What is the difference between domperidone and metoclopramide? Why is domperidone not always preferred, as it has less risk of CNS adverse effects? 

Gastrointestinal motility disorders and nausea are common clinical challenges, and two dopamine antagonists — domperidone and metoclopramide — are often used in their management. Although both act on dopamine D2 receptors, key differences in their pharmacokinetics, central nervous system penetration, and adverse effect profiles make the choice between them more than a matter of availability. Let’s unpack the differences.

Mechanism of Action

Both domperidone and metoclopramide exert prokinetic and antiemetic effects by blocking D₂ receptors:

  • At the chemoreceptor trigger zone (CTZ): This action helps reduce nausea and vomiting.
  • In the gastrointestinal tract: D₂ receptor blockade enhances acetylcholine release, promoting gastric emptying and increasing lower esophageal sphincter tone.

However, only metoclopramide significantly crosses the blood-brain barrier (BBB).

Key Differences at a Glance

Feature Domperidone Metoclopramide
BBB Penetration Minimal Significant
Extrapyramidal Symptoms Rare Common, especially in young and elderly
QT Prolongation Risk Yes (dose-dependent) Also present
Approved Use Restricted in some countries Widely used, more regulatory caution in recent years
Uses Gastroparesis, nausea, lactation off-label Gastroparesis, nausea, reflux, migraine-associated nausea
Prokinetic Action Strong Moderate
Additional MOA None significant 5-HT₄ agonist and weak 5-HT₃ antagonist

Clinical Implications

🧠 CNS Side Effects

Because metoclopramide penetrates the CNS, dystonia, akathisia, and even tardive dyskinesia may develop, particularly with prolonged use (>12 weeks). Domperidone’s limited CNS access makes it less likely to cause these effects.

❤️ Cardiac Safety

Both drugs can prolong the QT interval, raising concerns about torsades de pointes, especially at higher doses or in patients with electrolyte imbalances or on interacting medications. Regulators in some countries have placed more significant restrictions on the use of domperidone. However, there is ongoing debate in the literature as to whether domperidone indeed has more significant cardiovascular system risks than metoclopramide.

👶 Use in Pediatrics

Metoclopramide is generally avoided in children due to the risk of extrapyramidal symptoms (EPS). Domperidone, although theoretically safer, is also restricted in some regions for pediatric use due to cardiac concerns.

🍼 Use in Lactation

Domperidone has been used off-label to stimulate lactation, as dopamine inhibition raises prolactin levels. However, the Health Science Authority in Singapore recently issued an Adverse Drug Reaction News Bulletin warning that caution should be exercised as there is a potential risk of psychiatric withdrawal events following abrupt discontinuation of high-dose, prolonged domperidone use for lactation stimulation

Summary: Choosing Wisely

  • Use domperidone if you need a prokinetic with minimal CNS effects, especially for gastroparesis in patients sensitive to EPS. Be cautious of QT prolongation and regulatory restrictions.

  • Use metoclopramide if you need a centrally-acting antiemetic, especially in acute care settings like chemotherapy-induced nausea. Limit duration to reduce the risk of irreversible neurological side effects such as tardive dyskinesia.

Final Thoughts

Both domperidone and metoclopramide offer benefits, but they each come with caveats. Understanding their pharmacology helps clinicians make informed choices that balance efficacy with safety. Always consider individual patient factors, especially age, comorbidities, and concurrent medications.