Problems and unanswered questions concerning levodopa treatment in Parkinson's disease

The main problems in long-term treatment of Parkinson's disease with levodopa are: 1. progressive decline in efficacy; 2. psychiatric complications; 3. the development of motor fluctuations. These are discussed, and important unanswered questions addressed, including when levodopa therapy should be started and at what dose; whether levodopa is in fact harmful in any way; what is the pharmacological role of O-methyl-dopa, present in such high concentrations; and the best management of motor fluctuations.