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After several years of smooth and stable response to levodopa, many patients develop motor fluctuations manifested by "on" and "off" phases. There are various subtypes of motor fluctuations that have different underlying mechanisms and therapeutical strategies. The "wearing off" phenomenon may be mainly due to the loss of stratial dopamine storage capacity and short levodopa half-life. The "delayed on" and "no-on" phenomena may be due to impaired absorption of oral levodopa. Management include various combined approaches, such as administration of small multiple daily doses of levodopa, controlled release, dispersible and soluble levodopa formulations, oral dermal- patch and subcutaneous dopamine agonists, MAO-B and COMT inhibitors, and surgical approaches, i.e., subthalamic deep brain stimulation. Future strategies may include gene therapy (e.g., intrastriatal GDNF) or transplantation of stem cells that can either produce and release dopamine or generate trophical factors.
Melamed et al. (Mon,) studied this question.