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Reglan (Metoclopramide) For Migraines: An Emergency Abortive Therapy

Reglan (Metoclopramide) is a medication approved by the FDA for the treatment of gastroparesis or delayed stomach emptying.  Gastroparesis often occurs as a result of conditions such as GERD (gastroesophageal reflux disease) and diabetes, but is also sometimes experienced by patients following surgery (post-operative).  Assuming an individual postpones treatment of ongoing gastroparesis, stomach acid can damage the esophageal lining, and in serious cases, the upper throat and teeth.

Although seldom used as a first-line intervention, when conventional heartburn medications fail to attenuate gastroparesis, metoclopramide is frequently prescribed.  It functions by blocking dopamine receptors to enhance gastrointestinal motility and ultimately expedite gastric emptying.  The fact that metoclopramide is regarded as highly effective for the treatment of gastroparesis resulted in its inclusion on the World Health Organization’s “List of Essential Medicines,” or the most important drugs required in a basic healthcare setting.

In addition to being used for gastroparesis, metoclopramide is sometimes administered for the treatment of migraines.  Evidence suggests that metoclopramide may be effective as a standalone antimigraine intervention when administered intravenously.  It appears to alleviate migraine-related pain, as well as emetic reactions (e.g. nausea) associated with migraine attacks as well as various abortive therapies.

How Reglan May Treat Migraines (Mechanisms)

As of current, isn’t fully elucidated as to how the pharmacodynamics of Reglan (metoclopramide) are capable of attenuating migraine attacks, however, it is understood how metoclopramide affects neurochemistry.  It binds with high affinity to D2 receptor sites, acting as an antagonist to prevent receptor stimulation.  Blocking D2 receptor stimulation is understood to yield an antiemetic effect, a likely reason as to why individuals using metoclopramide report less nausea and vomiting during a migraine attack.

In addition, metoclopramide alters activation of multiple serotonin receptor sites including: 5-HT3 (as an antagonist) and 5-HT4 (as an agonist).  Some speculate that modification of serotonin systems may reduce migraine-related pain, as well as alleviate nausea.  Moreover, it should be considered that simultaneous (perhaps synergistic) dopaminergic and serotonergic receptor modulation treats migraine attacks and related symptoms.

D2 receptor antagonism: The chief mechanism by which metoclopramide functions is as a D2 receptor antagonist.  A plethora of studies indicate that administration of D2 receptor antagonists (e.g. antipsychotics) can successfully treat and prevent migraine attacks.  An opinion statement issued by Marmura (2012) notes that while dopamine receptor antagonists are principally indicated for the treatment of psychosis, they have “established a role in the treatment of migraine.”

Marmura further mentions that neuroleptics are frequently regarded as first-line interventions for emergency room patients with migraine – especially among patients with debilitating emetic symptoms (e.g. nausea).  An older report by Peroutka (1997) discussed the finding that dopaminergic abnormalities are often implicated in the pathogenesis of migraine.  Additionally, it was discovered that administration of D2 receptor agonists (e.g. apomorphine) are able to induce migraine attacks and secondary symptoms.

Researchers believe that a subset of migraine patients exhibit hypersensitivity of dopamine receptors.  In other words, it takes less dopamine to provoke an exaggerated response at dopamine receptor sites, ultimately provoking migraine attacks and related symptoms.  This hypersensitivity theory is bolstered by the finding that administration of a dopamine receptor agonist induces migraine attacks in migraine patients at a significantly lower dose than non-migraine patients.

What’s more, data collected from genetic studies reveals that dopamine receptor gene variants may increase (and possibly decrease) susceptibility to migraine attacks.  A report by Dusitanond and Young (2009) notes that polymorphisms of DRD2 genes (encoding for the D2 dopamine receptors) have been linked to migraine patients.  It is likely that these polymorphisms increase likelihood of D2 receptor hypersensitivity, ultimately leading to migraine and related symptoms.

Metoclopramide’s ability to antagonize D2 receptors may make it a highly effective abortive therapy (and possible prophylactic) among migraine patients with DRD2 polymorphisms.  The antagonism provide by metoclopramide reduces D2 hypersensitivity to alleviate an attack.  Some would conclude that modulation of dopamine receptors (as facilitated by metoclopramide) is the foremost mechanism by which it treats migraines.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/20021339
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/22012659
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/9305317
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/9642491

5-HT3 antagonism: It is necessary to consider that antagonism of the 5-HT3 receptor may contribute to metoclopramide’s therapeutic antimigraine (and antiemetic) effect.  Research has long linked abnormalities in the neurotransmission of serotonin to migraine attacks.  A majority of first-line abortive therapies modulate the neurotransmission of serotonin to alleviate migraine symptoms.

For example, most triptans stimulate serotonin receptor sites to induce vasoconstriction of intracranial blood vessels.  This vasoconstriction reduces the vasodilation associated with migraine attacks.  Although metoclopramide doesn’t agonize the same receptors as triptans, it is able to modulate activity of serotonin by antagonizing the 5-HT3 receptor.

A report published by Ferrari (1991) documented the effects of 5-HT3 antagonists for the treatment of migraines.  Following administration of 5-HT3 receptor antagonists, individuals experience reductions in pain and/or nausea resulting from excessive serotonergic stimulation at the 5-HT3 receptor site.  This is likely due to the fact that most 5-HT3 receptors are positioned within areas of the CNS capable of modulating pain and nausea.

Furthermore, 5-HT3 receptor antagonists are able to alleviate vascular pain as induced by inflammation, as well as serotonin stimulation.  Some researchers even hypothesize that 5-HT3 antagonists inhibit neurogenic inflammation within the trigeminal nerve – resulting in alleviation and/or prevention of migraines.  It is known that 5-HT3 antagonism decreases release of substance P from C-fibers, and since substance P is associated with neurogenic inflammation, this could be a modality by which metoclopramide treats migraine attacks.

As documented by Wolf (2000), it is apparent that 5-HT3 antagonists decrease nausea and vomiting in post-operative patients, as well as reduce experimentally-induce pain.  Wolf specifically notes that 5-HT3 antagonists appear moderately efficacious for the treatment of migraines.  Based on these findings, we should suspect that 5-HT3 antagonism exerted by metoclopramide contributes to its overall therapeutic antimigraine effect – reducing pain and nausea.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/2045832
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/11028830
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/11281817

5-HT4 agonism: The role of 5-HT4 receptors in migraine pathogenesis is poorly understood.  Since metoclopramide functions as a 5-HT4 receptor agonist, it is necessary to consider that 5-HT4 agonism may contribute to its antimigraine effect.  That said, most 5-HT4 agonists are not administered for the treatment of migraines and haven’t really been studied for migraine treatment.

It is thought that 5-HT4 receptors are positioned within nerve terminals on cholinergic interneurons and motor neurons.  Stimulating 5-HT4 receptors via agonism yields an increase in the release of acetylcholine.  The increased acetylcholine is understood to expedite activity within the gastrointestinal tract and colon – making 5-HT4 agonists useful for individuals with conditions such as constipation, gastroesophageal reflux disorder (GERD), and irritable bowel syndrome (IBS).

The increase in acetylcholine resulting from 5-HT4 agonism could also help migraine patients.  A report by Brown (1993) notes that migraine patients exhibit abnormal fluctuations in concentrations of acetylcholine, as well as serotonin.  A later report by Nicolodi and Sicuteri (1999) mentions the discovery that acetylcholinesterase inhibitors are capable of preventing migraine attacks.

