What are the first‑line and second‑line medication options for adult insomnia, and how should treatment be adjusted for elderly patients?

Medications for Insomnia: First-Line and Second-Line Options

Cognitive Behavioral Therapy for Insomnia (CBT-I) Must Come First

All adults with chronic insomnia should receive Cognitive Behavioral Therapy for Insomnia (CBT-I) as the initial treatment before or alongside any pharmacotherapy, as it demonstrates superior long-term efficacy with sustained benefits after medication discontinuation. 1, 2, 3

• CBT-I includes stimulus control therapy, sleep restriction therapy, cognitive restructuring, relaxation training, and sleep hygiene education 2, 3
• Delivery formats include individual therapy, group sessions, telephone-based programs, web-based modules, or self-help books—all showing effectiveness 2, 3
• Sleep hygiene education alone is insufficient as monotherapy and must be combined with other CBT-I components 1, 2

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First-Line Pharmacotherapy Options

For Sleep Onset and Maintenance Insomnia

When pharmacotherapy is necessary after initiating CBT-I, short/intermediate-acting benzodiazepine receptor agonists (BzRAs) or ramelteon are first-line agents. 1, 2, 3

Eszopiclone (Lunesta)

• Dose: 2–3 mg at bedtime 2, 3
• Indication: Both sleep onset and maintenance insomnia 2, 3
• Evidence: Moderate-quality evidence showing 28–57 minute increase in total sleep time and moderate-to-large improvement in sleep quality 2
• Elderly dosing: Start 1 mg, maximum 2 mg 2

Zolpidem (Ambien)

• Dose: 10 mg at bedtime (5 mg in elderly) 2, 3, 4
• Indication: Both sleep onset and maintenance insomnia 2, 3
• Evidence: Reduces sleep latency by 15–25 minutes and improves total sleep time by 29 minutes 2, 4
• Critical safety: Maximum 5 mg in elderly due to increased fall risk and cognitive impairment 2, 3

Zaleplon (Sonata)

• Dose: 10 mg at bedtime (5 mg in elderly) 2, 3, 5
• Indication: Sleep onset insomnia specifically 2, 3
• Advantage: Very short half-life with minimal residual sedation 2, 5
• Evidence: Superior to placebo in reducing sleep latency in transient and chronic insomnia 5

Temazepam (Restoril)

• Dose: 15 mg at bedtime 2
• Indication: Both sleep onset and maintenance insomnia 2

Ramelteon (Rozerem)

• Dose: 8 mg at bedtime 2, 3
• Indication: Sleep onset insomnia 2
• Advantage: Zero addiction potential, non-DEA scheduled, preferred for patients with substance abuse history 3, 6

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Second-Line Pharmacotherapy Options

Low-Dose Doxepin

• Dose: 3–6 mg at bedtime 2, 3
• Indication: Sleep maintenance insomnia specifically 2, 3
• Evidence: Moderate-quality evidence showing 22–23 minute reduction in wake after sleep onset, improves sleep efficiency, total sleep time, and sleep quality 2
• Advantage: Minimal anticholinergic effects at hypnotic doses, no abuse potential 2, 3
• Preferred in elderly: Safest choice for older adults transitioning off antihistamines 2

Suvorexant (Belsomra)

• Dose: 10 mg at bedtime 2
• Indication: Sleep maintenance insomnia 2
• Evidence: Moderate-quality evidence showing 16–28 minute reduction in wake after sleep onset 2
• Mechanism: Orexin receptor antagonist—different mechanism than BzRAs 2

Sedating Antidepressants (for Comorbid Depression/Anxiety)

• Preferred initial choice when comorbid depression or anxiety is present 1, 2, 6
• Options include mirtazapine, low-dose doxepin, and amitriptyline 1, 2
• Trazodone is explicitly NOT recommended due to cardiac risks, lack of efficacy data, and morning grogginess 2, 3, 6

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Medications Explicitly NOT Recommended

Over-the-Counter Antihistamines

• Diphenhydramine (Benadryl) and doxylamine are NOT recommended due to lack of efficacy data, daytime sedation, confusion, urinary retention, and tolerance development after 3–4 days 1, 2, 3, 6

