What are the extrapyramidal side effects of metoclopramide?

October 12, 2025 •

4 min read

While the incidence of extrapyramidal reactions to metoclopramide is approximately 0.2% in some studies, this can increase to as high as 25% in certain at-risk populations, such as children and the elderly. Understanding what are the extrapyramidal side effects of metoclopramide is crucial for both patients and healthcare providers to ensure prompt recognition and appropriate management.

Quick Summary

Metoclopramide, a dopamine antagonist, can cause movement disorders like dystonia, akathisia, and tardive dyskinesia by blocking central dopamine receptors. Risk factors include age, female gender, dose, and duration of use. Management involves drug discontinuation and specific treatments for symptom relief.

Key Points

Dopamine Blockade: Metoclopramide's ability to block central dopamine D2 receptors is the primary cause of its extrapyramidal side effects (EPS).
Types of EPS: The main extrapyramidal side effects include acute dystonia (muscle spasms), akathisia (restlessness), parkinsonism (tremors, rigidity), and tardive dyskinesia (involuntary movements).
Onset Varies: Acute dystonia and akathisia can occur soon after treatment begins, while tardive dyskinesia and parkinsonism are often associated with longer-term use.
Risk Factors: Higher doses, prolonged use, and specific patient factors like older age, female gender, and diabetes increase the risk of EPS.
Management: Immediate drug discontinuation is the first step, followed by specific treatments like anticholinergics (e.g., diphenhydramine) for acute dystonia.
FDA Black Box Warning: The FDA requires a black box warning for metoclopramide, advising against use beyond 12 weeks due to the risk of irreversible tardive dyskinesia.

What Are the Extrapyramidal Side Effects of Metoclopramide?

Metoclopramide is a medication widely used as an antiemetic to prevent nausea and vomiting and as a prokinetic agent to enhance gastrointestinal motility in conditions like gastroparesis. Its therapeutic effects stem from its activity as a dopamine D2 receptor antagonist, primarily in the chemoreceptor trigger zone (CTZ) of the brain. However, this same mechanism of action can disrupt the delicate balance of dopamine in the central nervous system's motor pathways, leading to extrapyramidal side effects (EPS).

The Mechanism Behind Metoclopramide's EPS

The extrapyramidal motor system, encompassing the basal ganglia and related neural pathways, is responsible for modulating and coordinating movement. Dopamine is a key neurotransmitter in this system. When metoclopramide blocks dopamine D2 receptors not just in the CTZ but also in the striatum, it can lead to a relative overactivity of acetylcholine pathways. This dopaminergic-cholinergic imbalance is the primary cause of the movement disorders known as EPS.

Types of Metoclopramide-Induced Extrapyramidal Effects

The adverse neurological reactions caused by metoclopramide can manifest in several distinct ways, with the onset ranging from minutes to years after starting the medication.

Acute Dystonia: These are involuntary, sustained, or spasmodic muscle contractions that lead to abnormal postures or repetitive movements. They can appear within the first 24 to 72 hours of treatment, sometimes after just a single dose.
- Common symptoms include:
  - Torticollis: Twisting of the neck to one side.
  - Oculogyric crisis: Involuntary, sustained upward or sideways deviation of the eyes.
  - Trismus: Spasm of the jaw muscles.
  - Opisthotonus: Severe muscle spasm that causes the head, neck, and spine to arch backward.
  - Facial grimacing and rhythmic tongue protrusion.
Akathisia: Characterized by a profound sense of inner restlessness, anxiety, and the irresistible urge to move. Patients may constantly pace, shift their weight, or fidget. This can occur shortly after beginning the medication and is often misinterpreted as simple agitation.
Parkinsonism: This set of symptoms mimics those of Parkinson's disease and is a result of the dopamine-blocking effects. It typically develops with longer-term use, often appearing within the first six months of treatment.
- Symptoms include:
  - Bradykinesia (slowness of movement).
  - Tremor, particularly a resting tremor.
  - Cogwheel rigidity.
  - A mask-like facial expression.
  - A shuffling gait.
Tardive Dyskinesia (TD): This is a potentially irreversible and serious movement disorder characterized by involuntary, repetitive movements, most often involving the face, tongue, and mouth. The FDA issued a black box warning for metoclopramide due to the risk of TD, especially with prolonged use (over 12 weeks).
- Common symptoms include:
  - Lip smacking or puckering.
  - Tongue protrusion.
  - Chewing motions or grimacing.
  - Involuntary movements of the trunk and extremities.

Risk Factors for Developing EPS

Certain patient populations and treatment characteristics increase the risk of metoclopramide-induced EPS.

