Neurology -- Correspondence for Friedman et al., 64 (3) 463-468

Correspondence published:

Reply to Allena et al: Benjamin W. Friedman, Jill Corbo, Richard B. Lipton, Polly E. Bijur, David Esses, and E. John Gallagher (26 May 2005)

A trial of metoclopramide vs sumatriptan for the emergency department treatment of migraines: Marta Allena, Delphine Magis, and Jean Schoenen (26 May 2005)

Reply to Brenner: Benjamin W Friedman, Jill Corbo, Richard B. Lipton, Polly E. Bijur, David Esses, E. John Gallagher (27 April 2005)

A trial of metoclopramide vs sumatriptan for the emergency department treatment of migraines: Steven R Brenner (27 April 2005)

Reply to Allena et al 26 May 2005

Benjamin W. Friedman,
Albert Einstein College of Medicine
111 East 210th Street, Bronx, NY 10467,
Jill Corbo, Richard B. Lipton, Polly E. Bijur, David Esses, and E. John Gallagher
Send Correspondence to journal:
Re: Reply to Allena et al

befriedm{at}montefiore.org Benjamin W. Friedman, et al.

We thank Allena et al for their review of the role of metoclopramide and diphenhydramine in the treatment of acute migraines. We agree that we tested the efficacy of metoclopramide combined with diphenhydramine in our study. [1] We recommend using the combination of metoclopramide and diphenhydramine for ED patients with acute migraines.
Allena et al hypothesize that the reason our anti-migraine regimen was effective was the unrecognized benefit of diphenhydramine. Although some data suggest efficacy of diphenhydramine alone as migraine treatment [2], we believe this is still unclear.
However, metoclopramide has been demonstrated to be more effective than placebo and other comparators in multiple studies (Table). A recent meta-analysis similarly concluded that metoclopramide was an effective anti-migraine treatment. [3]
We disagree with the Allena et al's interpretation of the study by Cete et al. [4] In this study, 65% of subjects randomized to placebo required rescue medication at 30 minutes, while only 38% of subjects randomized to metoclopramide required rescue medication. At 30 minutes, placebo patients had improved on the VAS by 25 while metoclopramide patients had improved by 40. This difference of 15 in the VAS point estimates suggests a clinically relevant difference [5], even if the study was not sufficiently powered to achieve statistical significance for this finding.
Perhaps the dose of metoclopramide is relevant. Of the trials listed in the table below, the two that used more aggressive dosing of metoclopramide (similar to our design) had excellent results. Dose-finding studies are needed to evaluate this hypothesis.
Table

References
1. Friedman BW, Corbo J, Lipton RB, et al. A trial of metoclopramide vs sumatriptan for the emergency department treatment of migraines. Neurology 2005;64:463-468.
2. Swidan SZ, Lake AE 3rd, Saper JR. Efficacy of intravenous diphenhydramine versus intravenous DHE-45 in the treatment of severe migraine headache. Curr Pain Headache Rep 2005;9:65-70.
3. Colman I, Brown MD, Innes GD, Grafstein E, Roberts TE, Rowe BH. Parenteral metoclopramide for acute migraine: meta-analysis of randomised controlled trials. BMJ 2004;329:1369-1373.
4. Cete Y, Dora B, Ertan C, Ozdemir C, Oktay C. A randomized prospective placebo-controlled study of intravenous magnesium sulphate vs. metoclopramide in the management of acute migraine attacks in the Emergency Department. Cephalalgia 2005;25:199-204.
5. Todd KH, Funk JP. The minimum clinically important difference in physician-assigned visual analog pain scores. Acad Emerg Med 1996;3:142-146.

A trial of metoclopramide vs sumatriptan for the emergency department treatment of migraines 26 May 2005

Marta Allena,
CHR de la Citadelle, Dept of Neurology , University of Liege
Bld du 12�me de Ligne,4000 Liege, Belgium,
Delphine Magis, and Jean Schoenen
Send Correspondence to journal:
Re: A trial of metoclopramide vs sumatriptan for the emergency department treatment of migraines

allmarta{at}hotmail.com Marta Allena, et al.

In their recent article, Friedman et al [1] conclude that metoclopramide 20mg IV may be preferable to sumatriptan 6mg subcut for the acute treatment of migraine attacks in the emergency department.
In the protocol of this study it appears that, in the metoclopramide arm, patients received 20mg IV infusions every 30 minutes (average 2.2 infusions) of which the first and third contained 25mg diphenhydramine, while the infusions in the sumatriptan arm only contained saline. If this is correct, it introduces considerable bias because diphenhydramine may have anti-migraine properties. Diphenhydramine is commonly used IV to treat migraine attacks alone [2] or combined with analgesics. [3] Histamine may trigger a migraine attack by increasing NO via H1 receptors. [4]
At best, the authors can conclude that the association of repeated high dose IV metoclopramide and diphenhydramine has (at 2hrs) comparable efficacy to a single subcutaneous sumatriptan injection in severe migraine attacks. Another recent study [5] suggested that metoclopramide alone may not be sufficient to interrupt a migraine attack showing that it was not better than placebo. However, in contrast to Friedman et al�s study [1], metoclopramide was given as a single 10mg injection and the primary outcome measure was pain relief at 30 minutes.
References
1. Friedman BW, Corbo J, Lipton RB, et al. A trial of metoclopramide vs sumatriptan for emergency department treatment of migraines. Neurology 2005;64:463-468.
2. Swidan SZ, Lake AE 3rd, Saper JR. Efficacy of intravenous diphenhydramine versus intravenous DHE-45 in the treatment of severe migraine headache. Curr Pain Headache Rep. 2005;9:65-70.
3. Vinson DR, Hurtado TR, Vandenberg JT, et al . Variations among emergency departments in the treatment of benign headache. Ann Emerg Med. 2003;41:90-7.
4. Lassen LH, Thomsen LL, Olesen J. Histamine induces migraine via the H1-receptor. Support for NO hypothesis of migraine. Neuroreport 1995;6:1475-1479.
5. Cete Y, Dora B, Ertan C, et al. A randomized prospective placebo-controlled study of intravenous magnesium sulphate vs metoclopramide in the management of acute migraine attacks in the Emergency Department. Cephalalgia 2005;25:199-204.

