Levadopa (L-dopa):

Levodopa, also called L-dopa, which is converted to dopamine in the brain, remains the gold standard for treating Parkinson's disease. The standard preparations (Sinemet, Atamet) combine levodopa with carbidopa, which improves the action of levodopa and reduces some of its side effects, particularly nausea. Dosages vary, although the preparation is usually taken in three or four divided doses per day.

Indications of Early Treatment Success or Failures

In general L-dopa has the following effects on Parkinson's disease:

• It is most effective against rigidity and slowness.
• It produces less benefit for tremor, balance, and gait.

In many patients, levodopa significantly improves the quality of life for many years.

Side Effects

The toxic effects of levodopa with or without carbidopa are considerable.

Physical Side Effects. The physical side effects include:

• Dyskinesia. Dyskinesia (the inability to control muscles) is a very distressing side effect of levodopa. Dyskinesia can take many forms, most often uncontrolled flailing of the arms and legs or chorea, rapid and repetitive motions that can affect the limbs, face, tongue, mouth, and neck. Dyskinesia is not painful. No specific drug can strongly be recommended to treat dyskinesia. Amantadine (Symmetrel) may help reduce stiffness and improve dyskinesia. There is also weak evidence that deep brain stimulation of the subthalamus area may be helpful.
• Low blood pressure. Low blood pressure is a common problem during the first few weeks, particularly if the initial dose is too high.
• Arrhythmia. In some cases the drug may cause abnormal heart rhythms.
• Gastrointestinal effects. Stomach and intestinal side effects are common even with carbidopa. Taking the drug with food can alleviate the nausea. However, proteins interfere with intestinal absorption of levodopa, and some doctors recommend not eating any protein until nighttime in order to avoid this interference. The drug can also cause gastrointestinal bleeding.
• Effects in the lung. Levodopa can cause disturbances in breathing function, although it may benefit patients who have upper airway obstruction.
• Hair loss.

Psychiatric and Mental Side Effects. The major adverse effects of the drug are psychiatric. Patients taking levodopa, especially in combination with other drugs, can experience:

• Confusion.
• Extreme emotional states, particularly anxiety.
• Vivid dreams.
• Visual and possibly auditory hallucinations. The drug may even unmask dementia that had not been previously noticed.
• Effects on learning. L-dopa appears to have mixed effects on learning. It may improve working memory. However, some evidence suggests that it impairs areas of the brain related to other learning functions and social behavior.
• Sleepiness and sleep attacks.

Levodopa causes fewer psychiatric side effects than other drugs used for Parkinson's disease, including anticholinergics, selegiline, amantadine, and dopamine agonists. Because psychiatric side effects often occur at night, if they are severe some doctors recommend reducing or stopping the evening dose.

The Wearing-Off Effect and Dyskinesia (Inability to Control Muscles)

Within 4 - 6 years of treatment with levodopa, the effects of the drug in many patients begin to last for shorter periods of time after a dose (called the wearing-off effect) and the following pattern may occur:

• Patients may first notice slowness (bradykinesia) or tremor in the morning before the next dose is due.
• Less commonly, some experience painful dystonia, muscle spasms that can cause sustained contortions of various parts of the body, particularly the neck, jaw, trunk, and eyes and possibly the feet.
• Patients must increase the frequency or the dose of levodopa. This puts them at risk for dyskinesia (the inability to control muscles), which usually occurs when the drug level peaks.
• In some people, eventually L-dopa is effective only for 1 - 2 hours, and most patients start to have motor fluctuations. In about 15 - 20% of patients, such fluctuations become extreme, a phenomenon known as the on-off effect, which consists of unpredictable, alternating periods of dyskinesia and immobility. Sometimes the symptoms switch back in forth within minutes or even seconds. (The transition may follow such symptoms as intense anxiety, sweating, and rapid heartbeats.)

Preventing the Wearing-Off Effect. To reduce the effects of fluctuation and the wearing-off effect, it is important to maintain as consistent a level of dopamine as possible. Unfortunately, levodopa is poorly absorbed and may remain in the stomach a long time. A number of strategies are being developed to take care of these problems:

• Some patients take multiple small doses on an empty stomach, crushing the pills and mixing them with a lot of liquid.
• A liquid form of Sinemet may produce fewer fluctuations and a prolonged "on" time compared with the tablet.
• A prolonged release version of levodopa and carbidopa (Sinemet CR) is also available to control fluctuations for some people. (Some evidence suggests that there is no actual difference in symptom control between the sustained and immediate release forms, but patients on Sinemet CR tend to experience a better quality of life.)