Age: Pediatric and elderly patients are particularly vulnerable. Younger patients are more prone to acute dystonia, while older patients, especially women, have a higher risk of developing tardive dyskinesia.
Dose and Duration: The risk of developing EPS is dose-related. The risk of tardive dyskinesia specifically increases with longer treatment durations and higher cumulative doses. For this reason, the FDA recommends against using metoclopramide for more than 12 weeks.
Other Medications: Concomitant use of other dopamine receptor-blocking agents, such as antipsychotics, further elevates the risk of EPS.
Underlying Conditions: Patients with pre-existing movement disorders, renal insufficiency, or diabetes mellitus are also at increased risk.

How Extrapyramidal Symptoms Are Managed

The management of EPS depends on the type and severity of the reaction, but the initial and most critical step is always to stop the offending medication.

Acute Dystonia and Akathisia: Prompt administration of an anticholinergic agent (e.g., benztropine) or an antihistamine with anticholinergic properties (e.g., diphenhydramine) is the standard of care. Intravenous administration is preferred for a rapid response, often resolving symptoms within minutes. Benzodiazepines like diazepam can also be used in some cases.
Parkinsonism: Symptoms generally subside slowly over several weeks to months after discontinuing metoclopramide. Specific antiparkinsonian agents are usually avoided unless symptoms persist and are severe.
Tardive Dyskinesia: No universally effective treatment exists once TD is established. Discontinuing metoclopramide is essential, and in some cases, symptoms may partially or completely resolve over time. Management often focuses on symptom control and long-term supportive care.

Metoclopramide vs. Domperidone: A Comparison of EPS Risk

Another medication, domperidone, is also a D2 antagonist used for similar gastrointestinal conditions. A key difference lies in their ability to cross the blood-brain barrier.


Feature	Metoclopramide	Domperidone
Mechanism of Action	D2 antagonist centrally and peripherally; 5-HT4 agonist.	Primarily a peripheral D2 antagonist.
Blood-Brain Barrier Crossing	Readily crosses the blood-brain barrier.	Minimally crosses the blood-brain barrier at usual doses.
Risk of EPS	Significant risk, especially with higher doses or prolonged use.	Much lower risk of EPS due to limited CNS penetration.
Cardiac Risk (QT Prolongation)	Can cause QT prolongation, but risk is generally considered lower than domperidone.	Greater risk of QT prolongation and cardiac side effects.
FDA Status	Black box warning for tardive dyskinesia due to chronic use.	Not FDA-approved for GI disorders in the U.S. due to cardiac concerns.

Conclusion

The extrapyramidal side effects of metoclopramide represent a significant risk associated with its use, particularly with long-term treatment. By understanding the different types of EPS—acute dystonia, akathisia, parkinsonism, and the potentially irreversible tardive dyskinesia—patients and clinicians can be better equipped to monitor for and manage these adverse events. Awareness of risk factors, including age, gender, and treatment duration, is critical for safe prescribing. Due to the high risk of tardive dyskinesia with long-term therapy, the FDA advises against using metoclopramide for more than 12 weeks. Proper management begins with immediate discontinuation of the drug and can involve specific medications to address acute symptoms, improving safety and patient outcomes. For more information, refer to the FDA Medication Guide for Metoclopramide.

Frequently Asked Questions

The primary cause is metoclopramide's action as a dopamine D2 receptor antagonist, which blocks dopamine in the brain's motor control centers and creates an imbalance with acetylcholine, leading to movement disorders.

Acute dystonia and akathisia can appear rapidly, sometimes within minutes or hours of a single dose, especially in young people and those receiving high doses.

Acute dystonia involves sudden, sustained muscle spasms that occur shortly after starting the drug. Tardive dyskinesia involves repetitive, involuntary movements that typically develop after prolonged or chronic use and can be irreversible.

Yes, pediatric patients are at an increased risk, particularly for developing acute dystonic reactions, which can be severe.

For acute dystonia, the drug should be stopped immediately and a parenteral anticholinergic (like benztropine) or antihistamine (like diphenhydramine) can be administered for rapid symptom relief. For tardive dyskinesia, there is no known effective treatment, and the focus is on stopping the drug and managing symptoms.

Tardive dyskinesia is a serious movement disorder that is often irreversible, meaning symptoms may not go away even after stopping the medication.

Domperidone has a much lower risk of causing extrapyramidal side effects because it primarily works on peripheral dopamine receptors and does not readily cross the blood-brain barrier, unlike metoclopramide.

In 2009, the FDA issued a black box warning for metoclopramide due to the risk of developing tardive dyskinesia, recommending against its use for longer than 12 weeks to minimize this risk.