What is the comparison between hydroxyzine and Benadryl (diphenhydramine) for insomnia treatment?

Hydroxyzine vs Benadryl (Diphenhydramine) for Sleep

Neither hydroxyzine nor diphenhydramine should be used for insomnia treatment, as both are first-generation antihistamines with minimal efficacy and significant anticholinergic risks that outweigh any marginal benefits. 1, 2

Why Both Should Be Avoided

Diphenhydramine Has Proven Inefficacy

• The American Academy of Sleep Medicine explicitly recommends against using diphenhydramine for sleep onset or sleep maintenance insomnia 1, 3
• Diphenhydramine reduces sleep latency by only 7.89 minutes on polysomnography and increases total sleep time by just 12.37 minutes—both falling well below clinically significant thresholds 1
• Meta-analysis shows subjective sleep latency improvement of only 2.47 minutes versus placebo (not statistically significant) 1
• No improvement in sleep quality compared to placebo 1, 2
• Tolerance develops after just 3-4 days of continuous use, eliminating even minimal short-term benefits 2

Hydroxyzine Lacks Evidence for Insomnia

• No direct comparative studies exist between hydroxyzine and diphenhydramine specifically for insomnia treatment
• The single study mentioning hydroxyzine for sleep used it in combination with barbiturates (Vesparax formulation), not as monotherapy 4
• Hydroxyzine causes significant drowsiness, dry mouth, and irritability even with evening dosing 5
• While evening dosing may mitigate some psychomotor impairment, subjective adverse symptoms remain significant 5

Serious Anticholinergic Harms Apply to Both Agents

Central Nervous System Effects

• Both medications cause delirium, slowed comprehension, cognitive impairment, and daytime sedation 2
• Psychomotor impairment occurs even without subjective awareness 3
• Significantly increased fall risk, especially in older adults 2, 3

Peripheral Anticholinergic Effects

• Vision impairment, urinary retention, and worsened constipation 2
• The 2019 Beers Criteria strongly recommend avoiding all antihistamines in older adults due to antimuscarinic adverse effects 2

Additional Safety Concerns

• Trazodone (another commonly used off-label sleep aid) shows 61% higher hazard of suicide attempt compared to zolpidem, while diphenhydramine showed no significant difference 6
• Neither diphenhydramine nor hydroxyzine have FDA approval for insomnia treatment

What to Use Instead

First-Line Treatment

• Cognitive Behavioral Therapy for Insomnia (CBT-I) is the recommended first-line treatment before any pharmacotherapy 3, 7

When Pharmacotherapy Is Necessary

For sleep onset insomnia:

• Zaleplon, zolpidem, ramelteon, or triazolam 7

For sleep maintenance insomnia:

• Eszopiclone, zolpidem extended-release, temazepam, or low-dose doxepin 7

For comorbid depression/anxiety:

• Consider sedating antidepressants as third-line options 3

Clinical Bottom Line

If forced to choose between hydroxyzine and diphenhydramine for sleep, neither should be selected—both are ineffective antihistamines with similar anticholinergic risk profiles. 1, 2 The evidence base for diphenhydramine is slightly more robust (showing clear lack of efficacy), while hydroxyzine has essentially no quality evidence supporting its use for insomnia as monotherapy. Both medications share the same fundamental problems: minimal to no clinically meaningful improvement in sleep parameters, rapid tolerance development, and significant anticholinergic adverse effects that are particularly dangerous in older adults. 2, 3