The once-held notion that the administration of l-dopa early in the disease might reduce the period over which it remains effective has been largely dispelled, but some neurologists continue to adhere to this idea. Cedarbaum and colleagues, who reviewed the course of the illness in 307 patients over a 7-year period, found no evidence that the early initiation of l-dopa treatment predisposed to the development of fluctuations in motor response or to dyskinesia and dementia. In fact, the findings of the “Elldopa” trial by The Parkinson Study Group (2004) were that functional and other measures were better in patients who had taken l-dopa for 40 weeks and then stopped the medications than in those who received no medication. This was tentatively taken to endorse the opposite notion, that l-dopa was somehow protective for the progress of disease but the alternative explanation was that the drug had a symptomatic carry over effect after it was stopped. This was addressed further in a trial conducted by
Verschuur and colleagues, who compared patients receiving l-dopa for 80 weeks to those in whom the start of treatment was delayed for the first 40 weeks and found no difference in outcomes or in the rates of progression of symptoms. Taken together, these results suggest the drug has no effect on the underlying disease in either direction, beyond the expected symptomatic improvement.
Neuropathologic study of the substantia nigra in the brains of Parkinson patients and their medication histories failed to corroborate a reduction in the number of pigmented neurons in relation to l-dopa (Parkkinen et al). Also, the multicenter study reported by Diamond and colleagues indicated that patients who were given l-dopa early in the disease actually survived longer and with less disability than those who began the medication late in the course; that is, l-dopa may have itself been neuroprotective. However, there have been many alternative interpretations of these data. The comparative effectiveness of l-dopa compared to the dopamine agonists is discussed below.
Dopamine agonists These drugs have a direct dopaminergic effect on striatal neurons, thereby partially bypassing the depleted nigral neurons. They have found a place both as the initial treatment, replacing l-dopa in this role, and in modulating the effects of l-dopa later in the illness. However, dopamine agonists are less potent than l-dopa in managing the main features of Parkinson disease and, in higher doses and in older individuals, they produce undesirable motor and cognitive side effects (see further on). They are favored because they are associated with fewer dyskinetic motor complications, or at least, delay the need for l-dopa and its dyskinetic effects. Bromocriptine and lisuride are synthetic ergot derivatives whose action in Parkinson disease is explained by their direct stimulating effect on dopamine (D2) receptors located on striate neurons. The nonergot dopamine agonists ropinirole and pramipexole have a similar type and duration of effectiveness and are used more widely because of their minimal ergot-like effects. Pergolide and the related drug cabergoline are no longer used because of the risk of cardiac valvular damage, particularly at higher dose levels.
The dopamine agonists are introduced gradually. For example, the initial dose of pramipexole is 0.125 mg tid, following which the dosage is doubled weekly to a total of 3 to 4.5 mg/d if the medication is used without l-dopa. If an individual is already taking l-dopa, these drugs usually permit a gradual reduction in levodopa-carbidopa dose by approximately 50 percent. Their duration of action is slightly longer than that of l-dopa and they cause less nausea. These medications may be also useful in reducing the motor fluctuations of l-dopa.