Dopamine Agonists for Parkinson’s Monotherapy

Abstract & Commentary

Source: Clarke CE, Guttman M. Dopamine agonist monotherapy in Parkinson’s disease. Lancet. 2002;360: 1767-1769.

The availability of new dopamine agonists, pergolide (Permax), ropinirole (Requip), and pramipexole (Mirapex) in the United States, and cabergoline in Europe has radically changed the treatment of patients with early Parkinson’s disease (PD). Ropinirole and Mirapex, the two nonergot dopamine agonists, were introduced to the US market in late 1997. Most neurologists are familiar with these drugs and use them in their routine practice. In this thoughtful, well-balanced review, Clarke and Guttman review the evidence for using these drugs to treat patients with early PD.

Ropinirole, pramipexole, pergolide, and cabergoline have been studied in early PD patients in large, multi-center, double-blind trials. In the pramipexole trial, 301 patients were randomized to receive pramipexole or levodopa, with adjuvant open-label rescue with levodopa if needed. Fifty-two percent of the pramipexole group developed motor complications after 4 years compared to 74% of the levodopa group, chiefly dyskinesias. However, those patients who received levodopa enjoyed greater improvements in motor performance, with fewer adverse events. In the ropinirole trial, 268 patients were treated over 5 years with either ropinirole or levodopa. Dyskinesias were less common in the ropinirole group, but again at the expense of less-robust motor improvement and increased side effects. Similar trials have been performed with pergolide and cabergoline.

Two imaging studies have examined the possibility that, in addition to their beneficial effects on symptoms, pramipexole and ropinirole may be neuroprotective (ie, they may reduce the rate of loss of dopaminergic neurons in the substantia nigra in affected patients). An imaging study of 82 patients who took part in the larger randomized, controlled trial of pramipexole in early PD used single-photon emission computed tomography and the radiotracer beta-CIT to measure the presynaptic dopamine transporter. The integrity of the dopamine transporter is a marker of the nigrostriatal dopaminergic projection. This study demonstrated a reduction in beta-CIT uptake of 16% in patients treated with pramipexole vs 25.5% in those treated with levodopa. A similar study performed in Europe examined 186 early PD patients enrolled in the ropinirole trial, using the presynaptic tracer 18-fluro-dopa and positron-emission tomography. Examining fluro-dopa uptake in the putamen (again, a measure of the integrity of the nigrostriatal projection), a 13% reduction was seen in the group treated with ropinirole vs a 20% reduction in those patients treated with levodopa. Both studies seemed to support the idea that treatment with a dopamine agonist (vs levodopa) results in slowing of loss of the dopaminergic projection from the substantia nigra to the striatum.

Commentary

These data were widely publicized by the pharmaceutical manufacturers of pramipexole and ropinirole as evidence that early treatment with the new, nonergot dopamine agonists is neuroprotective. However, the possibility exists that drug treatment itself affects the radioligand binding, compromising the ability of these methods to evaluate progression in PD. What evidence is there to support this possibility? Clarke and Guttman examined 30 untreated PD patients using PET and a related radiotracer that measures the dopamine transporter. They then repeated these evaluations 6 weeks after patients began treatment with either pramipexole or levodopa. Presumably 6 weeks is too short a time to see evidence of neuroprotection; nevertheless, they observed a 16% reduction of radiotracer uptake in the levodopa group vs a 7% reduction in the pramipexole group. This suggests that drug treatment affects the results of these neuroprotection studies and casts serious doubt on the imaging studies that are widely touted by the pharmaceutical manufacturers of these drugs.

How are neurologists to make sense of these data in their practice? Who should be treated with a dopamine agonist vs levodopa? There are no firm answers to these questions; however, movement disorder neurologists at Columbia-Presbyterian make every attempt to treat young (younger than 70 years old) PD patients with dopamine agonists first. Levodopa is then added, if and when it is needed. Patients with dementia, hallucinations, or orthostasis tolerate dopamine agonists poorly. The agonists are also extremely expensive, and it takes time to build up to an effective dose. These considerations should be weighed in the decision to treat with agonist or levodopa, an important question that remains unanswered. 

— Steven Frucht, MD, Assistant Professor of Neurology, Movement Disorders Division, Columbia-Presbyterian Medical Center, Assistant Editor, Neurology Alert.