What are pharmacological interventions for insomnia beyond Cognitive Behavioral Therapy (CBT)?

Pharmacological Interventions for Insomnia Beyond CBT

When CBT-I alone is insufficient, add short-term pharmacotherapy using a shared decision-making approach, with benzodiazepine receptor agonists (eszopiclone, zolpidem, zaleplon, temazepam) or ramelteon as first-line options, followed by low-dose doxepin for sleep maintenance or suvorexant as alternatives. 1, 2

When to Consider Pharmacotherapy

Medications should only be added after CBT-I has been attempted and proven unsuccessful, or as a temporary adjunct to ongoing CBT-I—never as monotherapy or first-line treatment. 1, 3 The American College of Physicians emphasizes this is a weak recommendation based on low-quality evidence, requiring careful discussion of benefits, harms, and costs with each patient. 1

First-Line Pharmacological Options

Benzodiazepine Receptor Agonists (BzRAs)

For sleep onset insomnia:

• Zaleplon 10 mg (5 mg in elderly) - ultra-short acting, ideal for difficulty falling asleep 2
• Zolpidem 10 mg (5 mg in elderly and women per FDA mandate) - effective for both sleep onset and maintenance 1, 2
• Triazolam 0.25 mg - effective but associated with rebound anxiety, not considered true first-line 2

For sleep maintenance insomnia:

• Eszopiclone 2-3 mg - moderate-quality evidence shows improvement in sleep onset latency, total sleep time, and wake after sleep onset 1, 2
• Temazepam 15 mg - intermediate-acting, effective for both onset and maintenance 2
• Zolpidem 10 mg (5 mg in elderly) - also effective for maintenance 2

Melatonin Receptor Agonist

Ramelteon 8 mg is suggested specifically for sleep onset insomnia. 2, 4 Low-quality evidence showed no statistically significant difference from placebo in some general population studies, but it demonstrated efficacy in older adults for decreasing sleep onset latency. 1 Ramelteon has no abuse potential and can be used long-term without dependence concerns. 4

Second-Line Pharmacological Options

Orexin Receptor Antagonist

Suvorexant is suggested for sleep maintenance insomnia, with moderate-quality evidence showing improved treatment response and sleep outcomes. 1, 2 This represents a newer mechanism of action compared to traditional hypnotics.

Low-Dose Sedating Antidepressant

Doxepin 3-6 mg (much lower than antidepressant doses) is suggested specifically for sleep maintenance insomnia. 1, 2 Moderate-quality evidence in older adults showed improved Insomnia Severity Index scores and sleep outcomes. 1

Medications NOT Recommended

The following should be avoided due to insufficient evidence, safety concerns, or lack of efficacy: 1, 2, 5

• Trazodone - despite widespread use, not recommended due to lack of studies meeting inclusion criteria for chronic insomnia 1, 2
• Over-the-counter antihistamines (diphenhydramine, doxylamine) - lack of efficacy data and significant safety concerns including daytime sedation, cognitive impairment, and delirium risk especially in older adults 1, 2, 5
• Melatonin supplements - insufficient evidence for efficacy in general adult population 1
• Herbal supplements (valerian, chamomile) - insufficient evidence of efficacy 1, 2
• Antipsychotics - should not be used as first-line due to problematic metabolic side effects 2, 5
• Anticonvulsants (tiagabine) - not recommended 2
• Older hypnotics (barbiturates, chloral hydrate) - not recommended 2

Critical Safety Considerations and Dosing

All hypnotic medications carry FDA warnings about serious adverse effects including: 1

• Daytime impairment and next-day driving impairment
• Complex sleep behaviors ("sleep-driving," eating, phone calls with amnesia)
• Cognitive and behavioral changes
• Worsening depression and suicidal ideation
• Risk of dependence and withdrawal

Observational studies have linked hypnotic use to infrequent but serious harms including dementia, serious injury, and fractures, particularly in older adults. 1

Elderly patients require lower doses: 2

• Zolpidem maximum 5 mg (not 10 mg)
• All BzRAs at reduced doses due to increased sensitivity
• Higher risk of falls, cognitive impairment, and complex sleep behaviors

Women require lower doses of zolpidem (5 mg) due to slower drug metabolism. 1

Duration of Treatment

Pharmacotherapy should be short-term only (4-5 weeks as FDA-approved), as evidence is insufficient to evaluate the balance of benefits and harms with long-term use. 1 Most studies examined short-term efficacy, and degradation of improvement following discontinuation is a concern. 1

When medications are used, they should be supplemented with behavioral and cognitive therapies whenever possible. 2, 3

Treatment Algorithm

1. Initiate CBT-I as sole treatment for all patients with chronic insomnia 1, 5, 3

2. If CBT-I insufficient after adequate trial (typically 4-8 weeks):

   • Use shared decision-making to discuss adding pharmacotherapy 1
   • Assess predominant symptom pattern:
     • Sleep onset difficulty → Consider zaleplon, ramelteon, or zolpidem 2
     • Sleep maintenance difficulty → Consider eszopiclone, temazepam, zolpidem, doxepin, or suvorexant 2
     • Both onset and maintenance → Consider eszopiclone, zolpidem, or temazepam 2

3. If first-line BzRA unsuccessful or contraindicated:

   • Try alternative BzRA from same class 2
   • Consider ramelteon for onset issues 2
   • Consider doxepin 3-6 mg for maintenance issues 2
   • Consider suvorexant for maintenance issues 2

4. For patients with comorbid depression/anxiety:

   • Consider sedating antidepressants as second-line option 1, 2
   • Continue CBT-I alongside any medication 3

5. Reassess after 1-2 weeks of medication initiation 3

   • Evaluate efficacy and adverse effects
   • Plan for discontinuation or taper when conditions allow 2

Common Pitfalls to Avoid

• Using medications as monotherapy without CBT-I - medications should supplement, not replace, behavioral interventions 1, 3
• Prescribing standard adult doses to elderly patients or women (for zolpidem) - always use reduced doses 1, 2
• Long-term prescribing without periodic reassessment - chronic use lacks evidence for benefit-harm balance 1, 2, 5
• Combining multiple sedative medications - significantly increases risks of cognitive impairment, falls, and complex sleep behaviors 2
• Using benzodiazepines as first-line in elderly - higher risk of adverse effects than newer agents 1
• Prescribing trazodone or OTC antihistamines - lack evidence and have concerning side effect profiles 1, 2
• Failing to warn patients about driving impairment and complex sleep behaviors - FDA mandates these warnings 1