What are the off-label uses for hydroxyzine (an antihistamine)?

Off-Label Uses for Hydroxyzine

Hydroxyzine has several established off-label uses beyond its FDA-approved indications for pruritus and anxiety, most notably for chemical restraint in agitated patients (particularly children and adolescents), adjunctive treatment of opioid-induced pruritus and nausea, and as a nighttime sedating antihistamine for urticaria patients with sleep disturbances. 1

Primary Off-Label Applications

Chemical Restraint in Agitated Patients

• The American Academy of Pediatrics recommends hydroxyzine for chemical restraint in agitated patients, with particular utility in children and adolescents 1
• This represents a practical application of hydroxyzine's sedative properties in acute behavioral emergencies

Opioid-Related Symptoms

• The National Comprehensive Cancer Network recommends hydroxyzine as an adjunctive treatment for both opioid-induced pruritus and nausea 1
• This dual benefit makes it particularly valuable in palliative care and cancer pain management settings

Sleep Disturbances in Urticaria

• For patients with urticaria experiencing sleep disturbances, hydroxyzine 10-50 mg at bedtime can be added to a non-sedating antihistamine during the day 1
• This AM/PM dosing strategy specifically targets nighttime symptoms while minimizing daytime sedation, though the prolonged half-life may still cause next-day drowsiness 1

Anxiety Management

• The British Journal of Dermatology acknowledges hydroxyzine for anxiety management at doses of 10-50 mg, though it is not considered first-line treatment due to limited high-quality evidence 1
• A 3-month double-blind study demonstrated efficacy in generalized anxiety disorder with mean HAM-A score improvements of -12.16 compared to -9.64 for placebo (p=0.019) 2
• However, a Cochrane review concluded that despite superiority over placebo, the high risk of bias in studies prevents recommending hydroxyzine as a reliable first-line GAD treatment 3

Critical Safety Considerations for Off-Label Use

Driving and Performance Impairment

• Drivers in fatal accidents were 1.5 times more likely to be taking first-generation antihistamines like hydroxyzine, and performance impairment can occur without subjective awareness of drowsiness 1, 4
• Between 2017-2024, hydroxyzine became the most identified antihistamine in driving under the influence investigations, surpassing diphenhydramine in 2023 5
• Impaired driving performance worsens significantly with concurrent cell phone use 4

QT Prolongation Risk

• Hydroxyzine is contraindicated in patients with prolonged QT interval and should be used with caution in those with risk factors for QT prolongation, congenital long QT syndrome, recent myocardial infarction, uncompensated heart failure, and bradyarrhythmias 6
• Caution is required with concomitant use of Class 1A or Class III antiarrhythmics, certain antipsychotics, antidepressants, and antibiotics known to prolong QT interval 6

Special Population Precautions

• Hydroxyzine is contraindicated in early pregnancy due to fetal abnormalities in animal studies at doses above human therapeutic range 1, 6
• Dose should be halved in moderate renal impairment and avoided in severe renal impairment 1, 4
• Elderly patients require lower starting doses due to increased sensitivity to psychomotor impairment and higher risk for falls, fractures, and anticholinergic effects 1, 4
• Neonatal withdrawal symptoms can occur with maternal use, lasting up to 5 weeks 4

Practical Dosing for Off-Label Uses

• For anxiety or chemical restraint: 10-50 mg per dose 1
• For nighttime sedation in urticaria: 10-50 mg at bedtime 1
• For opioid-induced symptoms: dosing as adjunctive therapy (specific doses not established in guidelines) 1
• Reduce doses in elderly patients and those with moderate renal impairment 1

Important Clinical Pitfalls

• Performance impairment persists longer than plasma levels due to prolonged half-lives of hydroxyzine and its metabolites 4
• Even bedtime-only dosing causes significant daytime drowsiness and performance impairment the following day 4
• CNS depressant dosages (narcotics, barbiturates, sedatives) must be reduced when used concomitantly with hydroxyzine 6
• Hydroxyzine may rarely cause acute generalized exanthematous pustulosis (AGEP); discontinue at first appearance of skin rash 6
• Avoid cetirizine or levocetirizine in patients who have experienced hypersensitivity reactions with hydroxyzine due to cross-sensitivity risk 6