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Treating the "off" periods in Parkinson's

By: Stewart A. Factor, D.O.M
Professor of Neurology and Riley Family Chair in Parkinson's Disease
Parkinson's Disease and Movement Disorders Center of Albany Medical Center
215 Washington Ave Ext
Albany, New York 12205

People with Parkinson's are all too familiar with the disease's initial symptoms - resting tremor, muscle stiffness and slowness of movement. Levodopa and dopamine agonists, the first lines of defense against PD, are very capable of improving and controlling these symptoms for several years.

Over time, however, patients start to develop motor fluctuations, the result of variations in the individual's response to levodopa. Motor fluctuations oscillate between "off" times, a state of decreased mobility, and "on" times, or periods when the medication is working and symptoms are controlled. It is estimated that 40 percent of Parkinson's patients will experience motor fluctuations within 4-6 years of onset increasing by 10 percent per year after that.

These fluctuations are not limited to the motor features of Parkinson's. Also affected are the non-motor features, such as sensory symptoms (e.g. pain, fatigue, and motor restlessness); autonomic symptoms (e.g. urinary incontinence and profuse sweats); and psychiatric disorders (e.g. depression, anxiety and psychosis). These symptoms are more disabling than motor changes in as many as one third of fluctuating patients.

The goals of therapy are obvious: to reduce "off" time as much as possible; to make it as predictable as possible; and to be able to treat it with as little medication as possible (so as to avoid side effects such as psychosis and dyskinesia).

Most of the treatments that are used as alternatives or adjuncts to levodopa were developed for the purpose of treating "off" periods. While they all have their place in the treatment of PD, none of them - whether taken alone or in combination with others has been able to eliminate this problem completely.

How then does each of them perform in providing relief from off periods? Let us look at them one by one.

First, controlled release levodopa. This variation was developed as a means to doubling the duration of the effect of standard levodopa. Unfortunately, it did not fulfill its promise. Only some patients enjoyed positive benefits; the decrease in "off" time was modest; and for many users, dyskinesias became more severe.

Dopamine agonists - today's most frequent choices for therapy, especially for early-stage Parkinson's stimulate dopamine receptors in a manner similar to dopamine, but have a longer lasting effect than levodopa.

By providing a smoother, more continuous stimulation of dopamine receptors these drugs are able to improve motor fluctuations and decrease "off" time by about 30 percent. But they can cause adverse side effects including hallucinations, low blood pressure, ankle swelling, sleep disorders and dyskinesia.

Selegiline (Elderpryl) is a selective MAO-B inhibitor that has shown modest improvement in motor fluctuations in some patients, but with worsening of dyskinesias and insomnia as common side effects.

The final medication class is the COMT inhibitors, which is primarily used as an adjunct to levodopa to enhance its effect. By inhibiting the enzyme COMT in the bloodstream and gastrointestinal tract, these drugs increase its absorption of levodopa in to the brain and allow levodopa to be effective longer. Tolcapone and entacapone are two COMT inhibitors currently available. Tolcapone (Tasmar) is more potent, but is associated with a small risk of serious liver toxicity. Entacapone (Comtan) has a modest but significant effect on decreasing "off" time. Both drugs can cause an increase in dyskinesia.

Although each of these options has its advantages, none of them reliably eliminates the "off" period, especially as PD progresses. What does one do when all medical options have been exhausted? Sometime - perhaps before year's end - we in the U.S. expect to have an additional remedy to offer: apomorphine. Long available in Europe and Canada, the drug is a unique dopamine agonist that is administered via subcutaneous injection as "rescue" therapy from "off" periods.

When apomorphine is injected under the skin, it has been shown to bring about an "on" time consistently in 5-12 minutes and to maintain the effect for all areas of fluctuations - motor, sensory and psychiatric - for a period of 30 to 120 minutes.

Apomorphine helps fill the "off" gaps that occur between doses. If patients can anticipate their "off" times, then they can minimize it. The "off" periods that kept them home because of unpredictable or disabling symptoms could be eliminated in five minutes with an injection given discreetly under the table or in the restroom. Side effects include dyskinesias, hallucinations, reduced blood pressure and the development of skin nodules at the site of injections. The latter is minimized by moving the site each time.

Besides treating "off" periods through medical treatments, patients can sometimes find help through dietary adjustments. Diets high in protein can interfere with the absorption of levodopa in the blood stream, limiting its effectiveness, and for some patients, reducing protein can improve the absorption of levodopa and thereby reduce "off" periods.

Others find it helpful to take their medications on an empty stomach, or to eat smaller and more frequent meals, waiting at least 30 minutes following their meal to take their levodopa.

There is no question that "off" periods frustrate the lives of Parkinson's patients and their caregivers. Until an effective treatment is developed that eliminates them, patients and caregivers can find some relief and hope in a variety of medical and non-medical alternatives.