Best Medication for Primary Insomnia
For primary insomnia, short-to-intermediate acting benzodiazepine receptor agonists (BzRAs)—specifically zolpidem, eszopiclone, or zaleplon—are the recommended first-line pharmacological treatments, with zolpidem and eszopiclone having the strongest evidence for both sleep onset and maintenance. 1, 2
Treatment Algorithm
Step 1: Cognitive Behavioral Therapy First
- Cognitive Behavioral Therapy for Insomnia (CBT-I) should be the initial treatment before any medication, as it demonstrates superior long-term outcomes with sustained benefits after discontinuation and no adverse effects 1, 2
- CBT-I includes stimulus control therapy, sleep restriction therapy, relaxation therapy, and cognitive therapy 1
- Pharmacotherapy should supplement—not replace—behavioral interventions when possible 1
Step 2: First-Line Pharmacotherapy (When CBT-I Fails or Is Unavailable)
Primary options include:
Zolpidem 10 mg (5 mg for elderly): Reduces sleep latency and improves sleep maintenance with moderate-to-low quality evidence 1, 3
Eszopiclone 3 mg (2 mg for elderly): Superior evidence for sleep maintenance 1, 6
Zaleplon: Best for sleep-onset insomnia with very short half-life and minimal residual sedation 2, 5
Ramelteon 8 mg: Particularly suitable for patients with substance use history due to no dependence potential 2
Step 3: Second-Line Options (If First-Line Fails)
- Alternate BzRA or ramelteon if initial agent unsuccessful 1, 2
- Low-dose doxepin 3-6 mg: Particularly effective for sleep maintenance with minimal side effects 2
Step 4: Third-Line Options
- Sedating antidepressants (trazodone, amitriptyline, doxepin, mirtazapine): Reserved for comorbid depression/anxiety 1, 2
- Used at lower than antidepressant doses when targeting insomnia alone 2
Step 5: Avoid These Medications
- Traditional benzodiazepines (lorazepam, temazepam): Higher risk of tolerance, dependence, falls, and cognitive impairment—especially in elderly 2
- Atypical antipsychotics (quetiapine, olanzapine): Explicitly warned against for primary insomnia due to weak evidence and significant adverse effects including weight gain and metabolic syndrome 2
- Over-the-counter antihistamines: Not recommended due to lack of efficacy and safety data 1
- Barbiturates and chloral hydrate: Not recommended 1
Critical Safety Considerations
Next-Day Impairment
- Zolpidem and eszopiclone cause psychomotor and memory impairment 7.5-11.5 hours post-dose, even when patients don't subjectively perceive sedation 6
- FDA mandates dose reduction in women and elderly due to driving impairment risk 1
Monitoring Requirements
- Follow patients every few weeks initially to assess effectiveness and side effects 1
- Use lowest effective maintenance dose 1
- Educate patients about anterograde amnesia risk, particularly at doses >10 mg zolpidem 3
- Gradual dose reduction when discontinuing to minimize withdrawal 1
Comparative Effectiveness
- Eszopiclone and zolpidem have the strongest evidence with low-to-moderate quality data showing small but significant improvements in global and sleep outcomes 1
- The newer suvorexant (orexin receptor antagonist) also shows efficacy but with less extensive long-term data 1
- Non-benzodiazepines cause less sleep architecture disruption, less psychomotor impairment, and milder withdrawal compared to traditional benzodiazepines 5, 8
Long-Term Safety Concerns
- Observational studies suggest hypnotic use may be associated with increased risk of dementia, fractures, and major injury, though causality is not established 1
- Prescribe for shortest duration necessary with regular reassessment 1, 8
The choice between zolpidem and eszopiclone depends on the primary sleep complaint: zolpidem for sleep onset, eszopiclone for sleep maintenance, though both address both domains. 2, 3, 6