRAs)—specifically eszopiclone, zolpidem, or zaleplon—are first-line medications, with the choice determined by whether the primary complaint is sleep onset versus sleep maintenance. 1, 2

Treatment Algorithm

Step 1: Start with CBT-I

• CBT-I is the gold standard first-line treatment for chronic insomnia in all adults, demonstrating superior long-term efficacy compared to medications with minimal adverse effects 1, 2
• CBT-I should include stimulus control therapy, sleep restriction therapy, relaxation techniques, and cognitive restructuring 1, 3
• Even when medications are used, behavioral techniques should continue alongside pharmacotherapy 4, 2

Step 2: First-Line Pharmacotherapy (When CBT-I Alone Is Insufficient)

For Sleep Onset Insomnia:

• Zaleplon 10 mg at bedtime (short-acting; can be used for middle-of-night awakening if ≥4 hours remain for sleep) 4, 1
• Zolpidem 10 mg at bedtime (5 mg in elderly; short-to-intermediate acting) 4, 1, 5
• Ramelteon 8 mg at bedtime (melatonin receptor agonist; no abuse potential, useful for patients with substance use history) 4, 1, 2
• Triazolam 0.25 mg at bedtime (0.125 mg in elderly; associated with rebound anxiety, not truly first-line) 4, 1

For Sleep Maintenance Insomnia:

• Eszopiclone 2-3 mg at bedtime (1 mg in elderly; intermediate-acting; no short-term usage restriction, proven effective up to 6 months) 4, 1, 6
• Zolpidem 10 mg or zolpidem controlled-release 12.5 mg at bedtime (6.25 mg in elderly) 4, 1, 5
• Temazepam 15-30 mg at bedtime (7.5 mg in elderly; benzodiazepine, short-to-intermediate acting) 4, 1

Step 3: Second-Line Options

If first-line BzRAs fail or are contraindicated:

• Low-dose doxepin 3-6 mg at bedtime for sleep maintenance insomnia (sedating antidepressant with histamine antagonism) 1, 3, 2
• Suvorexant (orexin receptor antagonist) for sleep maintenance 1, 2
• Consider alternative BzRAs with different duration of action based on residual symptoms 4

For patients with comorbid depression or anxiety:

• Sedating antidepressants such as trazodone, mirtazapine, or amitriptyline may be considered, though evidence for efficacy is relatively weak 4, 1
• Note that low-dose sedating antidepressants do not constitute adequate treatment for major depression 4

Step 4: Agents NOT Recommended

• Trazodone is NOT recommended for sleep onset or maintenance insomnia by current guidelines 1
• Over-the-counter antihistamines (diphenhydramine) are not recommended due to lack of efficacy data and safety concerns 1, 2
• Herbal supplements (valerian) and melatonin supplements lack sufficient evidence 1
• Antipsychotics (quetiapine) are not recommended as first-line due to metabolic side effects 3, 2
• Barbiturates and chloral hydrate are not recommended 1

Critical Safety Considerations

Duration of Use:

• FDA approval is for short-term use only (4-5 weeks) for most hypnotics 2
• Eszopiclone has no short-term usage restriction and has been studied for up to 6 months 4, 6
• Use the lowest effective dose for the shortest duration necessary 2

Next-Day Impairment:

• Eszopiclone 3 mg causes next-morning psychomotor and memory impairment that persists up to 11.5 hours post-dose, even when patients don't subjectively perceive impairment 6
• Zolpidem shows small but statistically significant decreases in performance on cognitive testing 5
• FDA labels warn of daytime impairment, "sleep driving," behavioral abnormalities, and worsening depression 2

Serious Risks:

• Hypnotic drugs are associated with dementia, injury, fractures, dependence, withdrawal reactions, and cognitive impairment, particularly in older adults 1, 2
• Anterograde amnesia can occur, predominantly at doses above 10 mg for zolpidem 5

Common Pitfalls to Avoid

• Never use benzodiazepines like lorazepam or clonazepam as first-line treatment—these are second or third-line options only 1
• Don't prescribe medications without implementing CBT-I techniques alongside pharmacotherapy 1, 7
• Avoid combining multiple sedative medications, which increases adverse effect risk 3
• Don't continue long-term pharmacotherapy without periodic reassessment and attempts at tapering 1, 2
• Don't ignore drug interactions and contraindications, particularly in elderly patients 1
• Avoid using sedating agents without matching them to the specific sleep complaint (onset vs. maintenance) 1

Medication Selection Nuances

The 2008 AASM guideline provides a practical framework: if a patient on a shorter-acting agent continues to complain of wake after sleep onset (WASO), prescribe a drug with longer half-life; if a patient complains of residual sedation, prescribe a shorter-acting drug 4

Flurazepam is rarely prescribed due to its extended half-life and risk of residual daytime drowsiness 4

Ramelteon offers unique advantages for patients with substance use history due to lower abuse potential, though evidence quality is lower than for BzRAs 2