Treating and preventing levodopa-induced dyskinesias: current and future strategies

Prevention of levodopa-induced dyskinesias is a therapeutic challenge for physicians. At present, it seems only possible to delay dyskinesias and motor fluctuations. In younger patients (aged <50 years), the strategy is to use a dopamine D2 agonist as monotherapy and then to add levodopa treatment when the parkinsonian symptoms progress. In older patients, (aged >50 years to <70 years), the therapeutic approach is to use early combination therapy of levodopa and a D2 agonist. The treatment of levodopa-induced dyskinesias must be considered in regard to the subtype and the severity of dyskinesias, and the patient. The general approach to the treatment of peak dose dyskinesias is to maintain dopamine brain stimulation at as stable a level as possible by keeping plasma and brain levodopa concentrations in the therapeutic range (above the therapeutic threshold but below the dyskinesia threshold). An appropriate strategy is to reduce the individual dose of levodopa, to spread out the daily levodopa dose and/or to try treatment with the sustained-release form of the drug. Combination treatment with the standard and sustained-release levodopa formulations is also possible. Stopping selegiline (deprenyl) therapy may reduce dyskinesias; reducing the dose of, or stopping treatment with, a dopamine agonist may also be beneficial. Anti-dyskinetic drugs such as amantadine, buspirone, fluoxetine, propanolol and principally clozapine may be used. In severe dyskinesias, apomorphine infusion may be tried. In refractory dyskinesia, surgical procedures such as pallidotomy and chronic deep brain stimulation (globus pallidus/subthalamic nucleus) may be proposed. Theoretically, treatment of diphasic dyskinesias requires the maintenance of plasma levodopa concentrations above the dyskinesia threshold. However, this approach leads to constant and severe dyskinesia after only a few weeks of treatment. Thus, the strategy used to treat diphasic dyskinesia is close to the treatment of peak-dose dyskinesias. Apomorphine (or the liquid form of levodopa) may be helpful to prevent diphasic dyskinesias. In selected patients, a midday rest in the 'off' phase may decrease the duration of dyskinesia. Treatment of early morning dystonia is based on the addition to the regimen of the sustained release formulation of levodopa before bedtime. Liquid levodopa and apomorphine injection may be used just before the appearance of the dystonic posture. Botulinum toxin may be helpful in severe dystonia.