NEWS: eBMJ: Ropinirole and treatment of early Parkinson's disease

[janet paterson <janet313@xxxxxxxxxxx>]

Editorials

Treatment of early Parkinson's disease
Ropinirole may improve function, while minimising involuntary movements

Parkinson's disease, a progressive neurodegenerative disorder, affects about 1% 
of the population
over the age of 50. While it has no cure, it is the only neurodegenerative 
disorder with a range of
medical and neurosurgical treatments that substantially reduce clinical 
symptoms.1 However, medical management of early Parkinson's
disease is controversial because of the potential risks and benefits to 
patients. Some clinicians prefer to use levodopa, a dopamine
precursor, since it promptly relieves symptoms. Others prescribe dopamine 
agonists and withhold levodopa because of its long term
complications, namely abnormal involuntary movements and potential 
neurotoxicity. Inevitably, managing the side effects of
antiparkinsonian drugs becomes a therapeutic focus along with treating the 
primary motor abnormalities.1 Extended controlled clinical
trials are the only means of obtaining evidence based guidance on the use of 
dopamine agonists or levodopa for the management of
early Parkinson's disease.

The results of a recent multisite, five year, randomised, double blind study 
comparing the incidence of dyskinesia with levodopa or
ropinirole, a dopamine D2 receptor agonist,2 should sway practitioners towards 
initial treatment with agonists for early Parkinson's
disease. In contrast to the hypokinesis that characterises Parkinson's disease, 
dyskinesias related to antiparkinsonian drugs involve
hyperkinetic choreoathetoid, lurching, and jerky movements. These movements are 
thought to be related to the underlying severity of
the disease and alterations in postsynaptic receptors, as well as pulsatile 
stimulation of dopamine receptors resulting from the shorter
half life of levodopa.3 For many patients, these abnormal involuntary movements 
are unsightly if not distracting, disfiguring,
exhausting, painful, or frankly disabling. They tend to coincide with peak 
effects of each levodopa dose, which is often when the
desired relief of the motor symptoms of Parkinson's disease (tremor, rigidity, 
gait disturbances, bradykinesia, and akinesia) occurs.
Accordingly, antiparkinsonian treatments that avoid or delay the onset of motor 
complications are needed.

Of 268 patients with mild to moderately severe Parkinson's disease (Hoehn and 
Yahr stages I-III) in the trial, 179 took ropinirole up to
24 mg/day and 89 took levodopa up to 1200 mg/day.2 If motor symptoms were not 
adequately controlled, participants were given
supplemental, open label levodopa (51% of patients receiving ropinirole and 35% 
of those receiving levodopa). At the end of five years,
motor deficits were slightly but significantly greater in the patients given 
ropinirole, but functional abilities were similar in the two
groups. However, the length of time until dyskinesia developed in the 25% of 
patients remaining in the study was 214 weeks for those
given ropinirole and 104 weeks for those given levodopa alone. Further, 
dyskinesias developed at a rate nearly three times slower in the
ropinirole treated patients compared with the levodopa only group. Moreover, 
the dyskinesias were disabling in 23% of the levodopa
treated patients compared with 8% of ropinirole treated patients. Before 
addition of supplementary levodopa, only 5% of patients
receiving ropinirole had dyskinesia compared with 36% of those receiving 
levodopa. Thus, although levodopa remains the optimal
treatment for Parkinson's disease, associated dyskinesia is a serious concern.

The results for those patients who completed the five year trial indicate that 
initial treatment with ropinirole in early Parkinson's disease
adequately controls symptoms (based on functional abilities) and delays onset 
of problematic motor complications. However, since
about half of each group withdrew during the study, neither ropinirole nor 
levodopa is an ideal treatment for many patients. Many
adverse effects not involving dyskinesia occurred, causing nearly a third of 
participants to withdraw from the trial. Nausea, a leading
reason why patients in our practice stop taking ropinirole, was reported by 
almost half of the participants in both groups. However,
domperidone, used to counteract nausea, presumably allowed all but about 5% of 
participants who were affected by nausea to finish
the trial. Hallucinations were a more serious complication of ropinirole (17% 
affected, causing 4% to quit the study) compared with
levodopa alone (6% affected, causing 2% to quit the study). Other adverse 
events and variables were similar in the two groups.

