As PD progresses there are fewer dopaminergic neurons in the substantia nigra as well as a progressively lower capacity to store exogenous levodopa and convert it to dopamine for storage and release in the remaining neurons. Additionally, as the dose requirements of levodopa increase, the patient's functioning is inhibited before his next dose of medication [
10]. This usually takes place 2–4 hours after a levodopa dose and may appear as sensory (pain, paraesthesiae), psychiatric (paranoia, anxiety, hallucinations, depression) or autonomic (sweating, belching, constipation, tachycardia, or breathlessness) symptom, or progression of motor symptoms or dystonia [
11]. This is called “end of dose wearing off”. Wearing off has not been fully explored, but may be connected to pharmacokinetic changes, and shortening of striatal levodopa half-life resulting from progressive degeneration of nigrostriatal dopaminergic terminals [
12]. To treat motor symptoms it is necessary to deliver medication effectively. Patients with advanced PD often notice that protein-rich meals will diminish the effectiveness of levodopa doses [
13]. This can be alleviated by reducing protein intake during daytime and limiting protein intake at night to 40 grams [
9]. There are some strategies to Improve absorption of Levodopa include: advise patients to take levodopa before meals, on an empty stomach [
14], advise patients to avoid protein-rich meals and bulk-forming foods [
15], advise patients against lying down, and encourage them to move around, after ingesting a dose [
16], and advise patients to mix levodopa, crushed into a powder, into sparkling liquid [17].
As the disease progresses, current levodopa doses give hyperkinesia due to the narrowing of the therapeutic window. In addition, patients on polypharmacy regimens are often on other anti PD drugs that commonly elicit side effects like hallucinations and/or dyskinesia. This implies that the patient often must have monotherapy with levodopa as this drug is least prone to have side effects and that the doses must be lower and carefully monitored.