What non‑controlled pharmacologic agents and behavioral measures are recommended as first‑line treatment for insomnia in patients who should avoid controlled‑substance hypnotics?

Non-Controlled Pharmacologic and Behavioral Management of Insomnia

First-Line Treatment: Cognitive Behavioral Therapy for Insomnia (CBT-I)

All adults with chronic insomnia must receive CBT-I as the initial intervention before or alongside any medication, as it provides superior long-term efficacy with sustained benefits after discontinuation. 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
• Delivery formats—individual therapy, group sessions, telephone-based, web-based modules, or self-help books—all demonstrate comparable effectiveness. 1
• Sleep hygiene education (consistent sleep-wake times, avoiding caffeine after 2 PM, limiting evening screen time, optimizing bedroom environment) must supplement other interventions but is insufficient as monotherapy. 1, 2, 3

First-Line Non-Controlled Pharmacologic Options

For Sleep-Onset Insomnia

• Ramelteon 8 mg at bedtime is the preferred non-controlled option, working through melatonin receptors with zero abuse potential, no DEA scheduling, and no withdrawal symptoms—making it ideal for patients with substance use history. 1, 2
• Zaleplon 10 mg (5 mg if age ≥65 years) has an ultrashort half-life (~1 hour) providing rapid sleep initiation with minimal next-day sedation; suitable for middle-of-night dosing when ≥4 hours remain before awakening. 1

For Sleep-Maintenance Insomnia

• Low-dose doxepin 3–6 mg at bedtime is the preferred first-line option, reducing wake after sleep onset by 22–23 minutes with minimal anticholinergic effects at hypnotic doses and no abuse potential. 1, 4
• Suvorexant 10 mg (orexin-receptor antagonist) reduces wake after sleep onset by 16–28 minutes with lower risk of cognitive and psychomotor impairment than benzodiazepine-type agents. 1

For Combined Sleep-Onset and Maintenance Insomnia

• Eszopiclone 2–3 mg (1 mg if age ≥65 years or hepatic impairment) increases total sleep time by 28–57 minutes and produces moderate-to-large improvements in subjective sleep quality; take within 30 minutes of bedtime with ≥7 hours remaining before awakening. 1
• Zolpidem 10 mg (5 mg if age ≥65 years) shortens sleep-onset latency by ~25 minutes and adds ~29 minutes to total sleep time. 1

Second-Line Options for Comorbid Depression or Anxiety

• Sedating antidepressants (mirtazapine 7.5–30 mg, low-dose doxepin) are appropriate when comorbid depression or anxiety is present, as they simultaneously address both conditions. 1, 2
• Mirtazapine at lower doses (7.5 mg) provides stronger sedation through H₁-receptor antagonism; paradoxically, higher doses are less sedating. 1

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, and 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), and develop tolerance within 3–4 days. 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 for chronic insomnia treatment. 1
• Herbal supplements (valerian, L-tryptophan) have insufficient evidence to support use for primary insomnia. 1

Treatment Algorithm

1. Initiate CBT-I immediately for all patients with chronic insomnia, incorporating stimulus control, sleep restriction, relaxation, cognitive restructuring, and sleep-hygiene education. 1, 2

2. Add first-line non-controlled pharmacotherapy if CBT-I alone is insufficient after 4–8 weeks:

   • Sleep-onset difficulty → ramelteon 8 mg or zaleplon 10 mg (dose-adjusted for age)
   • Sleep-maintenance difficulty → low-dose doxepin 3–6 mg or suvorexant 10 mg
   • Combined difficulty → eszopiclone 2–3 mg or zolpidem 10 mg (dose-adjusted for age) 1

3. If the chosen first-line agent fails after 1–2 weeks, switch to an alternative agent within the same class rather than adding a second hypnotic. 1

4. For comorbid depression or anxiety, consider sedating antidepressants (mirtazapine, low-dose doxepin) as second-line options. 1, 2

Special Population Dosing

• Elderly patients (≥65 years) require reduced maximum doses: eszopiclone 2 mg, zolpidem 5 mg, zaleplon 5 mg, doxepin 6 mg to minimize fall risk and cognitive impairment. 1, 2
• Patients with hepatic impairment require dose adjustments: eszopiclone maximum 2 mg, zaleplon maximum 5 mg due to reduced drug clearance. 1, 2

Safety Monitoring and Duration

• Reassess after 1–2 weeks to evaluate sleep-onset latency, total sleep time, nocturnal awakenings, daytime functioning, and adverse effects (morning sedation, cognitive impairment, complex sleep behaviors). 1
• FDA labeling recommends hypnotics for short-term use (≤4 weeks) for acute insomnia; evidence beyond 4 weeks is limited. 1
• Use the lowest effective dose for the shortest necessary duration, integrating CBT-I to enable eventual tapering. 1
• Screen for complex sleep behaviors (sleep-driving, sleep-walking, sleep-eating) at every visit; discontinue medication immediately if these occur. 1
• If insomnia persists beyond 7–10 days despite treatment, evaluate for underlying sleep disorders (sleep apnea, restless-legs syndrome, circadian-rhythm disorders). 1

Common Pitfalls to Avoid

• Initiating pharmacotherapy without first implementing CBT-I leads to less durable benefit and contravenes guideline recommendations. 1, 2
• Using adult dosing in older adults—age-adjusted dosing is essential to reduce fall risk and cognitive impairment. 1, 2
• Combining multiple sedative agents markedly increases risk of respiratory depression, cognitive impairment, falls, and complex sleep behaviors. 1
• Prescribing trazodone, OTC antihistamines, or antipsychotics despite lack of efficacy and significant safety concerns. 1, 2
• Continuing pharmacotherapy long-term without periodic reassessment (every 2–4 weeks during active treatment). 1, 2