Doxepin for Insomnia
Low-dose doxepin (3-6 mg) is highly effective for treating sleep maintenance insomnia in adults, with clinically significant improvements in wake after sleep onset, total sleep time, and sleep efficiency, and should be considered as a first-line pharmacological option when cognitive behavioral therapy is insufficient or unavailable. 1, 2
Evidence for Efficacy
Low-dose doxepin demonstrates robust efficacy specifically for sleep maintenance problems:
- Wake after sleep onset (WASO) improves by 22-23 minutes compared to placebo (95% CI: 14-30 minutes) 1, 2
- Total sleep time (TST) increases by 26-32 minutes compared to placebo (95% CI: 18-40 minutes) 1, 2
- Sleep efficiency (SE) shows clinically significant improvement at both 3 mg and 6 mg doses 1, 2
- Sleep quality demonstrates small-to-moderate improvement at 3 mg and mild improvement at 6 mg 2
The mechanism differs from traditional hypnotics—doxepin works through selective histamine H1-receptor antagonism at low doses, which promotes sleep initiation and maintenance without the broader tricyclic antidepressant effects seen at higher doses 3, 4
Dosing Specifics
Use 3-6 mg doses only—NOT higher doses like 20-25 mg or 50 mg. 1 The critical distinction is that low-dose doxepin (3-6 mg) provides selective H1-receptor antagonism, while higher doses shift to broader tricyclic antidepressant effects with significantly increased adverse effects 1. The 2008 guidelines mention doxepin among sedating antidepressants at higher doses for treatment failures 5, but the more recent evidence strongly supports the low-dose formulation as a primary option 1, 2.
Treatment Algorithm Position
First-line: Cognitive Behavioral Therapy for Insomnia (CBT-I) remains the initial treatment for all adults with chronic insomnia 2, 6
Second-line pharmacotherapy: When CBT-I is insufficient, unavailable, or the patient is unable/unwilling to receive it, low-dose doxepin (3-6 mg) is recommended alongside other options including 1, 2, 6:
- Eszopiclone 2-3 mg (TST improvement 28-57 minutes)
- Temazepam 15 mg (TST improvement 99 minutes)
- Suvorexant 10-20 mg (WASO reduction 16-28 minutes)
- Zolpidem 10 mg (TST improvement 29 minutes, WASO reduction 25 minutes)
The 2008 guidelines positioned sedating antidepressants including doxepin as third-line options after benzodiazepine receptor agonists 5, but the 2025 American Academy of Sleep Medicine guidelines elevate low-dose doxepin to a more prominent position based on stronger evidence 1, 2.
Safety Profile
Low-dose doxepin has a safety profile comparable to placebo in clinical trials 2:
- Somnolence occurs mildly at 6 mg doses 1
- Headache is reported but generally at placebo levels 1
- No evidence of tolerance, dependence, or rebound insomnia in trials up to 12 weeks 3, 4
- No psychomotor impairment or residual sedation at low doses 4
However, one study using higher doses (25-50 mg) reported specific adverse effects including elevated liver enzymes, leukopenia, and thrombopenia in 2 patients 7, reinforcing the importance of using only the 3-6 mg dosing.
Clinical Considerations and Pitfalls
Administer at the lowest effective dose (3 or 6 mg) for the shortest possible duration 2. Start with 3 mg and increase to 6 mg only if needed for adequate response.
Efficacy appears after a single dose with polysomnographic improvements evident on night 1 of treatment 3, though one pooled analysis showed the effect on sleep latency was statistically significant but small (22% improvement, 6.4-minute reduction overall) 8.
Doxepin is specifically effective for sleep maintenance, not sleep onset. If the primary complaint is difficulty falling asleep rather than staying asleep, consider zaleplon, ramelteon, or zolpidem instead 6. One recent study showed zolpidem had better sleep onset latency (20.3 vs 28.2 minutes) while doxepin had superior wake after sleep onset and total sleep time 9.
Supplement pharmacotherapy with behavioral interventions—medication should not replace CBT-I but rather augment it when necessary 2, 6.
Monitor for higher adverse event rates with longer treatment duration 2, and reassess periodically rather than continuing indefinitely without evaluation 6.
Avoid in pediatric populations—there is no FDA approval and limited safety data for children 1.
Comparative Effectiveness
A 2024 head-to-head trial found doxepin 6 mg superior to zolpidem 5-10 mg for sleep maintenance parameters (WASO: 80.3 vs 132.9 minutes; TST: 378.9 vs 333.2 minutes; SE: 77.8% vs 68.6%) and Pittsburgh Sleep Quality Index scores (6.1 vs 7.9) 9. Additionally, doxepin improved executive function more effectively than zolpidem, with better performance on Wisconsin Card Sorting Test measures of random errors and categories 9. However, zolpidem showed better sleep onset latency 9, confirming doxepin's primary role in sleep maintenance rather than sleep onset.