Metoclopramide (Reglan)


Indications

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


Pharmacology

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


Administration

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

Nasal Use for Gastroparesis (see Gastroparesis)

Oral (PO) Use for Antiemetic Effect (Undifferentiated or Vertigo-Associated Nausea/Vomiting) (see Nausea/Vomiting)

Oral (PO) Use for Gastroparesis (see Gastroparesis)

Oral (PO) Use for Hiccups (see Hiccups)

Intravenous Use for Acute Migraine-Associated Nausea/Vomiting (see Migraine)

Intravenous (IV) Use for Aspiration Prophylaxis in Patient Undergoing General Anesthesia

Intravenous (IV) Use for Antiemetic Effect (Undifferentiated or Vertigo-Associated Nausea/Vomiting) (see Nausea/Vomiting)

Intravenous (IV) Use for Hiccups (see Hiccups)

Dose Adjustment

Hepatic (Nasal)

Hepatic (Oral for Gastroparesis)

Hepatic (Intravenous)

Renal (Oral or Intravenous)

Use in Pregnancy (see Pregnancy)

Use During Breast Feeding

Drug Interactions


Adverse Effects

Allergic/Immunologic

Angioedema

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

Cardiovascular Adverse Effects

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
  • 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

Pulmonary Adverse Effects

Bronchospasm (see Bronchospasm)

  • Epidemiology
    • Frequency Has Not Been Well-Defined
  • Clinical

Renal Adverse Effects

Chromaturia (Urine Discoloration) (see Chromaturia)

  • Clinical
    • Green Urine


References

Indications

Administration

Adverse Effects