It is common experience that nausea can be a limiting side effect of dopaminergic replacement therapy (DRT) in Parkinson's disease (PD), particularly with dopamine agonists (DAs). Domperidone is a peripheral dopaminergic antagonist, chemically derived from butyrophenones, that has a poor penetration into the brain, therefore not inducing central adverse effects resulting from blocking of central dopaminergic receptors. Hence, it is routinely used in PD even in the preventive treatment of nausea and vomiting associated with DRT.
In April 2014, the European Medicines Agency recommended to restrict the use of domperidone after evaluating the available evidence on its benefits and possible cardiac risks. The injectable form of domperidone had been, in fact, already withdrawn back in 1985 because of such side effects (e.g., prolongation of the QT interval, arrhythmias, and sudden cardiac arrest). A number of reports have further shown that there is a risk for cardiac side effects also with the oral formulation of this drug. For instance, a case-control study has shown that the odds ratio of sudden cardiac arrest subsequent to domperidone use was 4.7 after adjusting for a number of potential confounders, including age, gender, cardiac arrhythmias or other cardiac diseases, diabetes mellitus, pulmonary disease, total number of current drugs, and concomitant use of antiarrhythmic drugs. Another study has estimated the risk for cardiac arrest or ventricular arrhythmia to be over 11-fold with the use of more than 30 mg of domperidone. Hence, the recommendation has been endorsed that domperidone should not be used at higher dosage than 30 mg in adults and for no longer than 1 week in the European Union, whereas it is not currently a legally marketed drug in the United States. Extra care should be taken for those patients who are on concomitant medications able to prolong the QT interval or that inhibit the cytochrome, CYP3A4, including, but not limited to, some drugs commonly used in clinical practice, such as omeprazole and ranitidine, or other medications also frequently used in the parkinsonian population, such as sertraline and high-dose entacapone. Obviously, domperidone should also be avoided in patients with concomitant cardiac diseases, and, in this regard, it is important to remember that serious cardiac side effects have also been associated with the use of nonergot DAs.[4, 5]
No studies have thus far entirely clarified which mechanisms underpin these side effects, and further research is needed to understand whether they are related to a particular subtype of the cardiac dopaminergic receptors. This will hopefully allow the development of new (selective) peripheral dopaminergic blockers without such cardiac risks. As for now, the use of domperidone in the parkinsonian population should be carefully evaluated in single cases, considering that the harm could well overwhelm the benefits.