Herbal Supplements and Melatonin

• Valerian, melatonin, and L-tryptophan are NOT recommended due to insufficient evidence of efficacy 1, 2, 3

Older Hypnotics

• Barbiturates, barbiturate-type drugs, and chloral hydrate are NOT recommended 1

Atypical Antipsychotics

• Quetiapine and olanzapine are NOT recommended due to insufficient evidence for insomnia treatment and significant metabolic side effects 2, 6

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Adjustments for Elderly Patients

Dose Reductions Required

• Zolpidem: Maximum 5 mg (not 10 mg) due to increased sensitivity, fall risk, and cognitive impairment 2, 3, 4
• Eszopiclone: Start 1 mg, maximum 2 mg 2
• Zaleplon: 5 mg (not 10 mg) 2, 3, 5

Preferred Agents in Elderly

• Low-dose doxepin 3 mg is the safest first-line choice for elderly patients with sleep maintenance insomnia due to minimal anticholinergic activity and no abuse potential 2
• Ramelteon 8 mg is also safe due to minimal fall risk and cognitive impairment 2

Avoid in Elderly

• Long-acting benzodiazepines (e.g., flurazepam) due to extended half-life, active metabolites, and impaired clearance 6
• Traditional benzodiazepines (e.g., diazepam, clonazepam) due to long half-life, drug accumulation, prolonged daytime sedation, and increased risk of falls and cognitive impairment 2

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Essential Prescribing Principles

Duration and Dosing

• Use the lowest effective dose for the shortest duration possible (typically less than 4 weeks for acute insomnia) 1, 2, 3
• Pharmacotherapy should supplement, not replace, CBT-I 1, 2, 3
• Long-term administration may be nightly, intermittent (e.g., three nights per week), or as needed 1

Monitoring and Follow-Up

• Reassess after 1–2 weeks to evaluate efficacy on sleep latency, sleep maintenance, daytime functioning, and adverse effects 2, 3
• Patients should be followed regularly, every few weeks in the initial period of treatment, to assess effectiveness, possible side effects, and need for ongoing medication 1
• Efforts should be made to taper medication when conditions allow, with CBT-I facilitating successful discontinuation 1, 2

Patient Education Requirements

• Treatment goals and expectations 1
• Safety concerns, including complex sleep behaviors (sleep-driving, sleep-walking, sleep-eating) 1, 2, 3
• Potential side effects and drug interactions 1
• Importance of behavioral treatments 1
• Potential for dosage escalation and rebound insomnia 1

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Critical Safety Warnings

Complex Sleep Behaviors

• All BzRAs may cause complex sleep behaviors including sleep-driving, sleep-walking, and sleep-eating 2, 3
• Medication should be stopped immediately if patient discovers they performed activities while not fully awake 2

Falls, Fractures, and Cognitive Impairment

• All hypnotic medications carry FDA warnings about daytime impairment, falls and fractures, cognitive impairment, worsening depression, dependence, and withdrawal 2, 3
• Observational studies link hypnotic use to increased fractures, major injuries, and possibly dementia 2

Drug Interactions

• Zaleplon is primarily metabolized by aldehyde oxidase and to a lesser extent by CYP3A4; inhibitors of these enzymes may decrease clearance 5
• Zaleplon has minimal effects on warfarin, imipramine, ethanol, ibuprofen, diphenhydramine, thioridazine, and digoxin 5

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Common Pitfalls to Avoid

• Failing to initiate CBT-I before or alongside pharmacotherapy 2, 3
• Using benzodiazepines as first-line treatment instead of BzRAs or ramelteon 1, 2
• Prescribing trazodone for insomnia despite explicit guideline recommendations against it 2, 3, 6
• Using over-the-counter sleep aids or herbal supplements with limited efficacy data 1, 2, 3
• Continuing pharmacotherapy long-term without periodic reassessment 1, 2, 3
• Failing to adjust doses in elderly patients (e.g., using zolpidem 10 mg instead of 5 mg) 2, 3