Acetylcholinesterase inhibitors block the enzymatic breakdown of acetylcholine, ultimately increasing its concentration.  Since inhibition of acetylcholinesterase ameliorates symptoms of migraine, it could be suggested that acetylcholine deficiencies induce migraine (in some patients).  Conversely, the 5-HT4 receptor stimulation provided by metoclopramide may reverse some of these deficiencies, leading to migraine relief and/or prevention.

What’s more, acetylcholine is associated with analgesia (pain relief) and increasing concentrations may alleviate some migraine-related pain.  A study conducted by Napoli et al. (2009) discovered that patients with migraine attacks exhibit decreased physiological reactivity to acetylcholine compared to non-migraine patients.  In theory, this reduced physiological reactivity may result from an underlying deficit in acetylcholine production.

It is possible that agonizing 5-HT4 increases acetylcholine to such an extent that physiological responses to acetylcholine become normal, or at least closer to the norm.  One may also hypothesize that agonism of 5-HT4 receptors provokes vasoconstriction of intracranial blood vessels (similar to agonists of other 5-HT receptor sites).  While agonism of 5-HT4 receptors may be less important than D2 and 5-HT3 antagonism in regards to treating migraines, it could still play a role.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/8350780
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/10721055
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/19528518

In summary, it is likely that a bulk of the antiemetic and antimigraine effect generated by metoclopramide results from D2 receptor antagonism.  That said, antagonism of 5-HT3 receptor sites can influence severity of migraine pain and nausea – possibly making significant contributions to metoclopramide’s therapeutic effect.  Furthermore, it is impossible to fully discount the role of 5-HT4 agonism in attenuating migraine-related symptoms.

Based upon the fact that dopamine and serotonin systems are implicated in migraine, and the understanding that metoclopramide modulates both, it is possible that this dual modulation yields maximal migraine relief.  Nonetheless, responses to metoclopramide may vary based upon interindividual variation in the pathoetiological underpinnings of migraine.  For example, someone with migraine caused primarily by D2 receptor hypersensitivity may derive significant benefit from metoclopramide.

On the other hand, someone without dopaminergic abnormalities experiencing a migraine attack may derive more benefit from the mixed 5-HT3 antagonism/5-HT4 agonism.  Others may find that metoclopramide is completely devoid of therapeutic efficacy for their specific migraine subtype.  Overall, a synergistic effect of: D2 antagonism, 5-HT3 antagonism, and 5-HT4 agonism can improve migraine and related symptoms – with D2 antagonism likely playing the most significant role.

  • Source: https://pubchem.ncbi.nlm.nih.gov/compound/metoclopramide
  • Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3737484/

Benefits of Reglan for Migraines (Possibilities)

There are many possible benefits associated with using Reglan (metoclopramide) as a treatment for migraines.  For some migraine sufferers, Reglan is capable of reducing severity of emetic symptoms such as nausea and vomiting, while simultaneously decreasing migraine pain.  Additionally, individuals who fail to derive sufficient symptomatic relief from a first-line abortive therapy (e.g. a triptan), Reglan serves as a viable alternative and/or adjunct.

  • Adjunctive option: Those who experience insufficient symptomatic reduction from administration of a triptan may find Reglan to be an effective adjunct. Studies assessing the efficacy of Sumatriptan (50 mg) compared to Sumatriptan (50 mg) plus Reglan (10 mg) found that the combined treatment was of superior efficacy in unresponsive migraine patients.  Other reports suggest that administration of Reglan as an adjunct to dihydroergotamine provides “excellent” headache relief.  Moreover, Reglan doesn’t appear to interact with many other first-line migraine medications – making it an ideal “add-on” therapy.
  • Alternative intervention: A subset of migraine patients won’t respond well to conventional treatments. For these patients, alternative therapies with unique mechanisms of action may be necessary.  Reglan is often regarded as a useful alternative medication for individuals that don’t respond well to triptans.  It modulates activity at dopamine receptor sites, as well as serotonin receptor sites – making it slightly different than triptans.
  • Comorbidities: In some cases, patients that experience migraines are dealing with comorbid health conditions. Assuming a migraine patient suffers from gastroparesis (delayed gastric emptying) resulting from diabetes, GERD, etc. – Reglan may alleviate symptoms of migraine and gastroparesis simultaneously.  Additionally, migraine patients undergoing chemotherapy or radiation may find Reglan helpful to decrease emetic reactions such as nausea and vomiting.
  • Efficacy: There are several well-designed trials documenting the efficacy of Reglan either as a standalone treatment or adjunct for the attenuation of migraine-related pain and secondary emetic symptoms. In other words, it appears as though Reglan is an effective abortive therapy (for certain individuals).  Though it doesn’t appear to be very effective when administered in the form of an oral tablet, its efficacy is significant when administered in the form of an intravenous infusion.  Interestingly, some randomized controlled trials (RCTs) have noted that metoclopramide may be of superior efficacy of Sumatriptan, a first-line abortive therapy.
  • Emetic symptoms: Individuals experiencing migraines often complain of concurrent emetic symptoms. Emetic reactions may emerge as a result of the migraine itself and/or treatment with triptans.  While nausea is the most common emetic reaction, some patients end up vomiting.  Since Reglan exhibits antiemetic properties, migraine patients with prominent nausea may experience noticeable relief from Reglan.  In fact, clinical practice guidelines as issued by the American Academy of Neurology recommends utilization of an antiemetic agent (such as metoclopramide) in migraine patients with significant nausea.
  • Enhanced absorption: Some researchers believe that Reglan (metoclopramide) enhances the absorption of first-line migraine treatments. The enhancement of absorption may result from expedited gastric emptying that occurs following Reglan administration.  Quicker gastric emptying is thought to increase bioavailability of agents that are absorbed predominantly through the small intestine.  It is necessary to consider that increased bioavailability may be a critical mechanism by which Reglan is an effective adjunct.
  • Headache treatment: It is understood that many migraine patients suffer from comorbid, non-migrainous headaches. Several investigations suggest that Reglan provides benefit to patients with non-migraine vascular headaches.  In one study, over 60% of patients receiving Reglan for vascular headaches experienced substantial symptomatic relief.  It is unclear as to whether Reglan effectively treats other headache subtypes, but it should be hypothesized to provide some benefit.
  • Pregnancy: Reglan is classified as a Category B drug during pregnancy in the United States and is considered safe for usage among pregnant women. Although it may be unwise to take any medication that could affect fetal development, studies assessing the effects of Reglan in pregnant women suggest that it is unlikely to cause birth defects.  Since other antimigraine agents may be contraindicated among pregnant women with migraines, Reglan may be a useful alternative.
  • Rebound migraine treatment: An advantage associated with using Reglan for migraines is that it may treat rebound migraines associated with overuse of abortive therapies. It is known that when acute antimigraine agents are administered excessively, they can often provoke rebound headaches.  These rebound headaches are disturbing and continue to worsen with additional administration of abortive medications. In most cases, patients are instructed to take a break from conventional therapies, but may still require pharmacological antimigraine therapy.  During these “breaks” from conventional therapies, intravenously administered metoclopramide plus dihydroergotamine rapidly treats rebound migraines stemming from medication overuse – making metoclopramide a helpful alternative. (Source: http://www.ncbi.nlm.nih.gov/pubmed/2370132).
  • Unique pharmacodynamics: Reglan functions primarily as a D2 receptor antagonist. It inhibits stimulation of D2 dopamine receptors, ultimately decreasing likelihood of nausea and vomiting.  Most conventional migraine therapies (e.g. triptans) function principally by agonizing serotonin receptors.  The fact that Reglan antagonizes dopamine receptors provides a unique modality by which migraines are treated.  Moreover, the drug acts by antagonizing 5-HT3 receptors and agonizing 5-HT4 receptors – each of which may also contribute to its unique antimigraine effect.
  • Well-tolerated: When administered at dosages in accordance with medical recommendations, likelihood of adverse reactions is low. In most studies, adverse effects resulting from Reglan didn’t differ from those associated with a placebo and/or other pharmacology.  Overall, this drug is considered well-tolerated regardless of whether administered as a standalone or adjunct.

