Review article: metoclopramide and tardive dyskinesia
Open accessAbstract
Summary: Background Metoclopramide is a dopamine receptor antagonist which has been used for treatment of a variety of gastrointestinal symptoms over the last thirty years. In 2009, the FDA issued a black box warning regarding long‐term or high‐dose use of this medication because of the risk of developing tardive dyskinesia. Aims To review the mechanism of action and pharmacokinetic properties of metoclopramide, the risk of metoclopramide‐induced tardive dyskinesia, potential mechanisms that may alter and to summarize the clinical context for appropriate use of the drug. Methods We conducted a PubMed search using the following key words and combined searches: metoclopramide, neuroleptics, tardive dyskinesia, incidence, prevalence, dopamine, receptors, pharmacokinetic, pharmacology, pharmacogenetics, DRD3 Ser9Gly polymorphism, cytochrome P450, p‐glycoprotein, risk factors, gastroparesis, outcome, natural history. Results Available data show that risk of tardive dyskinesia from metoclopramide use is likely to be <1%, much less than the estimated 1–10% risk previously suggested in national guidelines. Tardive dyskinesia may represent an idiosyncratic response to metoclopramide; pharmacogenetics affect pharmacokinetic and dopamine receptor pharmacodynamics in response to neuroleptic agents that cause similar neurological complications. Conclusion Community prevalence and pharmacogenetic mechanisms involved in metoclopramide‐induced tardive dyskinesia require further study to define the benefit‐risk ratio more clearly.
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Metoclopramide's most serious side effect is extrapyramidal movement disorders, tardive dyskinesia, and akathisia in 30-40% of patients; drowsiness, fatigue, and depression also occur frequently.
“Its most serious side effect is the occurrence of extrapyramidal movement disorders, tardive dyskinesia, and akathisia in a significant number of patients (30-40%). Drowsiness, fatigue, and depression also occur frequently.”
From Gastrointestinal symptoms in postural tachycardia syndrome: a systematic review (2018) · cites this paper as [56]
The FDA has a black box warning against chronic metoclopramide use.
“The Food and Drug Administration has a black box warning against the chronic use of metoclopramide [56].”
From Gastrointestinal symptoms in postural tachycardia syndrome: a systematic review (2018) · cites this paper as [56]
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“Introduction Tardive dyskinesia (TD) is an iatrogenic condition that results from the long-term use of dopaminergic antagonist medications, predominantly antipsychotics and metoclopramide, along with long-term use of dopamine (DA) agonists as treatment for Parkinson’s disease.(1,2) The term “tardive” refers to the del…”
Tardive dyskinesia and withdrawal emergent syndrome in children
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Gastrointestinal symptoms in postural tachycardia syndrome: a systematic review
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“The FDA has a black box warning against the chronic use of metoclopramide [56].”
Vanormelingen, C., Tack, J., & Andrews, C. (2013) · British Medical Bulletin · doi:10.1093/bmb/ldt003 · Cited by 28 · see citing works
Evaluation and management of gastrointestinal manifestations in scleroderma
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Tardive Dyskinesia in Older Persons Taking Antipsychotics
Citrome, L., Isaacson, S., Larson, D., & Kremens, D. E. (2021) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s328301 · Cited by 52 · see citing works
“psychotics (APs) and some agents used to treat nausea and gastrointestinal dysmotility, such as metoclopramide.(1) The Diagnostic and Statistical Manual of Mental Disorders, 5th edition, defines TD as involuntary athetoid or choreiform move-”
BackgroundTreatment of neurolept-induced tardive dyskinesia
Jankelowitz, S. K. (2013) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s30767 · Cited by 52 · see citing works
“Neuroleptic drugs are dopamine receptor blocking agents (DRBAs) and include metoclopramide, a dopamine antagonist used as an antiemetic, but which is also an antipsychotic at high doses and has a risk of TDK of 1%–10%.(2,3) TDK refers to the orobuccolingual movements, as”
Stein, B. N., Everhart, K. K., & Lacy, B. E. (2015) · Journal of Clinical Gastroenterology · doi:10.1097/mcg.0000000000000320 · Cited by 49 · see citing works
Gastroesophageal reflux disease: A clinical overview for primary care physicians
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Should we stop prescribing metoclopramide as a prokinetic drug in critically ill patients?
