What short‑term PRN medication (non‑benzodiazepine) can be used to treat anxiety and agitation in an adult without contraindications such as antihistamine hypersensitivity, severe cardiac arrhythmias, pregnancy, or lactation?

Non-Benzodiazepine PRN Options for Short-Term Anxiety and Agitation

For acute anxiety and agitation requiring PRN management, hydroxyzine 25–50 mg orally is the safest non-benzodiazepine first-line option, offering anxiolytic effects without dependence risk, though drowsiness is common. 1, 2

Primary Recommendation: Hydroxyzine

• Hydroxyzine demonstrates superior efficacy compared to placebo for generalized anxiety (OR 0.30,95% CI 0.15–0.58) and is well-tolerated with acceptable side-effect profiles 2
• Start with 25 mg orally PRN, may increase to 50 mg per dose if needed for breakthrough anxiety or agitation 1
• The main adverse effect is sedation/drowsiness, which occurs more frequently than with benzodiazepines but without addiction potential 2
• Hydroxyzine is particularly advantageous when substance-use history or dependence concerns exist, as it carries no tolerance or withdrawal risk 1

Advantages Over Benzodiazepines

• No risk of tolerance, addiction, or withdrawal syndrome that characterizes benzodiazepine use 3, 4
• Does not cause paradoxical agitation, which occurs in approximately 10% of patients (especially elderly) receiving benzodiazepines 5, 6
• Suitable for longer-term PRN use without the 2–4 week limitation recommended for benzodiazepines 1, 4

Important Caveats

• Anticholinergic properties may worsen confusion in elderly patients or those with cognitive impairment—use cautiously in this population 5
• Sedation is the most common side effect; patients should be warned about driving or operating machinery 2
• Hydroxyzine is equivalent in efficacy to benzodiazepines and buspirone but with a more favorable safety profile for PRN use 2

Alternative Option: Low-Dose Quetiapine

• Quetiapine 25 mg immediate-release orally PRN provides anxiolytic and sedative effects without benzodiazepine-related risks 1
• Particularly useful when mood instability or hypomanic features accompany anxiety, as it offers mood stabilization 1
• Quetiapine's sedating properties can be beneficial for acute agitation requiring rapid calming 6

When to Choose Quetiapine Over Hydroxyzine

• Presence of prominent hypomanic or manic symptoms alongside anxiety 1
• Need for mood stabilization in addition to anxiolysis 1
• Patient preference for less anticholinergic side effects 1

Monitoring Requirements

• Monitor for orthostatic hypotension, especially in elderly patients or those on antihypertensives 5
• Watch for excessive sedation, particularly when combined with other CNS depressants 1
• Be aware that very low doses (25 mg) may paradoxically worsen nightmares or hallucinations in elderly dementia patients due to histamine-mediated effects rather than dopamine antagonism 6

Agents to Avoid for PRN Anxiety

Buspirone

• Buspirone requires 2–4 weeks to achieve therapeutic effect and is therefore unsuitable for PRN or acute anxiety management 5
• Only appropriate for chronic anxiety when dosed regularly, not for breakthrough symptoms 5

SSRIs (Sertraline, Citalopram)

• SSRIs require 4–8 weeks for full anxiolytic effect at adequate dosing and are ineffective for acute PRN use 5
• Reserved for chronic anxiety disorders requiring daily maintenance therapy 4

Antipsychotics (Haloperidol, Risperidone, Olanzapine)

• Antipsychotics should be reserved for severe agitation with psychotic features or imminent risk of harm, not routine anxiety 5, 7
• Carry significant risks including extrapyramidal symptoms, metabolic effects, and increased mortality in elderly patients 5
• Haloperidol and other typical antipsychotics have high rates of extrapyramidal side effects and are inappropriate for anxiety without psychosis 7, 8

Clinical Decision Algorithm

1. First-line: Hydroxyzine 25–50 mg PO PRN for most patients with acute anxiety/agitation without contraindications 1, 2

2. Alternative: Quetiapine 25 mg PO PRN if mood instability present or anticholinergic effects are concerning 1

3. Avoid benzodiazepines unless hydroxyzine and quetiapine have failed, given dependence risk and paradoxical reactions 1, 3, 4

4. Monitor first dose for excessive sedation, dizziness, or (rarely) paradoxical worsening before authorizing continued PRN use 1, 2

Special Population Considerations

Elderly Patients (≥65 Years)

• Start hydroxyzine at 25 mg rather than 50 mg to minimize fall risk from sedation 1
• Avoid anticholinergic agents entirely in patients with dementia or cognitive impairment 5
• Quetiapine 12.5–25 mg may be safer than hydroxyzine in frail elderly due to lower anticholinergic burden 1

Patients with Cardiac Concerns

• Both hydroxyzine and quetiapine are safe from a cardiac conduction standpoint, unlike some benzodiazepines or antipsychotics 1
• Neither agent significantly prolongs QTc interval at recommended PRN doses 1

Substance Use History

• Hydroxyzine is strongly preferred over any benzodiazepine when addiction risk exists 1
• Quetiapine is also appropriate, though monitor for misuse potential in some populations 1

Duration and Reassessment

• PRN anxiolytics should be limited to short-term use (days to weeks) while addressing underlying triggers 4
• If anxiety persists beyond 2–4 weeks, transition to scheduled SSRI therapy rather than continuing PRN medications 4
• Reassess need for PRN medication at each clinical encounter and discontinue when acute stressor resolves 1