Prochlorperazine vs. Promethazine for Headache Treatment in the Emergency Department: A Randomized Controlled Trial

doi:10.1016/j.jemermed.2007.09.047

The Journal of Emergency Medicine

Volume 35, Issue 3, October 2008, Pages 247-253

This abstract was presented at the 2006 Society of Academic Emergency Medicine, resulting in the abstract being published in the May issue of the Journal of Emergency Medicine. It was also presented at the Naval Medical Center Portsmouth research competition in May 2006, and at the Government Services chapter meeting of the American College of Emergency Physicians in March 2006.

https://doi.org/10.1016/j.jemermed.2007.09.047 Get rights and content

Abstract

Headache is a very common medical complaint. Four to six percent of the population will have a debilitating headache in their lifetime; and 1–2% of all Emergency Department (ED) visits involve patients with headaches. Although promethazine is used frequently, it has never been studied as a single-agent treatment in undifferentiated headache. We hypothesized that promethazine would be superior to prochlorperazine in the treatment of headache. We conducted a prospective, double-blinded, randomized, controlled trial on patients presenting to our ED between May and August 2005 with a chief complaint of headache. Each subject was randomized to receive either intravenous promethazine 25 mg or prochlorperazine 10 mg, and graded the intensity of their headache on serial 100-mm visual analog scales (VAS). Patients with dystonic reactions or akathesia were treated with diphenhydramine. Adequate pain relief was defined as an absolute decrease in VAS score of 25 mm. After discharge from the ED, patients were queried regarding the recurrence of headache symptoms, the need for additional pain medications, and the occurrence of any side effects since discharge. Thirty-five patients were enrolled in each group. Both drugs were shown to be effective in treatment of headaches. Prochlorperazine provided a faster rate of pain resolution and less drowsiness when compared to promethazine. Both medications were individually effective as abortive therapy for headache. Prochlorperazine was superior to promethazine in the rate of headache reduction and rate of home drowsiness, with similar rates of akathesia, nausea resolution, patient satisfaction, and headache recurrence within 5 days of discharge.

Introduction

Headache is a very common medical complaint. Four to six percent of the population will have a debilitating headache in their lifetime, and 1–2% of all Emergency Department (ED) visits involve patients with headaches (1, 2). Potentially devastating medical illness is present in only a minority of cases. Most headaches are of benign etiology, such as a migraine, tension, or cluster headache. Strategies to treat headache vary substantially between regions and even within individual EDs. Treatment options commonly available to emergency physicians include ergot derivatives, triptans, anti-psychotics, non-steroidal anti-inflammatory drugs, steroids, anti-emetics, and opioids (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13).

Multiple studies have addressed various treatment regimens for headache. In EDs, the most effective medications have been shown to be the ergot derivatives, the triptans, and the phenothiazines (12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23). Lacking the vasoconstrictive properties of ergots and triptans, phenothiazines have recently received more attention. Their mechanism of action includes blockade of the central dopamine receptors that mediate meningeal artery vasodilatation, specifically D2, and variably D1, D3, D4, and D5 (24, 25). Additionally, phenothiazines have the added benefit of effectively treating the frequently associated symptoms of nausea and vomiting. Prochlorperazine (Compazine®, GlaxoSmithKline, Middlesex, UK) is the most commonly utilized and best-studied phenothiazine in headache abortive therapy. Promethazine (Phenergan®, Baxter, Deerfield, IL) gained popularity for headache treatment due to both a manufacturing shortage of prochlorperazine and the black box warning applied to droperidol. Because it is from the same class as prochlorperazine, it seemed logical that promethazine would be an effective therapy. Anecdotally this seemed to be true, yet no clinical trial has been performed to assess its efficacy as single-agent therapy.

In our experience, promethazine seemed to be superior to prochlorperazine in the treatment of headache and its associated symptoms. Therefore, we hypothesized that promethazine would be superior to prochlorperazine in both side-effect profile and efficacy in patients presenting to the ED with a primary benign headache.

