What are the first‑line medications for primary insomnia in adults, and which agents are preferred for older adults or patients at risk of dependence?

First-Line Medications for Insomnia

Cognitive Behavioral Therapy for Insomnia (CBT-I) must be initiated before or alongside any pharmacotherapy, as it provides superior long-term efficacy with sustained benefits after medication discontinuation. 1, 2

First-Line Pharmacologic Agents

When medication is necessary after initiating CBT-I, the following agents are recommended:

For Sleep-Onset Insomnia

• Zolpidem 10 mg (5 mg in elderly) reduces sleep latency by approximately 25 minutes and improves total sleep time by 29 minutes, with moderate-quality evidence supporting its use for both sleep onset and maintenance 1, 2
• Zaleplon 10 mg (5 mg in elderly) has a very short half-life providing rapid sleep initiation with minimal next-day sedation, specifically targeting sleep-onset problems 2
• Ramelteon 8 mg is a melatonin receptor agonist with zero addiction potential and no abuse liability, making it particularly suitable for patients with substance use history 2, 3

For Sleep-Maintenance Insomnia

• Low-dose doxepin 3–6 mg is the preferred first-line option for sleep maintenance, demonstrating a 22–23 minute reduction in wake after sleep onset with minimal anticholinergic effects at hypnotic doses and no abuse potential 1, 2, 4
• Eszopiclone 2–3 mg addresses both sleep onset and maintenance with moderate-to-large improvements in sleep quality and a 28–57 minute increase in total sleep time 2, 5

For Older Adults (≥65 Years)

• Ramelteon 8 mg or low-dose doxepin 3 mg are the safest first-line choices due to minimal fall risk and cognitive impairment 2, 3
• Zolpidem maximum dose must be reduced to 5 mg in elderly patients due to increased sensitivity and fall risk 1, 2
• Eszopiclone starting dose should be 1 mg (maximum 2 mg) in elderly or debilitated patients 5

Agents to Avoid as First-Line

• Traditional benzodiazepines (lorazepam, temazepam, triazolam) should NOT be used as first-line treatment due to higher risk of dependency, falls, cognitive impairment, and respiratory depression compared to non-benzodiazepines 2, 3
• Trazodone is explicitly NOT recommended for insomnia treatment, showing only minimal benefit (10 minutes reduction in sleep latency) with no improvement in subjective sleep quality and harms outweighing benefits 1, 2
• Over-the-counter antihistamines (diphenhydramine) are NOT recommended due to lack of efficacy data, strong anticholinergic effects causing confusion and fall risk, and tolerance developing after only 3–4 days 2, 3
• Antipsychotics (quetiapine, olanzapine) should NOT be used for primary insomnia due to insufficient evidence and significant metabolic side effects including weight gain and metabolic syndrome 2

Treatment Algorithm

1. Initiate CBT-I immediately for all patients with chronic insomnia, including stimulus control therapy, sleep restriction therapy, relaxation techniques, and cognitive restructuring 1, 2

2. If CBT-I alone is insufficient after 4–8 weeks, add pharmacotherapy using shared decision-making:

   • For sleep-onset problems: zaleplon, ramelteon, or zolpidem 2
   • For sleep-maintenance problems: low-dose doxepin 3–6 mg or eszopiclone 2, 4
   • For elderly patients: ramelteon 8 mg or doxepin 3 mg as safest options 2, 3

3. Use the lowest effective dose for the shortest duration possible (typically ≤4 weeks per FDA labeling), with reassessment after 1–2 weeks to evaluate efficacy and monitor for adverse effects 1, 2

4. If first-line agent unsuccessful, try an alternative agent within the same class before moving to second-line options 2

Critical Safety Monitoring

• Screen for complex sleep behaviors (sleep-driving, sleep-walking, sleep-eating) and discontinue medication immediately if these occur 2, 6
• Monitor for daytime impairment, particularly morning driving impairment, which can persist 7.5–11.5 hours after dosing with some agents 5
• Watch for falls and fractures, especially in elderly patients, as observational studies link hypnotic use to increased fracture risk 1, 7
• Assess for cognitive and behavioral changes, including memory impairment and confusion, particularly in older adults 5

Special Considerations for Patients at Risk of Dependence

• Ramelteon is the only appropriate first-line choice for patients with substance use history due to its zero abuse potential and non-DEA-scheduled status 2
• Avoid all benzodiazepines in this population due to high potential for developing tolerance, physical dependence, and severe withdrawal syndrome 2
• Non-benzodiazepine hypnotics (Z-drugs) have significantly lower addiction potential than traditional benzodiazepines but still carry some risk 2, 8

Common Pitfalls to Avoid

• Failing to initiate CBT-I before or alongside pharmacotherapy, as behavioral interventions provide more sustained effects than medication alone 1, 2
• Using doses appropriate for younger adults in older adults—zolpidem requires age-adjusted dosing with a maximum of 5 mg in elderly 2
• Continuing pharmacotherapy long-term without periodic reassessment, as evidence is insufficient to support use beyond 4 weeks and FDA labeling recommends short-term use only 1
• Prescribing medication without adequate patient education about treatment goals, safety concerns, potential side effects, and the importance of taking medication only when ≥7–8 hours of sleep time is available 2, 6