Acute Orthostatic Hypotension When Starting Dopamine Agonist Therapy in Parkinson Disease: The Role of Domperidone Therapy

I read with interest the article by Kujawa et al¹ regarding acute orthostatic hypotension on the initiation of dopamine agonist therapy in Parkinson disease. In this study, approximately 30% of patients met the criteria for orthostatic hypotension, and 30% of these were symptomatic from this complication. As the authors indicate, orthostatic hypotension is widely recognized, particularly on the initiation of dopamine agonist therapy. Indeed, a small proportion of patients experience quite significant difficulties with this adverse effect, and it is a common experience in movement disorders clinics to see patients who have previously discontinued treatment with several dopamine agonists very early because of symptomatic orthostatic hypotension.

One extremely effective treatment that the authors did not mention is the peripheral dopamine D₂ receptor antagonist domperidone. Although this is not marketed in the United States, it is widely available elsewhere (and many patients in the United States obtain it from Canada). In addition to controlling gastrointestinal adverse effects, domperidone is particularly effective in treating problematic early-onset orthostatic hypotension complicating the initiation of dopamine agonist therapy. The efficacy of this treatment became evident to me during a clinical trial of an experimental dopamine agonist that never reached the market (CQA 206-291). In this study,² single doses of the dopamine agonist were given every second weekday in the hospital first thing in the morning without other anti-parkinsonian drugs, increasing dosages through a schedule of 0.5, 1.0, 2.0, 4.0, 8.0, 15.0, and 20.0 mg. Only after a patient experienced "peripheral" adverse effects such as nausea, vomiting, or hypotension in response to one dose of the study drug could domperidone, 20 mg by mouth, be administered 30 to 60 minutes before subsequent doses. Six patients participated in this trial. Because of peripheral adverse effects, the first patient received the 2-mg dosage of CQA 206-291 a second time preceded by domperidone on the next experimental day, whereas the remaining patients continued to follow the prearranged dosage increment schedule. Supine mean arterial blood pressures fell in all patients, with a further decrease occurring upon standing. Excluding the one patient who was so akinetic that he could not stand even with assistance, all patients experienced a symptomatic orthostatic fall in blood pressure with the 1.0- or 2.0-mg dose. Two patients were unable to stand because of orthostatic hypotension; one had a supine mean arterial blood pressure fall of 70 mm Hg and the second had only a mild drop of 18 mm Hg. In all patients, domperidone administered before the next agonist dose significantly attenuated the effects on both supine and standing blood pressure and completely prevented the subjective sensation of orthostatic faintness. This is particularly impressive given the fact that the dosage escalation schedule remained unchanged in all patients with the exception of the single patient who received two 2.0-mg doses before continuing with the protocol.

The ameliorative effect of domperidone on early dopamine–agonist-induced hypotension can be pronounced. For example, hypotension severe enough to preclude standing occurred in 2 of our patients with 1.0- and 2.0-mg doses. This was completely prevented 2 days later when the patients underwent a challenge with the same or higher doses of the dopamine agonist preceded by domperidone. In routine practice since the completion of this trial, we have confirmed that domperidone is an extremely effective measure for preventing or treating early orthostatic hypotension, especially with less aggressive initiation of dopamine agonists, which is standard for outpatient clinical practice.