Parkinson's Disease

COMT Inhibitors

Inhibition of catechol O-methyltransferase (COMT) prevents conversion of levodopa to 3 O-methyldopa in the periphery, thus increasing the levodopa available for transport into the brain. Two COMT inhibitors are approved in the United States, entacapone and tolcapone. Neither has significant activity in the CNS. Both have been shown to decrease the duration of "off" time in patients with significant off time. Tolcapone is more effective than entacapone, reducing off time in clinical trials by 2 to 3 hours, versus 1 to 2 hours for entacapone. Both treatments usually allow reduction of levodopa dose in the range of 20% to 25%. Physicians often choose to commence COMT inhibitor therapy early in the week to be available by phone to help patients reduce their levodopa dose if dyskinesias develop.

Entacapone (Comtan®) is dosed at 200 mg with each levodopa dose. Diarrhea is the most common side effect, which may require stopping treatment in approximately 5% of patients. Diarrhea usually begins one to two weeks after therapy initiation.

A combination of levodopa, carbidopa, and entacapone in a single pill (Stalevo®) is also available, with a similar side effect profile to the agents used alone. Pills are available in a range of levodopa/carbidopa doses, each of which contains 200 mg entacapone.

Tolcapone (Tasmar®) is dosed at 100 or 200 mg tid. Side effects include diarrhea, which may preclude treatment in up to 15% of patients. Four cases of acute fulminant hepatic necrosis, with three deaths, have been reported, and led the FDA to issue a "black box" warning on tolcapone. This warning recommends that physicians only prescribe tolcapone for patients whose symptoms cannot be adequately controlled without it. Frequent liver function monitoring is required for patients commencing therapy. This requires a blood test every 2-4 weeks for the first 6 months, to be sure that certain critical liver function values are not rising. After that, blood tests are recommended at intervals deemed clinically relevant. Treatment should be discontinued if the ALT/AST levels rise above twice the upper limit of normal.