van der Meer, Y. G., Venhuizen, W. A., Heyland, D. K., & van Zanten, A. R. H. (2014) · Critical Care · doi:10.1186/s13054-014-0502-4 · Cited by 48 · see citing works
“High occurrence is attributed to chronic use (months to years) of approximately 30 ± 10 mg metoclopramide/day [6] and concerns mostly older (60 ± 22 years) women [5].”
BackgroundChronic intestinal pseudo‐obstruction: Progress in management?
Nardo, G. D., Karunaratne, T. B., Frediani, S., & GIORGIO, R. D. (2017) · Neurogastroenterology & Motility · doi:10.1111/nmo.13231 · Cited by 48 · see citing works
Tardive dyskinesia: Epidemiology
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Auvity, S., Caillé, F., Marie, S., Wimberley, C., Bauer, M., Langer, O., Buvat, I., Goutal, S., & Tournier, N. (2018) · Journal of Nuclear Medicine · doi:10.2967/jnumed.118.210104 · Cited by 45 · see citing works
“Frequent CNS effects have been reported, suggesting substantial brain distribution (17,18).”
BackgroundHernández-Mondragón, O. V., Contreras, L. F. G., Blanco‐Velasco, G., Solórzano-Pineda, O. M., Carrillo, D. M. C., & Pérez, E. M. (2022) · Gastrointestinal Endoscopy · doi:10.1016/j.gie.2022.03.025 · Cited by 45 · see citing works
Formulation and evaluation of metoclopramide solid lipid nanoparticles for rectal suppository
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Petri, M., Singh, I., Baker, C., Underkofler, C., & Rasouli, N. (2021) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2020.107733 · Cited by 50 · see citing works
Tardive Dyskinesia: Clinical Presentation and Treatment
van Harten, P. N., & Tenback, D. E. (2011) · International review of neurobiology · doi:10.1016/b978-0-12-381328-2.00008-0 · Cited by 43 · see citing works
Treatments of medical complications of anorexia nervosa and bulimia nervosa
Mehler, P. S., Krantz, M. J., & Sachs, K. V. (2015) · Journal of Eating Disorders · doi:10.1186/s40337-015-0041-7 · Cited by 43 · see citing works
“A meta-analysis suggests that the prevalence of this effect in the general population is in fact less than1%, a number that is significantly lower than the 1-10% risk quoted in national guidelines [31].”
BackgroundPathophysiology, Aetiology and Treatment of Gastroparesis
Sullivan, A., Temperley, L., & Ruban, A. (2020) · Digestive Diseases and Sciences · doi:10.1007/s10620-020-06287-2 · Cited by 43 · see citing works
Gastroparesis: a review of current and emerging treatment options
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Peroral endoscopic pyloromyotomy for gastroparesis: a systematic review and meta-analysis
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“This treatment has limited efficacy and carries a black-box warning for tardive dyskinesia [29, 30].”
BackgroundEffects of CYP2D6 genetic polymorphism on the pharmacokinetics of metoclopramide
Bae, J., Oh, K.-Y., Yoon, S., Shin, H.-B., Jung, E., Cho, C.-K., Lim, C.-W., Kang, P., Choi, C.-I., Jang, C., et al. (2020) · Archives of pharmacal research · doi:10.1007/s12272-020-01293-4 · Cited by 35 · see citing works
Gastroparesis: Concepts, Controversies, and Challenges
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“However, treatment duration was the one risk factor that can be targeted; expert consensus thus emphasizes the importance of patient education about the risk of metoclopramide therapy and the need to limit the cumulative daily dose and duration of its use [120, 133].”
