During the last months, we found an unusually high number of patients with movement disorders after clebopride, a dopamine antagonist with a selective affinity for dopamine D2 receptors used to treat functional gastrointestinal disorders. 1 Here, we describe five new cases (Video 1 and Table S1). We further conducted a literature search for reports indexed in PubMed/Medline using the keyword “clebopride.” Studies were only included if they were relevant or had the full text. Only studies with minimal individual clinical information (patient age, duration of clebopride intake, adverse effects, treatment) were included. Title and abstract screening and review of eligible articles were performed. From the initial 153 articles, a total of 17 articles, including 22 individual reports, were retrieved. Extracted data is presented in Table S1. We used descriptive statistics to summarize data.
Video 1.
Patients with movement disorders after clebopride. Individual data regarding each case is depicted below and in Table S1. Case 1: A 70‐year‐old female developed oromandibular dyskinesia and akathisia after taking clebopride for 12 months. Case 2: A 64‐year‐old female developed oromandibular dyskinesia after taking clebopride for 2 years. Case 3: A 73‐year‐old female developed akinetic parkinsonism after 2 years of clebopride intake. Case 4: A 71‐year‐old female developed a tremor‐dominant parkinsonism, which was unmasked by clebopride after 2 years. Case 5: A 83‐year‐old female developed oromandibular dyskinesia after taking clebopride for 4 years. She also had a shuffling gait and global bradykinesia.
A total of 27 patients (five from the authors’ cohort and 22 from the review) are described from five countries: Spain (48.1%), Portugal (18.5%), Italy (14.8%), South Korea (14.8%), and Japan (3.7%). Patients were mostly female (70.4%), and the median age was 65 (interquartile range = 36–75). Clebopride was always administered orally, and the mean total daily dose was 1.32 mg (±0.49). Adverse events varied between 1 hour and 14 years after clebopride first dose. Most events occurred between the first month and the first 2 years of clebopride intake (53.8%). In five patients (19.2%), events occurred acutely on the first day.
The most frequent clinical syndrome was parkinsonism, either tremor‐dominant, akinetic, or with a progressive supranuclear palsy phenotype (48.1%). Other movement disorders included dyskinesia (40.7%, mainly oromandibular), dystonia (25.9%), and akathisia, restless legs, and rabbit syndrome in one patient each. Seven patients (25.9%) received two diagnoses, most frequently parkinsonism and dyskinesia. In three patients, the parkinsonian syndrome was not classified as purely iatrogenic, and it was considered that clebopride unmasked symptoms that subsided after its stop, but reemerged a few months ago.
Clebopride was suspended in all patients. Management of clebopride adverse events included pharmacological treatment in 13 patients (48.1%). Most patients had complete recovery (70.4%), but symptoms relapsed a few months later in two patients. All acute cases had full recovered after pharmacological treatment. Follow‐up was diverse and lasted until 18 months.
To the best of our knowledge, these are the first cases of extrapyramidal side effects after clebopride described in Portugal. In Europe, clebopride is only licensed in three countries (Portugal, Spain, and Italy) by the European Medicines Agency, which may explain the lack of reporting from other countries. 2 Chronic extrapyramidal adverse events seem to be because of a class effect of the central D2‐receptors blockers. In a Spanish populational study, the estimated risk of movement disorders associated with the chronic use of clebopride was 4% (95% confidence interval, 2%–9%). 3 A head‐to‐head trial comparing metoclopramide and clebopride found a higher amount of extrapyramidal adverse events in the last one, attributed to its higher potency. 4 Nevertheless, accurate figures are difficult to ascertain because of a lack of reporting by gastroenterologists or neurologists or minor symptoms that subside rapidly after drug withdrawal.
Our clinical findings are in line with previous cohorts of extrapyramidal side‐effects associated with dopamine blocking agents. 5 Although we were not able to detect any demographic risk factors for the occurrence of the adverse events, we found a tendency for acute adverse events with good outcomes in younger adults. The chronic adverse events of clebopride arose preferentially in older adults after continued intake and had a worse outcome. Although outcomes of parkinsonism and oromandibular dystonia may be different, such distinction was not available when both syndromes were presented in our cohort. One report suggests the possibility of a genetic sensitivity of the basal ganglia common to diverse family members to medication‐associated movement disorders. 6 If available, DatScan may be helpful in distinguishing idiopathic from iatrogenic parkinsonism.
Medication withdrawal should be considered when possible in clebopride‐associated movement disorders, and a good outcome is usually expected.
Author Roles
(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.
D.R.C.: 1A, 1B, 1C, 2A, 2B, 3A
A.G.V.: 1A, 1B, 1C, 2C, 3C
R.A.: 1A, 1B, 1C, 2C, 3C
Disclosures
Ethical Compliance Statement: I have received the consent form from the patients’ and have them on file—it is written in Portuguese because that is patients’ native language. The obtention of a written informed consent in case reports imply that the study does not need Ethics Committee approval. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflicts of Interest: The authors declare that there are no conflicts of interest relevant to this work.
Financial Disclosures for the Previous 12 months: The authors declare that there are no additional disclosures to report.
Supporting information
Table S1. Demographics and clinical characteristics of 5 patients from the authors cohort and 22 patients from a scoping review of the literature.
Relevant disclosures and conflict of interest are listed at the end of this article.
References
- 1. Roberts DJ, Salazar W, Beckett PR, Nahorski SR. Clebopride, a new orthopramide with potent and selective central antidopaminergic properties. Arch Farmacol Toxicol 1978;4(1):102–104. [PubMed] [Google Scholar]
- 2. EMA . List of nationally authorised medicinal products; PSUSA/00000789/2019062020.
- 3. Sempere AP, Duarte J, García F, Cabezas C, Coria F, Clavería LE. An estimate of the risk of movement disorders associated with the chronic use of clebopride. Mov Disord 1996;11(5):582–583. 10.1002/mds.870110518. [DOI] [PubMed] [Google Scholar]
- 4. Cuena Boy R, Maciá Martínez MA. Extrapyramidal toxicity caused by metoclopramide and clebopride: study of voluntary notifications of adverse effects to the Spanish drug surveillance system. Aten Primaria. 1998;21(5):289–295. [PubMed] [Google Scholar]
- 5. Chouksey A, Pandey S. Clinical Spectrum of drug‐induced movement disorders: a study of 97 patients. Tremor Other Hyperkinet Mov (N Y) 2020;10:48. 10.5334/tohm.554. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Hernández J, Arés A, Cantarero S, García Ruiz PJ. Acute familial dystonia caused by antidopaminergic drugs. Neurologia 1999;14(1):45. [PubMed] [Google Scholar]
Associated Data
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Supplementary Materials
Table S1. Demographics and clinical characteristics of 5 patients from the authors cohort and 22 patients from a scoping review of the literature.