What is the role of doxepin in treating nightmares, particularly in patients with Post-Traumatic Stress Disorder (PTSD)?

Doxepin for Nightmares: Not Recommended

Doxepin is not recommended for the treatment of nightmares in patients with PTSD or nightmare disorder, as the available evidence shows it was ineffective in the only study that evaluated it for this indication. 1

Evidence Against Doxepin

The 2018 American Academy of Sleep Medicine position paper on nightmare disorder provides the only available data on doxepin for nightmares 1:

• A small case series of 10 Cambodian concentration camp survivors with PTSD-associated nightmares found that the two patients who failed to improve were both taking doxepin (either 100 mg alone or 150 mg in combination with other agents) 1

• This represents Level C evidence at best—a single small case series with negative findings 1

• The study did not provide clear dosing protocols or treatment duration details, further limiting its utility 1

Recommended Alternatives

First-Line Pharmacologic Treatment

Prazosin remains the first-choice pharmacologic agent for PTSD-associated nightmares despite recent mixed evidence 1:

• Multiple Level 1 randomized controlled trials demonstrated significant reduction in trauma-related nightmares (CAPS Item 2 scores improved from 4.8-6.9 to 3.2-3.6) 1

• Dosing typically starts at 1 mg at bedtime, titrated by 1-2 mg every few days to effect 1

• Effective doses range from 1-20 mg, with average doses around 9-15 mg for combat veterans 1

• Important caveat: A large 2018 VA study of 304 patients showed no benefit over placebo at 26 weeks, which has downgraded the recommendation strength 1

• Monitor for orthostatic hypotension, particularly during dose titration 1

Alternative Alpha-1 Antagonist

Doxazosin (not doxepin) may be considered as an alternative to prazosin for patients who cannot tolerate prazosin's short half-life or multiple daily dosing 2, 3, 4:

• A 2017 chart review of 51 patients with PTSD/BPD showed 25% achieved complete nightmare remission at 12 weeks 2

• Doxazosin has a longer half-life than prazosin, allowing once-daily dosing and potentially better adherence 4

• Typical dosing: 4-8 mg once daily 2, 3

• Better side effect profile than prazosin with less risk of first-dose hypotension 4

Other Pharmacologic Options

Topiramate may be considered as a second-line agent 1:

• One RCT in 40 civilian PTSD patients showed twice as many achieved remission versus placebo (median dose 150 mg/day) 1

• Case series data showed 79% reduction in nightmares with 50% achieving complete suppression 1

• Start at 12.5-25 mg daily, titrate by 25-50 mg every 3-4 days to effect (most responders at ≤100 mg/day) 1

• Significant side effects include cognitive impairment, acute angle-closure glaucoma, and emergent suicidal ideation in some patients 1

Trazodone has retrospective evidence for nightmare reduction 1:

• 60 of 74 VA patients maintained effective dosing with decreased nightmare frequency from 3.3 to 1.3 nights/week 1

• Mean effective dose: 212 mg/day 1

• Major concern: 5 cases of priapism reported, plus significant daytime sedation in many patients 1

Clinical Algorithm

1. First-line: Trial of prazosin 1 mg at bedtime, titrate to 9-15 mg based on response 1

2. If prazosin fails or causes intolerable side effects: Switch to doxazosin 4-8 mg once daily 2, 3, 4

3. If alpha-1 antagonists contraindicated or ineffective: Consider topiramate 12.5-100 mg daily 1

4. Avoid: Doxepin, benzodiazepines (clonazepam showed no benefit), and venlafaxine for nightmare-specific treatment 1

Common Pitfalls

• Do not confuse doxepin with doxazosin—they are entirely different medications with different mechanisms and evidence bases 2, 3, 4

• Doxepin is a tricyclic antidepressant with antihistaminic properties, while doxazosin is an alpha-1 antagonist similar to prazosin 2, 4

• The evidence for tricyclic antidepressants (including doxepin) in nightmare disorder is extremely limited and negative 1