Two COMT inhibitors are currently available for use as adjunctive therapy in PD, to be used in conjunction with levodopa and an AAAD inhibitor in patients, who have developed motor fluctuations with end-of-dose wearing off. Tolcapone is the more potent of the two and, with its longer T1/2 can be given on a TID basis. Its potential to produce hepatic failure has limited its use to individuals in whom entacapone has been ineffective or not tolerated (117). Because of the tolcapone-related safety issues, clinical use of COMT inhibition has largely centered on entacapone, despite its lesser relative potency. Because of its short T1/2 entacapone must be administered with each dose of levodopa. At first glance this seems inconvenient, but since it really does not entail any more frequent dosing than that already being employed for the levodopa, the inconvenience is more perceived than real. The additional one to two hours of "on" time per day that a COMT inhibitor typically affords to a fluctuating patient can be very welcome. A cost-effectiveness analysis of entacapone concluded that the additional drug costs when entacapone is employed are offset by reductions in other costs and improvement (6%) in "quality-adjusted life years" (118). Another study in Finland also concluded that entacapone (and the MAO-B inhibitor rasagiline) is cost-effective when used in conjunction with levodopa compared to levodopa alone and provides slightly over five months of quality-adjusted life years (119). Findley et al. (88) reached similar conclusions with regard to Stalevo.
While it is quite clear that COMT inhibitors provide quantifiable improvement in function for PD patients with motor fluctuations, their potential benefit in stable PD patients who have not yet developed motor fluctuations has received much less attention. Two clinical trials have addressed this question with tolcapone (120,121). In the larger of the two trials (120), significant improvement in both the activities of daily living and the motor sections of the UPDRS were documented. Improvement was most evident in more severely affected patients. Fewer patients in the tolcapone-treated group developed motor fluctuations during the duration of the trial, which extended to a maximum of 12 months for some participants (average 8.5 months). Adverse events were similar to those encountered in earlier trials described in the previous sections. The second, smaller, trial did not examine nonfluctuating PD patients, but rather evaluated individuals who had previously experienced wearing off with levodopa, which had been successfully controlled by levodopa dosage adjustment (121). A greater reduction of levodopa dosage was achieved in the tolcapone-treated group, but this was not significant. A single tolcapone trial in levodopa-untreated patients demonstrated no clinical benefit (122).
In a double-blind study involving 300 patients, 128 of whom were not experiencing motor fluctuations, entacapone produced improvement in both the fluctuating and the nonfluctuating groups (123). In the group without motor fluctuations, a significant improvement in UPDRS activities of daily living was evident in patients receiving entacapone compared with those receiving placebo, although no difference in motor scores was found. A larger increase in levodopa dosage in the placebo group also occurred. In another double-blind, placebo-controlled study involving a total of 750 levodopa-treated subjects who were not experiencing motor fluctuations, entacapone did not produce improvement in UPDRS motor scores, but a significant improvement was documented in some quality of life measures (124).
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