Treating Advanced Parkinson’s Disease

In advanced Parkinson’s disease, major motor and non-motor fluctuations increase and reduce quality of life. Long-term oral levodopa worsens involuntary movements – dyskinesia – and wearing off – off time or ‘untreated’ period of time between dose activity when motor fluctuations present.

Disabling motor fluctuations occur in 80% of patients with advanced disease. As Parkinson’s disease progresses the challenge is to stimulate dopamine receptors continuously but avoid unwanted involuntary movements.

Oral Levodopa Treatment Fails

Traditional treatments lose effectiveness later in disease course. Oral levodopa only stimulates dopamine receptors intermittently because of its short plasma half life (1.5-2 hours), and the erratic stomach emptying- seen in Parkinson’s patients –  slows absorption in the intestine.

Treatment induced dyskinesia results from the intermittent and pulsatile supply of levodopa, with variable plasma concentration and insufficient stimulating of dopamine receptors. Frequent reduced, divided dosing of oral levodopa given with catechol-O-methyltransferase inhibitors increases the plasma half life, but does not stabilise fluctuating plasma levels completely. Longer-acting dopamine agonists – eg slow release levodopa/carbidopa combinations – stimulate dopamine receptors continuously with less dyskinesia, but affect symptoms suboptimally.

Treatment Options

Three main choices exist for treating advanced Parkinson’s Disease: enteral infusions of levodopa/carbidopa (duodopa), subcutaneous infusions of apomorphine, and deep brain stimulation (DBS).

Duodopa Treatment

Duodopa is delivered continuously via a portable pump and provides smoother plasma levels than oral levodopa. Less motor fluctuations occur with off time reduced by 70-90%. Infusing duodopa into the duodenum  improves global functioning, walking, and lessens off time and motor fluctuations. It reduces the daily dose of levodopa required and eliminates delay due to gastric or absorbing the drug in the intestine. Keeping levodopa plasma levels constant limits severe fluctuations between extreme stiffness and involuntary movements. Most problems encountered occur when inserting the device. Contraindications include patients unfit for abdominal surgery, pronounced dementia, and inadequate patient compliance or support.

Apomorphine Pumps

Infusing apomorphine continuously into the skin via a pump reduces off time and is a viable alternative for some patients with advanced disease. Apomorphine contraindications include presence of dementia, hallucinations and the lack of compliance or support.

Deep Brain Stimulation

Stimulating specific regions of the brain electrically – deep brain stimulation – reduces symptoms in many patients. For deep brain stimulation, a surgeon places the stimulating device under the skin and attaches electrodes to the areas of the brain that control motor function. The device stimulates these areas and blocks the abnormal signals for tremor. Contraindications include patients over 70 years of age or unfit for brain surgery, presence of dementia, depression or anxiety.

Pump treatments and deep brain stimulation are best for motor and non-motor symptoms in advanced disease. In the future, the aim is to developing more physiological dopaminergic agents and even better forms of brain stimulation.


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