What are the appropriate pharmacologic treatment options for a patient with primary insomnia and no contraindicating medical conditions?

Pharmacologic Treatment of Primary Insomnia

For a patient with primary insomnia and no contraindications, start with short- or intermediate-acting benzodiazepine receptor agonists (BzRAs) such as zolpidem, eszopiclone, or zaleplon as first-line pharmacotherapy—but only after initiating Cognitive Behavioral Therapy for Insomnia (CBT-I), which must be delivered concurrently because it provides superior long-term outcomes. 1, 2

Mandatory First-Line Behavioral Intervention

• CBT-I is the standard of care and must be started before or alongside any medication—this is a strong recommendation from both the American Academy of Sleep Medicine and the American College of Physicians, based on evidence showing sustained benefits after treatment ends, whereas medication effects cease when stopped. 1, 2

• CBT-I includes stimulus control (use bed only for sleep, leave bed if unable to sleep within 20 minutes), sleep restriction (limit time in bed to actual sleep time plus 30 minutes), relaxation techniques, and cognitive restructuring of negative sleep beliefs. 1, 2

• Sleep hygiene education alone is insufficient as monotherapy but should supplement other CBT-I components: avoid caffeine/alcohol in evening, maintain consistent sleep-wake times, limit daytime naps to 30 minutes before 2 PM, optimize bedroom environment (dark, quiet, comfortable temperature). 1, 2

First-Line Pharmacologic Options (Match to Symptom Pattern)

For Sleep-Onset Insomnia

• Zolpidem 10 mg (5 mg if age ≥65 years) reduces sleep-onset latency by approximately 25 minutes and increases total sleep time by 29 minutes; take within 30 minutes of bedtime with at least 7 hours remaining before planned awakening. 2, 3

• Zaleplon 10 mg (5 mg if age ≥65 years) has an ultrashort half-life (~1 hour), provides rapid sleep initiation with minimal next-day sedation, and can be used for middle-of-night awakenings when ≥4 hours remain before awakening. 2

• Ramelteon 8 mg is a melatonin receptor agonist with no abuse potential, no DEA scheduling, and no withdrawal symptoms—making it the preferred choice for patients with substance use history. 2

For Sleep-Maintenance Insomnia

• Low-dose doxepin 3–6 mg reduces wake after sleep onset by 22–23 minutes through selective H₁-histamine antagonism, has minimal anticholinergic effects at hypnotic doses, and carries no abuse potential—this is the preferred first-line option for sleep maintenance. 2

• Suvorexant 10 mg (orexin receptor antagonist) reduces wake after sleep onset by 16–28 minutes through a completely different mechanism than BzRAs, with lower risk of cognitive and psychomotor impairment. 2

For Combined Sleep-Onset and Maintenance Insomnia

• Eszopiclone 2–3 mg (1 mg if age ≥65 years or hepatic impairment) improves both sleep onset and maintenance, increasing total sleep time by 28–57 minutes with moderate-to-large improvements in subjective sleep quality. 2

• Temazepam 15 mg is suggested for both sleep onset and maintenance, though it carries higher risks than non-benzodiazepine options. 2

Treatment Algorithm

1. Week 0: Initiate CBT-I immediately with all core components (stimulus control, sleep restriction, relaxation, cognitive restructuring). 1, 2

2. Week 0–1: If CBT-I alone is insufficient, add first-line pharmacotherapy matched to the primary complaint:

   • Sleep-onset difficulty → zaleplon, ramelteon, or zolpidem (age-adjusted dosing)
   • Sleep-maintenance difficulty → low-dose doxepin or suvorexant
   • Combined difficulty → eszopiclone 2

3. Week 1–2: Reassess sleep-onset latency, total sleep time, nocturnal awakenings, daytime functioning, and adverse effects (morning sedation, cognitive impairment, complex sleep behaviors); adjust dose or switch agents if response inadequate. 2

4. Week 4: If first-line agent fails, switch to an alternative within the same class rather than adding a second hypnotic. 2

