From the Guidelines
Long-term use of certain first-generation antihistamines, such as diphenhydramine and hydroxyzine, may be associated with an increased risk of dementia, particularly in older adults, due to their anticholinergic properties. These medications can cross the blood-brain barrier and potentially affect cognitive function over time by blocking acetylcholine, a neurotransmitter important for memory and learning 1. The risk appears to be dose-dependent and cumulative, with higher risk associated with longer duration of use and higher doses.
Key Considerations
- Second and third-generation antihistamines like loratadine (Claritin), cetirizine (Zyrtec), and fexofenadine (Allegra) have minimal anticholinergic activity and do not readily cross the blood-brain barrier, making them potentially safer alternatives for long-term use 1.
- Older adults are more sensitive to the psychomotor impairment promoted by first-generation antihistamines and are at increased risk for complications such as fractures and subdural hematomas caused by falls 1.
- Periodic cognitive assessments may be beneficial for those already using first-generation antihistamines, especially older adults, and the risk-benefit ratio should be regularly reevaluated.
Recommendations
- If you require ongoing antihistamine therapy, consider discussing with your healthcare provider about switching to second or third-generation antihistamines.
- For those already using first-generation antihistamines, especially older adults, regular review of the medication regimen and consideration of alternative treatments is crucial to minimize potential cognitive decline.
From the Research
Association Between Antihistamine Use and Dementia Risk
- The relationship between long-term antihistamine use and dementia risk has been explored in several studies 2.
- Research suggests that first-generation antihistamines (FGAs) are associated with a higher risk of dementia compared to second-generation antihistamines (SGAs) 2.
- A study found that FGAs were associated with an elevated dementia risk, with an adjusted hazard ratio (aHR) of 1.13 at less than 60 cumulative defined daily doses (cDDD), 1.29 at 60-120 cDDD, and 1.51 at more than 120 cDDD 2.
- SGAs also increased dementia risk, although to a lesser extent, with an aHR of 1.11 at less than 60 cDDD, 1.19 at 60-120 cDDD, and 1.26 at more than 120 cDDD 2.
Comparison of Specific Antihistamines
- Loratadine, a second-generation antihistamine, has been shown to have a low sedative profile and does not impair cognitive or psychomotor performance 3, 4.
- Cetirizine, another second-generation antihistamine, has been found to cause somnolence and decrease motivation, although to a lesser extent than first-generation antihistamines 5.
- Fexofenadine, a third second-generation antihistamine, has been shown to be nonsedating and does not impair cognitive or psychomotor performance 3.
Mechanisms and Implications
- The anticholinergic properties of antihistamines are thought to contribute to the increased risk of dementia 2.
- The use of antihistamines with lower lipid solubility and greater specificity, such as second-generation antihistamines, may provide an effective alternative for the relief of allergic symptoms while reducing neurologic side effects 6.
- Further clinical trials are necessary to confirm the association between antihistamine use and dementia risk 2.