Metoclopramide and Diphenhydramine: A Randomized Controlled Trial of a Treatment for Headache in Pregnancy when Acetaminophen Alone Is Ineffective (MAD Headache Study).

Objective: We investigated whether metoclopramide administered with diphenhydramine (MAD) relieves headache in pregnant women when acetaminophen alone is ineffective, using codeine for comparison.

Study Design: Normotensive pregnant women in the second or third trimester were randomized to MAD intravenously (10 mg and 25 mg, respectively) or codeine orally (30 mg) for headache after 650 to 1,000 mg of acetaminophen failed to relieve their headaches. Headache severity (pain score 0-10) was noted at intervals over 24 hours. The primary outcome was reduction in pain score 6 hours after medication administration. A sample size calculation of 35 patients per group was based on estimated reduction in headache pain score by at least two points, with an of 0.05 and a power of 80%.

Results: No difference was seen in the primary outcome. MAD pain scores were lower at 30 minutes (3 ± 2.8 versus 5.8 ± 2.3,  < 0.001), 1 hour (2.2 ± 2.3 vs. 4.1 ± 3;  < 0.01), and 12 hours (1.3 ± 2.5 vs. 2.7 ± 3;  < 0.05), but not at 6 hours. Time to perceived headache relief was shorter for MAD than for codeine (20.2 ± 13.4 vs. 62.4 ± 62.2 minutes;  < 0.001). More patients in the MAD group reported full headache relief within 24 hours (76.5 vs. 37.5%;  < 0.01).

Conclusion: MAD effectively relieves headaches in pregnant women when acetaminophen fails.