5. Beyond 4 weeks: FDA labeling indicates hypnotics are intended for short-term use (≤4 weeks); evidence for longer duration is insufficient, so document rationale for continuation and plan gradual taper while maintaining CBT-I. 1, 2

Second-Line Options (If First-Line Fails)

• Sedating antidepressants (mirtazapine, low-dose doxepin at antidepressant doses) are reserved for patients with comorbid depression/anxiety or when first-line agents are ineffective. 1, 2

• If switching within BzRA class, consider: eszopiclone → zolpidem for onset issues; doxepin → suvorexant for maintenance issues. 2

Medications Explicitly NOT Recommended

• Trazodone 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—harms outweigh minimal benefits. 1, 2

• Over-the-counter antihistamines (diphenhydramine, doxylamine) lack efficacy data, cause strong anticholinergic effects (confusion, urinary retention, falls, daytime sedation, delirium especially in elderly), and develop tolerance within 3–4 days. 1, 2

• Traditional benzodiazepines (lorazepam, clonazepam, diazepam) have long half-lives leading to drug accumulation, prolonged daytime sedation, higher fall and cognitive impairment risk, and associations with dementia and fractures. 1, 2

• Antipsychotics (quetiapine, olanzapine) have weak evidence for insomnia benefit and significant risks including weight gain, metabolic dysregulation, extrapyramidal symptoms, and increased mortality in elderly patients with dementia. 1, 2

• Melatonin supplements produce only ~9 minutes reduction in sleep latency with insufficient evidence of efficacy for chronic insomnia. 2

• Herbal supplements (valerian, L-tryptophan) have insufficient evidence to support use for primary insomnia. 2

Critical Safety Monitoring

• Screen for complex sleep behaviors (sleep-driving, sleep-walking, sleep-eating) at every visit; discontinue medication immediately if these occur—this is an FDA black-box warning for all BzRAs. 2

• All hypnotics carry risks of daytime impairment, driving impairment (lasting up to 11.5 hours with eszopiclone 3 mg), falls, fractures, and cognitive decline; observational data link hypnotic use to increased dementia risk. 2

• Age-adjusted dosing is mandatory for adults ≥65 years: zolpidem maximum 5 mg, eszopiclone maximum 2 mg, zaleplon maximum 5 mg, doxepin maximum 6 mg—to reduce fall risk and cognitive impairment. 2

• Hepatic impairment requires dose reduction: eszopiclone maximum 2 mg, zaleplon maximum 5 mg due to reduced drug clearance. 2

• Avoid alcohol while using these agents as it markedly increases risk of complex sleep behaviors and respiratory depression. 2

Common Pitfalls to Avoid

• Initiating pharmacotherapy without concurrent CBT-I violates strong guideline recommendations and yields less durable benefit—behavioral therapy provides more sustained effects than medication alone. 1, 2

• Using adult dosing in older adults increases fall risk; age-adjusted dosing is essential (e.g., zolpidem ≤5 mg for ≥65 years). 2

• Combining multiple sedative agents (e.g., adding benzodiazepine to a Z-drug) markedly increases risk of respiratory depression, cognitive impairment, falls, and complex sleep behaviors. 2

• Continuing pharmacotherapy beyond 4 weeks without periodic reassessment (every 2–4 weeks) contradicts FDA labeling and guideline advice that hypnotics are for short-term use only. 1, 2

• Prescribing agents without matching pharmacologic profile to insomnia phenotype—use zaleplon for onset only, doxepin for maintenance only, eszopiclone for combined symptoms. 2

• Using trazodone, OTC antihistamines, antipsychotics, or traditional benzodiazepines for primary insomnia despite lack of efficacy and significant safety concerns. 1, 2

• Failing to evaluate for underlying sleep disorders (sleep apnea, restless legs syndrome, periodic limb movement disorder, circadian rhythm disorders) if insomnia persists beyond 7–10 days despite appropriate treatment. 2