Lessons Learned about Levodopa
Motor fluctuations in Parkinson’s disease (PD) were described as early as 1969 by Cotzias et al.1 Subsequent studies showed that many motor fluctuations were associated with low plasma levodopa levels (troughs) that occurred between oral doses of levodopa.2This phenomenon was called the end-of-dose deterioration or ‘wearing-off’ effect. In the 1970s and 1980s, clinical pharmacology research provided a great deal of information about oral levodopa and its relationship to the ‘wearing-off’ effect.
Levodopa benefits the patient from the very first dose but requires a few weeks to reach optimum effect. The stronger the initial response to the drug, the more prominent the subsequent motor fluctuations.3 Increasing the dose of levodopa has been shown to prolong the duration of benefit, but does not increase the amplitude of response, and generally, the motor response wears off when plasma levodopa level drops to 50 % of the peak level, irrespective of the duration of benefit.4
The ‘On-off’ Phenomenon
The most common manifestation of the ‘on-off’ phenomenon is inter-dose or peak-dose dyskinesia, which occurs at a rate of approximately 10 % per treatment year. As a result, after 10 years of oral levodopa treatment, almost all patients who are on significant doses of levodopa will have developed some dyskinesias.5 Another form of dyskinesia is biphasic dyskinesias, which are much less frequent, partly because modern pharmacotherapies help to reduce their severity. These are particularly troublesome in young-onset patients, are extremely disabling and much more difficult to treat than peak-dose dyskinesias. ‘Off’-period dystonia is another form that is often forgotten. Therefore, dyskinesias are not just one simple pattern of peak-dose dyskinesias.
In the 1980s, it was not clear whether ‘off’ periods were treatable. One theory was that during ‘off’ periods, patients were unresponsive to dopaminergic drugs, even at a high dose. However, this view began to be challenged by studies using continuous delivery of dopaminergic drugs.
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