Metoclopramide works by blocking central and peripheral dopamine D2 receptors in the medullary chemoreceptor trigger zone, specifically in the area postrema, which is typically activated by levodopa or apomorphine. This action reduces the sensitivity of visceral afferent nerves that relay signals from the gastrointestinal system to the vomiting center in the area postrema [1]. Besides its effects on dopamine receptors, metoclopramide also acts as an antagonist at 5HT3 (serotonin type 3) receptors and an agonist at 5HT4 receptors [2,3]. Additionally, it counteracts the antiperistaltic effects of apomorphine, which helps to mitigate its inhibition of gastric emptying. This leads to faster gastric emptying by increasing the amplitude and duration of esophageal contractions. Metoclopramide, therefore, increases the resting tone of the lower esophageal sphincter while relaxing the pyloric sphincter and duodenal bulb, thereby encouraging peristalsis in the duodenum and jejunum [4,5].

The Food and Drug Administration (FDA) has approved metoclopramide to treat diabetic gastroparesis by enhancing stomach motility, as well as to treat nausea and vomiting in patients with gastroesophageal reflux disease (GERD) who do not respond to standard therapy [6,7]. Further, when treating chemotherapy patients with nausea and vomiting, the FDA has approved the use of metoclopramide injections [8,9]. When nasogastric suction is not needed or advisable, off-label use of metoclopramide helps to stop vomiting and nausea after surgery. It is especially effective for this purpose because it does not increase gastric secretions [10]. Metoclopramide is also used off-label in the emergency room to treat acute migraines, acting as an effective adjuvant to reduce nausea, vomiting, and headache intensity. Although the FDA has not specifically approved it for acute migraine treatment, it is considered a valuable alternative to opioids, which carry a risk of use disorder [11,12].

Adverse events (AEs) are common in medical settings, affecting at least one in ten patients. An AE refers to a harmful outcome that occurs as a result of medical care, which could include procedures, surgeries, or medications. Any patient undergoing treatment might experience an adverse effect, which could range from medication side effects to physical injury, psychological harm, or even death [13]. A crucial component of the FDA’s systems is its post-marketing surveillance and risk assessment programs, which are designed to identify adverse events that may not have been evident during the drug approval process. It is impossible to anticipate every possible adverse effect because pre-approval studies usually only include a few hundred to a few thousand patients [14,15]. The FDA's post-marketing safety surveillance is supported by the FDA Adverse Event Reporting System (FAERS) Database. As mandated by law, it collects adverse event reports from consumers, healthcare providers, and manufacturers [16].

Metoclopramide is used extensively, but comprehensive research on its side effects, particularly extrapyramidal symptoms, is limited. Enhancing patient safety, directing clinical judgment, and influencing regulatory oversight all depend on an understanding of these adverse events. After a product is approved and put into use, the FDA Adverse Event Reporting System (FAERS) offers real-time data on drug safety as a type of post-marketing surveillance. This study reviews metoclopramide's side effects using FAERS, providing information about its safety profile beyond controlled clinical trials.

The researchers analyzed reports submitted to the FDA Adverse Event Reporting System (FAERS) for this retrospective study. As a key step in the FDA’s monitoring of drugs, FAERS combines vast data from healthcare professionals, patients, and manufacturers. The researchers examined these reports to identify risks and safety concerns related to metoclopramide observed in real-world clinical practice.

The study included data for all adverse event reports associated with metoclopramide from the FDA Adverse Event Reporting System (FAERS) database that were submitted before January 01, 2025. The main sources of data were the FDA Adverse Event Reporting System (FAERS) public dashboard and quarterly data files. Reports where metoclopramide was the primary suspect drug were included to extract relevant cases. The search used the generic name “metoclopramide”, and did not limit by formulation. Adverse events were coded as Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms (PTs).

The study considered various potential adverse events associated with metoclopramide. Particular attention was given to extrapyramidal and other neurological events. The selected reports for the present study contained the necessary information (drug name, suspected ADR, and demographic details of the patient). The analysis included all metoclopramide-related reports submitted by healthcare providers or other stakeholders before January 1, 2025. Any case that was submitted after this date was omitted from the analysis.

Numerous factors linked to adverse events related to metoclopramide were investigated in the current study. The analysis examined the number of adverse event reports received and assessed their distribution over the years. In addition, details about the ages and genders of the patients, as well as the professional backgrounds of those filing the reports, were considered during the study. To highlight safety concerns and provide essential information to healthcare professionals, the research also assessed the most common related adverse events associated with metoclopramide.

The data was examined using descriptive statistics, and the information was presented as percentages and numbers. The formula used to find the percentage for each group or category was (Part / Whole) × 100. This formula uses “Part” to show the reported numbers in a category and “Whole” to show the total number of reports. This approach offers a precise, numerical representation of the data distribution.

Before January 01, 2025, 22,381 reports were filed with FAERS. The distribution of these reports by year is shown in Table 1. The highest number of reports was submitted in 2011, accounting for 37.45% of the total, followed by 2012 with 22.70%. Roughly 15% of the reports were filed within the previous five years.

