In the advanced stage, treatment of MS may take advantage of a combination of more drugs. Association of tolcapone or entacapone (COMT inhibitors) with l-dopa/dopa decarboxylase inhibitor produces a prolonged duration of antiparkinsonian action, improving motor function [100]. Many cases [101,102] of hepato-toxicity have been reported with the use of tolcapone, thus practical implication of this drug has been revised as “unlikely useful”. Conversely, because of its satisfactory profile, entacapone represents the drug of choice and the triple association entacapone/l-dopa/carbidopa has become available in a single formulation (Stalevo). Some trials [103,104] have evaluated its efficacy to reduce motor fluctuation onset. Due to its tonic stimulation of dopamine receptors in the striatum, it provides more stable plasma l-dopa levels and may decrease the risk of developing motor complications (dyskinesias and “on-off” phenomenon). Recently opicapone, a new COMT inhibitors, has been approved. Two studies [105] (BIPARK 1 and 2), in which opicapone was compared with entacapone and placebo in more than 250 patients, have examined its efficacy. Indeed, it reduced by 2 h off-time and increased on-time by 1 h without raising the frequency of dyskinesia, as compared with a placebo, and this benefit was maintained for at least 1 year of therapy without increasing l-dopa dose.