What are the recommended non-hypnotic sleep medicines for insomnia?

Non-Hypnotic Sleep Medicines for Insomnia

For chronic insomnia requiring pharmacotherapy, low-dose doxepin (3-6 mg) is the preferred non-hypnotic medication, particularly for sleep maintenance problems, followed by sedating antidepressants like trazodone (50 mg) or mirtazapine when comorbid depression/anxiety exists. 1

First-Line Treatment Framework

Before considering any medication, Cognitive Behavioral Therapy for Insomnia (CBT-I) must be the initial intervention for all patients with chronic insomnia. 2, 1 This is a strong recommendation based on moderate-quality evidence showing sustained benefits without tolerance or adverse effects. 3

• CBT-I produces results equivalent to sleep medication but with no side effects, fewer relapses, and continued improvement long after treatment ends. 4
• Components include sleep restriction, stimulus control, relaxation techniques, and cognitive restructuring. 1, 3
• Only after inadequate response to CBT-I should pharmacotherapy be considered through shared decision-making. 2

Recommended Non-Hypnotic Medications

Doxepin (Low-Dose: 3-6 mg)

This is the most evidence-based non-hypnotic option for sleep maintenance insomnia. 2, 1

• Efficacy data: Increases total sleep time by 26-32 minutes and reduces wake after sleep onset by 22-23 minutes compared to placebo. 2
• Works primarily as an H1 antagonist at low doses, avoiding significant anticholinergic or antidepressant effects. 5
• Available in liquid form, making it ideal for patients with PEG tubes or swallowing difficulties. 1
• Does not develop significant tolerance issues. 5

Sedating Antidepressants

These are primary non-scheduled options, especially when treating comorbid depression or anxiety. 1

Trazodone (typically 50 mg):

• Most commonly prescribed off-label for insomnia. 1, 6
• Should be taken shortly after a meal or light snack. 6
• Initial dosing starts at 150 mg/day for depression but lower doses (25-100 mg) are used for insomnia. 6
• Evidence is more limited compared to doxepin, but widely used in clinical practice. 2, 1
• Can be crushed and dissolved in water for administration difficulties. 1

Mirtazapine:

• Beneficial when comorbid depression and insomnia coexist. 1
• Sedating effects are paradoxically stronger at lower doses (7.5-15 mg). 1
• Can be crushed for alternative administration routes. 1

Amitriptyline:

• Listed as an option but has more anticholinergic side effects than other choices. 1
• Generally reserved for second- or third-line use. 2

Medications to AVOID

Over-the-counter antihistamines (diphenhydramine, doxylamine):

• The American Academy of Sleep Medicine explicitly does NOT recommend these due to lack of efficacy data and safety concerns. 2, 1
• Despite this, doxylamine shows some effectiveness for up to 4 weeks in research. 7
• Anticholinergic effects are particularly problematic in elderly patients. 2

Herbal supplements (valerian, etc.):

• Not recommended due to insufficient evidence and conflicting data. 2, 1
• Sparse evidence exists despite widespread use. 2

Melatonin:

• Insufficient evidence for chronic insomnia management in most populations. 2
• May have a role in patients over 55 years (prolonged-release formulation). 2
• Specifically NOT recommended for elderly patients with dementia. 5

Administration Guidelines

Start low and titrate carefully: 1

• Begin with the lowest effective dose for all agents. 2, 1
• Assess efficacy after 1-2 weeks of treatment initiation. 1
• In elderly patients, use even lower starting doses due to increased sensitivity. 2, 1

Combine with patient education: 1

• Discuss treatment goals, safety concerns, and potential side effects. 1
• Emphasize that medication should accompany CBT-I whenever possible. 2
• Address sleep hygiene: stable bed/wake times, avoid daytime napping after 2 PM, eliminate caffeine/nicotine/alcohol near bedtime. 2, 1

Special Population Considerations

Elderly patients with dementia:

• Sleep medications are explicitly contraindicated as first-line therapy due to increased risks of falls, cognitive impairment, and adverse outcomes. 5
• Light therapy should be the initial approach despite very low evidence quality. 5
• If medication becomes absolutely necessary after non-pharmacological failure, low-dose doxepin 3-6 mg is the safest choice. 5

Patients requiring PEG tube administration:

• Doxepin liquid is ideal. 1
• Trazodone and mirtazapine can be crushed and dissolved in water. 1

Monitoring and Follow-Up

• Assess response after 1-2 weeks initially. 1
• Long-term prescribing requires consistent follow-up every 2-4 weeks initially, then every 6 months during maintenance. 1, 8
• Monitor for adverse effects continuously. 1
• Gradually reduce dosage rather than abrupt discontinuation to avoid withdrawal phenomena. 6

Clinical Algorithm

1. Initiate CBT-I first for all patients with chronic insomnia. 2, 1
2. If inadequate response after 4-6 weeks of CBT-I:
   • For sleep maintenance insomnia: Doxepin 3-6 mg 2, 1
   • For comorbid depression/anxiety: Trazodone 50 mg or Mirtazapine 7.5-15 mg 1
3. Reassess at 1-2 weeks and titrate based on response and tolerability. 1
4. Continue CBT-I alongside medication whenever possible. 2
5. Plan for eventual medication taper once sleep patterns stabilize. 6