Should I mix Diphenhydramine (Benadryl), Ketorolac, and Promethazine in the Lactated Ringer's (LR) solution for IV migraine treatment or administer them separately?

IV Administration of Medications for Migraine Treatment

Do not mix diphenhydramine (Benadryl), ketorolac, and promethazine in the same IV solution; administer them separately through the IV line to prevent precipitation and medication incompatibility.

Proper Administration Method

Ketorolac and promethazine specifically should not be mixed together in the same syringe or IV solution, as stated in the FDA drug label for ketorolac: "Ketorolac tromethamine injection should not be mixed in a small volume (e.g., in a syringe) with promethazine hydrochloride; this will result in precipitation of ketorolac from solution" 1.

The correct administration sequence is:

1. Start the 1000cc LR fluid as the primary IV infusion
2. Administer each medication separately through the IV line:
   • Ketorolac 30mg - administer IV over at least 15 seconds
   • Diphenhydramine 50mg - administer IV separately
   • Promethazine 25mg - administer IV at a concentration no greater than 25 mg/mL and at a rate not exceeding 25 mg/minute

Important Administration Precautions

For Ketorolac:

• Must be given over no less than 15 seconds 1
• Maximum daily dose should not exceed 120mg for patients under 65 years of age
• Onset of analgesic effect begins in ~30 minutes with maximum effect in 1-2 hours

For Promethazine:

• Must be administered at a concentration no greater than 25 mg/mL
• Rate should not exceed 25 mg per minute 2
• Preferably inject through the tubing of an IV infusion set that is known to be functioning properly
• Stop injection immediately if patient complains of pain during administration
• Severe tissue injury, including gangrene, can result from improper administration

For Diphenhydramine:

• Standard parenteral dose is 25-50 mg 3
• Can be administered IV separately

Clinical Considerations for Migraine Treatment

• This combination of medications (LR fluid, ketorolac, diphenhydramine, and promethazine) addresses multiple aspects of migraine:

  • Ketorolac provides anti-inflammatory and analgesic effects
  • Diphenhydramine helps with potential side effects from promethazine
  • Promethazine addresses nausea and has sedative properties
  • IV fluid helps with hydration which may improve migraine symptoms

• Ketorolac has been shown to be effective for migraine treatment and is considered a Level A evidence medication for acute migraine 4

• Antiemetics like promethazine are considered Level B evidence for migraine treatment 4

Common Pitfalls to Avoid

1. Medication incompatibility: Never mix ketorolac with promethazine in the same syringe or solution 1

2. Too rapid administration: Administering promethazine too quickly can cause severe adverse reactions including hypotension

3. Extravasation risk: Carefully monitor IV site during administration, particularly with promethazine which can cause severe tissue damage if extravasated 2

4. Sedation effects: Be aware that both diphenhydramine and promethazine have sedative properties and may cause significant drowsiness

5. Duration of therapy: Ketorolac therapy should not exceed 5 days due to risk of adverse effects 1

By administering these medications separately through the IV line rather than mixing them in the LR solution, you ensure proper delivery while avoiding potential drug incompatibilities and precipitation that could compromise treatment efficacy and patient safety.