BackgroundLuttikhold, J., de Ruijter, F. M., van Norren, K., Diamant, M., Witkamp, R. F., van Leeuwen, P. A. M., & Vermeulen, M. A. R. (2013) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.12421 · Cited by 39 · see citing works
Zheng, T., & Camilleri, M. (2021) · PubMed Central · Cited by 37 · see citing works
Self-citationTherapeutic Options for Functional Dyspepsia
Vanheel, H., & Tack, J. F. (2014) · Digestive Diseases · doi:10.1159/000358111 · Cited by 37 · see citing works
Gastroparesis and Dumping Syndrome: Current Concepts and Management
Vavricka, S. R., & Greuter, T. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8081127 · Cited by 37 · see citing works
“Use of metoclopramide should, therefore, be restricted to a maximum of 3 months, at the lowest possible dose [75].”
BackgroundMedication overuse and chronic migraine: a critical review according to clinical pharmacology
Ferrari, A., Baraldi, C., & Sternieri, E. (2015) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2015.1043265 · Cited by 38 · see citing works
Movement Disorders From the Use of Metoclopramide and Other Antiemetics in the Treatment of Migraine
Wijemanne, S., Jankovic, J. J., & Evans, R. W. (2015) · Headache The Journal of Head and Face Pain · doi:10.1111/head.12712 · Cited by 36 · see citing works
“Recent data show that the risk of tardive syndrome due to metoclopramide is likely to be <1%, much less than the estimated 1–10% risk previously suggested in national guidelines.(43) The risk of DIMD is related to the duration of treatment and the total cumulative dose.”
BackgroundTherapeutic Applications of Ghrelin Agonists in the Treatment of Gastroparesis
Shin, A., & Wo, J. M. (2015) · Current Gastroenterology Reports · doi:10.1007/s11894-015-0430-8 · Cited by 35 · see citing works
Management of gastroparesis‐associated malnutrition
Bharadwaj, S. S., Meka, K., Tandon, P., Rathur, A., Rivas, J., Vallabh, H., Jevenn, A., Guirguis, J., Sunesara, I., Nischnick, A., et al. (2016) · Journal of Digestive Diseases · doi:10.1111/1751-2980.12344 · Cited by 34 · see citing works
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Advancement in the clinical management of intestinal pseudo-obstruction
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A Guide to the Extrapyramidal Side-Effects of Antipsychotic Drugs
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Gastric Emptying Scans: Poor Adherence to National Guidelines
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Tangible pathologies in functional dyspepsia
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Advances in the Pharmacogenomics of Adverse Drug Reactions
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“Metoclopramide [113]”
Drug‐drug interactions in pharmacologic management of gastroparesis
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“Thus, the available data suggested that the risk of TD is probably less than 1% with the consumption of metoclopramide (Rao & Camilleri, 2010).”
BackgroundAn examination of three prescribing cascades in a cohort of older adults with dementia
Trenaman, S., Bowles, S., Kirkland, S., & Andrew, M. (2021) · BMC Geriatrics · doi:10.1186/s12877-021-02246-2 · Cited by 26 · see citing works
“The 180 day timeframe chosen was consistent with the amount of time required for any of the three inciting medications to cause their associated adverse event; urinary incontinence due to cholinesterase inhibitors typically presents within 26 weeks (182 days) of medication initiation [45, 46], metoclopramide carries a…”
Lin, S. (2014) · Drug Discovery Today · doi:10.1016/j.drudis.2014.10.001 · Cited by 29 · see citing works
Tardive Dyskinesia: Treatment Update
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Movement Disorders and Psychosis, a Complex Marriage
van Harten, P. N., Bakker, P. R., Mentzel, C. L., Tijssen, M. A. J., & Tenback, D. E. (2015) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2014.00190 · Cited by 26 · see citing works
“, long-term use of metoclopramide to treat nausea, or antipsychotics for insomnia (18, 19).”
