Heterogeneous expression of neurotransmitter deficits results from onset and 
progression of Parkinson's disease. Intervals, characterized by reappearance of 
motor and associated certain nonmotor symptoms, determine the end of good 
tolerability and efficacy of oral levodopa therapy. These "OFF" states result 
from levodopa pharmacokinetics and disease progression-related deterioration of 
the central buffering capacity for fluctuations of dopamine levels. This review 
discusses safinamide as an add-on therapeutic agent in orally levodopa-treated 
patients with "OFF" phenomena. Safinamide provided beneficial effects on "OFF" 
symptoms in pivotal trials with doses of 50 or 100 mg once daily. Safinamide 
reversibly inhibits mono-amine oxidase B and declines abnormal glutamate release 
by modulation of potassium- and sodium ion channels. An ideal candidate for 
combination with safinamide is opicapone. This inhibitor of peripheral 
catechol-O-methyltransferase supports continuous brain delivery of levodopa and, 
thus, the continuous dopaminergic stimulation concept. Both compounds with their 
once-daily application and good tolerability may complement each other by 
reduction of necessary oral levodopa intakes and "OFF" times. Thus, a promising, 
future option will be combination of safinamide and opicapone in one 
formulation. It will reduce adherence issues and may complement levodopa 
treatment. It will probably cause less nausea and edema than a dopamine 
agonist/levodopa regimen.