Section snippets

Study Design

We conducted a prospective, double-blinded, randomized, controlled trial on consecutive patients presenting to our ED with the chief complaint of headache between May and August 2005. This study was in accord with the Standards of the Committee of Human Experimentation and was approved by the local Institutional Review Board.

Selection of Participants

In our young population, many patients claim they have “migraine” headaches without any formal diagnoses or without meeting the strict International Headache Society

Results

A total of 887 patients presented during the enrollment time frame with a chief complaint of headache. All patients were screened by departmental researchers. There were 753 patients who met at least one of the exclusion criteria. The vast majority of excluded patients described a headache that differed from prior headaches in either location or character. On chart review, most of these patients had a discharge diagnosis of benign headache, but at the time of initial evaluation were excluded

Discussion

Both prochlorperazine and promethazine effectively treated headache in the ED, but the rate by which prochlorperazine diminished headache was superior. At 30 min, significantly more patients in the prochlorperazine group had a reduction in their headache ≥ 25 mm. By 60 min, there was no statistically significant difference. It is possible that this was due to an inadequate number of patients reaching 60 min without rescue drugs. Thirty-four percent of patients in each group required a rescue

Acknowledgments

We would like to thank Mr. Timothy Gendron and the pharmacy staff for preparing the medications. We would especially like to thank the nurses, doctors, and staff for their outstanding support of this project.

