(1) When patients with
Parkinson's disease who are taking
levodopa develop motor fluctuations that do not respond to dose adjustments, the standard treatment is the addition of
bromocriptine, a
dopaminergic agonist. Evaluation of
entacapone fails to show whether the risk-benefit balance of this
catechol-O-methyltransferase (COMT) inhibitor is at least as favourable as that of
bromocriptine. (2)
Tolcapone, another COMT inhibitor, is back on the French market after being withdrawn because of serious hepatic effects. The summary of product characteristics (SPC) specifies that
tolcapone must only be used when
entacapone treatment fails or is poorly tolerated. (3) Renewal of marketing authorisation was based on one clinical trial in which about half the patients were probably not resistant to
entacapone. No difference in efficacy was found between
tolcapone and
entacapone. There is no firm evidence that
tolcapone is effective in a significant number of patients in whom
entacapone fails. (4) Placebo-controlled trials show that first-line treatment with
tolcapone 100 mg to 200 mg 3 times a day reduces the duration of motor freezing ("off") periods, but the global impact of
tolcapone on
parkinsonism appears to be limited. (5) Unblinded randomised controlled trials have failed to show that
tolcapone is more effective than
bromocriptine or
pergolide. There are no trials assessing the use of
tolcapone in combination with
dopamine agonists. (6) Adverse effects were frequent during clinical trials. They were mainly neurological and gastrointestinal, and differed from those associated with
bromocriptine. In 1988, shortly after worldwide marketing of
tolcapone, 3 cases of fatal
fulminant hepatitis were reported among about 60 000 patients who had taken this
drug. Some countries, including European Union member states, withdrew marketing authorisation. Other countries, including the United States, left
tolcapone on the market but required stringent monitoring of liver function. Due to a lack of transparency on the part of both the manufacturer and the health authorities, we do not know if these measures reduced the risk of severe
hepatitis. In the trial versus
entacapone, one of the 75 patients treated with
tolcapone 300 mg/day had an abnormal increase in serum
transaminase activity. (7) In practice,
tolcapone has a negative risk-benefit balance.