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Three Part Question

In an [adult presenting to the emergency department with an acute attack of migraine], is [Metoclopramide more effective than simple analgesia or placebo] as a single agent for [resolution of headache].

Clinical Scenario

A 35 year old woman presents to A&E with 3 hours of severe unilateral headache and photophobia. She has a history of migraines and has been given opiates and NSAIDS in the past with little success. You wonder whether you should try some IV metoclopramide for her headache.

Search Strategy

Medline (1950 to date), EMBASE (1974 to date) and CINAHL (1982 to date) using dialog datastar site
Search criteria used (full article search)– METOCLOPRAMIDE or REGLAN or MAXOLON AND HEADACHE or MIGRAINE
Results not limited to English

Search Outcome

This resulted in 2206 papers. Duplicates were removed and irrelevant papers were excluded. Also excluded were those relating to pregnancy, using metoclopramide in combination or not comparing metoclopramide to conventional analgesia unless they had a placebo arm.
This resulted in 8 papers

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Fernandes-Filho et al 2006 Brazil	31 Adult patients >18yrs or <55yrs with International Headache Society diagnostic criteria for migraine	Comparison of intravenous dipyrone to intravenous metoclopramide in the treatment of acute crisis of migraine	Reduction of pain score (Visual analogue score- VAS) at a maximum of 2 hours after treatment	Significant pain reduction in male group with MTC (p=0.0002)	Not properly blinded or randomised. No drug doses. No power calculation. Groups not matched
				Significant pain reduction in female group with dipyrone (p=0.008). Not significant for MTC in females (p=0.063)
Cete et al 2005 Turkey	113 Adult patients >18yrs with international headache society criteria for migraine	A randomized prospective placebo-controlled study of intravenous magnesium sulphate vs. metoclopramide in the management of acute migraine attacks in the Emergency Department	Reduction in VAS at 30 minutes	No significant reduction in pain between groups at 30 minutes (p>0.05).	reduction in pain' not quantified. Subgroup not sufficiently powered
			Secondary outcomes- need for rescue medication or recurrent headache at 24hrs	Higher need for rescue medication in placebo group
				No significant difference in recurrence rate at 24 hours between groups (MTC 43% Magnesium 52%, placebo 53%, p>0.05)
Ellis et al 1993 USA	40 Patients >18yrs with recurrent headache, initially unilateral, preceded by neurological symptoms and associated with mood changes, nausea or photophobia	The efficacy of metoclopramide in the treatment of migraine headache	Reduction in VAS score or improvement in nausea at 30 and 60 minutes	The MTC group was equivalent to MTC + ibuprofen group for reduction in pain.	Not properly randomized or blinded. No power calculation. reduction in pain' not quantified
				The MTC group was significantly better than ibuprofen at 30 and 60 minutes (p0.0443 & p.0.135 respectively) or placebo (p0.0449 & p0.0013 respectively)
Tek et al 1990 USA	50 Patients >18yrs with periodic throbbing headache and one of nausea or vomiting, unilaterality, family history, onset in adolescence or relief with ergotamine	A prospective, double-blind study of metoclopramide hydrochloride for the control of migraine in the emergency department	Degree of pain relief on a scale of 1- 4 at one hour	MTC group had significantly greater pain relief than control group (p <0.02)	No power calculation. No demographics included. Non accredited pain score. 'reduction in pain' not quantified
				67% of MTC group compared to 19% of placebo group had sufficient pain relief to be discharged without further treatment (p <0.001)
Cicek et al 2004 Turkey	Consecutive adult patients with headache lasting less than 7 days 336 Patients subdivided into tension headache group (140) or vascular headache (migraine) group (196)	Prospective, randomized, double blind, controlled comparison of metoclopramide and pethidine in the emergency treatment of acute primary vascular and tension type headache episodes.	Reduction in VAS at 15, 30 and 45 minutes	At 45 mins-mean VAS in both MTC + placebo and MTC + pethidine groups significantly lower than the pethidine + placebo group (p0.038)	IV fluid provides a confounding factor. Pethidine not commonly used in the UK
				Mean VAS in the MTC + placebo group was equal to the MTC plus pethidine group (p=1.00)
				Need for rescue medication-Vascular headache group: No difference in MTC and MTC + pethidine groups (p0.426).
				MTC alone significantly better than pethidine alone or placebo (p 0.000, p0.007 respectively)
Jones J et al 1996 USA	Adult patients over 16yrs with a primary diagnosis of migraine 88 patients: 28 prochlorperazine, 29 MTC, 29 placebo	Intramuscular prochlorperazine versus Metoclopramide as single-agent for the treatment of acute migraine headache *	Complete relief in pain on VAS 1hour after administration	Complete pain relief achieved in 32% prochlorperazine group, 14% MTC group, 7% placebo group ( =6.7, p0.4)	Patient numbers do not add up No direct analysis of MTC vs placebo
				Reduction in median VAS significantly higher in prochlorperazine group (67%), compared to MTC (34%) or placebo (16%)
				Rescue analgesia still required in the majority
Coppola et al 1995 USA	70 Patients 18 & 65yrs presenting with migraine (based on Ad Hoc committee on classification of migraine)	Randomised placebo-controlled evaluation of prochlorperazine versus Metoclopramide for emergency department treatment of migraine headache *	Patient satisfaction and decrease of 50% or more in the 30 minute pain score or absolute pain score of 2.5 or less on VAS	Success in 82% patients with prochlorperazine, 48% MTC, 29% placebo	Not intention to treat protocol – patients excluded due to side effects. Demographics not included. Not properly randomised.
				No significant difference between MTC and placebo ( p=0.37)
Colman et al 2004	13 studies found looking at MTC vs other analgesics, non analgesics and in combination	Parenteral metoclopramide for acute migraine: Meta-analysis of randomised cont trials	Relief of headache ('complete relief / significant decrease on basis of VAS') or significant reduction of pain 2 hours from treatment	5 studies MTC vs placebo – significant reduction in headache	Many studies of poor quality on small numbers of patients
				MTC vs other anti-emetics - MTC not as effective
				2studies MTC vs other drugs; better than NSAIDs,as good as triptans
				7 studies MTC combinations vs other drug combinations – MTC combinations better

