Antiemetic (see Nausea and Vomiting)

• Acute Migraine-Associated Nausea/Vomiting
  • Off-Label Use
• Chemotherapy-Associated Nausea/Vomiting
  • Metoclopramide is Not Considered a First-Line Antiemetic Agent for Nausea/Vomiting Associated with Chemotherapy, Due to Better Safety Profile of Other Antiemetic Agents
  • May Be Used as an Alternative to Neurokinin 1 (NK1) Receptor Antagonists (Aprepitant, Fosaprepitant, etc) in Patients Receiving Cisplatin
• Radiation Therapy-Associated Nausea/Vomiting (see Radiation Therapy)
  • Off-Label Use
• Undifferentiated Nausea/Vomiting
  • Off-Label Use
• Vertigo-Associated Nausea/Vomiting (see Vertigo)
  • Off-Label Use (Am Fam Physician, 2005) [MEDLINE]

Aspiration Prophylaxis (in Patient Undergoing General Anesthesia)

• Off-Label Use (Can Anaesth Soc J, 1986) [MEDLINE]

Enteral Feeding Intolerance in Critical Illness

Rationale

• Prokinetic Agent

Clinical Efficacy

• Meta-Analysis and Systematic Review of Prokinetic Agents in Critically Ill Patients Receiving Enteral Nutrition (Crit Care, 2016) [MEDLINE]
  • Prokinetic Agents Decrease Feeding Intolerance in Critically Ill Patients, as Compared to Placebo or No Intervention
  • However, the Impact of Prokinetic Agents on Other Outcomes (Such as Pneumonia, Mortality, and ICU Length of Stay is Unclear

Functional Dyspepsia

• Off-Label Use

Gastric Bezoar (see xxxx)

• xxxx

Gastroesophageal Reflux Disease (GERD) (see Gastroesophageal Reflux Disease)

• FDA-Approved for This Indication
  • Limited to ≤12 wks of therapy
  • Indicated for Refractory Gastroesophageal Reflux Disease in the Presence of Gastroparesis Only

Gastroparesis (see Gastroparesis)

• FDA-Approved for Diabetic Gastroparesis
  • Limited to ≤8 wks of Therapy
  • Generally Indicated Only After the Following Initial Therapies Fail
    • Dietary Therapy
    • Discontinuation of Medications Which Impair Gastrointestinal Motility
    • Improvement of Glycemic Control
  • Experts Suggest Limiting Metoclopramide Use to Severe, Refractory Diabetic Gastroparesis
• Off-Label Use for Nondiabetic Gastroparesis

Hiccups (see Hiccups)

• Off-Label Use

Lactation Stimulant

• xxxx

Partial Bowel Obstruction (Malignant, Inoperable)

• Off-Label Use
• Frequently Used in Combination with Corticosteroid, Antisecretory Agent, and Anticholinergic Agent
• Contraindicated in Following Cases
  • Abdominal Pain (see Abdominal Pain)
  • Colic
  • Suspected/Confirmed Complete Mechanical Obstruction

Tension Headache

• Off-Label Use

Tourette Syndrome (see Tourette Syndrome)

• xxx

Dopamine D1 and D2 Receptor Antagonist (in the Central Nervous System) (see Dopamine Receptor Antagonists)

• Occurs at Low Doses
• Central Nervous System Dopamine D2 Receptors are Located in the Central Nervous System Chemoreceptor Trigger Zone
  • Accounts for Antiemetic Effect
• Peripheral Dopamine D2 Receptors

Mixed Serotonin 5-HT3 Receptor Antagonist and Serotonin 5-HT4 Receptor Agonist (see Serotonin 5-HT3 Receptor Antagonists)

• Occurs at High Doses
• Accounts for Antiemetic Effect (When Used at Higher Doses)

Enhancement of Acetylcholine Release and Stimulation of Cholinergic Receptors on Gastric Smooth Muscle

