What is the preferred treatment between doxylamine succinate (antihistamine) and diphenhydramine (antihistamine) for insomnia?

Doxylamine Succinate vs Diphenhydramine for Insomnia Treatment

Neither doxylamine succinate nor diphenhydramine is recommended for the treatment of insomnia, as both have limited efficacy data and potential for adverse effects, particularly in older adults. 1

Efficacy Comparison

• Diphenhydramine shows minimal efficacy for insomnia with a mean sleep latency reduction of only 8 minutes compared to placebo (95% CI: 2 min increase to 17 min reduction) and minimal improvement in total sleep time of 12 minutes (95% CI: 13 min reduction to 38 min improvement) 1
• Diphenhydramine shows no improvement in sleep quality compared to placebo 1
• Doxylamine has limited evidence for efficacy in insomnia but may be effective for up to four weeks according to some sources 2
• The American Academy of Sleep Medicine explicitly recommends against using diphenhydramine for treating either sleep onset or sleep maintenance insomnia 1

Safety Concerns

• Both medications are first-generation antihistamines with significant anticholinergic effects including dry mouth, constipation, urinary retention, and increased risk for narrow-angle glaucoma 3
• First-generation antihistamines like doxylamine and diphenhydramine are associated with significant daytime sedation and performance impairment, even without subjective awareness of these effects 3
• Older adults are particularly susceptible to psychomotor impairment from these medications, with increased risk of falls and subdural hematomas 3

Pharmacokinetic Considerations

• Doxylamine has dose-proportional pharmacokinetics across its therapeutic range (12.5-25 mg), with predictable linear increases in systemic exposure 4
• Food intake does not significantly affect the pharmacokinetics of doxylamine 5

Recommended Alternatives for Insomnia

• Cognitive Behavioral Therapy for Insomnia (CBT-I) is recommended as the first-line treatment for chronic insomnia before considering pharmacological options 1, 3
• When pharmacotherapy is necessary, the American Academy of Sleep Medicine recommends:
  • First-line: Short/intermediate-acting benzodiazepine receptor agonists (zolpidem, eszopiclone, zaleplon) or ramelteon 1, 6
  • Second-line: Alternative BzRAs or ramelteon if the initial agent was not successful 6
  • Third-line: Sedating antidepressants, particularly when comorbid depression/anxiety exists 6

Treatment Algorithm for Insomnia

1. Begin with CBT-I as the foundation of treatment 1, 3
2. If pharmacotherapy is needed:
   • For sleep onset insomnia: Consider zaleplon, zolpidem, triazolam, or ramelteon 1
   • For sleep maintenance insomnia: Consider eszopiclone, zolpidem, temazepam, or doxepin (3-6 mg) 1
3. Use the lowest effective dose for the shortest period possible 3
4. Avoid diphenhydramine and doxylamine due to limited efficacy and potential for adverse effects 1

Special Considerations

• In older adults, all sedating antihistamines should be used with extreme caution due to increased sensitivity to anticholinergic and sedating effects 3
• For patients with a history of substance use disorders, non-scheduled medications like low-dose doxepin (3-6 mg) may be preferable to benzodiazepines or Z-drugs 6

Common Pitfalls to Avoid

• Using over-the-counter antihistamines as a long-term solution for insomnia 3
• Failing to address underlying causes of insomnia before initiating pharmacotherapy 1
• Not implementing proper sleep hygiene and behavioral interventions before or alongside medication use 1
• Overlooking the increased risk of adverse effects in older adults when prescribing sedating antihistamines 3