Emergency room doctors in the Bronx have successfully alleviated posttraumatic headache by combining the dopamine antagonist metoclopramide with diphenhydramine, better known as Benadryl, in a randomized, double-blind, placebo-controlled trial. An hour after treatment, patients who took the two drugs had less headache pain than patients who took a placebo.

"Very little is known about the treatment of posttraumatic headache," Benjamin Friedman, a professor in the Department of Emergency Medicine at the Albert Einstein College of Medicine and lead author of the study, published Wednesday in Neurology, told The Academic Times. "Patients with posttraumatic headache suffer acutely, and many of them suffer chronically — quite a few go on to suffer for months and years after the event. This is a combination of medications that we've used for years for migraine. We had done a pilot study looking at this combination of medications, and it showed some promise."

In the study, which was also registered at ClinicalTrials.gov, 81 people with posttraumatic headache were randomly assigned to get the drugs, while 79 others with the condition were randomly assigned to get the placebo. In both cases, a clinical nurse who was blinded to the treatment administered an IV drip to participants for 15 minutes — the real treatment combined the drugs with saline, while the placebo was saline alone.

Participants were asked to rate their headache pain on a scale of 0 to 10, from "no pain" to "the worst pain imaginable." They did so at baseline and then provided similar information one hour after treatment, 48 hours after treatment, and a week after treatment. In the first hour, patients who were given metoclopramide and diphenhydramine improved by 5.2 points on the 10-point pain scale, while patients who received the placebo improved by only 3.8 points.

"The most important finding is that it relieved acute pain in the setting of the emergency department," Friedman explained. "The finding that most impressed me was that we found some benefit one week later in terms of post-concussive symptoms."

The researchers asked participants about those symptoms, such as nausea and vomiting, both one hour and one week after treatment. Patients who got the drugs had better outcomes than the placebo patients after a week, but the link was more suggestive than significant. "The one-week findings are really just at the cusp of statistical significance," Friedman said. "Given the relatively small size of our study and the consistency of the results — the benefit at one hour and the similar benefit at one week — there probably is some real signal here, but we'll have to let somebody else try to replicate it."

According to Friedman, scientists do not yet understand why metoclopramide acts against headaches. "It's clear that dopamine pathways are involved in pain processing, but where exactly metoclopramide is acting, and whether this is truly the mechanism behind its efficacy, still is uncertain," he explained.

Diphenhydramine was included to curb the nastier side effects of metoclopramide. "We see this one in particular called akathisia — this weird symptom of restlessness and anxiety," Friedman said. "They feel like they need to jump out of their skin —they're agitated, they're anxious, they have to move, they can't stand still. Many times when this has happened, I've seen patients running out of the E.R., blood dripping behind them from the IV site, with not a care in the world except to get out of the E.R."

The one-two punch of metoclopramide and diphenhydramine left some patients reeling. 43% of patients who got both drugs reported adverse events, including akathisia and dizziness, as opposed to 28% of placebo patients.

"There's a real tradeoff," Friedman said. "Now, the side effects were for the most part nuisance side effects — nobody had to be admitted to the hospital or had persistent symptoms. One would have to have a real risk/benefit discussion with the patient before administering this combination of medication."

"Part of the reason the side effects were so high was because we gave a relatively high dose of medication," Friedman continued — patients were given 20 milligrams of metoclopramide and 25 milligrams of diphenhydramine. "Now that we know that the combination has some efficacy, I think we have to go about determining whether we can get away with lower doses."

Friedman also wonders if patients might benefit from taking the drugs a few times over several days instead of just once in the emergency room: "You could give someone a dose of metoclopramide in the E.D. and then give them few pills to go home with — that very well might be a reasonable strategy."

With 160 participants, the study was relatively small — and, as Friedman noted, it might not be easy to generalize from emergency room patients to soldiers, athletes and other groups that commonly suffer posttraumatic headaches. "It would be nice if it were replicated on a larger scale in multiple different settings," he said.

While he understands why some would remain skeptical until the result is replicated, he said he feels good about using the two drugs with his own patients. "We know by analogy that they work in other headache disorders," he said. "The fact that they have value with other headaches gives a lot of support."

"At some point in the not-too-distant future, I hope this will be practiced widely," he added.

The paper, "Randomized Study of Metoclopramide Plus Diphenhydramine for Acute Posttraumatic Headache," published March 24 in Neurology, was authored by Benjamin W. Friedman, Eddie Irizarry, Darnell Cain, Arianna Caradonna, David Zybert, Michael McGregor, Polly E. Bijur, and E. John Gallagher, Albert Einstein College of Medicine; Mia T. Minen, NYU Langone Health; and Clemencia Solorzano and Eleftheria Zias, Montefiore.

Correction: A previously published version of this article misidentified the journal in which the study was published. The error has been corrected.