What is doxepin and how is it used?

Doxepin: A Low-Dose Histamine H1 Antagonist for Sleep Maintenance Insomnia

Doxepin is a tricyclic compound that, at low doses (3-6 mg), functions as a selective histamine H1 receptor antagonist specifically approved for treating sleep maintenance insomnia in adults, with efficacy comparable to placebo in safety profile. 1, 2

What Doxepin Is

Doxepin is a dibenzoxepin tricyclic compound with dual clinical applications depending on dosage 3:

• At low doses (3-6 mg): Functions as a selective H1 histamine receptor antagonist for insomnia treatment, introduced to the U.S. market in 2005 4, 5
• At higher doses (25-300 mg): Acts as a traditional tricyclic antidepressant with broader receptor activity including anticholinergic and antinoradrenergic effects 3, 6

The mechanism at low doses involves selective antagonism of histamine H1 receptors with subnanomolar affinity, promoting sleep initiation and maintenance without the dose-limiting side effects seen at antidepressant doses 7, 8

Clinical Indications and Guideline Recommendations

Primary Indication

The American Academy of Sleep Medicine recommends low-dose doxepin (3-6 mg) specifically for sleep maintenance insomnia as a second-line option when Cognitive Behavioral Therapy for Insomnia (CBT-I) is insufficient, unavailable, or the patient is unable/unwilling to receive it. 1, 2

Treatment Algorithm

• First-line: CBT-I for all patients with chronic insomnia 1
• Second-line: Low-dose doxepin (3 or 6 mg) for patients with predominant sleep maintenance problems (difficulty staying asleep, early morning awakening) 1, 2
• Not recommended: Use in pediatric populations due to lack of FDA approval and safety data 2, 3

Historical Context

At higher antidepressant doses (25-300 mg), doxepin is FDA-approved for treating depression and anxiety in psychoneurotic patients, depression associated with alcoholism or organic disease, and psychotic depressive disorders 3. However, this review focuses on its modern low-dose hypnotic application.

Efficacy Profile

Sleep Maintenance Parameters

Low-dose doxepin demonstrates clinically significant improvements in objective polysomnographic measures 1, 2:

• Wake After Sleep Onset (WASO): Reduction of 22-23 minutes compared to placebo (95% CI: 14-30 minutes) 2
• Total Sleep Time (TST): Improvement of 26-32 minutes compared to placebo (95% CI: 18-40 minutes) 2, 8
• Sleep Efficiency (SE): Clinically significant improvement in percentage of time asleep while in bed 1, 2
• Sleep Quality: Moderate improvement at 3 mg dose, mild improvement at 6 mg dose 1

Onset and Duration of Action

• Significant improvements evident after single-dose administration on polysomnographic recordings 8
• Efficacy maintained for up to 12 weeks of continuous administration without evidence of tolerance 8, 9
• Effect size: Small to medium against placebo for sleep maintenance and duration 9

Comparative Effectiveness

In head-to-head trials, doxepin 6 mg was superior to zolpidem 5-10 mg for sleep maintenance parameters including WASO, TST, and sleep efficiency. 2 This represents a critical clinical distinction, as zolpidem remains the most widely prescribed hypnotic medication 4.

Safety Profile

Adverse Effects

Low-dose doxepin (3-6 mg) has a safety profile comparable to placebo in clinical trials, with only mild increases in somnolence at the 6 mg dose. 1, 2

Common adverse effects include 1, 2, 8:

• Somnolence/sedation: Primarily at 6 mg dose, mainly at placebo level or less
• Headache: Most common adverse event alongside somnolence
• No significant next-day residual effects or psychomotor impairment in trials up to 3 months 8, 9

Withdrawal and Dependence

• No evidence of physical dependence after up to 12 weeks of administration 8
• No rebound insomnia upon discontinuation 7, 8
• No discontinuation symptoms in trials up to 3 months duration 7

Important Safety Considerations

The American Academy of Sleep Medicine and VA/DoD guidelines note that adverse event rates may increase with longer treatment duration, emphasizing the need for shortest possible treatment duration 1.

Critical caveat: At higher antidepressant doses, doxepin carries significant cardiotoxicity risk on overdosage and anticholinergic side effects (dry mouth, constipation, postural hypotension), but these are not relevant at the 3-6 mg hypnotic doses 3, 6.

Dosing Recommendations

Evidence-Based Dosing

Administer doxepin at 3-6 mg doses only—NOT 20 mg or higher—as doses above 6 mg shift from selective H1-receptor antagonism to broader tricyclic antidepressant effects with increased adverse effects. 2

• Starting dose: 3 mg once daily at bedtime 2
• Maximum dose: 6 mg once daily at bedtime 2
• Duration: Shortest possible duration, with efficacy data supporting up to 12 weeks 1, 8

Formulation

Available as oral capsules in 3 mg and 6 mg strengths for insomnia; higher strengths (10 mg, 25 mg, 50 mg, 75 mg, 100 mg) are for antidepressant use only 3

Contraindications and Precautions

Absolute Contraindications

• Hypersensitivity to doxepin or other dibenzoxepines 3
• Pediatric patients under 12 years of age (lack of safety data and FDA approval for this population) 2, 3

Black Box Warning

The FDA requires a black box warning for all tricyclic antidepressants, including doxepin, regarding increased risk of suicidal thinking and behavior in children, adolescents, and young adults with major depressive disorder. 3 However, this warning applies to antidepressant doses (25-300 mg), not the low-dose hypnotic formulation (3-6 mg).

Drug Interactions

• At clinical dosages up to 150 mg/day, doxepin does not block the antihypertensive effect of guanethidine; blocking may occur above 150 mg/day 3
• Avoid concomitant alcohol use when prescribed for depression/anxiety associated with alcoholism 3

Clinical Positioning Among Hypnotics

Alternative First-Line Options for Sleep Maintenance

When comparing doxepin to other hypnotics for sleep maintenance insomnia 2:

• Eszopiclone 2-3 mg: TST improvement 28-57 minutes, moderate-to-large sleep quality improvement
• Temazepam 15 mg: TST improvement 99 minutes, limited WASO data
• Suvorexant 10-20 mg: WASO reduction 16-28 minutes
• Zolpidem 10 mg: TST improvement 29 minutes, WASO reduction 25 minutes

Doxepin's advantage lies in its superior sleep maintenance profile compared to zolpidem and its placebo-level safety profile, making it particularly suitable for elderly patients and those requiring longer-term treatment. 2, 8

Prescribing Trends

In recent NHANES data (1999-2010), doxepin represented a small but growing proportion of insomnia medications, with BzRAs (predominantly zolpidem) most commonly prescribed (1.23% of population), followed by trazodone (0.97%), BZDs (0.4%), quetiapine (0.32%), and doxepin 4

Common Pitfalls to Avoid

• Do not prescribe doses above 6 mg for insomnia: This eliminates the selective H1 antagonism and introduces tricyclic side effects 2
• Do not use in pediatric populations: No safety data or FDA approval exists for patients under 12 years 2, 3
• Do not assume tolerance will develop: Unlike benzodiazepines, low-dose doxepin shows no evidence of tolerance development over 12 weeks 8
• Do not confuse with antidepressant formulations: The 3-6 mg hypnotic doses are pharmacologically distinct from 25-300 mg antidepressant doses 2, 3
• Do not overlook CBT-I as first-line: Doxepin is second-line therapy; CBT-I should always be considered first 1, 2