Table 2 presents the age distribution of patients who experienced adverse events. The majority of patients were between the ages of 18 and 64, while 25.17% of the patients were aged between 65 and 85 years.

Table 3 presents the gender distribution of patients who experienced adverse events. The majority of patients were female, making up 67.90%, while males accounted for 32.10%.

Table 4 presents the specialties of the individuals who submitted the reports. Only 29.21% of the reports were submitted by healthcare professionals, whereas the remaining 70.79% were reported by consumers.

Table 5 displays the most frequently reported adverse events associated with metoclopramide. The most commonly reported events were tardive dyskinesia (59.74%), extrapyramidal disorder (52.83%), nervous system disorder (32.31%), and dystonia (30.35%).

The purpose of this study was to examine and characterize the side effects of metoclopramide. Most adverse event reports involving metoclopramide were filed between 2011 and 2012. The medication being prescribed less frequently or for shorter periods may have decreased the likelihood of adverse events, which could account for the recent decline in reports. To manage symptoms, Alkhowaiter et al. recommended the use of the lowest effective dose of metoclopramide for the shortest possible duration [17]. Furthermore, patients and healthcare professionals may now be more aware of the drug's possible adverse effects, which has improved management and decreased reporting. The present study showed that the majority of patients who reported metoclopramide side effects were either adults or the elderly. Adults, particularly those with chronic conditions or undergoing treatments that cause nausea (such as chemotherapy or post-surgery recovery), are more likely to use metoclopramide, which could explain the higher number of adverse event reports in this group. Lau Moon et al. stated that drug regulatory organizations in Canada and the European Union have changed the metoclopramide label, contraindicating its use in children under one year of age, cautioning against its use in children under five years, and advising against taking it for more than five days [18].

The present study found that the most commonly reported adverse events associated with metoclopramide were extrapyramidal symptoms, such as acute dystonia, parkinsonism, akathisia, and tardive dyskinesia, in addition to nervous system disorders. Previous studies have highlighted that, despite its effectiveness, metoclopramide may be linked to serious side effects, including extrapyramidal symptoms, hyperprolactinemia, and, in rare cases, neuroleptic malignant syndrome. Other common adverse events include headache, drowsiness, dizziness, diarrhea, and cardiac issues such as tachycardia, palpitations, and QT prolongation [19,20,21]. Lau Moon et al. reported that in children, the most frequently observed adverse effects are diarrhea and sedation [18]. Isola et al. and Donnet et al. found that extrapyramidal symptoms, such as torticollis, trismus, opisthotonus, akathisia, dystonia, oculogyric crisis, laryngospasm, hyperprolactinemia, tardive dyskinesia, parkinsonism, and neuroleptic malignant syndrome, are common adverse effects of metoclopramide use [22,23]. Gupta et al. noted that a rare but severe adverse event is neuroleptic malignant syndrome, which can present with hyperthermia, lead-pipe rigidity, leukocytosis, elevated creatine phosphokinase levels, altered consciousness, autonomic instability (e.g., diaphoresis, tachycardia, incontinence), pallor, irregular blood pressure or pulse, and cardiac arrhythmias [24]. Metoclopramide can also cause oculogyric crises and metoclopramide-induced hyperprolactinemia [25]. Additionally, metoclopramide may increase serum aldosterone levels, leading to fluid retention and potential volume overload, so it should be used cautiously in patients with heart failure or cirrhosis of the liver [26]. It has also been shown to cause a non-thrombocytopenic purpuric rash, which resolves after discontinuation of the drug [27].

Metoclopramide is extensively used and effective for treating nausea and vomiting. However, it is connected with various adverse consequences. According to Sridharan and Sivaramakrishnan, metoclopramide is especially effective in treating diabetic gastroparesis and postoperative nausea and vomiting. However, concerns regarding the danger of dyskinesias have spurred a rethinking of its application. Experts recommend that metoclopramide be started at the lowest possible dose and for the shortest term practicable. While it is beneficial in the short term, its central nervous system (CNS) side effects are a source of concern [28]. Isola et al. underlined that metoclopramide is routinely used in hospitals to treat gastroparesis, as well as postoperative nausea and vomiting, but healthcare practitioners should be aware of its possible risks. Thus, an interprofessional team approach is required. Before delivering the medicine, the nurse, pharmacist, and prescriber should obtain the patient's informed consent. Patients should be made aware of their risk of developing dyskinesias before starting treatment. The pharmacist should suggest a different course of treatment for the doctor to consider if the patient is more likely to experience adverse events [22].

This descriptive analysis of adverse events connected with metoclopramide, which uses the FAERS database, demonstrates the significant risk of side effects associated with its use. The most commonly reported adverse effects were tardive dyskinesia, extrapyramidal diseases, nervous system disorders, and dystonia. These side effects highlight the significance of careful monitoring and dosing while administering metoclopramide, especially in high-risk patients. While metoclopramide remains an effective treatment for nausea and vomiting, healthcare practitioners must exercise caution while managing its potential side effects.