BARCELONA—No clear winner, yet. That appeared to be the consensus following reports on the results of three clinical trials involving the dopamine agonists pergolide, pramipexole, and ropinirole. Despite differences, all appeared to have efficacy as treatment for Parkinson's disease—either as monotherapy or in conjunction with levodopa. However, none of the study results reported at the Sixth International Congress of Parkinson's Disease and Movement Disorders were from trials that lasted more than five years. It was generally agreed that more studies are needed to determine the long-term effects of these dopamine agonists, as well as levodopa, on disease progression.

PERGOLIDE VERSUS LEVODOPA

Data from an interim analysis of the PELMOPET trial (Pergolide versus Levodopa in Early Parkinson's Disease) were presented by Wolfgang Oertel, MD, Chairman of the Department of Neurology at the University Hospital of Philipps University in Marburg, Germany.

A total of 294 patients with idiopathic Parkinson's disease were randomly assigned to either pergolide (mean daily dose, 3.23 mg) or levodopa (mean daily dose, 504 mg). Patients with previous anti-Parkinson's disease treatment were excluded from the study.

Both treatments provided improvements on the motor and daily living sections of the Unified Parkinson's Disease Rating Scale (UPDRS), Dr. Oertel reported. He noted, however, that onset of motor complications was significantly delayed in the pergolide group. The dyskinesia subscore provided an even greater contrast, Dr. Oertel pointed out. After one year of treatment, three times as many patients in the levodopa group had developed dyskinesia than those in the pergolide group. After three years, 32.9% of the levodopa group and 16.3% of the pergolide group had developed dyskinesia.

Both pergolide monotherapy and levodopa monotherapy produced a significant and sustained improvement of Parkinson's disease symptoms, but it will be interesting to see how the two drugs compare for longer treatment periods, the researchers said.

PRAMIPEXOLE VERSUS LEVODOPA

Preliminary results from the ongoing CALM-PD trial (Comparison of the Agonist Pramipexole Versus Levodopa on Motor Complications in Parkinson's Disease) were discussed by Ira Shoulson, MD, Professor of Neurology at the University of Rochester, New York.

A total of 301 patients with early Parkinson's disease were randomized to receive either pramipexole (1.5 mg, 3.0 mg, or 4.5 mg) or carbidopa/levodopa (75/300 mg, 112.5/450 mg, or 150/600 mg) daily. Patients with previous anti-Parkinson's disease treatment were excluded from the study. After week 11, supplementary levodopa was allowed in 48% of the pramipexole group and 36% of the levodopa group because of emerging disabilities, Dr. Shoulson noted. The patients were followed for 23.5 months, and an extended study is currently underway to determine the longer-term impact of these dopaminergic treatments, he said.

After two years of treatment, 51% of the levodopa-treated group had developed motor complications, compared with 28% of the pramipexole-treated group, Dr. Shoulson reported. Similarly, a greater percentage of levodopa-treated patients (31%) than pramipexole-treated patients (10%) developed dyskinesia, he continued. Pramipexole use, however, was associated with a greater likelihood of a "wearing off" effect (24%) than was levodopa (5%). Dopamine transporter imaging was assessed in a subgroup of patients by [123I]ß-CIT single photon emission computed tomography (SPECT). Compared with baseline, the pramipexole group showed a 10% annual decline in striatal [123I]ß-CIT uptake, whereas the levodopa group showed a 12% annual decline.

An extended study of this cohort is planned to determine the long-term effects of pramipexole on safety, functional status, economic outcomes, quality of life, and dopamine transporter neuroimaging, Dr. Shoulson said.

ROPINIROLE VERSUS LEVODOPA

With regard to dyskinesia, ropinirole was more favorable than levodopa treatment, according to Olivier Rascol, MD, of the University of Toulouse, France, who summarized the findings of the 056 Study Group. Results of the study, which compared ropinirole and levodopa, were also published in the May 18 issue of the New England Journal of Medicine.