Drawbacks of Reglan for Migraines (Possibilities)

Despite the fact that some migraine patients may derive significant benefit from the administration of Reglan, it is not FDA-approved as a first-line abortive therapy.  Additionally, many people that use Reglan report no significant antimigraine effect.  Other possible drawbacks associated with Reglan usage for migraines include: adverse effects, intravenous route of administration, and the occurrence of post-treatment rebound headaches.

  • Adverse reactions: Individuals taking Reglan may experience unwanted and/or serious adverse reactions such as agitation, akathisia, depression, difficulty breathing, dystonia, muscle stiffness, and tardive dyskinesia. Though there are some ways in which patients may be able to mitigate these adverse reactions (e.g. concurrent diphenhydramine), not all of these mitigation strategies are effective.  Additionally, while the risk of adverse reactions from metoclopramide is considered low when utilized in accordance with medical instruction, they still may occur.  Those who experience adverse reactions may regret pursuing this treatment.
  • Intravenous administration: To derive maximal benefit from Reglan for migraines, it is required to be administered via intravenous infusion (at a dosage of around 10 mg). Though it can be taken orally (in the form of a tablet), oral formats are not considered effective for the treatment of migraines.  Since intravenous infusions yield greatest therapeutic benefit but are difficult for patients to self-administer, patients usually must visit an emergency room to receive intravenous Reglan (from a medical professional).
  • Long-term effects: Among those taking Reglan over an extended duration for the treatment of migraines, it is unclear as to whether deleterious long-term effects could emerge. Some evidence suggests that long-term effects can occur. It is unclear as to whether the cumulative neurophysiological alterations induced by Reglan lead to adverse long-term effects and/or if deleterious long-term effects are provoked by dosage adjustments (over an extended term).  That said, patients should be concerned with the possible onset of tardive dyskinesia or dystonia after an extended term of Reglan administration.
  • Questionable efficacy: Not all studies have found Reglan effective for the treatment of migraines. Some studies, especially those investigating the oral administration of Reglan, discovered that it was not significantly effective for treating migraine.  Due to some evidence suggesting that it may lack efficacy as an abortive migraine therapy, as well as no formal FDA approval (for treatment of migraine) – a subset of professionals may believe metoclopramide shouldn’t be used among migraine patients.
  • Side effects: In addition to potential serious adverse effects, some users will experience unwanted side effects resulting from Reglan administration. Examples of common side effects include: diarrhea, dizziness, drowsiness, headache, insomnia, low energy, nausea, and vomiting.  Should side effects become severe, patients may find it difficult to tolerate Reglan and may wish to pursue alternative treatments.
  • Superior treatments: Due to the fact that triptans have been FDA approved as an abortive therapy for migraines, they are commonly prescribed as a first-line intervention. Although most studies suggest metoclopramide is effective for migraine reduction (when compared to a placebo), some research suggests there are superior treatments.  In particular, orally administered triptans and dihydroergotamine are thought to be of superior efficacy.  Additionally, even other D2 receptor antagonists such as prochlorperazine, chlorpromazine, and haloperidol appear more effective than Reglan for the treatment of migraines.
  • Tardive dyskinesia: Those taking Reglan run the risk of developing a serious condition known as tardive dyskinesia. This condition occurs in a modest number of patients as a result of excessive D2 receptor antagonism.  Tardive dyskinesia is a neurological disorder characterized by abnormal and involuntary movements of the face and body.  In some cases, tardive dyskinesia can be offset by concurrent or pre-administration of diphenhydramine.  However, since some individuals may experience permanent tardive dyskinesia (even after cessation of Reglan), it is concerning; over 5,000 lawsuits have been filed against Reglan manufacturers due to inadequate warnings of this potential reaction.  (Source: http://www.ncbi.nlm.nih.gov/pubmed/19886950).
  • Tolerance: It is possible that some migraine patients may develop tolerance to the effect of Reglan when administered regularly. Most professionals recommend against long-term usage of Reglan due to lack of efficacy and safety data.  Should a patient become tolerant to its effects, patients may find that its efficacy decreases and that they need to utilize a higher dose to cope with migraine attacks.  This higher dose may present additional problems such as severe adverse effects.  The possibility of tolerance onset and associated implications should be perceived potential drawbacks of Reglan.
  • Unsustainable efficacy: Some suspect that the efficacy of Reglan diminishes over a long-term. Although it appears effective as an emergency treatment for migraines and is useful on an intermittent basis, it’s long-term efficacy hasn’t been proven.  In studies administering Reglan for the treatment of gastric abnormalities, its efficacy appears reduced after 1 month of regular administration.  It could be that a similar trend would be observed among patients taking Reglan for migraines.
  • Withdrawal symptoms: Some individuals may experience severe, debilitating withdrawal symptoms upon discontinuation of Reglan. Even if Reglan is utilized for a short, transient duration – discontinuation effects can linger.  A case study of a woman using metoclopramide to manage nausea and vomiting documented effects lasting 13 months after her final dose.  For 10 of these 13 months, the effects were described as “debilitating.” (Source: http://www.ncbi.nlm.nih.gov/pubmed/24677122).

Reglan (Metoclopramide) For Migraines (Review of Research)

Included below is a synopsis of the literature (from 1980 to 2015) investigating the efficacy of Reglan (Metoclopramide) for the treatment of migraines.  Most studies and/or scientific reports suggest that metoclopramide is an effective intervention for the attenuation of migraine pain.  Moreover, while metoclopramide may lack efficacy as a standalone agent (in certain cases), it appears valuable as an adjunct treatment when combined with either: triptans, dihydroergotamine, or an analgesic (e.g. paracetamol).

2015: A Randomized Controlled Trial of Intravenous Haloperidol vs. Intravenous Metoclopramide for Acute Migraine Therapy in the Emergency Department.

A randomized controlled trial (RCT) conducted by Gaffigan et al. (2015) sought to compare the efficacy of intravenous metoclopramide (Reglan) to the antipsychotic haloperidol (Haldol) for the treatment of migraines.  Both interventions are thought to function as abortive therapies in that they rapidly attenuate migraine symptoms, but are not prophylactics.  Each therapy is sometimes administered on an “as-needed” basis among those with migraine attacks.

These abortive therapies are perhaps most frequently utilized among emergency department patients with severe, unremitting headaches.  Researchers organized a double-blinded trial featuring 64 adults (between age 18 and 50) that had visited the emergency department as a result of severe migraines.  Of the 64 patients, 31 received haloperidol (5 mg, oral), whereas the remaining 33 received metoclopramide (10 mg, intravenous).