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Status migrainosus is one of the recognized complications of migraine with or without aura, defined as a persistent debilitating migraine attack lasting for more than 72 h with little reprieve, leading to functional disability. The individual impact of status migrainosus and the substantial healthcare burden are highlighted. Current case series which inform our understanding of this condition are examined with two groups emergent, those with classic status migrainosus and those with episodic status migrainosus. The question as to whether status migrainosus is a distinct biological state beyond the established migraine pathophysiology is examined. With the underlying pathophysiology not fully understood, attention is turned to therapeutic considerations and the available evidence informing practice. A practical approach to treatment of status migrainosus is presented. Given the severity and need for emergency care, options detailed are in line with recommendations for acute migraine care: with a staged approach initially combining subcutaneous sumatriptan with parenteral options including dopamine receptor antagonists, nonsteroidal anti-inflammatories and acetaminophen. The place of combination treatment with parenteral magnesium sulfate, dihydroergotamine, antiepileptics, corticosteroids, and anesthetic agents is outlined. With a paucity of high-quality evidence to consolidate current clinical approaches, consideration of future therapies and research questions is raised.
A Comparison of Headache Treatment in the Emergency Department: Prochlorperazine Versus Ketamine
2018, Annals of Emergency Medicine
Citation Excerpt :
Among the available options, dopamine antagonists appear to be the most effective, with multiple studies demonstrating their superiority over opioids,3 nonsteroidal anti-inflammatory drugs,4 triptans,5 and antiepileptics.6 A commonly used dopamine antagonist, and one that has a great deal of evidence to support its use for benign headaches, is prochlorperazine.5-10 Although some data suggest that droperidol may be even more effective than prochlorperazine,11 the current national shortage limits its use.
Intravenous subdissociative-dose ketamine has been shown to be effective for pain management, but has not been specifically studied for headaches in the emergency department (ED). For this reason, we designed a study to compare standard treatment (prochlorperazine) with ketamine in patients with benign headaches in the ED.
This study was a multicenter, double-blind, randomized, controlled trial with a convenience sample of patients presenting to the ED with benign headaches. Patients were randomized to receive either prochlorperazine and diphenhydramine or ketamine and ondansetron. Patients' headache severity was measured on a 100-mm visual analog scale (VAS) at 0, 15, 30, 45, and 60 minutes. Nausea, vomiting, anxiety, and the need for rescue medications were also tracked. Patients were contacted at 24 to 48 hours posttreatment to rate their satisfaction and to determine whether they were still experiencing a headache.
There were a total of 54 subjects enrolled. Two patients in the ketamine group and one in the prochlorperazine group withdrew because of adverse effects of the medications. In regard to the primary outcome, at 60 minutes, the prochlorperazine group had a mean improvement in VAS pain scores of 63.5 mm compared with 43.5 mm in the ketamine group, corresponding to a between-groups difference of 20.0 mm (95% confidence interval [CI] 2.8 to 37.2 mm) and a P value of .026. At 45 minutes, the prochlorperazine group had a mean improvement in pain scores of 56.1 mm compared with 38.0 mm in the ketamine group, a difference of 18.1 mm (95% CI 1.0 to 35.2 mm). At 24- to 48-hour follow-up, the mean satisfaction score was 8.3 of 10 for prochlorperazine and 4.9 of 10 for ketamine, a difference of 3.4 (95% CI 1.2 to 5.6). There was not a statistically significant difference in the percentage of patients who had a headache at follow-up or in other secondary outcomes.
Prochlorperazine appears to be superior to ketamine for the treatment of benign headaches in the ED.
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Current first-line ED therapies typically include a dopamine receptor antagonist like prochlorperazine or metoclopramide, often combined with diphenhydramine. Studies have shown these medications to be safe and more effective than opiates, nonsteroidal anti-inflammatory medications, and sumatriptan (2–5). Haloperidol is another venerable dopamine antagonist, of the butyrophenone class.
Emergency Department (ED) headache patients are commonly treated with neuroleptic antiemetics like metoclopramide. Haloperidol has been shown to be effective for migraine treatment.
Our study compared the use of metoclopramide vs. haloperidol to treat ED migraine patients.
A prospective, double-blinded, randomized control trial of 64 adults aged 18–50 years with migraine headache and no recognized risks for QT-prolongation. Haloperidol 5 mg or metoclopramide 10 mg was given intravenously after 25 mg diphenhydramine. Pain, nausea, restlessness (akathisia), and sedation were assessed with 100-mm visual analog scales (VAS) at baseline and every 20 min, to a maximum of 80 min. The need for rescue medications, side effects, and subject satisfaction were recorded. QTc intervals were measured prior to and after treatment. Follow-up calls after 48 h assessed satisfaction and recurrent or persistent symptoms.
Thirty-one subjects received haloperidol, 33 metoclopramide. The groups were similar on all VAS measurements, side effects, and in their satisfaction with therapy. Pain relief averaged 53 mm VAS over both groups, with equal times to maximum improvement. Subjects receiving haloperidol required rescue medication significantly less often (3% vs. 24%, p < 0.02). Mean QTcs were equal and normal in the two groups and did not change after treatment. In telephone follow-up, 90% of subjects contacted were “happy with the medication” they had received, with haloperidol-treated subjects experiencing more restlessness (43% vs. 10%).
Intravenous haloperidol is as safe and effective as metoclopramide for the ED treatment of migraine headaches, with less frequent need for rescue medications.
A Prospective, Randomized Trial of Intravenous Prochlorperazine Versus Subcutaneous Sumatriptan in Acute Migraine Therapy in the Emergency Department
2010, Annals of Emergency Medicine
Intravenous (IV) prochlorperazine with diphenhydramine is superior to subcutaneous sumatriptan in the treatment of migraine patients presenting to the emergency department (ED).
In this randomized, double-blind, placebo-controlled trial, after providing written informed consent, patients presenting to the ED with a chief complaint of migraine received a 500-mL bolus of IV saline solution and either 10 mg prochlorperazine with 12.5 mg diphenhydramine IV plus saline solution placebo subcutaneously or saline solution placebo IV plus 6 mg sumatriptan subcutaneously. Pain intensity was assessed with 100-mm visual analog scales (visual analog scale at baseline and every 20 minutes for 80 minutes). The primary outcome was change in pain intensity from baseline to 80 minutes or time of ED discharge if subjects remained in the ED for fewer than 80 minutes after treatment. Sedation and nausea were assessed every 20 minutes with visual analog scale scales, and subjects were contacted within 72 hours to assess headache recurrence.
Sixty-eight subjects entered the trial, with complete data for 66 subjects. Baseline pain scores were similar for the prochlorperazine/diphenhydramine and sumatriptan groups (76 versus 71 mm). Mean reductions in pain intensity at 80 minutes or time of ED discharge were 73 mm for the prochlorperazine/diphenhydramine group and 50 mm for those receiving sumatriptan (mean difference 23 mm; 95% confidence interval 11 to 36 mm). Sedation, nausea, and headache recurrence rates were similar.
IV prochlorperazine with diphenhydramine is superior to subcutaneous sumatriptan in the treatment of migraine.
Antipsychotics for Acute and Chronic Pain in Adults
2010, Journal of Pain and Symptom Management
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For one further study, the study authors could not be identified, and it was, therefore, excluded. An update of the search strategy in February 2009 produced another 82 hits, including two potentially relevant studies.20,21 Both studies were excluded because the analgesic efficacy of each antipsychotic component was tested against a component without proven analgesic effect.
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We included 11 studies involving a total number of 770 participants. Data from five randomized, double-blind studies showed beneficial effects of antipsychotics in the treatment of acute and chronic pain. Because of the clinical heterogeneity of painful conditions studied and significant statistical heterogeneity, the intended meta-analysis was omitted. The most frequently reported adverse effects were extrapyramidal (i.e., involuntary movements, parkinsonism, and akathisia) and sedating effects.
Because of limitations in the available evidence, further research is needed to understand whether antipsychotics are effective for acute or chronic pain or specific pain conditions.
Pitfalls in the Management of Headache in the Emergency Department
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The dopamine antagonists, including droperidol, prochlorperazine, metochlopramide, and chlorpromazine, have a less well-delineated mechanism of action than the more migraine-specific DHE and triptans, which activate serotonin 1B/1D receptors. Nonetheless, these agents, when used alone93–99 or in combination with other drugs,100 have been shown to be equivalent or superior to drugs from all other classes in multiple controlled trials. Droperidol seems to be more efficacious than prochlorperazine,101,102 which in turn seems to be more efficacious as a single agent than metochlopramide.103,104

