Does Hydroxyzine Cause Respiratory Depression?
Hydroxyzine does not cause clinically significant respiratory depression at recommended therapeutic doses, according to FDA labeling, though respiratory depression can occur with intravenous administration or doses considerably higher than recommended. 1
Evidence from FDA Drug Labeling
The FDA-approved prescribing information explicitly states: "Clinically significant respiratory depression has not been reported at recommended doses." 1 This represents the highest-quality regulatory guidance available and should frame clinical decision-making for standard oral hydroxyzine use.
Context: Intravenous and Supratherapeutic Dosing
While therapeutic oral doses are safe, important caveats exist:
- Intravenous hydroxyzine (100 mg) causes respiratory depression lasting greater than 3 hours, as demonstrated in controlled human studies measuring respiratory response curves. 2
- The respiratory depressant effect of IV hydroxyzine is not reversible with naloxone, indicating a non-opioid mechanism. 2
- The FDA label notes that involuntary motor activity, tremor, and convulsions have been reported "usually with doses considerably higher than those recommended." 1
Evidence in Vulnerable Populations
In patients with chronic obstructive pulmonary disease (COPD), hydroxyzine 1.5 mg/kg IV caused no significant changes in PaO2, PaCO2, or pH, providing reassurance even in this high-risk population. 3 This dose exceeds maximum therapeutic intramuscular dosing, suggesting that standard oral/IM administration carries minimal respiratory risk even in compromised patients. 3
Central Nervous System Depression Profile
Hydroxyzine's primary safety concern is CNS depression rather than respiratory depression:
- Drowsiness is the most common side effect (28% vs 14% with placebo), typically transient and appearing during the first week of treatment. 4
- In overdose analysis comparing 17,265 hydroxyzine exposures to 102,354 diphenhydramine exposures, hydroxyzine-poisoned patients had lower rates of respiratory depression than diphenhydramine-poisoned patients. 5
- Mild CNS depression was more common than antimuscarinic toxidrome in hydroxyzine overdose. 5
- Mortality in hydroxyzine overdose was rare (0.02% in the National Poison Data System). 5
Critical Drug Interaction Warning
The combination of hydroxyzine with other CNS depressants (opioids, benzodiazepines, alcohol) significantly enhances performance impairment and sedation risk. 6
- When hydroxyzine was combined with meperidine 1.5 mg/kg IV in COPD patients, there was no greater ventilatory depression than meperidine alone, indicating no potentiation of respiratory effects. 3
- However, guidelines for benzodiazepine-opioid combinations emphasize that such combinations produce synergistic respiratory depression (92% hypoxemia rate, 50% apnea rate in volunteer studies). 7
- While hydroxyzine itself may not potentiate respiratory depression with opioids based on the meperidine study, the enhanced CNS depression warrants caution. 6, 3
Clinical Recommendations
For standard oral/IM hydroxyzine at therapeutic doses: No special respiratory monitoring is required in patients without severe pulmonary disease. 1
Avoid or use extreme caution in:
- Severe pulmonary insufficiency 8
- Concurrent use with high-dose benzodiazepines (particularly olanzapine, where fatalities have been reported) 8
- Elderly patients, who are more sensitive to psychomotor impairment and at increased risk for falls 6
If using IV hydroxyzine or supratherapeutic doses: Anticipate respiratory depression lasting >3 hours and ensure appropriate monitoring and airway management capabilities. 2
Common Pitfall to Avoid
Do not assume hydroxyzine behaves like diphenhydramine in overdose. Hydroxyzine produces less antimuscarinic toxicity and more pure CNS depression, with a different clinical presentation. 5 Clinicians should not generalize the illness script of diphenhydramine exposures to hydroxyzine. 5