Both the Haldol (5 mg) and Reglan (10 mg) were administered after initial treatment with diphenhydramine (25 mg).  To determine the respective efficacies of each intervention, researchers used the 100-mm Visual Analogue Scale (VAS) to measure pain, nausea, restlessness, and sedation.  The Visual Analogue Scale was administered prior to treatment and at four 20 minute intervals (until the 80-minute mark was reached).

Usage of additional medications, side effects, and participant satisfaction (with treatment) were also documented.  Researchers also followed up with the patients with phone calls 2 days after the trial determine treatment satisfaction and degree of sustained symptomatic reduction.  Results indicated that the groups receiving Haldol (5 mg) and Reglan (10 mg) experienced analogous: improvements in Visual Analogue Scale measures, side effects, treatment satisfaction, and speed of symptomatic reduction.

Based on this information, we can conclude that Reglan and Haldol are effective abortive therapies for emergency migraine patients.  It was discovered that Haldol usage resulted in less of a need for additional rescue medication when compared to Reglan, but patients taking Haldol also experienced more restlessness.  Ultimately, metoclopramide and haloperidol are efficacious antimigraine interventions, but haloperidol may be preferred due to reduced need for additional rescue medications.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/26048068

2015: Comparison of therapeutic effects of magnesium sulfate vs. dexamethasone/metoclopramide on alleviating acute migraine headache.

A study by Shahrami et al. (2015) compared the efficacy of metoclopramide and dexamethasone (combined) to that of magnesium sulfate.  The impetus for the study stemmed from the fact that various migraine treatments are considered controversial, particularly non-pharmacological interventions such as magnesium.  The study assessed the metoclopramide/dexamethasone and magnesium sulfate among 70 emergency department patients with migraine headaches.

Baseline severity of migraine pain was assessed with a numeric rating scale (NRS).  The combination of metoclopramide/dexamethasone was administered to 35 patients, whereas the magnesium sulfate was administered to the other 35 patients.  After baseline assessments were collected, migraine severity was reassessed after 20 minutes, 1 hour, and 2 hours post-treatment.

The results suggested that there were no substantial differences in severity of migraine pain at baseline (between each group).  Those receiving the combination of metoclopramide plus dexamethasone experienced pain reduction from ~8 to 7.4 (20 minutes), to 6.0 (1 hour), and 2.5 (2 hours).  Comparatively, those taking the magnesium experienced pain reduction from ~8 to 5.2 (20 minutes), 2.3 (1 hour), and 1.3 (2 hours).

While both interventions are effective for treating migraine-related pain, magnesium sulfate was clearly faster acting – and slightly more effective.  I’ve already written about using magnesium for migraines and this publication showcases its efficacy over a pharmaceutical cocktail.  While it is also obvious that Reglan is capable of attenuating migraine symptoms, it is slower acting by comparison (to magnesium).

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25278139

2014: PURLs: Treating migraine: The case for aspirin

A report by medical doctors Ingledue and Mounsey (2014) emphasized the usefulness of aspirin for the treatment of migraines.  These doctors reviewed published randomized controlled trials (RCTs) and recommended that professionals consider aspirin at 975 mg (3 tablets) as a first-line intervention for acute migraine.  They also noted that aspirin augmented with metoclopramide (10 mg) can help migraine patients attain maximal symptomatic relief.

Although metoclopramide can reduce the severity of migraine (acting synergistically with aspirin), it may be most beneficial for attenuation of emetic symptoms of migraine (e.g. nausea and vomiting).  The recommendations made by Ingledue and Mounsey were based off of data from a Cochrane meta-analysis incorporating 13 high-quality, randomized controlled trials encompassing 4222 participants.

In these trials, a total of 5261 moderate-to-severe migraines were treated with either standalone aspirin or aspirin plus metoclopramide.  Of the 13 randomized controlled trials, 5 were placebo-controlled, 4 utilized active-controls, and the remaining 4 implemented active and placebo controls.  Efficacy of interventions were determined based on degree of migraine pain mitigation 2 hours post-administration, as well as reduction in headache severity (e.g. from severe to moderate).

Researchers also assessed whether headache relief was sustained after 24 hours of medication administration.  Self-assessments were completed by patients to measure headache pain using a 100-mm Visual Analogue Scale or a 4-point categorical scale.   Results from studies comparing aspirin to a placebo documented that aspirin as a standalone treatment was significantly more effective for the attenuation of acute migraine.

The studies comparing aspirin plus metoclopramide to a placebo discovered that the combination treatment was significantly more effective than the placebo in reducing migraine symptoms.  Additionally, results suggested that the aspirin plus metoclopramide intervention was more effective than standalone aspirin for migraine relief by 2-hours (post-administration), as well as for reducing nausea and vomiting (emetic symptoms).  From this we can conclude that some patients may benefit more from metoclopramide with aspirin compared to aspirin-only.

No significant adverse reactions were associated with metoclopramide plus aspirin for migraines.  This report highlights the efficacy of aspirin, but also that of metoclopramide can be used successfully as an adjunct.  Medical professionals may want to consider the usefulness of metoclopramide as an abortive antimigraine therapy, especially among patients who fail to derive sufficient benefit from a first-line intervention and/or those with debilitating emetic symptoms.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/24527476

2013: Metoclopramide versus sumatriptan for treatment of migraine headache: A randomized clinical trial.

It is well-understood that an array of antimigraine interventions are efficacious in emergency management of migraine attacks.  However, certain agents may be more effective when compared to others and thus may warrant first-line usage.  A study carried out by Talabi et al. (2013) compared the efficacy of metoclopramide to sumatriptan (a popular abortive therapy) for the treatment of migraines.

The study was randomized, double-blinded, and incorporated 124 adults diagnosed with migraines (in accordance with International Headache Society criteria).  All patients were between 20 and 60 years of age, and had been recruited by emergency doctors between 2010 and 2011.  Of the 124 adults, patients were assigned to receive either: metoclopramide (20 mg, intravenous) OR sumatriptan (6 mg, subcutaneous).

To determine whether one treatment was of superior efficacy to the other, researchers measured changes in pain intensity (with the 10-cm Visual Analogue Scale) from baseline to 60 minutes post-treatment.  Results indicated that the group receiving metoclopramide exhibited changes in pain scores from 6.47 (at baseline) to 0.66 (60 minutes post-treatment).  Individuals receiving sumatriptan exhibited changes in pain scores from 6.12 (baseline) to 1.1 (60 minutes post-treatment).

With some basic subtraction, it becomes apparent that the metoclopramide reduced migraine severity by ~5.81 and sumatriptan reduced migraine severity by ~5.02.  Upon comparison of the final pain scores of 0.66 (metoclopramide) and 1.1 (sumatriptan), it becomes apparent that metoclopramide is the more effective intervention.  Among patients in-need of emergency migraine treatment, intravenous metoclopramide is not only effective, but of superior efficacy to subcutaneous sumatriptan.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/24379846

2013: Aspirin with or without an antiemetic for acute migraine headaches in adults.

An update to a Cochrane review from 2010 was published in 2013 by Kirthi, Derry, and Moore.  Researchers discuss the fact that migraine patients often don’t seek professional help for management of symptoms, rather, they rely on over-the-counter medications.  For this reason, researchers sought to analyze the efficacy of aspirin, a popular over-the-counter agent, as a migraine treatment.

