Neurogastroenterology & Motility. 2019;31:e13617. wileyonlinelibrary.com/journal/nmo | 1 of 9 https://doi.org/10.1111/nmo.13617 © 2019 John Wiley & Sons Ltd 1 | INTRODUCTION The treatment of gastroparesis and development of tardive dyskinesia after prolonged treatment and/or with oral doses of metoclopramide exceeding 10 mg 3‐4 times daily is a matter of concern because of associated side effects and medicolegal risks. 1 In February 2009, the Food and Drug Administration (FDA) issued a boxed warning regard‐ ing metoclopramide, restricting its use to a maximum of 3 months, based on published reports and spontaneous reports of tardive dyski‐ nesia in patients who used metoclopramide. The FDA warning directly Received: 26 November 2018 | Revised: 13 April 2019 | Accepted: 17 April 2019 DOI: 10.1111/nmo.13617 CLINICAL REVIEW Gastroparesis, metoclopramide, and tardive dyskinesia: Risk revisited Ahmad Al‐Saffar 1 | Hans Lennernäs 2 | Per M. Hellström 1 1 Department of Medical Sciences, Uppsala University, Uppsala, Sweden 2 Department of Pharmacy, Uppsala University, Uppsala, Sweden Correspondence Per M. Hellström, Department of Medical Sciences, Uppsala University Hospital, bldg. 40, SE‐75185 Uppsala, Sweden. Email: Per.Hellstrom@medsci.uu.se Funding information Uppsala University Abstract Background: Metoclopramide is primarily a dopamine receptor antagonist, with 5HT 3 receptor antagonist and 5HT 4 receptor agonist activity, and used as an an‐ tiemetic and gastroprokinetic since almost 50 years. Regulatory authorities issued restrictions and recommendations regarding long‐term use of the drug at oral doses exceeding 10 mg 3‐4 times daily because of the risk for development of tardive dyskinesia. The aim of our study was to review mechanism(s) of action and phar‐ macokinetic‐pharmacodynamic properties of metoclopramide, as well as the risk of metoclopramide‐induced tardive dyskinesia, factors that may change drug ex‐ posure in humans, and to summarize the clinical context for appropriate use of the drug. Methods: A PubMed, Google Scholar, and Cross Reference search was done using the key words and combined searches: drug‐drug interaction, gastroparesis, meto‐ clopramide, natural history, pharmacokinetics, pharmacodynamics, drug‐drug inter‐ action, outcome, risk factors, tardive dyskinesia. Key results: Data show that the risk of tardive dyskinesia from metoclopramide is low, in the range of 0.1% per 1000 patient years. This is far below a previously es‐ timated 1%‐10% risk suggested in treatment guidelines by regulatory authorities. High‐risk groups are elderly females, diabetics, patients with liver or kidney failure, and patients with concomitant antipsychotic drug therapy, which reduces the thresh‐ old for neurological complications. Conclusions & Inferences: The risk of tardive dyskinesia due to metoclopramide is far below approximated numbers in treatment guidelines. This risk and the influence of known risk factors should be considered when starting a course of metoclopramide for treatment of gastroparesis. KEYWORDS adverse effect, diabetes, dopamine, gastroprokinetic, serotonin