Richard Carlton MD asked me to post abstracts related to the well-established but under-appreciated dopamine-blocking effect of metoclopramide.
Ned Tijdschr Geneeskd. 2013;157(26):A6037.
Severe parkinsonism due to Reglan (metoclopramide): the importance of early recognition.
[Article in Dutch]
de Ronde MW1, Kingma HJ, Munts AG.
1Kennemer Gasthuis, afd. Neurologie, Haarlem, the Netherlands. firstname.lastname@example.org
In this article, we present 3 women aged 73, 85 and 88 years who developed metoclopramide-induced parkinsonism. Shortly after starting metoclopramide, bradykinesia and rigidity developed in all 3 patients; tremor and postural instability in 2 of them. We discontinued the metoclopramide after 3-6 months; 2 of the patients had fully recovered 4-6 months later. The 3rd patient died from pneumonia, however, 2 months after discontinuation. Metoclopramide, a dopamine D2-antagonist, is a frequently prescribed anti-emetic drug; however, evidence of its efficacy is limited. In many patients, domperidone, another dopamine D2-antagonist, seems to be a better alternative. Movement disorders due to domperidone are uncommon, presumably because it does not cross the blood-brain barrier. It is likely that metoclopramide-induced parkinsonism is not uncommon; however, it is under-recognized. Risk factors are female sex, advanced age, diabetes mellitus and polypharmacy. Follow-up on patients using metoclopramide is advised.
Zhonghua Nei Ke Za Zhi. 1988 Jun;27(6):358-60, 390.
Adverse neurologic effects of Reglan (metoclopramide). Report of 60 cases.
[Article in Chinese]
Sun B, Cao QL, Ou XR.
Am J Gastroenterol. 2013 Jun;108(6):866-72. doi: 10.1038/ajg.2012.300.
The metoclopramide black box warning for tardive dyskinesia: effect on clinical practice, adverse event reporting, and prescription drug lawsuits.
Ehrenpreis ED1, Deepak P, Sifuentes H, Devi R, Du H, Leikin JB.
1Department of Gastroenterology, Evanston Hospital, NorthShore University HealthSystem, Evanston, Illinois 60201, USA. email@example.com
OBJECTIVES: We examined the effects of the black box warning about the risk of tardive dyskinesia (TD) with chronic use of metoclopramide on management of gastroparesis within a single clinical practice, and on reporting of adverse events.
METHODS: Medical records of gastroparesis patients were evaluated for physician management choices. The FDA Adverse Event Reporting System (FAERS) was analyzed for event reports, and for lawyer-initiated reports, with metoclopramide from 2004 to 2010. Google Scholar was searched for court opinions against metoclopramide manufacturers.
RESULTS: Before the black box warning, 69.8% of patients received metoclopramide for gastroparesis, compared with 23.7% after the warning. Gastroenterologists prescribed domperidone more often after than before the warning. Metoclopramide prescriptions decreased after 2008. Adverse event reporting increased after the warning. Only 3.6% of all FAERS reports but 70% of TD reports were filed by lawyers, suggesting a distortion in signal. Forty-seven legal opinions were identified, 33 from 2009-2010.
CONCLUSIONS: The black box warning for metoclopramide has decreased its usage and increased its rate of adverse event reporting. Lawyer-initiated reports of TD hinder pharmacovigilance.
Ned Tijdschr Geneeskd. 2002 Jan 26;146(4):175-7.
Severe parkinsonism due to Reglan (metoclopramide) in a patient with polypharmacy.
[Article in Dutch]
Hoogendam A1, Hofmeijer J, Frijns CJ, Heeringa M, Schouten-Tjin a Tsoi SL, Jansen PA.
1Afd. Klinische Geriatrie, Universitair Medisch Centrum, Utrecht. firstname.lastname@example.org
A 73-year-old woman, with tuberculosis of the large intestine, developed nausea as a side effect of the antituberculosis drugs. The nausea was treated with metoclopramide. Subsequently she developed severe medication-induced parkinsonism. As her symptoms initially mimicked a depressive disorder, drug-induced parkinsonism was only considered at a later stage. Due to drug-induced impaired function of the liver and kidney the patient had received a toxic dose of metoclopramide. Treatment with biperiden and withdrawal of the metoclopramide resulted in a reduction of the complaints within 3 months, after which the anti-tuberculosis medication could be reintroduced. Adjusting the dose of metoclopramide could possibly have prevented this severe side effect.
Psychiatry Clin Neurosci. 2007 Apr;61(2):193-5.
Persistent generalized anxiety after brief exposure to the dopamine antagonist Reglan (metoclopramide).
Kluge M1, Schüssler P, Steiger A.