In the study, 268 patients with early Parkinson's disease were randomly assigned to receive either ropinirole (mean daily dose, 16.5 mg) or levodopa treatment (mean daily dose, 753 mg). A total of 56 patients in the ropinirole group (66%) received supplementary levodopa, Dr. Rascol noted.

After five years of treatment, 20% of the ropinirole group had developed dyskinesia, compared with 46% of the levodopa group, the researchers reported. However, there was no difference with regard to the UPDRS activities of daily living subscores among those who completed the study. Adverse events led to early withdrawal of 48 patients in the ropinirole group (27%) and 26 patients in the levodopa group (29%), he noted.

These results suggest that patients with early Parkinson's disease can be "managed successfully for up to five years with a reduced risk of dyskinesia by initiating treatment with ropinirole alone and supplementing it with levodopa if necessary," Dr. Rascol said.

EARLY VERSUS LATER LEVODOPA

One persistent question that has been plaguing neurologists is whether levodopa, the gold standard therapy for Parkinson's disease, is actually harmful to dopaminergic neurons in the substantia nigra.

Although enrollment is not yet complete, the ELLDOPA (Earlier versus Later Levodopa in Parkinson's Disease) study is expected to provide a definitive answer to that question within the next few years. It is high time to answer this question, as the debate has been going on since the 1980s, commented Stanley Fahn, MD, Chief of the Movement Disorder Clinic, Presbyterian Hospital and Neurological Institute of New York, and H. Houston Merritt Professor of Neurology, College of Physicians and Surgeons of Columbia University in New York City.

Motor fluctuations and dyskinesias are often associated with long-term levodopa use, Dr. Fahn said, and many studies have proposed that the "wearing-off" effect is related to the loss of remaining cells in the substantia nigra. The ELLDOPA study, he explained, was designed to assess whether levodopa itself hastens or slows the loss of dopamine neurons. In other words, does levodopa accelerate or retard the progression of Parkinson's disease?

So far, two thirds of the total of 360 subjects with early, mild Parkinson's disease have been recruited from 35 sites across North America. The subjects will be randomly assigned to one of four treatment groups: placebo; low- dose carbidopa/levodopa (12.5/50 mg tid); medium-dose carbidopa/ levodopa (25/100 mg tid); or high-dose carbidopa/levodopa (50/200 mg tid). Although a longer duration of treatment would be desirable, the researchers limited the trial to 40 weeks "to keep all subjects in the study and minimize premature terminations from the trial," Dr. Fahn noted. In order to avoid the possible confounding influence of other drugs, no other anti-Parkinson's disease treatment will be allowed, he said.

After the treatment period, there will be a three-day washout period and a 14-day follow-up. Clinical efficacy will be determined using the UPDRS. Factors such as drug dose, efficacy over time, and the presence of fatigue will be noted.

With regard to underlying pathologic processes, [123I]ß-CIT SPECT will be used to determine dopamine transporter activity. Because dopamine is oxidized, the metabolites of dopamine could "accelerate oxidative stress and the loss of dopamine neurons," Dr. Fahn proposed. Supplying exogenous levodopa could augment any oxidative stress, he said. On the other hand, low concentrations of levodopa may be protective. Studies in animal models of Parkinson's disease have provided mixed results, and "we need to know what happens in patients," he said.

—Jean McCann

Suggested Reading
Agid Y, Ahlskog E, Albanese A, et al. Levodopa in the treatment of Parkinson's disease: a consensus meeting. Mov Disord. 1999;14:911-913.
Fahn S. The spectrum of levodopa-induced dyskinesias. Ann Neurol. 2000;47:S2-S9.
Holloway R, Shoulson I, Fahn S, et al. A randomized controlled trial comparing pramipexole with levodopa in early Parkinson's disease: design and methods of the CALM-PD study. Clin Neuropharmacol. 2000; 23:34-44.
Kunig G, Pogarell O, Moller JC, et al. Pramipexole, a nonergot dopamine agonist, is effective against rest tremor in intermediate to advanced Parkinson's disease. Clin Neuropharmacol. 1999;22:301-305.
Rascol O, Brooks DJ, Korczyn AD, et al. A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med. 2000;342:1484-1491.

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