Levodopa remains the gold standard drug for the treatment of Parkinson's disease, but the combination of disease progression and prolonged treatment can lead to ``wearing-off'' problems in the majority of patients. This constitutes the onset of motor fluctuations which includes nonmotor sensory, psychiatric, and autonomic ``off '' symptoms. There are several pharmacologic options to minimize the ``wearing-off'' phenomenon, including adjustment of levodopa treatment, the use of long-acting dopamine agonists, monoamine oxidase type B inhibition, or catechol-O-methyl-transferase inhibition in combination with levodopa. Dopamine agonists may reduce levodopa requirements. Monoamine oxidase type B inhibition can increase dopamine availability by preventing its metabolism. Similarly catechol-O-methyl-transferase inhibitors can increase the half-life of levodopa and the amount available to cross the blood-brain barrier by preventing its breakdown. The selection of a treatment for the management of ``wearing off'' should consider the relief of symptoms and also the potential adverse effects of adjunctive therapy.
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