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COMT inhibitors in Parkinson’s disease

Can they prevent and/or reverse levodopa-induced motor complications?

From the Department of Neurology, Mount Sinai School of Medicine, New York, New York (Dr. Olanow) and the Department of Neuroscience and "Neuromed," University La Sapienza, Rome, Italy (Dr. Stocchi).

Address correspondence and reprint requests to Prof. C. Warren Olanow, Department of Neurology, Mount Sinai School of Medicine, Annenberg 14-94, One Gustave L. Levy Place, Box 1137, New York, NY 10028.

COMT inhibitors have historically been used as adjuncts to levodopa in fluctuating PD patients to increase "on" time and reduce "off" time. Evidence that motor complications are related to intermittent or pulsatile stimulation of striatal dopamine receptors has led to the use of long-acting dopaminergic therapies that provide more continuous dopaminergic stimulation (CDS). CDS-based therapies are associated with the prevention and reversal of levodopa-related motor complications in MPTP-lesioned primates and PD patients. However, levodopa remains the most effective and widely used anti-parkinsonian agent and is eventually required in all PD patients. The standard oral formulation of levodopa has a relatively short half-life and is associated with the development of motor complications when used as either initial or supplemental therapy. The CDS concept raises the possibility that administration of levodopa in combination with a COMT inhibitor to extend its half-life might reduce the risk of inducing motor complications. This article considers the possibility that combining levodopa with entacapone may prevent or reverse motor complications.