It was also hypothesized that concurrent administration of an antiemetic may be useful for the attenuation of migraine-related nausea and vomiting.  Databases such as the Cochrane Center Register of Controlled Trials, ClinicalTrials.gov, and MEDLINE – were utilized to compile results from studies dating through January 2013.  To meet inclusion criteria, studies needed to be randomized, double-blinded, placebo-controlled OR active-controlled OR both – plus needed to assess the efficacy of aspirin as a migraine treatment – and include at least 10 individuals.

Trial quality and data extraction was completed independently by two of the authors.  Researchers were unable to find any “newer” studies to include in this updated review (by 3-years).  Results indicated that sumatriptan (100 mg) was of superior efficacy to the combination of aspirin plus metoclopramide for pain relief at 2-hours post-administration.  It was noted that metoclopramide substantially decreased symptoms of nausea and vomiting compared to other standalone treatments.  This review indicates that metoclopramide is useful for the treatment of migraines as an adjunct.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23633350

2011: Metoclopramide for acute migraine: a dose-finding randomized clinical trial.

As of 2011, intravenous metoclopramide was considered an effective intervention as a migraine abortive therapy.  However, it remained unclear as to what the optimal dose of metoclopramide would be in terms of efficacy and safety.  Friedman et al. (2011) conducted a randomized, double-blinded trial comparing intravenous metoclopramide at three separate doses for the treatment of acute migraine.

A total of 356 emergency department patients diagnosed with common migraine were set to receive either 10 mg, 20 mg, or 40 mg of metoclopramide.  Diphenhydramine was coadministered with the intent of preventing extrapyramidal reactions.  Efficacy of each dose was determined based upon symptomatic improvements on an 11-point rating scale after 1-hour.

A secondary assessment documented pain relief after 48 hours and adverse reactions to treatment.  The results noted improvement on the 11-point rating scale by: 4.7 points (10 mg), 4.9 points (20 mg), and 5.3 points (40 mg).  Sustainability of pain relief after 48 hours in each of the three groups was reported as: 16% (10 mg), 20% (20 mg), and 21% (40 mg).

All three doses appeared equally well-tolerated with drowsiness and akathisia being the most common side effects.  Although there was a trend showing slightly greater average benefit from the 40 mg dose compared to the 10 mg dose, none of the three doses was significantly more effective than the other.  In other words, 10 mg metoclopramide is effective for the treatment of migraines and no additional benefits are attained from higher doses.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/21227540

2011: Metoclopramide as an analgesic in severe migraine attacks: an open, single-blind, parallel control study.

An open-label, single-blinded, parallel control study by Salazar et al. (2011) tested the efficacy of metoclopramide as an analgesic.  Researchers highlighted the fact that metoclopramide elicits central and peripheral effects, and that it may bolster the efficacy of analgesics when administered as an adjunct for migraine attacks.  For example, metoclopramide along with non-steroidal anti-inflammatory drugs (NSAID) appears more effective than standalone NSAIDs for the treatment of certain migraine symptoms.

This study recruited 93 patients with severe migraine attacks and randomized them to receive either: metoclopramide (10 mg, intravenous) OR paracetamol (1 gram, intravenous).  To determine the respective efficacies of each therapy, patients were evaluated at pre-treatment baseline, as well as 15 minutes, 30 minutes, 60 minutes, and 120 minutes – after administration.  After getting discharged from the emergency room, patients were contacted 48 hours later via phone to partake in a follow-up questionnaire.

Analysis of results indicated that patients in both the metoclopramide and paracetamol groups experienced significant pain reduction by 120 minutes post-administration.  That said, the patients receiving metoclopramide experienced more significant improvement at the 15-minute and 30-minute post-administration, evaluatory checkpoints.  It was concluded that administration of metoclopramide yields significantly quicker migraine-related pain relief compared to paracetamol.  Authors concluded that metoclopramide, as well as other dopamine antagonists, warrant consideration for the treatment of severe migraine attacks.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/21585330

2008: Oral metoclopramide as an adjunct to analgesics for the outpatient treatment of acute migraine.

A review of literature was conducted by Azzopardi and Brooks (2008) to assess whether orally administered metoclopramide was useful as an adjuvant migraine treatment.  Specifically, researchers wanted to determine how the efficacy of metoclopramide with an analgesic compared to a standalone triptan for the treatment of outpatient migraines.  Data was compiled from studies in PubMed, EMBASE, as well as International Pharmaceutical Abstracts.

To be included in this review, studies needed to compare the safety and efficacy of orally-administered metoclopramide to that of orally-administered triptans.  Non-oral formats of metoclopramide (e.g. intravenous) were not taken into consideration for this review.  Of the studies that fit inclusion criteria, oral metoclopramide had been administered along with aspirin (or an analogous agent).

Efficacy of oral metoclopramide was determined based upon improvement in headache severity using a 4-point scale (the higher the number, the more pain).  Relief of headache symptoms was considered a decrease in headache pain by at least 1 point on the scale at 2-hours post-administration.  The data revealed that standalone triptans were of equal or greater efficacy when compared to orally-administered metoclopramide plus aspirin.

What’s more, the administration of oral metoclopramide with aspirin did not appear more effective than triptans in reducing emetic symptoms.  That said, the combined intervention of metoclopramide and aspirin was better tolerated than triptans.  It was concluded that oral metoclopramide plus an analgesic (e.g. aspirin) effectively treats migraines and may be an ideal combination for patients unable to tolerate triptans.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/18285561

2008: Metoclopramide versus hydromorphone for the emergency department treatment of migraine headache.

A retrospective cohort study by Griffith, Mycyk, and Kyriacou (2008) compared the effect of metoclopramide to hydromorphone as abortive migraine therapies among emergency department patients.  To determine whether one intervention was more effective than the other, researchers assessed the degree of improvement in self-reported pain scores at (pre-treatment) baseline compared to post-treatment.  Researchers also calculated crude and adjusted relative risks to account for possible confounds (resulting from age, gender, race, pain scores).

This study included 200 individuals: 51 of which received hydromorphone (IV or IM), 95 of which received metoclopramide (IV), and 54 of which received alternative medications.  Pain of each patient was determined with a standardized pain scale (from 0 to 10, with 10 being the highest).  Results from the study indicated that hydromorphone (IV or IM) reduced migraine-related pain scores by 2.3 points (on average), whereas metoclopramide reduced migraine-related pain scores by 3.7 points.

Other treatments combined decreased migraine-related pain scores by 2.8 points.  Furthermore, metoclopramide administration resulted in fewer administrations of rescue pharmaceuticals and quicker times to discharge (from the emergency room).  There were no substantial differences in the frequencies of adverse effects resulting from each medication.

Results from this study highlight the fact that metoclopramide is an effective first-line therapy for migraine headaches among emergency-room patients.  Authors note that a robustly designed (double-blind, randomized, placebo-controlled) trial is warranted to confirm speculation that metoclopramide may yield greater therapeutic value than hydromorphone for migraines.  This study provides more evidence indicating that metoclopramide is useful as an antimigraine therapy.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/17981511

2008: [Metoclopramide as a painkiller for intense migraine headache in emergency departments].

A Spanish report by Salazar-Tortolero et al. (2008) was translated to English and documents the effect of metoclopramide as an analgesic for intense migraine headaches among emergency department patients.  Authors of the report note that migraines are disabling, leading a subset of sufferers to go to the emergency room, often complaining of head pain and emetic symptoms.  Various interventions such as triptans and NSAIDs (non-steroidal anti-inflammatory drugs) are often administered intravenously to attenuate symptoms.