Several other issues warrant consideration in interpreting and applying the 
results from this study. Firstly, initial treatment for early
Parkinson's disease is not restricted to levodopa or dopamine agonists. 
Amantadine, anticholinergic drugs, selegiline, and
non-pharmacological treatments (such as physical therapy) provide symptomatic 
relief in mildly affected patients. Thus, use of
levodopa and dopamine agonists can be delayed until symptoms are clinically 
disabling.4 Whether initial treatment with these alternative
agents influences subsequent development of motor complications is unknown.

Secondly, the study did not examine the effects of disease severity or duration 
on the incidence of dyskinesia and other adverse
effects. Such information would influence treatment, since the six month 
interim analysis of the study patients showed that levodopa
was associated with significantly better motor function compared with 
ropinirole in patients with more advanced disease (Hoehn and
Yahr stage >II) but that motor function was similar with either drug among less 
affected patients.5

Finally, the role of concurrent psychiatric illnesses was not addressed. 
Depressive and anxiety disorders affect at least half of patients
with Parkinson's disease but are underrecognised and inadequately treated.6 
Thus, they potentially contribute to the perceived
inefficacy of antiparkinsonian drugs and heighten the risk of premature 
withdrawal of the drug or the development of dyskinesias with
increases in drug dose.

Despite the remaining unanswered questions, ropinirole seems to be an effective 
treatment for early Parkinson's disease. Although
levodopa remains the optimal treatment for Parkinson's disease, ropinirole 
provides similar improvements in functional abilities while
minimising abnormal involuntary movements.

Laura Marsh, director, Clinical Research Program.
Ted M Dawson, director.

Morris K Udall Parkinson's Disease Research Center of Excellence, Johns Hopkins 
University School of Medicine, 600 N Wolfe Street, Carnegie
2-214, Baltimore, MD 21287, USA (tdawson@xxxxxxxx)

Acknowledgments

TMD and LM are supported by the Morris K Udall Parkinson's Disease Research 
Center of Excellence (NIH-P50-NS38377) and TMD
is supported by the Edward O and Anna Mitchell Family Foundation. LM has 
received funding from Eli Lilly to conduct clinical trials in
Parkinson's disease and schizophrenia and from Zeneca Pharmaceuticals for 
speaking on psychiatric aspects of Parkinson's disease.
Under an agreement between Johns Hopkins University and Guilford 
Pharmaceuticals, TMD is entitled to a share of sales royalty
received by the university from Guilford. TMD and the university also own 
Guilford stock, and the university stock is subject to
certain restrictions under university policy. The terms of this arrangement are 
being managed by the university in accordance with its
conflict of interest policies.

Footnotes

Ropinirole is made by SmithKline Beecham.



 1.
    Olanow CW, Koller WC. An algorithm (decision tree) for the management of 
Parkinson's disease: treatment guidelines. Neurology
    1998; 50(suppl 3): S1-57[Medline].
 2.
    Rascol O, Brooks DJ, Korczyn AD, De Deyn P, Clarke CE, Lang AE, for the 056 
Study Group. A five-year study of the
    incidence of dyskinesia in patients with early Parkinson's disease who were 
treated with ropinirole or levodopa. N Engl J Med
    2000; 342: 1484-1491[Medline].
 3.
    Chase TN. Levodopa therapy: consequences of nonphysiologic replacement of 
dopamine. Neurology 1998; 50(suppl 5):
    S17-S25[Medline].
 4.
    Poewe W. Should treatment of Parkinson's disease be started with a dopamine 
agonist? Neurology 1998; 51(suppl 2):
    S21-S24[Medline].
 5.
    Rascol O, Brooks DJ, Korczyn AD, Poewe WH, Stocchi F. Ropinirole in the 
treatment of early Parkinson's disease: a 6-month
    interim report of a 5-year L-dopa controlled study. Mov Disord 1998; 13: 
39-45[Medline].
 6.
    Marsh L. Neuropsychiatric aspects of Parkinson's disease. Psychosomatics 
2000; 41: 15-23[Abstract/Full Text].



BMJ 2000;321:1-2 ( 1 July )
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janet paterson
53 now / 41 dx / 37 onset
613 256 8340 / PO Box 171 Almonte Ontario K0A 1A0 Canada
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