Is it safe to give diphenhydramine (Benadryl) + metoclopramide (Reglan) + prochlorperazine (Compazine) to an 18-week pregnant individual for a refractory headache?

Safety of Diphenhydramine, Metoclopramide, and Prochlorperazine in Pregnancy for Refractory Headache

The combination of diphenhydramine (Benadryl), metoclopramide (Reglan), and prochlorperazine (Compazine) can be used with caution for refractory headache at 18 weeks of pregnancy, with metoclopramide being the safest option of the three medications.

Safety Profile of Individual Medications

Metoclopramide (Reglan)

• Considered safe for use during pregnancy, including the second trimester (18 weeks) 1
• No increased risk of congenital defects has been reported with metoclopramide use during pregnancy 1
• Recommended by ACOG as part of a step-up approach for treating nausea and vomiting in pregnancy, which supports its safety profile 1
• Potential side effects include extrapyramidal symptoms (dystonia, drowsiness, dizziness) which may require discontinuation if they occur 1

Diphenhydramine (Benadryl)

• Generally considered safe during pregnancy but should be used with some caution 1
• Although frequently used by pregnant patients, there have been some historical concerns about a possible association with cleft palate, though recent studies have not consistently confirmed this risk 1
• When combined with metoclopramide, diphenhydramine has shown effectiveness for headache relief in pregnancy when acetaminophen fails 2
• Often administered with metoclopramide (81% of cases in one study) to reduce the risk of extrapyramidal side effects 3

Prochlorperazine (Compazine)

• Limited specific pregnancy safety data in the provided evidence
• As a phenothiazine, it may carry a risk of extrapyramidal side effects similar to metoclopramide 1
• Considered unlikely to be harmful during pregnancy according to some sources 4
• Should be used with more caution than metoclopramide due to less robust safety data in pregnancy

Evidence for Combination Therapy

• A randomized controlled trial showed that combination metoclopramide and diphenhydramine was more effective than codeine for treating headache in pregnancy when acetaminophen failed 2
• This combination provided faster relief (20.2 vs 62.4 minutes) and more complete headache relief within 24 hours (76.5% vs 37.5%) compared to codeine 2
• In clinical practice, metoclopramide is frequently administered with diphenhydramine (81% of cases) to counteract potential extrapyramidal side effects 3

Recommended Approach for Refractory Headache at 18 Weeks

1. First-line therapy:

   • Acetaminophen (paracetamol) up to 1000 mg should be tried first 1, 4
   • Non-drug therapies should be attempted (relaxation, sleep, massage, ice packs) 4

2. If acetaminophen fails:

   • Metoclopramide (10 mg) with diphenhydramine (25 mg) is a reasonable next step 2, 3
   • This combination has demonstrated effectiveness for headache relief when acetaminophen fails 2

3. If additional treatment is needed:

   • Prochlorperazine may be added with caution 4
   • Monitor closely for extrapyramidal side effects with both metoclopramide and prochlorperazine 1

Important Considerations and Precautions

• Avoid NSAIDs at 18 weeks if possible, as they may be safer in the second trimester but should generally be avoided in the third trimester due to risks of premature closure of the ductus arteriosus 1
• Opioids and butalbital should be avoided for migraine treatment during pregnancy due to potential risks and lower efficacy 1, 3
• Triptans should only be used under specialist supervision during pregnancy, with sumatriptan having the most safety data 1
• Monitor for drowsiness and extrapyramidal symptoms, which are the most common side effects of these medications 1, 3
• If extrapyramidal symptoms occur (dystonia, akathisia), the medication should be discontinued 1

Conclusion

The combination of diphenhydramine, metoclopramide, and prochlorperazine can be used for refractory headache at 18 weeks of pregnancy, with metoclopramide having the strongest safety profile. Diphenhydramine helps counteract the side effects of metoclopramide, and this combination has demonstrated effectiveness. Prochlorperazine should be used with more caution due to limited specific pregnancy safety data.