Researchers highlight the fact that when orally administered, the triptans and NSAIDs are often of limited efficacy in reducing emetic symptoms such as vomiting.  Metoclopramide is regarded as an effective antiemetic agent and may be useful as a standalone antimigraine treatment.  This article analyzes 14 individuals diagnosed with severe migraine attacks presenting comorbid digestive symptoms.

It was discovered that among these migraine patients, intravenous metoclopramide (10 mg) resulted in significant symptomatic improvement.  In other words, not only did metoclopramide reduce migraine severity, but also combatted the difficult-to-treat digestive comorbidities.  Though this was only a small-scale analysis (with just 14 patients) and not a robustly designed study, it suggests that metoclopramide may be valuable as an abortive therapy for migraine patients.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/19012253

2008: A randomized controlled trial of prochlorperazine versus metoclopramide for treatment of acute migraine.

Friedman et al. (2008) designed a randomized, double-blind, controlled clinical trial comparing the efficacy of 2 dopamine antagonists for the treatment of acute migraine.  A total of 152 patients were recruited for participation, but following a screening process, 97 were deemed eligible, and only 77 were assigned at random to receive either intravenous: prochlorperazine (10 mg) or metoclopramide (20 mg).  Each of the interventions were administered 15 minutes after 25 mg diphenhydramine which is known to prevent extrapyramidal effects.

Before administration of the aforestated interventions, baseline pain scores (on a numeric rating scale) were recorded.  Pain scores were reassessed every 30 minutes post-treatment for a total of 2 hours.   Additionally, 24 hours after patients were discharged from the hospital, each was phoned for additional follow-up data.

Efficacy of interventions was determined based on change on the numeric pain scale from baseline to 1-hour post-administration.  Secondary measures consisted of average change in numeric pain scale at 2 hours and 24 hours post-administration, as well as degree of headache relief, adverse reactions, and treatment desirability.  Among those receiving prochlorperazine, change in numeric pain scale after 1 hour was ~5.5, whereas individuals receiving metoclopramide experienced a change of ~5.2.

Results indicated that administration of dopamine receptor antagonists (metoclopramide and prochlorperazine) alleviated acute migraine among emergency room patients.  Both interventions were administered intravenously and following diphenhydramine (25 mg).  Approximately 75% of all patients reported a desire to utilize the same medication for future migraine attacks.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/18006188

2007: Intravenous administration of metoclopramide by 2 min bolus vs 15 min infusion: does it affect the improvement of headache while reducing the side effects?

Parlak et al. (2007) noted that while most headaches are benign, they are the primary complaint in 1-3% of all emergency department patients.  Though there are an array of recommended abortive therapies for headache, not everyone responds well to first-line interventions.  Some of the most frequently administered treatments for headache in U.S. emergency departments include: meperidine (30%), ketorolac (21.4%), and prochlorperazine (16.7%).

Authors of the study conferred that antiemetic agents may also alleviate headache among emergency room patients.  Some evidence suggested that administration of metoclopramide as an intravenous infusion was significantly more effective compared to a placebo.  Furthermore, another study indicated that metoclopramide was an efficacious anti-headache agent for approximately 67.5% of all patients.

Based on some evidence highlighting the usefulness of metoclopramide for headaches, researchers opted to test its efficacy for the treatment of vascular headache.  They administered it intravenously as an infusion spanning over a duration of 15 minutes.  They compared the 15-minute infusion to that of a bolus intravenous injection to determine whether the span of administration could influence its efficacy.

A total of 120 emergency department patients experiencing benign vascular-type headaches participated in the study.  Of the 120 participants, 62 received metoclopramide (10 mg) intravenously as a 15-minute infusion, whereas the remaining 58 participants received an intravenous bolus 2-minute infusion of metoclopramide (10 mg).  To determine the efficacy of each intervention, headache scores of all participants were collected at baseline (pre-treatment) and compared to post-treatment time intervals (5 minutes, 15 minutes, 30 minutes, and 60 minutes).

Tolerability was also evaluated based on side effects experienced in each of the treatment groups. Of the group receiving the 2-minute bolus infusion, 17 participants experienced akathisia (29.3%) whereas only 4 in the group receiving the 15-minute infusion reported this side effect.  Other than akathisia occurring more frequently among those in the 2-minute bolus group, there were no differences in adverse effects or tolerability.

Results indicated that both the 2-minute and 15-minute infusions of metoclopramide significantly attenuated vascular headaches.  However, neither group experienced greater symptomatic relief compared to the other.  In conclusion, metoclopramide infusions effectively treat benign vascular headaches, however, rate of infusion does not influence efficacy.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/17916877

2003: Sumatriptan plus metoclopramide in triptan-nonresponsive migraineurs.

A study by Schulman and Dermott (2003) tested the efficacy of a pharmacological combination among migraine patients unresponsive to conventional triptans.  Triptans are generally regarded as effective, first-line abortive therapies for migraine patients.  However, a subset of migraine patients fails to derive sufficient symptomatic relief from their administration.

For this reason, researchers decided to test whether the efficacy of Sumatriptan combined with metoclopramide would be superior compared to that of standalone Sumatriptan – when administered as abortive therapies.  A total of 16 adults diagnosed with migraines (in accordance with International Headache Society criteria) were recruited for participation.  All participants had previously failed to derive adequate symptomatic relief from properly-dosed triptans on at least 2 occasions (prior to this trial).

The study was randomized, placebo-controlled, and implemented a crossover design.  Participants received either Sumatriptan (50 mg) plus a placebo OR Sumatriptan (50 mg) plus metoclopramide (10 mg).  To determine efficacy of each intervention, symptomatic severity was recorded by patients prior to treatment, as well as at intervals of 30, 60, 90, 120 minutes and 24 hours – post-administration.

Results indicated that 10/16 patients experienced significant symptomatic relief as a result of Sumatriptan (50 mg) plus metoclopramide (10 mg).  Comparatively, only 5/16 patients experienced significant symptomatic relief as a result of Sumatriptan (50 mg) plus the placebo.  After 2 hours, headache pain was reduced in 44% of those receiving the combined treatment, whereas headache pain reduction was experienced by just 31% of those receiving standalone Sumatriptan.

There were no significant differences between groups in regards to tolerability.  Based upon the results, researchers concluded that a combination of Sumatriptan (50 mg) plus metoclopramide (10 mg) is capable of attenuating migraines among those who derive insufficient relief from standalone triptans.  It is possible that metoclopramide acts synergistically with triptans to alleviate symptoms in difficult-to-treat migraine patients.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/12890127

2001: Randomized clinical trial of intravenous magnesium sulfate as an adjunctive medication for emergency department treatment of migraine headache.

A trial conducted by Corbo et al. (2001) investigated the additive efficacy of intravenous magnesium sulfate when combined with metoclopramide for the treatment of acute migraine.  Researchers recruited 44 patients from emergency departments to participate in a randomized, double-blind, placebo-controlled trial.  Patients were slated to receive either: intravenous metoclopramide (20 mg) plus magnesium sulfate (2 grams) OR intravenous metoclopramide (20 mg) plus a placebo (saline).

