What is the best first-generation antihistamine (antihistamine)?

Best First-Generation Antihistamine for Allergic Rhinitis

Second-generation antihistamines are strongly preferred over first-generation antihistamines for treating allergic rhinitis due to their superior safety profile and similar efficacy. 1

First-Generation Antihistamine Limitations

First-generation antihistamines have significant drawbacks that limit their clinical utility:

• Associated with sedation, drowsiness, and performance impairment that may occur without subjective awareness by the patient 1
• Linked to increased risk of motor vehicle accidents (drivers in fatal accidents were 1.5 times more likely to be taking first-generation antihistamines) 1
• Cause impaired learning and decreased school performance in children 1
• Produce anticholinergic effects including dry mouth, dry eyes, constipation, urinary retention, and risk of narrow-angle glaucoma exacerbation 1
• Have prolonged plasma half-lives with effects that persist longer than plasma levels of the parent compound 1
• Particularly problematic in older adults who are more sensitive to psychomotor impairment and at increased risk for falls, fractures, and subdural hematomas 1
• Associated with workplace accidents and decreased productivity 1, 2

If a First-Generation Antihistamine Must Be Used

If a first-generation antihistamine must be used (though this is generally not recommended), the following considerations apply:

• Diphenhydramine (Benadryl):

  • Effective for allergic rhinitis symptoms 3
  • Has a half-life of 2.6-4.3 hours 1
  • Associated with significant sedation (50% of patients) 1
  • Has been called for removal from over-the-counter status due to safety concerns 4, 5

• Chlorpheniramine:

  • Has a longer half-life (12-24 hours) 1
  • Lower sedation rate (approximately 45%) compared to diphenhydramine 1
  • May be slightly better tolerated than diphenhydramine 1

• Hydroxyzine:

  • Long half-life (20 hours) 1
  • Very high sedation rate (80%) 1
  • Associated with significant driving impairment that worsens with cellular phone use 1

• Clemastine:

  • Intermediate half-life (21 hours) 1
  • Lower reported sedation rate (14%) than diphenhydramine 1

Important Caveats

• First-generation antihistamines should only be used with caution and after ensuring the patient understands the risks and availability of safer alternatives 1
• Bedtime dosing of first-generation antihistamines can still cause next-day sedation and performance impairment 1
• The AM/PM dosing strategy (second-generation in morning, first-generation at night) is not recommended due to prolonged effects of first-generation agents 1
• Concomitant use of alcohol, sedatives, or other CNS-active medications further increases impairment risk 1

Recommendation

If a first-generation antihistamine must be used, chlorpheniramine would be the most reasonable choice due to its relatively lower sedation profile compared to diphenhydramine and hydroxyzine, while maintaining efficacy for allergic rhinitis symptoms. 1, 6

However, the evidence strongly supports that second-generation antihistamines (particularly fexofenadine, loratadine, or desloratadine) should be the first-line treatment for allergic rhinitis due to their favorable efficacy and safety profile. 1, 5