COMT inhibitors have proven to be effective in wearing-off. Moreover, Opicapone seems to be more powerful, effective, and safer than other COMT inhibitors. It has also the advantage of daily single administration [172]. Opicapone consistently reduces off-time and increases on-time without rising dyskinesia frequency [173]. When most of dopaminergic projections from substantia nigra to striatum are lost, motor complications can occur due to pharmacokinetics of l-dopa itself [174]. In fact, striatal dopamine levels become strictly dependent on peripheral availability of l-dopa, whose plasma levels are fluctuating in relation to pulsatile oral administration [175]. Therefore, continuous l-dopa infusion has proven to be more similar to physiological striatal settings, reducing the occurrence and severity of dyskinesia and off-time [176]. Several novel l-dopa formulations are under investigation with innovative routes of administration (intestinal infusion, transcutaneous, or inhaled l-dopa). ND062L is a transcutaneous formulation of l-dopa/carbidopa in a patch-pump device [177]. CVT-301 is a l-dopa inhalation, used as a “rescue” therapy for sudden off: a single dose of 84 mg, administered in association with oral l-dopa/carbidopa, for early morning off symptoms seems to be well-tolerated and effective [178,179]. A randomized controlled trial (RCT) has shown that Levodopa-carbidopa intestinal gel (LCIG), administered by continuous intra-intestinal infusion (Duodopa®), was more effective than oral l-dopa regarding motor fluctuations. After 12 weeks on LCIG, off-time was reduced by 4 h compared to baseline and 1.91 h compared to standard oral formulation. Moreover, there was an increase in on-time without troublesome dyskinesia (TSD) [180]. Since there were no difference in UPDRS motor scores, it is unlikely that the greater reduction in off-time was attributable to disproportion in l-dopa dosing [181]. Since LCIG is delivered continuously to the proximal jejunum via percutaneous gastrojejunostomy (PEG-J), adverse effects are primarily related to surgical procedure or device, including pump malfunction, obstruction of catheter, tube displacement, and abdominal pain, usually occurring within the first 2 weeks [182]. Therefore, LCIG is efficacious but requires specialized monitoring to avoid possible complications [183]. All these therapeutic strategies are designed to increase LD bioavailability. In addition to l-dopa formulations, other drugs acting with different mechanisms are under investigation. Tozadenant, an adenosine A2A antagonist, has been conceived for motor fluctuations. Due to contrasting results, the current role of A2A antagonists in PD seem to be contradictory [184]. As previously mentioned, Safinamide seems to reduce off-periods without increasing dyskinesias, although long-term effects require further studies [185].