Can diphenhydramine (antihistamine) be used as an antiemetic?

Diphenhydramine as an Antiemetic: Limited Role as Adjunctive Therapy Only

Diphenhydramine should not be used as a primary antiemetic agent but may serve as an adjunct to first-line antiemetics in specific situations. 1 The most recent evidence from the 2017 American Society of Clinical Oncology (ASCO) guidelines explicitly removed diphenhydramine from its recommended adjunctive antiemetic regimens, as the rationale for its inclusion no longer exists with modern antiemetic protocols 1.

Current Role of Diphenhydramine in Antiemetic Therapy

Primary Antiemetic Use

• Diphenhydramine is not recommended as a single-agent antiemetic according to multiple guidelines 1
• More effective antiemetic agents are available as first-line options:
  • 5-HT3 receptor antagonists (ondansetron, granisetron, palonosetron)
  • NK1 receptor antagonists
  • Dexamethasone
  • Metoclopramide
  • Prochlorperazine

Adjunctive Role

Diphenhydramine may be used as an adjunct in specific situations:

1. Managing extrapyramidal symptoms: When using dopamine antagonists like metoclopramide or prochlorperazine that can cause akathisia 2, 3

   • Dosing: 25-50 mg IV/PO
   • Administration: Can be given prophylactically or as treatment when symptoms occur

2. Pruritus management: For opioid-induced pruritus, particularly when using morphine or codeine 1

   • Non-sedating antihistamines are preferred first-line
   • Diphenhydramine can be used if sedation is not problematic

3. Anaphylaxis management: As part of the treatment protocol for anaphylactic reactions 1

   • Dose: 1-2 mg/kg or 25-50 mg parenterally
   • Note: Always secondary to epinephrine, never as sole therapy

Evidence Against Primary Antiemetic Use

The 2017 ASCO guidelines specifically removed diphenhydramine as an adjunctive antiemetic, stating:

"Diphenhydramine was incorporated into antiemetic regimens primarily to prevent the adverse effects from dopaminergic blockade—for example, akathisia—that were anticipated with the use of high-dose metoclopramide before the introduction of selective 5-HT3 receptor antagonists. With high doses of metoclopramide rarely used for the prevention of anti-neoplastic agent-induced nausea and vomiting, the rationale for the inclusion of diphenhydramine no longer exists." 1

A 1991 randomized controlled trial specifically examining diphenhydramine as an adjuvant antiemetic with metoclopramide for cisplatin chemotherapy concluded that "diphenhydramine is not a useful adjuvant drug in the antiemetic therapy" 4.

Adverse Effects and Limitations

• Sedation: Significant sedative effects that may limit patient activities 4
• Anticholinergic effects: Dry mouth, blurred vision, urinary retention 1
• Cardiovascular effects: Hypotension 1
• Safety concerns: Recent research suggests diphenhydramine has a problematic therapeutic ratio, particularly in children and older adults 5

Algorithm for Antiemetic Selection

1. First-line antiemetics (based on cause of nausea/vomiting):

   • Chemotherapy-induced: 5-HT3 antagonist + dexamethasone ± NK1 antagonist 1
   • General nausea/vomiting: Metoclopramide, ondansetron, or prochlorperazine 2

2. When to consider diphenhydramine:

   • If using dopamine antagonists (metoclopramide, prochlorperazine) AND:
     • Patient has history of extrapyramidal symptoms
     • Akathisia develops during treatment
   • When sedation is desirable alongside antiemetic effect
   • As part of anaphylaxis management protocol

3. Diphenhydramine dosing when indicated:

   • 25-50 mg IV/PO/IM
   • Duration of effect: 4-6 hours 1

Special Considerations

• Endoscopic procedures: Diphenhydramine has been studied as an adjunct for sedation during endoscopic procedures, where it may help reduce the required doses of other sedatives 1
• Elderly patients: Use with caution due to increased risk of anticholinergic effects and sedation 6
• Pediatric patients: Alternative antiemetics are generally preferred 7

In conclusion, while diphenhydramine has historically been used as an antiemetic, current evidence and guidelines support its use only as an adjunctive therapy in specific situations, particularly for managing side effects of primary antiemetics rather than as a first-line antiemetic agent itself.