What are the potential interactions between trazodone (an antidepressant) and antihistamines (e.g. diphenhydramine, a first-generation antihistamine)?

Potential Interactions Between Trazodone and Antihistamines

The concurrent use of trazodone and first-generation antihistamines (such as diphenhydramine) should be avoided due to additive CNS depression effects that can significantly increase the risk of psychomotor impairment, potentially leading to serious adverse outcomes including accidents and injuries. 1

Mechanism of Interaction

• Both trazodone and first-generation antihistamines have sedative properties that work through different mechanisms - trazodone primarily through 5-HT2 receptor antagonism and antihistamines through H1 receptor blockade 2, 3
• When combined, these medications can cause additive central nervous system depression, potentially leading to excessive sedation and impaired psychomotor function 1
• The combination may further enhance performance impairment beyond what either medication would cause individually 1

Specific Risks of Concurrent Use

Enhanced Sedation and Impairment

• First-generation antihistamines like diphenhydramine already cause significant sedation and performance impairment in school and driving that can exist without subjective awareness 1
• Trazodone is associated with significant sedative effects that can persist into the following day 1, 3
• The combination may significantly increase the risk of:
  • Motor vehicle accidents 1
  • Occupational accidents 1
  • Falls, especially in elderly patients 1

Anticholinergic Effects

• First-generation antihistamines have anticholinergic properties that can cause dry mouth, dry eyes, constipation, urinary retention, and increased risk of narrow-angle glaucoma 1
• These effects may be particularly problematic in older adults who are more sensitive to anticholinergic side effects 1
• Trazodone does not have significant anticholinergic properties but may compound other adverse effects 4

Special Population Considerations

Elderly Patients

• Older adults are at significantly higher risk for adverse effects from this combination due to:
  • Increased sensitivity to psychomotor impairment 1
  • Higher risk of falls and fractures 1
  • Greater likelihood of pre-existing comorbid conditions (prostatic hypertrophy, elevated IOP, cognitive impairment) 1
  • Altered drug metabolism and clearance 4

Patients with Sleep Disorders

• Despite both medications being used off-label for insomnia, guidelines explicitly advise against using trazodone for chronic insomnia disorder 1, 5
• First-generation antihistamines are also not recommended for insomnia due to tolerance development after 3-4 days of continuous use and potential for adverse effects 1
• The American Academy of Sleep Medicine recommends against using either medication for insomnia 5

Alternative Approaches

• For insomnia treatment, cognitive behavioral therapy for insomnia (CBT-I) should be the first-line treatment 1, 5
• If pharmacotherapy is necessary for insomnia, non-benzodiazepine BZRAs (zolpidem, eszopiclone, zaleplon) or ramelteon are preferred over trazodone or antihistamines 1, 5
• For allergic rhinitis, second-generation antihistamines (cetirizine, loratadine, fexofenadine) are preferred over first-generation antihistamines due to less sedation and fewer drug interactions 1

Clinical Recommendations

• Avoid concurrent use of trazodone and first-generation antihistamines whenever possible 1
• If a patient is taking trazodone for depression and requires antihistamine therapy, select a second-generation antihistamine with minimal sedative properties (fexofenadine, loratadine, desloratadine) 1
• Patients should be counseled about the risks of excessive sedation, impaired driving, and increased fall risk if both medications must be used 1, 6
• Monitor patients closely for signs of excessive sedation, confusion, or impaired coordination if concurrent use cannot be avoided 1, 4

Common Pitfalls

• Assuming that administering first-generation antihistamines only at bedtime eliminates daytime impairment - their effects can persist into the following day due to long half-lives 1
• Failing to recognize that patients may not subjectively perceive their level of impairment while objectively demonstrating significant performance deficits 1
• Overlooking the increased risk of suicide attempts associated with trazodone when used for insomnia (61% higher than zolpidem) 6
• Underestimating the additive effects when combining CNS depressants, which can be greater than the sum of individual effects 1