What is the role of hydroxyzine (an antihistamine) in treating anxiety and insomnia in a general adult population without specified comorbidities or previous substance abuse?

Hydroxyzine for Anxiety and Insomnia

Hydroxyzine is not recommended as a first-line treatment for either anxiety or insomnia in adults, despite FDA approval for anxiety, due to insufficient high-quality evidence, significant sedation concerns, and the availability of superior alternatives with better-established efficacy and safety profiles.

Evidence Against Hydroxyzine for Insomnia

The major insomnia treatment guidelines from the American Academy of Sleep Medicine and American College of Physicians do not include hydroxyzine as a recommended treatment option 1, 2, 3. Over-the-counter antihistamines (including hydroxyzine) are explicitly not recommended for insomnia due to lack of efficacy data, strong anticholinergic effects causing confusion and urinary retention, fall risk in elderly patients, daytime sedation, and rapid tolerance development after only 3-4 days of continuous use 2, 3.

The 2019 Beers Criteria carry a strong recommendation to avoid antihistamines in older adults due to these safety concerns 2.

Limited Evidence for Anxiety Treatment

While hydroxyzine is FDA-approved for "symptomatic relief of anxiety and tension associated with psychoneurosis," the label explicitly states: "The effectiveness of hydroxyzine as an antianxiety agent for long term use, that is more than 4 months, has not been assessed by systematic clinical studies" 4.

A 2010 Cochrane systematic review found that although hydroxyzine showed some superiority over placebo for generalized anxiety disorder (GAD), the authors concluded: "Due to the high risk of bias of the included studies, the small number of studies and the overall small sample size, it is not possible to recommend hydroxyzine as a reliable first-line treatment in GAD" 5. The review included only 5 studies with 884 participants, and all had significant methodological limitations 5.

Individual studies from the 1990s showed hydroxyzine 50 mg/day produced anxiolytic effects beginning in the first week, but the most common side effect was transient sleepiness (28% vs 14% with placebo) 6.

Recommended Treatment Algorithm

For Insomnia:

First-line treatment: Cognitive Behavioral Therapy for Insomnia (CBT-I) should be initiated for all adults with chronic insomnia before any pharmacotherapy 1, 3. CBT-I demonstrates superior long-term efficacy compared to medications with sustained benefits after discontinuation 1, 3.

Second-line pharmacotherapy (if CBT-I insufficient):

• For sleep onset insomnia: Zaleplon 10 mg, ramelteon 8 mg, or zolpidem 10 mg (5 mg in elderly) 2, 3
• For sleep maintenance insomnia: Low-dose doxepin 3-6 mg (first choice), eszopiclone 2-3 mg, or suvorexant 2, 3

Low-dose doxepin reduces wake after sleep onset by 22-23 minutes with minimal anticholinergic effects at hypnotic doses and no weight gain 2.

For Anxiety:

First-line treatment: Selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) are the evidence-based first-line pharmacological treatments for GAD, combined with cognitive behavioral therapy 5.

Alternative options: Buspirone or short-term benzodiazepines may be considered, though benzodiazepines carry significant risks of dependence and should be avoided in patients with substance use history 2.

Critical Safety Concerns with Hydroxyzine

• Alpha-adrenergic antagonism: Despite being an antihistamine, hydroxyzine has alpha-adrenergic blocking activity, which has been implicated in rare but serious adverse events including priapism when combined with other alpha-blocking medications like risperidone 7
• Sedation profile: The 28% rate of sleepiness with hydroxyzine makes it problematic for daytime anxiety management 6
• Anticholinergic burden: Like other first-generation antihistamines, hydroxyzine carries anticholinergic risks particularly concerning in elderly patients 2
• Tolerance development: Antihistamines develop tolerance rapidly, typically within 3-4 days of continuous use 2

Common Pitfalls to Avoid

• Using hydroxyzine as a sleep aid: This bypasses evidence-based treatments (CBT-I and FDA-approved hypnotics) with superior efficacy and safety profiles 2, 3
• Prescribing for long-term anxiety: The FDA label and evidence base only support short-term use (less than 4 months) 4
• Failing to implement CBT-I: Behavioral interventions provide more sustained effects than any medication alone and should always be the foundation of insomnia treatment 1, 3
• Combining with other sedating medications: This significantly increases risks of cognitive impairment, falls, and complex sleep behaviors 2

If a patient specifically requests hydroxyzine or has failed other options, limit use to short-term situational anxiety (less than 4 months) at 50 mg/day, monitor closely for excessive sedation, and always combine with appropriate behavioral interventions 4, 6.