Does Tolerance Develop to Levodopa

The Parkinson's-Reversing Breakthrough

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The lay literature is replete with information suggesting that levodopa loses its effect after about five years. This leads to some trepidation on the part of the patient and physician in initiating therapy. If that were the case, it would indicate that tolerance is a possible concern and would argue for delaying treatment. It is conceivable that, when all nigrostriatal cells are depleted, levodopa would lose all effectiveness since these are the cells that convert levodopa and release dopamine. Lesser et al. (70) found that longer duration of disease did not appear to adversely affect response to levodopa at the time of initiation of therapy, yet they demonstrated deterioration in response that did not correlate with duration of disease. Those receiving levodopa longer had more severe disease. The assumption made by the authors was that PD patients developed tolerance. Despite these findings, the authors did not rule out the possibility that those receiving levodopa longer had a more progressive disease. However, Blin et al. (65) noted that chronic treatment does not lead to decreased effectiveness. Evidence indicates that conversion of dopa to dopamine can occur at sites other than dopaminergic terminals in the striatum. Thus, levodopa continues to be effective throughout the disease course.

Markham and Diamond (117,118) demonstrated that the potency of levodopa does not change with chronic use when they studied three groups of patients: those starting levodopa after one to three years of disease, four to six years, and seven to nine years. This study was started when levodopa was introduced so that they could assess whether the apparent loss of efficacy could relate to the disease duration or the duration of drug therapy. After six years of follow-up, they noted the following: (i) the disability scores were different for the three groups at initiation of levodopa and remained different thereafter; (ii) disability scores were the same for the three groups when they were matched for disease duration despite varied durations of therapy; and (iii) there was no significant difference with respect to the incidence of dyskine-sia. In projecting the course of disease, it was found that all three groups ultimately followed the same predictable course of progression independent of the duration of levodopa therapy. This was confirmed after 12 years of follow-up of the first group (119,120). The authors concluded that levodopa works at all stages of PD, does not result in tolerance over time but does not stop progression of disease. In other words, changes in disability of PD are related to the duration of disease and not the duration of therapy or tolerance to levodopa. Aside from progression of disease, another cause of the apparent loss of efficacy relates to narrowing of the therapeutic window, resulting in increased sensitivity to adverse effects such as dyskinesia and hallucinations (64,65). The worsening of disease also comes from the onset and progression of symptoms not attributable to dopamine systems, such as postural instability, freezing, and dementia (65,121).

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