Each treatment was administered at intervals of 15 minutes following a migraine headache for a maximum of 3 doses.  Prior to treatment, intensity of migraine was recorded with a Visual Analogue Scale (VAS) and recorded again at 15 minutes, 30 minutes, and 45 minutes – post-treatment.  Efficacy of each intervention was determined based upon degree of pain alleviation as measured by the Visual Analogue Scale.

Results of the study indicated that both groups exhibited 50-mm improvements on Visual Analogue Scale scores throughout the trial.  That said, it appeared as though the group receiving magnesium sulfate (2 grams) experienced less improvement than those receiving the placebo (saline).  Further analysis indicated that the addition of magnesium sulfate to metoclopramide inhibits the efficacy of metoclopramide as an abortive therapy.

In other words, for maximal migraine relief, magnesium sulfate should not be administered along with metoclopramide.  It was speculated that magnesium may facilitate cerebral vasodilation, thereby counteracting the [hypothesized] vasoconstrictive effect provided by metoclopramide.  Since magnesium sulfate appears efficacious as a standalone migraine prophylactic, and this study was relatively small-scale (with mostly women), further research is warranted to elucidate mechanisms by which poorer responses occur among as a result of metoclopramide plus magnesium.

Nonetheless, standalone metoclopramide appears to alleviate migraine symptoms.  Furthermore, magnesium sulfate may provide some benefit when administered as a standalone (some studies suggest that it may be an effective abortive therapy).  It would be interesting if, in future studies, researchers sought to compare the standalone efficacy of magnesium sulfate to that of metoclopramide.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/11719739

1995: Randomized, placebo-controlled evaluation of prochlorperazine versus metoclopramide for emergency department treatment of migraine headache.

A randomized, placebo-controlled, double-blinded trial was conducted by Coppola, Yealy, and Leibold (1995) to compare the efficacy of metoclopramide to that of prochlorperazine for the attenuation of migraine headaches.  Researchers recruited 70 adults with migraine from emergency departments to participate in the study.  All participants had experienced at least 1 migraine prior to their emergency room visit and none had administered metoclopramide or prochlorperazine within 48 hours of the trial.

At random, participants received either: metoclopramide (10 mg), prochlorperazine (10 mg), or a placebo (saline solution).  During the study, none of the patients were permitted to use adjunct analgesics.  To determine efficacies of each intervention, patients rated their degree of nausea, pain, and sedation prior to receiving one of the three aforestated treatments, as well as after 30 minutes post-treatment.

A successful treatment was documented as either of the following: patient satisfaction and decrease of at least 50% in migraine-related pain score (by 30 minutes post-treatment) OR absolute pain scores of 2.5 m or less.  If neither of the aforestated criteria were met, treatments were considered a failure.  Measures indicated that prior to treatment, all groups exhibited similar degrees of nausea, pain, and sedation.

Within 30 minutes post-treatment, pain scores significantly changed based upon the treatment that was administered.  Assessments at 30 minutes (post-administration) indicated the following:  individuals treated with prochlorperazine exhibited average pain scores of 1.1 cm, those treated with metoclopramide exhibited pain scores of 3.9 cm, and patients receiving the placebo exhibited pain scores of 6.1 cm.  The most effective antimigraine intervention of the three was prochlorperazine, alleviating symptoms in 82% of patients.

Of those receiving metoclopramide, around 46% derived symptomatic benefit and among individuals receiving the placebo, just 29% experienced improvement.  Despite trends that metoclopramide was more effective than the placebo, responses didn’t significantly differ.  Additionally, only the prochlorperazine reduce nausea significantly after 30 minutes when compared to the metoclopramide and placebo.

This suggests that of the three antimigraine interventions presented in this study, prochlorperazine appears to be fastest acting and most efficacious.  Since the metoclopramide and placebo groups provided no significant benefit to migraine patients, both were regarded as ineffective.  Upon assessment of the study results, metoclopramide cannot be recommended as an abortive migraine therapy.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/7486359

1995: Dihydroergotamine and metoclopramide in the treatment of organic headache.

A report published by Gross, Donat, and Boyle (1995) highlights the usefulness of dihydroergotamine plus metoclopramide for the management of benign headache.  Authors highlight the fact that each therapy has been utilized for many years as an anti-headache treatment.  At this time, it was thought that each drug functioned by stimulating serotonin receptors to yield a vasoconstrictive effect (and offset the vasodilation implicated in migraines).

Now we are aware that dihydroergotamine functions similarly to triptans in that it stimulates the 5-HT1D receptor site (as an agonist), but also modulates activity at dopamine receptor sites.  Furthermore, metoclopramide acts as a 5-HT3 receptor agonist, 5-HT4 receptor antagonist, and antagonizes D2 receptor sites.  In other words, both target different receptors but modulate serotonin and dopamine to alleviate migraine symptoms.

In this report, several cases were documented in which patients with organic headaches were successfully treated with a combination of dihydroergotamine plus metoclopramide.  Two of the patients experienced headaches resulting from meningitis, whereas the other experienced headaches from carcinomatosis.  Authors noted that simultaneous administration of dihydroergotamine with metoclopramide provides “excellent” headache relief.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/8550366

1993: The efficacy of metoclopramide in the treatment of migraine headache.

At a hospital, Ellis et al. (1993) compared the efficacy of metoclopramide to that of ibuprofen for the treatment of migraine headache.  They set-up a double-blind, placebo-controlled, randomized study with adult migraine patients.  All patients had experienced recurring headaches with one or more of the following criteria: unilaterality, neurological symptoms, emetic symptoms (e.g. nausea and vomiting), sensory sensitivity (e.g. photophobia), or mood changes.

Participants received either: metoclopramide (10 mg) plus a placebo (saline), ibuprofen (600 mg) plus a placebo (saline), metoclopramide (10 mg) plus ibuprofen (600 mg), OR a placebo plus a placebo (dual saline).  A Visual Analogue Scale (VAS) determined efficacy of each intervention.  Specifically, changes in scores on a Visual Analogue Scale was recorded at pre-treatment baseline and compared at intervals of 30 and 60 minutes post-treatment.

Results suggested that the groups receiving metoclopramide (10 mg) plus the placebo AND metoclopramide plus ibuprofen experienced significantly greater pain reduction as compared to the other groups (ibuprofen plus placebo and placebo-placebo).  What’s more, the groups receiving metoclopramide plus placebo AND the metoclopramide plus ibuprofen experienced significantly less nausea than the remaining groups.  Comparatively, there were no differences in pain or symptomatic among the groups receiving metoclopramide/placebo AND metoclopramide/ibuprofen.

This indicates that metoclopramide is clearly the most efficacious agent of the bunch.  Furthermore, we can conclude that metoclopramide as a standalone intervention is as effective as metoclopramide plus ibuprofen – implying no therapeutic need for an ibuprofen adjunct.  In conclusion, metoclopramide appears efficacious for the attenuation of migraine-related pain, as well as emetic symptoms such as nausea.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/8427430

1992: Abortive migraine therapy with oral naproxen sodium plus metoclopramide plus ergotamine tartrate with caffeine.

A report by Saadah (1992) discussed the efficacy of polypharmacy for the treatment of acute migraine.  The polypharmacy combination consisted of:  naproxen sodium (550 mg), metoclopramide (10 mg), ergotamine tartate (1 mg), and caffeine (100 mg).  A total of 63 patients were able to test this concoction as an abortive migraine therapy.

