Metoclopramide for Migraines: The Underrated Drug You Should Know About

When an antiemetic becomes an analgesic: strong evidence for a clinical use that is still not widespread in Italy

If I told you that your medicine cabinet already has an effective painkiller for migraines, with an NNT of 2-3 and proven superiority over a placebo, you'd probably think of NSAIDs or triptans. Instead, I'm talking about metoclopramide—yes, the one you usually use for nausea.

In Italy, the use of metoclopramide for the direct treatment of migraine is still surprisingly limited, despite decades of solid scientific evidence supporting its efficacy. The time has come to rediscover this "old" drug in a new clinical light.

🔬 The pharmacological rationale: more than meets the eye

Metoclopramide's effectiveness in migraine is not accidental or merely a side effect of its antiemetic action. Its mechanism of action involves neurochemical pathways directly implicated in migraine pathophysiology.

As an antagonist of central dopamine D₂ receptors , metoclopramide acts at the level of the area postrema and the trigeminovascular system, interrupting the neuroinflammatory cascade typical of migraine attacks (2). But there is more: the drug also has activity on serotoninergic receptors - it acts as a 5-HT₃ antagonist and 5-HT₄ agonist - modulating pain transmission systems through mechanisms independent of its gastrokinetic action.

This dual activity explains why metoclopramide is particularly effective in migraine attacks characterized by predominant nausea, but also why it maintains analgesic efficacy regardless of the presence of gastrointestinal symptoms.

📚 The scientific evidence: 35 years of convincing data

Pioneering studies

The efficacy of metoclopramide in migraine is not a recent discovery. Already in 1990 , Tek and colleagues published in the Annals of Emergency Medicine a randomized, controlled, double-blind study that demonstrated impressive results: 67% of patients treated with metoclopramide 10 mg IV obtained effective relief within one hour, compared to only 19% of the placebo group (p<0.001) (2).

A Number Needed to Treat of 2-3 that would make many modern painkillers envious.

Modern confirmations

Meta-analyses in recent years have consolidated this evidence. A 2023 systematic review of 16 studies and 1,934 patients confirmed the efficacy of metoclopramide in reducing the intensity of acute headaches, with benefits sustained for up to 24 hours after administration (3).

Of particular interest is how modern meta-analyses consistently confirm the superiority of metoclopramide over placebo, with a generally favorable tolerability profile compared to other agents used in acute migraine.

Recognition of the guidelines

International guidelines have progressively recognized the value of metoclopramide: the American Headache Society recommends it as a second-line therapy for acute migraine, particularly in the presence of significant nausea. However, this recommendation has not yet been adequately implemented clinically in Italy.

📊 The study that changes perspective: Barbera 2025

The recent study by Barbera and colleagues, published in the Journal of Emergency Medicine , adds an important piece to this puzzle by highlighting not only the efficacy of metoclopramide, but also the operational advantages of the intramuscular route (1).

The numbers that strike

In this retrospective study of 1,445 total visits; 522 included in the propensity-matched analysis (261 + 261) with acute headaches, researchers compared metoclopramide 10 mg intramuscularly versus intravenously. Results showed significantly reduced emergency department stay times : 67 minutes (median) for the IM route versus 168 minutes for the IV route, with equivalent analgesic efficacy.

The practical implication

This study suggests that not only does metoclopramide work for migraine, but the intramuscular route may be as effective as the intravenous route, with the added benefit of significantly speeding up emergency department flow. For patients with "clear" migraine—young, with a known history, and typical symptoms—the IM route eliminates the need for immediate intravenous access.

🤔 A necessary critical reflection

Before radically changing our clinical practice, it is important to consider some methodological aspects of Barbera's study.

The limits to keep in mind

The retrospective design does not allow for definitive causal relationships to be established. The lack of information on the diagnostic workup performed in the two groups represents a significant gap: we do not know whether patients treated IM were systematically different from those treated IV.

The sample imbalance (only 10% IM vs. 90% IV) suggests that clinicians intuitively selected different patients for the two routes. It's possible that the IM route was reserved for cases of "clear migraine," while the IV route was reserved for "undifferentiated headaches" that required further investigation.

💡 Implications for Italian clinical practice

A necessary paradigm shift

The available evidence should encourage Italian clinicians to consider metoclopramide as the first choice for acute migraine , especially in the presence of nausea. The standard dose of 10 mg (IV or IM) has demonstrated consistent efficacy and a favorable safety profile.

Practical information

• For typical migraines with nausea : Metoclopramide 10 mg IM may be the optimal choice, avoiding venous access

• For headaches requiring workup : IV remains appropriate if vascular access needs to be maintained

• Prevention of side effects : Consider premedication with diphenhydramine in patients with a history of extrapyramidal reactions.

Systemic benefits

Adopting IM metoclopramide for selected migraines may:

• Significantly reduce time spent in the emergency room

• Improving patient satisfaction

• Optimizing the allocation of nursing resources

• Facilitate flow management during peak influxes

🎯 The final message

Metoclopramide for migraine is not an experimental novelty, but an evidence-based therapy that deserves greater consideration in Italian clinical practice. Barbera's study reminds us that, in addition to its already demonstrated efficacy, the intramuscular route can offer significant operational advantages.

It's not about revolutionizing existing protocols, but about intelligently integrating an underutilized therapeutic option into our clinical arsenal. In an era where efficiency and quality must go hand in hand, metoclopramide is a perfect example of how "old" drugs can still teach us new strategies.

The next time you see a patient with a typical migraine, remember: the solution may be simpler—and closer—than you think.

Bibliography

1. Barbera AR, Gould LA, Wills WB, et al. Examining the Effect of Intramuscular versus Intravenous Metoclopramide for Treatment of Acute Headaches to Expedite Throughput in the Emergency Department. J Emerg Med . 2025;73:52-62. doi:10.1016/j.jemermed.2025.01.007

2. Tek DS, McClellan DS, Olshaker JS, Allen CL, Arthur DC. A prospective, double-blind study of metoclopramide hydrochloride for the control of migration in the emergency department. Ann Emerg Med . 1990;19(10):1083-1087. doi:10.1016/S0196-0644(05)81508-2

3. Abdelmonem H, Abdelhay HM, Abdelwadoud GT, et al. The efficacy and safety of metoclopramide in relieving acute migraine attacks compared with other anti-migraine drugs: a systematic review and network meta-analysis of randomized controlled trials. BMC Neurol . 2023;23(1):221. doi:10.1186/s12883-023-03259-7

4. Eken C. Critical reappraisal of intravenous metoclopramide in migraine attack: a systematic review and meta-analysis. Am J Emerg Med . 2015;33(3):331-337. doi:10.1016/j.ajem.2014.11.013