Medication for Sleep Onset and Maintenance Insomnia
First-Line Recommendation
For an adult with both sleep onset and maintenance insomnia, start eszopiclone 2–3 mg at bedtime—but only after initiating Cognitive Behavioral Therapy for Insomnia (CBT-I), which must be delivered concurrently because pharmacotherapy alone produces inferior long-term outcomes. 1, 2
Treatment Algorithm
Step 1: Initiate CBT-I Immediately (Mandatory Foundation)
CBT-I is the standard of care and must precede or accompany any medication; it provides superior long-term efficacy with sustained benefits after drug discontinuation, whereas medications lose effectiveness once stopped. 1, 2, 3
Core components to implement:
- Stimulus control: Leave bed when unable to sleep; use bedroom only for sleep and sex. 1, 4
- Sleep restriction: Limit time in bed to actual sleep time plus 30 minutes to consolidate sleep. 1, 4
- Relaxation techniques: Progressive muscle relaxation, guided imagery, or diaphragmatic breathing. 1, 3, 4
- Cognitive restructuring: Challenge dysfunctional beliefs about sleep (e.g., "I must get 8 hours or I'll be ruined"). 1, 4
- Sleep hygiene: Fixed wake time, avoid caffeine after noon, no alcohol in evening, no heavy meals within 3 hours of bedtime, limit daytime naps to 15–20 minutes before 3 PM. 2, 5
CBT-I can be delivered via individual therapy, group sessions, telephone programs, web-based modules, or self-help books—all formats demonstrate efficacy. 1, 2
Step 2: Add First-Line Pharmacotherapy (If CBT-I Alone Insufficient After 4–8 Weeks)
Eszopiclone 2–3 mg (Preferred for Combined Sleep Onset + Maintenance)
Dosing: Start 2 mg at bedtime (1 mg if age ≥65 years or hepatic impairment); take within 30 minutes of bedtime with at least 7 hours remaining before planned awakening. 1, 2, 6
Efficacy: Reduces sleep onset latency by ~19 minutes, increases total sleep time by 28–57 minutes, and produces moderate-to-large improvement in subjective sleep quality. 1, 2, 6
Titration: If 2 mg is well tolerated but insufficient after 1–2 weeks, increase to 3 mg. 1, 2, 6
Duration: FDA labeling indicates short-term use (≤4 weeks) for acute insomnia; evidence beyond 4 weeks is insufficient, though 6-month trials exist. 1, 2, 6
Monitoring: Reassess at 1–2 weeks for changes in sleep onset latency, total sleep time, nocturnal awakenings, daytime functioning, and adverse effects (somnolence, bitter taste, headache, memory impairment). 1, 2, 6
Step 3: Alternative First-Line Options (If Eszopiclone Fails or Is Contraindicated)
For Persistent Sleep-Onset Problems:
Zolpidem 10 mg (5 mg if age ≥65 years): Shortens sleep onset latency by ~25 minutes and increases total sleep time by ~29 minutes; take within 30 minutes of bedtime with ≥7 hours remaining. 1, 2
Zaleplon 10 mg (5 mg if age ≥65 years): Very short half-life (~1 hour) provides rapid sleep initiation with minimal next-day sedation; suitable for middle-of-night dosing when ≥4 hours remain before awakening. 1, 2
Ramelteon 8 mg: Melatonin-receptor agonist with no abuse potential, no DEA scheduling, and no withdrawal symptoms; appropriate for patients with substance-use history. 1, 2
For Persistent Sleep-Maintenance Problems:
Low-dose doxepin 3–6 mg: Reduces wake after sleep onset by 22–23 minutes via selective H₁-histamine antagonism, with minimal anticholinergic effects and no abuse potential; start 3 mg, increase to 6 mg if insufficient after 1–2 weeks. 1, 2, 7
Suvorexant 10 mg: Orexin-receptor antagonist reduces wake after sleep onset by 16–28 minutes; lower risk of cognitive and psychomotor impairment than benzodiazepine-type agents. 1, 2, 7
Step 4: If Multiple First-Line Agents Fail
Switch to an alternative agent within the same class (e.g., eszopiclone → zolpidem for onset; doxepin → suvorexant for maintenance). 1, 2
Consider sedating antidepressants (e.g., low-dose doxepin, mirtazapine) if comorbid depression or anxiety is present. 1, 2
Critical Safety Warnings
Complex Sleep Behaviors (Highest Priority)
All benzodiazepine-receptor agonists (eszopiclone, zolpidem, zaleplon) carry FDA warnings for complex sleep behaviors: sleep-driving, sleep-walking, sleep-eating, and other activities performed while not fully awake. 1, 2, 6
Discontinue medication immediately if patient reports performing activities while not fully awake. 1, 6
Counsel patients to avoid alcohol while on these agents, as it markedly increases risk. 1, 6
Next-Day Impairment
Eszopiclone 3 mg causes next-morning psychomotor and memory impairment that is most severe at 7.5 hours but still present and potentially clinically meaningful at 11.5 hours. 6