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: The views expressed in this article are those of the author(s) and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government. The Chief, Navy Bureau of Medicine and Surgery, Washington, DC, Clinical Investigation Program sponsored this study (CIP #P05-005). The local Institutional Review Board approved this study and written consent was obtained by all participants before being enrolled. I am a military service member (or employee of the U.S. Government). This work was prepared as part of my official duties. Title 17 U.S.C. 105 provides that ‘Copyright protection under this title is not available for any work of the United States Government.' Title 17 U.S.C. 101 defines a United States Government work as a work prepared by a military service member or employee of the United States Government as part of that person's official duties.

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Original contributionProchlorperazine vs. Promethazine for Headache Treatment in the Emergency Department: A Randomized Controlled Trial

Abstract

Introduction

Section snippets

Study Design

Selection of Participants

Results

Discussion

Acknowledgments

Ann Emerg Med

Ann Emerg Med

Ann Emerg Med

Neurol Clin

Ann Emerg Med

Ann Emerg Med

Am J Emerg Med

Am J Emerg Med

Ann Emerg Med

Ann Emerg Med

Ann Emerg Med

J Emerg Med

Chronic headache: new advances in treatment strategies

Neurology

Efficacy of oral ketoprofen in acute migraine: a double blind randomized clinical trial

Neurology

Recent advances in the acute management of migraine and cluster headaches

J Gen Intern Med

Original contribution
Prochlorperazine vs. Promethazine for Headache Treatment in the Emergency Department: A Randomized Controlled Trial