• Over time and with the progression of the disease, Parkinson's disease treatments can become less effective, and new symptoms may appear that do not respond to your current therapy.
  
• Therapies such as dopamine agonists can be useful on their own (as monotherapy) in the earlier stages of Parkinson's, when symptoms are relatively mild. As symptoms progress, levodopa is usually required.
  
• Even though levodopa provides the best symptom control, its effectiveness can also decline after years of treatment. This may give rise to periods of time when symptoms, including tremor, rigidity and bradykinesia, can no longer be constantly controlled. This is known as the 'wearing- off' of symptom control.
  
• In some people, this can eventually develop into sudden switches from periods of time when symptoms are fully controlled, known as 'on'- time, to periods of poor response and the re- appearance of symptoms, known as 'off '- time - resulting in the 'on- off' phenomenon.
  
• Other motor complications can also emerge, including unwanted drug- induced involuntary movements, known as dyskinesias. These can often be controlled by your doctor, using a variety of treatment options.
  
• Researchers now believe that the complications associated with traditional levodopa therapy may relate to a combination of factors
  
  • As Parkinson's disease progresses the number of dopamine cells in the brain continues to decrease and the brain has fewer cells that can take up and store the drug for later release - in these circumstances the brain is said to have lost it's 'buffering' capacity
    
  • As a result of this loss of 'buffering', changes of the level of drug in the blood (peaks and troughs) with standard levodopa formulations can no longer be compensated for and these variations are associated with variations in the availability of dopamine in the brain
    
• Researchers believe that the fluctuating levels of levodopa in the blood and brain in the advanced stages of Parkinson's disease result in changes to the internal circuitry of the brain. This changes how the brain processes information and causes the development of dyskinesia.
  
• It is currently thought that by maintaining more stable levodopa levels in the blood stream and reducing the variations of dopamine levels in the brain these complications may be reduced, delayed and perhaps reversed.
  
• Dopamine agonists provide smoother dopaminergic stimulation by mimicking the activity of dopamine in the brain.
  
• Continuous intravenous infusion of levodopa is an experimental way of providing smoother, more stable levodopa blood levels in Parkinson's disease, and providing more continuous levels of the drug to the brain.
  
• A more practical way of extending and smoothing levodopa levels is with the addition of drugs, such as DDC inhibitors and COMT inhibitors that reduce the breakdown of levodopa and optimize its therapeutic effects.