• Accounts for Gastrointestinal Prokinetic Effect

Physiologic Effects

• Antiemetic Effect
  • Mediated by Antagonism at Dopamine D2 Receptors in the Chemoreceptor Trigger Zone of the Central Nervous System
  • May Alse Be Mediated by Antagonism at the 5-HT3 Receptor When Used at Higher Doses
• Gastroprokinetic Effect: may contribute to the antiemetic effect
  • Mediated by muscarinic activity, dopamine D2 receptor antagonist activity, and 5-HT4 receptor agonist activity
• Increased Lower Esophageal Sphincter Tone

Metabolism

• Renal: 85% of oral dose appears in the urine within 72 hrs (50% is present as free or conjugated metoclopramide)
• Half-Life: 5-6 hrs

Beers Criteria for Potentially Inappropriate Medication Use in Older Adults (≥65 y/o) (Am Fam Physician, 2020) [MEDLINE]

• Metoclopramide Has Been Identified in the Beers Criteria as a Potentially Inappropriate Medication to Be Avoided in Patients ≥65 y/o (with a Recommended Treatment Duration <12 wks)
  • Due to Potential for Extrapyramidal Side Effects (Including Tardive Dyskinesia)
  • Risks May Be Increased in Frail, Older Adults and with Longer Treatment Duration

Allergic/Immunologic

Angioedema

• Epidemiology
  • Cases Have Been Reported (with Undefined Frequency) (Postepy Dermatol Alergol, 2013) [MEDLINE]
• Clinical
  • Lingual Edema

Cardiovascular Adverse Effects

Atrioventricular Block

• Epidemiology
  • Frequency of Atrioventricular Block Has Not Been Well-Defined
  • Sinoatrial Arrest Has Been Associated with Rapid Intravenous Administration or Use of High Doses (Ann Pharmacother, 1995) [MEDLINE]
• Clinical
  • First Degree Atrioventricular Block (see First Degree Atrioventricular Block)
  • Second Degree Atrioventricular Block-Mobitz Type I (Wenckebach) (see Second Degree Atrioventricular Block-Mobitz Type I)
  • Second Degree Atrioventricular Block-Mobitz Type II (see Second Degree Atrioventricular Block-Mobitz Type II)
  • Third Degree Atrioventricular Block (see Third Degree Atrioventricular Block)

Congestive Heart Failure (CHF) (see Congestive Heart Failure)

• Epidemiology
  • Cases Have Been Reported (South Med J, 1991) [MEDLINE]
• Physiology
  • Due to Increased Aldosterone Secretion, Resulting in Fluid Retention

Hypertension (see Hypertension)

• Epidemiology
  • Cases of Severe Hypertension Associated with Previously Undiagnosed Pheochromocytoma Have Been Reported (Am J Emerg Med, 2018) [MEDLINE]
• Physiology
  • Intravenous Metoclopramide Causes the Release of Catecholamines

Hypotension (see Hypotension)

• Epidemiology
  • Cases Have Been Reported (Ann Pharmacother, 2013) [MEDLINE]

QT Prolongation with Unclear Association with Torsade (see Torsade)

• Epidemiology
  • Unclear Association with Torsade

Sinus Bradycardia (see Sinus Bradycardia)

• Epidemiology
  • Frequency of Bradycardia Has Not Been Well-Defined
  • Sinoatrial Arrest Has Been Associated with Rapid Intravenous Administration or Use of High Doses (Ann Pharmacother, 1995) [MEDLINE]

Dermatologic Adverse Effects

Flushing (see Flushing)

• Epidemiology
  • Flushing Occurs with High Intravenous Doses

Urticaria (see Urticaria)

• Epidemiology
  • Cases Have Been Reported

Endocrine Adverse Effects

Amenorrhea (see Amenorrhea)

• Epidemiology
  • May Occur within the First Week of Metoclopramide Therapy or Up to 4 mos After Metoclopramide Initiation
• Physiology
  • Due to Dopamine Receptor Antagonism

Erectile Dysfunction (see Erectile Dysfunction)

