Fear of levodopa: Does it stop working?

Short answer:  All patients require increasing doses of levodopa over time and some develop on-off fluctuations, but this is not because the drug stops working.

Longer answer:  The two major problems with levodopa are that, over time, many patients start to experience dyskinesia (which I will discuss separately) and on-off fluctuations, in which the drug does a relatively good job of controlling symptoms during certain times, but seems to stop working at other times, frequently near the end of the interval between doses.  The transitions between the “on” and “off” states can be dramatic and sometimes very rapid, and clearly have a very negative impact on quality of life.  For this reason, many patients, sometimes based on advice from their doctors, choose to delay the use of levodopa as long as possible, to try to “save” its use until it is really needed and delay the onset of on-off fluctuations.

This makes intuitive sense:  If, for example, a patient started taking levodopa 8 years ago, and now she takes 5 times as much and has on-off fluctuations, the drug stopped working.  Right?

Not necessarily … A lot has changed over those 8 years, and the question is whether the decreasing effectiveness of the drug is due to taking the drug for 8 years, or due to changes in her brain associated with disease progression.  This is the critical question in deciding whether it is better delay using levodopa and/or use as little as possible (so called levodopa-sparing therapy).  In the hypothetical example, if the patient had waited two more years before starting levodopa, would her on-off fluctuations have appeared two years later, or at the same time?  Or if she had decided to start taking levodopa earlier, would her on-off fluctuations be even worse now?

Multiple clinical trials have addressed this question, and there is little evidence supporting the concept that levodopa loses effectiveness, simply as a result of prolonged use.  To the contrary, the PD-MED clinical trial, which involved 1600 patients over many years (possibly the largest clinical trial ever performed for Parkinson’s disease), concluded:

… during 7 years of follow-up, we showed no indication of any cumulative adverse effect of levodopa therapy, with no loss of benefit with time.  … No short-term or long-term benefit was seen from initiation of treatment of patients with early Parkinson’s disease with levodopa-sparing therapy— dopamine agonists or MAOBI—rather than levodopa.

The design of the PD-MED study was fundamentally rather simple:  just randomly assign newly diagnosed Parkinson’s patients either to start immediately on levodopa, or to initially use a dopamine agonist or MAO-B inhibitor, following the most common levodopa-sparing strategies.  Over time, almost all of the patients eventually wound up taking levodopa, but the ones who started right away on levodopa did no worse than those who delayed its use, on a wide array of measures, and by certain metrics were actually faring slightly better, on average.  In an even-handed commentary on the results of this clinical trial, Drs. Anthony Lang and Connie Marras (U. Toronto) ended with the following sentence:

Finally, and perhaps most importantly, the results of this study will help to persuade physicians and reassure patients that the fears that have served as the groundwork in establishing levodopa phobia—that often results in patients experiencing unnecessary and easily managed disability and reduction in quality of life in the early years of their disease—are unfounded.

Other clinical trials have come to similar conclusions.  In another large, long-term clinical trial, the Parkinson’s Disease Research Group of the United Kingdom (PDRG-UK) found that

Initial treatment with the dopamine agonist bromocriptine did not reduce mortality or motor disability and the initially reduced frequency in motor complications was not sustained. We found no evidence of a long-term benefit or clinically relevant disease-modifying effect with initial dopamine agonist treatment.

A recently-reported clinical trial conducted in Ghana, although much smaller in scope, is interesting because it addressed the issue in a different way.  Many Parkinson’s patients in Ghana do not receive levodopa until many years after diagnosis, not by choice but because they have relatively poor access to medical care.  The researchers compared these Ghanian patients (average 4 years from diagnosis to levodopa treatment) to Italian patients (average 2 years from diagnosis to levodopa treatment), and once again came to a similar conclusion:

We conclude that motor fluctuations and dyskinesias are not associated with the duration of levodopa therapy, but rather with longer disease duration and higher levodopa daily dose. Hence, the practice to withhold levodopa therapy with the objective of delaying the occurrence of motor complications is not justified.

Overall, evidence from multiple recently-reported clinical trials, including some of the largest and longest clinical trials on Parkinson’s, indicates that levodopa does not “stop working”, in the sense that the symptomatic benefit does not decrease with total levodopa exposure (length of time on the drug, or total amount consumed), and the development of on-off fluctuations appears to be due primarily to disease progression rather than the drug itself.  To be clear, there were earlier clinical trials which came to somewhat different conclusions (such as this one and this one); however, these were shorter in duration and/or involved fewer patients than PD-MED, PDRG-UK, or the ELLDOPA study discussed here.  As stated at the outset, I have deliberately not focused on dyskinesias here, because that is a more complicated topic deserving a separate discussion.  Some of the cited studies and commentaries on them lump together on-off fluctuations and dyskinesias as “motor complications”, but these really are distinct issues.