Results indicated that around 84% of all headaches were completely mitigated by this combination.  Around 40% of all patients reported some side effects (of minor severity) and 87% of all individuals regarded this combination as being more effective than all previous interventions.  This suggests that metoclopramide may be highly effective as an abortive treatment when administered with a multitude of other interventions.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/1551794

1980: A double blind study of metoclopramide in the treatment of migraine attacks.

One of the first studies to evaluate the therapeutic antimigraine efficacy of metoclopramide was conducted by Tfelt-Hansen et al. (1980) at the Copenhagen acute migraine clinic.  A total of 150 individuals that had been diagnosed with classic or common migraine (based on Ad Hoc Committee on Classification of Headache) participated in the trial.  All patients had visited the Copenhagen acute migraine clinic for treatment of acute attacks, and experienced emetic symptoms (e.g. nausea and/or vomiting).

In around 60% of participants, migraine attacks had occurred for over 15 years with an approximate frequency of 1 to 5 migraines per month.  Initially, researchers determined the severity of headache, nausea, and vomiting with a scale from 0 to 3 (with 3 being the highest).  To test the efficacy of metoclopramide, researchers assigned: 51 participants to receive a placebo (intramuscular) plus placebo (suppository); 49 participants to receive 10 mg metoclopramide (intramuscular) plus placebo (suppository); and 50 participants to receive a placebo (intramuscular) plus 10 mg metoclopramide (suppository).

Thereafter, all patients received paracetamol (1 gram) and diazepam (5 mg) – either simultaneously or 30 minutes after metoclopramide administration.  Efficacy of each intervention was determined based upon changes on rating scale scores from (pre-treatment) baseline to post-treatment.  To accurately determine results, patients that violated the protocol (as laid out by researchers) were excluded from evaluation, and confounds were ruled out based upon the finding that the three groups didn’t differ in factors such as: age, sex, duration of disease, prophylactic interventions, attacks per year, vomiting, nausea, etc.

Results indicated that metoclopramide administration treated nausea in around 86% of patients whereas the placebo treated nausea in 71% of patients.  This was the first controlled trial demonstrating efficacy of metoclopramide plus an analgesic for the treatment of migraine attacks.  Though the placebo effect was substantial, metoclopramide was still statistically superior for attenuation of migraine-related symptoms when combined with an analgesic.

  • Source: http://jnnp.bmj.com/content/43/4/369.full.pdf

Limitations associated with research of Reglan for migraines

There are some limitations associated with the research of Reglan for migraines.  Currently, it is unclear as to whether the drug is safe and/or effective among pediatrics with refractory migraine – and the optimal dosage that should be taken by younger patients.  There is also mixed evidence regarding Reglan’s antimigraine efficacy compared to other drugs – and no documentation of patients being treated with it over a long-term.

  • Age groups: The principal limitation is that it hasn’t been studied thoroughly among children and adolescents (possibly for good reason).  The risks of adverse reactions aren’t significant, but could be amplified among those with developing brains.  Some evidence suggests that Reglan is well-tolerated among adolescents, but extrapyramidal reactions are more frequent among children compared to adults.  Pretreatment with diphenhydramine is usually helpful for offsetting the extrapyramidal effects.  Nonetheless, further research is warranted to determine safety of Reglan as an antimigraine among pediatrics.
  • Comparative efficacy: Some head-to-head comparison studies have been published, comparing metoclopramide to triptans and other D2 receptor antagonists. Certain results suggest that Reglan may be more effective than conventional abortive migraine therapies, while other results indicate that it may be less effective.  To determine how it really stacks up in terms of efficacy and tolerability, additional research is warranted.
  • Long-term effects: The consequences associated with long-term Reglan administration are unclear. Some studies indicate that there are often prolonged withdrawal symptoms and/or side effects that linger long after Reglan discontinuation.  It may be necessary to elucidate the possible neurophysiological consequences of regular Reglan treatment over a long-term.
  • Migraine subtypes: It seems as though Reglan is equally effective among migraine patients – regardless of whether they have classic or common migraine (aura vs. non-aura). That said, the drug may be more useful among patients with certain types of migraine compared to others.  Further research should attempt to pinpoint whether patients with certain biomarkers or genetic expression benefit more from Reglan than others.
  • Outpatient usage: A majority of Reglan usage is confined to an in-patient, emergency room setting. It is unclear as to whether the drug would be useful if prescribed for outpatient administration.  Since the oral format is currently considered ineffective for migraine treatment, and intravenous injections aren’t easily done by patients, outpatient usage may not be recommended.  Nonetheless, some researches may wish to investigate its efficacy when administered “as-needed” in an outpatient setting.
  • Study designs: Not all studies investigating the antimigraine properties of Reglan are flawless in terms of design. Ideally, all research would be placebo-controlled, double-blinded, and incorporate randomization.  Additionally, only specific migraine patients would be allowed to participate based on certain inclusion criteria (as developed by researchers).  Moreover, a large sample size in a robustly designed study would help evaluate the full extent of Reglan’s antimigraine efficacy.

Verdict: Reglan an unconventional, yet effective therapy for migraines

Based on the available scientific literature analyzing the administration of Reglan (metoclopramide) as an intervention for migraines, it appears to be an effective treatment.  Some research goes as far as to highlight the superior efficacy of Reglan compared to first-line drugs such as Sumatriptan.  That said, most professionals would agree that Reglan is a less preferred intervention compared to many other medications – for a multitude of reasons.

It is important to underscore that Reglan is not FDA approved for the treatment of migraines and its manufacturers do not currently intend for its usage as an antimigraine.  Certain studies have documented Reglan as being an effective treatment, but less effective than triptans and dihydroergotamine.  Other comparison studies note that similar functioning dopamine (D2) receptor antagonists such as prochlorperazine, chlorpromazine, and haloperidol – are more effective than Reglan for migraines.

Although conventional antimigraine pharmaceuticals are generally preferred over Reglan due to FDA approval and thoroughly established efficacy, some patients do not respond to conventional therapies.  Among the subset of patients with refractory migraine, intravenous Reglan (as opposed to orally administered) remains an effective alternative abortive therapy to consider.  In summary, intravenous Reglan is an effective antimigraine therapy, but its off-label usage is only warranted among patients that are unresponsive to standardized interventions; preferably in an emergency setting.

Have you utilized Reglan (metoclopramide) for migraines?

If you’ve used metoclopramide (brand name “Reglan”) for the treatment of migraine headaches, feel free to share your experience in the comments section below.  To help others get a better understanding of your situation, mention whether you received Reglan intravenously in an emergency room setting OR orally in an outpatient setting.  In your experience, how would you rate the efficacy of Reglan for the treatment of migraines?

Did you find it most helpful in reducing migraine-related pain, emetic symptoms (e.g. nausea), or equally effective for pain and emetic symptoms?  In your comment, consider including additional information such as: the dosage of Reglan administered, whether you were using any other substances (drugs or supplements) along with it, and whether you experienced any unwanted adverse effects resulting following treatment.  Realize that although Reglan is often an effective abortive therapy for migraine, it does not work well for everyone.

Some patients may not experience any therapeutic benefit, while others may find it immensely helpful for reducing migraine-related pain and nausea.  It may be an ideal ideal for patients with migraine induced by dopamine receptor hypersensitivity – and an optimal adjunct for individuals presenting migraine with emetic features.  If you have additional questions regarding Reglan (metoclopramide) for migraines, be sure to consult a licensed medical professional.

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