• Epidemiology
  • May Occur within the First Week of Metoclopramide Therapy or Up to 4 mos After Metoclopramide Initiation
• Physiology
  • Due to Dopamine Receptor Antagonism
• Management
  • Generally Reversible with Metoclopramide Discontinuation

Galactorrhea (see Galactorrhea)

• Epidemiology
  • May Occur within the First Week of Metoclopramide Therapy or Up to 4 mos After Metoclopramide Initiation
• Physiology
  • Due to Dopamine Receptor Antagonism, Resulting in Hyperprolactinemia (see Hyperprolactinemia)
    • While Galactorrhea is Typically Associated with Prolactin Levels of 25-100 mcg/L, Metoclopramide Use May Lead to Prolactin Levels >200 mcg/L
• Management
  • Generally Reversible with Metoclopramide Discontinuation

Gynecomastia (see Gynecomastia)

• Epidemiology
  • May Occur within the First Week of Metoclopramide Therapy or Up to 4 mos After Metoclopramide Initiation
• Physiology
  • Due to Dopamine Receptor Antagonism
• Management
  • Generally Reversible with Metoclopramide Discontinuation

Gastrointestinal Adverse Effects

Diarrhea (se Diarrhea)

• Epidemiology
  • May Occur in Some Cases

Hematologic Adverse Effects

Leukopenia/Neutropenia (see Leukopenia and Neutropenia)

• Epidemiology
  • Cases Have Been Reported

Methemoglobinemia (see Methemoglobinemia)

• Epidemiology
  • Cases Have Been Reported

Sulfhemoglobinemia (see Sulfhemoglobinemia)

• Epidemiology
  • Cases Have Been Reported (Am J Gastroenterol, 1995) [MEDLINE]

Neurologic Adverse Effects

Delirium/Confusion (see Delirium)

• Risk Factors
  • Age >65 y/o (Eur J Clin Pharmacol, 2018) [MEDLINE]
  • Concurrent Use of Central Nervous System Depressants
  • Chronic Kidney Disease (CKD) (see Chronic Kidney Disease)
• Physiology
  • Due to Dopamine Receptor Antagonism
• Clinical
  • Dose-Related
  • Onset is Typically within the First 5 Days of Use (Median: 1 Day) (Eur J Clin Pharmacol, 2018) [MEDLINE]

Depression (see Depression)

• Epidemiology
  • Cases Have Been Reported (Int Marit Health, 2014) [MEDLINE]

Drowsiness/Lethargy/Obtundation (see Coma-Obtundation)

• Epidemiology
  • Drowsiness Occurs in 10-70% of Patients (and is Dose-Related)
• Risk Factors
  • Age >65 y/o (Eur J Clin Pharmacol, 2018) [MEDLINE]
  • Concurrent Use of Central Nervous System Depressants
  • Chronic Kidney Disease (CKD) (see Chronic Kidney Disease)
• Physiology
  • Due to Dopamine Receptor Antagonism
• Clinical
  • Dose-Related
  • Onset is Typically within the First 5 Days of Use (Median: 1 Day) (Eur J Clin Pharmacol, 2018) [MEDLINE]

Extrapyramidal Symptoms (see Extrapyramidal Symptoms)