Reply to Brenner 27 April 2005

Benjamin W Friedman,
Albert Einstein College of Medicine
111 East 210th Street,
Jill Corbo, Richard B. Lipton, Polly E. Bijur, David Esses, E. John Gallagher
Send Correspondence to journal:
Re: Reply to Brenner

befriedm{at}montefiore.org Benjamin W Friedman, et al.

We thank Dr. Brenner for his relevant and informative summary of the role of diphenhydramine in migraines.
We agree that we tested the efficacy of metoclopramide combined with diphenhydramine in our study. [1] We recommend using the combination of metoclopramide and diphenhydramine for ED patients with acute migraines. Although some data exist supporting a role for diphenhydramine alone as migraine treatment [2], this is not yet established.
We agree that there might be a role for combination therapy in ED patients with severe migraines. As yet, there is no treatment paradigm for ED care comparable to the stratified care plan developed for outpatient migraine management. [3] Thus, we do not know which ED patients with acute migraines require multi-drug therapy initially and which patients will be satisfactorily treated with a single agent.
References
1. Friedman BW, Corbo J, Lipton RB, et al. A trial of metoclopramide vs sumatriptan for the emergency department treatment of migraines. Neurology 2005; 64:463-8.
2. Swidan SZ, Lake AE, 3rd, Saper JR. Efficacy of intravenous diphenhydramine versus intravenous DHE-45 in the treatment of severe migraine headache. Curr Pain Headache Rep 2005; 9:65-70.
3. Lipton RB, Stewart WF, Stone AM, Lainez MJ, Sawyer JP. Stratified care vs step care strategies for migraine: the Disability in Strategies of Care (DISC) Study: A randomized trial. Jama 2000; 284:2599-605.

A trial of metoclopramide vs sumatriptan for the emergency department treatment of migraines 27 April 2005

Steven R Brenner,
St. Louis VA Medical Center and Saint Louis University Neurology Dept.
Dept. Neurology, Routing Symbol #127, Cochran VA Hospital, 915 North Grand, Saint Louis, MO 63106
Send Correspondence to journal:
Re: A trial of metoclopramide vs sumatriptan for the emergency department treatment of migraines

SBren20979{at}aol.com Steven R Brenner

Friedman et al [1] compared metoclopramide vs. sumatriptan for the emergency department treatment of migraine with interest. Utilizing diphenhydramine in combination with metoclopramide may have affected the results of the comparison since diphenhydramine has been used independently as a treatment for migraine. The suggested treatment is one to three doses daily (25-50 mg) either intramuscularly or intravenously and is used essentially as an abortive agent. [2] Diphenhydramine has also been recommended for severe attacks of migraine during pregnancy, with metoclopramide being restricted to the third trimester. [3]
There has been a recent study comparing intravenous diphenhydramine versus intravenous DHE-45 in the treatment of severe migraine headache. [4] Combination treatment may provide benefit for patients who don�t respond to individual agents, such as combining metoclopramide with a triptan in triptan-nonresponsive migraineurs. [5]
Used alone, diphenhydramine may have therapeutic effectiveness for headaches in addition to preventing akathisias and other dystonic reactions for which it was utilized in the present study. It has been used independently as a treatment for migraine and could have some potential for enhancing the effect of triptans in triptan nonresponders if used in combination therapy.
However, the combination of metoclopramide and diphenhydramine appears to be a reasonable treatment based on the favorable outcome on headache noted in the comparison with sumatriptan.
References
1. Friedman A, Corbo J, Lipton R, et al. A trial of metoclopramide vs sumatripan for the emergency department treatment of migraines. Neurology 2005; 64: 463-468.
2. Saper J. Table 9. Selected drugs used in the pharmacotherapy of head, neck and face pain, (Modified with permission from Saper, et al. Handbook of Headache Management, Lippincott Williams and Wilkins, 1999)
3. Aube M. Migraine in pregnancy. Neurology . 1999; 53 (4 Suppl 1): S26-8.
4. Swidan S, Lake A, Saper J. Efficacy of intravenous diphenhydramine versus intravenous DHE-45 in the treatment of severe migraine headache. Cur Pain Headache Rep. 2005; 9: 65-70.
5.Schulman EA, Dermott KF. Sumatriptan plus metoclopramide in triptan- nonresponsive migraineurs. Headache. 2003; 43: 446-447.