BackgroundRelamorelin for the treatment of gastrointestinal motility disorders
Chedid, V. G., & Camilleri, M. (2017) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2017.1373088 · Cited by 26 · see citing works
Self-citationGastric per-oral endoscopic myotomy: Current status and future directions
Podboy, A. J., Hwang, J. H., Nguyen, L. A. B., García, P., Zikos, T. A., Kamal, A., Triadafilopoulos, G., & Clarke, J. O. (2019) · World Journal of Gastroenterology · doi:10.3748/wjg.v25.i21.2581 · Cited by 26 · see citing works
Medical Treatment of Gastroesophageal Reflux Disease
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“Metoclopramide may cause CNS side effects including drowsiness, agitation, irritability, depression, dystonic reaction, and rarely (\1% of patients) tardive dyskinesia [52].”
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Zikos, T. A., Nguyen, L. A. B., Kamal, A., Fernandez‐Becker, N., Regalia, K. A., Nandwani, M. C. R., Sonu, I. S., Garcia, M., Okafor, P. N., Neshatian, L., et al. (2020) · Digestive Diseases and Sciences · doi:10.1007/s10620-020-06195-5 · Cited by 23 · see citing works
Gastric per-Oral Endoscopic Myotomy for Refractory Gastroparesis: A Meta-Analysis
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“Currently, the first-line therapies for treating gastroparesis are lifestyle modification, diet modification, and antiemetic and/or pro-kinetic medications; however, only metoclopramide is approved by the US Food and Drug Administration, and its long-term efficacy was limited with a black-box warning for tardive dyski…”
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“Metoclopramide, the only US Food and Drug Administration (FDA)-approved medication for gastroparesis treatment in the United States, currently carries a black-box warning of tardive dyskinesia, and prolonged use is associated with tachyphylaxis.(22) Gastric electrical stimulation is currently FDA-approved on protocol…”
BackgroundIdentification and management of tardive dyskinesia: A case series and literature review
Khouzam, H. R. (2015) · Postgraduate Medicine · doi:10.1080/00325481.2015.1074031 · Cited by 23 · see citing works
“The various TD risk factors are summarized in Table 2 [18-23].”
BackgroundBapaye, A., Korrapati, S. K., Dharamsi, S., & Dubale, N. A. (2019) · Journal of Clinical Gastroenterology · doi:10.1097/mcg.0000000000001296 · Cited by 23 · see citing works
Latest developments in chronic intestinal pseudo-obstruction
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“Lower doses (25–50 mg) are associated with a very low incidence (<1%) of dyskinetic or extrapyramidal symptoms [31].”
BackgroundThe investigational drug camicinal for the treatment of gastroparesis
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“It is not indicated for longer than a 12-week period [9], as it may have extrapyramidal side effects such as akathisia through its central D2 antagonism [10].”
Background
- Authors
- RAO, A. S., & CAMILLERI, M.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- CAMILLERI, M.
- ORCID
- CAMILLERI, M.
- Venue
- Alimentary Pharmacology & Therapeutics
- Publisher
- Wiley
- Published
- 2009-12-02
- Volume
- 31
- Issue
- 1
- Pages
- 11-19
- ISSN
- 0269-2813 (ISSN-L)
- 1365-2036
- OpenAlex
- W2049233278
- Cited by
- 316
- References
- 38
- Citations by year
- 2026: 15 · 2025: 8 · 2024: 11 · 2023: 16 · 2022: 33 · 2021: 21 · 2020: 24 · 2019: 28 · 2018: 24 · 2017: 21 · 2016: 22 · 2015: 25 · 2014: 18 · 2013: 21 · 2012: 12
- FWCI
- 1.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Alimentary Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Surgery › Nausea and vomiting management
- Keywords
- metoclopramide, tardive dyskinesia, dopamine antagonists, pharmacokinetics, pharmacogenetics, cytochrome P450, P-glycoprotein, gastroparesis, black box warning, risk factors, risk-benefit assessment
- MeSH terms
- Dyskinesia, Drug-Induced, Humans, Metoclopramide, Risk Factors, Prevalence, Odds Ratio, Dopamine Antagonists
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