| ① Increase the frequency of drug taking with the same daily dose, or appropriately increase the total daily dose.|
② Switch immediate-release levodopa to controlled-release levodopa or extended-release levodopa to prolong the action of levodopa. They are more appropriate for the wearing-off phenomenon in early-stage PD. The dosage of controlled-release levodopa should be increased by 20 − 30 % after switching from immediate-release levodopa, because of its low bioavailability. The US guidelines reported that this could not decrease the off stage (Level C evidence) , while the UK NICE guidelines recommended this application in advanced-stage PD, but not as the first choice (Level B evidence) .
③ Add long half-life dopamine agonists, including pramipexole and ropinirole (Level B evidence), cabergoline and apomorphine (Level C evidence) ; however, bromocriptine could not shorten the off stage (Level C evidence) . Other dopamine agonists could be used to replace the currently used dopamine agonists that lose their efficacy.
④ Add COMT inhibitors to generate continuous dopaminergic stimulation to the striatum, including entacapone (Level A evidence) and tolcapone (Level B evidence) .
⑤ Add MAO-B inhibitors, such as rasagiline (Level A evidence) and selegiline (Level C evidence) .
⑥ Minimize the impact of protein diet on the uptake and blood − brain barrier crossing of levodopa. Drugs should be taken 1 h before or 1.5 h after meals.
⑦ Surgical intervention, such as DBS of the subthalamic nucleus (STN) (Level C evidence), is helpful.