Patients may not perceive their own impairment despite objective deficits; warn against driving or operating machinery until fully awake. 6
Falls, Fractures, and Cognitive Decline
All hypnotics increase risk of falls, fractures, and cognitive impairment, particularly in elderly patients (age ≥65 years). 1, 2, 5
Observational data link hypnotic use to increased dementia risk, though causality is unproven. 1, 2
Dose Adjustments for Special Populations
Age ≥65 years: Eszopiclone maximum 2 mg, zolpidem maximum 5 mg, zaleplon maximum 5 mg. 1, 2, 5, 6
Hepatic impairment: Eszopiclone maximum 2 mg, zaleplon maximum 5 mg. 1, 2, 6
Medications Explicitly NOT Recommended
Trazodone
- The American Academy of Sleep Medicine explicitly recommends against trazodone for insomnia: yields only ~10 minutes reduction in sleep latency and ~8 minutes reduction in wake after sleep onset, with no improvement in subjective sleep quality; adverse events occur in ~75% of older adults (headache, somnolence), and harms outweigh minimal benefits. 1, 2, 7
Over-the-Counter Antihistamines (Diphenhydramine, Doxylamine)
- The American Academy of Sleep Medicine explicitly recommends against diphenhydramine and other antihistamines: lack efficacy data, cause strong anticholinergic effects (confusion, urinary retention, falls, daytime sedation, delirium), and develop tolerance within 3–4 days. 1, 2, 5
Traditional Benzodiazepines (Lorazepam, Clonazepam, Diazepam)
- The American Academy of Sleep Medicine recommends against traditional benzodiazepines as first-line treatment: long half-lives lead to drug accumulation, prolonged daytime sedation, higher fall and cognitive-impairment risk, and associations with dementia and fractures. 1, 2, 5
Antipsychotics (Quetiapine, Olanzapam)
- The American Academy of Sleep Medicine recommends against antipsychotics for insomnia: weak evidence for benefit and significant risks (weight gain, metabolic dysregulation, extrapyramidal symptoms, increased mortality in elderly patients with dementia). 1, 2
Melatonin Supplements
- The American Academy of Sleep Medicine recommends against melatonin for insomnia: produces only ~9 minutes reduction in sleep latency with insufficient evidence of efficacy. 1, 2, 7
Herbal Supplements (Valerian, L-Tryptophan)
- The American Academy of Sleep Medicine recommends against herbal supplements: insufficient evidence to support use for primary insomnia. 1, 2
Common Pitfalls to Avoid
Initiating pharmacotherapy without first employing CBT-I: Behavioral interventions provide more durable benefits than medication alone and must be the foundation of treatment. 1, 2, 3
Using adult dosing in older adults: Age-adjusted dosing (e.g., eszopiclone ≤2 mg, zolpidem ≤5 mg for age ≥65 years) is essential to reduce fall risk. 1, 2, 5, 6
Combining multiple sedative agents: Markedly increases risk of respiratory depression, cognitive impairment, falls, and complex sleep behaviors. 1, 2
Failing to reassess pharmacotherapy regularly: Evaluate efficacy, side effects, and continued need every 2–4 weeks; plan tapering after 3–6 months if effective. 1, 2, 6
Prescribing agents without matching pharmacologic profile to insomnia phenotype: Use zaleplon for onset only, doxepin for maintenance only, eszopiclone for combined onset + maintenance. 1, 2, 7
Continuing pharmacotherapy long-term without periodic reassessment: FDA labeling indicates hypnotics are intended for short-term use; evidence does not support routine use beyond 4 weeks. 1, 2, 6
Using trazodone, OTC antihistamines, antipsychotics, or traditional benzodiazepines: These agents lack efficacy and carry significant safety concerns. 1, 2, 5, 7
Practical Implementation Summary
Start CBT-I immediately (stimulus control, sleep restriction, relaxation, cognitive restructuring, sleep hygiene). 1, 2, 3, 4
Add eszopiclone 2 mg at bedtime (1 mg if age ≥65 years) within 30 minutes of bedtime with ≥7 hours remaining. 1, 2, 6
Reassess at 1–2 weeks; if insufficient, increase to 3 mg (2 mg maximum if age ≥65 years). 1, 2, 6
Monitor for complex sleep behaviors, next-day impairment, falls, and cognitive changes at every visit. 1, 2, 6
If eszopiclone fails after 1–2 weeks, switch to zolpidem, zaleplon, or ramelteon (for onset) or doxepin or suvorexant (for maintenance). 1, 2, 7
Use lowest effective dose for shortest necessary duration; attempt taper after 3–6 months, using CBT-I to support discontinuation. 1, 2, 6
If insomnia persists beyond 7–10 days despite treatment, evaluate for comorbid sleep disorders (sleep apnea, restless-legs syndrome, circadian-rhythm disorders). 1, 2