Comment(s)

There is some evidence to support MTC may work and its pharmacological properties provide biological plausibility why this may be so. However, due to the poor quality and conflicting results of the various trials, there is no conclusive evidence for the continued use of MTC as a single agent on patients with migraine until further studies are carried out. There may be some benefit in continuing to use it as an adjunctive therapy with other analgesics or trying MTC as the initial medication and adding in a further analgesic if no response after a set time such as 30 minutes once it has had a chance to be absorbed.

Clinical Bottom Line

There needs to be further, properly randomised, blinded, large scale trials before the use of metoclopramide in migraine can be fully justified.

References

1. FERNANDES FILHO, Sérgio Murilo Maciel, COSTA, Márcio Santos, FERNANDES, Mariana Torres et al. (translated from portugese) Comparison of intravenous dipyrone to intravenous metoclopramide in the treatment of acute crisis of migraine Arquivos de Neuro-Psiquiatria Dec. 2006, vol.64, no.4, p.1005-1008.
2. Cete, Dora, Ertan, Ozdemir, Oktay, A randomized prospective placebo-controlled study of intravenous magnesium sulphate vs. metoclopramide in the management of acute migraine attacks in the Emergency Department Cephalalgia, Vol 25, No 3, March 2005 , pp. 199-204(6)
3. GL Ellis, J Delaney, DA DeHart, A Owens The efficacy of metoclopramide in the treatment of migraine headache Ann Emerg Med Feb;22(2):191-5
4. Tek DS, McClellan DS, Olshaker JS, Allen CL, Arthur DC. A prospective, double-blind study of metoclopramide hydrochloride for the control of migraine in the emergency department Ann Emerg Med 1990 Oct;19(10):1083-7
5. M Cicek, O Karcioglu, Parlak, V Ozturk, O Duman, M Serinken, M Guryay Prospective, randomised, double blind, controlled comparison of metoclopramide and pethidine in the emergency treatment of acute primary vascular and tension type headache episodes Emerg Med J. 2004; 21: 323-326
6. JONES J, PACK S, CHUN E. Intramuscular prochlorperazine versus metoclopramide as single-agent therapy for the treatment of acute migraine headache Am. j. emerg. med Volume 13, Number 3, May 1996
7. M. Coppola, D. Yealy, R. Leibold Randomized, Placebo-Controlled Evaluation of Prochlorperazine Versus Metoclopramide for Emergency Department Treatment of Migraine Headache Annals of Emergency Medicine Volume 26, Issue 5, Pages 541-546
8. Ian Colman, Michael D Brown, Grant D Innes, Eric Grafstein, Ted E Roberts, Brian H Rowe Parenteral metoclopramide for acute migraine: meta-analysis of randomised controlled trials BMJ 2004;329:1369 (11 December), doi:10.1136/bmj.38281.595718.7C (published 18 November 2004)