Levodopa and the progression of Parkinson’s disease
The Parkinson Study Group;
Commented by , 22 Feb 2005
Aim of the study
To assess the effect of levodopa on the rate of progression of Parkinson's disease.
Methods
This was a randomized, double blind, placebo controlled trial. A total of 361 patients with early Parkinson's disease were assigned to receive either carbidopa-levodopa at daily doses of 12.5/50, 25/100 or 50/200 mg tid, or placebo for a period of 40 weeks.
They then underwent withdrawal of treatment for 2 weeks. The primary outcome was the change in UPDRS scores between baseline and 42 weeks. Neuroimaging studies were performed in 142 subjects at baseline and at week 40 in order to assess striatal dopamine transporter density using beta-CIT and SPECT.
Results
The severity of parkinsonism as assessed by UPDRS increased more in the placebo group as compared to three groups receiving levodopa. The mean difference between total UPDRS scores at baseline and at 42 weeks was
- 7.8 units in the placebo group
- 1.9 units in levodopa 150 mg/day
- 1.9 in 300 mg/day
- -1.4 in the 600 mg/day groups (p<0.001).
In contrast, the mean percent decline in the beta-CIT uptake as measured in 116 patients was significantly greater with levodopa than placebo (-6% in levodopa 150 mg/day, -4% in 300 mg/day and -7.2% in the 600 mg/day groups as compared to -1.4% in the placebo group) (p=0.036).
The subjects receiving the highest dose of levodopa had significantly more dyskinesia, hypertonia, infection, headache, and nausea than those receiving placebo.
Professor Emre's comments
There has been an ongoing controversy on the potential toxicity of levodopa treatment on dopaminergic nerve terminals due to increased dopamine turnover in the synaptic cleft, as levodopa and dopamine can generate reactive oxygen species.
In vitro they can induce degeneration of cultured dopamine neurons providing evidence for this assumption (ref. 1) whereas levodopa is not toxic in animals and may even be trophic promoting the functional recovery of damaged nigral neurones (ref. 2).
This important study was designed to answer this question, both with clinical measures and by indirectly imaging nigro-striatal dopaminergic terminal density using a marker of dopamine transporter, which is located on presynaptic terminals.
Another important aspect of this study was that it is the first large, placebo controlled, long-term, dose response study of levodopa, although it has been used for treatment of PD almost for 40 years.
The results revealed that all doses were better than placebo, there was a clear dose response curve, the highest dose providing the best efficacy. The clinical data suggested that levodopa either slows the progression of PD or has a prolonged effect on the symptoms of the disease, as patients in levodopa groups had still better UPDRS scores as compared to those receiving placebo, two weeks after withdrawal of treatment.
The neuroimaging results, however, were at odds with the clinical results: the imaging data suggested that levodopa either accelerates the loss of nigrostriatal dopaminergic nerve terminals or that its pharmacologic effects modify the dopamine transporter.
Therefore, despite this carefully designed and conducted, sufficiently powered study the potential long-term effects of levodopa on the progression of PD still remain uncertain.
Future studies would have to include a longer withdrawal time in order to exclude prolonged symptomatic effects and also include measures to account for the pharmacological effects of levodopa on dopamine transporter.
Two previous studies with a similar objective, conducted with dopamine agonists versus levodopa had also remained inconclusive because of similar problems, i.e. potential differential pharmacological effects of agonists and levodopa on dopamine transporter or levodopa metabolism (ref. 3, ref. 4).
References
1. Barzilai A, Melamed E, Shirvan A. Is there a rationale for neuroprotection against dopamine toxicity in Parkinson's disease? Cell Mol Neurobiol 2001; 21; 215-35.
2. Murer MG, Dziewczapolski G, Menalled LB, et al. Chronic levodopa is not toxic for remaining dopamine neurones, but instead promotes their recovery, in rats with moderate nigrostriatal lesions. Ann Neurol 1998; 43; 561-75.
3. Parkinson Study Group. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 2002; 287; 1653-61.
4. Whone AL, Watts RL, Stoessl AJ, et al. Slower progression of Parkinson's disease with ropinirole versus levodopa: the REAL-PET study. Ann Neurol 2003; 54; 93-101.