Optimizing pharmacotherapy: strategies to manage the wearing-off phenomenon

Levodopa is extremely effective in controlling many of the symptoms of Parkinson's disease (PD) and will be required by most patients during the course of the disease. However,levodopa therapy is associated with certain drawbacks, including the inability to control some PD symptoms, such as autonomic disturbances and neuropsychiatric symptoms, and the occurrence of motor complications with chronic treatment. Wearing off refers to a waning of response to levodopa prior to the next dose, resulting in fluctuations in motor function. AsPD progresses, the therapeutic window of response to levodopa narrows, making it difficult to find a dose that controls symptoms without resulting in dyskinesia. Motor complications are believed to be due to the progressive loss of dopaminergic neurons that results in a decreased ability to buffer fluctuations in dopamine levels in the brain,coupled with the short half-life of levodopa. Motor complications occur in over 90% of patients who have been treated with levodopa for more than 10 years and are associated with reduced function, reduced quality of life, and high treatment costs. Strategies to manage motor complications include delaying the initiation of levodopa therapy when possible, altering levodopa doses or frequency of administration, and adding adjunct therapies. Catechol-O-methyltransferase (COMT)inhibitors extend the half-life of levodopa and result in significant reductions in off times in patients with motor fluctuations. Dopamine agonists, monoamine oxidase-B (MAO-B)inhibitors, and amantadine are other candidates for adjunct therapies. Dyskinesia is usually managed through changes in levodopa dosing or administration; changing the doses of adjunct therapies also may be helpful.