Is low‑dose doxepin preferable to trazodone for treating insomnia to minimize next‑day grogginess in an otherwise healthy adult?

Low-Dose Doxepin is Preferable to Trazodone for Minimizing Next-Day Grogginess

For an otherwise healthy adult with insomnia, low-dose doxepin (3-6 mg) is clearly superior to trazodone for avoiding next-day grogginess, as doxepin shows no difference from placebo on objective measures of morning sleepiness while trazodone causes significant morning grogginess (15% vs 5% with other agents) and lacks evidence of efficacy for insomnia treatment. 1, 2

Evidence Against Trazodone

The American Academy of Sleep Medicine explicitly recommends against using trazodone for insomnia treatment (weak recommendation), based on the following critical findings: 1

• No clinically significant efficacy: At 50 mg, trazodone reduced sleep latency by only 10.2 minutes and increased total sleep time by only 21.8 minutes—both falling below clinical significance thresholds 1
• High adverse event burden: 75% of trazodone patients experienced adverse events versus 65.4% on placebo, with headache (30% vs 19%) and somnolence (23% vs 8%) being most common 1
• Morning grogginess is a documented problem: In a 2024 comparative study, trazodone caused morning grogginess in 15% of patients compared to only 5% with melatonin 2
• Additional risks: Orthostatic hypotension (10%), dizziness, and increased fall risk, particularly problematic in elderly patients 3, 2

Evidence Supporting Low-Dose Doxepin

Low-dose doxepin (3-6 mg) has a weak recommendation for use in sleep maintenance insomnia from the American Academy of Sleep Medicine, with a critical advantage regarding next-day effects: 1

Next-Day Residual Effects Profile

• No objective next-day impairment: Studies showed no difference between doxepin 3 mg or 6 mg and placebo on the Digit Symbol Substitution Test (DSST), Symbol Copying Test, or visual analogue scales for morning sleepiness 1
• Minimal somnolence risk: Only a +0.01 risk difference at 3 mg (essentially no increase) and +0.04 risk difference at 6 mg compared to placebo 1
• Preserved cognitive function: No memory impairment or hangover effects reported in clinical trials 4
• Better tolerability profile: In the 2024 comparative study, doxepin had lower rates of morning grogginess than trazodone while maintaining efficacy 2

Efficacy Data

• Clinically significant improvements in wake after sleep onset (WASO), total sleep time (TST), and sleep efficiency (SE) at both 3 mg and 6 mg doses 1
• Sleep maintenance throughout the night: Efficacy persisted into the final third of the night, with no rebound insomnia upon discontinuation 5, 4
• Rapid onset: Significant improvements evident after a single dose 5

Practical Prescribing Algorithm

Start with doxepin 3 mg taken 30 minutes before bedtime: 1

• This dose provides clinically significant improvements in sleep maintenance with essentially no increase in next-day somnolence versus placebo 1
• If inadequate response after 3-7 nights, increase to 6 mg (which has slightly higher but still minimal somnolence risk at +0.04 risk difference) 1
• Efficacy is maintained for up to 12 weeks without evidence of tolerance or dependence 5

Avoid trazodone entirely for primary insomnia: 1, 3

• The evidence does not support its use, and the adverse effect profile (particularly morning grogginess and orthostatic hypotension) outweighs any potential benefits
• If a patient is already on trazodone for insomnia, consider switching to an evidence-based alternative

Important Caveats

Elderly patients require special consideration: 3

• Both medications carry increased risks in older adults (falls, confusion, cardiac events)
• Doxepin still has a superior next-day profile, but start at the lowest dose (3 mg) and monitor closely for excessive sedation
• The risk-benefit ratio still favors doxepin over trazodone in this population 2

Cardiac monitoring considerations: 6

• Trazodone carries risks of QT prolongation, arrhythmias, and orthostatic hypotension 6
• Doxepin at low doses (3-6 mg) has minimal cardiac effects, though tricyclic-related risks increase at higher antidepressant doses 6

First-line treatment should be non-pharmacologic: 3

• Cognitive behavioral therapy for insomnia (CBT-I) is recommended as initial treatment by major guidelines
• Pharmacotherapy should be reserved for cases where CBT-I is unavailable, ineffective, or as adjunctive therapy

Direct Comparison Summary

When specifically comparing next-day grogginess between these two agents:

• Doxepin: No difference from placebo on objective measures of morning sleepiness, minimal somnolence risk, preserved cognitive function 1, 4
• Trazodone: 15% morning grogginess rate, 23% somnolence rate (vs 8% placebo), lacks efficacy evidence for insomnia 1, 2

The choice is clear: low-dose doxepin is superior to trazodone for minimizing next-day grogginess while providing evidence-based efficacy for sleep maintenance insomnia. 1, 2