Is there evidence for the use of doxylamine in treating insomnia?

Evidence for Doxylamine in Insomnia Treatment

There is insufficient evidence to support the use of doxylamine for chronic insomnia disorder, and it should not be recommended as a primary treatment option due to limited efficacy data and potential safety concerns.

Current Evidence and Recommendations

The American College of Physicians (ACP) and American Academy of Sleep Medicine (AASM) guidelines do not recommend doxylamine as a first-line or even well-supported second-line agent for insomnia treatment:

• Cognitive Behavioral Therapy for Insomnia (CBT-I) is the first-line treatment for chronic insomnia disorder 1
• When pharmacotherapy is needed, there are several agents with better evidence than doxylamine:
  • Low-dose doxepin (3-6mg) has moderate-quality evidence for improving sleep outcomes 1, 2
  • Eszopiclone has low-quality evidence showing improvement in global and sleep outcomes 1, 2
  • Suvorexant has moderate-quality evidence showing improved treatment response 1, 2

Doxylamine-Specific Evidence

Doxylamine is an over-the-counter antihistamine marketed as a sleep aid (e.g., Unisom SleepTabs) 3, but:

1. The ACP guidelines do not mention doxylamine as a recommended treatment for chronic insomnia 1
2. A 2015 systematic review of OTC sleep aids concluded that antihistamines like diphenhydramine (which has a similar mechanism to doxylamine) demonstrated "limited beneficial effects" 4
3. Available studies on doxylamine for insomnia are limited:
   • A 2017 Russian study showed some efficacy for short-term insomnia, but was not placebo-controlled 5
   • A 2020 French publication suggested doxylamine might be appropriate for treating insomnia in the last third of the night, but this was based on theoretical considerations rather than robust clinical evidence 6

Safety Considerations

When considering doxylamine for insomnia, be aware of these important safety concerns:

• FDA has approved pharmacologic therapy for insomnia only for short-term use (4-5 weeks) 1
• Observational studies have shown that hypnotic drugs may be associated with serious adverse effects including dementia, injury, and fractures 1
• First-generation antihistamines like doxylamine can cause:
  • Daytime sedation and impairment
  • Anticholinergic side effects (dry mouth, blurred vision, urinary retention)
  • Potential cognitive impairment, especially concerning in older adults

Treatment Algorithm for Insomnia

1. First-line: CBT-I - Includes stimulus control, sleep restriction, cognitive therapy, and relaxation training 1, 2

2. If CBT-I is unsuccessful or unavailable:

   • For sleep onset insomnia: Consider ramelteon (8mg) 2
   • For sleep maintenance insomnia: Consider low-dose doxepin (3-6mg) 1, 2
   • For mixed insomnia: Consider eszopiclone (2-3mg) or suvorexant (10-20mg) 1, 2

3. Follow-up within 7-10 days to evaluate treatment response and consider further evaluation if insomnia persists 1

Key Pitfalls to Avoid

1. Long-term use of any sleep medication - FDA approves pharmacologic therapy only for short-term use (4-5 weeks) 1

2. Overreliance on OTC antihistamines like doxylamine - These have limited evidence for efficacy and potential for side effects 4

3. Failure to address underlying causes - Patients with insomnia that does not remit within 7-10 days should be further evaluated 1

4. Neglecting CBT-I - This remains the standard of treatment with the most favorable benefit-risk ratio 1

In conclusion, while doxylamine is available over-the-counter for occasional sleep difficulties, the evidence does not support its use for chronic insomnia disorder when compared to other available treatments with better efficacy and safety profiles.