1Max Planck Institute of Psychiatry, Munich, Germany. email@example.com
The authors describe a 31-year-old woman who developed persistent generalized anxiety after brief exposure to the dopamine antagonist metoclopramide. Independently of that, she had experienced a panic attack followed by dystonias, shortly after a single dose of that drug, 17 years before. Both temporal association and recurrence of anxiety symptoms after re-challenge with metoclopramide suggest a causal relationship. The case might provide an initial piece of evidence that dopaminergic neurotransmission can be involved in the pathogenesis of generalized anxiety disorder.
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Ceylon Med J. 1996 Sep;41(3):125.
Parkinsonism: an under-recognised complication of Reglan (metoclopramide) use.
[No authors listed
Acta Neurol (Napoli). 1992 Apr;14(2):130-3.
Reglan (Metoclopramide)-induced parkinsonism and depression.
Jibiki I1, Maeda T, Yamaguchi N.
1Department of Neuropsychiatry, Kanazawa University School of Medicine, Japan.
A 46-year-old female patient with metoclopramide-induced parkinsonism and depression was reported in view of the rarity of the concurrent development of these side effects. A risk of metoclopramide administration is suggested
South Med J. 1989 Dec;82(12):1581-2.
Reglan (Metoclopramide)-induced parkinsonism.
Sethi KD1, Patel B, Meador KJ.
1Department of Neurology, Medical College of Georgia, Augusta 30912-2366.
Metoclopramide hydrochloride (Reglan) is a widely prescribed drug for treatment of upper gastrointestinal symptoms. Although the drug is relatively safe, a growing body of literature has noted movement disorders after its administration. We have reported six cases of metoclopramide-induced parkinsonism seen in consultation over a two-year period. Five of these six patients had renal failure. Their parkinsonism improved on discontinuation of metoclopramide therapy. Metoclopramide-induced parkinsonism is not rare, and appropriate dose reduction in patients with renal failure will help reduce the incidence of this morbidity.
J Emerg Med. 2006 May;30(4):411-3.
Abdominal pain with rigidity secondary to the anti-emetic drug Reglan (metoclopramide).
Khan NU1, Razzak JA.
1Section of Emergency Medicine, Department of Medicine, The Aga Khan University, Karachi, Pakistan.
We report a case of abdominal pain with rigidity, mimicking an acute abdomen, caused by metoclopramide, a common anti-emetic drug. Extrapyramidal symptoms are commonly reported side-effects of this medication. They generally include involuntary movements of limbs, torticollis, oculogyric crisis, rhythmic protrusion of tongue, trismus, or dystonic reactions resembling tetanus, etc. Abdominal rigidity due to this medication, resembling an acute abdomen, has not been reported previously. This case report illustrates the importance of considering medication side-effects when evaluating a patient with abdominal pain and rigidity.
Synapse. 2011 Feb;65(2):119-24. doi: 10.1002/syn.20825.
Antipsychotic drug binding in the substantia nigra: an examination of high Reglan (metoclopramide) binding in the brains of normal, Alzheimer’s disease, Huntington’s disease, and Multiple Sclerosis patients, and its relation to tardive dyskinesia.
Chen S1, Seeman P, Liu F.
1Department of Neuroscience, Centre for Addiction and Mental Health, Clarke Division, Toronto, Ontario, Canada M5T 1R8.
This project was done in order to determine why the annual incidence of metoclopramide-associated tardive dyskinesia is much higher than that for the commonly used antipsychotics. To test the hypothesis that metoclopramide tardive dyskinesia may be associated with high concentrations of metoclopramide in the substantia nigra under clinical conditions, the nonspecific binding of tritiated antipsychotics to the dissected melaninized regions of postmortem human substantia nigra was measured. The nonspecific binding at 1 nM [³H]ligand was 7.3, 4.2, 2.6, 0.91 and 0.66 fmoles/mg for [³H]haloperidol, [³H]clozapine, [³H]raclopride, [³H]metoclopramide, and [³H]olanzapine, respectively. After adjusting these values for the known free concentrations of these drugs in plasma or spinal fluid, the amounts that would be bound under clinical conditions would be 231, 113, 15, 11, and 3.4 fmoles/mg for metoclopramide, clozapine, raclopride, haloperidol, and olanzapine, respectively. Using rat striatum as baseline to define antipsychotic binding to nonnigral tissue, the excess amount of binding to the Alzheimer nigral tissue under clinical conditions would be 209, 19, 0, 3.4 and 0.8 fmole/mg for metoclopramide, clozapine, raclopride, haloperidol, and olanzapine, respectively, with a similar pattern for nigral tissues from Huntington and Multiple Sclerosis patients. The high accumulation of metoclopramide is sufficiently high to cause nigral nerve cell membrane damage by metoclopramide’s detergent-like action, possibly explaining metoclopramide’s toxic ability to elicit early tardive dyskinesia. In addition, the nonspecific binding of metoclopramide was much higher in Alzheimer-diseased substantia nigra, consistent with the fact that older individuals are relatively more vulnerable to metoclopramide tardive dyskinesia.