Drug combo provided faster, sustained pain relief in more patients
by Kristin Jenkins, Contributing Writer, MedPage Today October 19, 2017

Action Points
• Note that this single-center randomized trial found that IV prochlorperazine + diphenhydramine was superior to IV hydromorphone for the treatment of acute migraine.
• Be aware that similar effects in terms of sedation and dizziness were seen in both arms.
An opioid commonly used in the emergency department (ED) to treat patients with acute migraine should be replaced with a dopamine agonist/anti-histamine combination that demonstrated “overwhelming superiority” in achieving sustained headache relief, researchers said.

A randomized, double-blind study provided Class I evidence that single-dose intravenous (IV) prochlorperazine (Compazine) plus diphenhydramine (Benadryl) was 28% more effective than single-dose IV hydromorphone for achieving 48 hours of headache relief without the need for rescue medication, according to Benjamin W. Friedman, MD, of Albert Einstein College of Medicine in New York City, and colleagues.
A total of 37 of 62 (60%) study participants receiving single-dose IV prochlorperazine plus diphenhydramine — given to prevent akathisia, a common side effect of IV prochlorperazine — had little or no pain within 2 hours of drug administration compared with 20 of 64 (31%) participants who received IV hydromorphone, they reported online in Neurology.
Patients treated with hydromorphone were also more likely to require additional treatment for headache, and related symptoms such as dizziness, drowsiness and agitation. They also spent more time in the ED.
“IV hydromorphone is substantially less effective than IV prochlorperazine for the treatment of acute migraine in the ED and should not be used as first-line therapy,” the authors wrote.
Hydromorphone, the parenteral opioid used most commonly in U.S. EDs, is administered in 25% of all migraine visits even though experts warn against it, citing a lack of high quality evidence. In a recent guideline, the American Headache Society stated that no randomized studies of hydromorphone for the treatment of acute migraine could be identified.
In a statement, Friedman emphasized that the study findings should not be seen as an indictment of IV opioids or taken as a carte blanche to avoid their use. “While this study demonstrates the overwhelming superiority of prochlorperazine over hydromorphone for initial treatment of acute migraine, the results do not suggest that treatment with IV opioids leads to long-term addiction. In addition, the results should not be used to avoid the use of opioids for people who have not responded well to anti-dopaminergic drugs.”
The study was carried out at two EDs in Montefiore Medical Center and began enrollment in March 2015. Participants met the international criteria for migraine, hadn’t used an opioid in the month prior to enrollment, and many didn’t self-medicate prior to presenting.
Participants were randomized to either prochlorperazine 10 mg IV administered over 5 minutes with co-administration of diphenhydramine 25 mg, or hydromorphone 1 mg IV administered over 5 minutes plus a normal saline placebo.
Sustained headache relief was defined as having a pain level of mild or none within 2 hours of drug administration and not relapsing for 48 hours. Outcomes were assessed for up to 4 4 hours in the ED and through phone interviews 48 hours after discharge, and again at 1 and 3 months after leaving the ED.
One hour after receiving the initial medication infusion, participants were offered a second dose of the same medication. In the hydromorphone group, 31% of participants asked for a second dose compared with 8% in the prochlorperazine group (without a second dose of diphenhydramine). Participants in the opioid group were also more likely to request other pain medication: 36% versus 6% of those who received prochlorperazine.
In June 2017, after 127 patients had been enrolled, the study was halted because of the “overwhelming superiority” of results in participants randomized to the prochlorperazine plus diphenhydramine treatment arm.
In patients receiving prochlorperazine, the most common adverse symptom was anxiety and restlessness, reported in three patients. Dizziness or weakness was reported by nine of 62 patients in the hydromorphone group.
In the first 48 hours after discharge, patient outcomes, including rates of headache relapse, started to converge between the two groups. Of the 52 patients in the prochlorperazine arm who had no or mild headache prior to discharge, 15 (29%) reported a moderate or severe headache within 48 hours of leaving the ED. By comparison, 13 (33%) of the 39 patients in the hydromorphone arm reported return of moderate to severe headache.
Symptoms of drowsiness and restlessness were also similar between the groups. Participants asked if they would like to receive the same medication during a subsequent ED visit, nearly 75% of the prochlorperazine group and two-thirds of the hydromorphone group said “yes.”
Followup data at 1 and 3 months after ED discharge revealed that the number of headache days, return visits to EDs, and functional disability scores were comparable in participants from both treatment arms.
This study “provides high-grade evidence consistent with the longstanding clinical impression that dopamine antagonists, such as metoclopramide (Reglan) and prochlorperazine, are effective for treating acute migraine,” Mitchell S. V. Elkind, MD, of Columbia University in New York City told MedPage Today.
“What is surprising is just how much more effective the dopamine antagonists are than opioids — about twice as effective,” said Elkind, who was not involved in the study.
Many study participants who achieved acute migraine relief with prochlorperazine went on to have recurrence of pain in just 2 days, suggesting that more needs to be done. “For sustained relief, patients may require education about migraine triggers, such as specific foods and alcohol,” Elkind said. Rescue medications, such as oral triptans, or additional doses of prochlorperazine, may also be needed, and when appropriate, initiation of prophylactic medications.
The lack of difference in the longer-term outcomes between the hydromorphone and prochlorperazine treatment groups was notable, Elkind pointed out. The study population may be somewhat different from other patients with migraine who experience more frequent headaches and self-medicate with opioids, he suggested. “So the answer to the question of the relative longer term benefits with dopaminergic agents or serotonergic agents warrants further study.”

Friedman and co-authors disclosed no relevant relationships with industry.
• Reviewed by F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner
• Primary Source
Neurology
Source Reference: Friedman BW, et al “Randomized study of IV prochlorperazine plus diphenhydramine vs IV hydromorphone for migraine” Neurology 2017; DOI: 10.1212/WNL.0000000000004642.