• Epidemiology
  • Extrapyramidal Symptoms are Associated with Duration of Treatment and the Total Cumulative Metoclopramide Dose
  • Risk Factors
    • Age ≥60 y/o (and Pediatric Use)
    • Chronic Kidney Disease (CKD) (see Chronic Kidney Disease)
    • Concurrent Use of Strong CYP2D6 Inhibitors (Such as Bupropion, Fluoxetine, and Paroxetine)
    • CYP2D6 Poor Metabolizers
    • Concurrent Use of Other Medications Which Cause Extrapyramidal Side Effects (Such as Antipsychotics)
    • Diabetes Mellitus (see Diabetes Mellitus)
    • Female Sex
    • Higher than Recommended Dose
    • Longer Durations of Therapy (>12 wks)
• Physiology
  • Due to Dopamine D1 and D2 Receptor Antagonism
• Clinical
  • Akathisia (see Akathisia)
    • Epidemiology
      • Akathisia Occurs in 10% of Patients (and is Dose-Related)
      • Generally Occurs within the First Few Hours (Up to 48 hrs) After the Initiation of Metoclopramide
      • Risk Factors: rapid intravenous administration (i.e. bolus over 2 min)
    • Clinical Features
      • Motor Restlessness (Anxiety, Agitation, Insomnia, Inability to Sit Still, Pacing, Foot Tapping)
    • Management
      • Akathisia is Typically Reversible with Metoclopramide Discontinuation or Dose Reduction
  • Dystonia (see Dystonia)
    • Epidemiology
      • Dystonia Occurs in ≤25% of Patients (and is Dose-Related)
      • Generally Occurs within the First 24-48 hrs After the Initiation of Metoclopramide
      • Risk Factors: age <30 y/o
    • Clinical Features
      • Continuous Spasms/Muscle Contractions (Resembling Tetanus), Trismus, Involuntary Limb Movement, Facial Grimacing, Torticollis, Oculogyric Crisis, Rhythmic Tongue Protrusion, Bulbar Type of Speech, Stridor (Rare), Dyspnea (Rare)
    • Management
      • Acute Dystonic Reactions are Typically Reversible with Metoclopramide Discontinuation and May Require Intervention
  • Tardive Dyskinesia (see Tardive Dyskinesia)
    • Epidemiology
      • FDA Has Issued a Black Box Warning Regarding Long-Term/High-Dose Metoclopramide Use [MEDLINE]
      • Risk of Developing Tardive Dyskinesia Increases with the Duration of Treatment and the Total Cumulative Metoclopramide Dose
      • Delayed Onset (Typically Occurs After the First 12 wks of Metoclopramide Therapy)
    • Clinical
      • Irregular, Jerky Movements
    • Prevention
      • Avoid Use of Metoclopramide for >12 wks
    • Management
      • Discontinue Metoclopramide
      • In Some Patients, Tardive Dyskinesia Symptoms May Lessen or Resolve After Metoclopramide Discontinuation (Aliment Pharmacol Ther, 2010) [MEDLINE]
  • Parkinsonism (see Parkinson’s Disease)
    • Epidemiology
      • Delayed Onset (Typically Occurs within the First 6 mos of Metoclopramide Therapy, But May Occur Later in Some Cases)
      • Risk Factors: history of Parkinson disease or concurrent use of dopamine agonists and drugs which increase dopamine
    • Clinical Features
      • Cogwheel Rigidity, Bradykinesia, Tremor, Mask-Like Facies
    • Management
      • Parkinsonism Typically Resolve within 2-3 mos After Metoclopramide Discontinuation

Fatigue (see Fatigue)

• Epidemiology
  • Fatigue Occurs in 10% of Patients (and is Dose-Related)

Neuroleptic Malignant Syndrome (NMS)

• Epidemiology
  • Well-Known Association (Am J Ther, 2016) [MEDLINE]
• Physiology
  • Predominant Mechanism is Believed to Be Dopamine Receptor Blockade
• Clinical
  • Altered Mental Status
    • Delirium (see Delirium)
  • Hyperpyrexia (see Fever)
  • Muscle Rigidity
  • Rhabdomyolysis (see Rhabdomyolysis)
• Therapy
  • Discontinue Metoclopramide
  • Dantrolene (see Dantrolene)

Otolaryngologic Adverse Effects

Laryngeal Edema/Laryngospasm (see Laryngospasm)

• Epidemiology
  • Frequency of Laryngeal Edema Has Not Been Well-Defined
  • Laryngospasm is Rare
• Clinical
  • Stridor (see Stridor)

Pulmonary Adverse Effects

Bronchospasm (see Bronchospasm)

• Epidemiology
  • Frequency Has Not Been Well-Defined
• Clinical
  • Wheezing (see Wheezing)

Renal Adverse Effects

Chromaturia (Urine Discoloration) (see Chromaturia)

• Clinical
  • Green Urine