Best Medication for Sleep‑Maintenance Insomnia
For an adult with sleep‑maintenance insomnia (difficulty staying asleep), low‑dose doxepin 3–6 mg is the single best first‑line pharmacologic option after initiating Cognitive Behavioral Therapy for Insomnia (CBT‑I), based on superior efficacy, minimal side effects, and no abuse potential. 1, 2
Why Low‑Dose Doxepin Is the Top Choice
Doxepin 3–6 mg reduces wake after sleep onset by 22–23 minutes (95% CI: 14–30 min) and increases total sleep time by 26–32 minutes (95% CI: 18–40 min) compared with placebo, with moderate‑quality evidence supporting these outcomes. 1, 2
At hypnotic doses (3–6 mg), doxepin exhibits minimal anticholinergic activity, avoiding the confusion, urinary retention, and fall risk seen with higher antidepressant doses or over‑the‑counter antihistamines. 1, 2
Doxepin has no abuse potential and no DEA scheduling, making it safer than benzodiazepine‑receptor agonists (BzRAs) for long‑term use when needed. 1, 2
The American Academy of Sleep Medicine (AASM) and the American College of Physicians (ACP) both position low‑dose doxepin as a preferred first‑line agent specifically for sleep‑maintenance insomnia. 1, 2
Dosing and Administration
Start doxepin 3 mg at bedtime; if sleep maintenance remains inadequate after 1–2 weeks, increase to 6 mg. 1, 2
Take within 30 minutes of bedtime with at least 7 hours remaining before planned awakening to minimize next‑day sedation. 1
Reassess after 1–2 weeks to evaluate reduction in nocturnal awakenings, total sleep time, and daytime functioning, and monitor for adverse effects such as morning sedation or headache. 1, 2
Alternative Second‑Line Options (If Doxepin Fails or Is Contraindicated)
For Persistent Sleep‑Maintenance Problems
Suvorexant 10 mg (orexin‑receptor antagonist) reduces wake after sleep onset by 16–28 minutes via a mechanism distinct from BzRAs, with a lower risk of cognitive and psychomotor impairment. 1, 3, 4
Eszopiclone 2–3 mg (BzRA) increases total sleep time by 28–57 minutes and improves both sleep onset and maintenance, but carries higher risks of complex sleep behaviors, falls, and cognitive impairment compared with doxepin. 1, 5
Zolpidem 10 mg (5 mg for adults ≥65 years) shortens sleep‑onset latency by ~25 minutes and adds ~29 minutes to total sleep time, but is less effective for sleep maintenance than doxepin or suvorexant. 1, 5
Agents Explicitly Not Recommended for Sleep‑Maintenance Insomnia
Trazodone – Provides only ~10 min reduction in sleep latency and ~8 min reduction in wake after sleep onset, with no improvement in subjective sleep quality; adverse events occur in ~75% of older adults (headache, somnolence). The AASM recommends against its use. 1
Over‑the‑counter antihistamines (diphenhydramine, doxylamine) – Lack efficacy data, cause strong anticholinergic effects (confusion, urinary retention, falls, daytime sedation), and develop tolerance within 3–4 days. The AASM recommends against their use. 1
Traditional benzodiazepines (lorazepam, clonazepam, diazepam) – Long half‑lives lead to drug accumulation, prolonged daytime sedation, higher fall and cognitive‑impairment risk, and are linked to dementia and fractures. The AASM recommends against their use as first‑line treatment. 1
Antipsychotics (quetiapine, olanzapine) – Weak evidence for insomnia benefit and significant risks (weight gain, metabolic dysregulation, extrapyramidal symptoms, increased mortality in elderly with dementia). The AASM recommends against their use. 1
Melatonin supplements – Produce only ~9 min reduction in sleep latency; evidence of efficacy is insufficient for chronic insomnia. The AASM recommends against their use. 1
Essential Non‑Pharmacologic Foundation: CBT‑I
All adults with chronic insomnia must receive Cognitive Behavioral Therapy for Insomnia (CBT‑I) as the initial treatment, either alone or alongside any medication, because CBT‑I demonstrates superior long‑term efficacy with sustained benefits after drug discontinuation. 1
Core CBT‑I components include:
- Stimulus control – Use the bed only for sleep; leave the bed if unable to fall asleep within ~20 minutes. 1
- Sleep restriction – Limit time in bed to approximate actual sleep time plus a short buffer (e.g., total sleep time + 30 min). 1
- Relaxation techniques – Progressive muscle relaxation, guided imagery, or breathing exercises. 1
- Cognitive restructuring – Modify negative beliefs about sleep (e.g., "I must get 8 hours or I'll be useless"). 1
CBT‑I can be delivered via individual therapy, group sessions, telephone, web‑based modules, or self‑help books, all of which show comparable effectiveness. 1
Treatment Duration and Safety Monitoring
FDA labeling recommends hypnotics for short‑term use (≤4 weeks) for acute insomnia; evidence beyond 4 weeks is limited, though 12‑week trials of doxepin show maintained efficacy. 1, 2
Use the lowest effective dose for the shortest necessary duration, integrating CBT‑I to enable eventual tapering. 1
Monitor for complex sleep behaviors (e.g., sleep‑driving, sleep‑walking, sleep‑eating) at every visit; discontinue the medication immediately if such behaviors occur. 1, 5, 3
Screen for daytime impairment, falls, and cognitive changes, especially in older adults (≥65 years). 1, 6
If insomnia persists beyond 7–10 days despite appropriate therapy, evaluate for comorbid sleep disorders (e.g., sleep apnea, restless‑legs syndrome, periodic limb movement disorder, circadian‑rhythm disorders). 1
Special Population Adjustments
Older Adults (≥65 Years)
Start doxepin 3 mg (maximum 6 mg) in older adults; this is the safest first‑line option due to minimal fall risk and cognitive impairment. 1, 2
If a BzRA is necessary, reduce doses: zolpidem ≤5 mg, eszopiclone ≤2 mg, zaleplon ≤5 mg. 1, 5
Hepatic Impairment
Doxepin remains safe in mild‑to‑moderate hepatic impairment; no dose adjustment is required. 2
Eszopiclone and zaleplon require dose reduction (maximum 2 mg and 5 mg, respectively) due to reduced drug clearance. 1
Patients with Substance‑Use History
Ramelteon 8 mg (melatonin‑receptor agonist) is the only appropriate choice for sleep‑onset insomnia in this population due to zero abuse potential and no DEA scheduling. 1
Doxepin 3–6 mg is appropriate for sleep‑maintenance insomnia in this population because it has no abuse potential. 1, 2
Common Pitfalls to Avoid
Starting hypnotic therapy without first implementing CBT‑I – Leads to less durable benefit and higher risk of long‑term medication dependence. 1
Using trazodone, OTC antihistamines, or antipsychotics for primary insomnia despite lack of efficacy and significant safety concerns. 1
Combining multiple sedative agents (e.g., adding a benzodiazepine or Z‑drug to doxepin) – Markedly increases risk of respiratory depression, cognitive impairment, falls, and complex sleep behaviors. 1
Failing to reassess pharmacotherapy regularly (every 2–4 weeks) to evaluate efficacy, side effects, and ongoing medication need. 1
Continuing hypnotic therapy long‑term without periodic reassessment – FDA labeling indicates short‑term use; routine use beyond 4 weeks is not supported by evidence. 1
Using adult dosing in older adults – Age‑adjusted dosing (e.g., doxepin ≤6 mg, zolpidem ≤5 mg) is essential to reduce fall risk. 1, 6