Following this same line of reasoning, several studies, some still disputed or unconfirmed, have suggested that ropinirole, pramipexole, and even l-dopa have “neuroprotective” effects in Parkinson disease. The issues relating to l-dopa are addressed above. However, slowing of the progression of symptoms, as measured by a variety of scales, has not been corroborated. Technical problems in interpreting these results are discussed in reviews by
Wooten and by Clarke and Guttman. The uncertainties have to do with clinical grading systems, functional imaging techniques, and points of comparison to treatment with l-dopa.
Finally, attempts to slow the disease by vitamin antioxidants such as vitamin E have met with generally negative, results. A possible exception was the trial of coenzyme Q10 by Shults and colleagues. Massive doses of this agent, 1,200 mg/d, were found to offer marginal advantages on the progression over 6 to 18 months as measured by certain scores of overall daily functions, but not on most neurologic scales.
Side effects of dopamine treatments and their management The side effects of l-dopa are at times significant to the degree that its continuation cannot be tolerated. Some patients are at first troubled by nausea, although this can be mitigated by taking the medication with meals. Nausea usually disappears after several weeks of continued use or can be allayed by the specific dopaminergic chemoreceptor antagonist domperidone. A few have mild orthostatic hypotensive episodes.
The most troublesome effects of l-dopa as the disease advances, usually after several years of treatment, are end-of-dose reduction in efficacy and the induction of involuntary “dyskinetic” movements—restlessness, head wagging, grimacing, lingual-labial dyskinesia, blepharospasm, and especially, choreoathetosis and dystonia of the limbs, neck, and trunk. A decline in efficacy at the end of the dose interval, typically 2 to 4 h, may be treated by more frequent dosing, the addition of dopaminergic agonist, or a COMT inhibitor.
The on–off or off phenomenon is a rapid and sometimes unpredictable change—in a matter of minutes or from 1 h to the next—from a state of relative freedom from symptoms to one of nearly complete immobility. Both dyskinesias and severe “off” periods appear in approximately 75 percent of patients within 5 years. Few patients escape these opposing effects, forcing an increased frequency of administration and usually a reduction in dosage.
If involuntary dyskinetic movements are induced by relatively small doses of l-dopa, the problem may be suppressed to some extent by the addition of direct-acting dopaminergic agents or by the concurrent administration of amantadine (see Verhagen et al), or by the use of an oral suspension of l-dopa as mentioned earlier. The use of lower doses of long-acting preparations of l-dopa may be helpful in reducing dyskinesias and the atypical antipsychotic medications have been said to be useful for this purpose but carry their own risks.