Therapies start, depending on the age of the patient, either with levodopa and/or dopamine agonists. In the moderate/intermediate phase additional therapies are added. Patients typically experience a very good response to levodopa during the early stages of treatment. As the disease progresses, however, the effect of levodopa starts to wear off. This phenomenon may be explained by the ability of dopaminergic nerve terminals to store and release dopamine early in the course of the disease. With advanced stages and degeneration of dopamine terminals, the concentration of dopamine in the basal ganglia is more dependent upon plasma levodopa levels.
Plasma levels may fluctuate erratically because of the short minute half-life of levodopa and the unpredictable intestinal absorption of this medication. Patients with moderate/intermediate and advanced PD start to be aware of a "wearing-off" or "end-of-dose" effect.
Intermittent or pulsatile stimulation of dopamine receptors is thought to be responsible for the development of the motor fluctuations and dyskinesias that complicate the long-term use of levodopa therapy in Parkinson’s disease.1
Frequently, a combination including two or more of the following therapies is used; levodopa, dopamine agonists, COMT-inhibitors, optional MAO-B-inhibitors and/or anticholinergics. The moderate/intermediate and advanced phases often become more complicated to treat as patients have increasing periods of “off” time and levodopa-induced dyskinesias. In addition to the motor fluctuations during long term levodopa there may also be cognitive and/or psychiatric symptoms.2
NICE guidance, NG71, recommends offering people with advance PD best medical therapy, which may include intermittent apomorphine injection and/or continuous subcutaneous apomorphine infusion.3
1. Nutt J.G., Obeso J.A., Stocchi F.(2000) Continuous dopamine-receptor stimulation in advanced Parkinson's disease. Trends Neurosci 23: S109–S115
2. Chaudhuri KR, Rizos AM, Sethi KD. Motor and nonmotor complications in Parkinson's disease: An argument for continuous drug delivery? Journal of Neural Transmission, 2013
3. NICE Guidance NG 71, published July 2017. https://www.nice.org.uk/guidance/ng71/chapter/Recommendations#pharmacological-management-of-non-motor-symptoms. Accessed March 2021